Amc Data 2011–2017

Home , Delafloxacin, Kanamycin A, Pefloxacin, Pipemidic acid, Polymyxin B, Tebipenem

ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK, AMC DATA 2011–2017

WHO Regional Of ce for Europe Antimicrobial Medicines Consumption (AMC) Network

AMC data 2011–2017

WHO Regional Office for Europe Antimicrobial Medicines Consumption (AMC) Network

AMC data 2011–2017 Abstract This report updates analyses of data on antimicrobial medicines consumption collected for the period from 2011 to 2017 from non-European Union countries and areas in the WHO European Region. The update includes analyses of trends over time for key metrics of antibiotic consumption, considers new metrics to inform the responsible use of antibiotics and examines the impact of changes to defined daily doses that came into force on 1 January 2019. The WHO Regional Office for Europe and its partners remain committed to supporting countries and areas in these endeavours through the activities of the WHO Europe Antimicrobial Medicines Consumption Network.

Keywords ANTIMICROBIAL MEDICINES CONSUMPTION NATIONAL SURVEILLANCE NETWORKS ANTI-INFECTIVE AGENTS – THERAPEUTIC USE ANTIBIOTICS EPIDEMIOLOGICAL MONITORING DATA COLLECTION RESPONSIBLE USE OF ANTIBACTERIALS EASTERN EUROPE AND CENTRAL ASIA

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ISBN 978-92-8905-474-4

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Acknowledgements ��vii

Abbreviations �� viii

Summary ��ix

1..Introduction ��1

2.. The WHO Europe Antimicrobial Medicines Consumption (AMC) Network ��4 2.1 Background ��4 2.2 Participating countries and areas ��5

3.. Data collection and analysis ��7 3.1 Methodology ��7 3.2 Data collection ��11 3.3 Data analysis ��12 3.4 Data interpretation ��14

4..Albania ��18 4.1 Data source and years of data collection ��18 4.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) ��18 4.3 Relative consumption by choice of agent ��20 4.4 The 10 most consumed agents ��22 4.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics ��23 4.6 Analyses based on DDDs applied in 2019 ��24 4.7 Discussion ��28

5..Armenia ��31 5.1 Data source and years of data collection ��31 5.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) ��31 5.3 Relative consumption by choice of agent ��33 5.4 The 10 most consumed agents ��35 5.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics ��36 5.6 Analyses based on DDDs applied in 2019 ��37 5.7 Discussion ��41

6..Azerbaijan ��44 6.1 Data source and years of data collection ��44 6.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) ��44 6.3 Relative consumption by choice of agent ��46 6.4 The 10 most consumed agents ��47 6.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics ��49 6.6 Analyses based on DDDs applied in 2019 ��50 6.7 Discussion ��54

iii 7..Belarus ��56 7.1 Data source and years of data collection ��56 7.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) ��56 7.3 Relative consumption by choice of agent ��58 7.4 The 10 most consumed agents ��59 7.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics ��61 7.6 Analyses based on DDDs applied in 2019 ��62 7.7 Discussion ��66

8.. Bosnia and Herzegovina ��69 8.1 Data source and years of data collection ��69 8.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) ��69 8.3 Relative consumption by choice of agent ��71 8.4 The 10 most consumed agents ��72 8.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics ��73 8.6 Analyses based on DDDs applied in 2019 ��75 8.7 Discussion ��78

9..Georgia ��81 9.1 Data source and years of data collection ��81 9.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) ��81 9.3 Relative consumption by choice of agent ��83 9.4 The 10 most consumed agents ��84 9.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics ��86 9.6 Analyses based on DDDs applied in 2019 ��87 9.7 Discussion ��91

10..Kazakhstan ��94 10.1 Data source and years of data collection ��94 10.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) ��94 10.3 Relative consumption by choice of agent ��96 10.4 The 10 most consumed agents ��97 10.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics ��99 10.6 Analyses based on DDDs applied in 2019 �� 100 10.7 Analysis by community and hospital sectors �� 104 10.8 Discussion �� 107

11..Kyrgyzstan ��110 11.1 Data source and years of data collection �� 110 11.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) �� 110 11.3 Relative consumption by choice of agent �� 112 11.4 The 10 most consumed agents �� 113 11.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics �� 114 11.6 Analyses based on DDDs applied in 2019 �� 116 11.7 Discussion �� 119

12..Montenegro ��121 12.1 Data source and years of data collection �� 121 12.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) �� 121 12.3 Relative consumption by choice of agent �� 122 12.4 The 10 most consumed agents �� 124 12.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics �� 125 12.6 Analyses based on DDDs applied in 2019 �� 127

iv 12.7 Analysis by community and hospital sectors �� 130 12.9 Discussion �� 134

13.. North Macedonia ��137 13.1 Data source and years of data collection �� 137 13.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) �� 137 13.3 Relative consumption by choice of agent �� 138 13.4 The 10 most consumed agents – oral formulations �� 140 13.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics �� 141 13.6 Analyses based on DDDs applied in 2019 �� 142 13.7 Discussion �� 145

14.. Republic of Moldova ��147 14.1 Data source and years of data collection �� 147 14.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) �� 147 14.3 Relative consumption by choice of agent �� 149 14.4 The 10 most consumed agents �� 150 14.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics �� 152 14.6 Analyses based on DDDs applied in 2019 �� 153 14.7 Discussion �� 157

15.. Russian Federation ��160 15.1 Data source and years of data collection �� 160 15.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) �� 160 15.3 Relative consumption by choice of agent �� 162 15.4 The 10 most consumed agents �� 163 15.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics �� 165 15.6 Analyses based on DDDs applied in 2019 �� 166 15.7 Analysis by community and hospital sectors �� 170 15.8 Discussion �� 174

16..Serbia ��176 16.1 Data source and years of data collection �� 176 16.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) �� 176 16.3 Relative consumption by choice of agent �� 177 16.4 The 10 most consumed agents �� 179 16.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics �� 180 16.6 Analyses based on DDDs applied in 2019 �� 182 16.7 Discussion �� 185

17..Tajikistan ��188 17.1 Data source and years of data collection �� 188 17.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) �� 188 17.3 Relative consumption by choice of agent �� 190 17.4 The 10 most consumed agents �� 191 17.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics �� 193 17.6 Analyses based on DDDs applied in 2019 �� 194 17.7 Discussion �� 198

18..Turkey ��200 18.1 Data source and years of data collection �� 200 18.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) �� 200 18.3 Relative consumption by choice of agent �� 202

v 18.4 The 10 most consumed agents ��203 18.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics ��205 18.6 Analyses based on DDDs applied in 2019 ��206 18.7 Analysis by community and hospital sectors ��210 18.8 Discussion ��214

19..Uzbekistan ��217 19.1 Data source and years of data collection ��217 19.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) ��217 19.3 Relative consumption by choice of agent ��218 19.4 The 10 most consumed agents ��219 19.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics ��221 19.6 Analyses based on DDDs applied in 2019 ��222 19.7 Discussion ��226

20..Kosovo1 ��228 20.1 Data source and years of data collection ��228 20.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) ��228 20.3 Relative consumption by choice of agent ��230 20.4 The 10 most consumed agents ��231 20.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics ��233 20.6 Analyses based on DDDs applied in 2019 ��234 20.7 Discussion ��238

21.. Comparisons of 2017 antimicrobial medicines consumption across the AMC Network �� 241 21.1 Background ��241 21.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) ��241 21.3 Relative consumption by choice of agent ��243 21.4 Relative consumption of Core Access, Watch and Reserve groups of antibiotics ��245 21.5 Analyses based on DDDs applied in 2019 ��246 21.6 Comparisons with ESAC-Net antimicrobial quality indicators ��248

22..Discussion ��250

1 All references to Kosovo in this document should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

vi ACKNOWLEDGEMENTS

The WHO Regional Office for Europe would like to thank the WHO Europe Antimicrobial Medicines Consumption (AMC) Network members for providing antimicrobial consumption data and for their valuable contributions to this report.

The WHO Regional Office for Europe would also like to acknowledge the European Centre for Disease Prevention and Control, specifically Dr Klaus Weist and Dr Dominique Monnet, for their ongoing support and valued collaboration.

The database for data analysis was developed in conjunction with Public Health Expertise, Paris, France.

The report was written by Dr Jane Robertson, Ms Kotoji Iwamoto and Ms Hanne Bak Pedersen of the Health Technologies and Pharmaceuticals Programme, WHO Regional Office for Europe.

WHO Europe AMC Network activities are coordinated by the WHO Regional Office for Europe. The financial support of the Ministry of Health, Welfare and Sport of the Netherlands and the German Collaboration Programme are gratefully acknowledged.

vii ABBREVIATIONS

AMC antimicrobial medicines consumption AMR antimicrobial resistance ATC Anatomical Therapeutic Chemical (classification system) AWaRe WHO Access, Watch and Reserve (classification) DDD defined daily dose DID defined daily doses per 1000 inhabitants per day ECDC European Centre for Disease Prevention and Control EEA European Economic Area EML WHO Model List of Essential Medicines for adults EMLc WHO Model List of Essential Medicines for children ESAC-Net European Surveillance of Antimicrobial Consumption Network EU European Union GAP WHO global action plan on antimicrobial resistance MDR-TB multidrug-resistant tuberculosis SDGs (United Nations) Sustainable Development Goals TB tuberculosis TESSy the European Surveillance System

Abbreviations of country and area names used in some tables and figures

ALB Albania ARM Armenia AZE Azerbaijan BLR Belarus BIH Bosnia and Herzegovina GEO Georgia KAZ Kazakhstan KGZ Kyrgyzstan MDA Republic of Moldova MNE Montenegro MKD North Macedonia RUS Russian Federation SRB Serbia TJK Tajikistan TUR Turkey UZB Uzbekistan KOS Kosovo2

2 All references to Kosovo in this document should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

viii SUMMARY

The WHO Europe Antimicrobial Medicines Consumption (AMC) Network aims to support all countries and areas in the WHO European Region that are not part of the European Surveillance of Antimicrobial Consumption Network (ESAC-Net) coordinated by the European Centre for Disease Prevention and Control (ECDC).

This is the second WHO Europe AMC Network report. It sets out and analyses AMC data for 16 of the participating countries as well as for Kosovo3 in which the ministry of health and public health authorities approved data-sharing and publication. The report includes analyses of trends over time (2011–2017) for key metrics of antibacterial consumption, applies the WHO Core Access, Watch and Reserve classification of antibiotics, and examines the impact of proposed changes to defined daily doses (DDDs) in 2019 for some commonly used antibiotics. Results are compared with ESAC-Net quality indicator estimates for 2017. Analyses are presented for each AMC Network country and area separately, with comparisons across the AMC Network for selected metrics.

Key findings

Data on total consumption of antibacterials for systemic use (Anatomical Therapeutic Chemical (ATC) classification group J01) were available for 16 countries as well as for Kosovo.3 There was large variability in reported consumption of J01 antibacterials across the AMC Network – ranging from 8.5 defined daily doses per 1000 inhabitants per day (DID) (Azerbaijan) to 36.4 DID (Turkey) in 2017. The population-weighted mean consumption across the 17 datasets was 21.1 DID (median consumption 20.3 DID). These consumption estimates were mostly lower than those reported in 2011 (range 6.4 DID Uzbekistan to 42.3 DID for Turkey, mean 23.6 DID) and in 2015 (range 8.0 DID for Azerbaijan to 41.5 DID for Turkey, mean 21.2 DID). ESAC-Net analyses also show considerable variability in total J01 consumption, ranging from 11.0 DID in the Netherlands to 34.1 DID in Spain in 2017 (ECDC, 2018).

The extent of consumption of parenteral formulations also varied widely – 4% in Turkey and 5% in Bosnia and Herzegovina, up to 45% in Kyrgyzstan and 50% in Uzbekistan in 2017.

The most commonly consumed subgroup of antibacterials was beta-lactams (ATC group J01C), with a range of 28.2% (Kazakhstan) to 54.3% (Kosovo3) of total J01 consumption in 2017. Cephalosporins (J01D) represented between 9% (Armenia) and 27.5% (Uzbekistan) of J01 consumption; quinolones (J01M) made up 22.9% of J01 consumption in Tajikistan.

3 All references to Kosovo in this publication should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

ix Choice of cephalosporins varied widely in 2017. Overall, consumption of fourth-generation agents was limited (mostly < 0.1 DID). Consumption of first-generation agents varied from very low in Azerbaijan to 59% of total cephalosporin consumption in Serbia, and second-generation agents from very low consumption (< 0.1 DID) in several settings to 51% of cephalosporin consumption (4.9 DID) in Turkey. Third-generation agent consumption ranged from 22% (Bosnia and Herzegovina) to 88% (Azerbaijan and Tajikistan) of total cephalosporin consumption and represented more than 50% of total cephalosporin consumption in nine of the 17 datasets.

Consumption of Core Access agents dominated in all AMC Network countries and areas, representing between 46.4% (Georgia) and 72.3% (Bosnia and Herzegovina) of total antibacterial consumption in 2017. Watch group agents represented between 22.9% (Bosnia and Herzegovina) and 44.4% (Tajikistan) of total consumption. Consumption of Reserve group agents was uniformly low across the Network.

Changes to DDDs implemented in January 2019 impacted on both total and relative consumption estimates, driven mostly by DDD changes for several commonly used beta-lactam penicillins. Total J01 consumption estimates decreased from a range of 8.5–36.4 DID using 2018 DDD values to 7.8–31.0 DID using 2019 DDD values. The percentage reductions in total DIDs ranged from 8.0–15.9%, with mean DID reductions of 12.9%. However, there was limited impact on rankings from highest to lowest total consumption in DIDs. The data from 2015–2017 with 2019 DDD values applied will provide new baseline trend data against which data for future years will be compared.

It was possible to examine consumption patterns in community and hospital settings separately in four cases (Kazakhstan, Montenegro, the Russian Federation and Turkey). Most consumption occurs in the community and choices of antibiotics differ considerably in the two settings. This is important information as interventions are developed to target problem prescribing practices with antibiotics.

Conclusions

The results presented in this report document trends in consumption of antibacterial agents across parts of non-European Union Europe. The notable feature is the wide variability of estimates (both volumes of consumption and selection of agents) across the WHO Europe AMC Network. While the quantitative metrics presented have limited application in assessing the appropriateness of prescribing, they illustrate differing patterns of antibiotic consumption over time and point to potential problems in antibiotic use. The variability seen is unlikely to be explained by different patterns or burden of disease alone. The reasons for such variability require further investigation. The relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities supported by evidence-based guidelines and treatment algorithms.

A full exploration of reasons for the changes in consumption patterns reported in each of the 17 AMC Network countries and areas is beyond the scope of this report. However, the impact of locally produced antibiotics on treatment choices, pharmaceutical industry promotion, perverse incentives to prescribe and dispense antibiotics, and availability and use of up-to-date guidelines all need to be considered in developing interventions to improve antibiotic use.

Reference

ECDC (2018). Antimicrobial consumption. In: ECDC. Annual epidemiological report 2017. Stockholm: ECDC (https://ecdc.europa.eu/sites/portal/files/documents/ESAC-NET-reportAER-2017-updated. pdf, accessed 1 April 2019). x Introduction

1. INTRODUCTION

The human and financial costs of antimicrobial resistance (AMR) are well recognized. Estimates suggest 700 000 deaths globally due to drug-resistant infections (O’Neill, 2016), with the world losing 3.8% of its annual gross domestic product by 2050 (World Bank, 2017) and concerns about the risks of AMR to the achievement of the United Nations Sustainable Development Goals (SDGs) (United Nations Interagency Coordination Group on Antimicrobial Resistance, 2017). Progress to address AMR relies on coordinated responses across the human and animal health sectors, as well as the environment, trade, intellectual property and innovation sectors (Wernli et al., 2017).

The momentum to address AMR continues to grow after the adoption of the WHO Global action plan on antimicrobial resistance (GAP) in 2015 (WHO, 2015), as reflected in the agendas of many high-level meetings such as the United Nations General Assembly in 2016 (United Nations, 2016), the G7 summit under the German Presidency in 2016, and again under German leadership the G20 summit in 2017. The European Union (EU) has underscored the importance of the One Health approach, launching the One Health antimicrobial resistance action plan in 2017 (European Commission, 2017).

Member States adopted the GAP at the Sixty-eighth World Health Assembly in May 2015. The resolution urged Member States to implement the GAP, recognizing that it might need to be adapted to specific contexts and national priorities. Two specific objectives of the GAP are supported by the work described in this report on monitoring of AMC:

• strengthening surveillance and research (Objective 2) • optimizing the use of antimicrobial medicines (Objective 4).

Data from selected countries and areas of the WHO Europe Antimicrobial Medicines Consumption (AMC) Network in 2011 were published in 2014 (Versporten et al., 2014) and an analysis of AMC data for 2011–2014 in 2017 (WHO Regional Office for Europe, 2017). Both analyses reported total consumption of Anatomical Therapeutic Chemical (ATC) J01 group antibacterials for systemic use (defined daily dose (DDD) per 1000 inhabitants per day (DID)) and the relative use of different pharmacological subgroups, including tetracyclines, penicillins, cephalosporins, aminoglycosides, macrolides and quinolones. These analyses also reported the relative consumption of agents recommended as second-line treatment choices, including cephalosporins (particularly third- and fourth-generation agents) and quinolones, on the basis that these metrics might focus attention on areas where antibiotic use could be improved.

Despite some differences in data sources used and differences in levels of expenditure on medicines between western and eastern Europe (Jakovljevic et al., 2016), comparisons between European Surveillance of Antimicrobial Consumption Network (ESAC-Net) and AMC data were presented, giving a pan-European perspective on antibiotic consumption (Versporten et al., 2014; WHO Regional Office for Europe, 2017; WHO, 2018).

Since then, a new classification of antibiotics introduced by WHO – the Access, Watch and Reserve groups of antibiotics (WHO, 2017a, 2017b) – and some significant changes to DDD values that took effect in January 2019 (WHO Collaborating Centre for Drug Statistics Methodology, 2018) have

1 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

increased the range of metrics that might be reported. The changes in DDD values also affect the interpretation of some existing measures of antibiotic consumption.

Data from the AMC Network in 2015 were published in 2019 (Robertson et al., 2019). This publication presented updated data from the WHO Europe AMC Network using cross-national and area comparisons of 2015 antibiotic consumption data for 16 Network members where the ministry of health and public health authorities approved data-sharing and publication. Consumption estimates for 2011 and 2015 were compared; the WHO Watch and Reserve classifications of antibiotics were applied, and the impact of changes to DDDs in 2019 were examined.

This report extends the reporting from the 2019 publication and includes trends over time between 2011 and 2017, with analyses using existing DDD values and repeated for the years 2015–2017 with the new 2019 DDDs applied. Both sets of data are presented to illustrate the impact of the changes in DDD values on volumes of consumption and proportion estimates. The data from 2015–2017 with 2019 DDD values applied will provide new baseline trend data against which data for future years will be compared.

References

European Commission (2017). A European One Health action plan against antimicrobial resistance. Brussels: European Commission (https://ec.europa.eu/health/amr/action_eu_en, accessed 1 April 2019).

Jakovljevic M, Lazarevic M, Milovanovic O, Kanjevac T (2016). The new and old Europe: east–west split in pharmaceutical spending. Front Pharmacol. 7:18. doi:10.3389/fphar.2016.00018.

O’Neill J (2016). Review on Antimicrobial Resistance. Securing new drugs for future generations: the pipeline of antibiotics. London: HM Government (https://amr-review.org/Publications.html, accessed 1 April 2019).

Robertson J, Iwamoto K, Hoxha I, Ghazaryan L, Abilova V, Cvijanovic A et al. (2019). Antimicrobial medicines consumption in eastern Europe and central Asia – an updated cross-national study and assessment of quantitative metrics for policy action. Front Pharmacol. 9:1156. doi:10.3389/fphar.2018.01156.

United Nations (2016). General Assembly of the United Nations. High-level meeting on antimicrobial resistance. 21 September 2016. New York (NY): United Nations (https://www.un.org/pga/71/event- latest/high-level-meeting-on-antimicrobial-resistance/, accessed 1 April 2019).

United Nations Interagency Coordination Group on Antimicrobial Resistance (2017). AMR framework for action supported by the IACG. Working document. Geneva: World Health Organization (http:// www.who.int/antimicrobial-resistance/interagency-coordination-group/20170818_AMR_FfA_v01. pdf, accessed 1 April 2019).

Versporten A, Bolokhovets G, Ghazaryan L, Abilova V, Pyshnik G, Spasojevic T et al., on behalf of the WHO/Europe-ESAC Project Group (2014). Antibiotic use in eastern Europe: a cross-national database study in coordination with the WHO Regional Office for Europe. Lancet Infect Dis. 14:381–7 (http://dx.doi.org/10.1016/S1473-3099(14)70071-4, accessed 1 April 2019).

Wernli D, Jørgensen PS, Harbarth S, Carroll SP, Laxminarayan R, Levrat N et al. (2017). Antimicrobial resistance: the complex challenge of measurement to inform policy and the public. PLoS Med. 14(8):e1002378 (https://doi.org/10.1371/journal.pmed.1002378, accessed 1 April 2019).

2 Introduction

World Bank (2017). Drug-resistant infections: a threat to our economic future. Washington (DC): World Bank (http://documents.worldbank.org/curated/en/323311493396993758/pdf/114679-REVISED- v2-Drug-Resistant-Infections-Final-Report.pdf, accessed 1 April 2019).

World Health Organization (2015). Global action plan on antimicrobial resistance. Geneva: World Health Organization (http://www.who.int/antimicrobial-resistance/publications/global-action-plan/ en/, accessed 1 April 2019).

World Health Organization (2017a). Comprehensive review of antibiotic medicines: 21st expert committee on the selection and use of essential medicines. Geneva: World Health Organization (http://www. who.int/selection_medicines/committees/expert/21/applications/comprehensive_antibiotics_rev/ en/, accessed 1 April 2019).

World Health Organization (2017b). The selection and use of essential medicines. Report of the WHO Expert Committee, 2017 (including the 20th WHO Model List of Essential Medicines and the 6th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization (WHO Technical Report Series, No. 1006; https://apps.who.int/iris/bitstream/handle/10665/259481/9789241210157- eng.pdf?sequence=1, accessed 1 April 2019).

World Health Organization (2018). WHO report on surveillance of antibiotic consumption 2016–2018: early implementation. Geneva: World Health Organization (https://www.who.int/medicines/areas/ rational_use/who-amr-amc-report-20181109.pdf?ua=1, accessed 1 April 2019).

WHO Collaborating Centre for Drug Statistics Methodology (2018). Updates included in the ATC/DDD Index. In: WHO Collaborating Centre for Drug Statistics Methodology [website]. Oslo: WHO Collaborating Centre for Drug Statistics Methodology (https://www.whocc.no/atc_ddd_index/updates_included_ in_the_atc_ddd_index/, accessed 1 April 2019).

WHO Regional Office for Europe (2017). Antimicrobial Medicines Consumption (AMC) Network. AMC data 2011–2014. Copenhagen: WHO Regional Office for Europe (http://www.euro.who.int/en/health-topics/ Health-systems/health-technologies-and-medicines/publications/2017/antimicrobial-medicines- consumption-amc-network.-amc-data-20112014-2017, accessed 1 April 2019).

3 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

2. THE WHO EUROPE ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

2.1 Background

The WHO Europe AMC Network is an initiative of the WHO Regional Office for Europe and aims to support all countries and areas in the Region that are not part of ESAC-Net, coordinated by the European Centre for Disease Prevention and Control (ECDC) in the EU. A brief description of the two networks follows, with a fuller description available in the Europe chapter of the WHO report on surveillance of antibiotic consumption 2016–2018: early implementation (WHO, 2018).

2.1.1 European Surveillance of Antimicrobial Consumption Network (ESAC-Net)

ESAC-Net is a network of national surveillance systems that provides reference data on antimicrobial consumption from the 28 Member States of the EU and two countries in the European Economic Area (EEA) (Iceland and Norway) using the European Surveillance System (TESSy) (ECDC, 2018, 2019). Nominated national focal points provide the antimicrobial consumption data.

ESAC-Net publishes annual reports of antimicrobial consumption data based on a standard reporting framework from the community and hospital sectors, using medicines sales or reimbursement data. Antimicrobial consumption data are collected using the ATC classification system and DDD methodology. The data are presented up to the fourth level of ATC coding (pharmacological subgroup). In addition to annual reports, downloadable files show trends in consumption of antimicrobials and an interactive database can provide overviews of country data, data sources, geographical distribution of antibiotic consumption, rates and trends by country, and several quality indicators for antibiotic consumption in the community. Data are available from 1997 onwards.

Within the perspective of a One Health approach, a set of primary and secondary outcome indicators for antimicrobial consumption in the community and the hospital sector has been developed for humans and for the veterinary sector by the ECDC, the European Food and Safety Authority and the European Medicines Agency. The aim is to enable monitoring of antimicrobial consumption and tailor interventions for antimicrobial stewardship programmes (ECDC et al., 2017a, 2017b).

4 The WHO Europe Antimicrobial Medicines Consumption (AMC) Network

2.1.2 WHO Europe Antimicrobial Medicines Consumption Network

The WHO Europe AMC Network is an initiative of the WHO Regional Office for Europe that follows from a pilot project on data collection in 2011 involving the University of Antwerp (Belgium), the ECDC and the WHO Collaborating Centre for Drug Statistics Methodology (Norway). It aims to support countries and areas in the WHO European Region that are not part of ESAC-Net, currently consisting of 17 Member States as well as Kosovo.4 The methodology used by the WHO Europe AMC Network is closely aligned with that used by the ECDC to facilitate comparisons between EU and non-EU Member States in the Region. Data collection predates the formation of the WHO Europe AMC Network in several member countries and areas.

Data collection follows a standardized protocol, using a common Excel template based on a complete register of antimicrobial medicines with marketing authorization. The ATC classification system is used with data presented up to the fifth level of coding (individual medicine). Nominated focal points for antimicrobial consumption provide the consumption data.

2.2 Participating countries and areas

Albania, Armenia, Azerbaijan, Belarus, Bosnia and Herzegovina, Georgia, Kazakhstan, Kyrgyzstan, Montenegro, North Macedonia, the Republic of Moldova, the Russian Federation, Serbia, Tajikistan, Turkey, Ukraine and Uzbekistan, as well as Kosovo,2 currently are engaged in the WHO Europe AMC Network. Of these, 16 countries and Kosovo2 gave permission by the cut-off date of 20 March 2019 for the data to be published.

References

ECDC (2018). European Surveillance of Antimicrobial Consumption Network (ESAC-Net). In: European Centre for Disease Prevention and Control [website]. Solna: ECDC (https://ecdc. europa.eu/en/about- us/partnerships-and-networks/disease-and-laboratory-networks/esac-net, accessed 1 April 2019).

ECDC (2019). ESAC-Net Reporting Protocol 2018. Solna: ECDC (https://ecdc.europa.eu/en/publications- data/esac-net-reporting-protocol-2018, accessed 1 April 2019).

ECDC, European Food and Safety Authority, European Medicines Agency (2017a). ECDC/EFSA/ EMA second joint report on the integrated analysis of the consumption of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from humans and food-producing animals. Joint Interagency Antimicrobial Consumption and Resistance Analysis (JIACRA) report. EFSA J. 15(7):4872. doi:10.2903/j. efsa.2017.4872.

ECDC, European Food and Safety Authority, European Medicines Agency (2017b). Joint scientific opinion on a list of outcome indicators as regards surveillance of antimicrobial resistance and antimicrobial consumption in humans and food-producing animals. Stockholm: European Centre for Disease Prevention and Control, European Food Safety Authority, European Medicines Agency; 2017 (https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2017.5017, accessed 1 April 2019).

4 All references to Kosovo in this publication should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

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World Health Organization (2018). WHO report on surveillance of antibiotic consumption 2016–2018: early implementation. Geneva: World Health Organization (https://www.who.int/medicines/areas/ rational_use/oms-amr-amc-report-2016-2018/en/, accessed 1 April 2019).

6 Data collection and analysis

3. DATA COLLECTION AND ANALYSIS

3.1 Methodology

3.1.1 Definitions

As in the previous WHO Regional Office for Europe report (WHO Regional Office for Europe, 2017) and in line with the WHO global protocol for data collection (WHO, 2016), a distinction is made between consumption data and antimicrobial-use data. This is done to recognize differences in the data sources and in the type of information that may be obtained from each approach.

• Consumption data are used to refer to estimates derived from aggregated data sources such as import or wholesaler data or aggregated health insurance data, where no information is available on the patients receiving the medicines or why the antimicrobials are used. These data sources provide a proxy estimate of use of antimicrobials. Consumption data may be presented as total consumption for a country/area or may be disaggregated by setting (community or hospital; public or private sectors). • Antimicrobial-use data are used to refer to estimates derived from patient-level data. These may allow disaggregation based on patient characteristics (such as gender or age) or indications for which the medicine is being used.

3.1.2 Antimicrobials included in monitoring

The WHO Europe AMC Network programme focuses only on antimicrobials for systemic use – it excludes topical antimicrobials. The core set of agents that all countries and areas include in their monitoring is as follows:

• antibacterials (J01) • antibiotics for alimentary tract and metabolism (A07AA) • nitroimidazole derivatives against amoebiasis and other protozoal diseases (P01AB).

In addition, the WHO surveillance programme includes an optional list of antimicrobials that countries and areas may include in their surveillance programmes according to local needs and resources:

• antimycotics for systemic use (J02) • antifungals for systemic use (D01BA) • antivirals for systemic use (J05) • drugs for treatment of tuberculosis (J04A) • antimalarials (P01B).

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This report builds on the early experience of data collection at country and area levels. It provides an analysis of data collected between 2011 and 2017 and includes several comparisons across the AMC Network for selected measures of AMC. The results mainly relate to analyses of antimicrobial agents in ATC group J01.

3.1.3 Health-care sectors monitored

In most of the countries and areas participating in the WHO Europe AMC Network, it is not possible to disaggregate data by sector (community or hospital; public or private), so total consumption data are reported in most cases. Analyses are also reported by community and hospital sectors separately where disaggregated data are available.

3.1.4 Measurements used

The WHO Europe AMC Network uses the ATC classification system, and the most commonly used measurement metric is the number of DDDs/1000 inhabitants per day. The ATC classification system allows flexibility in reporting by medicine or groups of medicines (WHO Collaborating Centre for Drug Statistics Methodology, 2018a). Medicines are classified in groups at five levels. Most antimicrobial agents are classified in ATC main group J: anti-infectives for systemic use.

The DDD is the assumed average maintenance dose per day for a medicine used for its main indication in adults (WHO Collaborating Centre for Drug Statistics Methodology, 2018b). The DDD is a technical unit of use and does not necessarily reflect the recommended or average prescribed daily dose. It is a useful metric that allows comparisons within and between countries and areas.

3.1.4.1 Changes to DDD values in 2019 In October 2017, following an application from the ECDC, the WHO International Working Group for Drug Statistics Methodology recommended changes to the DDDs for seven commonly used antibiotics (mainly penicillins) and endorsed new DDDs for oral colistin along with changes for several other products (Table 3.1) (WHO Collaborating Centre for Drug Statistics Methodology, 2018c). The changes were requested given evidence that current DDD allocations for commonly used medicines differed substantially from recommended doses and doses used in clinical practice. The DDD changes have been adopted fully since January 2019 and will affect estimates of total AMC and relative use of classes of antibiotics. The interpretation of national estimates and comparisons across the AMC Network over time will need to take account of these changed DDD values.

In addition to the changes shown in Table 3.1, new DDDs were assigned in 2019 for kanamycin oral (A07AA08), colistin oral (A07AA10), cefroxadine (J01DB11), cefteram (J01DD18), ceftriaxone and beta- lactamase inhibitor (J01DD63), tebipenem pivoxil (J01DH06), faropenem (J01DI03), midecamycin (J01FA03), lomefloxacin (J01MA07), gemifloxacin (J01MA15), garenoxacin (J01MA19), tosufloxacin (J01MA22) and delafloxacin (J01MA23).

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Table 3.1 2019 changes to DDDs for commonly prescribed J01 antibacterials

ATCa code Medicine Previous DDDb New DDD J01CA04 Amoxicillin 1 g Oc 1.5g O J01CA04 Amoxicillin 1 g Pd 3g P J01CA17 Temocillin 2 g 3 g P J01CR02 Amoxicillin and beta-lactamase inhibitor 1 g O 1.5g O J01CA01 Ampicillin 2 g P 6g P J01DE01 Cefepime 2 g P 4g P J01DH02 Meropenem 2 g P 3g P J01MA02 Ciprofloxacin 0.5 g P 0.8g P J01XB01 Colistin 3 MUe P 9 MU P a ATC: Anatomical Therapeutic Chemical. b DDD: defined daily dose. c O: oral. d P: parenteral. e MU: million units. Source: WHO Collaborating Centre for Drug Statistics Methodology (2018d).

3.1.4.2 Consumption according to the WHO Access, Watch and Reserve group classification In April 2017, the Expert Committee on the Selection and Use of Essential Medicines recommended changes to the WHO model lists of essential medicines for adults (EML) and children (EMLc) following a comprehensive review of sections 6.2.1 (Beta-lactam medicines) and 6.2.2 (Other antibacterials) (WHO, 2017a, 2017b; Sharland et al., 2018). The Committee identified empirical first- and second-choice treatments for a number of common, community-acquired infections, focusing on treatment choices broadly applicable in most countries and areas. The Expert Committee also proposed a categorization of antibiotics into Access, Watch and Reserve groups (Table 3.2–3.5). Not all medicines on the model lists were assigned to the three groups, leaving a fourth “ungrouped” category, with the classification to be revised as additional clinical syndromes are reviewed. However, this classification could support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The Access group includes first- and second-choice antibiotics that should be widely available in all countries and areas. They should be affordable and quality-assured.

The Watch group includes antibiotic classes that generally are considered to have higher resistance potential and which remain recommended as first- or second-choice treatments but for a limited number of indications. These medicines should be “prioritized as key targets of local and national stewardship programmes and monitoring” (WHO, 2017a). The group includes the highest-priority agents on the critically important antibiotics list (World Organisation for Animal Health 2015; WHO, 2017c) and/or antibiotics that are at relatively high risk of selection of bacterial resistance.

The Reserve group of antibiotics includes antibiotics and antibiotic classes that the Expert Committee considered as last-resort agents, that is, those to be used when other alternatives would be inadequate or have already failed in, for example, serious life-threatening infections due to multidrug-resistant bacteria.

It is therefore useful to monitor the relative use of these classes of agents that should be used sparingly and judiciously to preserve their value for clinical medicine. Several agents in the Watch list are also included in the Access list but only for use in specific, limited indications. The analyses presented in this report use a Core Access group of agents that has no overlap with the Watch group antibiotics (see Table 3.3). The report also includes an assessment of the extent to which Watch and Reserve group antibiotics are included in the top 10 consumed oral and parenteral agents.

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Table 3.2 WHO categories of antibiotics – descriptions

Group Definition First- and second-choice antibiotics that should be widely available in all countries and Access group areas; they should be affordable and quality-assured First- and second-choice antibiotics that should be used only for a specific, limited number Watch group of indications due to higher resistance potential Last-resort antibiotics that should be used only when other antibiotics have failed or for Reserve group infections of multi-resistant bacteria Ungrouped Medicines not specifically identified in the groups described above

Table 3.3 Access group

Medicine ATC codea Medicine ATC codea Beta-lactam medicines Other antibacterials amoxicillin J01CA04 amikacin J01GB06 amoxicillin + clavulanic acid J01CR02 azithromycinb – ampicillin J01CA01 chloramphenicol J01BA01 benzathine benzylpenicillin J01CE08 ciprofloxacinb – benzylpenicillin J01CE01 clarithromycinb – cefalexin J01DB01 clindamycin J01FF01 cefazolin J01DB04 doxycycline J01AA02 cefiximeb – gentamicin J01GB03 cefotaximeb – metronidazole J01XD01, P01AB01 ceftriaxoneb – nitrofurantoin J01XE01 cloxacillin J01CF02 spectinomycin J01XX04 phenoxymethylpenicillin J01CE02 sulfamethoxazole + trimethoprim J01EE01 piperacillin + tazobactamb – vancomycin (oral, parenteral)b – procaine benzylpenicillin J01CE09 – – a ATC codes shown for medicines in the core access list – that is, no overlap with Watch group antibiotics. b Watch group antibiotics included in the EML/EMLc only for specific, limited indications.

Table 3.4 Watch group

Medicines ATC code Quinolones and fluoroquinolones J01MA, J01MB such as ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin Third-generation cephalosporins (with or without beta-lactamase inhibitor) J01DD such as cefixime, ceftriaxone, cefotaxime, ceftazidime Macrolides J01FA such as azithromycin, clarithromycin, erythromycin Glycopeptides J01XA, A07AA09 such as teicoplanin, vancomycin Antipseudomonal penicillins with beta-lactamase inhibitor J01CR03, J01CR05 such as piperacillin + tazobactam Carbapenems J01DH such as meropenem, imipenem + cilastatin Penems J01DI03 such as faropenem

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Table 3.5 Reserve group

Medicine ATC code Aztreonam J01DF01 Fourth-generation cephalosporins J01DE such as cefepime Fifth-generation cephalosporins J01DI02, J01DI01, J01DI54 such as ceftaroline Fosfomycin IV J01XX01 (Only parenteral) Oxazolidinone J01XX08, J01XX11 such as linezolid Polymxyins J01XB, A07AA10, A07AA05 such as polymyxin B, colistin Tigecycline J01AA12 Daptomycin J01XX09 Note: medicines not specifically identified in the groups described form an “ungrouped” medicines category.

A more detailed description of the WHO Access, Watch and Reserve (AWaRe) classification is available in the WHO global report on antimicrobial medicines consumption (WHO, 2018).

3.2 Data collection

3.2.1 Sources of antimicrobial consumption data 2011–2017

Most countries and areas participating in the WHO Europe AMC Network use import data (from customs records and declaration forms) as the source of information on antimicrobial consumption. These are supplemented with sales records from market authorization holders or local manufacturing estimates where there is local pharmaceutical manufacturing. In some cases, data from wholesalers are used. Increasingly, data on antimicrobial use are available from health insurance programmes.

Table 3.6 summarizes the years of data, health-care sector coverage and data sources used in each of the settings included in this report.

Table 3.6 Sources of data used for consumption estimates (2011–2017)

Health-care sector Country or area Years of data Data sources for consumption estimates coverage Albania 2011–2017 Total care Import records Import records Armenia 2011–2017 Total care Sales records from local manufacturers Azerbaijan 2011–2017 Total care Import records Sales records of wholesalers and local Bosnia and Herzegovina 2011–2017 Total care manufacturers Import records Belarus 2011–2015 Total care Sales records from local manufacturers Georgia 2011–2017 Total care Import records Total care 2012–2014 Import records Kazakhstan Community and 2015–2017 VIORTIS hospitala Import records Kyrgyzstan 2011–2017 Total care Sales records from wholesalers

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Table 3.6 contd

Health-care sector Country or area Years of data Data sources for consumption estimates coverage Community and Montenegro 2011–2017 Sales records from wholesalers Hospital North Macedonia 2012–2017 Community Health insurance records Import records Republic of Moldova 2011–2017 Total care Manufacturing records from local manufacturers Community and Russian Federation 2011–2017 IQVIA hospital Serbia

Serbia excluding Kosovob 2011–2017 Total care Sales records from marketing authorization holders Kosovob 2011–2017 Total care Import records Import records Tajikistan 2011–2017 Total care Certification records Community IQVIA 2011–2012 Turkey Community and Wholesaler records from pharmaceutical 2013–2017 hospital track and trace system Import records Uzbekistan 2011–2017 Total care Sales records from local manufacturers a Commercial data source provides coverage of around 80–85% of hospital and community sales. b All references to Kosovo in this publication should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

3.3 Data analysis

3.3.1 Consumption estimates

Once the datasets are agreed, the WHO regional team analyses the data. The number of packages of each product is multiplied by the number of DDDs per package to calculate the total number of DDDs for each product. These are aggregated to give the total number of DDDs at the desired ATC code level.

Population-adjusted estimates of consumption are automatically calculated with embedded macros for calculation of consumption estimates in DDD per 1000 inhabitants per day (DID).

3.3.2 Metrics reported

The use of the ATC classification permits analyses at five different levels – from main class (level 1) to individual medicine (level 5). The AMC data for ATC category J01 are analysed to give country- or area-specific trends in antimicrobial consumption and trends across the AMC Network.

This report focuses on five types of key measure used to examine trends over time (Table 3.7):

• volume of consumption measures, reported as numbers of DID using DDD values relevant to the specific year of data (2011–2017) then applying the DDD values implemented in January 2019; • relative consumption measures, expressed as a percentage of total consumption of a group of antimicrobials; • the agents consumed, reflecting the choice of specific antimicrobial agents within a class and allowing more focused assessment of whether the choices align with recommended best practices and clinical practice guidelines;

12 Data collection and analysis

• consumption according to the WHO AWaRE group classification; and • utilization of the 10 most consumed agents (oral and parenteral agents separately).

Table 3.7 Metrics used in analyses and included in this report

Category Unit Estimates of volumes of consumption of antibacterials for systemic use (J01) Total consumption of J01 antibacterials by route of administration DIDa Total consumption of J01 antibacterials by pharmacological subgroup: • tetracyclines (J01A) • amphenicols (J01B) • beta-lactams (J01C) • other beta-lactams (includes cephalosporins) (J01D) DID • sulfonamides and trimethoprim (J01E) • macrolides, lincosamides and streptogramins (J01F) • quinolone antibacterials (J01M) • other J01 antibacterials (J01G, J01R, J01X) Relative consumption of J01 antibacterials by subgroup Relative consumption of J01 antibacterials by pharmacological subgroup % Relative consumption by choice of agent Relative consumption of agents of cephalosporins by generation: • choice of first-generation cephalosporins (J01DB) • choice of second-generation cephalosporins (J01DC) DID, % • choice of third-generation cephalosporins (J01DD) • choice of fourth-generation cephalosporins (J01DE) Relative consumption of agents within fluoroquinolones (J01MA) DID, % Relative consumption of WHO Core Access, Watch, Reserve antibioticsb Relative consumption of Core Access agents, Watch group agents, Reserve group agents % The 10 most consumed agents The 10 most consumed agents – oral formulation DID, % The 10 most consumed agents – parenteral formulation DID, % a DID: DDD/1000 inhabitants per day. b Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

3.3.2.1 Route of administration Oral administration is generally regarded as the most acceptable and economical method of administration of antimicrobials. Hospitalized patients initially on intravenous antibiotics can often safely be switched to an oral equivalent once they are clinically stable. Oral medication is associated with fewer complications, lower health-care costs and earlier hospital discharge. Nevertheless, it must be recognized that there may also be cultural and medical practice traditions that favour use of parenteral formulations in some settings.

This report includes analyses of use of oral and parenteral formulations for J01 medicines. Where use of parenteral formulations is comparatively high, there may be opportunities to increase use of oral formulations without loss of clinical efficacy.

3.3.2.2 Total consumption in DDDs per 1000 inhabitants per day The DDD per 1000 inhabitants per day (abbreviated to DID) is the most commonly reported metric of antimicrobial consumption and the most frequently used measure in cross-national comparisons (Versporten et al., 2014; WHO Regional Office for Europe, 2017; ECDC, 2019).

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It should be noted that only medicines assigned an ATC code and DDD are included in the analyses reported here. Several medicines without such codes are consumed by the population in some countries and areas of the WHO Europe AMC Network. Exclusion of these medicines means that data are missing in the numerator for the calculation, and the resulting DID estimates will underestimate total antimicrobial consumption in the country/area.

3.3.2.3 Quinolones and cephalosporins Quinolones and cephalosporins are broad-spectrum antibiotics and are considered second-line antibiotics in most prescribing guidelines (Adriaenssens et al., 2011). Their use should therefore be restricted to ensure availability as second-line therapy should first-line antibiotics fail.

WHO identifies fluoroquinolones, third- and fourth-generation cephalosporins, macrolides and glycopeptides as being of highest priority for risk management to ensure that critically important antimicrobials are used prudently both in human and veterinary medicine (World Organisation for Animal Health, 2015; WHO, 2017c).

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins and fluoroquinolones are part of the WHO Watch group of antibiotics (see Table 3.4) while fourth- and fifth-generation cephalosporins are included in the WHO Reserve group of agents (Table 3.5).

3.3.2.4 WHO Access, Watch and Reserve agents For the preceding relative use measures, the denominator for calculation of the relative proportions of consumption is total J01 consumption. The Access, Watch and Reserve groups include several agents other than those in the J01 category, namely:

• metronidazole (oral) – ATC code P01AB01 • vancomycin (oral) – A07AA09 • polymyxin B (oral) – A07AA10 • colistin (oral) – A07AA05.

Total consumption of antibiotics for this calculation therefore includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

3.4 Data interpretation

For a correct assessment of the magnitude and trends of antimicrobial consumption in the country or area and to allow comparison of results across the AMC Network and with other international data sets, the data are required to be both valid and reliable. The validity and reliability of data may be compromised at different points, however. These include:

• incomplete registration of antimicrobial products in circulation in the country or area • incomplete capture and reporting of data • double counting of medicines from different data sources • errors in data entry that were not identified during data validation • failure to account adequately for export of locally produced antimicrobial agents • data excluded from calculations where no ATC or DDD is assigned for the medicine.

14 Data collection and analysis

Together, these errors will affect the absolute values for antimicrobial consumption (measured in DID).

Incomplete data capture may occur when not all wholesalers provide data on products sold. Sales data from local manufacturers need to distinguish between medicines for local consumption and medicines exported.

No ATC or DDD is assigned to a considerable number of products in several countries and areas participating in the WHO Europe AMC Network. Consumption of these medicines is excluded from the analyses reported here, meaning that total consumption estimates presented will underestimate actual consumption of antibacterials. The WHO Regional Office for Europe is working with participants in the WHO Europe AMC Network and the WHO Collaborating Centre for Drug Statistics Methodology to identify products without codes and to resolve these for future analyses.

3.4.1 Import data

An issue with data derived from importation records is that the estimates will be affected by the cycles of procurement and delivery. This may give rise to fluctuations in estimates of consumption that do not relate to use of antibacterials by patients and health-care facilities.

Import cycles are also likely to mean that different products are received at different times, so relative use estimates may also be affected. Notwithstanding these limitations, it is reasonable to assume that over a longer period the relative use estimates will stabilize and more closely reflect the relative consumption of different antibacterial agents. Consequently, trends over time need to be interpreted carefully. In general, import data should not be used to make comparisons on monthly or quarterly consumption.

The analyses in this report provide annual consumption estimates. The fluctuations in total consumption estimates from several countries and areas, however, suggest that import cycles may contribute in part to the patterns of consumption shown. In the absence of universal health coverage or e-prescribing, widespread availability of antibiotics without prescription, few mechanisms to engage private wholesalers and limited ability to disaggregate data to hospital and community sectors, import records remain the most feasible data source in most AMC Network countries and areas.

3.4.2 Information value

The data presented may not yet be optimal, or systemic issues may lead to biased estimates, but recognizing these limitations may encourage the use of different data sources, such as wholesaler rather than import data. Later, as information systems develop, it may be possible to derive consumption estimates from reimbursement records from health insurance agencies and e-prescribing platforms. Already the situation is changing, with several countries and areas now reporting data disaggregated to community and hospital sectors and a number with the ability to use health insurance data to assess patterns of use of antimicrobials.

Even with the data limitations, the variability of consumption patterns within and between countries and areas provides a basis for further investigation to better understand how antibacterials are used in practice. The consumption data need to be interpreted with an understanding of the local context, taking account of changes in regulations (including enforcement of prescription-only access), data sources, resistance patterns and the potential impact of interventions to change practices.

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References

Adriaenssens N, Coenen S, Tonkin-Crine S, Verheij TJ, Little P, Goossens H (2011). European Surveillance of Antimicrobial Consumption (ESAC): disease-specific quality indicators for outpatient antibiotic prescribing. BMJ Quality & Safety 20:764–7 (http://dx.doi.org/10.1136/bmjqs.2010.049049, accessed 1 April 2019).

ECDC (2019). ESAC-Net reporting protocol 2019. In: European Centre for Disease Prevention and Control [website]. Solna: ECDC (https://ecdc.europa.eu/en/publications-data/esac-net-reporting- protocol-2019, accessed 1 April 2019).

Sharland M, Pulcini C, Harbarth S, Zeng M, Gandra S, Mathur S et al., on behalf of the 21st WHO Expert Committee on Selection and Use of Essential Medicines (2018). Classifying antibiotics in the WHO Essential Medicines List for optimal use – be AWaRe. Lancet Infect Dis. 18:18–20. doi:https:// doi.org/10.1016/S1473-3099(17)30724-7, accessed 1 April 2019.

WHO Collaborating Centre for Drug Statistics Methodology (2018a). Anatomical Therapeutic Chemical (ATC) classification system: guidelines for ATC classification and DDD assignment. Oslo: WHO Collaborating Centre for Drug Statistics Methodology (http://www.whocc.no/atc_ddd_methodology/ purpose_of_the_atc_ddd_system/, accessed 1 April 2019).

WHO Collaborating Centre for Drug Statistics Methodology (2018b). DDD: definition and general considerations. In: WHO Collaborating Centre for Drug Statistics Methodology [website]. Oslo: WHO Collaborating Centre for Drug Statistics Methodology (https://www.whocc.no/ddd/definition_and_ general_considera/, accessed 1 April 2019).

WHO Collaborating Centre for Drug Statistics Methodology (2018c). Updates included in the ATC/DDD index. In: WHO Collaborating Centre for Drug Statistics Methodology [website]. Oslo: WHO Collaborating Centre for Drug Statistics Methodology (https://www.whocc.no/atc_ddd_index/updates_included_ in_the_atc_ddd_index/, accessed 1 April 2019).

WHO Collaborating Centre for Drug Statistics Methodology (2018d). Alterations in ATC/DDD. In: WHO Collaborating Centre for Drug Statistics Methodology [website]. Oslo: WHO Collaborating Centre for Drug Statistics Methodology (https://www.whocc.no/atc/lists_of_new_atc_ddds_and_altera/ alterations_in_atc_ddd/, accessed 1 April 2019).

World Health Organization (2016). WHO methodology for a global programme on surveillance of antimicrobial consumption. Geneva: World Health Organization (https://www.who.int/medicines/ areas/rational_use/WHO_AMCsurveillance_1.0.pdf?ua=1, accessed 1 April 2019).

World Health Organization (2017a). The selection and use of essential medicines. Report of the WHO Expert Committee, 2017 (including the 20th WHO Model List of Essential Medicines and the 6th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization (WHO Technical Report Series, No. 1006; http://apps.who.int/iris/bitstream/10665/259481/1/9789241210157-eng. pdf?ua=1, accessed 1 April 2019).

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World Health Organization (2017b). Comprehensive Review of Antibiotic Medicines: 21st Expert Committee on the Selection and Use of Essential Medicines. Geneva: World Health Organization (http://www. who.int/selection_medicines/committees/expert/21/applications/comprehensive_antibiotics_rev/ en/, accessed 1 April 2019).

World Health Organization (2017c). Critically important antimicrobials for human medicine – 5th revision 2016. Geneva: World Health Organization (http://apps.who.int/iris/bitstre am/10665/255027/1/9789241512220-eng.pdf?ua=1, accessed 1 April 2019).

World Health Organization (2018) WHO report on surveillance of antibiotic consumption 2016–2018: early implementation. Geneva: World Health Organization (https://www.who.int/medicines/areas/ rational_use/oms-amr-amc-report-2016-2018/en/, accessed 1 April 2019).

World Organisation for Animal Health (2015). OIE list of antimicrobial agents of veterinary importance. Paris: World Organisation for Animal Health (http://www.oie.int/fileadmin/Home/eng/Our_scientific_ expertise/docs/pdf/Eng_OIE_List_antimicrobials_May2015.pdf, accessed 1 April 2019).

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4. ALBANIA

4.1 Data source and years of data collection

Albania has provided data for each of the seven years of data collection (2011–2017). The main sources of data are import records provided by the drug agency.

4.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

Total consumption of antibacterials for systemic use (ATC class J01) is examined by route of administration (oral and parenteral formulations) and by pharmacological subgroup (Fig. 4.1 and Table 4.1).

30 Other J01 antibacterials (J01G, J01R, J01X) 25 a Quinolone antibacterials (J01M) 20 Macrolides, lincosamides and streptogramins (J01F) 15 Sulfonamides and trimethoprim (J01E)

10 Other beta-lactams (includes cephalosporins) (J01D) Beta-lactams (J01C) DDD/1000 inhabitants per day 5 Amphenicols (J01B) Tetracyclines (J01A) 0

ALB ALB ALB ALB ALB ALB ALB 2011 2012 2013 2014 2015 2016 2017

Fig. 4.1 Total consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose.

The data show fluctuations in consumption of J01 antibacterials over time, although with the suggestion of a trend towards increases in consumption between 2015 and 2017.

The relative consumption of parenteral antibacterials represented 5–9% of total J01 consumption (Table 4.1).

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Table 4.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 Route of administration 23.8 19.6 16.3 21 16.8 16.9 20.1 Oral J01 (95) (93) (93) (92) (93) (91) (91) 1.4 1.5 1.3 1.8 1.4 1.6 1.9 Parenteral J01 (5) (7) (7) (8) (7) (9) (9) Total 25.1 21.1 17.5 22.7 18.2 18.5 22.1 Class of antibacterial agents 7.8 0.9 2.3 3.6 2.6 2.7 0.5 Tetracyclines (J01A) (31.1) (4.3) (13.1) (15.9) (14.3) (14.6) (2.3) 0.2 0.1 0.1 0.1 0.1 Amphenicols (J01B) – – (0.8) (0.5) (0.6) (0.4) (0.5) 8.6 9.6 7.8 9.9 5.6 6.2 10 Beta-lactams (J01C) (34.3) (45.5) (44.6) (43.6) (30.8) (33.5) (45.2) Other beta-lactams (includes 2.7 3.3 2.4 3.6 3.5 4.8 5.9 cephalosporins) (J01D) (10.8) (15.6) (13.7) (15.9) (19.2) (25.9) (26.7) 0.9 0.8 0.5 0.2 0.3 0.3 Sulfonamides and trimethoprim (J01E) – (3.6) (3.8) (2.9) (0.9) (1.6) (1.6) Macrolides, lincosamides and 1.3 1.5 2.1 2 2 1.6 2.1 streptogramins (J01F) (5.2) (7.1) (12) (8.8) (11) (8.6) (9.5) 2.7 3.6 1.9 2.4 3.3 2.4 3.3 Quinolone antibacterials (J01M) (10.8) (17.1) (10.9) (10.6) (18.1) (13) (14.9) 1 1.2 0.5 0.8 0.8 0.5 0.3 Other J01 antibacterials (J01G, J01R, J01X) (4) (5.7) (2.9) (3.5) (4.4) (2.7) (1.4) Total 25.1 21.1 17.5 22.7 18.2 18.5 22.1 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The highest levels of consumption were in beta-lactams (J01C), at 8.6 DID in 2011 and 10 DID in 2017. There were increases in consumption of cephalosporins (J01D), at 2.7 DID in 2011 and 5.9 DID in 2017, the macrolides group, at 1.3 DID in 2011 and 2.1 DID in 2017, and quinolones (J01M), at 2.7 DID in 2011 and 3.3 DID in 2017. Consumption of tetracyclines (J01A) decreased substantially from 7.8 DID in 2011 to 0.5 DID in 2017.

These observations relate to total consumption. Different patterns of consumption would be expected in the hospital and community sectors.

Beta-lactam consumption fluctuated across the years analysed and represented 45.2% of J01 consumption in 2017. There is evidence of increasing relative consumption of cephalosporins (J01D), at 10.8% in 2011 and 26.7% in 2017, macrolides (J01F), at 5.2% in 2011 and 9.5% in 2017, and quinolones (J01M), at 10.8% in 2011 and 14.9% in 2011. The relative consumption of tetracyclines (J01A) decreased from 31.1% in 2011 to 2.3% in 2017.

The relative consumption of cephalosporins and quinolones combined increased over time, at 21.6% in 2011 and 41.6% in 2017.

19 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

4.3 Relative consumption by choice of agent

4.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2011–2017 is shown in Fig. 4.2 and summarized in Table 4.2. Table 4.3 shows the most consumed agents within each of the generations of cephalosporin agents.

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 ALB ALB ALB ALB ALB ALB ALB 2011 2012 2013 2014 2015 2016 2017

Fig. 4.2 Relative consumption of cephalosporins by generation

Table 4.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 0.7 1.1 0.5 0.9 0.6 0.7 0.7 First-generation (J01DB) (28) (34) (21) (24) (16) (15) (12) 1.4 1.5 1.3 1.7 1.6 2.5 2.9 Second-generation (J01DC) (53) (45) (54) (46) (46) (53) (50) 0.5 0.7 0.6 1.1 1.3 1.5 2.2 Third-generation (J01DD) (19) (21) (24) (30) (37) (32) (37) Fourth-generation (J01DE) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Total 2.7 3.3 2.4 3.6 3.5 4.8 5.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Some decreases in consumption of first-generation agents were seen, at 28% of total cephalosporin use in 2011 and 12% in 2017. Cefalexin (80%) and cefazolin (20%) were the most consumed first- generation agents in 2017. Second-generation agents, mostly cefuroxime and cefaclor, represented 50% of cephalosporin consumption in 2017. Consumption of Watch group third-generation agents increased, at 19% of cephalosporin consumption in 2011 and 37% in 2017. Ceftriaxone (1 DID) and cefixime (0.8 DID) comprised 48% and 37% respectively of third-generation agent consumption in 2017. Only very small volumes of consumption of fourth-generation cephalosporins (Reserve agents) were reported. 20 Albania

Table 4.3 Most consumed agents within generation of cephalosporins

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) 0.5 0.8 0.4 0.4 0.3 0.4 0.6 Cefalexin (74) (75) (71) (47) (58) (52) (80) 0.2 0.3 0.1 0.4 0.2 0.3 0.1 Cefazolin (26) (25) (28) (53) (42) (48) (20) Second-generation (J01DC) 0.6 0.6 0.8 1.1 1.1 2 2.2 Cefuroxime (46) (40) (64) (64) (70) (78) (75) 0.7 0.8 0.4 0.5 0.4 0.4 0.6 Cefaclor (52) (58) (33) (33) (25) (16) (21) 0.2 0.1 Cefprozil < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 (6) (4) Third-generation (J01DD) 0.3 0.3 0.3 0.6 0.4 0.7 1 Ceftriaxone (55) (44) (48) (52) (30) (48) (48) 0.2 0.3 0.2 0.4 0.8 0.6 0.8 Cefixime (40) (50) (42) (38) (59) (40) (37) 0.1 Cefpodoxime – – – < 0.1 < 0.1 < 0.1 (5) 0.2 Cefdinir – – < 0.1 < 0.1 < 0.1 < 0.1 (9) a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for the nominated generation of cephalosporins.

4.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) represented 3.3 DID (14.9%) of total J01 consumption in 2017, with fluoroquinolones comprising essentially all quinolone consumption. Ciprofloxacin and levofloxacin consumption dominated, representing 66% and 21% respectively of fluoroquinolone consumption in 2017 (Table 4.4).

Table 4.4 Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 1.3 1.9 1.6 1.8 2.4 1.4 2.1 Ciprofloxacin (52) (53) (86) (79) (74) (61) (66) 0.2 0.3 0.1 0.3 0.3 Norfloxacin < 0.1 < 0.1 (7) (9) (5) (10) (8) 0.1 0.1 0.1 0.3 0.5 0.7 0.7 Levofloxacin (6) (4) (8) (15) (14) (29) (21) 0.9 1.2 0.2 0.1 Moxifloxacin < 0.1 < 0.1 < 0.1 (36) (34) (7) (5) Total 2.4 3.5 1.8 2.3 3.2 2.3 3.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

21 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

4.4 The 10 most consumed agents

While the number of J01 antibacterial agents available is large, there is considerable evidence from ESAC-Net and other analyses that consumption tends to be concentrated in a relatively small number.

4.4.1 The 10 most consumed agents – oral formulation

Table 4.5 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

Table 4.5 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Amoxicillin and enzyme 5.23 5.23 5.23 5.23 5.23 5.23 5.23 5.23 5.23 5.23 inhibitor Amoxicillin 4.36 4.36 4.36 4.36 4.36 4.36 4.36 4.36 4.36 Cefuroxime 2.12 2.12 2.12 2.12 2.12 2.12 2.12 2.12 Ciprofloxacin 2.08 2.08 2.08 2.08 2.08 2.08 2.08 Azithromycin 1.16 1.16 1.16 1.16 1.16 1.16 Clarithromycin 0.89 0.89 0.89 0.89 0.89 Cefixime 0.81 0.81 0.81 0.81 Levofloxacin 0.67 0.67 0.67 Cefaclor 0.61 0.61 Cefalexin 0.59 Total consumption for 18.53 17.95 17.34 16.66 15.85 14.96 13.80 11.72 9.59 5.23 this group of agents Total consumption for all 20.15 20.15 20.15 20.15 20.15 20.15 20.15 20.15 20.15 20.15 oral J01 agents Proportion (%) of total consumption for oral J01 92.0% 89.1% 86.0% 82.7% 78.7% 74.3% 68.5% 58.2% 47.6% 26.0% antibacterials a DDD: daily defined dose.

The 10 listed oral agents represent 92% of total oral J01 antibiotic consumption in 2017. Of the top 10 oral agents, five are included in the WHO Watch group of antibacterials – ciprofloxacin and levofloxacin (quinolones), azithromycin and clarithromycin (macrolides), and cefixime (third- generation cephalosporin).

The Watch group agents ciprofloxacin (10.3%), levofloxacin (3.3%), azithromycin (5.8%), clarithromycin (4.4%) and cefixime (4%) together comprised 27.8% of J01 oral agent consumption in 2017.

4.4.2 The 10 most consumed agents – parenteral formulation

Table 4.6 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

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Table 4.6 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Ceftriaxone 1.05 1.05 1.05 1.05 1.05 1.05 1.05 1.05 1.05 1.05 Ampicillin 0.23 0.23 0.23 0.23 0.23 0.23 0.23 0.23 0.23 Cefazolin 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15 Gentamicin 0.11 0.11 0.11 0.11 0.11 0.11 0.11 Amikacin 0.10 0.10 0.10 0.10 0.10 0.10 Cefuroxime 0.09 0.09 0.09 0.09 0.09 Metronidazole 0.07 0.07 0.07 0.07 Ciprofloxacin 0.06 0.06 0.06 Cefotaxime 0.03 0.03 Levofloxacin 0.02 Total consumption for 1.91 1.88 1.86 1.80 1.73 1.64 1.54 1.43 1.28 1.05 this group of agents Total consumption for all 1.94 1.94 1.94 1.94 1.94 1.94 1.94 1.94 1.94 1.94 parenteral J01 agents Proportion (%) of total consumption 98.1% 96.9% 95.5% 92.4% 88.7% 84.3% 79.0% 73.4% 65.9% 53.9% for parenteral J01 antibacterials a DDD: daily defined dose.

As shown in Table 4.1, parenteral agents comprised 9% of total J01 consumption in 2017. Within this, the Watch group third-generation cephalosporin ceftriaxone constituted 53.9% of the consumption of J01 injection formulations.

4.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 4.3 and Fig. 4.4, and is summarized in Table 4.7.

Table 4.7 Relative consumption of Core Access, Watch and Reserve classification antibacterials

Percentage of total consumptiona Antibiotic group 2011 2012 2013 2014 2015 2016 2017 Core Access group 49.7 63.8 59.4 57.0 44.1 47.9 51.8 Watch group 17.7 27.4 25.3 24.1 36.2 29.3 33.9 Reserve group 0.08 0.00 0.12 0.10 0.04 0.04 0.11 Ungrouped 32.5 8.8 15.2 18.7 19.7 22.7 14.2 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

23 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

100

60 Other

40 Core Access group

Proportion (%) Proportion 64 59 57 50 48 52 20 44

0 ALB ALB ALB ALB ALB ALB ALB 2011 2012 2013 2014 2015 2016 2017

Fig. 4.3 Relative consumption of Core Access antibiotics as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

100

60 Other Watch group 40 Proportion (%) Proportion

20 36 34 27 25 29 18 24 0 ALB ALB ALB ALB ALB ALB ALB 2011 2012 2013 2014 2015 2016 2017

Fig. 4.4 Relative consumption of Watch group antibiotics as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Consumption of Core Access agents dominated across all years analysed, at 51.8% of consumption in 2017. The relative consumption of Watch agents increased over time, from 17.7% of total consumption in 2011 to 33.9% in 2017. There was considerable consumption of agents currently ungrouped, at 14.2% of total consumption in 2017.

4.6 Analyses based on DDDs applied in 2019

To provide new baseline trend data for AMC estimates, analyses for 2015, 2016 and 2017 have been re-run, applying the new DDD values that came into effect in January 2019. Data are presented with both existing and new DDDs to illustrate the impact of the changes.

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4.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

Consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 4.5 (DDD values relevant to year) and Fig. 4.6 (2019 DDD values), and is summarized in Table 4.8.

25 25

20 20

15 15 Parenteral Parenteral antibacterials antibacterials 10 Oral 10 Oral antibacterials antibacterials 5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 ALB ALB ALB ALB ALB ALB 2015 2016 2017 2015 2016 2017

Fig. 4.5 Total consumption of J01 Fig. 4.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values)

Table 4.8 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 16.8 (93) 16.9 (91) 20.1 (91) 15.1 (93) 15 (91) 17 (91) Parenteral J01 1.4 (7) 1.6 (9) 1.9 (9) 1.2 (7) 1.5 (9) 1.8 (9) Total 18.2 18.5 22.1 16.3 16.5 18.7 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 22.1 DID in 2017 using DDD values relevant to year of data to 18.7 DID applying the 2019 DDD values – a reduction of 15.3%.

The relative consumption of oral and parenteral formulations does not change with the application of the 2019 DDDs.

4.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 4.7 (DDD values relevant to year) and Fig. 4.8 (2019 DDD values), and is summarized in Table 4.9. As noted in section 4.6.1, total DIDs decreased by 15.3% in 2017.

25 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

25 Other J01 25 Other J01 antibacterials antibacterials (J01G, J01R, (J01G, J01R, J01X) J01X) 20 Quinolone 20 Quinolone antibacterials antibacterials (J01M) (J01M) 15 Macrolides, 15 Macrolides, lincosamides and lincosamides and streptogramins streptogramins (J01F) (J01F) 10 Sulfonamides 10 Sulfonamides and trimethoprim and trimethoprim (J01E) (J01E) Other beta-lactams Other beta-lactams DDD/1000 inhabitants per day DDD/1000 inhabitants per day 5 (includes 5 (includes cephalosporins) cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols ALB ALB ALB (J01B) ALB ALB ALB (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 4.7 Total consumption of J01 Fig. 4.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

Table 4.9 Consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Tetracyclines (J01A) 2.6 (14.3) 2.7 (14.6) 0.5 (2.3) 2.6 (16) 2.7 (16.4) 0.5 (2.7) Amphenicols (J01B) 0 (0) 0.1 (0.5) 0 (0) 0 (0) 0.1 (0.6) 0 (0) Beta-lactams (J01C) 5.6 (30.8) 6.2 (33.5) 10 (45.2) 3.7 (22.7) 4.2 (25.5) 6.7 (35.8) Other beta-lactams (includes 3.5 (19.2) 4.8 (25.9) 5.9 (26.7) 3.5 (21.5) 4.8 (29.1) 5.9 (31.6) cephalosporins) (J01D) Sulfonamides and trimethoprim 0.3 (1.6) 0.3 (1.6) – 0.3 (1.8) 0.3 (1.8) – (J01E) Macrolides, lincosamides and 2 (11) 1.6 (8.6) 2.1 (9.5) 2.1 (12.9) 1.6 (9.7) 2.1 (11.2) streptogramins (J01F) Quinolone antibacterials (J01M) 3.3 (18.1) 2.4 (13) 3.3 (14.9) 3.2 (19.6) 2.4 (14.5) 3.2 (17.1) Other J01 antibacterials (J01G, 0.8 (4.4) 0.5 (2.7) 0.3 (1.4) 0.8 (4.9) 0.5 (3) 0.3 (1.6) J01R, J01X) Total 18.2 18.5 22.1 16.3 16.5 18.7 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 10 DID in 2017 using the DDD values relevant to the year of data to 6.7 DID applying the 2019 DDD values – a reduction of 33% in absolute values. Relative consumption of beta-lactams falls from 45.2% to 35.8% of total J01 consumption when the 2019 DDD values are applied.

As the total DIDs decrease with application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta-lactams generally increases: cephalosporins, for example, increased from 26.7% to 31.6%, the macrolides group from 9.5% to 11.2% and quinolones from 14.9% to 17.1% in 2017.

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4.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 4.9 (DDD values relevant to year) and Fig. 4.10 (2019 DDD values) for Core Access antibiotics, Fig. 4.11 (DDD values relevant to year) and Fig. 4.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 4.10.

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group Proportion (%) Proportion (%) Proportion 48 52 20 44 20 38 42 43

0 0 ALB ALB ALB ALB ALB ALB 2015 2016 2017 2015 2016 2017

Fig. 4.9 Relative consumption of Core Access Fig. 4.10 Relative consumption of Core group antibacterials (applying DDD values Access group antibacterials (applying 2019 relevant to year)a DDD values)a

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion

20 36 20 40 40 29 34 33

0 0 ALB ALB ALB ALB ALB ALB 2015 2016 2017 2015 2016 2017

Fig. 4.11 Relative consumption of Watch Fig. 4.12 Relative consumption of Watch group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year)a DDD values)a

a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The effect of applying the 2019 DDD values is to decrease slightly the proportion of total use that is Core Access group antibiotics (from 52% to 43% in 2017) and increase slightly the proportion of total use that is Watch group antibiotics (from 33.9% to 40% in 2017).

27 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 4.10 Relative consumption of Core Access, Watch and Reserve group antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 8 (44) 9 (48) 11.6 (52) 6.2 (38) 7 (42) 8.2 (43) Watch group 6.6 (36.2) 5.5 (29.3) 7.6 (33.9) 6.6 (40) 5.5 (33) 7.6 (40) Reserve group 0.(0) 0.(0) 0 (0) 0.(0) 0.(0) 0.(0) Ungrouped 3.6 (20) 4.3 (23) 3.2 (14) 3.6 (22) 4.3 (26) 3.2 (17) Total 18.26 18.85 22.33 16.35 16.78 18.95 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

4.7 Discussion

The analyses in this report are based on import records provided by the drug agency. Data are presented as total consumption estimates.

Estimates of total consumption of J01 antibacterials fluctuated over time, although with the suggestion of a trend towards increases in consumption between 2015 and 2017. Around 9% of consumption in 2017 was parenteral formulations.

Relative consumption of beta-lactams fluctuated over time and represented 45.2% of J01 consumption in 2017. There were increases in the relative consumption of cephalosporin, macrolide and quinolone antibacterials over the period analysed.

Of the top 10 oral agents, five are included in the WHO Watch group of antibacterials – ciprofloxacin and levofloxacin (quinolones), azithromycin and clarithromycin (macrolides), and cefixime (third-generation cephalosporin). Ciprofloxacin (10.3%), levofloxacin (3.3%), azithromycin (5.8%), clarithromycin (4.4%) and cefixime (4%) together comprised 27.8% of J01 oral agent consumption in 2017.

The Watch group third-generation cephalosporin ceftriaxone constituted 53.9% of the total consumption of J01 parenteral formulations in 2017.

Watch group agents (oral and parenteral combined) comprised 33.9% of total consumption in 2017.

These relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities. For example, the WHO EML (WHO, 2017) suggests limited indications for use of ciprofloxacin, levofloxacin, azithromycin, clarithromycin, cefixime and ceftriaxone.

Azithromycin is listed on the EML/EMLc as a first-choice option for trachoma, yaws, Chlamydia trachomatis, cholera and Neisseria gonorrhoeae, and as a second-choice option for acute invasive bacterial diarrhoea/dysentery and Neisseria gonorrhoeae.

Ciprofloxacin is listed on the WHO EML as a first-choice agent for acute invasive bacterial diarrhoea/dysentery, low-risk febrile neutropenia and mild-to-moderate pyelonephritis or

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prostatitis. It is a second-choice agent for the treatment of cholera and mild-to-moderate complicated intra-abdominal infections.

Clarithromycin is listed on the EML as a first-choice option for severe community-acquired pneumonia and as a second-choice option for pharyngitis.

Cefixime is not listed as a first-choice treatment option for any specific indications on the EML/EMLc, but is a second-choice treatment for acute invasive bacterial diarrhoea/dysentery and for the treatment of Neisseria gonorrhoeae. In injection formulation, it is third-generation cephalosporin of choice for use in hospitalized neonates.

Levofloxacin is listed on the WHO EML as a reserve second-line drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) that should be used in specialized centres adhering to WHO standards for tuberculosis (TB) control.

Ceftriaxone is listed on the EML/EMLc as a first-choice option for acute bacterial meningitis, severe community-acquired pneumonia, complicated intra-abdominal infections (mild to moderate), hospital-acquired pneumonia, Neisseria gonorrhoeae, and severe pyelonephritis or prostatitis. Ceftriaxone is listed as a second-choice agent for acute invasive bacterial diarrhoea/ dysentery, bone and joint infections, mild-to-moderate pyelonephritis or prostatitis, and sepsis.

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with EML recommendations.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 22.1 DID in 2017 using existing DDD values to 18.7 DID applying the 2019 DDD values – a reduction of 15.3%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 10 DID in 2017 using the DDD values relevant to the year of data to 6.7 DID applying the 2019 DDD values – a reduction of 33% in absolute values.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in Albania and can help to identify areas for further investigation, allowing the development of targeted interventions to address potential problems identified in the consumption of antibacterials. Interventions targeting medicines should be supported by evidence-based guidelines and treatment protocols.

Not all antibiotics have been classified by WHO into the Access, Watch and Reserve groups. The lists of Watch and Reserve medicines will be modified as evidence emerges and more clinical conditions are reviewed. The estimates presented here are based on total consumption – the relative use of Watch and Reserve group antibiotics would be substantially higher in a hospital-based analysis.

Total DIDs decreased by 15.3% when the new 2019 DDDs were applied, independent of any intervention by government, agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

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Reference

World Health Organization (2017). WHO Model List of Essential Medicines. 20th list (March 2017). Geneva: World Health Organization (https://apps.who.int/iris/bitstream/handle/10665/273826/ EML-20-eng.pdf?ua=1, accessed 1 April 2019).

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5. ARMENIA

5.1 Data source and years of data collection

Armenia provided data for each of the seven years of data collection (2011–2017). The main sources were import records from the drug agency and information provided by local pharmaceutical manufacturers. Data derived from importation records will be affected by the cycles of procurement and delivery, potentially giving rise to fluctuations in estimates of consumption that do not relate to actual use of antibacterials by patients and health-care facilities. Local manufacturer records need to be disaggregated to products for local consumption and products exported to other countries.

5.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

The data show fluctuations in total consumption of J01 antibacterials over time. While the data for 2014 and 2015 suggest decreases in total consumption, 2017 estimates returned to 2013 levels.

There is some evidence that data for 2016 relate to a lower-than-usual level of imports into Armenia. This would in part explain the apparent reductions in total consumption in 2016 and make the 2016 data less reliable for interpreting trends over time. The 2016 estimates also illustrate the challenges of using import records as a surrogate measure of AMC. It nevertheless is possible to use the 2016 data, and it is important to interpret the estimates cautiously and in the light of known limitations.

The relative consumption of parenteral antibacterials remained reasonably stable across the years analysed, at around 10–12% of total J01 consumption (Table 5.1).

The highest levels of consumption were in beta-lactams (J01C), at 6.3 DID in 2011 and 5.6 DID in 2017. There is some evidence of decreasing consumption of quinolone antibacterials (J01M), with 2.0 DID in 2011 and 1.3 DID in 2017.

These observations relate to total consumption. Different patterns of consumption would be expected in the hospital and community sectors.

31 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

20 Other J01 antibacterials (J01G, J01R, J01X) a Quinolone antibacterials 15 (J01M) Macrolides, lincosamides and streptogramins (J01F) 10 Sulfonamides and trimethoprim (J01E) Other beta-lactams (includes cephalosporins) (J01D) 5 Beta-lactams (J01C) DDD/1000 inhabitants per day Amphenicols (J01B) Tetracyclines (J01A) 0 ARM ARM ARM ARM ARM ARM ARM 2011 2012 2013 2014 2015 2016 2017

Fig. 5.1 Total consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose.

Table 5.1 Total consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 Route of administration 14.2 10 12.2 12.9 9.5 8.7 12.5 Oral J01 (89) (88) (88) (90) (89) (85) (90) 1.7 1.4 1.7 1.5 1.2 1.6 1.3 Parenteral J01 (11) (12) (12) (10) (11) (15) (10) Total 15.9 11.4 13.9 14.4 10.7 10.3 13.9 Class of antibacterial agents 2.1 2.2 1.5 2 0.8 1.6 1.5 Tetracyclines (J01A) (13.2) (19.3) (10.8) (13.9) (7.5) (15.5) (10.8) 0.4 0.4 0.5 0.4 0.3 0.2 0.4 Amphenicols (J01B) (2.5) (3.5) (3.6) (2.8) (2.8) (1.9) (2.9) 6.3 3.5 5.5 5.6 4.3 2.9 5.6 Beta-lactams (J01C) (39.6) (30.7) (39.6) (38.9) (40.2) (28.2) (40.3) Other beta-lactams (includes cephalosporins) 1.2 1.2 1.2 1.4 1 1.3 1.3 (J01D) (7.5) (10.5) (8.6) (9.7) (9.3) (12.6) (9.4) 1.5 1.3 1.2 1.4 1.1 0.9 1.2 Sulfonamides and trimethoprim (J01E) (9.4) (11.4) (8.6) (9.7) (10.3) (8.7) (8.6) Macrolides, lincosamides and streptogramins 1.3 0.9 1.4 1.4 0.9 1.4 1.5 (J01F) (8.2) (7.9) (10.1) (9.7) (8.4) (13.6) (10.8) 2 1.1 1.5 1.5 1.3 1.2 1.3 Quinolone antibacterials (J01M) (12.6) (9.6) (10.8) (10.4) (12.1) (11.7) (9.4) 1.1 0.8 1.1 0.7 0.9 0.6 1 Other J01 antibacterials (J01G, J01R, J01X) (6.9) (7) (7.9) (4.9) (8.4) (5.8) (7.2) Total 15.9 11.4 13.9 14.4 10.7 10.3 13.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

There is some evidence of increasing relative consumption of cephalosporins (J01D), at 7.5% in 2011 and 9.4% in 2017, and decreasing relative consumption of quinolones (J01M), at 12.6% in 2011 and 9.4% in 2017 (Table 5.1).

32 Armenia

The relative consumption of cephalosporins and quinolones combined remained reasonably stable over time (20% in 2011, 19% in 2017), with decreases in quinolone consumption (12.6% in 2011, 9.4% in 2017) offset to some extent by small increases in consumption of cephalosporins (7.5% in 2011, 9.4% in 2017).

5.3 Relative consumption by choice of agent

5.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2011–2017 is shown in Fig. 5.2 and summarized in Table 5.2. Table 5.3 shows the most consumed agents within each of the generations of cephalosporin agents.

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 ARM ARM ARM ARM ARM ARM ARM 2011 2012 2013 2014 2015 2016 2017

Fig. 5.2 Relative consumption of cephalosporins by generation

Table 5.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 0.4 0.2 0.4 0.2 0.2 0.1 0.2 First-generation (J01DB) (32) (20) (34) (18) (18) (8) (12) 0.1 0.1 0.1 0.1 Second-generation (J01DC) < 0.1 < 0.1 < 0.1 (10) (11) (9) (10) 0.7 0.8 0.7 1 0.7 1.1 0.9 Third-generation (J01DD) (61) (70) (59) (74) (70) (83) (76) Fourth-generation (J01DE) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Total 1.2 1.2 1.2 1.4 1.0 1.3 1.2 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

33 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 5.3 Most consumed agents within each generation of cephalosporins

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) Cefalexin 0.1 (28) < 0.1 0.1 (24) 0.1 (47) 0.1 (68) < 0.1 < 0.1 Cefazolin 0.3 (72) 0.1 (62) 0.3 (76) 0.1 (53) < 0.1 < 0.1 < 0.1 Second-generation (J01DC) 0.1 0.1 0.1 0.1 Cefuroxime < 0.1 < 0.1 < 0.1 (100) (100) (100) (100) Third-generation (J01DD) Ceftriaxone 0.7 (91) 0.7 (90) 0.6 (87) 0.9 (91) 0.6 (89) 0.9 (82) 0.7 (70) Cefixime < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 0.2 (14) 0.2 (24) a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for the nominated generation of cephalosporins.

Decreases in consumption of first-generation agents were seen (32% of total cephalosporin use in 2011 and 12% in 2017). Second-generation agents, mostly cefuroxime, represented 10% of cephalosporin consumption in 2017. Consumption of Watch group third-generation agents dominated and increased over time (61% of total cephalosporin use in 2011 and 76% in 2017). Ceftriaxone and cefixime comprised 70% and 24% of third-generation agent consumption in 2017. Only small volumes of consumption of fourth-generation cephalosporins (Reserve agents) were reported.

5.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) represented 1.3 DID (9.4%) of total J01 consumption in 2017, with fluoroquinolones comprising 1.2 DID – 92% of quinolone consumption. Three fluoroquinolones – ciprofloxacin, levofloxacin and moxifloxacin – dominated, representing 57%, 17% and 13% of fluoroquinolone consumption in 2017 (Table 5.4). The overall pattern, however, was of some reductions in levels of consumption of fluoroquinolones.

Table 5.4 Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 Ofloxacin 0.1 (6) 0.2 (20) 0.1 (8) 0.2 (11) < 0.1 < 0.1 < 0.1 Ciprofloxacin 1.1 (58) 0.5 (52) 1 (72) 1 (71) 0.8 (63) 0.5 (43) 0.7 (57) Norfloxacin 0.1 (6) 0.1 (10) 0.1 (8) < 0.1 < 0.1 0.1 (9) < 0.1 Levofloxacin 0.5 (25) < 0.1 < 0.1 < 0.1 0.1 (11) 0.4 (33) 0.2 (17) Moxifloxacin < 0.1 0.1 (10) < 0.1 0.1 (10) 0.2 (14) 0.1 (9) 0.2 (13) Total 1.9 1.0 1.4 1.4 1.2 1.1 1.2 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption of fluoroquinolones.

34 Armenia

5.4 The 10 most consumed agents

5.4.1 The 10 most consumed agents – oral formulation

Table 5.5 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

Table 5.5 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Amoxicillin 3.39 3.39 3.39 3.39 3.39 3.39 3.39 3.39 3.39 3.39 Amoxicillin and enzyme 2.09 2.09 2.09 2.09 2.09 2.09 2.09 2.09 2.09 inhibitor Doxycycline 1.39 1.39 1.39 1.39 1.39 1.39 1.39 1.39 Sulfamethoxazole and 1.18 1.18 1.18 1.18 1.18 1.18 1.18 trimethoprim Azithromycin 1.03 1.03 1.03 1.03 1.03 1.03 Ciprofloxacin 0.65 0.65 0.65 0.65 0.65 Nitrofurantoin 0.65 0.65 0.65 0.65 Chloramphenicol 0.40 0.40 0.40 Clarithromycin 0.27 0.27 Cefixime 0.22 Total consumption for 11.29 11.06 10.79 10.39 9.74 9.08 8.05 6.87 5.48 3.39 this group of agents Total consumption for all 12.51 12.51 12.51 12.51 12.51 12.51 12.51 12.51 12.51 12.51 oral J01 agents Proportion (%) of total consumption for oral J01 90.2% 88.4% 86.2% 83.0% 77.8% 72.6% 64.3% 54.9% 43.8% 27.1% antibacterials a DDD: daily defined dose.

The 10 listed oral agents represent just over 90% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, four are included in the WHO Watch group of antibacterials – azithromycin and clarithromycin (macrolides), ciprofloxacin (quinolones) and cefixime (third-generation cephalosporins).

Azithromycin (8.3%), ciprofloxacin (5.2%), clarithromycin (2.2%) and cefixime (1.8%) combined constituted around 17.5% of total consumption of J01 oral antibacterials in 2017.

5.4.2 The 10 most consumed agents – parenteral formulation

Table 5.6 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

35 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 5.6 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Ceftriaxone 0.66 0.66 0.66 0.66 0.66 0.66 0.66 0.66 0.66 0.66 Streptomycin 0.12 0.12 0.12 0.12 0.12 0.12 0.12 0.12 0.12 Metronidazole 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.08 Benzylpenicillin 0.06 0.06 0.06 0.06 0.06 0.06 0.06 Cefazolin 0.06 0.06 0.06 0.06 0.06 0.06 Ampicillin 0.05 0.05 0.05 0.05 0.05 Moxifloxacin 0.05 0.05 0.05 0.05 Ciprofloxacin 0.04 0.04 0.04 Combinations 0.04 0.04 Cefotaxime 0.03 Total consumption for 1.20 1.16 1.12 1.08 1.04 0.98 0.92 0.86 0.78 0.66 this group of agents Total consumption for all 1.34 1.34 1.34 1.34 1.34 1.34 1.34 1.34 1.34 1.34 parenteral J01 agents Proportion (%) of total consumption 89.7% 87.1% 84.1% 81.0% 77.6% 73.6% 69.1% 64.4% 58.1% 49.2% for parenteral J01 antibacterials a DDD: daily defined dose.

As shown in Table 5.1, parenteral agents comprised around 10% of total J01 consumption in 2017. Within this, the Watch group third-generation cephalosporins ceftriaxone (49.2%) and cefotaxime (2.6%) constituted just over half of the consumption of J01 injection formulations.

5.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 5.3 and Fig. 5.4, and is summarized in Table 5.7.

Table 5.7 Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

Percentage of total consumptiona Antibiotic group 2011 2012 2013 2014 2015 2016 2017 Core Access group 68.4 65.7 65.2 68.8 70.1 57.0 69.3 Watch group 25.4 25.3 25.8 26.9 25.4 36.0 26.3 Reserve group 0.01 0.00 0.01 0.04 0.09 0.12 0.24 Ungrouped 6.2 9.0 9.0 4.3 4.5 6.8 4.1 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

36 Armenia

100

60 Other

40 Core Access group 68 66 65 69 70 69 Proportion (%) Proportion 57 20

0 ARM ARM ARM ARM ARM ARM ARM 2011 2012 2013 2014 2015 2016 2017

Fig. 5.3 Relative consumption of Core Access group of antibiotics as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

100

60 Other Watch group 40 Proportion (%) Proportion

20 36 25 25 26 27 25 26

0 ARM ARM ARM ARM ARM ARM ARM 2011 2012 2013 2014 2015 2016 2017

Fig. 5.4 Relative consumption of Watch group of antibiotics as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Most antibiotic consumption came from agents in the Core Access group. Notwithstanding the anomalous data for 2016, the relative consumption of Watch agents remained consistent at around 25–26% of total antibiotic consumption. Consumption of Reserve group agents was low.

5.6 Analyses based on DDDs applied in 2019

To provide new baseline trend data for AMC estimates, analyses for 2015, 2016 and 2017 have been re-run applying the new DDD values that came into effect in January 2019. Data are presented with both existing and new DDDs to illustrate the impact of the changes.

37 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

5.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 5.5 (DDD values relevant to year) and Fig. 5.6 (2019 DDD values), and is summarized in Table 5.8.

15 15

10 10 Parenteral Parenteral antibacterials antibacterials Oral Oral 5 5 antibacterials antibacterials DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 ARM ARM ARM ARM ARM ARM 2015 2016 2017 2015 2016 2017

Fig. 5.5 Total consumption of J01 Fig. 5.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values)

Table 5.8 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 9.5 (89) 8.7 (85) 12.5 (90) 8.2 (88) 7.8 (84) 10.7 (89) Parenteral J01 1.2 (11) 1.6 (15) 1.3 (10) 1.2 (12) 1.5 (16) 1.3 (11) Total 10.7 10.3 13.9 9.4 9.3 12.0 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The relative consumption of oral and parenteral formulations does not change substantially with the application of the 2019 DDDs (oral 90% applying older values and 89% with the 2019 DDD values in 2017).

5.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 5.7 (DDD values relevant to year) and Fig. 5.8 (2019 DDD values), and is summarized in Table 5.9. As noted in section 5.6.1, total DIDs decreased by 13.6% in 2017.

38 Armenia

DDD/1000 inhabitants per day (includes DDD/1000 inhabitants per day (includes cephalosporins) cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols ARM ARM ARM (J01B) ARM ARM ARM (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 5.7 Total consumption of J01 Fig. 5.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

Table 5.9 Relative consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 0.8 1.6 1.5 0.8 1.6 1.5 Tetracyclines (J01A) (7.5) (15.5) (10.8) (8.5) (17.2) (12.5) 0.3 0.2 0.4 0.3 0.2 0.4 Amphenicols (J01B) (2.8) (1.9) (2.9) (3.2) (2.2) (3.3) 4.3 2.9 5.6 3 2 3.8 Beta-lactams (J01C) (40.2) (28.2) (40.3) (31.9) (21.5) (31.7) Other beta-lactams (includes 1 1.3 1.3 1 1.3 1.2 cephalosporins) (J01D) (9.3) (12.6) (9.4) (10.6) (14) (10) Sulfonamides and trimethoprim 1.1 0.9 1.2 1.1 0.9 1.2 (J01E) (10.3) (8.7) (8.6) (11.7) (14) (10) Macrolides, lincosamides and 0.9 1.4 1.5 0.8 1.4 1.5 streptogramins (J01F) (8.4) (13.6) (10.8) (8.5) (15.1) (12.5) 1.3 1.2 1.3 1.3 1.2 1.3 Quinolone antibacterials (J01M) (12.1) (11.7) (10.8) (13.8) (12.9) (10.8) Other J01 antibacterials (J01G, 0.9 0.6 1 0.9 0.6 1 J01R, J01X) (8.4) (5.8) (7.2) (9.6) (6.5) (8.3) Total 10.7 10.3 13.9 9.4 9.3 12.0 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 5.6 DID in 2017 using the DDD values relevant to the year of data to 3.8 DID applying the 2019 DDD values – a reduction of 32.1% in absolute values. Relative consumption of beta-lactams falls from 40.3% to 31.7% of total J01 consumption when the 2019 DDD values are applied.

39 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

As the total DIDs decrease with the application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta-lactams generally increases: tetracyclines, for example, increased from 10.8% to 12.5%, cephalosporins from 9.4% to 10% and the macrolides group from 10.8% to 12.5% in 2017.

5.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 5.9 (DDD values relevant to year) and Fig. 5.10 (2019 DDD values) for Core Access antibiotics, Fig. 5.11 (DDD values relevant to year) and Fig. 5.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 5.10.

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group 70 69 Proportion (%) Proportion (%) Proportion 66 65 57 53 20 20

0 0 ARM ARM ARM ARM ARM ARM 2015 2016 2017 2015 2016 2017

Fig. 5.9 Relative consumption of Core Access Fig. 5.10 Relative consumption of Core group antibacterials (applying DDD values Access group antibacterials (applying 2019 relevant to year) DDD values)

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion

20 36 20 39 25 26 29 30

0 0 ARM ARM ARM ARM ARM ARM 2015 2016 2017 2015 2016 2017

Fig. 5.11 Relative consumption of Watcha Fig. 5.12 Relative consumption of Watcha group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year) DDD values)

a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01)

40 Armenia

Table 5.10 Relative consumption of Core Access, Watch and Reserve groups of antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 7.9 (70) 6 (57) 9.8 (69) 6.5 (66) 5.1 (53) 8 (65) Watch group 2.9 (25.4) 3.8 (36) 3.7 (26.3) 2.8 (29) 3.8 (39) 3.7 (30) Reserve group 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Ungrouped 0.5 (4) 0.7 (7) 0.6 (4) 0.6 (6) 0.7 (8) 0.6 (5) Total 11.3 10.5 14.2 9.9 9.6 12.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05, and metronidazole (P01AB01).

5.7 Discussion

The analyses in this report are based on import records and information from local pharmaceutical manufacturers. There is some evidence that data for 2016 relate to a lower-than-usual level of imports into Armenia. This would in part explain the apparent reductions in total consumption in 2016 and make the 2016 data less reliable for interpreting trends over time.

The data show fluctuations in estimates of total consumption of J01 antibacterials over time. While the data for 2014 and 2015 suggest decreases in total consumption, 2017 estimates returned to 2013 levels. Parenteral antibacterials constituted 10–12% of total J01 consumption across the years analysed.

Relative consumption of beta-lactams remained reasonably stable over time, with some evidence of increasing consumption of cephalosporins and decreases in relative consumption of quinolones.

Of the top 10 oral agents, four are included in the WHO Watch group of antibacterials – azithromycin and clarithromycin (macrolides), ciprofloxacin (quinolones) and cefixime (third-generation cephalosporins). Azithromycin (8.3%), ciprofloxacin (5.2%), clarithromycin (2.2%) and cefixime (1.8%) together constituted around 17.5% of total consumption of J01 oral antibacterials in 2017.

The Watch group third-generation cephalosporins ceftriaxone (49.2%) and cefotaxime (2.6%) constituted just over half of the consumption of J01 injection formulations.

Watch group agents (oral and parenteral combined) comprised 26.3% of total consumption in 2017.

These relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities. For example, the WHO EML (WHO, 2017) suggests limited indications for use of azithromycin, clarithromycin, ciprofloxacin, cefixime and ceftriaxone.

41 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Clarithromycin is listed on the EML as a first-choice option for severe community-acquired pneumonia and as a second-choice option for pharyngitis.

Ciprofloxacin is listed on the WHO EML as a first-choice agent for acute invasive bacterial diarrhoea/dysentery, low-risk febrile neutropenia and mild-to-moderate pyelonephritis or prostatitis. It is a second-choice agent for the treatment of cholera and mild-to-moderate complicated intra-abdominal infections.

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with WHO EML recommendations.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 13.9 DID in 2017 using existing DDD values to 12.0 DID applying the 2019 DDD values – a reduction of 15.7%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 5.6 DID in 2017 using the DDD values relevant to the year of data to 3.8 DID applying the 2019 DDD values – a reduction of 32.2% in absolute values.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in Armenia and can help to identify areas for further investigation, allowing the development of targeted interventions to address potential problems identified in the consumption of antibacterials. Interventions targeting medicines should be supported by evidence-based guidelines and treatment protocols.

Total DIDs decreased by 15.7% when the new 2019 DDDs were applied, independent of any intervention by government, agencies or professional groups. Communication strategies will be required so

42 Armenia

stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

Reference

43 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

6. AZERBAIJAN

6.1 Data source and years of data collection

Azerbaijan provided data for each of the seven years of data collection (2011–2017). The main sources were import records provided by the drug agency. Data derived from importation records will be affected by the cycles of procurement and delivery, potentially giving rise to fluctuations in estimates of consumption that do not relate to actual use of antibacterials by patients and health-care facilities.

6.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

The data show fluctuations in total consumption of J01 antibacterials over time, with a general trend towards lower consumption, at 17.1 DID in 2011, 10.1 DID in 2016 and 8.5 DID in 2017. The reasons for the apparent increase in consumption in 2016 requires local investigation, but may relate in part to variations in import cycles.

The relative consumption of parenteral antibacterials changed substantially over time, ranging from 47–69% between 2011 and 2014 to 22–25% between 2015 and 2017 (Table 6.1). These substantial changes may relate to country-level interventions to reduce consumption of injection formulations.

The highest levels of consumption were in beta-lactams (J01C), at 11.3 DID in 2011 and 2.5 DID in 2017. There is some evidence of increasing consumption of cephalosporin antibacterials (J01D), with 0.8 DID in 2011 and 1.5 DID in 2017.

These observations relate to total consumption. Different patterns of consumption would be expected in the hospital and community sectors.

Relative consumption of beta-lactams (J01C) decreased over time, from 66.1% in 2011 to 29.4% in 2017. There is some evidence of increasing relative consumption of cephalosporins (J01D), at 4.7% in 2011 and 17.6% in 2017, and quinolones (J01M), at 4.7% in 2011 and 10.6% in 2017 (Table 6.1).

The relative consumption of cephalosporins and quinolones combined increased over time, from 9.4% in 2011 to 28.2% in 2017), with increases in both cephalosporin and quinolone consumption.

44 Azerbaijan

25 Other J01 antibacterials (J01G, J01R, J01X) a 20 Quinolone antibacterials (J01M) Macrolides, lincosamides 15 and streptogramins (J01F) Sulfonamides and trimethoprim (J01E) 10 Other beta-lactams (includes cephalosporins) (J01D) Beta-lactams (J01C)

DDD/1000 inhabitants per day 5 Amphenicols (J01B) Tetracyclines (J01A) 0

AZE AZE AZE AZE AZE AZE AZE 2011 2012 2013 2014 2015 2016 2017

Fig. 6.1 Total consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose.

Table 6.1 Total consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 Route of administration 9.1 9.6 5.7 2.6 6.3 7.8 6.4 Oral J01 (53) (47) (48) (31) (78) (78) (75) 8 10.9 6.1 5.8 1.7 2.3 2.1 Parenteral J01 (47) (53) (52) (69) (22) (22) (25) Total 17.1 20.5 11.7 8.5 8.0 10.1 8.5 Class of antibacterial agents 1.4 2.2 0.8 0.6 1.8 1.4 1.3 Tetracyclines (J01A) (8.2) (10.7) (6.8) (7.1) (22.5) (13.9) (15.3) 0.5 0.6 0.3 0.1 0.2 0 0 Amphenicols (J01B) (2.9) (2.9) (2.6) (1.2) (2.5) (0) (0) 11.3 13.8 6.6 5.6 2 2.6 2.5 Beta-lactams (J01C) (66.1) (67.3) (56.4) (65.9) (25) (25.7) (29.4) Other beta-lactams (includes cephalosporins) 0.8 0.7 0.5 0.5 0.7 1.6 1.5 (J01D) (4.7) (3.4) (4.3) (5.9) (8.8) (15.8) (17.6) 0.8 0.3 0.9 0.5 0.7 0.7 0.5 Sulfonamides and trimethoprim (J01E) (4.7) (1.5) (7.7) (5.9) (8.8) (6.9) (5.9) Macrolides, lincosamides and streptogramins 1 1.3 0.9 0.6 1 1.2 1 (J01F) (5.8) (6.3) (7.7) (7.1) (12.5) (11.9) (11.8) 0.8 1 0.7 0.4 0.8 1.6 0.9 Quinolone antibacterials (J01M) (4.7) (4.9) (6) (4.7) (10) (15.8) (10.6) 0.6 0.6 1 0.3 0.8 1.1 0.7 Other J01 antibacterials (J01G, J01R, J01X) (3.5) (2.9) (8.5) (3.5) (10) (10.9) (8.2) Total 17.1 20.5 11.7 8.5 8 10.1 8.5 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

45 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

6.3 Relative consumption by choice of agent

6.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2011–2017 is shown in Fig. 6.2 and summarized in Table 6.2. Table 6.3 shows the most consumed agents within each of the generations of cephalosporin agents.

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 AZE AZE AZE AZE AZE AZE AZE 2011 2012 2013 2014 2015 2016 2017

Fig. 6.2 Relative consumption of cephalosporins by generation

Table 6.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 0.1 (8) < 0.1 Second-generation (J01DC) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 0.1 (7) < 0.1 Third-generation (J01DD) 0.6 (80) 0.6 (85) 0.4 (78) 0.4 (76) 0.6 (82) 1.3 (85) 1.3 (88) Fourth-generation (J01DE) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 – Total 0.8 0.7 0.5 0.5 0.7 1.6 1.5 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Consumption of first- and second-generation cephalosporins was low across all the years analysed. Consumption of third-generation agents dominated, representing 88% of cephalosporin consumption in 2017. Ceftriaxone comprised 92% of third-generation agent consumption in 2017. Only small volumes of consumption of fourth-generation cephalosporins (Reserve agents) were reported.

46 Azerbaijan

Table 6.3 Most consumed agents within each generation of cephalosporins

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) Cefazolin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 0.1 (100) < 0.1 Third-generation (J01DD) Cefotaxime < 0.1 0.1 (19) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Ceftriaxone 0.5 (80) 0.5 (77) 0.3 (83) 0.3 (83) 0.5 (88) 1.2 (89) 1.2 (92) Cefixime < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 0.1 (8) < 0.1 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for the nominated generation of cephalosporins.

6.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) represented 0.9 DID (10.6%) of total J01 consumption in 2017, almost all of which was consumption of fluoroquinolones. Levofloxacin and ofloxacin represented 68% and 15% respectively of fluoroquinolone consumption in 2017 (Table 6.4).

Table 6.4 Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 Ofloxacin 0.2 (25) 0.3 (27) 0.2 (29) 0.1 (35) 0.3 (38) 0.4 (28) 0.1 (15) Ciprofloxacin 0.2 (31) 0.2 (23) 0.2 (23) < 0.1 < 0.1 0.2 (11) < 0.1 Norfloxacin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Levofloxacin 0.3 (42) 0.4 (39) 0.2 (33) 0.1 (38) 0.4 (50) 0.8 (53) 0.6 (68) Moxifloxacin < 0.1 0.1 (10) 0.1 (14) < 0.1 < 0.1 0.1 (7) < 0.1 Gemifloxacin – – – < 0.1 – – – Total 0.8 1.0 0.7 0.4 0.8 1.5 0.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

6.4 The 10 most consumed agents

6.4.1 The 10 most consumed agents – oral formulation

Table 6.5 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

The 10 listed oral agents represent around 85% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, three are included in the WHO Watch group of antibacterials – azithromycin and clarithromycin (macrolides), and levofloxacin (quinolones).

47 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 6.5 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Amoxicillin 1.25 1.25 1.25 1.25 1.25 1.25 1.25 1.25 1.25 1.25 Tetracycline 0.81 0.81 0.81 0.81 0.81 0.81 0.81 0.81 0.81 Azithromycin 0.63 0.63 0.63 0.63 0.63 0.63 0.63 0.63 Amoxicillin and enzyme 0.57 0.57 0.57 0.57 0.57 0.57 0.57 inhibitor Levofloxacin 0.54 0.54 0.54 0.54 0.54 0.54 Doxycycline 0.49 0.49 0.49 0.49 0.49 Sulfamethoxazole and 0.49 0.49 0.49 0.49 trimethoprim Nitrofurantoin 0.31 0.31 0.31 Ampicillin 0.20 0.20 Clarithromycin 0.17 Total consumption for this 5.45 5.28 5.08 4.77 4.29 3.80 3.26 2.69 2.06 1.25 group of agents Total consumption for all 6.40 6.40 6.40 6.40 6.40 6.40 6.40 6.40 6.40 6.40 oral J01 agents Proportion (%) of total consumption for oral J01 85.2% 82.6% 79.4% 74.6% 67.0% 59.4% 50.9% 42.0% 32.1% 19.5% antibacterials a DDD: daily defined dose.

Azithromycin (9.9%), levofloxacin (8.5%) and clarithromycin (2.6%) combined constituted around 21% of total consumption of J01 oral antibacterials in 2017.

6.4.2 The 10 most consumed agents – parenteral formulation

Table 6.6 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

Table 6.6 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Ceftriaxone 1.22 1.22 1.22 1.22 1.22 1.22 1.22 1.22 1.22 1.22 Ampicillin 0.21 0.21 0.21 0.21 0.21 0.21 0.21 0.21 0.21 Combinations 0.21 0.21 0.21 0.21 0.21 0.21 0.21 0.21 Streptomycin 0.10 0.10 0.10 0.10 0.10 0.10 0.10 Cefazolin 0.08 0.08 0.08 0.08 0.08 0.08 Levofloxacin 0.06 0.06 0.06 0.06 0.06 Gentamicin 0.06 0.06 0.06 0.06 Ampicillin and enzyme 0.05 0.05 0.05 inhibitor Cefotaxime 0.04 0.04 Amikacin 0.02 Total consumption for this 2.04 2.02 1.98 1.93 1.88 1.81 1.73 1.63 1.43 1.22 group of agents Total consumption for all 2.11 2.11 2.11 2.11 2.11 2.11 2.11 2.11 2.11 2.11 parenteral J01 agents Proportion (%) of total consumption for parenteral 96.7% 95.7% 94.0% 91.6% 88.9% 85.9% 82.1% 77.5% 67.7% 57.6% J01 antibacterials a DDD: daily defined dose.

48 Azerbaijan

As shown in Table 6.1, parenteral agents comprised around 25% of total J01 consumption in 2017. Within this, the Watch group third-generation cephalosporin ceftriaxone constituted 57.6% of the J01 injection formulations.

6.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 6.3 and Fig. 6.4, and is summarized in Table 6.7.

100

60 Other Core Access group 40 72 74

Proportion (%) Proportion 64 63 53 45 20 42

0 AZE AZE AZE AZE AZE AZE AZE 2011 2012 2013 2014 2015 2016 2017

Fig. 6.3 Relative consumption of Core Access group of antibiotics as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

100

60 Other Watch group 40 Proportion (%) Proportion

20 39 30 32 13 14 17 15 0 AZE AZE AZE AZE AZE AZE AZE 2011 2012 2013 2014 2015 2016 2017

Fig. 6.4 Relative consumption of Watch group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

49 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 6.7 Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

Percentage of total consumptiona Antibiotic group 2011 2012 2013 2014 2015 2016 2017 Core Access group 71.6 64.2 62.9 73.7 42.4 45.5 53.2 Watch group 13.2 14.2 17.3 15.4 29.5 38.7 31.9 Reserve group 0.03 0.00 0.01 0.00 0.01 0.00 0.00 Ungrouped 15.2 21.6 19.7 10.9 28.1 15.9 14.8 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Most antibiotic consumption came from agents in the Core Access group. The relative consumption of Watch agents increased over time, from 13.2% of total antibiotic consumption in 2011 to 31.9% in 2017. Consumption of Reserve group agents was low. There was considerable consumption of ungrouped agents across all years analysed.

6.6 Analyses based on DDDs applied in 2019

6.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 6.5 (DDD values relevant to year) and Fig. 6.6 (2019 DDD values), and is summarized in Table 6.8.

15 15

10 10 Parenteral Parenteral antibacterials antibacterials Oral Oral 5 5 antibacterials antibacterials DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 AZE AZE AZE AZE AZE AZE 2015 2016 2017 2015 2016 2017

Fig. 6.5 Total consumption of J01 Fig. 6.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values)

50 Azerbaijan

Table 6.8 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 6.3 (78) 7.8 (78) 6.4 (75) 5.9 (80) 7 (77) 5.9 (75) Parenteral J01 1.7 (22) 2.3 (22) 2.1 (25) 1.5 (20) 2.1 (23) 2 (25) Total 8.0 10.1 8.5 7.3 9.1 7.8 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The relative consumption of oral and parenteral formulations does not change substantially with the application of the 2019 DDDs (oral agents 75% applying both older values and 2019 DDD values in 2017).

6.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 6.7 (DDD values relevant to year) and Fig. 6.8 (2019 DDD values), and is summarized in Table 6.9. As noted in section 6.6.1, total DIDs decreased by 8.2% in 2017.

DDD/1000 inhabitants per day (includes DDD/1000 inhabitants per day (includes cephalosporins) cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols AZE AZE AZE (J01B) AZE AZE AZE (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 6.7 Total consumption of J01 Fig. 6.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

51 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 6.9 Relative consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 1.8 1.4 1.3 1.8 1.4 1.3 Tetracyclines (J01A) (22.5) (13.9) (15.3) (24.7) (15.4) (16.7) 0.2 0 0 0.2 0 0 Amphenicols (J01B) (2.5) (0) (0) (2.7) (0) (0) 2 2.6 2.5 1.4 1.8 1.8 Beta-lactams (J01C) (25) (25.7) (29.4) (19.2) (19.8) (23.1) Other beta-lactams (includes 0.7 1.6 1.5 0.7 1.6 1.5 cephalosporins) (J01D) (8.8) (15.8) (17.6) (9.6) (17.6) (19.2) Sulfonamides and trimethoprim 0.7 0.7 0.5 0.7 0.7 0.5 (J01E) (8.8) (6.9) (5.9) (9.6) (7.7) (6.4) Macrolides, lincosamides and 1 1.2 1 1 1.2 1 streptogramins (J01F) (12.5) (11.9) (11.8) (13.7) (13.2) (12.8) 0.8 1.6 0.9 0.8 1.5 1 Quinolone antibacterials (J01M) (10) (15.8) (10.6) (11) (16.5) (12.8) Other J01 antibacterials (J01G, 0.8 1.1 0.7 0.8 1.1 0.7 J01R, J01X) (10) (10.9) (8.2) (11) (12.1) (9) Total 8 10.1 8.5 7.3 9.1 7.8 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 2.5 DID in 2017 using the DDD values relevant to the year of data to 1.8 DID applying the 2019 DDD values – a reduction of 28% in absolute values. Relative consumption of beta-lactams falls from 29.4% to 23.1% of total J01 consumption when the 2019 DDD values are applied.

As the total DIDs decrease with the application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta-lactams generally increases; tetracyclines, for example, increased from 15.3% to 16.7%, cephalosporins from 17.6% to 19.2% and quinolones from 10.6% to 12.8% in 2017.

6.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 6.9 (DDD values relevant to year) and Fig. 6.10 (2019 DDD values) for Core Access antibiotics, Fig. 6.11 (DDD values relevant to year) and Fig. 6.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 6.10.

The effect of applying the 2019 DDD values is to decrease slightly the proportion of total use that is Core Access group antibiotics (from 69% to 65% in 2017) and increase slightly the proportion of total use that is Watch group antibiotics (from 26.3% to 30% in 2017). The higher estimate of total antibiotic consumption in 2017 of 10.3 DID compared to 8.5 DID in Table 6.1 reflects the inclusion of metronidazole (1.8 DID, ATC P01AB01) in the calculations of Core Access and Watch antibacterials.

52 Azerbaijan

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group Proportion (%) Proportion (%) Proportion 53 49 20 42 45 20 39 41

0 0 AZE AZE AZE AZE AZE AZE 2015 2016 2017 2015 2016 2017 Fig. 6.9 Relative consumption of Core Access Fig. 6.10 Relative consumption of Core group antibacterials (applying DDD values Access group antibacterials (applying 2019 relevant to year)a DDD values)a

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion

20 39 20 42 30 32 32 35

0 0 AZE AZE AZE AZE AZE AZE 2015 2016 2017 2015 2016 2017

Fig. 6.11 Relative consumption of Watch Fig. 6.12 Relative consumption of Watch group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year)a DDD values)a

a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 6.10 Relative consumption of Core Access, Watch and Reserve groups of antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 3.5 (42) 4.7 (45) 5.5 (53) 3 (39) 3.9 (41) 4.7 (49) Watch group 2.4 (29.5) 4 (38.7) 3.3 (31.9) 2.4 (32) 4 (42) 3.3 (35) Reserve group 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Ungrouped 2.3 (28) 1.7 (16) 1.5 (15) 2.2 (29) 1.7 (17) 1.5 (16) Total 8.2 10.4 10.3 7.6 9.5 9.6 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

53 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

6.7 Discussion

The analyses in this report are based on import records.

The relative consumption of parenteral antibacterials changed substantially over time, ranging from 47–69% between 2011 and 2014 and reducing to 22–25% between 2015 and 2017. These substantial changes may relate to country-level interventions to reduce consumption of injection formulations.

Relative consumption of beta-lactams (J01C) decreased over time, at 66.1% in 2011 and 29.4% in 2017. There is some evidence of increasing relative consumption of cephalosporins (J01D), at 4.7% in 2011 and 17.6% in 2017, and quinolones (J01M), at 4.7% in 2011 and 10.6% in 2017 (Table 6.1).

Relative consumption of beta-lactams decreased over time, with some evidence of increasing relative consumption of cephalosporins and quinolones.

Of the top 10 oral agents, three are included in the WHO Watch group of antibacterials – azithromycin and clarithromycin (macrolides), and levofloxacin (quinolones). Azithromycin (9.9%), levofloxacin (8.5%) and clarithromycin (2.6%) combined constituted around 21% of total consumption of J01 oral antibacterials in 2017.

The Watch group third-generation cephalosporin ceftriaxone constituted 57.6% of the consumption of J01 injection formulations in 2017.

Watch group agents (oral and parenteral combined) comprised 31.9% of total consumption in 2017.

These relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities. For example, the WHO EML (WHO, 2017) suggests limited indications for use of azithromycin, clarithromycin, levofloxacin and ceftriaxone.

Clarithromycin is listed on the EML as a first-choice option for severe community-acquired pneumonia and as a second-choice option for pharyngitis.

Levofloxacin is listed on the WHO EML as a reserve second-line drug for the treatment of MDR-TB that should be used in specialized centres adhering to WHO standards for TB control.

54 Azerbaijan

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with WHO EML recommendations.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 8.5 DID in 2017 using DDD values relevant to year of data to 7.8 DID applying the 2019 DDD values – a reduction of 8.2%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 2.5 DID in 2017 using the DDD values relevant to the year of data to 1.8 DID applying the 2019 DDD values – a reduction of 28% in absolute values.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in Azerbaijan and can help to identify areas for further investigation, allowing development of targeted interventions to address potential problems identified in the consumption of antibacterials. Interventions targeting medicines should be supported by evidence-based guidelines and treatment protocols.

Total DID decreased by 8.2% when the new 2019 DDDs were applied, independent of any intervention by government, agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

Reference

55 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

7. BELARUS

7.1 Data source and years of data collection

Belarus data were available for each of the seven years of data collection (2011–2017). The main sources were import records from the drug agency and information provided by local pharmaceutical manufacturers. Data derived from importation records will be affected by the cycles of procurement and delivery, potentially giving rise to fluctuations in estimates of consumption that do not relate to actual use of antibacterials by patients and health-care facilities. Data of local manufacturer records are disaggregated only to products for local consumption.

7.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

The data show fluctuations in total consumption of J01 antibacterials over time, with a trend to increases in total consumption between 2015 and 2017. The reasons for this require further investigation. There may be some influence of medicine import cycles or supplies of local manufacturers.

DDD/1000 inhabitants per day 5 Amphenicols (J01B) Tetracyclines (J01A) 0

BLR BLR BLR BLR BLR BLR BLR 2011 2012 2013 2014 2015 2016 2017

Fig. 7.1 Total consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose.

56 Belarus

The relative consumption of parenteral antibacterials varied over the years analysed and represented 11% of total J01 consumption in 2017.

The highest levels of consumption were in beta-lactams (J01C), at 6.7 DID in 2011 and 11 DID in 2017. There is evidence of increasing consumption of macrolides (J01F), with 1.6 DID in 2011 and 3.1 DID in 2017, and quinolone antibacterials (J01M), with 1.5 DID in 2011 and 2.1 DID in 2017.

These observations relate to total consumption. Different patterns of consumption would be expected in the hospital and community sectors.

Table 7.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 Route of administration 15.3 16.3 19.3 16.7 15.4 16.3 21.2 Oral J01 (85) (88) (84) (84) (81) (84) (89) 2.6 2.2 3.7 3.3 3.6 3.1 2.5 Parenteral J01 (15) (12) (16) (16) (19) (16) (11) Total 17.9 18.6 23.1 20.0 19.0 19.4 23.7 Class of antibacterial agents 3 3.3 2.9 2.7 3 2.5 2.8 Tetracyclines (J01A) (16.8) (17.7) (12.6) (13.5) (15.8) (12.9) (11.8) 0.4 0.2 0.3 0.2 0.1 0.1 0.1 Amphenicols (J01B) (2.2) (1.1) (1.3) (1) (0.5) (0.5) (0.4) 6.7 5.9 8.2 7.1 7.5 7.3 11 Beta-lactams (J01C) (37.4) (31.7) (35.5) (35.5) (39.5) (37.6) (46.4) Other beta-lactams (includes cephalosporins) 2.3 2.1 3.5 3.1 3 2.8 2.7 (J01D) (12.8) (11.3) (15.2) (15.5) (15.8) (14.4) (11.4) 0.1 0.3 0.3 0.1 0.1 0.1 Sulfonamides and trimethoprim (J01E) 0 (0.6) (1.6) (1.3) (0.5) (0.5) (0.4) Macrolides, lincosamides and streptogramins 1.6 2.7 3.1 2.8 2.4 3 3.1 (J01F) (8.9) (14.5) (13.4) (14) (12.6) (15.5) (13.1) 1.5 1.9 2.3 2.5 1.7 1.9 2.1 Quinolone antibacterials (J01M) (8.4) (10.2) (10) (12.5) (8.9) (9.8) (8.9) 2.3 2.2 2.4 1.6 1.2 1.7 1.7 Other J01 antibacterials (J01G, J01R, J01X) (12.8) (11.8) (10.4) (8) (6.3) (8.8) (7.2) Total 17.9 18.6 23.1 20.0 19.0 19.4 23.7 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

There is evidence of increasing relative consumption of beta-lactams (J01C), at 37.4% in 2011 and 46.4% in 2017, and macrolides (J01F), at 8.9% in 2011 and 13.1% in 2017.

The relative consumption of cephalosporins and quinolones combined varied a little over the years analysed, representing between 21% and 27% of J01 consumption (21% in 2017).

57 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

7.3 Relative consumption by choice of agent

7.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2011–2017 is shown in Fig. 7.2 and summarized in Table 7.2. Table 7.3 shows the most consumed agents within each of the generations of cephalosporin agents.

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 BLR BLR BLR BLR BLR BLR BLR 2011 2012 2013 2014 2015 2016 2017

Fig. 7.2 Relative consumption of cephalosporins by generation

Table 7.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) 0.3 (12) 0.4 (19) 0.4 (11) 0.4 (13) 0.3 (10) 0.3 (11) 0.3 (12) Second-generation (J01DC) 0.1 (5) 0.1 (7) 0.2 (6) 0.3 (9) 0.2 (8) 0.4 (13) 0.7 (29) Third-generation (J01DD) 1.8 (80) 1.4 (70) 2.7 (79) 2 (66) 2.2 (77) 1.9 (72) 1.4 (53) Fourth-generation (J01DE) < 0.1 < 0.1 0.1 (4) 0.4 (13) 0.1 (5) 0.1 (4) 0.2 (7) Total 2.3 2.1 3.4 3.0 2.9 2.7 2.6 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Consumption of first-generation agents remained reasonably stable across the years analysed (12% of total cephalosporin in 2017). While cefalexin was the most consumed first-generation agent between 2011 and 2014, the most consumed first-generation agent between 2015 and 2017 was cefazolin. Cefuroxime represented 97% of second-generation cephalosporin consumption in 2017. Consumption of Watch group third-generation agents decreased over time, at 80% of total cephalosporin use in 2011 and 53% in 2017. Ceftriaxone and cefotaxime comprised 58% and 25% of third-generation agent consumption respectively in 2017. Consumption of the fourth-generation cephalosporin cefepime (Reserve agent) increased over time (0.2 DID in 2017).

58 Belarus

Table 7.3. Most consumed agents within each generation of cephalosporins

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) Cefalexin 0.2 (62) 0.3 (82) 0.3 (85) 0.3 (64) < 0.1 0.1 (42) < 0.1 Cefazolin 0.1 (38) < 0.1 < 0.1 0.1 (36) 0.2 (84) 0.2 (58) 0.2 (67) Second-generation (J01DC) Cefuroxime < 0.1 0.1 (79) 0.2 (98) 0.2 (96) 0.2 (86) 0.3 (94) 0.7 (97) Third-generation (J01DD) Cefotaxime 0.7 (35) 0.6 (40) 0.6 (22) 0.4 (22) 0.4 (20) 0.4 (19) 0.3 (25) Ceftriaxone 1.2 (64) 0.8 (56) 2 (75) 1.5 (77) 1.7 (79) 1.5 (77) 0.8 (58) Fourth-generation (J01DE) Cefepime < 0.1 < 0.1 0.1 (100) 0.4 (100) 0.1 (100) 0.1 (100) 0.2 (100) a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for the nominated generation of cephalosporins.

7.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) represented 2.1 DID (8.9%) of total J01 consumption in 2017, with fluoroquinolones comprising almost all quinolone consumption. Two fluoroquinolones dominated, with ciprofloxacin and levofloxacin representing 53% and 28% of fluoroquinolone consumption in 2017 (Table 7.4).

Table 7.4 Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 Ofloxacin 0.4 (27) 0.4 (23) 0.3 (14) 0.3 (10) 0.2 (12) 0.2 (8) 0.2 (8) Ciprofloxacin 0.5 (37) 0.7 (36) 0.8 (35) 1.4 (59) 0.6 (34) 1 (51) 1.1 (53) Norfloxacin 0.2 (17) 0.3 (17) 0.3 (11) 0.2 (8) 0.2 (11) 0.1 (7) 0.2 (8) Levofloxacin 0.2 (17) 0.4 (22) 0.8 (37) 0.5 (20) 0.6 (36) 0.6 (33) 0.6 (28) Moxifloxacin < 0.1 < 0.1 < 0.1 < 0.1 0.1 (7) < 0.1 < 0.1 Total 1.5 1.9 2.3 2.4 1.7 1.9 2.1 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption of fluoroquinolones.

7.4 The 10 most consumed agents

7.4.1 The 10 most consumed agents – oral formulation

Table 7.5 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

59 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 7.5 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per day a Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Amoxicillin 6.70 6.70 6.70 6.70 6.70 6.70 6.70 6.70 6.70 6.70 Amoxicillin and enzyme 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 inhibitor Doxycycline 2.73 2.73 2.73 2.73 2.73 2.73 2.73 2.73 Azithromycin 1.75 1.75 1.75 1.75 1.75 1.75 1.75 Clarithromycin 1.01 1.01 1.01 1.01 1.01 1.01 Ciprofloxacin 0.99 0.99 0.99 0.99 0.99 Cefuroxime 0.72 0.72 0.72 0.72 Nitrofurantoin 0.58 0.58 0.58 Furazidin 0.53 0.53 Levofloxacin 0.45 Total consumption for 19.45 19.01 18.47 17.89 17.17 16.18 15.18 13.43 10.70 6.70 this group of agents Total consumption for 21.16 21.16 21.16 21.16 21.16 21.16 21.16 21.16 21.16 21.16 all oral J01 agents Proportion (%) of total consumption for oral 91.9% 89.8% 87.3% 84.5% 81.1% 76.5% 71.7% 63.5% 50.6% 31.6% J01 antibacterials a DDD: daily defined dose.

The 10 listed oral agents represent almost 92% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, four are included in the WHO Watch group of antibacterials – azithromycin and clarithromycin (macrolides), and ciprofloxacin and levofloxacin (quinolones).

Azithromycin (8.2%) and clarithromycin (4.8%) combined constituted 13% of total consumption of J01 oral antibacterials in 2017. Together, the four Watch agents comprised 19.7% of J01 oral agent consumption (8.2% + 4.8% + 4.6% + 2.1%).

7.4.2 The 10 most consumed agents – parenteral formulation

Table 7.6 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

As shown in Table 7.1, parenteral agents comprised around 11% of total J01 consumption in 2017. Within this, the Watch group agents ceftriaxone (31.4%), meropenem (3.4%) and imipenem and enzyme inhibitor (2.3%) constituted 37.1% of the consumption of J01 injection formulations. The Reserve agent cefepime represented 7.2% of parenteral agent consumption in 2017.

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Table 7.6 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Ceftriaxone 0.78 0.78 0.78 0.78 0.78 0.78 0.78 0.78 0.78 0.78 Cefotaxime 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 Cefazolin 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 Cefepime 0.18 0.18 0.18 0.18 0.18 0.18 0.18 Levofloxacin 0.14 0.14 0.14 0.14 0.14 0.14 Amikacin 0.14 0.14 0.14 0.14 0.14 Metronidazole 0.13 0.13 0.13 0.13 Ciprofloxacin 0.11 0.11 0.11 Meropenem 0.08 0.08 Imipenem and enzyme 0.06 inhibitor Total consumption for this 2.16 2.11 2.02 1.91 1.78 1.65 1.51 1.33 1.13 0.78 group of agents Total consumption for all 2.49 2.49 2.49 2.49 2.49 2.49 2.49 2.49 2.49 2.49 parenteral J01 agents Proportion (%) of total consumption for parenteral 86.7% 84.4% 81.0% 76.7% 71.5% 66.1% 60.5% 53.3% 45.3% 31.4% J01 antibacterials a DDD: daily defined dose

7.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 7.3 and Fig. 7.4, and is summarized in Table 7.7.

100

60 Other

40 Core Access group 67 Proportion (%) Proportion 64 62 59 63 59 65 20

0 BLR BLR BLR BLR BLR BLR BLR 2011 2012 2013 2014 2015 2016 2017

Fig. 7.3 Relative consumption of Core Access group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

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100

60 Other Watch group 40 Proportion (%) Proportion

20 34 35 35 26 31 33 27

0 BLR BLR BLR BLR BLR BLR BLR 2011 2012 2013 2014 2015 2016 2017

Fig. 7.4 Relative consumption of Watch group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 7.7 Relative consumption of Core Access, Watch and Reserve group antibacterials

Percentage of total consumptiona Category 2011 2012 2013 2014 2015 2016 2017 Core Access group 67.2 63.7 62.2 58.7 63.2 58.7 64.9 Watch group 26.2 31.2 33.9 35.2 32.7 34.5 27.5 Reserve group 0.37 0.46 0.55 1.88 0.83 0.80 1.10 Ungrouped 6.2 4.7 3.4 4.2 3.3 6.0 6.5 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Some fluctuations in relative use of the Core Access and Watch groups have been seen over time. Consumption of Core Access agents dominated in all years, representing 64.9% of total consumption in 2017. Watch group agents represented 27.5% of total consumption in 2017.

7.6 Analyses based on DDDs applied in 2019

7.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 7.5 (DDD values relevant to year) and Fig. 7.6 (2019 DDD values), and is summarized in Table 7.8.

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25 25

20 20

15 15 Parenteral Parenteral antibacterials antibacterials 10 Oral 10 Oral antibacterials antibacterials 5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 BLR BLR BLR BLR BLR BLR 2015 2016 2017 2015 2016 2017

Fig. 7.5 Total consumption of J01 Fig. 7.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values)

Table 7.8 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 15.4 (81) 16.3 (84) 21.2 (89) 13.6 (80) 14 (83) 17.6 (88) Parenteral J01 3.6 (19) 3.1 (16) 2.5 (11) 3.5 (20) 3 (17) 2.3 (12) Total 19.0 19.4 23.7 17.0 16.9 20.0 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The relative consumption of oral and parenteral formulations does not change substantially with the application of the 2019 DDDs (oral agents 89% applying older values and 88% with the 2019 DDD values).

7.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 7.7 (DDD values relevant to year) and Fig. 7.8 (2019 DDD values), and is summarized in Table 7.9. As noted in section 7.6.1, total DIDs decreased by 15.6% in 2017.

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 11 DID in 2017 using the DDD values relevant to the year of data to 7.5 DID applying the 2019 DDD values – a reduction of 31.8% in absolute values. Relative consumption of beta-lactams falls from 46.4% to 37.5% of total J01 consumption when the 2019 DDD values are applied.

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DDD/1000 inhabitants per day 5 (includes DDD/1000 inhabitants per day 5 (includes cephalosporins) cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols BLR BLR BLR (J01B) BLR BLR BLR (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 7.7 Total consumption of J01 Fig. 7.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

Table 7.9 Relative consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 3 2.5 2.8 3 2.5 2.8 Tetracyclines (J01A) (15.8) (12.9) (11.8) (17.6) (14.8) (14) 0.1 0.1 0.1 0.1 0.1 0.1 Amphenicols (J01B) (0.5) (0.5) (0.4) (0.6) (0.6) (0.5) 7.5 7.3 11 5.1 5 7.5 Beta-lactams (J01C) (39.5) (37.6) (46.4) (30) (29.6) (37.5) Other beta-lactams (includes 3 2.8 2.7 2.9 2.7 2.6 cephalosporins) (J01D) (15.8) (14.4) (11.4) (17.1) (16) (13) Sulfonamides and trimethoprim 0.1 0.1 0.1 0.1 0.1 0.1 (J01E) (0.5) (0.5) (0.4) (0.6) (0.6) (0.5) Macrolides, lincosamides and 2.4 3 3.1 2.4 3 3.1 streptogramins (J01F) (12.6) (15.5) (13.1) (14.1) (17.8) (15.5) 1.7 1.9 2.1 1.6 1.8 2 Quinolone antibacterials (J01M) (8.9) (9.8) (8.9) (9.4) (10.7) (10) Other J01 antibacterials (J01G, 1.2 1.7 1.7 1.7 1.7 1.7 J01R, J01X) (6.3) (8.8) (7.2) (10) (10.1) (8.5) Total 19 19.4 23.7 17 16.9 20 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

As the total DIDs decrease with the application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta-lactams generally increases; tetracyclines, for example, increased from 11.8% to 14%, cephalosporins 11.4% to 13% and the macrolides group from 13.1% to 15.5% in 2017.

64 Belarus

7.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 7.9 (DDD values relevant to year) and Fig. 7.10 (2019 DDD values) for Core Access antibiotics, Fig. 7.11 (DDD values relevant to year) and Fig. 7.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 7.10.

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group

Proportion (%) Proportion 63 65 (%) Proportion 59 56 53 59 20 20

0 0 BLR BLR BLR BLR BLR BLR 2015 2016 2017 2015 2016 2017

Fig. 7.9 Relative consumption of Core Access Fig. 7.10 Relative consumption of Core group antibacterials (applying DDD values Access group antibacterials (applying 2019 relevant to year) DDD values)

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion

20 35 20 36 39 33 27 32

0 0 BLR BLR BLR BLR BLR BLR 2015 2016 2017 2015 2016 2017

Fig. 7.11 Relative consumption of Watcha Fig. 7.12 Relative consumption of Watcha group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year) DDD values)

a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The effect of applying the 2019 DDD values is to decrease slightly the proportion of total use that is Core Access group antibiotics (from 65% to 59% in 2017) and increase slightly the proportion of total use that is Watch group antibiotics (from 27.5% to 32% in 2017).

65 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 7.10 Relative consumption of Core Access, Watch and Reserve group antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 12.2 (63) 11.6 (59) 15.7 (65) 9.8 (56) 9.3 (53) 12.1 (59) Watch group 6.3 (32.7) 6.8 (34.5) 6.6 (27.5) 6.3 (36) 6.8 (39) 6.6 (32) Reserve group 0.2 (1) 0.2 (1) 0.3 (1) 0.1 (0) 0.1 (1) 0.2 (1) Ungrouped 0.6 (3) 1.2 (6) 1.6 (6) 1.1 (7) 1.2 (7) 1.6 (8) Total 19.33 19.83 24.17 17.37 17.40 20.46 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

7.7 Discussion

The analyses in this report are based on import records and information from local pharmaceutical manufacturers.

Estimates of total consumption fluctuated over the period 2011–2017 (31.4 DID in 2017), with a trend towards increases in total consumption between 2015 and 2017 (19.0 DID in 2015, 23.7 DID in 2017). Around 11% of consumption in 2017 was parenteral formulations.

Relative consumption of beta-lactams and macrolides increased over time.

Of the top 10 oral agents, four are included in the WHO Watch group of antibacterials – azithromycin and clarithromycin (macrolides), and ciprofloxacin and levofloxacin (quinolones). Azithromycin (8.6%), clarithromycin (4.8%), ciprofloxacin (4.6%) and levofloxacin (2.1%) combined constituted 19.7% of total consumption of J01 oral antibacterials in 2017.

The Watch group agents ceftriaxone (31.4%), meropenem (3.4%) and imipenem and enzyme inhibitor (2.3%) constituted 37.1% of consumption of J01 injection formulations. The Reserve agent cefepime represented 7.2% of parenteral agent consumption in 2017.

Watch group agents (oral and parenteral combined) comprised 27.5% of total consumption in 2017.

These relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities. For example, the WHO EML (WHO, 2017) suggests limited indications for use of azithromycin, clarithromycin, ciprofloxacin, levofloxacin and ceftriaxone.

Clarithromycin is listed on the EML as a first-choice option for severe community-acquired pneumonia and as a second-choice option for pharyngitis.

66 Belarus

Levofloxacin is listed on the WHO EML as a reserve second-line drug for the treatment of MDR-TB that should be used in specialized centres adhering to WHO standards for TB control.

Ceftriaxone is listed on the EML/EMLc as a first-choice option for acute bacterial meningitis, severe community-acquired pneumonia, complicated intra-abdominal infections (mild to moderate), hospital-acquired pneumonia, Neisseria gonorrhoeae and severe pyelonephritis or prostatitis. Ceftriaxone is listed as a second-choice agent for acute invasive bacterial diarrhoea/ dysentery, bone and joint infections, mild-to-moderate pyelonephritis or prostatitis, and sepsis in neonates and children.

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with WHO EML recommendations.5

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 23.7 DID in 2017 using DDD values relevant to year of data to 20.0 DID applying the 2019 DDD values – a reduction of 15.6%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 11 DID in 2017 using the DDD values relevant to the year of data to 7.5 DID applying the 2019 DDD values – a reduction of 31.8% in absolute values.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in Belarus and can help to identify areas for further investigation, allowing the development of targeted interventions to address potential problems identified. Interventions targeting medicines should be supported by evidence-based guidelines and treatment protocols.

Total DID decreased by 15.6% when the new 2019 DDDs were applied, independent of any intervention by government, agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

5 The current clinical guide “Diagnosis and treatment of patients (adults) with infectious and parasitic diseases”, approved by the decree of the Ministry of Health of the Republic of Belarus of December 13, 2014 No. 94, was developed on the basis of the clinical requirements of medical care for a patient with an infectious pathology and takes into account the recommendations outlined in paragraphs 7.7.

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Reference

68 Bosnia and Herzegovina

8. BOSNIA AND HERZEGOVINA

8.1 Data source and years of data collection

Bosnia and Herzegovina provided data for each of the seven years of data collection (2011–2017). The main sources of data were sales records of wholesalers and local manufacturers provided by the drug agency. The data cover imported and locally manufactured medicines. Local manufacturer records needed to be disaggregated to products for local consumption and products exported to other countries.

8.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

The data show reasonably stable consumption of J01 antibacterials over time, although with the suggestion of small increases in consumption in 2016 and 2017.

DDD/1000 inhabitants per day 5 Amphenicols (J01B) Tetracyclines (J01A) 0

BIH BIH BIH BIH BIH BIH BIH 2011 2012 2013 2014 2015 2016 2017

Fig. 8.1 Total consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose.

69 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

The relative consumption of parenteral antibacterials represented 4–7% of total J01 consumption.

The highest levels of consumption were in beta-lactams (J01C), at 9.2 DID in 2011 and 10.1 DID in 2017. There were some increases in consumption of the macrolides group (1.5 DID in 2011 and 2.0 DID in 2017). Consumption of other pharmacological subgroups remained reasonably stable over time.

These observations relate to total consumption. Different patterns of consumption would be expected in the hospital and community sectors.

Beta-lactam consumption represents almost half of J01 consumption across the years analysed (49.8% in 2017). There is some evidence of increasing relative consumption of macrolides (J01F), at 8.2% in 2011 and 9.9% in 2017.

The relative consumption of cephalosporins and quinolones combined remained reasonably stable over time (23% in 2017).

Table 8.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017

Route of administration

17.3 16.9 16.9 16.5 18.3 20 19.3 Oral J01 (94) (93) (94) (94) (96) (96) (95)

1.1 1.2 1.2 1 0.7 0.9 1 Parenteral J01 (6) (7) (6) (6) (4) (4) (5)

Total 18.4 18.1 18.0 17.5 19.0 20.8 20.3

Class of antibacterial agents

1.3 1.1 1.2 1.2 1.3 1.9 1.4 Tetracyclines (J01A) (7.1) (6.1) (6.7) (6.9) (6.8) (9.1) (6.9)

Amphenicols (J01B) – – – – – – –

9.2 8.9 8.9 8.1 9.5 10.2 10.1 Beta-lactams (J01C) (50) (49.2) (49.4) (46.3) (50) (49) (49.8)

Other beta-lactams (includes cephalosporins) 2.3 2.3 2.2 2.2 2.1 2.4 2.5 (J01D) (12.5) (12.7) (12.2) (12.6) (11.1) (11.5) (12.3)

1.6 1.7 1.4 1.5 1.5 1.5 1.5 Sulfonamides and Trimethoprim (J01E) (8.7) (9.4) (7.8) (8.6) (7.9) (7.2) (7.4)

Macrolides, Lincosamides and 1.5 1.5 1.5 1.6 2 1.7 2 Streptogramins (J01F) (8.2) (8.3) (8.3) (9.1) (10.5) (8.2) (9.9)

2.1 2.2 2.1 2.1 2 2.5 2.3 Quinolone antibacterials (J01M) (11.4) (12.2) (11.7) (12) (10.5) (12) (11.3)

0.4 0.4 0.7 0.8 0.7 0.7 0.6 Other J01 antibacterials (J01G, J01R, J01X) (2.2) (2.2) (3.9) (4.6) (3.7) (3.4) (3)

Total 18.4 18.1 18.0 17.5 19.0 20.8 20.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

70 Bosnia and Herzegovina

8.3 Relative consumption by choice of agent

8.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2011–2017 is shown in Fig. 8.2 and summarized in Table 8.2.

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 BIH BIH BIH BIH BIH BIH BIH 2011 2012 2013 2014 2015 2016 2017

Fig. 8.2 Relative consumption of cephalosporins by generation

Table 8.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) 1.2 (53) 1.1 (52) 1.2 (53) 1.1 (51) 1 (50) 1.3 (54) 1.1 (45) Second-generation (J01DC) 0.8 (36) 0.7 (33) 0.7 (32) 0.7 (32) 0.7 (32) 0.7 (30) 0.8 (33) Third-generation (J01DD) 0.2 (11) 0.3 (15) 0.3 (15) 0.4 (17) 0.4 (17) 0.4 (16) 0.5 (22) Fourth-generation (J01DE) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Total 2.2 2.2 2.2 2.2 2.1 2.3 2.4 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Some decreases in consumption of first-generation agents were seen (53% of total cephalosporin use in 2011 and 45% in 2017). The most consumed first-generation agents were cefalexin (85%) and cefazolin (15%). Second-generation agents, mostly cefuroxime, represented 33% of cephalosporin consumption in 2017. Consumption of Watch group third-generation agents increased (11% of cephalosporin consumption in 2011 and 22% in 2017). Ceftriaxone (0.2 DID) and cefixime (0.3 DID) comprised 41% and 58% of third-generation agent consumption in 2017. Very small volumes of consumption of fourth-generation cephalosporins (Reserve agents) were reported.

71 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

8.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) represented 2.3 DID (11.3%) of total J01 consumption in 2017, with fluoroquinolones comprising 2.2 DID (95.6%) of quinolone consumption. Ciprofloxacin consumption dominated, representing 82% of fluoroquinolone consumption in 2017 (Table 8.3).

Table 8.3 Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 Ofloxacin < 0.1 < 0.1 < 0.1 – – – – Ciprofloxacin 1.8 (91) 1.8 (84) 1.7 (86) 1.8 (88) 1.6 (82) 1.9 (82) 1.8 (82) Pefloxacin < 0.1 < 0.1 < 0.1 – – – – Norfloxacin 0.1 (6) 0.3 (14) 0.2 (12) 0.2 (11) 0.2 (12) 0.2 (9) 0.2 (9) Levofloxacin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 0.2 (8) 0.2 (8) Moxifloxacin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Total 2.0 2.1 2.0 2.0 1.9 2.4 2.2 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

8.4 The 10 most consumed agents

8.4.1 The 10 most consumed agents – oral formulation

Table 8.4 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

Table 8.4 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Amoxicillin 4.42 4.42 4.42 4.42 4.42 4.42 4.42 4.42 4.42 4.42 Amoxicillin and enzyme 4.19 4.19 4.19 4.19 4.19 4.19 4.19 4.19 4.19 inhibitor Ciprofloxacin 1.79 1.79 1.79 1.79 1.79 1.79 1.79 1.79 Sulfamethoxazole and 1.52 1.52 1.52 1.52 1.52 1.52 1.52 trimethoprim Doxycycline 1.40 1.40 1.40 1.40 1.40 1.40 Azithromycin 0.91 0.91 0.91 0.91 0.91 Cefalexin 0.91 0.91 0.91 0.91 Clarithromycin 0.78 0.78 0.78 Ampicillin 0.74 0.74 Cefuroxime 0.73 Total consumption for this 17.39 16.67 15.92 15.14 14.23 13.32 11.92 10.40 8.61 4.42 group of agents Total consumption for all 19.31 19.31 19.31 19.31 19.31 19.31 19.31 19.31 19.31 19.31 oral J01 agents Proportion (%) of total consumption for oral J01 90.1% 86.3% 82.4% 78.4% 73.7% 69.0% 61.7% 53.9% 44.6% 22.9% antibacterials a DDD: daily defined dose.

72 Bosnia and Herzegovina

The 10 listed oral agents represent just over 90% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, three are included in the WHO Watch group of antibacterials – ciprofloxacin (quinolones), azithromycin and clarithromycin (macrolides).

Ciprofloxacin (9.3%), azithromycin (4.7%), and clarithromycin (4.0%) combined constituted 18% of total consumption of J01 oral antibacterials in 2017.

8.4.2 The 10 most consumed agents – parenteral formulation

Table 8.5 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

Table 8.5 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Gentamicin 0.23 0.23 0.23 0.23 0.23 0.23 0.23 0.23 0.23 0.23 Ceftriaxone 0.22 0.22 0.22 0.22 0.22 0.22 0.22 0.22 0.22 Cefazolin 0.16 0.16 0.16 0.16 0.16 0.16 0.16 0.16 Ampicillin 0.07 0.07 0.07 0.07 0.07 0.07 0.07 Amoxicillin and enzyme 0.05 0.05 0.05 0.05 0.05 0.05 inhibitor Combinations 0.05 0.05 0.05 0.05 0.05 Imipenem and enzyme 0.05 0.05 0.05 0.05 inhibitor Metronidazole 0.05 0.05 0.05 Ciprofloxacin 0.04 0.04 Amikacin 0.02 Total consumption for this 0.93 0.91 0.87 0.82 0.77 0.72 0.67 0.61 0.45 0.23 group of agents Total consumption for all 1.02 1.02 1.02 1.02 1.02 1.02 1.02 1.02 1.02 1.02 parenteral J01 agents Proportion (%) of total consumption for parenteral 91.5% 89.3% 85.4% 80.9% 76.2% 71.3% 66.3% 59.7% 44.2% 22.7% J01 antibacterials a DDD: daily defined dose.

As shown in Table 8.1, parenteral agents comprised around 5% of total J01 consumption in 2017. Within this, the Watch group agents ceftriaxone (19.5%), imipenem + cilastatin (4.7%) and ciprofloxacin (2.6%) constituted 28.8% of the consumption of J01 injection formulations.

8.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 8.3 and Fig. 8.4, and is summarized in Table 8.6.

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100

60 Other Core Access group 40 74 73 74 73 74 75 72 Proportion (%) Proportion

0 BIH BIH BIH BIH BIH BIH BIH 2011 2012 2013 2014 2015 2016 2017

Fig. 8.3 Relative consumption of Core Access antibiotics as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

100

60 Other Watch group 40 Proportion (%) Proportion

20 21 22 21 22 22 21 23 0 BIH BIH BIH BIH BIH BIH BIH 2011 2012 2013 2014 2015 2016 2017

Fig. 8.4 Relative consumption of Watch group antibiotics as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 8.6 Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

Percentage of total consumptiona Antibiotic group 2011 2012 2013 2014 2015 2016 2017 Core Access group 74.4 73.0 74.1 73.1 73.9 74.9 72.3 Watch group 20.5 22.4 21.1 22.3 22.0 21.1 22.9 Reserve group 0.00 0.01 0.01 0.01 0.02 0.04 0.04 Ungrouped 5.1 4.5 4.7 4.5 4.1 4.0 4.8 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Consumption of Core Access agents dominated across all years analysed (72.3% of consumption in 2017). The relative consumption of Watch agents remained consistent at around 21–23% of total antibiotic consumption.

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8.6 Analyses based on DDDs applied in 2019

8.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 8.5 (DDD values relevant to year) and Fig. 8.6 (2019 DDD values), and is summarized in Table 8.7.

25 25

20 20

15 15 Parenteral Parenteral antibacterials antibacterials 10 Oral 10 Oral antibacterials antibacterials 5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 BIH BIH BIH BIH BIH BIH 2015 2016 2017 2015 2016 2017

Fig. 8.5 Total consumption of J01 Fig. 8.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values)

Table 8.7 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 18.3 (96) 20 (96) 19.3 (95) 15.5 (96) 17.1 (96) 16.5 (95) Parenteral J01 0.7 (4) 0.9 (4) 1 (5) 0.7 (4) 0.8 (4) 0.9 (5) Total 19.0 20.8 20.3 16.2 17.9 17.4 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The relative consumption of oral and parenteral formulations does not change with the application of the 2019 DDDs (oral formulations 95% applying older and 2019 DDD values).

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8.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 8.7 (DDD values relevant to year) and Fig. 8.8 (2019 DDD values), and is summarized in Table 8.8. As noted in section 8.6.1, total DID decreased by 14.3% in 2017.

DDD/1000 inhabitants per day 5 (includes DDD/1000 inhabitants per day 5 (includes cephalosporins) cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols BIH BIH BIH (J01B) BIH BIH BIH (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 8.7 Total consumption of J01 Fig. 8.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

Table 8.8 Consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 1.3 1.9 1.4 1.3 1.9 1.4 Tetracyclines (J01A) (6.8) (9.1) (6.9) (8) (10.6) (8) Amphenicols (J01B) – – – – – – 9.5 10.2 10.1 6.7 7.2 7.1 Beta-lactams (J01C) (50) (49) (49.8) (41.4) (40.2) (40.8) Other beta-lactams (includes 2.1 2.4 2.5 2.1 2.4 2.4 cephalosporins) (J01D) (11.1) (11.5) (12.3) (13) (13.4) (13.8) Sulfonamides and trimethoprim 1.5 1.5 1.5 1.5 1.5 1.5 (J01E) (7.9) (7.2) (7.4) (9.3) (8.4) (8.6) Macrolides, lincosamides and 2 1.7 2 2.1 1.8 2 streptogramins (J01F) (10.5) (8.2) (9.9) (13) (10.1) (11.5) 2 2.5 2.3 2 2.4 2.3 Quinolone antibacterials (J01M) (10.5) (12) (11.3) (12.3) (13.4) (13.2) Other J01 antibacterials (J01G, 0.7 0.7 0.6 0.7 0.7 0.6 J01R, J01X) (3.7) (3.4) (3) (4.3) (3.9) (3.4) Total 19 20.8 20.3 16.2 17.9 17.4 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

76 Bosnia and Herzegovina

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 10.1 DID in 2017 using the DDD values relevant to the year of data to 7.1 DID applying the 2019 DDD values – a reduction of 29.7% in absolute values. Relative consumption of beta-lactams falls from 49.8% to 40.8% of total J01 consumption when the 2019 DDD values are applied.

As the total DIDs decrease with the application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta-lactams generally increases; tetracyclines, for example, increased from 6.9% to 8%, cephalosporins 12.3% to 13.8%, the macrolides group from 9.9% to 11.5% and quinolones from 11.3% to 13.2% in 2017.

8.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 8.9 (DDD values relevant to year) and Fig. 8.10 (2019 DDD values) for Core Access antibiotics, Fig. 8.11 (DDD values relevant to year) and Fig. 8.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 8.9.

Table 8.9 Relative consumption of Core Access and Watch group antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 14.3 (74) 15.9 (75) 15 (72) 11.5 (69) 12.9 (71) 12.1 (68) Watch group 4.2 (22) 4.5 (21.1) 4.7 (22.9) 4.3 (26) 4.5 (25) 4.8 (27) Reserve group 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Ungrouped 0.8 (4) 0.8 (4) 1 (5) 0.8 (5) 0.8 (5) 1 (6) Total 19.3 21.2 20.7 16.6 18.3 17.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

100 100

80 80

60 Other 60 Other Core Access Core Access 40 75 group 40 group 74 72 69 71 68 Proportion (%) Proportion (%) Proportion

20 20

0 0 BIH BIH BIH BIH BIH BIH 2015 2016 2017 2015 2016 2017

Fig. 8.9 Relative consumption of Core Access Fig. 8.10 Relative consumption of Core group antibacterials (applying DDD values Access group antibacterials (applying 2019 relevant to year)a DDD values)a

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100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion

20 20 22 21 23 26 25 27 0 0 BIH BIH BIH BIH BIH BIH 2015 2016 2017 2015 2016 2017 Fig. 8.11 Relative consumption of Watch Fig. 8.12 Relative consumption of Watch group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year)a DDD values)a

a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The effect of applying the 2019 DDD values is to decrease slightly the proportion of total use that is Core Access group antibiotics (from 72% to 68% in 2017) and increase slightly the proportion of total use that is Watch group antibiotics (from 23 to 27% in 2017).

8.7 Discussion

The analyses in this report are based on sales records of wholesalers and records of local manufacturers. Data are presented as total consumption estimates.

Estimates of total consumption were reasonably stable in the period 2011–2017 (20.3 DID in 2017). Around 5% of consumption in 2017 was parenteral formulations.

Relative consumption of beta-lactams was stable over time, representing almost 50% of J01 consumption in 2017. Small increases in relative consumption of macrolide antibiotics were seen over the period analysed.

Of the top 10 oral agents, three are included in the WHO Watch group of antibacterials – ciprofloxacin (quinolones), and azithromycin and clarithromycin (macrolides). Ciprofloxacin (9.3%), azithromycin (4.7%) and clarithromycin (4.0%) combined constituted 18% of total consumption of J01 oral antibacterials in 2017.

The Watch group agents ceftriaxone (19.5%), imipenem + cilastatin (4.7%) and ciprofloxacin (2.6%) together constituted 28.8% of the total consumption of J01 parenteral formulations in 2017.

Watch group agents (oral and parenteral combined) comprised almost 23% (22.9%) of total consumption in 2017.

These relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities. For example, the WHO EML (WHO, 2017) suggests limited indications for use of ciprofloxacin, azithromycin, clarithromycin, ceftriaxone and imipenem + cilostatin.

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Clarithromycin is listed on the EML as a first-choice option for severe community-acquired pneumonia and as a second-choice option for pharyngitis.

Imipenem + cilastatin is a carbapenem and shares a square box listing with meropenem. It is listed on the WHO EML as an alternative to meropenem as a second-choice agent for severe complicated intra-abdominal infections and high-risk febrile neutropenia.

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with EML recommendations.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 20.3 DID in 2017 using DDD values relevant to year of data to 17.4 DID applying the 2019 DDD values – a reduction of 14.3%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 10.1 DID in 2017 using the DDD values relevant to the year of data to 7.1 DID applying the 2019 DDD values – a reduction of 29.7% in absolute values.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in Bosnia and Herzegovina and can help to identify areas for further investigation, allowing the development of targeted interventions to address potential problems identified in the consumption of antibacterials. Interventions targeting medicines should be supported by evidence- based guidelines and treatment protocols.

Total DID decreased by 14.3% with the new 2019 DDDs applied, independent of any intervention by government, agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

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Reference

80 Georgia

9. GEORGIA

9.1 Data source and years of data collection

Georgia provided data for each of the seven years of data collection (2011–2017). The main sources of data were import records of wholesalers provided by the drug agency. Data derived from importation records will be affected by the cycles of procurement and delivery, potentially giving rise to fluctuations in estimates of consumption that do not relate to actual use of antibacterials by patients and health- care facilities. No data on medicines produced by local manufacturers are available.

9.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

The data show reasonably stable consumption of J01 antibacterials over time, apart from 2017 data, which suggest a substantial increase in antibiotic consumption (23.7 DID in 2016, 31.5 DID in 2017). This reported change in consumption in 2017 requires local confirmation.

35 Other J01 antibacterials 30 (J01G, J01R, J01X) a Quinolone antibacterials 25 (J01M) Macrolides, lincosamides 20 and streptogramins (J01F) Sulfonamides and 15 trimethoprim (J01E) Other beta-lactams 10 (includes cephalosporins) (J01D) Beta-lactams (J01C) DDD/1000 inhabitants per day 5 Amphenicols (J01B) Tetracyclines (J01A) 0

GEO GEO GEO GEO GEO GEO GEO 2011 2012 2013 2014 2015 2016 2017

Fig. 9.1 Total consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose.

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The relative consumption of parenteral antibacterials varied widely over the years of analysis, representing 36%, 13% and 22% of total J01 consumption in 2015, 2016 and 2017 respectively.

The highest levels of consumption in 2011 were in beta-lactams (J01C), at 14.9 DID. Consumption of beta-lactams had decreased to 1.8 DID in 2016 but were reported to have increased to 12.3 DID in 2017. There were substantial shifts in consumption of cephalosporins over the same time period, at 1.9 DID in 2011, 4.9 DID in 2015, 2.2 DID in 2016 and 3.6 DID reported in 2017 (Table 9.1). Different patterns of consumption would be expected in the hospital and community sectors.

Table 9.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 Route of administration 18.5 19.9 13.3 15.4 16.3 20.7 24.5 Oral J01 (84) (84) (64) (75) (64) (87) (78) 3.5 3.8 7.3 5.1 9.2 3 7 Parenteral J01 (16) (16) (36) (25) (36) (13) (22) Total 22.0 23.6 20.6 20.4 25.5 23.7 31.5 Class of antibacterial agents 0.5 0.3 0.5 0.1 0.4 1.2 1.2 Tetracyclines (J01A) (2.3) (1.3) (2.4) (0.5) (1.6) (5.1) (3.8) 0.1 0.1 0.8 0 0.2 0.8 0.7 Amphenicols (J01B) (0.5) (0.4) (3.9) (0) (0.8) (3.4) (2.2) 14.9 14.2 3.9 6.9 4.1 1.8 12.3 Beta-lactams (J01C) (67.7) (60.2) (18.9) (33.8) (16.1) (7.6) (39) Other beta-lactams (includes 1.9 2.3 6.8 4.6 4.9 2.2 3.6 cephalosporins) (J01D) (8.6) (9.7) (33) (22.5) (19.2) (9.3) (11.4) 0.3 0.2 2.3 0.3 6.7 9.8 6.8 Sulfonamides and trimethoprim (J01E) (1.4) (0.8) (11.2) (1.5) (26.3) (41.4) (21.6) Macrolides, lincosamides and 1.7 2.8 2.4 3.4 1.9 1.9 2.2 streptogramins (J01F) (7.7) (11.9) (11.7) (16.7) (7.5) (8) (7) 2.3 3.5 2.4 4 6.3 3.2 2.4 Quinolone antibacterials (J01M) (10.5) (14.8) (11.7) (19.6) (24.7) (13.5) (7.6) Other J01 antibacterials (J01G, J01R, 0.2 0.2 1.5 1 1 2.7 2.3 J01X) (0.9) (0.8) (7.3) (4.9) (3.9) (11.4) (7.3) Total 22 23.6 20.6 20.4 25.5 23.7 31.5 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The relative consumption of beta-lactam antibacterials varied considerably over time, at 67.7% of J01 consumption in 2011, 33.8% in 2014, 7.6% in 2016 and 39% in 2017 (Table 9.1). There is evidence of increasing relative consumption of cephalosporins (J01D), at 8.6% in 2011, 19.2% in 2015, 9.3% in 2016 and 11.4% in 2017.

The relative consumption of cephalosporins and quinolones combined varied considerably over time, at 19% of J01 consumption in 2011, 45% in 2013, 23% in 2016 and 19% in 2017.

82 Georgia

9.3 Relative consumption by choice of agent

9.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2011–2017 is shown in Fig. 9.2 and summarized in Table 9.2. Table 9.3 shows the most consumed agents within each of the generations of cephalosporin agents.

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 GEO GEO GEO GEO GEO GEO GEO 2011 2012 2013 2014 2015 2016 2017

Fig. 9.2 Relative consumption of cephalosporins by generation

Table 9.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 0.1 (4) Second-generation (J01DC) 0.1 (6) 0.4 (17) 0.3 (4) 1 (22) 0.4 (8) 0.6 (27) 0.7 (21) Third-generation (J01DD) 1.8 (92) 1.9 (82) 6.4 (95) 3.4 (74) 4.3 (90) 1.5 (67) 2.6 (74) Fourth-generation (J01DE) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Total 1.9 2.3 6.8 4.6 4.8 2.2 3.6 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Levels of consumption of first- and fourth-generation agents were low. Consumption of second- generation agents, mostly cefuroxime, varied across the years analysed, reaching 27% of total cephalosporin consumption in 2016 and 21% in 2017. Consumption of Watch group third-generation agents dominated in all years of analysis, representing 74% of total cephalosporin consumption in 2017. Ceftriaxone alone constituted 94% and 77% of all third-generation agent consumption in 2015 and 2017 respectively.

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Table 9.3 Most consumed agents within each generation of cephalosporins

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) Cefazolin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 0.1 (98) Second-generation (J01DC) 0.1 0.6 Cefuroxime 0.4 (97) 0.3 (98) 1 (99) 0.4 (97) 0.7 (98) (100) (100) Third-generation (J01DD) Ceftriaxone 1.6 (88) 1.7 (92) 6.2 (96) 2.8 (82) 4.1 (94) 1 (71) 2 (77) Cefixime 0.1 (6) < 0.1 < 0.1 0.2 (7) 0.1 (2) 0.2 (16) 0.2 (9) Cefdinir – – – – – < 0.1 0.2 (6) Cefpodoxime < 0.1 < 0.1 < 0.1 – – < 0.1 0.1 (4) a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for the nominated generation of cephalosporins.

9.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) represented 2.4 DID (5.5%) of total J01 consumption in 2017, with fluoroquinolones comprising 2.3 DID (95.8%) of quinolone consumption. Three agents – ciprofloxacin (49%), levofloxacin (33%) and moxifloxacin (12%) – dominated consumption, together representing 94% of fluoroquinolone consumption in 2017 (Table 9.4).

Table 9.4 Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 Ofloxacin 0.2 (10) 0.2 (7) 0.4 (16) 0.2 (5) 0.4 (6) 1.3 (41) <0.1 Ciprofloxacin 0.6 (28) 1.2 (40) 1.4 (62) 2.5 (65) 1.4 (22) 1 (32) 1.1 (49) Pefloxacin < 0.1 < 0.1 < 0.1 – – – – Norfloxacin 0.8 (34) 0.6 (20) 0.1 (5) 0.2 (4) < 0.1 0.1 (4) < 0.1 Sparfloxacin < 0.1 < 0.1 < 0.1 – – – – Rufloxacin < 0.1 < 0.1 < 0.1 < 0.1 – < 0.1 – Levofloxacin 0.6 (27) 0.9 (32) 0.4 (16) 0.9 (23) 4.3 (69) 0.6 (18) 0.8 (33) Moxifloxacin < 0.1 < 0.1 < 0.1 < 0.1 0.1 (2) 0.2 (6) 0.3 (12) Gemifloxacin – – – – – < 0.1 < 0.1 Total 2.2 2.9 2.3 3.9 6.2 3.1 2.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

9.4 The 10 most consumed agents

84 Georgia

9.4.1 The 10 most consumed agents – oral formulation

Table 9.5 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

Table 9.5 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Trimethoprim 6.74 6.74 6.74 6.74 6.74 6.74 6.74 6.74 6.74 6.74 Amoxicillin and enzyme 6.47 6.47 6.47 6.47 6.47 6.47 6.47 6.47 6.47 inhibitor Amoxicillin 1.59 1.59 1.59 1.59 1.59 1.59 1.59 1.59 Azithromycin 1.32 1.32 1.32 1.32 1.32 1.32 1.32 Ciprofloxacin 1.14 1.14 1.14 1.14 1.14 1.14 Doxycycline 1.12 1.12 1.12 1.12 1.12 Nitrofurantoin 1.04 1.04 1.04 1.04 Chloramphenicol 0.72 0.72 0.72 Levofloxacin 0.71 0.71 Cefuroxime 0.69 Total consumption for 21.55 20.86 20.15 19.42 18.38 17.26 16.12 14.80 13.21 6.74 this group of agents Total consumption for 24.50 24.50 24.50 24.50 24.50 24.50 24.50 24.50 24.50 24.50 all oral J01 agents Proportion (%) of total consumption for oral 88.0% 85.1% 82.3% 79.3% 75.0% 70.5% 65.8% 60.4% 53.9% 27.5% J01 antibacterials a DDD: daily defined dose.

The apparently high level of consumption of trimethoprim requires further clarification. It is likely that a large part of the imported drug subsequently was exported and therefore not consumed in Georgia.

The 10 listed oral agents represent almost 88% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, three are included in the WHO Watch group of antibacterials – azithromycin (macrolides), and ciprofloxacin and levofloxacin (quinolones).

The Watch agents azithromycin (5.4%), ciprofloxacin (4.7%) and levofloxacin (2.8%) together comprised 12.9% of J01 oral agent consumption in 2017.

9.4.2 The 10 most consumed agents – parenteral formulation

Table 9.6 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

As shown in Table 9.1, parenteral agents comprised around 22% of total J01 consumption in 2017. Within this, the Watch group third-generation cephalosporin ceftriaxone alone accounted for 29.1% of injection consumption. A small amount of consumption of the Reserve agent vancomycin was reported in 2017.

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Table 9.6 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Benzathine benzylpenicillin 2.78 2.78 2.78 2.78 2.78 2.78 2.78 2.78 2.78 2.78 Ceftriaxone 2.04 2.04 2.04 2.04 2.04 2.04 2.04 2.04 2.04 Combinations 0.85 0.85 0.85 0.85 0.85 0.85 0.85 0.85 Ampicillin 0.30 0.30 0.30 0.30 0.30 0.30 0.30 Cefazolin 0.13 0.13 0.13 0.13 0.13 0.13 Piperacillin and enzyme 0.11 0.11 0.11 0.11 0.11 inhibitor Amikacin 0.09 0.09 0.09 0.09 Streptomycin 0.09 0.09 0.09 Metronidazole 0.09 0.09 Vancomycin 0.09 Total consumption for this 6.57 6.48 6.40 6.31 6.21 6.10 5.97 5.67 4.82 2.78 group of agents Total consumption for all 7.01 7.01 7.01 7.01 7.01 7.01 7.01 7.01 7.01 7.01 parenteral J01 agents Proportion (%) of total consumption for parenteral 93.7% 92.5% 91.3% 90.0% 88.7% 87.0% 85.2% 80.9% 68.7% 39.6% J01 antibacterials a DDD: daily defined dose.

9.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 9.3 and Fig. 9.4, and is summarized in Table 9.7.

100

60 Other

40 Core Access group 70 Proportion (%) Proportion 57 46 20 37 36 21 20 0 GEO GEO GEO GEO GEO GEO GEO 2011 2012 2013 2014 2015 2016 2017

Fig. 9.3 Relative consumption of Core Access antibiotics as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

86 Georgia

100

60 Other Watch group 40 Proportion (%) Proportion 54 54 49 20 34 26 28 24 0 GEO GEO GEO GEO GEO GEO GEO 2011 2012 2013 2014 2015 2016 2017

Fig. 9.4 Relative consumption of Watch group antibiotics as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 9.7 Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

Percentage of total consumptiona Antibiotic group 2011 2012 2013 2014 2015 2016 2017 Core Access group 70.3 56.6 36.7 36.2 21.0 19.8 46.4 Watch group 26.3 34.0 53.8 53.6 49.5 28.3 23.6 Reserve group 0.12 0.03 0.23 0.63 0.25 5.3 0.37 Ungrouped 3.3 9.3 9.3 9.5 29.3 46.6 29.7 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The relative consumption of Watch agents varied considerably across the years of analysis, representing 26.3% of total consumption in 2011, 53.6% in 2014, 28.3% in 2016 and 23.6% in 2017. The relative consumption of Watch agents was higher than the consumption of Core Access agents in each of the years from 2013 to 2017.

There was considerable consumption of Reserve agents reported in 2016 that included linezolid (1.12 DID), cefipime (0.09 DID) and fosfomyicn IV (0.05 DID).

9.6 Analyses based on DDDs applied in 2019

9.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 9.5 (DDD values relevant to year) and 9.6 (2019 DDD values), and is summarized in Table 9.8.

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35 35

30 30

25 25

20 Parenteral 20 Parenteral antibacterials antibacterials 15 15 Oral Oral 10 antibacterials 10 antibacterials

5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 GEO GEO GEO GEO GEO GEO 2015 2016 2017 2015 2016 2017

Fig. 9.5 Total consumption of J01 Fig. 9.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values)

Table 9.8 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 16.3 (64) 20.7 (87) 24.5 (78) 15.2 (63) 20.7 (88) 21.9 (76) Parenteral J01 9.2 (36) 3 (13) 7 (22) 9 (37) 2.9 (12) 6.8 (24) Total 25.5 23.7 31.5 24.2 23.6 28.7 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 31.5 DID in 2017 using DDD values relevant to year of data to 28.7 DID applying the 2019 DDD values – a reduction of 8.9%. The relative consumption of oral and parenteral formulations does not change substantially with the application of the 2019 DDDs (oral formulations 78% applying older DDD values and 76% using 2019 DDD values).

9.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 9.7 (DDD values relevant to year) and 9.8 (2019 DDD values), and is summarized in Table 9.9. As noted in section 9.6.1, total DIDs decreased by 8.9% in 2017.

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 12.3 DID in 2017 using the DDD values relevant to the year of data to 9.4 DID applying the 2019 DDD values – a reduction of 23.6% in absolute values. Relative consumption of beta-lactams falls from 39% to 32.8% of total J01 consumption when the 2019 DDD values are applied.

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35 Other J01 35 Other J01 antibacterials antibacterials (J01G, J01R, (J01G, J01R, 30 J01X) 30 J01X) Quinolone Quinolone 25 antibacterials 25 antibacterials (J01M) (J01M) Macrolides, Macrolides, 20 lincosamides and 20 lincosamides and streptogramins streptogramins (J01F) (J01F) 15 15 Sulfonamides Sulfonamides and trimethoprim and trimethoprim 10 (J01E) 10 (J01E) Other beta-lactams Other beta-lactams

DDD/1000 inhabitants per day (includes DDD/1000 inhabitants per day (includes 5 cephalosporins) 5 cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols GEO GEO GEO (J01B) GEO GEO GEO (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 9.7 Total consumption of J01 Fig. 9.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

Table 9.9 Absolute and relative consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 0.4 1.2 1.2 0.4 1.2 1.2 Tetracyclines (J01A) (1.6) (5.1) (3.8) (1.7) (5.1) (4.2) 0.2 0.8 0.7 0.2 0.8 0.7 Amphenicols (J01B) (0.8) (3.4) (2.2) (0.8) (3.4) (2.4) 4.1 1.8 12.3 2.9 1.7 9.4 Beta-lactams (J01C) (16.1) (7.6) (39) (12) (7.2) (32.8) Other beta-lactams (includes 4.9 2.2 3.6 4.8 2.2 3.6 cephalosporins) (J01D) (19.2) (9.3) (11.4) (19.8) (9.3) (12.5) Sulfonamides and trimethoprim 6.7 9.8 6.8 6.7 9.8 6.8 (J01E) (26.3) (41.4) (21.6) (27.7) (41.5) (23.7) Macrolides, lincosamides and 1.9 1.9 2.2 1.9 1.9 2.2 streptogramins (J01F) (7.5) (8) (7) (7.9) (8.1) (7.7) 6.3 3.2 2.4 6.3 3.3 2.4 Quinolone antibacterials (J01M) (24.7) (13.5) (7.6) (26) (14) (8.4) Other J01 antibacterials (J01G, 1 2.7 2.3 1 2.6 2.3 J01R, J01X) (3.9) (11.4) (7.3) (4.1) (11) (8) Total 25.5 23.7 31.5 24.2 23.6 28.7 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Using 2016 estimates, the changes in DDDs are much smaller. The total DIDs decreased from 23.7 DID using the DDD values relevant to the year of data to 23.6 DID applying the 2019 DDD values. This is explained by low levels of consumption of beta-lactams reported in 2016 (1.8 DID, 7.6% of total J01 consumption).

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As the total DIDs decrease with the application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta-lactams generally increases: cephalosporins, for example, increased from 11.4% to 12.5% and quinolones from 7.6% to 8.4% in 2017.

9.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 9.9 (DDD values relevant to year) and 9.10 (2019 DDD values) for Core Access antibiotics, Fig. 9.11 (DDD values relevant to year) and 9.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 9.10.

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group Proportion (%) Proportion (%) Proportion 46 20 20 41 21 20 18 20 0 0 GEO GEO GEO GEO GEO GEO 2015 2016 2017 2015 2016 2017

Fig. 9.9 Relative consumption of Core Access Fig. 9.10 Relative consumption of Core group antibacterials (applying DDD values Access group antibacterials (applying 2019 relevant to year)a DDD values)a

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion 49 52 20 20 28 24 29 26 0 0 GEO GEO GEO GEO GEO GEO 2015 2016 2017 2015 2016 2017

Fig. 9.11 Relative consumption of Watch Fig. 9.12 Relative consumption of Watch group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year)a DDD values)a

* a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

90 Georgia

Table 9.10 Relative consumption of Core Access and Watch group antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 5.4 (21) 4.7 (20) 14.7 (46) 4.3 (18) 4.7 (20) 11.9 (41) Watch group 12.7 (49.5) 6.8 (28.3) 7.5 (23.6) 12.7 (52) 6.8 (29) 7.5 (26) Reserve group 0.1 (0) 1.3 (5) 0.1 (0) 0 (0) 1.2 (5) 0.1 (0) Ungrouped 7.5 (29) 11.1 (47) 9.4 (30) 7.4 (30) 11.1 (47) 9.5 (33) Total 25.7 23.9 31.8 24.4 23.8 28.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The effect of applying the 2019 DDD values is to decrease slightly the proportion of total use that is Core Access group antibiotics (from 46% to 41% in 2017) and increase slightly the proportion of total use that is Watch group antibiotics (from 23.6 to 26% in 2017).

As noted in section 9.6.2, the effects of changes to DIDs are more modest using 2016 consumption estimates. The proportion of Watch group agents changed slightly from 28.3% to 29% with application of the 2019 DDD values. Significant relative consumption of ungrouped agents (47%) was reported in 2016. Further local-level investigation is needed to identify which of the ungrouped agents are being consumed.

9.7 Discussion

The analyses in this report are based on import records of wholesalers. Data are presented as total consumption estimates. No information is available on the medicines manufactured by local producers.

Estimates of total consumption of J01 antibacterials were reasonably stable over time, apart from 2017 data that suggest a substantial increase in antibiotic consumption (23.7 DID in 2016, 31.5 DID in 2017).

The relative consumption of parenteral antibacterials varied widely over the years of analysis, representing 36%, 13% and 22% of total J01 consumption in 2015, 2016 and 2017 respectively.

The reported changes in consumption in 2017 require local confirmation.

One explanation for the high consumption in 2017 is that the importation of some products was much more extensive than in previous years (it has been suggested that there was double importation of several high-consumption products in 2017). Another is failure adequately to account for exports of locally produced products. The reported high levels of consumption of medicines in the sulphonamide and trimethoprim group lends some support to this explanation. Estimates of consumption of J01E antibacterials increased from 0.3 DID in 2014 to 6.7 DID, 9.8 DID and 6.8 DID in the following years (2015–2017) (Table 9.1). The agent trimethoprim was the most consumed oral antibacterial in 2017 (Table 9.4) with 6.74 DID, representing 27.5% of total oral consumption. Given that trimethoprim is used primarily to treat urinary tract infections, this level of local consumption seems improbable.

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This highlights some of the limitations of the use of import records as a surrogate measure of consumption of antibacterials. Importation records will be affected by the cycles of procurement and delivery, potentially giving rise to fluctuations in estimates of consumption that do not relate to actual use of antibacterials by patients and health-care facilities.

These uncertainties about the validity and reliability of the 2017 estimates make it difficult to comment on possible trends over time in the data for Georgia.

Of the top 10 oral agents, three are included in the WHO Watch group of antibacterials – azithromycin (macrolides), and ciprofloxacin and levofloxacin (quinolones). Azithromycin (5.4%), ciprofloxacin (4.7%) and levofloxacin (2.8%) together comprised 12.9% of J01 oral agent consumption in 2017.

The Watch group third-generation cephalosporin ceftriaxone constituted 29.1% of the consumption of J01 injection formulations in 2017.

Watch group agents (oral and parenteral combined) comprised 23.6% of total consumption in 2017.

The relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities.

For example, the WHO EML (WHO, 2017) suggests limited indications for use of azithromycin, ciprofloxacin, levofloxacin and ceftriaxone.

Levofloxacin is listed on the WHO EML as a reserve second-line drug for the treatment of MDR-TB that should be used in specialized centres adhering to WHO standards for TB control.

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with WHO EML recommendations.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 31.5 DID in 2017 using DDD values relevant to year of data to 28.7 DID applying the 2019 DDD values – a reduction of 8.9%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 12.3 DID in 2017 using the DDD values relevant to the year of data to 9.4 DID applying the 2019 DDD values – a reduction of 23.6% in absolute values.

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The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in Georgia and can help to identify areas for further investigation, allowing development of targeted interventions to address potential problems identified in the consumption of antibacterials. Interventions targeting medicines should be supported by evidence-based guidelines and treatment protocols.

Total DID decreased by 8.9% when the new 2019 DDDs were applied, independent of any intervention by government, agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

Reference

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10. KAZAKHSTAN

10.1 Data source and years of data collection

Kazakhstan provided data for each of the six years of data collection, 2012–2017. The main sources were procurement records provided by the Ministry of Health for 2012–2014 data and sales records provided by VIORTIS for 2015–2017 data. Problems with data collection in 2014 prompted the change to a commercial provider. VIORTIS, the commercial data source, provides coverage of around 80–85% of hospital and community sales. VIORTIS data can be disaggregated to consumption in the community and hospital sectors.

10.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

Total consumption of antibacterials for systemic use (ATC class J01) is examined by route of administration (oral and parenteral formulations) and by route of administration and pharmacological subgroup (Fig. 10.1 and Table 10.1).

KAZ KAZ KAZ KAZ KAZ KAZ 2012 2013 2014b 2015 2016 2017

Fig. 10.1 Consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose. b Data for 2014 were not available.

It is difficult to interpret trends over all the years of analysis, given the change to use of a commercial data source for the period 2015–2017. The commercial data source covers only around 80–85%, so total estimates for the period 2015–2017 will be underestimates of total consumption in Kazakhstan.

94 Kazakhstan

Notwithstanding this limitation, the data suggest some reductions in levels of consumption over this period, at 18.2 DID in 2015 and 15.7 DID in 2017.

Estimates of relative consumption of parenteral antibacterials fluctuated considerably over time. During the period 2015–2017, parenteral antibacterial consumption decreased from 39% to 27% of total J01 consumption (Table 10.1).

The highest levels of consumption in the period 2015–2017 were in beta-lactams (J01C), at 4.4 DID in both 2015 and 2017. These observations relate to total consumption. Different patterns of consumption would be expected in the hospital and community sectors (see Section 10.7).

Table 10.1 Consumption of J01 antibacterials by route of administration and pharmacological subgroup

a b Route of administration, DDD/1 000 inhabitants per day (% of total ) Class of antibacterial agents 2012 2013 2014c 2015 2016 2017 Route of administration Oral J01 7.8 (64) 11.7 (82) – 11.1 (61) 11.5 (68) 11.4 (73) Parenteral J01 4.3 (36) 2.5 (18) – 7.1 (39) 5.5 (32) 4.3 (27) Total 12.1 14.3 – 18.2 17.0 15.7 Class of antibacterial agents – Tetracyclines (J01A) 0 (0) 0 (0) – 1.3 (7.1) 1 (5.9) 0.9 (5.7) Amphenicols (J01B) 0.1 (0.8) 0 (0) – 0.5 (2.7) 0.4 (2.4) 0.8 (5.1) Beta-lactams (J01C) 3.3 (27.3) 3 (21) – 4.4 (24.2) 4.6 (27.1) 4.4 (28) Other beta-lactams (includes 1 (8.3) 1.1 (7.7) – 2.8 (15.4) 2.8 (16.5) 3 (19.1) cephalosporins) (J01D) Sulfonamides and trimethoprim 0 (0) 0.4 (2.8) – 0.6 (3.3) 0.5 (2.9) 0.5 (3.2) (J01E) Macrolides, lincosamides and 0.8 (6.6) 1.4 (9.8) – 1.5 (8.2) 1.6 (9.4) 1.5 (9.6) streptogramins (J01F) Quinolone antibacterials (J01M) 6.5 (53.7) 7.2 (50.3) – 2.7 (14.8) 2.9 (17.1) 2.8 (17.8) Other J01 antibacterials (J01G, J01R, 0.4 (3.3) 1.2 (8.4) – 4.3 (23.6) 3.3 (19.4) 1.7 (10.8) J01X) Total 12.1 14.3 – 18.2 17 15.7 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Data for 2014 were not available.

There is some evidence of increasing relative consumption of: beta-lactams (J01C), at 24.2% in 2015 and 28% in 2017; cephalosporins (J01D), at 15.4% in 2015 and 19.1% in 2017; macrolides (J01F), at 8.2% in 2015 and 9.6% in 2017; and quinolones (J01M), at 14.8% in 2015 and 17.8% in 2017 (Table 10.1). There has been a substantial reduction in consumption of the category “Other J01 antibacterials”, from 23.6% in 2015 to 10.8% in 2017.

The relative consumption of cephalosporins and quinolones combined increased over time (from 30.2% in 2015 to 36.9% in 2017), with increases in both quinolone and cephalosporin consumption.

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10.3 Relative consumption by choice of agent

10.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2012–2017 is shown in Fig. 10.2 and summarized in Table 10.2. Table 10.3 shows the most consumed agents within each of the generations of cephalosporin agents.

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 KAZ KAZ KAZ KAZ KAZ KAZ 2012 2013 2014a 2015 2016 2017

Fig. 10.2 Relative consumption of cephalosporins by generation a Data were not available for 2014

Table 10.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2012 2013 2014c 2015 2016 2017 First-generation (J01DB) 0.5 (48) 0.5 (46) – 0.9 (33) 1.2 (43) 1.2 (41) Second-generation (J01DC) 0.2 (20) 0.2 (22) – 0.3 (11) 0.3 (12) 0.3 (11) Third-generation (J01DD) 0.3 (29) 0.3 (29) – 1.5 (55) 1.2 (44) 1.4 (47) Fourth-generation (J01DE) < 0.1 < 0.1 – < 0.1 < 0.1 < 0.1 Total 1.0 1.0 2.8 2.8 3.0 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Data for 2014 were not available.

Consumption of first-generation agents, almost exclusively cefazolin, increased between 2015 and 2017 (33% of total cephalosporin consumption in 2015 and 41% in 2017). Second-generation agent consumption, mostly cefuroxime, remained stable at around 11–12% in the period 2015–2017. Consumption of Watch group third-generation agents fluctuated over time, constituting 47% of total cephalosporin consumption in 2017. Ceftriaxone comprised 89% of third-generation agent consumption in 2017. Only small volumes of consumption of fourth-generation cephalosporins (Reserve agents) were reported.

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Table 10.3 Most consumed agents within each generation of cephalosporins

DDD/1 000 inhabitants per daya (% of totalb) Agents 2012 2013 2014c 2015 2016 2017 First-generation (J01DB) Cefazolin 0.5 (100) 0.5 (100) – 0.9 (100) 1.2 (100) 1.2 (100) Second-generation (J01DC) Cefuroxime 0.2 (100) 0.2 (100) – 0.3 (93) 0.3 (94) 0.3 (94) Third-generation (J01DD) Ceftriaxone 0.2 (66) 0.2 (73) – 0.8 (54) 1.1 (90) 1.3 (89) Cefoperazone < 0.1 < 0.1 – 0.6 (39) < 0.1 < 0.1 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Data for 2014 were not available. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for the nominated generation of cephalosporins.

10.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) represented 2.8 DID (17.8%) of total J01 consumption in 2017, with fluoroquinolones comprising 2.7 DID – 96.4% of quinolone consumption. Ciprofloxacin (1.5 DID) and levofloxacin (0.8 DID) together represented 87% of fluoroquinolone consumption in 2017 (Table 10.4).

Table 10.4 Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2012 2013 2014c 2015 2016 2017 Ofloxacin 4.2 (65) 1.6 (23) – 0.3 (13) 0.1 (5) 0.2 (6) Ciprofloxacin 0.7 (11) 0.5 (6) – 1.3 (51) 1.3 (49) 1.5 (56) Pefloxacin < 0.1 < 0.1 – < 0.1 < 0.1 < 0.1 Norfloxacin < 0.1 < 0.1 – 0.1 (6) 0.2 (6) 0.1 (5) Levofloxacin 1.5 (22) 4.7 (65) – 0.7 (28) 1.1 (39) 0.8 (31) Moxifloxacin < 0.1 0.4 (5) – < 0.1 < 0.1 < 0.1 Gemifloxacin < 0.1 < 0.1 – < 0.1 < 0.1 < 0.1 Total 6.5 7.2 – 2.5 2.8 2.7 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Data for 2014 were not available.

10.4 The 10 most consumed agents

10.4.1 The 10 most consumed agents – oral formulation

Table 10.5 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

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Table 10.5 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Amoxicillin 2.02 2.02 2.02 2.02 2.02 2.02 2.02 2.02 2.02 2.02 Ciprofloxacin 1.42 1.42 1.42 1.42 1.42 1.42 1.42 1.42 1.42 Amoxicillin and enzyme 1.11 1.11 1.11 1.11 1.11 1.11 1.11 1.11 inhibitor Chloramphenicol 0.80 0.80 0.80 0.80 0.80 0.80 0.80 Levofloxacin 0.78 0.78 0.78 0.78 0.78 0.78 Azithromycin 0.76 0.76 0.76 0.76 0.76 Doxycycline 0.67 0.67 0.67 0.67 Ampicillin 0.64 0.64 0.64 Sulfamethoxazole and 0.51 0.51 trimethoprim Clarithromycin 0.43 Total consumption for this 9.15 8.72 8.21 7.56 6.89 6.13 5.35 4.54 3.44 2.02 group of agents Total consumption for all 11.36 11.36 11.36 11.36 11.36 11.36 11.36 11.36 11.36 11.36 oral J01 agents Proportion (%) of total consumption for oral J01 80.5% 76.7% 72.2% 66.6% 60.6% 54.0% 47.0% 40.0% 30.3% 17.8% antibacterials a DDD: daily defined dose.

The 10 listed oral agents represent 80.5% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, four are included in the WHO Watch group of antibacterials – ciprofloxacin and levofloxacin (quinolones), and azithromycin and clarithromycin (macrolides).

The Watch group agents ciprofloxacin (12.5%), levofloxacin (7%), azithromycin (6.6%) and clarithromycin (3.8%) combined constituted 29.9% of total consumption of J01 oral antibacterials in 2017.

10.4.2 The 10 most consumed agents – parenteral formulation

Table 10.6 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

Table 10.6 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per day a Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Ceftriaxone 1.26 1.26 1.26 1.26 1.26 1.26 1.26 1.26 1.26 1.26 Cefazolin 1.23 1.23 1.23 1.23 1.23 1.23 1.23 1.23 1.23 Ampicillin 0.48 0.48 0.48 0.48 0.48 0.48 0.48 0.48 Metronidazole 0.36 0.36 0.36 0.36 0.36 0.36 0.36 Gentamicin 0.20 0.20 0.20 0.20 0.20 0.20 Amikacin 0.11 0.11 0.11 0.11 0.11 Benzylpenicillin 0.10 0.10 0.10 0.10 Cefuroxime 0.10 0.10 0.10 Lincomycin 0.09 0.09 Ciprofloxacin 0.07 Total consumption for this 4.00 3.93 3.84 3.74 3.64 3.53 3.33 2.96 2.48 1.26 group of agents Total consumption for all 4.31 4.31 4.31 4.31 4.31 4.31 4.31 4.31 4.31 4.31 parenteral J01 agents Proportion (%) of total consumption for parenteral 92.8% 91.2% 89.1% 86.8% 84.5% 81.9% 77.2% 68.8% 57.6% 29.1% J01 antibacterials a DDD: daily defined dose.

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As shown in Table 10.1, parenteral agents comprised around 27% of total J01 consumption in 2017. Within this, the Watch group third-generation cephalosporin ceftriaxone constituted 29.1% of the consumption of J01 injection formulations.

10.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 10.3 and 10.4, and is summarized in Table 10.7.

100

60 Other

40 Core Access group

Proportion (%) Proportion 64 59 57 20 33 34

0 KAZ KAZ KAZ KAZ KAZ KAZ 2012 2013 2014b 2015 2016 2017

Fig. 10.3 Relative consumption of Core Access group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01). a Data for 2014 were not available.

100

60 Other Watch group 40

Proportion (%) Proportion 63 63 63 63 20 35 31 32

0 KAZ KAZ KAZ KAZ KAZ KAZ 2012 2013 2014b 2015 2016 2017

Fig. 10.4 Relative consumption of Watch group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01). b Data for 2014 were not available.

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Table 10.7 Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

Percentage of total consumptiona Antibiotic group 2012 2013 2014b 2015 2016 2017 Core Access group 33.3 34.1 – 64.0 59.4 56.7 Watch group 63.0 63.1 – 30.7 32.4 35.1 Reserve group 0.19 0.17 – 0.10 0.10 0.13 Ungrouped 3.5 2.6 – 5.2 8.1 8.0 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01). b Data for 2014 were not available.

Consumption of Core Access antibiotics dominated in the period 2015–2017, with 56.7% of consumption in 2017. The relative consumption of Watch agents increased over time from 30.7% in 2015 to 35.1% in 2017.

10.6 Analyses based on DDDs applied in 2019

10.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 10.5 (DDD values relevant to year) and Fig. 10.6 (2019 DDD values), and is summarized in Table 10.8.

20 20

15 15

Parenteral Parenteral 10 10 antibacterials antibacterials Oral Oral antibacterials antibacterials 5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 KAZ KAZ KAZ KAZ KAZ KAZ 2015 2016 2017 2015 2016 2017

Fig. 10.5 Total consumption of J01 Fig. 10.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values)

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Table 10.8 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 11.1 (61) 11.5 (68) 11.4 (73) 10.7 (61) 10.6 (67) 10.4 (72) Parenteral J01 7.1 (39) 5.5 (32) 4.3 (27) 6.7 (39) 5.2 (33) 3.9 (28) Total 18.2 17.0 15.7 17.4 15.7 14.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Application of the 2019 DDD values has an impact on the estimates of total consumption of J01 antibacterials, reducing from 15.7 DID in 2017 using DDD values relevant to year of data to 14.3 DID applying the 2019 DDD values – a reduction of 8.9%.

The relative consumption of oral and parenteral formulations does not change substantially with the application of the 2019 DDDs (oral 73% applying older values and 72% with the 2019 DDD values).

10.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 10.7 (DDD values relevant to year) and Fig. 10.8 (2019 DDD values), and is summarized in Table 10.9. As noted in section 10.6.1, total DIDs decreased by 8.9% in 2017.

20 Other J01 20 Other J01 antibacterials antibacterials (J01G, J01R, (J01G, J01R, J01X) J01X) Quinolone Quinolone 15 15 antibacterials antibacterials (J01M) (J01M) Macrolides, Macrolides, lincosamides and lincosamides and 10 streptogramins 10 streptogramins (J01F) (J01F) Sulfonamides Sulfonamides and trimethoprim and trimethoprim (J01E) (J01E) 5 5 Other beta-lactams Other beta-lactams DDD/1000 inhabitants per day DDD/1000 inhabitants per day (includes (includes cephalosporins) cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols KAZ KAZ KAZ (J01B) KAZ KAZ KAZ (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 10.7 Total consumption of J01 Fig. 10.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

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Table 10.9 Absolute and relative consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 1.3 1 0.9 1.3 1 0.9 Tetracyclines (J01A) (7.1) (5.9) (5.7) (7.5) (6.4) (6.3) 0.5 0.4 0.8 0.5 0.4 0.8 Amphenicols (J01B) (2.7) (2.4) (5.1) (2.9) (2.5) (5.6) 4.4 4.6 4.4 3.1 3.3 3.1 Beta-lactams (J01C) (24.2) (27.1) (28) (17.8) (21) (21.7) Other beta-lactams (includes 2.8 2.8 3 2.8 2.8 3 cephalosporins) (J01D) (15.4) (16.5) (19.1) (16.1) (17.8) (21) Sulfonamides and trimethoprim 0.6 0.5 0.5 0.6 0.5 0.5 (J01E) (3.3) (2.9) (3.2) (3.4) (3.2) (3.5) Macrolides, lincosamides and 1.5 1.6 1.5 1.6 1.7 1.6 streptogramins (J01F) (8.2) (9.4) (9.6) (9.2) (10.8) (11.2) 2.7 2.9 2.8 2.7 2.8 2.7 Quinolone antibacterials (J01M) (14.8) (17.1) (17.8) (15.5) (17.8) (18.9) Other J01 antibacterials (J01G, 4.3 3.3 1.7 4.7 3.3 1.7 J01R, J01X) (23.6) (19.4) (10.8) (27) (21) (11.9) Total 18.2 17 15.7 17.4 15.7 14.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 4.4 DID in 2017 using the DDD values relevant to the year of data to 3.1 DID applying the 2019 DDD values – a reduction of 29.5% in absolute values. Relative consumption of beta-lactams falls from 28% to 21.7% of total J01 consumption when the 2019 DDD values are applied.

As the total DIDs decrease with the application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta- lactams generally increases; cephalosporins, for example, increased from 19.1% to 21%, the macrolides group from 9.6% to 11.2%, and quinolones from 17.8% to 18.9% in 2017.

10.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 10.9 (DDD values relevant to year) and Fig. 10.10 (2019 DDD values) for Core Access antibiotics, Fig. 10.11 (DDD values relevant to year) and Fig. 10.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 10.10.

The effect of applying the 2019 DDD values is to decrease slightly the proportion of total use that is Core Access antibiotics (from 57% to 53% in 2017) and increase slightly the proportion of total use that is Watch group antibiotics (from 35.1% to 39%).

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100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group Proportion (%) Proportion 64 (%) Proportion 59 57 60 56 53 20 20

0 0 KAZ KAZ KAZ KAZ KAZ KAZ 2015 2016 2017 2015 2016 2017 Fig.10.9 Relative consumption of Core Fig. 10.10 Relative consumption of Core Access group antibacterials (applying DDD Access group antibacterials (applying 2019 values relevant to year)a DDD values)a

100 100

80 80

60 60 Other Other Watch group 40 40 Watch group Proportion (%) Proportion Proportion (%) Proportion

20 20 39 31 32 35 33 35

0 0 KAZ KAZ KAZ KAZ KAZ KAZ 2015 2016 2017 2015 2016 2017

Fig. 10.11 Relative consumption of Watch Fig. 10.12 Relative consumption of Watch group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year)a DDD values)a

a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 10.10 Relative consumption of Core Access, Watch and Reserve group antibacterials

DDD/1 000 inhabitants per daya (% of totalb)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 11.9 (64) 10.4 (59) 9.1 (57) 10.6 (60) 9.1 (56) 7.7 (53) Watch group 5.7 (30.7) 5.7 (32.4) 5.6 (35.1) 5.8 (33) 5.7 (35) 5.7 (39) Reserve group 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Ungrouped 1 (5) 1.4 (8) 1.3 (8) 1.4 (8) 1.4 (9) 1.3 (9) Total 18.6 17.5 16.1 17.8 16.2 14.7 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

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10.7 Analysis by community and hospital sectors

The analyses presented in sections 10.1–10.6 are based on estimates of total consumption. Different patterns of consumption would be expected in the hospital and community sectors. Analyses by sector can provide more detailed information to support stewardship activities. Disaggregated data for Kazakhstan for 2015–2017 are presented in this report.

10.7.1 Consumption of antibacterials for systemic use (J01) in community and hospital sectors by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 10.13 (community consumption) and Fig. 10.14 (hospital consumption), and is summarized in Table 10.11.

15 15

10 10 Parenteral Parenteral antibacterials antibacterials Oral Oral 5 antibacterials 5 antibacterials DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 KAZ KAZ KAZ KAZ KAZ KAZ 2015 2016 2017 2015 2016 2017

Fig. 10.13 Community consumption of J01 Fig. 10.14 Hospital consumption of J01 antibacterials by route of administration antibacterials by route of administration

Table 10.11 Community and hospital consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration Community consumption Hospital consumption

2015 2016 2017 2015 2016 2017 Oral J01 9.6 (82) 9.8 (80) 9.8 (79) 1.5 (48) 1.8 (55) 1.5 (48) Parenteral J01 2.1 (18) 2.5 (20) 2.6 (21) 1.6 (52) 1.5 (45) 1.7 (52) Total 11.7 12.2 12.4 3.2 3.4 3.2 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Community consumption represented 79% of total J01 consumption in 2017, at 12.4 DID in the community sector and 3.2 DID in the hospital sector.

Oral consumption dominated in the community sector, at 79% oral and 21% parenteral consumption in 2017. Hospital consumption slightly favoured parenteral forms, at 52% of hospital consumption in 2017.

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10.7.2 Consumption of antibacterials for systemic use (J01) in community and hospital sectors by pharmacological subgroup

The consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 10.15 (community consumption) and Fig. 10.16 (hospital consumption), and is summarized in Table 10.12.

15 Other J01 15 Other J01 antibacterials antibacterials (J01G, J01R, (J01G, J01R, J01X) J01X) Quinolone Quinolone antibacterials antibacterials 10 (J01M) 10 (J01M) Macrolides, Macrolides, lincosamides and lincosamides and streptogramins streptogramins (J01F) (J01F) Sulfonamides Sulfonamides 5 and trimethoprim 5 and trimethoprim (J01E) (J01E) Other beta-lactams Other beta-lactams DDD/1000 inhabitants per day DDD/1000 inhabitants per day (includes (includes cephalosporins) cephalosporins) (J01D) (J01D) 0 Beta-lactams 0 Beta-lactams (J01C) (J01C) Amphenicols KAZ KAZ KAZ Amphenicols KAZ KAZ KAZ (J01B) (J01B) 2015 2016 2017 2015 2016 2017 Tetracyclines Tetracyclines (J01A) (J01A) Fig. 10.15 Community consumption of J01 Fig. 10.16 Hospital consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup

Table 10.12 Absolute and relative consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup Community consumption Hospital consumption

2015 2016 2017 2015 2016 2017 1.3 0.9 0.8 0.1 0.1 0.1 Tetracyclines (J01A) (11.1) (7.4) (6.5) (3.1) (2.9) (3.1) 0.5 0.4 0.8 Amphenicols (J01B) – – – (4.3) (3.3) (6.5) 3.7 4 3.8 0.6 0.6 0.6 Beta-lactams (J01C) (31.6) (32.8) (30.6) (18.8) (17.6) (18.8) Other beta-lactams (includes 1.4 1.9 2 0.8 0.9 1 cephalosporins) (J01D) (12) (15.6) (16.1) (25) (26.5) (31.3) Sulfonamides and trimethoprim 0.6 0.5 0.5 – – – (J01E) (5.1) (4.1) (4) Macrolides, lincosamides and 1.3 1.4 1.2 0.2 0.3 0.3 streptogramins (J01F) (11.1) (11.5) (9.7) (6.3) (8.8) (9.4) 1.8 1.9 1.9 0.9 1.1 0.8 Quinolone antibacterials (J01M) (15.4) (15.6) (15.3) (28.1) (32.4) (25) Other J01 antibacterials (J01G, 1.1 1.4 1.3 0.5 0.4 0.4 J01R, J01X) (9.4) (11.5) (10.5) (15.6) (11.8) (12.5) Total 11.7 12.2 12.4 3.2 3.4 3.2 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

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Patterns of consumption were completely different in the community and hospital sectors. Beta- lactams (J01C) represented 30.6% of consumption in the community sector and 18.8% in the hospital sector in 2017. Cephalosporin consumption dominated in the hospital sector, at 31.3% of hospital consumption and 16.1% of community consumption.

There are insufficient data to conclude trends in consumption of different pharmacological subgroups in each of the two sectors.

10.7.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics in community and hospital sectors

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 10.17 (community) and Fig. 10.18 (hospital) for Core Access antibiotics, Fig. 10.19 (community) and Fig. 10.20 (hospital) for Watch group antibiotics, and is summarized in Table 10.13.

100 100

80 80

60 60 Other Other Core Access Core Access 40 group 40 group Proportion (%) Proportion 62 58 59 (%) Proportion 51 49 20 20 45

0 0 KAZ KAZ KAZ KAZ KAZ KAZ 2015 2016 2017 2015 2016 2017

Fig. 10.17 Relative consumption of Fig. 10.18 Relative consumption of Core Access group antibacterials – Core Access group antibacterials – community sectora hospital sectora

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion 51 48 20 20 45 30 32 32

0 0 KAZ KAZ KAZ KAZ KAZ KAZ 2015 2016 2017 2015 2016 2017

Fig. 10.19 Relative consumption of Watch Fig. 10.20 Relative consumption of Watch group antibacterials – community sectora group antibacterials – hospital sectora

a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

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Table 10.13 Relative consumption of Core Access, Watch and Reserve group antibacterials

DDD/1 000 inhabitants per daya (% of totalb)

Category Community sector Hospital sector

2015 2016 2017 2015 2016 2017 Core Access group 7.5 (62) 7.3 (58) 7.5 (59) 1.6 (51) 1.5 (45) 1.6 (49) Watch group 3.7 (30.4) 4 (31.9) 4.1 (31.9) 1.4 (45.3) 1.7 (51) 1.5 (47.7) Reserve group – – – < 0.1 (1) 0 (0) < 0.1 (1) Ungrouped 0.9 (7) 1.3 (10) 1.2 (9) 0.1 (3) 0.1 (4) 0.1 (3) Total 12.1 12.7 12.8 3.2 3.4 3.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The relative consumption of Core Access antibiotics was greater in the community sector (59% community, 49% hospital) in 2017, while consumption of Watch agents was greater in the hospital sector (47.7%), compared to 31.9% in the community.

10.8 Discussion

The analyses for the years 2015–2017 in this report are based on information provided by a commercial data source. VIORTIS data covers around 80–85% of hospital and community sales and can be disaggregated to consumption in the community and hospital sectors. As coverage is not complete, consumption estimates presented in this report will be underestimates of total consumption in Kazakhstan.

Notwithstanding the limitations of the data source, the estimates suggest some reductions in levels of consumption over this period, at 18.2 DID in 2015 and 15.7 DID in 2017. Around 27% of consumption in 2017 was parenteral formulations.

Relative consumption of beta-lactams, cephalosporins, macrolides and quinolones increased slightly over time, offset by decreases in estimates of the relative consumption of “Other J01 antibacterials”.

Of the top 10 oral agents in the J01 class, four are included in the WHO Watch group of antibacterials – ciprofloxacin and levofloxacin (quinolones), and azithromycin and clarithromycin (macrolides). Ciprofloxacin (12.5%), levofloxacin (7%), azithromycin (6.6%) and clarithromycin (3.8%) combined constituted 29.9% of total consumption of J01 oral antibacterials in 2017.

The Watch group third-generation cephalosporin ceftriaxone constituted 29.1% of the consumption of J01 injection formulations in 2017.

Watch group agents (oral and parenteral combined) comprised 35.1% of total consumption in 2017.

These relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities. For example, the WHO EML (WHO, 2017) suggests limited indications for use of azithromycin, ciprofloxacin, clarithromycin, levofloxacin and ceftriaxone.

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Ciprofloxacin is listed in the WHO EML as a first-choice agent for acute invasive bacterial diarrhoea/dysentery, low-risk febrile neutropenia and mild-to-moderate pyelonephritis or prostatitis. It is a second-choice agent for the treatment of cholera and mild-to-moderate complicated intra-abdominal infections.

Clarithromycin is listed on the EML as a first-choice option for severe community-acquired pneumonia and as a second-choice option for pharyngitis.

Levofloxacin is listed on the WHO EML as a reserve second-line drug for the treatment of MDR-TB that should be used in specialized centres adhering to WHO standards for TB control.

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with WHO EML recommendations.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 15.7 DID in 2017 using DDD values relevant to year of data to 14.3 DID applying the 2019 DDD values – a reduction of 8.9%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 4.4 DID in 2017 using the DDD values relevant to the year of data to 3.1 DID applying the 2019 DDD values – a reduction of 29.5% in absolute values.

Disaggregated data for 2015–2017 are presented in this report. The data illustrate that most consumption occurred in the community (79% of total J01 consumption) and show substantial differences in patterns of consumption of pharmacological subgroups in the two sectors. The relative consumption of beta- lactams (J01C) was higher in the community than hospital sector, while cephalosporin consumption was greater in the hospital than community. The relative consumption of Watch group agents was 47.7% in the hospital sector compared to 31.9% in the community sector. These analyses by sector can provide more detailed information to support stewardship activities.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in Kazakhstan and can help to identify areas for further investigation, allowing the development of targeted interventions to address potential problems identified in the consumption of antibacterials. Interventions targeting medicines should be supported by evidence-based guidelines and treatment protocols.

108 Kazakhstan

Total DID decreased by 8.9% when the new 2019 DDDs are applied, independent of any intervention by government, agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

Reference

109 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

11. KYRGYZSTAN

11.1 Data source and years of data collection

Kyrgyzstan provided data for each of the seven years of data collection (2011–2017). The main sources were import records provided by the drug agency and information provided by wholesalers. Data derived from importation records will be affected by the cycles of procurement and delivery, potentially giving rise to fluctuations in estimates of consumption that do not relate to actual use of antibacterials by patients and health-care facilities.

11.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

The data show fluctuations in total consumption of J01 antibacterials over time. Within this, there appear to be some anomalies with 2014 data that cannot fully be explained. There may be some influence of medicine import cycles on the patterns observed.

40 Other J01 antibacterials 35 (J01G, J01R, J01X) a Quinolone antibacterials 30 (J01M)

25 Macrolides, lincosamides and streptogramins (J01F) 20 Sulfonamides and trimethoprim (J01E) 15 Other beta-lactams (includes cephalosporins) (J01D) 10 Beta-lactams (J01C) DDD/1000 inhabitants per day 5 Amphenicols (J01B) Tetracyclines (J01A) 0 KGZ KGZ KGZ KGZ KGZ KGZ KGZ 2011 2012 2013 2014 2015 2016 2017

Fig. 11.1 Total consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose.

110 Kyrgyzstan

The relative consumption of parenteral antibacterials varied considerably across the years analysed, at 72% in 2011 and 45% in 2017, and as low as 22% in 2014 and 23% in 2016. The reasons for these variations require further investigation (Table 11.1).

The highest levels of consumption were in beta-lactams (J01C), at 8.5 DID in 2011 and 9.9 DID in 2017 (Table 11.1). There is evidence of increasing consumption of cephalosporins (J01D), with 1.8 DID in 2011 and 5 DID in 2017. The large variations in quinolone antibacterial (J01M) consumption over time require further investigation.

These observations relate to total consumption. Different patterns of consumption would be expected in the hospital and community sectors.

Table 11.1 Total consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 Route of administration 6.7 7.3 10.7 28.7 11.8 18.9 11.5 Oral J01 (28) (34) (49) (78) (58) (77) (55) 17.3 14 11 8.1 8.6 5.6 9.3 Parenteral J01 (72) (66) (51) (22) (42) (23) (45) Total 24.0 21.3 21.7 36.8 20.5 24.5 20.8 Class of antibacterial agents 0.6 0.6 0.7 2.1 1.1 1.7 2 Tetracyclines (J01A) (2.5) (2.8) (3.2) (5.7) (5.4) (6.9) (9.6) 0.5 0.5 0.4 0.3 0.1 0.3 0.4 Amphenicols (J01B) (2.1) (2.3) (1.8) (0.8) (0.5) (1.2) (1.9) 8.5 8.6 10.1 16.7 11.6 10.9 9.9 Beta-lactams (J01C) (35.4) (40.4) (46.5) (45.4) (56.6) (44.5) (47.6) Other beta-lactams (includes cephalosporins) 1.8 4.4 4 4.7 2.2 2.9 5 (J01D) (7.5) (20.7) (18.4) (12.8) (10.7) (11.8) (24) 1 0.8 1.7 1.5 0.8 0.9 Sulfonamides and Trimethoprim (J01E) – (4.2) (3.8) (7.8) (4.1) (3.9) (3.7) Macrolides, Lincosamides and Streptogramins 0.8 1.1 1.5 4.1 0.9 2 1 (J01F) (3.3) (5.2) (6.9) (11.1) (4.4) (8.2) (4.8) 0.5 0.4 0.4 5 1.8 2.3 0.1 Quinolone antibacterials (J01M) (2.1) (1.9) (1.8) (13.6) (8.8) (9.4) (0.5) 10.4 4.8 3 2.4 2 3.4 2.5 Other J01 antibacterials (J01G, J01R, J01X) (43.3) (22.5) (13.8) (6.5) (9.8) (13.9) (12) Total 24.0 21.3 21.7 36.8 20.5 24.5 20.8 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

There is evidence of increasing relative consumption of: tetracyclines (J01A), at 2.5% in 2011 and 9.6% in 2017; beta-lactams (J01C), at 35.4% in 2011 and 47.6% in 2017; and cephalosporins (J01D), at 7.5% in 2011 and 24% in 2017. Consumption of quinolones (J01M) decreased, at 2.1% in 2011 and 0.5% in 2017 (Table 11.1). Relative consumption of quinolones was as high as 13.6% in 2014.

Overall consumption of cephalosporins and quinolones combined varied substantially across the years analysed (9% in 2011, 25% in 2017), with large fluctuations in extent of relative use of both cephalosporins and quinolones.

111 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

11.3 Relative consumption by choice of agent

11.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2011–2017 is shown in Fig. 11.2 and summarized in Table 11.2.

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 KGZ KGZ KGZ KGZ KGZ KGZ KGZ 2011 2012 2013 2014 2015 2016 2017

Fig. 11.2 Relative consumption of cephalosporins by generation

Table 11.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) 0.7 (39) 0.9 (19) 1.8 (45) 0.8 (17) 1 (44) 0.6 (20) 0.6 (13) Second-generation (J01DC) < 0.1 < 0.1 < 0.1 0.1 (2) 0.1 (7) 0.2 (8) < 0.1 Third-generation (J01DD) 1 (59) 3.5 (79) 2.1 (53) 3.8 (80) 1.1 (49) 2 (72) 4.3 (86) Fourth-generation (J01DE) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 – < 0.1 Total 1.8 4.4 4.0 4.7 2.2 2.9 5.0 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Decreases in consumption of first-generation agents were seen, at 39% of total cephalosporin consumption in 2011 and 13% in 2017. Cefazolin was the most consumed first-generation agent across the years analysed. Consumption of second-generation agents was low. Consumption of Watch group third-generation agents dominated, generally increasing over time (59% of total cephalosporin consumption in 2011 and 86% in 2017). Ceftriaxone and cefixime comprised 95% and 5% of third- generation agent consumption in 2017. Only small volumes of consumption of fourth-generation cephalosporins (Reserve agents) were reported.

112 Kyrgyzstan

11.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) consumption varied widely, representing 0.5 DID (2.1%) of total J01 consumption in 2011, 2.3 DID in 2016 (9.4%) and 0.1 DID (0.5%) of total J01 consumption in 2017, with fluoroquinolones comprising essentially all quinolone consumption (Tables 11.1, 11.3). Consumption of three fluoroquinolones – ciprofloxacin, norfloxacin and levofloxacin – dominated across most of the years analysed (Table 11.3). Fluoroquinolone data for 2017 require further investigation at national level.

Table 11.3 Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 Ofloxacin < 0.1 < 0.1 < 0.1 < 0.1 – < 0.1 < 0.1 Ciprofloxacin 0.3 (65) 0.1 (30) 0.1 (28) 2.3 (46) 0.8 (49) 2 (85) – Norfloxacin 0.1 (21) 0.2 (38) 0.1 (35) 0.2 (3) 0.1 (7) 0.1 (5) – Levofloxacin < 0.1 0.1 (24) 0.1 (26) 2.4 (48) 0.7 (42) 0.2 (7) < 0.1 Total 0.5 0.4 0.4 5.0 1.7 2.3 0.1 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption of fluoroquinolones

11.4 The 10 most consumed agents

11.4.1 The 10 most consumed agents – oral formulation

Table 11.4 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

Table 11.4 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Amoxicillin 7.61 7.61 7.61 7.61 7.61 7.61 7.61 7.61 7.61 7.61 Doxycycline 1.18 1.18 1.18 1.18 1.18 1.18 1.18 1.18 1.18 Tetracycline 0.80 0.80 0.80 0.80 0.80 0.80 0.80 0.80 Azithromycin 0.50 0.50 0.50 0.50 0.50 0.50 0.50 Chloramphenicol 0.37 0.37 0.37 0.37 0.37 0.37 Amoxicillin and enzyme 0.31 0.31 0.31 0.31 0.31 inhibitor Cefixime 0.20 0.20 0.20 0.20 Clarithromycin 0.11 0.11 0.11 Erythromycin 0.09 0.09 Roxithromycin 0.08 Total consumption for 11.25 11.17 11.08 10.97 10.77 10.45 10.09 9.59 8.79 7.61 this group of agents Total consumption for 11.52 11.52 11.52 11.52 11.52 11.52 11.52 11.52 11.52 11.52 all oral J01 agents Proportion (%) of total consumption for oral 97.7% 97.0% 96.2% 95.2% 93.5% 90.8% 87.6% 83.3% 76.3% 66.1% J01 antibacterials a DDD: daily defined dose.

113 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

The 10 listed oral agents represent almost 98% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, five are included in the WHO Watch group of antibacterials – azithromycin, clarithromycin, erythromycin and roxithromycin (macrolides), and cefixime (third-generation cephalosporins).

Azithromycin (4.3%), cefixime (1.7%), clarithromycin (1%), erythromycin (0.8%) and roxithromycin (0.7%) together comprised around 8.5% of J01 oral agent consumption in 2017.

11.4.2 The 10 most consumed agents – parenteral formulation

Table 11.5 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

Table 11.5 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Ceftriaxone 4.05 4.05 4.05 4.05 4.05 4.05 4.05 4.05 4.05 4.05 Kanamycin 2.16 2.16 2.16 2.16 2.16 2.16 2.16 2.16 2.16 Ampicillin 1.08 1.08 1.08 1.08 1.08 1.08 1.08 1.08 Combinations 0.80 0.80 0.80 0.80 0.80 0.80 0.80 Cefazolin 0.64 0.64 0.64 0.64 0.64 0.64 Streptomycin 0.25 0.25 0.25 0.25 0.25 Azithromycin 0.09 0.09 0.09 0.09 Gentamicin 0.08 0.08 0.08 Benzylpenicillin 0.03 0.03 Cefotaxime 0.03 Total consumption for this 9.20 9.17 9.14 9.06 8.97 8.72 8.08 7.28 6.21 4.05 group of agents Total consumption for all 9.29 9.29 9.29 9.29 9.29 9.29 9.29 9.29 9.29 9.29 parenteral J01 agents Proportion (%) of total consumption for parenteral 99.1% 98.8% 98.5% 97.6% 96.6% 93.9% 87.0% 78.5% 66.9% 43.6% J01 antibacterials a DDD: daily defined dose.

As shown in Table 11.1, parenteral agents comprised around 45% of total J01 consumption in 2017. Within this, the Watch group third-generation cephalosporin ceftriaxone alone constituted 43.6% of the consumption of J01 injection formulations.

11.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 11.3 and Fig. 11.4, and is summarized in Table 11.6.

114 Kyrgyzstan

100

60 Other Core Access group 40 73

Proportion (%) Proportion 60 52 57 54 20 37 29

0 KGZ KGZ KGZ KGZ KGZ KGZ KGZ 2011 2012 2013 2014 2015 2016 2017

Fig. 11.3 Relative consumption of Core Access group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

100

60 Other Watch group 40 Proportion (%) Proportion

20 34 25 26 23 18 17 9 0 KGZ KGZ KGZ KGZ KGZ KGZ KGZ 2011 2012 2013 2014 2015 2016 2017

Fig. 11.4 Relative consumption of Watch group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 11.6. Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

Percentage of total consumptiona Category 2011 2012 2013 2014 2015 2016 2017 Core Access group 28.9 37.3 52.1 60.0 72.7 57.2 54.4 Watch group 9.4 23.3 18.2 34.0 17.3 25.0 25.8 Reserve group 0.01 0.02 0.02 0.03 0.01 0.01 0.07 Ungrouped 61.7 39.4 29.7 6.0 10.0 17.8 19.7 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

115 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Consumption of Core Access agents has dominated since 2014, representing 54.4% of total consumption in 2017. Watch agents constituted 25–26% of total antibiotic consumption in 2016 and 2017. Consumption of Reserve group agents was low.

11.6 Analyses based on DDDs applied in 2019

11.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 11.5 (DDD values relevant to year) and Fig. 11.6 (2019 DDD values), and is summarized in Table 11.7.

30 30

25 25

20 20 Parenteral Parenteral 15 15 antibacterials antibacterials Oral Oral 10 10 antibacterials antibacterials

5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 KGZ KGZ KGZ KGZ KGZ KGZ 2015 2016 2017 2015 2016 2017

Fig. 11.5 Total consumption of J01 Fig. 11.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values)

Table 11.7 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 11.8 (58) 18.9 (77) 11.5 (55) 9.9 (59) 15.7 (74) 8.9 (51) Parenteral J01 8.6 (42) 5.6 (23) 9.3 (45) 6.8 (41) 5.6 (26) 8.6 (49) Total 20.5 24.5 20.8 16.7 21.3 17.5 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

116 Kyrgyzstan

The relative consumption of oral and parenteral formulations does not change substantially with the application of the 2019 DDDs (oral 55% applying older values and 51% with the 2019 DDD values).

11.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 11.7 (DDD values relevant to year) and Fig. 11.8 (2019 DDD values), and is summarized in Table 11.8. As noted in section 11.6.1, total DID decreased by 15.9% in 2017.

30 Other J01 30 Other J01 antibacterials antibacterials (J01G, J01R, (J01G, J01R, 25 J01X) 25 J01X) Quinolone Quinolone antibacterials antibacterials 20 (J01M) 20 (J01M) Macrolides, Macrolides, lincosamides and lincosamides and 15 streptogramins 15 streptogramins (J01F) (J01F) Sulfonamides Sulfonamides 10 and trimethoprim 10 and trimethoprim (J01E) (J01E) Other beta-lactams Other beta-lactams DDD/1000 inhabitants per day DDD/1000 inhabitants per day 5 (includes 5 (includes cephalosporins) cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols KGZ KGZ KGZ (J01B) KGZ KGZ KGZ (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 11.7 Total consumption of J01 Fig. 11.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

Table 11.8 Consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019 2015 2016 2017 2015 2016 2017 1.1 1.7 2 1.1 1.7 2 Tetracyclines (J01A) (5.4) (6.9) (9.6) (6.6) (8) (11.4) 0.1 0.3 0.4 0.1 0.3 0.4 Amphenicols (J01B) (0.5) (1.2) (1.9) (0.6) (1.4) (2.3) 11.6 10.9 9.9 7.7 7.7 6.5 Beta-lactams (J01C) (56.6) (44.5) (47.6) (46.1) (36.2) (37.1) Other beta-lactams (includes 2.2 2.9 5 2.2 2.9 5 cephalosporins) (J01D) (10.7) (11.8) (24) (13.2) (13.6) (28.6) Sulfonamides and trimethoprim 0.8 0.9 0.8 0.9 – – (J01E) (3.9) (3.7) (4.8) (4.2) Macrolides, lincosamides and 0.9 2 1 0.9 2 1 streptogramins (J01F) (4.4) (8.2) (4.8) (5.4) (9.4) (5.7) 1.8 2.3 0.1 1.8 2.3 0.1 Quinolone antibacterials (J01M) (8.8) (9.4) (0.5) (10.8) (10.8) (0.6) Other J01 antibacterials (J01G, 2 3.4 2.5 2.1 3.5 2.5 J01R, J01X) (9.8) (13.9) (12) (12.6) (16.4) (14.3) Total 20.5 24.5 20.8 16.7 21.3 17.5 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. 117 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 9.9 DID in 2017 using the DDD values relevant to the year of data to 6.5 DID applying the 2019 DDD values – a reduction of 34.4% in absolute values. Relative consumption of beta-lactams falls from 47.6% to 37.1% of total J01 consumption when the 2019 DDD values are applied.

As the total DIDs decrease with the application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta-lactams generally increases; tetracyclines, for example, increased from 9.6% to 11.4%, cephalosporins from 24% to 28.6% and the macrolides group from 4.8% to 5.7% in 2017.

11.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 11.9 (DDD values relevant to year) and Fig. 11.10 (2019 DDD values) for Core Access antibiotics, Fig. 11.11 (DDD values relevant to year) and Fig. 11.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 11.9.

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group 73 68 Proportion (%) Proportion (%) Proportion 57 54 51 20 20 46

0 0 KGZ KGZ KGZ KGZ KGZ KGZ 2015 2016 2017 2015 2016 2017

Fig. 11.9 Relative consumption of Core Fig. 11.10 Relative consumption of Core Access group antibacterials (applying DDD Access group antibacterials (applying 2019 values relevant to year)a DDD values)a

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion

20 20 25 26 29 31 17 21 0 0 KGZ KGZ KGZ KGZ KGZ KGZ 2015 2016 2017 2015 2016 2017

Fig. 11.11 Relative consumption of Watch Fig. 11.12 Relative consumption of Watch group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year)a DDD values)a

a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01). 118 Kyrgyzstan

Table 11.9 Relative consumption of Core Access, Watch and Reserve group antibacterials

DDD/1 000 inhabitants per daya (% of totalb)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 15.4 (73) 14.5 (57) 11.3 (54) 11.9 (68) 11.2 (51) 8 (46) Watch group 3.7 (17.3) 6.3 (25) 5.4 (25.8) 3.7 (21) 6.3 (29) 5.4 (31) Reserve group 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Ungrouped 2.1 (10) 4.5 (18) 4.1 (20) 1.8 (10) 4.6 (21) 4.1 (23) Total 21.2 25.3 20.8 17.4 22.2 17.5 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The effect of applying the 2019 DDD values is to decrease slightly the proportion of total use that is Core Access group antibiotics (from 54% to 46% in 2017) and increase slightly the proportion of total use that is Watch group antibiotics (from 25.8% to 31% in 2017).

11.7 Discussion

The analyses in this report are based on import records and information provided by wholesalers.

Estimates of total consumption of J01 antibacterials fluctuated over the period 2011–2017. Within this, there appear to be some anomalies with 2014 data that cannot fully be explained.

There was increasing relative consumption of beta-lactams, tetracyclines and cephalosporins, and decreasing and quite variable consumption of quinolones.

Of the top 10 oral agents in the J01 class, five are included in the WHO Watch group of antibacterials – azithromycin, clarithromycin, erythromycin and roxithromycin (macrolides), and cefixime (third-generation cephalosporins). Azithromycin (4.3%), cefixime (1.7%), clarithromycin (1%), erythromycin (0.8%) and roxithromycin (0.7%) together comprised around 8.5% of J01 oral agent consumption in 2017.

The Watch group agent ceftriaxone constituted 43.6% (4.05 DID) of the consumption of J01 injection formulations in 2017.

Watch group agents (oral and parenteral combined) comprised 25.8% of total consumption in 2017.

These relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities. For example, the WHO EML (WHO, 2017) suggests limited indications for use of azithromycin, cefixime, clarithromycin and ceftriaxone.

119 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Clarithromycin is listed on the EML as a first-choice option for severe community-acquired pneumonia and as a second-choice option for pharyngitis.

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with WHO EML recommendations.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 20.8 DID in 2017 using DDD values relevant to year of data to 17.5 DID applying the 2019 DDD values – a reduction of 15.9%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 9.9 DID in 2017 using the DDD values relevant to the year of data to 6.5 DID applying the 2019 DDD values – a reduction of 34.4% in absolute values.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in Kyrgyzstan and can help to identify areas for further investigation, allowing the development of targeted interventions to address potential problems identified in the consumption of antibacterials. Interventions targeting medicines should be supported by evidence-based guidelines and treatment protocols.

Total DID decreased by 15.9% when the new 2019 DDDs were applied, independent of any intervention by government, agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

Reference

120 Montenegro

12. MONTENEGRO

12.1 Data source and years of data collection

Montenegro provided data for each of the seven years of data collection (2011–2017). The main sources were sales records of wholesalers provided by the drug agency. Data can be disaggregated to consumption in the community and hospital sectors.

12.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

The data show some fluctuations in total consumption of J01 antibacterials over time, but on a general trend of decreasing consumption from 38.3 DID in 2011 to 31.4 DID in 2017.

The relative consumption of parenteral antibacterials remained reasonably stable across the years analysed, at around 7% of total J01 consumption.

The highest levels of consumption were in beta-lactams (J01C), at 16.4 DID in 2011 and 13.8 DID in 2017. Different patterns of consumption would be expected in the hospital and community sectors.

45 Other J01 antibacterials 40 (J01G, J01R, J01X) a 35 Quinolone antibacterials (J01M) 30 Macrolides, lincosamides and streptogramins (J01F) 25 Sulfonamides and 20 trimethoprim (J01E)

15 Other beta-lactams (includes cephalosporins) (J01D) 10 Beta-lactams (J01C) DDD/1000 inhabitants per day 5 Amphenicols (J01B) Tetracyclines (J01A) 0 MNE MNE MNE MNE MNE MNE MNE 2011 2012 2013 2014 2015 2016 2017

Fig. 12.1 Consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose.

121 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 12.1 Consumption of J01 antibacterials by route of administration and pharmacological subgroup

a b Route of administration, DDD/1 000 inhabitants per day (% of total ) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 Route of administration 35.8 30.1 32.8 31 30.9 31.1 29 Oral J01 (94) (95) (95) (95) (91) (93) (93) 2.5 1.7 1.7 1.7 3 2.5 2.3 Parenteral J01 (6) (5) (5) (5) (9) (7) (7) Total 38.3 31.8 34.6 32.7 33.9 33.5 31.4 Class of antibacterial agents 1.7 1.2 1 1.1 1.3 1.4 1.4 Tetracyclines (J01A) (4.4) (3.8) (2.9) (3.4) (3.8) (4.2) (4.5) Amphenicols (J01B) – – – – – – – 16.4 14.4 14.7 15.4 15.4 14.8 13.8 Beta-lactams (J01C) (42.8) (45.3) (42.5) (47.1) (45.4) (44.2) 43.9) Other beta-lactams (includes 6.7 5 5.4 4.9 6 5.5 5.3 cephalosporins) (J01D) (17.5) (15.7) (15.6) (15) (17.7) (16.4) (16.9) Sulfonamides and Trimethoprim 1.7 1.1 1.1 1.1 1.1 0.9 0.8 (J01E) (4.4) (3.5) (3.2) (3.4) (3.2) (2.7) (2.5) Macrolides, Lincosamides and 6.2 5.2 7.2 5.3 5.5 5.3 4.8 Streptogramins (J01F) (16.2) (16.4) (20.8) (16.2) (16.2) (15.8) (15.3) 4.5 3.9 3.9 3.7 3.6 3.4 3.2 Quinolone antibacterials (J01M) (11.7) (12.3) (11.3) (11.3) (10.6) (10.1) (10.2) Other J01 antibacterials (J01G, J01R, 1.1 1.2 1.2 1.2 1.2 2.3 2.1 J01X) (2.9) (3.8) (3.5) (3.7) (3.5) (6.9) (6.7) Total 38.3 31.8 34.6 32.7 33.9 33.5 31.4 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

There is some evidence of increasing consumption of beta-lactams, at 42.8% in 2011 and 43.9% in 2017, and small decreases in consumption of cephalosporins (J01D), at 17.5% in 2011 and 16.9% in 2017, macrolides (J01F), at 16.2% in 2011 and 15.3% in 2017, and quinolones (J01M), at 11.7% in 2011 and 10.2% in 2017 (Table 12.1).

The relative consumption of cephalosporins and quinolones combined remained reasonably stable over time (29.2% in 2011, 27.1% in 2017).

12.3 Relative consumption by choice of agent

12.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2011–2017 is shown in Fig. 12.2. and summarized in Table 12.2. Table 12.3 shows the most consumed agents within each of the generations of cephalosporin agents.

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100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 MNE MNE MNE MNE MNE MNE MNE 2011 2012 2013 2014 2015 2016 2017

Fig. 12.2 Relative consumption of cephalosporins by generation

Table 12.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) 3 (45) 2.8 (56) 3 (56) 2.9 (59) 2.6 (45) 2.7 (49) 2.5 (48) Second-generation (J01DC) 0.3 (5) 0.2 (4) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Third-generation (J01DD) 3.3 (50) 1.9 (40) 2.3 (43) 1.9 (39) 3.2 (54) 2.8 (51) 2.7 (51) Fourth-generation (J01DE) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Total 6.6 4.9 5.3 4.9 5.9 5.5 5.2 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Table 12.3 Most consumed agents within generation of cephalosporins

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) Cefalexin 3 (99) 2.8 (99) 2.9 (99) 2.8 (98) 2.6 (98) 2.6 (98) 2.4 (97) Second-generation (J01DC) Cefaclor 0.2 (69) 0.1 (61) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Third-generation (J01DD) Ceftriaxone 1.1 (33) 0.2 (11) 0.3 (13) 0.1 (6) 1.2 (36) 1 (37) 1 (35) Cefixime 2.2 (66) 1.7 (87) 1.9 (85) 1.7 (90) 2 (62) 1.7 (61) 1.7 (63) a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for the nominated generation of cephalosporins.

There were some decreases in relative consumption of first-generation agents, at 56% of total cephalosporin use in 2012 and 48% in 2017, with cefalexin the most consumed agent (2.4 DID in 2017). Consumption of second-generation agents was low. Around half of cephalosporin consumption was Watch group third-generation agents (51% in 2017). Ceftriaxone (1.0 DID) and cefixime (1.7 DID) comprised 35% and 63% respectively of third-generation agent consumption in 2017. Only small volumes of consumption of fourth-generation cephalosporins (Reserve agents) were reported.

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12.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) represented 3.2 DID (10.2%) of total J01 consumption in 2017, with fluoroquinolones comprising 2.0 DID – 62.5% of quinolone consumption. Ciprofloxacin alone represented 1.9 DID (93%) of fluoroquinolone consumption in 2017 (Table 12.4).

The remaining quinolone consumption reflects use of pipemidic acid (1.19 DID in 2017).

Table 12.4 Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 Ofloxacin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Ciprofloxacin 2.8 (95) 2.5 (96) 2.4 (95) 2.2 (95) 2.1 (94) 1.9 (94) 1.9 (93) Norfloxacin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Levofloxacin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 0.1 (6) Moxifloxacin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Total 3.0 2.6 2.5 2.3 2.2 2.0 2.0 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

12.4 The 10 most consumed agents

12.4.1 The 10 most consumed agents – oral formulation

Table 12.5 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

Table 12.5 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Amoxicillin 8.86 8.86 8.86 8.86 8.86 8.86 8.86 8.86 8.86 8.86 Amoxicillin and enzyme 3.82 3.82 3.82 3.82 3.82 3.82 3.82 3.82 3.82 inhibitor Azithromycin 2.49 2.49 2.49 2.49 2.49 2.49 2.49 2.49 Cefalexin 2.44 2.44 2.44 2.44 2.44 2.44 2.44 Ciprofloxacin 1.79 1.79 1.79 1.79 1.79 1.79 Cefixime 1.71 1.71 1.71 1.71 1.71 Doxycycline 1.33 1.33 1.33 1.33 Erythromycin 1.23 1.23 1.23 Pipemidic acid 1.19 1.19 Nitrofurantoin 1.08 Total consumption for 25.93 24.85 23.66 22.44 21.11 19.40 17.61 15.17 12.68 8.86 this group of agents Total consumption for 29.03 29.03 29.03 29.03 29.03 29.03 29.03 29.03 29.03 29.03 all oral J01 agents Proportion (%) of total consumption for oral 89.3% 85.6% 81.5% 77.3% 72.7% 66.8% 60.7% 52.3% 43.7% 30.5% J01 antibacterials a DDD: daily defined dose.

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The 10 listed oral agents represent almost 90% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, five are included in the WHO Watch group of antibacterials – azithromycin, erythromycin (macrolides), ciprofloxacin and pipemidic acid (quinolones), and cefixime (third- generation cephalosporins).

The Watch agents azithromycin (8.6%), ciprofloxacin (6.1%), cefixime (5.9%), erythromycin (3.8%) and pipemidic acid (4.1%) combined constituted 28.5% of total consumption of J01 oral antibacterials in 2017.

12.4.2 The 10 most consumed agents – parenteral formulation

Table 12.6 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

Table 12.6 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Ceftriaxone 0.95 0.95 0.95 0.95 0.95 0.95 0.95 0.95 0.95 0.95 Gentamicin 0.72 0.72 0.72 0.72 0.72 0.72 0.72 0.72 0.72 Combinations 0.12 0.12 0.12 0.12 0.12 0.12 0.12 0.12 Amikacin 0.11 0.11 0.11 0.11 0.11 0.11 0.11 Metronidazole 0.11 0.11 0.11 0.11 0.11 0.11 Cefazolin 0.07 0.07 0.07 0.07 0.07 Ciprofloxacin 0.07 0.07 0.07 0.07 Meropenem 0.06 0.06 0.06 Vancomycin 0.04 0.04 Ampicillin 0.02 Total consumption for this 2.27 2.25 2.21 2.15 2.08 2.01 1.91 1.80 1.67 0.95 group of agents Total consumption for all 2.35 2.35 2.35 2.35 2.35 2.35 2.35 2.35 2.35 2.35 parenteral J01 agents Proportion (%) of total consumption for parenteral 96.7% 95.8% 94.1% 91.4% 88.5% 85.6% 81.1% 76.4% 71.2% 40.5% J01 antibacterials a DDD: daily defined dose.

As shown in Table 12.1, parenteral agents comprised around 7% of total J01 consumption in 2017. Within this, the Watch group agents ceftriaxone (40.5%), ciprofloxacin (2.9%) and meropenem (2.7%) constituted just over 46% of the consumption of J01 injection formulations.

12.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

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The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 12.3 and Fig. 12.4, and is summarized in Table 12.7.

100

60 Other

40 Core Access group 66 Proportion (%) Proportion 62 64 60 62 64 64 20

0 MNE MNE MNE MNE MNE MNE MNE 2011 2012 2013 2014 2015 2016 2017

Fig. 12.3 Relative consumption of Core Access group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

100

60 Other Watch group 40 Proportion (%) Proportion

20 36 34 38 33 35 34 33

0 MNE MNE MNE MNE MNE MNE MNE 2011 2012 2013 2014 2015 2016 2017

Fig. 12.4 Relative consumption of Watch group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 12.7 Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

Percentage of total consumptiona Antibiotic group 2011 2012 2013 2014 2015 2016 2017 Core Access group 61.8 63.7 60.1 66.0 62.4 63.6 64.0 Watch group 36.2 34.2 38.3 32.8 35.4 33.7 33.2 Reserve group 0.00 0.00 0.01 0.02 0.02 0.02 0.02 Ungrouped 2.1 2.1 1.7 1.2 2.1 2.7 2.8 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

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Consumption of Core Access antibiotics dominated, at 61.8% of consumption in 2011 and 64% in 2017. The relative consumption of Watch agents remained reasonably stable at 36.2% of consumption in 2011 and 33.2% in 2017.

12.6 Analyses based on DDDs applied in 2019

12.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 12.5 (DDD values relevant to year) and Fig. 12.6 (2019 DDD values), and is summarized in Table 12.8.

40 40 35 35 30 30 25 25 Parenteral Parenteral 20 20 antibacterials antibacterials 15 Oral 15 Oral antibacterials antibacterials 10 10 5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 MNE MNE MNE MNE MNE MNE 2015 2016 2017 2015 2016 2017

Fig. 12.5 Total consumption of J01 Fig. 12.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values)

Table 12.8 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 30.9 (91) 31.1 (93) 29 (93) 26.1 (90) 26.5 (92) 24.8 (92) Parenteral J01 3 (9) 2.5 (7) 2.3 (7) 2.9 (10) 2.4 (8) 2.3 (8) Total 33.9 33.5 31.4 29.0 28.9 27.1 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

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The relative consumption of oral and parenteral formulations does not change substantially with the application of the 2019 DDDs (oral agents 93% applying older values and 92% with the 2019 DDD values).

12.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 12.7 (DDD values relevant to year) and Fig. 12.8 (2019 DDD values), and is summarized in Table 12.9. As noted in section 12.6.1, total DIDs decreased by 13.7% in 2017.

DDD/1000 inhabitants per day (includes DDD/1000 inhabitants per day (includes 5 cephalosporins) 5 cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols MNE MNE MNE (J01B) MNE MNE MNE (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 12.7 Total consumption of J01 Fig. 12.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 13.8 DID in 2017 using the DDD values relevant to the year of data to 9.6 DID applying the 2019 DDD values – a reduction of 30.4% in absolute values. Relative consumption of beta-lactams falls from 43.9% to 35.4% of total J01 consumption when the 2019 DDD values are applied.

As the total DIDs decrease with the application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta-lactams generally increases: cephalosporins, for example, increased from 16.9% to 19.6%, the macrolides group from 15.3% to 17.7% and quinolones from 10.2% to 11.8% in 2017.

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Table 12.9 Absolute and relative consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 1.3 1.4 1.4 1.3 1.4 1.4 Tetracyclines (J01A) (3.8) (4.2) (4.5) (4.5) (4.8) (5.2) Amphenicols (J01B) – – – – – – 15.4 14.8 13.8 10.5 10.2 9.6 Beta-lactams (J01C) (45.4) (44.2) (43.9) (36.2) (35.3) (35.4) Other beta-lactams (includes 6 5.5 5.3 6 5.5 5.3 cephalosporins) (J01D) (17.7) (16.4) (16.9) (20.7) (19) (19.6) Sulfonamides and trimethoprim 1.1 0.9 0.8 1.1 0.9 0.8 (J01E) (3.2) (2.7) (2.5) (3.8) (3.1) (3) Macrolides, lincosamides and 5.5 5.3 4.8 5.5 5.3 4.8 streptogramins (J01F) (16.2) (15.8) (15.3) (19) (18.3) (17.7) 3.6 3.4 3.2 3.5 3.4 3.2 Quinolone antibacterials (J01M) (10.6) (10.1) (10.2) (12.1) (11.8) (11.8) Other J01 antibacterials (J01G, 1.2 2.3 2.1 1.2 2.3 2.1 J01R, J01X) (3.5) (6.9) (6.7) (4.1) (8) (7.7) Total 33.9 33.5 31.4 29 28.9 27.1 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

12.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 12.9 (DDD values relevant to year) and Fig. 12.10 (2019 DDD values) for Core Access antibiotics, Fig. 12.11 (DDD values relevant to year) and Fig. 12.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 12.10.

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group

Proportion (%) Proportion 64 64 (%) Proportion 62 56 58 59 20 20

0 0 MNE MNE MNE MNE MNE MNE 2015 2016 2017 2015 2016 2017

Fig. 12.9 Relative consumption of Core Fig. 12.10 Relative consumption of Core Access group antibacterials (applying DDD Access group antibacterials (applying 2019 values relevant to year)a DDD values)a

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100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion

41 20 35 34 33 20 39 38

0 0 MNE MNE MNE MNE MNE MNE 2015 2016 2017 2015 2016 2017 Fig. 12.11 Relative consumption of Watch Fig. 12.12 Relative consumption of Watch group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year)a DDD values)a

a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 12.10 Relative consumption of Core Access, Watch and Reserve group antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 21.5 (62) 21.6 (64) 20.4 (64) 16.6 (56) 17.1 (58) 16.2 (59) Watch group 12.2 (35.4) 11.4 (33.7) 10.6 (33.2) 12.1 (41) 11.4 (39) 10.5 (38) Reserve group 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Ungrouped 0.7 (2) 0.9 (3) 0.9 (3) 0.7 (2) 0.9 (3) 0.9 (3) Total 34.4 34.0 31.9 29.5 29.4 27.6 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The effect of applying the 2019 DDD values is to decrease slightly the proportion of total use that is Core Access antibiotics (from 64% to 59% in 2017) and increase slightly the proportion of total use that is Watch group antibiotics (from 33% to 38%).

12.7 Analysis by community and hospital sectors

The analyses presented in sections 12.1–12.6 are based on estimates of total consumption. Different patterns of consumption would be expected in the hospital and community sectors. Analyses by sector can provide more detailed information to support stewardship activities. Disaggregated data for Montenegro for the years 2015–2017 are presented in this report.

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12.7.1 Consumption of antibacterials for systemic use (J01) in community and hospital sectors by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 12.13 (community consumption) and Fig. 12.14 (hospital consumption), and is summarized in Table 12.11.

35 35

30 30

25 25

20 Parenteral 20 Parenteral antibacterials antibacterials 15 15 Oral Oral 10 antibacterials 10 antibacterials

5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 MNE MNE MNE MNE MNE MNE 2015 2016 2017 2015 2016 2017

Fig. 12.13 Community consumption of J01 Fig. 12.14 Hospital consumption of J01 antibacterials by route of administration antibacterials by route of administration

Table 12.11 Community and hospital consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration Community consumption Hospital consumption

2015 2016 2017 2015 2016 2017 Oral J01 30.2 (95) 30.4 (96) 28.5 (96) 0.7 (35) 0.7 (33) 0.6 (30) Parenteral J01 1.6 (5) 1.1 (4) 1.1 (4) 1.3 (65) 1.3 (67) 1.3 (70) Total 31.9 31.5 29.5 2.0 2.0 1.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Community consumption represented 93.9% of total J01 consumption in 2017, at 29.5 DID in the community sector and 1.9 DID in the hospital sector.

Oral consumption dominated in the community sector, at 96% oral and 4% parenteral consumption in 2017. Hospital consumption was predominantly parenteral forms, at 70% of hospital consumption in 2017.

12.7.2 Consumption of antibacterials for systemic use (J01) in community and hospital sectors by pharmacological subgroup

The consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 12.15 (community consumption) and Fig. 12.16 (hospital consumption), and is summarized in Table 12.12.

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35 Other J01 35 Other J01 antibacterials antibacterials 30 (J01G, J01R, 30 (J01G, J01R, J01X) J01X) Quinolone Quinolone 25 antibacterials 25 antibacterials (J01M) (J01M) Macrolides, Macrolides, 20 20 lincosamides and lincosamides and streptogramins streptogramins 15 (J01F) 15 (J01F) Sulfonamides Sulfonamides and trimethoprim and trimethoprim 10 (J01E) 10 (J01E) Other beta-lactams Other beta-lactams DDD/1000 inhabitants per day (includes DDD/1000 inhabitants per day (includes 5 cephalosporins) 5 cephalosporins) (J01D) (J01D) 0 Beta-lactams 0 Beta-lactams (J01C) (J01C) Amphenicols Amphenicols MNE MNE MNE (J01B) MNE MNE MNE (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 12.15 Community consumption of J01 Fig. 12.16 Hospital consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup

Table 12.12 Absolute and relative consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup Community consumption Hospital consumption

2015 2016 2017 2015 2016 2017 1.3 1.3 1.4 Tetracyclines (J01A) – – – (4.1) (4.1) (4.7) Amphenicols (J01B) – – – – – – 15.1 14.6 13.7 0.2 0.2 0.1 Beta-lactams (J01C) (47.3) (46.3) (46.4) (10) (10) (5.3) Other beta-lactams (includes 4.9 4.5 4.4 1.1 1.1 1 cephalosporins) (J01D) (15.4) (14.3) (14.9) (55) (55) (52.6) Sulfonamides and trimethoprim 1 0.8 0.8 – – – (J01E) (3.1) (2.5) (2.7) Macrolides, lincosamides and 5.3 5.1 4.6 0.2 0.2 0.1 streptogramins (J01F) (16.6) (16.2) (15.6) (10) (10) (5.3) 3.4 3.2 3 0.2 0.2 0.2 Quinolone antibacterials (J01M) (10.7) (10.2) (10.2) (10) (10) (10.5) Other J01 antibacterials (J01G, 0.8 1.9 1.7 0.3 0.3 0.4 J01R, J01X) (2.5) (6) (5.8) (15) (15) (21.1) Total 31.9 31.5 29.5 2.0 2.0 1.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Patterns of consumption were completely different in the community and hospital sectors. Beta- lactam (J01C) consumption dominated in the community sector, at 46.4% of community consumption and 5.3% of hospital consumption in 2017. Cephalosporin consumption dominated in the hospital sector, at 52.6% of hospital consumption and 14.9% of community consumption.

There are insufficient data to conclude trends in consumption of different pharmacological subgroups in each of the two sectors.

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12.7.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics in community and hospital sectors

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 12.17 (community) and Fig. 12.18 (hospital) for Core Access antibiotics, Fig. 12.19 (community) and Fig. 12.20 (hospital) for Watch group antibiotics, and is summarized in Table 12.13.

100 100

80 80

60 60 Other Other Core Access Core Access 40 group 40 group 66 Proportion (%) Proportion 64 66 (%) Proportion

20 20 35 34 36

0 0 MNE MNE MNE MNE MNE MNE 2015 2016 2017 2015 2016 2017

Fig. 12.17 Relative consumption of Fig. 12.18 Relative consumption of Core Access group antibacterials – Core Access group antibacterials – community sectora hospital sectora

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion 64 65 63 20 20 34 32 31

0 0 MNE MNE MNE MNE MNE MNE 2015 2016 2017 2015 2016 2017

Fig. 12.19 Relative consumption of Watch Fig. 12.20 Relative consumption of Watch group antibacterials – community sectora group antibacterials – hospital sectora a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07A5A10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Consumption of Core Access antibiotics dominated in the community sector (66% community, 36% hospital in 2017), while consumption of Watch agents dominated in the hospital sector (63%, compared to 31% in the community sector).

The Watch agents azithromycin (2.44 DID, 8.6%), ciprofloxacin (1.68 DID, 6.0%), cefixime (1.63 DID, 5.7%), erythromycin (1.2 DID, 4.2%) and pipemidic acid (1.17 DID, 4.1%) combined constituted 28.6% of community consumption of J01 oral antibacterials in 2017. Levels of consumption of azithromycin

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(0.05 DID), ciprofloxacin (0.11 DID), cefixime (0.08 DID) and erythromycin (0.03 DID) were relatively low in the hospital sector.

Table 12.13 Relative consumption of Core Access, Watch and Reserve group antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category Community sector Hospital sector

2015 2016 2017 2015 2016 2017 Core Access group 20.7 (64) 20.9 (66) 19.8 (66) 0.7 (35) 0.7 (34) 0.7 (36) Watch group 10.9 (34) 10.1 (32) 9.4 (31) 1.3 (64) 1.3 (65) 1.2 (63) Reserve group 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Ungrouped 0.7 (2) 0.9 (3) 0.9 (3) 0 (0) 0 (1) 0 (1) Total 32.3 32.0 30.0 2.1 2.0 1.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculatio‑n includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

As shown in Table 12.1, parenteral agents comprised around 7% of total J01 consumption in 2017, but represented 4% of community consumption and 70% of hospital consumption (Table 12.10). Within this, the Watch group third-generation cephalosporin ceftriaxone represented 0.28 DID (26.2%) of community injection consumption and 0.67 DID (52.2%) of hospital injection consumption in 2017.

12.9 Discussion

The analyses in this report are based on sales records of wholesalers.

Estimates of total consumption fluctuated over the period 2011–2017, with a general trend of decreasing J01 consumption between 2011 and 2017 (38.3 DID in 2011, 31.4 DID in 2017).

Around 7% of consumption in 2017 was parenteral formulations.

Relative consumption of beta-lactams increased slightly over time, offset by small decreases in relative consumption of cephalosporins, macrolides and quinolones.

Of the top 10 oral agents in the J01 class, three are included in the WHO Watch group of antibacterials – azithromycin and erythromycin (macrolides), ciprofloxacin and pipemidic acid (quinolones), and cefixime (third-generation cephalosporins). Azithromycin (8.6%), ciprofloxacin (6.1%), cefixime (5.9%), erythromycin (3.8%) and pipemidic acid (4.1%) combined constituted 28.5% of total consumption of J01 oral antibacterials in 2017.

The Watch group agents ceftriaxone (40.5%), ciprofloxacin (2.9%) and meropenem (2.7%) constituted just over 46% of the consumption of J01 injection formulations.

Watch group agents (oral and parenteral combined) comprised 33.2% of total consumption in 2017.

These relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities. For example, the WHO EML (WHO, 2017) suggests limited indications for use of azithromycin, ciprofloxacin, cefixime and ceftriaxone.

134 Montenegro

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with WHO EML recommendations.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 31.4 DID in 2017 using DDD values relevant to year of data to 27.1 DID applying the 2019 DDD values – a reduction of 13.7%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 13.8 DID in 2017 using the DDD values relevant to the year of data to 9.6 DID applying the 2019 DDD values – a reduction of 30.4% in absolute values.

Disaggregated data for the years 2015-2017 are presented in this report. The data illustrate that most consumption occurred in the community (93.9% of total J01 consumption) and show substantial differences in patterns of consumption of pharmacological subgroups in the two sectors. Beta- lactam (J01C) consumption dominated in the community sector, while cephalosporin consumption dominated in the hospital sector. The consumption of Watch group agents dominated in the hospital sector (63% compared to 31% in the community sector). These analyses by sector can provide more detailed information to support stewardship activities.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in Montenegro and can help to identify areas for further investigation, allowing the development of targeted interventions to address potential problems identified in the consumption of antibacterials. Interventions targeting medicines should be supported by evidence-based guidelines and treatment protocols.

Not all antibiotics have been classified by WHO into the Access, Watch and Reserve groups. The lists of Watch and Reserve medicines will be modified as evidence emerges and more clinical conditions

135 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

are reviewed. The estimates presented here are based on total consumption – the relative use of Watch and Reserve group antibiotics would be substantially higher in a hospital-based analysis.

Total DID decreased by 13.7% when the new 2019 DDDs were applied, independent of any intervention by government, agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

Reference

136 North Macedonia

13. NORTH MACEDONIA

13.1 Data source and years of data collection

North Macedonia provided data for each of six years of data collection (2012–2017). The main sources were reimbursement records provided by the Health Insurance Fund (Table 13.1). Only data for community consumption of antibacterials are presented in this report.

13.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

Community consumption of antibacterials for systemic use (ATC class J01) is examined by pharmacological subgroup (Fig. 13.1 and Table 13.1).

Community consumption of J01 antibacterials was reasonably stable over the period 2014–2017, at around 19–20 DID. Only oral agents were prescribed in the community.

The highest levels of consumption were in beta-lactams (J01C), at 8.8 DID in 2011 and 10.4 DID in 2017 (Table 13.1). Macrolide group (J01F) consumption increased from 1.9 DID in 2011 to 3.2 DID in 2017. There is some evidence of decreasing consumption of cephalosporins (J01D), with 4.6 DID in 2011 and 3.7 DID in 2017, and quinolone antibacterials (J01M), with 2.7 DID in 2011 and 2.3 DID in 2017.

These observations relate to community consumption. Different patterns of consumption would be expected in the hospital and community sectors.

DDD/1000 inhabitants per day 5 Amphenicols (J01B) Tetracyclines (J01A) 0 MKD MKD MKD MKD MKD MKD 2012 2013 2014 2015 2016 2017

Fig. 13.1 Community consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose.

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Table 13.1 Community consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2012 2013 2014 2015 2016 2017 Tetracyclines (J01A) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Amphenicols (J01B) – – – – – – 8.8 8.7 9.8 10.2 10.5 10.4 Beta-lactams (J01C) (47.8) (50) (51.6) (52) (52.2) (52) Other beta-lactams (includes cephalosporins) 4.6 3.7 4 3.8 3.7 3.7 (J01D) (25) (21.3) (21.1) (19.4) (18.4) (18.5) 0.3 0.4 0.4 0.4 0.5 0.4 Sulfonamides and trimethoprim (J01E) (1.6) (2.3) (2.1) (2) (2.5) (2) Macrolides, lincosamides and streptogramins 1.9 1.8 2.1 2.7 3 3.2 (J01F) (10.3) (10.3) (11.1) (13.8) (14.9) (16) 2.7 2.7 2.7 2.5 2.3 2.3 Quinolone antibacterials (J01M) (14.7) (15.5) (14.2) (12.8) (11.4) (11.5) Other J01 antibacterials (J01G, J01R, J01X) – – – – – – Total 18.4 17.4 19.0 19.6 20.1 20.0 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

There is some evidence of decreasing relative consumption of cephalosporins (J01D), at 25% in 2011 and 18.5% in 2017, and quinolones (J01M), at 14.7% in 2011 and 11.5% in 2017 (Table 13.1). In contrast, increases were seen in relative consumption of beta-lactams (J01C), at 47.8% in 2011 and 52% in 2017, and macrolides (J01F), at 10.3% in 2011 and 16% in 2017.

The relative consumption of cephalosporins and quinolones combined decreased over time (40% in 2011, 30% in 2017), with decreases in both quinolone and cephalosporin consumption.

13.3 Relative consumption by choice of agent

13.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2011–2017 is shown in Fig. 13.2 and summarized in Table 13.2. Table 13.3 shows the most consumed agents within each of the generations of cephalosporin agents.

Decreases in consumption of first-generation agents were seen (36% of total cephalosporin use in 2011 and 23% in 2017). Most first-generation consumption was cefalexin. Second-generation agents, mostly cefuroxime, represented 43% of cephalosporin consumption in 2017. Consumption of Watch group third-generation agents, almost all cefixime, increased over time (18% of total cephalosporin use in 2011 and 34% in 2017). There was no reported consumption of fourth-generation cephalosporins (Reserve agents).

138 North Macedonia

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 MKD MKD MKD MKD MKD MKD 2012 2013 2014 2015 2016 2017

Fig. 13.2 Relative consumption of cephalosporins by generation

Table 13.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2012 2013 2014 2015 2016 2017 First-generation (J01DB) 1.6 (36) 1.3 (34) 1.2 (29) 1.1 (29) 1 (27) 0.9 (23) Second-generation (J01DC) 2.1 (46) 1.8 (47) 1.9 (47) 1.7 (44) 1.6 (43) 1.6 (43) Third-generation (J01DD) 0.8 (18) 0.7 (19) 0.9 (23) 1 (27) 1.1 (30) 1.3 (34) Fourth-generation (J01DE) – – – – – – Total 4.6 3.7 4.0 3.8 3.7 3.7 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Table 13.3 Most consumed agents within each generation of cephalosporins

DDD/1 000 inhabitants per daya (% of totalb) Agents 2012 2013 2014 2015 2016 2017 First-generation (J01DB) Cefalexin 1.2 (76) 1 (82) 1 (85) 1 (89) 0.9 (88) 0.8 (89) Cefadroxil 0.4 (24) 0.2 (18) 0.2 (15) 0.1 (11) 0.1 (12) < 0.1 Second-generation (J01DC) Cefuroxime 1.7 (81) 1.5 (83) 1.6 (86) 1.5 (88) 1.4 (88) 1.4 (89) Cefaclor 0.4 (19) 0.3 (17) 0.3 (14) 0.2 (12) 0.2 (12) 0.2 (11) Third-generation (J01DD) Cefixime 0.8 (100) 0.7 (100) 0.9 (100) 1 (100) 1.1 (100) 1.3 (100) a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for the nominated generation of cephalosporins.

13.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) represented 2.3 DID (11%) of total J01 consumption in 2017, with fluoroquinolones comprising 1.9 DID – 82.3% of quinolone consumption. Two fluoroquinolones – ciprofloxacin and norfloxacin – dominated, representing 83% and 16% of fluoroquinolone consumption respectively in 2017 (Table 13.4). The overall pattern, however, was of some reductions in levels of fluoroquinolone consumption.

139 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

A pyridopyrimidine antibiotic, pipemidic acid, constituted much of the remaining quinolone consumption (0.38 DID in 2017).

Table 13.4 Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2012 2013 2014 2015 2016 2017 Ciprofloxacin 1.8 (82) 1.9 (83) 1.9 (83) 1.7 (83) 1.6 (84) 1.6 (83) Pefloxacin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Norfloxacin 0.3 (15) 0.3 (15) 0.4 (16) 0.3 (15) 0.3 (15) 0.3 (16) Total 2.2 2.3 2.3 2.1 2.0 1.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

13.4 The 10 most consumed agents – oral formulations

Table 13.5 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

Table 13.5 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Amoxicillin and enzyme 7.36 7.36 7.36 7.36 7.36 7.36 7.36 7.36 7.36 7.36 inhibitor Amoxicillin 2.43 2.43 2.43 2.43 2.43 2.43 2.43 2.43 2.43 Clarithromycin 1.84 1.84 1.84 1.84 1.84 1.84 1.84 1.84 Ciprofloxacin 1.59 1.59 1.59 1.59 1.59 1.59 1.59 Cefuroxime 1.40 1.40 1.40 1.40 1.40 1.40 Cefixime 1.27 1.27 1.27 1.27 1.27 Azithromycin 1.12 1.12 1.12 1.12 Cefalexin 0.76 0.76 0.76 Benzathine 0.66 0.66 phenoxymethylpenicillin Pipemidic acid 0.38 Community consumption 18.80 18.42 17.76 17.00 15.88 14.61 13.22 11.63 9.79 7.36 for this group of agents Community consumption 20.03 20.03 20.03 20.03 20.03 20.03 20.03 20.03 20.03 20.03 for all oral J01 agents Proportion (%) of Community consumption 93.8% 92.0% 88.7% 84.9% 79.3% 72.9% 66.0% 58.0% 48.9% 36.7% for oral J01 antibacterials a DDD: daily defined dose.

The 10 listed oral agents represent almost 94% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, four are included in the WHO Watch group of antibacterials – clarithromycin

140 North Macedonia

and azithromycin (macrolides), ciprofloxacin and pipemidic acid (quinolones), and cefixime (third- generation cephalosporins).

Together, the four Watch agents clarithromycin (9.1%), ciprofloxacin (8%), pipemidic acid (1.8%), cefixime (6.4%) and azithromycin (5.6%) comprised 30.9% of J01 oral agent consumption.

13.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 13.3 and Fig. 13.4, and is summarized in Table 13.6.

100

60 Other

40 Core Access group

Proportion (%) Proportion 53 54 59 56 56 55 20

0 MKD MKD MKD MKD MKD MKD 2012 2013 2014 2015 2016 2017

Fig. 13.3 Relative consumption of Core Access group of antibiotics classes as a proportion of total consumptiona a Community consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

100

60 Other Watch group 40 Proportion (%) Proportion

20 28 29 29 31 31 33

0 MKD MKD MKD MKD MKD MKD 2012 2013 2014 2015 2016 2017 Fig. 13.4 Relative consumption of Watch group of antibiotics classes as a proportion of Community consumptiona a Community consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

141 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 13.6 Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

Percentage of community consumptiona Category 2012 2013 2014 2015 2016 2017 Core Access group 52.7 53.9 59.5 55.6 56.4 55.1 Watch group 28.4 28.9 28.7 30.5 31.0 32.5 Reserve group 0.00 0.00 0.00 0.00 0.00 0.00 Ungrouped 18.9 17.3 11.8 13.8 12.6 12.4 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The relative consumption of Watch agents remained reasonably consistent, at 28–32% of total antibiotic consumption across the years analysed. No community consumption of Reserve group agents was reported.

The 2017 Watch group estimate differs slightly from that shown in the top 10 oral agent analysis in section 13.4 (30.9% versus 32.5%). This occurs because section 13.4 refers only to the top 10 most consumed agents of J01 class antibacterials, not all consumption. The all-agents consumption estimate will also include oral metronidazole (P01AB01), which is not included in analyses of J01 agents.

13.6 Analyses based on DDDs applied in 2019

13.6.1 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The community consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 13.5 (DDD values relevant to year) and Fig. 13.6 (2019 DDD values), and is summarized in Table 13.7.

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 10.4 DID in 2017 using the DDD values relevant to the year of data to 7.2 DID applying the 2019 DDD values – a reduction of 30.8% in absolute values. Relative consumption of beta-lactams falls from 52% to 42.6% of total J01 consumption when the 2019 DDD values are applied.

As the total DIDs decrease with the application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta-lactams generally increases: cephalosporins, for example, increased from 18.5% to 21.9%, the macrolides group from 16% to 20.1% and quinolones from 11.5% to 13.6% in 2017.

142 North Macedonia

DDD/1000 inhabitants per day 5 (includes DDD/1000 inhabitants per day 5 (includes cephalosporins) cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols MKD MKD MKD (J01B) MKD MKD MKD (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 13.5 Total consumption of J01 Fig. 13.6 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

Table 13.7 Relative consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Tetracyclines (J01A) – – – – – – Amphenicols (J01B) – – – – – – 10.2 10.5 10.4 7 7.2 7.2 Beta-lactams (J01C) (52) (52.2) (52) (41.9) (42.4) (42.6) Other beta-lactams (includes 3.8 3.7 3.7 3.8 3.7 3.7 cephalosporins) (J01D) (19.4) (18.4) (18.5) (22.8) (21.8) (21.9) Sulfonamides and trimethoprim 0.4 0.5 0.4 0.4 0.5 0.4 (J01E) (2) (2.5) (2) (2.4) (2.9) (2.4) Macrolides, lincosamides and 2.7 3 3.2 3 3.2 3.4 streptogramins (J01F) (13.8) (14.9) (16) (18) (18.8) (20.1) 2.5 2.3 2.3 2.5 2.3 2.3 Quinolone antibacterials (J01M) (12.8) (11.4) (11.5) (15) (13.5) (13.6) Other J01 antibacterials (J01G, – – – – – – J01R, J01X) Total 19.6 20.1 20 16.7 17 16.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

13.6.2 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 13.7 (DDD values relevant to year) and Fig. 13.8 (2019 DDD values) for Core Access antibiotics, Fig. 13.9 (DDD values relevant to year) and Fig. 13.10 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 13.8.

143 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group

Proportion (%) Proportion 56 56 55 (%) Proportion 47 47 46 20 20

0 0 MKD MKD MKD MKD MKD MKD 2015 2016 2017 2015 2016 2017 Fig. 13.7 Relative consumption of Core Fig. 13.8 Relative consumption of Core Access group antibacterials (applying DDD Access group antibacterials (applying 2019 values relevant to year)a DDD values)a

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion

20 20 37 38 39 31 31 33

0 0 MKD MKD MKD MKD MKD MKD 2015 2016 2017 2015 2016 2017

Fig. 13.9 Relative consumption of Watch Fig. 13.10 Relative consumption of Watch group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year)a DDD values)a

a Community consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 13.8 Relative consumption of Core Access and Watch group antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 11 (56) 11.4 (56) 11.1 (55) 7.8 (47) 8.1 (47) 7.9 (46) Watch group 6 (30.5) 6.3 (31) 6.6 (32.5) 6.3 (37) 6.5 (38) 6.7 (39) Reserve group 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Ungrouped 2.7 (14) 2.5 (13) 2.5 (12) 2.7 (16) 2.6 (15) 2.5 (15) Total 19.77 20.26 20.16 16.84 17.15 17.07 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Community consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

144 North Macedonia

The effect of applying the 2019 DDD values is to decrease slightly the proportion of total use that is Core Access group antibiotics (from 55% to 46% in 2017) and increase slightly the proportion of total use that is Watch group antibiotics (from 32.5% to 39% in 2017).

13.7 Discussion

The analyses in this report are based on reimbursement records provided by the Health Insurance Fund.

Community consumption of J01 antibacterials was reasonably stable over the period 2014–2017, at around 19–20 DID. Only oral agents were prescribed in the community.

Relative consumption of beta-lactams increased over time, offset by decreases in relative consumption of cephalosporin and quinolone antibacterials.

Of the top 10 oral agents, four are included in the WHO Watch group of antibacterials – clarithromycin and azithromycin (macrolides), ciprofloxacin (quinolones) and cefixime (third-generation cephalosporins). Clarithromycin (9.1%), ciprofloxacin (8%), pipemidic acid (1.8%), cefixime (6.4%) and azithromycin (5.6%) together comprised 30.9% of J01 oral agent consumption.

Watch group agents comprised almost one third (32.5%) of total consumption in 2017.

These relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities. For example, the WHO EML (WHO, 2017) suggests limited indications for use of azithromycin, clarithromycin, cefixime and ciprofloxacin.

Clarithromycin is listed on the EML as a first-choice option for severe community-acquired pneumonia and as a second-choice option for pharyngitis.

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with WHO EML recommendations.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 20.0 DID in 2017 using DDD values relevant to year of data to 16.9 DID applying the 2019 DDD values – a reduction of 15.5%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 10.4 DID

145 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

in 2017 using the DDD values relevant to the year of data to 7.2 DID applying the 2019 DDD values – a reduction of 30.8% in absolute values.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in North Macedonia and can help to identify areas for further investigation, allowing the development of targeted interventions to address potential problems identified in the consumption of antibacterials.

The WHO Watch and Reserve group classifications offer promise as metrics that indicate actions required and lend themselves to prescribing targets, with lower absolute and relative levels of consumption of these groups of antibiotics desirable. Interventions targeting medicines should be supported by evidence-based guidelines and treatment protocols.

Total DID decreased by 15.5% when the new 2019 DDDs were applied, independent of any intervention by government, agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

Reference

146 Republic of Moldova

14. REPUBLIC OF MOLDOVA

14.1 Data source and years of data collection

The Republic of Moldova provided data for each of the seven years of data collection (2011–2017). The main sources were import records from the drug agency and information provided by local pharmaceutical manufacturers. Data derived from importation records will be affected by the cycles of procurement and delivery, potentially giving rise to fluctuations in estimates of consumption that do not relate to actual use of antibacterials by patients and health-care facilities. Local manufacturer records need to be disaggregated to products for local consumption and products exported to other countries.

14.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

The data show fluctuations in total consumption of J01 antibacterials over time. While the data suggest a trend to reductions in total consumption between 2013 and 2015, the 2016–2017 estimates are higher. The reasons for this fluctuating pattern are unclear and require further investigation.

DDD/1000 inhabitants per day 5 Amphenicols (J01B) Tetracyclines (J01A) 0 MDA MDA MDA MDA MDA MDA MDA 2011 2012 2013 2014 2015 2016 2017

Fig. 14.1 Total consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose.

147 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Except for 2015 estimates, the relative consumption of parenteral antibacterials remained reasonably stable, at around 18–21% of total J01 consumption (Table 14.1).

The highest levels of consumption were in beta-lactams (J01C), at 7.5 DID in 2011 and 6.9 DID in 2017 (Table 14.1). There is some evidence of increasing consumption of cephalosporin antibacterials (J01D), with 3.2 DID in 2011 and 4.3 DID in 2017.

These observations relate to total consumption. Different patterns of consumption would be expected in the hospital and community sectors.

Table 14.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 Route of administration 17.2 11 18.6 14 12.1 14.8 15.5 Oral J01 (81) (81) (82) (79) (88) (79) (79) 4.1 2.6 4.1 3.7 1.7 3.9 4 Parenteral J01 (19) (19) (18) (21) (12) (21) (21) Total 21.3 13.6 22.8 17.7 13.8 18.7 19.5 Class of antibacterial agents 1.2 0.7 1.9 0.6 1.1 0.8 1 Tetracyclines (J01A) (5.6) (5.1) (8.3) (3.4) (8) (4.3) (5.1) 0.2 0.2 0.2 0.1 Amphenicols (J01B) – – – (0.9) (0.9) (1.1) (0.7) 7.5 4 9.5 6.6 5.4 6.6 6.9 Beta-lactams (J01C) (35.2) (29.4) (41.7) (37.3) (39.1) (35.3) (35.4) Other beta-lactams (includes cephalosporins) 3.2 2.1 3.1 3.7 2.2 4.1 4.3 (J01D) (15) (15.4) (13.6) (20.9) (15.9) (21.9) (22.1) 1.7 0.9 1.1 1 0.9 0.9 0.9 Sulfonamides and Trimethoprim (J01E) (8) (6.6) (4.8) (5.6) (6.5) (4.8) (4.6) Macrolides, Lincosamides and Streptogramins 2.2 1.6 2.1 1.9 1.7 2.1 2.2 (J01F) (10.3) (11.8) (9.2) (10.7) (12.3) (11.2) (11.3) 2.7 1.9 2.7 3 1.7 2.7 2.4 Quinolone antibacterials (J01M) (12.7) (14) (11.8) (16.9) (12.3) (14.4) (12.3) 2.5 2.4 2.2 0.7 0.7 1.4 1.8 Other J01 antibacterials (J01G, J01R, J01X) (11.7) (17.6) (9.6) (4) (5.1) (7.5) (9.2) Total 21.3 13.6 22.8 17.7 13.8 18.7 19.5 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

There is evidence of increasing relative consumption of cephalosporins (J01D), at 15% in 2011 and 22.1% in 2017, and decreasing consumption of sulphonamide group antibacterials (J01E), at 8% in 2011 and 4.6% in 2017.

The relative consumption of cephalosporins and quinolones combined increased slightly over time (28% in 2011, 34% in 2017), mostly due to increases in consumption of cephalosporins.

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14.3 Relative consumption by choice of agent

14.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2011–2017 is shown in Fig. 14.2 and summarized in Table 14.2. Table 14.3 summarizes the most consumed cephalosporins within each generation of agent.

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 MDA MDA MDA MDA MDA MDA MDA 2011 2012 2013 2014 2015 2016 2017

Fig. 14.2 Relative consumption of cephalosporins by generation

Table 14.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) 1.3 (41) 0.6 (27) 0.5 (16) 1 (28) 0.3 (16) 0.6 (14) 0.4 (9) Second-generation (J01DC) 0.5 (15) 0.6 (26) 0.7 (24) 1 (26) 1 (45) 1.3 (31) 1.9 (44) Third-generation (J01DD) 1.4 (43) 1 (47) 1.9 (61) 1.7 (45) 0.9 (39) 2.3 (55) 2 (47) Fourth-generation (J01DE) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Total 3.2 2.1 3.1 3.7 2.2 4.1 4.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Substantial decreases in consumption of first-generation agents were seen (41% of total cephalosporin consumption in 2011 and 9% in 2017). Consumption of second-generation agents, mostly cefuroxime, increased over time, representing 44% of cephalosporin consumption in 2017. Ceftriaxone comprised 78% of third-generation agent consumption in 2017. Only small volumes of consumption of fourth- generation cephalosporins (Reserve agents) were reported.

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Table 14.3 Most consumed agents within each generation of cephalosporins

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) Cefalexin 0.5 (36) 0.2 (28) 0.2 (38) 0.3 (34) 0.2 (72) 0.1 (21) 0.2 (54) Cefazolin 0.8 (64) 0.4 (72) 0.3 (62) 0.7 (66) < 0.1 0.4 (79) 0.2 (46) Second-generation (J01DC) Cefuroxime 0.5 (96) 0.5 (86) 0.7 (99) 0.9 (90) 0.9 (92) 1.2 (95) 1.8 (96) Third-generation (J01DD) Cefotaxime 0.2 (12) < 0.1 0.2 (13) 0.2 (11) < 0.1 0.2 (8) < 0.1 Ceftazidime 0.1 (8) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Ceftriaxone 0.9 (66) 0.7 (69) 1.3 (75) 1.1 (66) 0.5 (56) 1.7 (77) 1.5 (78) Cefixime 0.2 (12) 0.2 (19) 0.1 (6) 0.2 (10) 0.1 (15) 0.1 (6) < 0.1 Cefoperazone < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 0.1 (5) a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for the nominated generation of cephalosporins.

14.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) represented 2.4 DID (12%) of total J01 consumption in 2017, with fluoroquinolones comprising 2.2 DID – 92% of quinolone consumption. Two fluoroquinolones – ciprofloxacin and levofloxacin – dominated, representing 40% and 41% of fluoroquinolone consumption in 2017 (Table 14.4).

Table 14.4 Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 Ofloxacin 0.1 (5) 0.2 (14) 0.3 (12) 0.3 (10) 0.2 (11) 0.2 (7) 0.1 (6) Ciprofloxacin 1.3 (50) 0.7 (42) 1 (39) 1.1 (39) 0.7 (42) 0.8 (33) 0.9 (40) Pefloxacin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Norfloxacin 0.4 (15) < 0.1 0.3 (13) 0.3 (9) 0.3 (18) 0.3 (14) 0.2 (8) Levofloxacin 0.7 (27) 0.6 (37) 0.8 (32) 1 (38) 0.4 (25) 1 (43) 0.9 (41) Moxifloxacin < 0.1 < 0.1 < 0.1 0.1 (5) < 0.1 < 0.1 0.1 (5) Gemifloxacin – – – < 0.1 < 0.1 < 0.1 < 0.1 Gatifloxacin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Total 2.5 1.7 2.5 2.8 1.5 2.4 2.2 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

14.4 The 10 most consumed agents

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14.4.1 The 10 most consumed agents – oral formulation

Table 14.5 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

Table 14.5 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Amoxicillin and enzyme 2.99 2.99 2.99 2.99 2.99 2.99 2.99 2.99 2.99 2.99 inhibitor Amoxicillin 2.41 2.41 2.41 2.41 2.41 2.41 2.41 2.41 2.41 Cefuroxime 1.36 1.36 1.36 1.36 1.36 1.36 1.36 1.36 Azithromycin 1.10 1.10 1.10 1.10 1.10 1.10 1.10 Doxycycline 0.91 0.91 0.91 0.91 0.91 0.91 Sulfamethoxazole and 0.87 0.87 0.87 0.87 0.87 trimethoprim Levofloxacin 0.85 0.85 0.85 0.85 Ciprofloxacin 0.84 0.84 0.84 Clarithromycin 0.75 0.75 Furazidin 0.59 Total consumption for this 12.67 12.08 11.33 10.48 9.63 8.76 7.85 6.76 5.39 2.99 group of agents Total consumption for all 15.50 15.50 15.50 15.50 15.50 15.50 15.50 15.50 15.50 15.50 oral J01 agents Proportion (%) of total consumption for oral J01 81.7% 77.9% 73.1% 67.6% 62.1% 56.5% 50.7% 43.6% 34.8% 19.3% antibacterials a DDD: daily defined dose.

The 10 listed oral agents represent just under 82% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, four are included in the WHO Watch group of antibacterials – azithromycin and clarithromycin (macrolides), and levofloxacin and ciprofloxacin (quinolones).

Azithromycin (7.1%), levofloxacin (5.5%), ciprofloxacin (5.5%) and clarithromycin (4.8%) combined constituted around 23% of total consumption of J01 oral antibacterials in 2017.

14.4.2 The 10 most consumed agents – parenteral formulation

Table 14.6 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

As shown in Table 14.1, parenteral agents comprised around 21% of total J01 consumption in 2017. Within this, the Watch group third-generation cephalosporins ceftriaxone (38.6%) and cefotaxime (2.4%) constituted 41% of the consumption of J01 injection formulations.

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Table 14.6 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Ceftriaxone 1.54 1.54 1.54 1.54 1.54 1.54 1.54 1.54 1.54 1.54 Amoxicillin 0.68 0.68 0.68 0.68 0.68 0.68 0.68 0.68 0.68 Cefuroxime 0.47 0.47 0.47 0.47 0.47 0.47 0.47 0.47 Ampicillin 0.22 0.22 0.22 0.22 0.22 0.22 0.22 Cefazolin 0.18 0.18 0.18 0.18 0.18 0.18 Amoxicillin and enzyme 0.12 0.12 0.12 0.12 0.12 inhibitor Metronidazole 0.11 0.11 0.11 0.11 Cefoperazone 0.11 0.11 0.11 Cefotaxime 0.10 0.10 Gentamicin 0.09 Total consumption for this 3.62 3.53 3.43 3.33 3.22 3.09 2.91 2.70 2.23 1.54 group of agents Total consumption for all 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 parenteral J01 agents Proportion (%) of total consumption for parenteral 90.6% 88.3% 85.9% 83.2% 80.5% 77.4% 72.9% 67.5% 55.7% 38.6% J01 antibacterials a DDD: daily defined dose.

14.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 14.3 and Fig. 14.4, and is summarized in Table 14.7.

100

60 Other

40 Core Access group

Proportion (%) Proportion 64 58 63 59 56 51 52 20

0 MDA MDA MDA MDA MDA MDA MDA 2011 2012 2013 2014 2015 2016 2017

Fig. 14.3 Relative consumption of Core Access group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

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100

60 Other Watch group 40 Proportion (%) Proportion

20 36 28 31 28 30 34 33

0 MDA MDA MDA MDA MDA MDA MDA 2011 2012 2013 2014 2015 2016 2017

Fig. 14.4 Relative consumption of Watch group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 14.7 Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

Percentage of total consumptiona Category 2011 2012 2013 2014 2015 2016 2017 Core Access group 63.8 57.9 63.0 55.8 58.7 50.7 51.7 Watch group 27.7 31.3 28.4 36.3 30.0 34.3 32.6 Reserve group 0.08 0.06 0.00 0.02 0.01 0.01 0.09 Ungrouped 8.4 10.8 8.6 7.9 11.3 15.0 15.6 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The relative consumption of Watch agents was 33–34% of total antibiotic consumption in 2016 and 2017. Consumption of Reserve group agents was low.

14.6 Analyses based on DDDs applied in 2019

14.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 14.5 (DDD values relevant to year) and Fig. 14.6 (2019 DDD values), and is summarized in Table 14.8.

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25 25

20 20

15 15 Parenteral Parenteral antibacterials antibacterials 10 Oral 10 Oral antibacterials antibacterials 5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 MDA MDA MDA MDA MDA MDA 2015 2016 2017 2015 2016 2017

Fig. 14.5 Total consumption of J01 Fig. 14.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values)

Table 14.8 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 12.1 (88) 14.8 (79) 15.5 (79) 11.4 (88) 13.5 (81) 13.7 (80) Parenteral J01 1.7 (12) 3.9 (21) 4 (21) 1.5 (12) 3.2 (19) 3.4 (20) Total 13.8 18.7 19.5 12.9 16.7 17.1 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The relative consumption of oral and parenteral formulations does not change substantially with the application of the 2019 DDDs (oral 79% applying older values and 80% with the 2019 DDD values).

14.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 14.7 (DDD values relevant to year) and Fig. 14.8 (2019 DDD values), and is summarized in Table 14.9. As noted in section 14.6.1, total DID decreased by 12.3% in 2017.

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DDD/1000 inhabitants per day 5 (includes DDD/1000 inhabitants per day 5 (includes cephalosporins) cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols MDA MDA MDA (J01B) MDA MDA MDA (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 14.7 Total consumption of J01 Fig. 14.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

Table 14.9 Relative consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 1.1 0.8 1 1.1 0.8 1 Tetracyclines (J01A) (8) (4.3) (5.1) (8.5) (4.8) (5.8) 0.1 0 0 0.1 0 0 Amphenicols (J01B) (0.7) (0) (0) (0.8) (0) (0) 5.4 6.6 6.9 3.8 4.3 4.6 Beta-lactams (J01C) (39.1) (35.3) (35.4) (29.5) (25.7) (26.9) Other beta-lactams (includes 2.2 4.1 4.3 2.2 4.1 4.3 cephalosporins) (J01D) (15.9) (21.9) (22.1) (17.1) (24.6) (25.1) Sulfonamides and trimethoprim 0.9 0.9 0.9 0.9 0.9 0.9 (J01E) (6.5) (4.8) (4.6) (7) (5.4) (5.3) Macrolides, lincosamides and 1.7 2.1 2.2 1.8 2.2 2.2 streptogramins (J01F) (12.3) (11.2) (11.3) (14) (13.2) (12.9) 1.7 2.7 2.4 1.7 2.6 2.4 Quinolone antibacterials (J01M) (12.3) (14.4) (12.3) (13.2) (15.6) (14) Other J01 antibacterials (J01G, 0.7 1.4 1.8 1.3 1.9 1.8 J01R, J01X) (5.1) (7.5) (9.2) (10.1) (11.4) (10.5) Total 13.8 18.7 19.5 12.9 16.7 17.1 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 6.9 DID in 2017 using the DDD values relevant to the year of data to 4.6 DID applying the 2019 DDD values – a reduction of 33.3% in absolute values. Relative consumption of beta-lactams falls from 35.4% to 26.9% of total J01 consumption when the 2019 DDD values are applied.

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As the total DID decrease with the application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta-lactams generally increases: tetracyclines, for example, increased from 5.1% to 5.8%, cephalosporins from 22.1% to 25.1%, the macrolides group from 11.3% to 12.9% and quinolones from 12.3% to 14% in 2017.

14.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 14.9 (DDD values relevant to year) and Fig. 14.10 (2019 DDD values) for Core Access antibiotics, Fig. 14.11 (DDD values relevant to year) and Fig. 14.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 14.10.

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group

Proportion (%) Proportion 59 (%) Proportion 51 52 51 20 20 42 45

0 0 MDA MDA MDA MDA MDA MDA 2015 2016 2017 2015 2016 2017

Fig. 14.9 Relative consumption of Core Fig. 14.10 Relative consumption of Core Access group antibacterials (applying DDD Access group antibacterials (applying 2019 values relevant to year)a DDD values)a

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion

20 20 38 37 30 34 33 33

0 0 MDA MDA MDA MDA MDA MDA 2015 2016 2017 2015 2016 2017

Fig. 14.11 Relative consumption of Watch Fig. 14.12 Relative consumption of Watch group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year)a DDD values)a a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

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Table 14.10 Relative consumption of Core Access and Watch group antibacterials

DDD/1 000 inhabitants per daya (% of totalb)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 8.4 (59) 9.7 (51) 10.3 (52) 6.8 (51) 7.3 (42) 7.9 (45) Watch group 4.3 (30) 6.5 (34.3) 6.5 (32.6) 4.3 (33) 6.6 (38) 6.5 (37) Reserve group 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Ungrouped 1.6 (11) 2.9 (15) 3.1 (16) 2.2 (16) 3.3 (19) 3.1 (18) Total 14.2 19.0 19.9 13.3 17.2 17.5 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The effect of applying the 2019 DDD values is to decrease slightly the proportion of total use that is Core Access group antibiotics (from 52% to 45% in 2017) and increase slightly the proportion of total consumption that is Watch group antibiotics (from 32.6% to 37% in 2017).

14.7 Discussion

The analyses in this report are based on import records and information provided by local pharmaceutical manufacturers.

Estimates of total consumption show fluctuations over time, with a trend towards decreasing consumption between 2013 and 2015 and higher consumption estimates in 2016 and 2017.

Except for 2015 estimates, the relative consumption of parenteral antibacterials remained reasonably stable, at around 18–21% of total J01 consumption.

Relative consumption of cephalosporins increased over time, offset by decreases in relative consumption of sulphonamide group antibacterials.

Of the top 10 oral agents, four are included in the WHO Watch group of antibacterials – azithromycin and clarithromycin (macrolides), and levofloxacin and ciprofloxacin (quinolones). Azithromycin (7.1%), levofloxacin (5.5%), ciprofloxacin (5.5%) and clarithromycin (4.8%) combined constituted around 23% of total consumption of J01 oral antibacterials in 2017.

The Watch group agent ceftriaxone (third-generation cephalosporin) constituted 38.6% of the total consumption of J01 parenteral formulations in 2017.

Watch group agents (oral and parenteral combined) comprised almost one third (32.6%) of total consumption in 2017.

These relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities. For example, the WHO EML (WHO, 2017) suggests limited indications for use of azithromycin, clarithromycin, ciprofloxacin, levofloxacin and ceftriaxone.

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Clarithromycin is listed on the EML as a first-choice option for severe community-acquired pneumonia and as a second-choice option for pharyngitis.

Levofloxacin is listed on the WHO EML as a reserve second-line drug for the treatment of MDR-TB that should be used in specialized centres adhering to WHO standards for TB control.

Ceftriaxone is listed on the EML/EMLc as a first-choice option for acute bacterial meningitis, severe community-acquired pneumonia, complicated intra-abdominal infections (mild to moderate), hospital-acquired pneumonia, Neisseria gonorrhoeae, and severe pyelonephritis or prostatitis. Ceftriaxone is listed as a second-choice agent for acute invasive bacterial diarrhoea/dysentery, bone and joint infections, mild-to-moderate pyelonephritis or prostatitis, and sepsis in neonates and children.

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with WHO EML recommendations.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 19.5 DID in 2017 using DDD values relevant to year of data to 17.1 DID applying the 2019 DDD values – a reduction of 12.3%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 6.9 DID in 2017 using the DDD values relevant to the year of data to 4.6 DID applying the 2019 DDD values – a reduction of 33.3% in absolute values.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in the Republic of Moldova and can help to identify areas for further investigation, allowing the development of targeted interventions to address potential problems identified in the consumption of antibacterials.

Total DID decreased by 12.3% when the new 2019 DDDs were applied, independent of any intervention by government, agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

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Reference

159 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

15. RUSSIAN FEDERATION

15.1 Data source and years of data collection

The Russian Federation provided data for each of the seven years of data collection (2011–2017). The report is based on IQVIA data and include government tenders for the hospital sector, hospital purchases from wholesalers (tenders and self-procurement) and pharmacy purchases from wholesalers. Estimates are available for total care as well as disaggregated estimates for community and hospital sectors separately.

15.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

The data show reasonably stable consumption of J01 antibacterials over time, although with the suggestion of small increases in consumption in 2016 and 2017.

The relative consumption of parenteral antibacterials represented 12–14% of total J01 consumption across the years analysed.

The highest levels of consumption were in beta-lactams (J01C), at 5 DID in 2011 and 6.1 DID in 2017. There have been some small increases in consumption of cephalosporins (J01D), at 1.4 DID in 2011 and 1.9 DID in 2017, and the macrolides group, at 2.1 DID in 2011 and 2.7 DID in 2017.

These observations relate to total consumption. Different patterns of consumption would be expected in the hospital and community sectors (see section 15.7).

There is some evidence of increasing relative consumption of beta-lactams (J01C), at 32.7% in 2011 and 35.9% in 2017, cephalosporins (J01D), at 9.2% in 2011 and 11.2% in 2017, and macrolides (J01F), at 13.7% in 2011 and 15.9% in 2017 (Table 15.1).

Overall consumption of cephalosporins and quinolones combined remained reasonably stable over time, at 26% in 2011 and 28% in 2017.

160 Russian Federation

20 Other J01 antibacterials (J01G, J01R, J01X) a Quinolone antibacterials 15 (J01M) Macrolides, lincosamides and streptogramins (J01F) 10 Sulfonamides and trimethoprim (J01E) Other beta-lactams (includes cephalosporins) (J01D) 5 Beta-lactams (J01C) DDD/1000 inhabitants per day Amphenicols (J01B) Tetracyclines (J01A) 0 RUS RUS RUS RUS RUS RUS RUS 2011 2012 2013 2014 2015 2016 2017

Fig.15.1 Total consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose.

Table 15.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 Route of administration 13.1 13.4 12.9 12.6 13.4 14.9 14.9 Oral J01 (86) (86) (86) (86) (86) (88) (88) 2.1 2.3 2.1 2.1 2.1 2 2.1 Parenteral J01 (14) (14) (14) (14) (14) (12) (12) Total 15.3 15.7 15.0 14.7 15.5 16.9 17.0 Class of antibacterial agents 1.5 1.5 1.3 1.2 1.3 1.3 1.4 Tetracyclines (J01A) (9.8) (9.6) (8.7) (8.2) (8.4) (7.7) (8.2) 0.4 0.3 0.3 0.3 0.1 0.1 0.1 Amphenicols (J01B) (2.6) (1.9) (2) (2) (0.6) (0.6) (0.6) 5 5.1 5.1 5.1 5.6 6.3 6.1 Beta-lactams (J01C) (32.7) (32.5) (34) (34.7) (36.1) (37.3) (35.9) Other beta-lactams (includes cephalosporins) 1.4 1.6 1.6 1.6 1.8 1.8 1.9 (J01D) (9.2) (10.2) (10.7) (10.9) (11.6) (10.7) (11.2) 0.8 0.7 0.6 0.5 0.6 0.6 0.5 Sulfonamides and trimethoprim (J01E) (5.2) (4.5) (4) (3.4) (3.9) (3.6) (2.9) Macrolides, lincosamides and streptogramins 2.1 2.3 2.4 2.5 2.5 2.8 2.7 (J01F) (13.7) (14.6) (16) (17) (16.1) (16.6) (15.9) 2.6 2.7 2.5 2.4 2.6 2.7 2.9 Quinolone antibacterials (J01M) (17) (17.2) (16.7) (16.3) (16.8) (16) (17.1) 1.5 1.4 1.3 1.1 1 1.2 1.4 Other J01 antibacterials (J01G, J01R, J01X) (9.8) (8.9) (8.7) (7.5) (6.5) (7.1) (8.2) Total 15.3 15.7 15.0 14.7 15.5 16.9 17.0 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

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15.3 Relative consumption by choice of agent

15.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. WHO has identified third- and fourth-generation cephalosporins as some of the agents of highest priority for risk management to ensure that critically important antimicrobials are used prudently both in human and veterinary medicine. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2011–2017 is shown in Fig. 15.2 and summarized in Table 15.2. Table 15.3 shows the most consumed agents within each of the generations of cephalosporin agents.

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 RUS RUS RUS RUS RUS RUS RUS 2011 2012 2013 2014 2015 2016 2017

Fig. 15.2 Relative consumption of cephalosporins by generation

Table 15.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) 0.4 (31) 0.4 (26) 0.3 (22) 0.3 (19) 0.3 (18) 0.3 (14) 0.2 (13) Second-generation (J01DC) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Third-generation (J01DD) 0.9 (66) 1.1 (70) 1.1 (73) 1.2 (77) 1.3 (77) 1.5 (80) 1.5 (81) Fourth-generation (J01DE) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Total 1.4 1.6 1.5 1.6 1.7 1.8 1.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Consumption of first-generation agents decreased from 31% of total cephalosporin use in 2011 to 13% in 2017. Cefazolin was most consumed first-generation agent. There were low levels of consumption of second- and fourth-generation agents across all the years analysed. Consumption of Watch group third-generation agents dominated and increased over time (66% of total cephalosporin use in 2011 and 81% in 2017). Ceftriaxone (64%), cefixime (21%) and cefotaxime (14%) were most consumed third-generation agents in 2017.

162 Russian Federation

Table 15.3 Most consumed agents within each generation of cephalosporins

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) Cefazolin 0.4 (84) 0.3 (85) 0.3 (82) 0.2 (79) 0.2 (79) 0.2 (73) 0.2 (72) Third-generation (J01DD) Cefotaxime 0.2 (24) 0.2 (22) 0.2 (20) 0.2 (19) 0.2 (17) 0.2 (13) 0.2 (14) Ceftriaxone 0.5 (60) 0.7 (62) 0.7 (64) 0.7 (63) 0.9 (65) 0.9 (65) 1 (64) Cefixime 0.1 (13) 0.1 (12) 0.1 (12) 0.2 (15) 0.2 (16) 0.3 (19) 0.3 (21) a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for the nominated generation of cephalosporins.

15.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) represented 2.9 DID (17.1%) of total J01 consumption in 2017, with fluoroquinolones comprising 2.8 DID – 97% of quinolone consumption. Three fluoroquinolones – ciprofloxacin, levofloxacin and norfloxacin – dominated, representing 43%, 30% and 16% of fluoroquinolone consumption in 2017 (Table 15.4). The overall pattern, however, was of some reductions in levels of consumption of fluoroquinolones.

Table 15.4 Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 Ofloxacin 0.3 (11) 0.3 (12) 0.2 (10) 0.1 (6) 0.2 (7) 0.1 (5) 0.1 (4) Ciprofloxacin 1.3 (53) 1.3 (50) 1.3 (52) 1.2 (52) 1.3 (50) 1.3 (48) 1.2 (43) Norfloxacin 0.5 (21) 0.5 (20) 0.5 (21) 0.5 (20) 0.5 (19) 0.5 (18) 0.5 (16) Levofloxacin 0.2 (9) 0.3 (11) 0.3 (14) 0.4 (18) 0.5 (21) 0.7 (25) 0.9 (30) Moxifloxacin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Total 2.5 2.7 2.4 2.3 2.6 2.6 2.8 a DDD: daily defined dose b Total amounts and percentages may vary slightly owing to rounding Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for fluoroquinolones.

15.4 The 10 most consumed agents

15.4.1 The 10 most consumed agents – oral formulation

Table 15.5 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

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Table 15.5 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Amoxicillin 3.52 3.52 3.52 3.52 3.52 3.52 3.52 3.52 3.52 3.52 Amoxicillin and enzyme 2.33 2.33 2.33 2.33 2.33 2.33 2.33 2.33 2.33 inhibitor Azithromycin 1.76 1.76 1.76 1.76 1.76 1.76 1.76 1.76 Doxycycline 1.25 1.25 1.25 1.25 1.25 1.25 1.25 Ciprofloxacin 1.18 1.18 1.18 1.18 1.18 1.18 Levofloxacin 0.79 0.79 0.79 0.79 0.79 Clarithromycin 0.62 0.62 0.62 0.62 Norfloxacin 0.46 0.46 0.46 Nitrofurantoin 0.44 0.44 Sulfamethoxazole and 0.39 trimethoprim Total consumption for 12.74 12.35 11.91 11.45 10.83 10.04 8.86 7.62 5.85 3.52 this group of agents Total consumption for all 14.94 14.94 14.94 14.94 14.94 14.94 14.94 14.94 14.94 14.94 oral J01 agents Proportion (%) of total consumption for oral J01 85.3% 82.7% 79.7% 76.6% 72.5% 67.2% 59.3% 51.0% 39.2% 23.6% antibacterials a DDD: daily defined dose.

The 10 listed oral agents represent just over 85% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, five are included in the WHO Watch group of antibacterials – azithromycin and clarithromycin (macrolides), and ciprofloxacin, levofloxacin and norfloxacin (quinolones).

Azithromycin (12.8%), ciprofloxacin (7.9%), levofloxacin (5.3%), clarithromycin (4.1%) and norfloxacin (3.1%) together comprised around 33.2% of J01 oral agent consumption in 2017. One third of the consumption of J01 oral agents therefore was Watch group macrolides (16.9%) and quinolones (16.3%).

15.4.2 The 10 most consumed agents – parenteral formulation

Table 15.6 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

As shown in Table 15.1, parenteral agents comprised 12% of total J01 consumption in 2017. Within this, the Watch group third-generation cephalosporins ceftriaxone (46.1%) and cefotaxime (9.7%) constituted almost 56% of the consumption of J01 injection formulations.

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Table 15.6 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Ceftriaxone 0.97 0.97 0.97 0.97 0.97 0.97 0.97 0.97 0.97 0.97 Cefotaxime 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 Cefazolin 0.18 0.18 0.18 0.18 0.18 0.18 0.18 0.18 Amikacin 0.13 0.13 0.13 0.13 0.13 0.13 0.13 Metronidazole 0.10 0.10 0.10 0.10 0.10 0.10 Levofloxacin 0.07 0.07 0.07 0.07 0.07 Gentamicin 0.07 0.07 0.07 0.07 Ciprofloxacin 0.05 0.05 0.05 Amoxicillin and enzyme 0.03 0.03 inhibitor Kanamycin 0.03 Total consumption for this 1.82 1.79 1.76 1.71 1.64 1.58 1.48 1.35 1.17 0.97 group of agents Total consumption for all 2.10 2.10 2.10 2.10 2.10 2.10 2.10 2.10 2.10 2.10 parenteral J01 agents Proportion (%) of total consumption for parenteral 86.7% 85.3% 83.9% 81.3% 78.2% 75.0% 70.4% 64.2% 55.8% 46.1% J01 antibacterials a DDD: daily defined dose.

15.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 15.3 and Fig. 15.4, and is summarized in Table 15.7.

100

60 Other

40 Core Access group

Proportion (%) Proportion 57 55 54 55 55 55 55 20

0 RUS RUS RUS RUS RUS RUS RUS 2011 2012 2013 2014 2015 2016 2017

Fig. 15.3 Relative consumption of Core Access group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

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100

60 Other Watch group 40 Proportion (%) Proportion

20 35 37 38 39 40 40 39

0 RUS RUS RUS RUS RUS RUS RUS 2011 2012 2013 2014 2015 2016 2017

Fig. 15.4 Relative consumption of Watch group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 15.7 Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

Percentage of total consumptiona Category 2011 2012 2013 2014 2015 2016 2017 Core Access group 56.9 55.0 54.5 55.3 55.2 54.6 54.8 Watch group 34.9 37.3 38.5 39.1 39.8 39.6 39.0 Reserve group 0.12 0.21 0.22 0.24 0.20 0.18 0.22 Ungrouped 8.1 7.5 6.8 5.4 4.9 5.6 6.0 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

There is evidence of increasing relative consumption of Watch agents over time, at 34.9% in 2011 and 39% in 2017. Consumption of Reserve group agents was low.

15.6 Analyses based on DDDs applied in 2019

15.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 15.5 (DDD values relevant to year) and Fig. 15.6 (2019 DDD values), and is summarized in Table 15.8.

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20 20

15 15

Parenteral Parenteral 10 10 antibacterials antibacterials Oral Oral antibacterials antibacterials 5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 RUS RUS RUS RUS RUS RUS 2015 2016 2017 2015 2016 2017

Fig. 15.5 Total consumption of J01 Fig. 15.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values)

Table 15.8 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 13.4 (86) 14.9 (88) 14.9 (88) 12.1 (86) 13 (87) 13 (87) Parenteral J01 2.1 (14) 2 (12) 2.1 (12) 2 (14) 1.9 (13) 2 (13) Total 15.5 16.9 17.0 14.1 14.9 15.0 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The relative consumption of oral and parenteral formulations does not change substantially with the application of the 2019 DDDs (oral 88% applying older values and 87% with the 2019 DDD values).

15.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 15.7 (DDD values relevant to year) and Fig. 15.8 (2019 DDD values), and is summarized in Table 15.9. As noted in section 15.6.1, total DID decreased by 11.8% in 2017.

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 6.1 DID in 2017 using the DDD values relevant to the year of data to 4.1 DID applying the 2019 DDD values – a reduction of 32.8% in absolute values. Relative consumption of beta-lactams falls from 35.9% to 27.3% of total J01 consumption when the 2019 DDD values are applied.

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generally increases: tetracyclines, for example, increased from 8.2% to 9.3%, cephalosporins from 11.2% to 12.7% and the macrolides group from 15.9% to 18% in 2017.

20 Other J01 20 Other J01 antibacterials antibacterials (J01G, J01R, (J01G, J01R, J01X) J01X) Quinolone Quinolone 15 antibacterials 15 antibacterials (J01M) (J01M) Macrolides, Macrolides, lincosamides and lincosamides and 10 streptogramins 10 streptogramins (J01F) (J01F) Sulfonamides Sulfonamides and trimethoprim and trimethoprim (J01E) (J01E) 5 Other beta-lactams 5 Other beta-lactams

DDD/1000 inhabitants per day (includes DDD/1000 inhabitants per day (includes cephalosporins) cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols RUS RUS RUS (J01B) RUS RUS RUS (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 15.7 Total consumption of J01 Fig. 15.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

Table 15.9 Consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 1.3 1.3 1.4 1.3 1.3 1.4 Tetracyclines (J01A) (8.4) (7.7) (8.2) (9.2) (8.7) (9.3) 0.1 0.1 0.1 0.1 0.1 0.1 Amphenicols (J01B) (0.6) (0.6) (0.6) (0.7) (0.7) (0.7) 5.6 6.3 6.1 3.8 4.3 4.1 Beta-lactams (J01C) (36.1) (37.3) (35.9) (27) (28.9) (27.3) Other beta-lactams (includes 1.8 1.8 1.9 1.7 1.8 1.9 cephalosporins) (J01D) (11.6) (10.7) (11.2) (12.1) (12.1) (12.7) Sulfonamides and trimethoprim 0.6 0.6 0.5 0.6 0.6 0.5 (J01E) (3.9) (3.6) (2.9) (4.3) (4) (3.3) Macrolides, lincosamides and 2.5 2.8 2.7 2.6 2.9 2.7 streptogramins (J01F) (16.1) (16.6) (15.9) (18.4) (19.5) (18) 2.6 2.7 2.9 2.6 2.7 2.9 Quinolone antibacterials (J01M) (16.8) (16) (17.1) (18.4) (18.1) (19.3) Other J01 antibacterials (J01G, 1 1.2 1.4 1.4 1.2 1.4 J01R, J01X) (6.5) (7.1) (8.2) (9.9) (8.1) (9.3) Total 15.5 16.9 17 14.1 14.9 15 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

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15.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 15.9 (DDD values relevant to year) and Fig. 15.10 (2019 DDD values) for Core Access antibiotics, Fig.15.11 (DDD values relevant to year) and Fig. 15.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 15.10.

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group Proportion (%) Proportion (%) Proportion 55 55 55 48 49 49 20 20

0 0 RUS RUS RUS RUS RUS RUS 2015 2016 2017 2015 2016 2017

Fig. 15.9 Relative consumption of Core Fig. 15.10 Relative consumption of Core Access group antibacterials (applying DDD Access group antibacterials (applying 2019 values relevant to year)a DDD values)a

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion

20 40 40 39 20 44 45 44

0 0 RUS RUS RUS RUS RUS RUS 2015 2016 2017 2015 2016 2017

Fig. 15.11 Relative consumption of Watch Fig. 15.12 Relative consumption of Watch group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year)a DDD values)a

a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

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Table 15.10 Relative consumption of Core Access and Watch group antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 8.9 (55) 9.6 (55) 9.9 (55) 7.1 (48) 7.5 (49) 8 (49) Watch group 6.4 (39.8) 6.9 (39.6) 7.1 (39) 6.5 (44) 7 (45) 7.1 (44) Reserve group 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Ungrouped 0.8 (5) 1 (6) 1.1 (6) 1.1 (7) 1 (6) 1.1 (7) Total 16.2 17.5 18.2 14.7 15.5 16.2 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The effect of applying the 2019 DDD values is to decrease slightly the proportion of total use that is Access group antibiotics (from 55% to 49% in 2017) and increase slightly the proportion of total use that is Watch group antibiotics (from 39% to 44%% in 2017).

15.7 Analysis by community and hospital sectors

The analyses presented in sections 15.1–15.6 are based on estimates of total consumption. Different patterns of consumption would be expected in the hospital and community sectors. Analyses by sector can provide more detailed information to support stewardship activities. Disaggregated data for the Russian Federation for the years 2015–2017 are presented in this report.

15.7.1 Consumption of antibacterials for systemic use (J01) in community and hospital sectors by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 15.13 (community consumption) and Fig. 15.14 (hospital consumption), and is summarized in Table 15.11.

20 20

15 15

Parenteral Parenteral 10 antibacterials 10 antibacterials Oral Oral antibacterials antibacterials 5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 RUS RUS RUS RUS RUS RUS 2015 2016 2017 2015 2016 2017

Fig. 15.13 Community consumption of J01 Fig. 15.14 Hospital consumption of J01 antibacterials by route of administration antibacterials by route of administration

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Table 15.11 Community and hospital consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration Community consumption Hospital consumption

2015 2016 2017 2015 2016 2017 Oral J01 12.4 (95) 13.8 (95) 13.5 (95) 1 (42) 1.1 (44) 1.4 (50) Parenteral J01 0.7 (5) 0.7 (5) 0.6 (5) 1.4 (58) 1.3 (56) 1.5 (50) Total 13.1 14.5 14.2 2.5 2.4 2.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Community consumption represented 83% of total J01 consumption in 2017, at 14.2 DID in the community sector and 2.9 DID in the hospital sector.

Oral consumption dominated in the community sector, at 95% oral and 5% parenteral consumption in 2017. Parenteral forms constituted 50% of hospital consumption in 2017.

15.7.2 Consumption of antibacterials for systemic use (J01) in community and hospital sectors by pharmacological subgroup

The consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 15.15 (community consumption) and Fig. 15.16 (hospital consumption), and is summarized in Table 15.12.

20 Other J01 20 Other J01 antibacterials antibacterials (J01G, J01R, (J01G, J01R, J01X) J01X) Quinolone Quinolone 15 15 antibacterials antibacterials (J01M) (J01M) Macrolides, Macrolides, lincosamides and lincosamides and 10 streptogramins 10 streptogramins (J01F) (J01F) Sulfonamides Sulfonamides and trimethoprim and trimethoprim (J01E) (J01E) 5 5 Other beta-lactams Other beta-lactams DDD/1000 inhabitants per day DDD/1000 inhabitants per day (includes (includes cephalosporins) cephalosporins) (J01D) (J01D) 0 Beta-lactams 0 Beta-lactams (J01C) (J01C) Amphenicols Amphenicols RUS RUS RUS (J01B) RUS RUS RUS (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 15.15 Community consumption of J01 Fig. 15.16 Hospital consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup

Patterns of consumption were substantially different in the community and hospital sectors. Beta- lactam (J01C) consumption dominated in the community sector, at 39.4% of community consumption and 17.2% of hospital consumption in 2017. Cephalosporin and quinolone consumption dominated in the hospital sector, with cephalosporins at 34.5% in hospitals and 7% in the community and quinolones at 27.6% in hospitals and 14.8% in the community.

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Table 15.12 Consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup Community consumption Hospital consumption

2015 2016 2017 2015 2016 2017 1.2 1.2 1.2 0.1 0.1 0.1 Tetracyclines (J01A) (9.2) (8.3) (8.5) (4) (4.2) (3.4) 0.1 0.1 0.1 Amphenicols (J01B) – – – (0.8) (0.7) (0.7) 5.2 5.8 5.6 0.4 0.5 0.5 Beta-lactams (J01C) (39.7) (40) (39.4) (16) (20.8) (17.2) Other beta-lactams (includes 0.8 1 1 0.9 0.9 1 cephalosporins) (J01D) (6.1) (6.9) (7) (36) (37.5) (34.5) Sulfonamides and trimethoprim 0.6 0.6 0.5 – – – (J01E) (4.6) (4.1) (3.5) Macrolides, lincosamides and 2.3 2.6 2.5 0.2 0.2 0.2 streptogramins (J01F) (17.6) (17.9) (17.6) (8) (8.3) (6.9) 2.1 2.2 2.1 0.5 0.5 0.8 Quinolone antibacterials (J01M) (16) (15.2) (14.8) (20) (20.8) (27.6) Other J01 antibacterials (J01G, 0.7 1 1.1 0.3 0.3 0.3 J01R, J01X) (5.3) (6.9) (7.7) (12) (12.5) (10.3) Total 13.1 14.5 14.2 2.5 2.4 2.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

There are insufficient data to conclude trends in consumption of different pharmacological subgroups in each of the two sectors.

15.7.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics in community and hospital sectors

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 15.17 (community) and Fig. 15.18 (hospital) for Core Access antibiotics, Fig. 15.19 (community) and Fig. 15.20 (hospital) for Watch group antibiotics, and is summarized in Table 15.13.

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group

Proportion (%) Proportion 59 57 59 (%) Proportion 20 20 36 38 35

0 0 RUS RUS RUS RUS RUS RUS 2015 2016 2017 2015 2016 2017

Fig. 15.17 Relative consumption of Fig. 15.18 Relative consumption of Core Access group antibacterials – Core Access group antibacterials – community sectora hospital sectora

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100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion 58 57 61 20 36 37 35 20

0 0 RUS RUS RUS RUS RUS RUS 2015 2016 2017 2015 2016 2017 Fig. 15.19 Relative consumption of Watch Fig. 15.20 Relative consumption of Watch group antibacterials – community sectora group antibacterials – hospital sectora

a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 15.13 Relative consumption of Core Access, Watch and Reserve group antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category Community sector Hospital sector

2015 2016 2017 2015 2016 2017 Core Access group 8 (59) 8.6 (57) 8.9 (59) 0.9 (36) 0.9 (38) 1 (35) Watch group 4.9 (36) 5.5 (37) 5.3 (35) 1.5 (58) 1.4 (57) 1.8 (61) Reserve group 0 (0) 0 (0) 0 (0) 0 (1) 0 (1) 0 (1) Ungrouped 0.7 (5) 0.9 (6) 1 (6) 0.1 (5) 0.1 (4) 0.1 (3) Total 13.6 15.1 15.2 2.6 2.5 3.0 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Consumption of Core Access antibiotics dominated in the community sector, at 59% in the community and 35% in hospitals in 2017, while consumption of Watch agents dominated in the hospital sector (61% compared to 35% in the community sector).

The Watch agents azithromycin (1.63 DID, 12.1%), ciprofloxacin (1.01 DID, 7.5%), clarithromycin (0.54 DID, 4%), levofloxacin (0.50 DID, 3.8%) and norfloxacin (0.44 DID, 3.2%) combined constituted 30.6% of community consumption of J01 oral antibacterials in 2017. There were relatively lower levels of consumption of these agents in the hospital sector (azithromycin (0.13 DID), ciprofloxacin (0.17 DID), clarithromycin (0.08 DID), levofloxacin (0.29 DID) and norfloxacin were not included in the top 10 oral agents).

As shown in Table 15.1, parenteral agents comprised 12–14% of total J01 consumption in 2017, but represented 5% of community consumption and 50% of hospital consumption (Table 15.11). Within this, the Watch group third-generation cephalosporin ceftriaxone represented 0.40 DID (61.9%) of community injection consumption and 0.57 DID (39.1%) of hospital injection consumption in 2017.

173 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

15.8 Discussion

The analyses in this report are based on sales records of the commercial provider, IQVIA. Data are presented as total consumption estimates along with estimates for community and hospital sectors separately.

Estimates of total consumption have been reasonably stable over time, although with the suggestion of small increases in consumption in 2016 and 2017. Around 12% of consumption in 2017 was parenteral formulations.

Relative consumption of beta-lactams increased over time, representing 35.9% of J01 consumption in 2017. Relative consumption of cephalosporins and macrolide antibiotics showed small increases over the period analysed.

Of the top 10 oral agents, five are included in the WHO Watch group of antibacterials – azithromycin and clarithromycin (macrolides), and ciprofloxacin, levofloxacin and norfloxacin (quinolones). Azithromycin (12.8%), ciprofloxacin (7.9%), levofloxacin (5.3%), clarithromycin (4.1%) and norfloxacin (3.1%) together comprised around 33.2% of J01 oral agent consumption in 2017.

The Watch group third-generation cephalosporins ceftriaxone (46.1%) and cefotaxime (9.7%) constituted almost 56% of the consumption of J01 injection formulations in 2017.

Watch group agents (oral and parenteral combined) comprised 39% of total consumption in 2017.

These relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities. For example, the WHO EML (WHO, 2017) suggests limited indications for use of azithromycin, clarithromycin, ciprofloxacin, levofloxacin and ceftriaxone.

Clarithromycin is listed on the EML as a first-choice option for severe community-acquired pneumonia and as a second-choice option for pharyngitis.

Levofloxacin is listed on the WHO EML as a reserve second-line drug for the treatment of MDR-TB that should be used in specialized centres adhering to WHO standards for TB control.

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with EML recommendations.

174 Russian Federation

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 17 DID in 2017 using DDD values relevant to year of data to 15 DID applying the 2019 DDD values – a reduction of 11.8%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 6.1 DID in 2017 using the DDD values relevant to the year of data to 4.1 DID applying the 2019 DDD values – a reduction of 32.8% in absolute values.

Disaggregated data for the years 2015-2017 are presented in this report. The data illustrate that most consumption occurred in the community (83% of total J01 consumption) and show substantial differences in patterns of consumption of pharmacological subgroups in the two sectors. Beta- lactam (J01C) consumption dominated in the community sector, while cephalosporin and quinolone consumption dominated in the hospital sector. The relative consumption of Watch group agents dominated in the hospital sector, at 61% compared to 35% in the community sector.

These analyses by sector can provide more detailed information to support stewardship activities.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in the Russian Federation and can help to identify areas for further investigation, allowing the development of targeted interventions to address potential problems identified in the consumption of antibacterials. Interventions targeting medicines should be supported by evidence- based guidelines and treatment protocols.

Total DID decreased by 13.1% when the new 2019 DDDs were applied, independent of any intervention by government, agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

Reference

175 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

16. SERBIA6

16.1 Data source and years of data collection

Serbia provided data for each of the seven years of data collection (2011–2017). The main sources were sales records of marketing authorization holders provided by the drug agency.

16.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

The data show some fluctuations in total consumption of J01 antibacterials over time, but with a trend to reductions in levels of consumption between 2015 and 2017 (36.5 DID in 2015, 24.5 DID in 2017).

40 Other J01 antibacterials 35 (J01G, J01R, J01X) a Quinolone antibacterials 30 (J01M)

SRB SRB SRB SRB SRB SRB SRB 2011 2012 2013 2014 2015 2016 2017

Fig. 16.1 Total consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose.

The relative consumption of parenteral antibacterials remained reasonably stable across the years analysed, at around 5–7% of total J01 consumption (Table 16.1).

6 Data for Kosovo (all references to Kosovo in this publication should be understood to be in the context of United Nations Security Council resolution 1244 (1999)) are presented separately.

176 Serbia

The highest levels of consumption were in beta-lactams (J01C), at 11.2 DID in 2011 and 9.8 DID in 2017. These observations relate to total consumption. Different patterns of consumption would be expected in the hospital and community sectors.

Table 16.1 Total consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 Route of administration 24.9 25.7 25.9 27.8 34.6 28.5 22.8 Oral J01 (94) (93) (94) (94) (95) (95) (93) 1.5 1.9 1.6 1.7 1.9 1.5 1.7 Parenteral J01 (6) (7) (6) (6) (5) (5) (7) Total 26.4 27.6 27.5 29.5 36.5 30.1 24.5 Class of antibacterial agents 2.3 2.1 2.9 2.1 2.3 2.2 1.4 Tetracyclines (J01A) (8.7) (7.6) (10.5) (7.1) (6.3) (7.3) (5.7) Amphenicols (J01B) – – – – – – – 11.2 11.3 11.6 13.7 17.1 12.3 9.8 Beta-lactams (J01C) (42.4) (40.9) (42.2) (46.4) (46.8) (40.9) (40) Other beta-lactams (includes cephalosporins) 3.7 4.7 4.1 4.4 5.3 5.2 4.3 (J01D) (14) (17) (14.9) (14.9) (14.5) (17.3) (17.6) 0.7 0.5 0.9 1.1 1.1 1 0.8 Sulfonamides and trimethoprim (J01E) (2.7) (1.8) (3.3) (3.7) (3) (3.3) (3.3) Macrolides, lincosamides and streptogramins 5 4.1 4.1 3.9 5.9 5.1 3.5 (J01F) (18.9) (14.9) (14.9) (13.2) (16.2) (16.9) (14.3) 2.6 3.8 3.1 3.3 3.9 3.6 3.8 Quinolone antibacterials (J01M) (9.8) (13.8) (11.3) (11.2) (10.7) (12) (15.5) 0.8 1.1 0.9 1 1 0.8 0.9 Other J01 antibacterials (J01G, J01R, J01X) (3) (4) (3.3) (3.4) (2.7) (2.7) (3.7) Total 26.4 27.6 27.5 29.5 36.5 30.1 24.5 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

There is some evidence of decreasing relative consumption of beta-lactams (J01C), at 42.4% in 2011 and 40% in 2017, and macrolides (J01F), at 18.9% in 2011 and 14.3% in 2017. Conversely, there was increasing relative consumption of cephalosporins (J01D), at 14% in 2011 and 17.6% in 2017, and quinolones (J01M), at 9.8% in 2011 and 15.5% in 2014 (Table 16.1).

The relative consumption of cephalosporins and quinolones combined increased over time (24% in 2011, 34% in 2017), with increases in both quinolone and cephalosporin consumption.

16.3 Relative consumption by choice of agent

16.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2011–2017 is shown in Fig. 16.2 and summarized in Table 16.2. Table 16.3 shows the most consumed agents within each of the generations of cephalosporin agents.

177 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 SRB SRB SRB SRB SRB SRB SRB 2011 2012 2013 2014 2015 2016 2017

Fig. 16.2 Relative consumption of cephalosporins by generation

Table 16.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) 2.3 (64) 3.5 (75) 3 (74) 3.5 (80) 3.7 (71) 3.7 (72) 2.5 (59) Second-generation (J01DC) 0.4 (11) 0.3 (7) 0.2 (5) 0.2 (4) 0.2 (4) 0.2 (3) 0.2 (4) Third-generation (J01DD) 0.9 (25) 0.8 (18) 0.8 (21) 0.7 (16) 1.3 (25) 1.2 (24) 1.5 (36) Fourth-generation (J01DE) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Total 3.6 4.7 4.0 4.4 5.2 5.2 4.2 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Consumption of first-generation agents, mostly cefalexin, dominated, although there were some decreases in consumption over time (64% of total cephalosporin use in 2011 and 59% in 2017). Consumption levels of second-generation agents were low (4% of cephalosporin consumption in 2017). Consumption of Watch group third-generation agents increased over time, constituting 25% of total cephalosporin use in 2011 and 36% in 2017. Ceftriaxone and cefixime comprised 27% and 65% respectively of third-generation agent consumption in 2017. Only small volumes of consumption of fourth-generation cephalosporins (Reserve agents) were reported.

Table 16.3 Most consumed agents within each generation of cephalosporins

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) Cefalexin 2.3 (98) 3.5 (99) 2.9 (97) 3.4 (99) 3.6 (98) 3.7 (98) 2.4 (94) Second-generation (J01DC) Cefuroxime 0.3 (82) 0.2 (56) 0.1 (51) < 0.1 < 0.1 < 0.1 < 0.1 Third-generation (J01DD) Ceftriaxone 0.3 (34) 0.3 (38) 0.3 (38) 0.4 (61) 0.4 (34) 0.3 (21) 0.4 (27) Cefixime 0.5 (59) 0.5 (54) 0.4 (49) 0.2 (22) 0.8 (60) 0.9 (70) 1 (65) a DDD: daily defined dose b Total amounts and percentages may vary slightly owing to rounding Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for the nominated generation of cephalosporins.

178 Serbia

16.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) represented 3.8 DID (16%) of total J01 consumption in 2017, with fluoroquinolones comprising 3.2 DID – 84% of quinolone consumption. Two fluoroquinolones dominated, with ciprofloxacin and levofloxacin representing 52% and 39% of fluoroquinolone consumption in 2017 (Table 16.4).

Table 16.4. Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 Ofloxacin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Ciprofloxacin 1.3 (76) 1.6 (59) 1.3 (59) 1.4 (59) 2 (66) 1.5 (52) 1.6 (52) Norfloxacin 0.3 (17) 0.3 (13) 0.4 (17) 0.3 (13) 0.3 (10) 0.3 (10) 0.3 (8) Levofloxacin < 0.1 0.8 (29) 0.5 (24) 0.6 (25) 0.7 (23) 1 (34) 1.3 (39) Total 1.7 2.7 2.2 2.4 2.9 2.9 3.2 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption of fluoroquinolones.

16.4 The 10 most consumed agents

16.4.1 The 10 most consumed agents – oral formulation

Table 16.5 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

Table 16.5 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Amoxicillin 6.37 6.37 6.37 6.37 6.37 6.37 6.37 6.37 6.37 6.37 Amoxicillin and enzyme 2.96 2.96 2.96 2.96 2.96 2.96 2.96 2.96 2.96 inhibitor Cefalexin 2.36 2.36 2.36 2.36 2.36 2.36 2.36 2.36 Ciprofloxacin 1.57 1.57 1.57 1.57 1.57 1.57 1.57 Doxycycline 1.36 1.36 1.36 1.36 1.36 1.36 Azithromycin 1.35 1.35 1.35 1.35 1.35 Levofloxacin 1.20 1.20 1.20 1.20 Clarithromycin 1.10 1.10 1.10 Cefixime 0.98 0.98 Sulfamethoxazole and 0.78 trimethoprim Total consumption for this 20.04 19.26 18.28 17.19 15.99 14.63 13.27 11.69 9.33 6.37 group of agents Total consumption for all 22.78 22.78 22.78 22.78 22.78 22.78 22.78 22.78 22.78 22.78 oral J01 agents Proportion (%) of total consumption for oral J01 88.0% 84.6% 80.3% 75.5% 70.2% 64.2% 58.3% 51.3% 41.0% 28.0% antibacterials a DDD: daily defined dose.

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The 10 listed oral agents represent 88% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, five are included in the WHO Watch group of antibacterials – ciprofloxacin and levofloxacin (quinolones), azithromycin and clarithromycin (macrolides), and cefixime (third- generation cephalosporin).

The Watch agents ciprofloxacin (7.0%), azithromycin (6%), levofloxacin (5.3%), clarithromycin (4.8%) and cefixime (4.3%) together comprised around 27.4% of J01 oral agent consumption in 2017.

16.4.2 The 10 most consumed agents – parenteral formulation

Table 16.6 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

Table 16.6 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Gentamicin 0.45 0.45 0.45 0.45 0.45 0.45 0.45 0.45 0.45 0.45 Ceftriaxone 0.41 0.41 0.41 0.41 0.41 0.41 0.41 0.41 0.41 Metronidazole 0.16 0.16 0.16 0.16 0.16 0.16 0.16 0.16 Amikacin 0.08 0.08 0.08 0.08 0.08 0.08 0.08 Combinations 0.08 0.08 0.08 0.08 0.08 0.08 Ciprofloxacin 0.07 0.07 0.07 0.07 0.07 Cefuroxime 0.06 0.06 0.06 0.06 Cefazolin 0.06 0.06 0.06 Meropenem 0.05 0.05 Levofloxacin 0.05 Total consumption for this 1.48 1.42 1.37 1.31 1.24 1.17 1.09 1.01 0.85 0.45 group of agents Total consumption for all 1.74 1.74 1.74 1.74 1.74 1.74 1.74 1.74 1.74 1.74 parenteral J01 agents Proportion (%) of total consumption for parenteral 84.9% 81.9% 78.8% 75.1% 71.4% 67.5% 62.9% 58.2% 49.1% 25.6% J01 antibacterials a DDD: daily defined dose.

As shown in Table 16.1, parenteral agents comprised around 7% of total J01 consumption in 2017. The Watch group third-generation cephalosporin ceftriaxone (23.5%) and quinolones ciprofloxacin (3.9%) and levofloxacin (3%) constituted just over 30% of the consumption of J01 injection formulations. Reserve group meropenem represented 3.1% of injection consumption.

16.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

180 Serbia

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 16.3 and Fig. 16.4, and is summarized in Table 16.7.

100

60 Other

40 Core Access group 66 67 70 73 70 68

Proportion (%) Proportion 65 20

0 SRB SRB SRB SRB SRB SRB SRB 2011 2012 2013 2014 2015 2016 2017

Fig. 16.3 Relative consumption of Core Access group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

100

60 Other Watch group 40 Proportion (%) Proportion

20 33 31 30 28 25 29 31

0 SRB SRB SRB SRB SRB SRB SRB 2011 2012 2013 2014 2015 2016 2017

Fig. 16.4 Relative consumption of Watch group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 16.7 Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

Percentage of total consumptiona Category 2011 2012 2013 2014 2015 2016 2017 Core Access group 65.9 67.1 70.2 73.0 69.6 67.8 64.6 Watch group 31.4 30.3 27.8 25.4 28.8 30.9 33.2 Reserve group 0.01 0.01 0.04 0.06 0.09 0.13 0.23 Ungrouped 2.6 2.6 2.0 1.6 1.4 1.2 1.9 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

181 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

The relative consumption of Watch agents remained reasonably consistent at around 30–33% of total antibiotic consumption. Consumption of Reserve group agents was low.

16.6 Analyses based on DDDs applied in 2019

16.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 16.5 (DDD values relevant to year) and Fig. 16.6 (2019 DDD values), and is summarized in Table 16.8.

40 40 35 35 30 30 25 25 Parenteral Parenteral 20 20 antibacterials antibacterials 15 Oral 15 Oral antibacterials antibacterials 10 10 5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 SRB SRB SRB SRB SRB SRB 2015 2016 2017 2015 2016 2017

Fig. 16.5 Total consumption of J01 Fig. 16.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values)

Table 16.8 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 34.6 (95) 28.5 (95) 22.8 (93) 29.2 (94) 24.7 (94) 19.7 (92) Parenteral J01 1.9 (5) 1.5 (5) 1.7 (7) 1.8 (6) 1.5 (6) 1.6 (8) Total 36.5 30.1 24.5 31.0 26.2 21.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

182 Serbia

The relative consumption of oral and parenteral formulations does not change substantially with the application of the 2019 DDDs (oral 93% applying older values and 92% with the 2019 DDD values).

16.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 16.7 (DDD values relevant to year) and Fig. 16.8 (2019 DDD values), and is summarized in Table 16.9. As noted in section 16.6.1, total DID decreased by 13.1% in 2017.

40 Other J01 40 Other J01 antibacterials antibacterials 35 (J01G, J01R, 35 (J01G, J01R, J01X) J01X) Quinolone Quinolone 30 antibacterials 30 antibacterials (J01M) (J01M) 25 Macrolides, 25 Macrolides, lincosamides and lincosamides and 20 streptogramins 20 streptogramins (J01F) (J01F) Sulfonamides Sulfonamides 15 15 and trimethoprim and trimethoprim (J01E) (J01E) 10 Other beta-lactams 10 Other beta-lactams DDD/1000 inhabitants per day (includes DDD/1000 inhabitants per day (includes 5 cephalosporins) 5 cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols SRB SRB SRB (J01B) SRB SRB SRB (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 16.7 Total consumption of J01 Fig. 16.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 9.8 DID in 2017 using the DDD values relevant to the year of data to 6.7 DID applying the 2019 DDD values – a reduction of 31.6% in absolute values. Relative consumption of beta-lactams falls from 40% to 31.5% of total J01 consumption when the 2019 DDD values are applied.

As the total DIDs decrease with the application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta-lactams generally increases: tetracyclines, for example, increased from 5.7% to 6.6%, cephalosporins from 17.6% to 20.2%, the macrolides group from 14.3% to 16.4% and quinolones from 15.5% to 17.8% in 2017.

183 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 16.9 Relative consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 2.3 2.2 1.4 2.3 2.2 1.4 Tetracyclines (J01A) (6.3) (7.3) (5.7) (7.4) (8.4) (6.6) Amphenicols (J01B) – – – – – – 17.1 12.3 9.8 11.6 8.4 6.7 Beta-lactams (J01C) (46.8) (40.9) (40) (37.4) (32.1) (31.5) Other beta-lactams (includes 5.3 5.2 4.3 5.3 5.2 4.3 cephalosporins) (J01D) (14.5) (17.3) (17.6) (17.1) (19.8) (20.2) Sulfonamides and trimethoprim 1.1 1 0.8 1.1 1 0.8 (J01E) (3) (3.3) (3.3) (3.5) (3.8) (3.8) Macrolides, lincosamides and 5.9 5.1 3.5 5.9 5.1 3.5 streptogramins (J01F) (16.2) (16.9) (14.3) (19) (19.5) (16.4) 3.9 3.6 3.8 3.8 3.5 3.8 Quinolone antibacterials (J01M) (10.7) (12) (15.5) (12.3) (13.4) (17.8) Other J01 antibacterials (J01G, 1 0.8 0.9 1 0.8 0.9 J01R, J01X) (2.7) (2.7) (3.7) (3.2) (3.1) (4.2) Total 36.5 30.1 24.5 31 26.2 21.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

16.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 16.9 (DDD values relevant to year) and Fig. 16.10 (2019 DDD values) for Core Access antibiotics, Fig. 16.11 (DDD values relevant to year) and Fig. 16.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 16.10.

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group 70 68 Proportion (%) Proportion 65 (%) Proportion 65 63 60 20 20

0 0 SRB SRB SRB SRB SRB SRB 2015 2016 2017 2015 2016 2017

Fig. 16.9 Relative consumption of Core Fig. 16.10 Relative consumption of Core Access group antibacterials (applying DDD Access group antibacterials (applying 2019 values relevant to year)a DDD values)a

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100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion

20 20 35 38 29 31 33 34

0 0 SRB SRB SRB SRB SRB SRB 2015 2016 2017 2015 2016 2017 Fig. 16.11 Relative consumption of Watch Fig. 16.12 Relative consumption of Watch group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year)a DDD values)a

a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 16.10 Relative consumption of Core Access and Watch group antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 25.8 (70) 20.7 (68) 16.3 (65) 20.4 (65) 16.9 (63) 13.2 (60) Watch group 10.7 (28.8) 9.5 (30.9) 8.4 (33.2) 10.6 (34) 9.4 (35) 8.3 (38) Reserve group 0 (0) 0 (0) 0.1 (0) 0 (0) 0 (0) 0 (0) Ungrouped 0.5 (1) 0.4 (1) 0.5 (2) 0.5 (2) 0.4 (1) 0.5 (2) Total 37.1 30.6 25.3 31.6 26.7 22.1 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The effect of applying the 2019 DDD values is to decrease slightly the proportion of total use that is Core Access group antibiotics (from 65% to 60% in 2017) and increase slightly the proportion of total use that is Watch group antibiotics (from 33.2% to 38% in 2017).

16.7 Discussion

The analyses in this report are based on sales records of marketing authorization holders.

Relative consumption of parenteral antibacterials remained reasonably stable across the years, analysed at around 5–7% of total J01 consumption.

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Of the top 10 oral agents, five are included in the WHO Watch group of antibacterials – ciprofloxacin and levofloxacin (quinolones), azithromycin and clarithromycin (macrolides), and cefixime (third-generation cephalosporin). Ciprofloxacin (7.0%), azithromycin (6%), levofloxacin (5.3%), clarithromycin (4.8%) and cefixime (4.3%) together comprised around 27.4% of J01 oral agent consumption in 2017.

The Watch group third-generation cephalosporin ceftriaxone (23.5%) and quinolones ciprofloxacin (3.9%) and levofloxacin (3%) constituted just over 30% of the consumption of J01 injection formulations. Reserve group meropenem represented 3.1% of injection consumption.

Watch group agents (oral and parenteral) comprised one third (33.2%) of total consumption in 2017.

These relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities. For example, the WHO EML (WHO, 2017) suggests limited indications for use of azithromycin, clarithromycin, cefixime, ciprofloxacin, levofloxacin and ceftriaxone.

Clarithromycin is listed on the EML as a first-choice option for severe community-acquired pneumonia and as a second-choice option for pharyngitis.

Levofloxacin is listed on the WHO EML as a reserve second-line drug for the treatment of MDR-TB that should be used in specialized centres adhering to WHO standards for TB control.

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with WHO EML recommendations.

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Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 24.5 DID in 2017 using DDD values relevant to year of data to 21.3 DID applying the 2019 DDD values – a reduction of 13.1%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 9.8 DID in 2017 using the DDD values relevant to the year of data to 6.7 DID applying the 2019 DDD values – a reduction of 31.6% in absolute values.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in Serbia and can help to identify areas for further investigation, allowing the development of targeted interventions to address potential problems identified in the consumption of antibacterials.

Reference

187 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

17. TAJIKISTAN

17.1 Data source and years of data collection

Tajikistan provided data for each of the seven years of data collection (2011–2017). The main sources were import records and certification records provided by the State Surveillance Service for Pharmaceutical Activities. The data cover imported, locally produced and donated medicines. Data derived from importation records will be affected by the cycles of procurement and delivery, potentially giving rise to fluctuations in estimates of consumption that do not relate to actual use of antibacterials by patients and health-care facilities.

17.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

The data show some fluctuations in total consumption of J01 antibacterials over time, with a trend to reductions in total consumption between 2014 and 2017. The estimate of total consumption in 2017 (18.3 DID) was only half that reported in 2011 (36.6 DID). The reasons for this fluctuating pattern and considerable changes are unclear and require further investigation. In addition to positive efforts to influence antibiotic consumption, there may be some influence of medicine import cycles.

The relative consumption of parenteral antibacterials varied across the years analysed. Injections constituted 36% of total J01 consumption in 2017 (Table 17.1).

The highest levels of consumption were in beta-lactams (J01C), at 20.5 DID in 2011 and 6.6 DID in 2017. There is some evidence of increasing consumption of macrolide antibacterials (J01F), with 0.7 DID in 2011 and 1.3 DID in 2017, and quinolones (J01M), with 3.5 DID in 2011 and 4.2 DID in 2017. Consumption of cephalosporin antibacterials (J01D) decreased, with 5.7 DID in 2011 and 3.3 DID in 2017.

These observations relate to total consumption. Different patterns of consumption would be expected in the hospital and community sectors.

Relative consumption of beta-lactams decreased from 56% in 2011 to 36.1% in 2017. There is evidence of increasing relative consumption of cephalosporins (J01D), at 15.6% in 2011 and 18% in 2017, macrolides (J01F), at 1.9% in 2011 and 7.1% in 2017, and quinolones (J01M), at 9.6% in 2011 and 23% in 2017.

The relative consumption of cephalosporins and quinolones combined increased substantially over time (25% in 2011, 41% in 2017), mainly driven by increases in quinolone consumption (9% in 2011, 23% in 2017).

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45 Other J01 antibacterials 40 (J01G, J01R, J01X) a 35 Quinolone antibacterials (J01M) 30 Macrolides, lincosamides and streptogramins (J01F) 25 Sulfonamides and 20 trimethoprim (J01E)

15 Other beta-lactams (includes cephalosporins) (J01D) 10 Beta-lactams (J01C) DDD/1000 inhabitants per day 5 Amphenicols (J01B) Tetracyclines (J01A) 0 TJK TJK TJK TJK TJK TJK TJK 2011 2012 2013 2014 2015 2016 2017

Fig. 17.1 Total consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose.

Table 17.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 Route of administration 22.7 25.5 15.9 27.7 15 18.1 11.8 Oral J01 (62) (61) (56) (72) (58) (75) (64) 14 16.1 12.3 11 10.8 6 6.5 Parenteral J01 (38) (39) (44) (28) (42) (25) (36) Total 36.6 41.6 28.2 38.7 25.8 24.2 18.3 Class of antibacterials 1.1 1.2 0.9 1.4 1.2 0.8 0.6 Tetracyclines (J01A) (3) (2.9) (3.2) (3.6) (4.7) (3.3) (3.3) 0.6 0.6 0.3 0.5 0.3 0.1 0.2 Amphenicols (J01B) (1.6) (1.4) (1.1) (1.3) (1.2) (0.4) (1.1) 20.5 23.8 15.3 20.7 11.3 11.5 6.6 Beta-lactams (J01C) (56) (57.2) (54.3) (53.5) (43.8) (47.5) (36.1) Other beta-lactams (includes cephalosporins) 5.7 6.7 6.1 7 4.7 2.8 3.3 (J01D) (15.6) (16.1) (21.6) (18.1) (18.2) (11.6) (18) 1.9 2.2 1.1 1.7 1.6 0.8 0.9 Sulfonamides and trimethoprim (J01E) (5.2) (5.3) (3.9) (4.4) (6.2) (3.3) (4.9) Macrolides, lincosamides and streptogramins 0.7 0.8 0.8 0.9 0.9 0.8 1.3 (J01F) (1.9) (1.9) (2.8) (2.3) (3.5) (3.3) (7.1) 3.5 4 2.2 4 3.2 4.4 4.2 Quinolone antibacterials (J01M) (9.6) (9.6) (7.8) (10.3) (12.4) (18.2) (23) 2.7 2.3 1.6 2.6 2.5 3.1 1.4 Other J01 antibacterials (J01G, J01R, J01X) (7.4) (5.5) (5.7) (6.7) (9.7) (12.8) (7.7) Total 36.6 41.6 28.2 38.7 25.8 24.2 18.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

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17.3 Relative consumption by choice of agent

17.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2011–2017 is shown in Fig. 17.2 and summarized in Table 17.2. Table 17.3 shows the most consumed agents within each of the generations of cephalosporin agents.

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 TJK TJK TJK TJK TJK TJK TJK 2011 2012 2013 2014 2015 2016 2017

Fig. 17.2 Relative consumption of cephalosporins by generation

Table 17.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) 1 (17) 1.2 (17) 1.7 (27) 1.2 (17) 0.4 (9) 0.3 (12) 0.4 (12) Second-generation (J01DC) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 – Third-generation (J01DD) 4.7 (82) 5.5 (82) 4.4 (72) 5.8 (83) 4.3 (90) 2.4 (87) 2.9 (88) Fourth-generation (J01DE) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Total 5.7 6.7 6.1 7.0 4.7 2.8 3.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Small decreases in consumption of first-generation agents were seen (17% of total cephalosporin use in 2011 and 12% in 2017). Cefazolin constituted 97% of consumption of first-generation agents in 2017. Second-generation agent consumption was low. Consumption of Watch group third-generation agents dominated and increased over time (82% of total cephalosporin use in 2011 and 88% in

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2017). Ceftriaxone and cefotaxime comprised 83% and 13% of third-generation agent consumption respectively in 2017. Only small volumes of consumption of fourth-generation cephalosporins (Reserve agents) were reported.

Table 17.3 Most consumed agents within each generation of cephalosporins

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) Cefazolin 0.9 (95) 1.1 (96) 1.6 (100) 1.1 (94) 0.4 (98) 0.3 (98) 0.4 (97) Third-generation (J01DD) Cefotaxime < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 0.4 (13) Ceftriaxone 4.6 (97) 5.4 (97) 4.1 (95) 5.5 (95) 4 (93) 2.2 (93) 2.4 (83) Cefixime < 0.1 < 0.1 0.2 (3) 0.2 (3) 0.2 (5) 0.1 (5) 0.1 (4) a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for the nominated generation of cephalosporins

17.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) represented 4.2 DID (23%) of total J01 consumption in 2017, essentially all of which was fluoroquinolones. Ciprofloxacin consumption increased over time, at 57% of quinolone consumption in 2011 and 85% in 2017. There was decreasing consumption of ofloxacin, with 25% in 2011 and 6% in 2017, and levofloxacin, with 16% in 2011 and 7% in 2017 (Table 17.4). The overall pattern was one of increasing levels of consumption of fluoroquinolones.

Table 17.4 Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 Ofloxacin 0.8 (25) 1 (25) 0.2 (10) 0.1 (4) 0.1 (4) 0.1 (2) 0.2 (6) Ciprofloxacin 1.9 (57) 2.3 (58) 1.6 (77) 3.1 (81) 2.3 (74) 3.8 (88) 3.6 (85) Levofloxacin 0.6 (16) 0.6 (15) 0.2 (12) 0.5 (14) 0.6 (20) 0.4 (9) 0.3 (7) Total 3.4 3.9 2.0 3.9 3.1 4.3 4.2 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption of fluoroquinolones.

17.4 The 10 most consumed agents

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17.4.1 The 10 most consumed agents – oral formulation

Table 17.5 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

Table 17.5 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Ciprofloxacin 3.50 3.50 3.50 3.50 3.50 3.50 3.50 3.50 3.50 3.50 Amoxicillin 3.28 3.28 3.28 3.28 3.28 3.28 3.28 3.28 3.28 Ampicillin 1.22 1.22 1.22 1.22 1.22 1.22 1.22 1.22 Sulfamethoxazole and 0.94 0.94 0.94 0.94 0.94 0.94 0.94 trimethoprim Azithromycin 0.87 0.87 0.87 0.87 0.87 0.87 Doxycycline 0.45 0.45 0.45 0.45 0.45 Erythromycin 0.28 0.28 0.28 0.28 Levofloxacin 0.25 0.25 0.25 Ofloxacin 0.23 0.23 Chloramphenicol 0.15 Total consumption for 11.17 11.02 10.79 10.53 10.25 9.80 8.94 8.00 6.78 3.50 this group of agents Total consumption for all 11.80 11.80 11.80 11.80 11.80 11.80 11.80 11.80 11.80 11.80 oral J01 agents Proportion (%) of total consumption for oral J01 94.7% 93.4% 91.4% 89.3% 86.9% 83.1% 75.7% 67.8% 57.4% 29.6% antibacterials a DDD: daily defined dose.

The 10 listed oral agents represent almost 95% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, five are included in the WHO Watch group of antibacterials – ciprofloxacin, levofloxacin and ofloxacin (quinolones), and azithromycin and erythromycin (macrolides).

Ciprofloxacin alone comprised 29.6% of oral agent consumption in 2017. Together, the five Watch agents comprised around 43.5% of J01 oral agent consumption (29.6% + 7.4% + 2.4% + 2.1% + 2%).

17.4.2 The 10 most consumed agents – parenteral formulation

Table 17.6 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

As shown in Table 17.1, parenteral agents comprised around 36% of total J01 consumption in 2017. Within this, the Watch group third-generation cephalosporins ceftriaxone (36.1%) and cefotaxime (5.6%) constituted just under 42% of the consumption of J01 injection formulations.

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Table 17.6 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Ceftriaxone 2.36 2.36 2.36 2.36 2.36 2.36 2.36 2.36 2.36 2.36 Ampicillin 1.22 1.22 1.22 1.22 1.22 1.22 1.22 1.22 1.22 Metronidazole 0.51 0.51 0.51 0.51 0.51 0.51 0.51 0.51 Gentamicin 0.43 0.43 0.43 0.43 0.43 0.43 0.43 Combinations of penicillins 0.42 0.42 0.42 0.42 0.42 0.42 Cefazolin 0.37 0.37 0.37 0.37 0.37 Cefotaxime 0.37 0.37 0.37 0.37 Amikacin 0.25 0.25 0.25 Amoxicillin 0.15 0.15 Ciprofloxacin 0.07 Total consumption for this 6.14 6.08 5.93 5.69 5.32 4.94 4.52 4.09 3.58 2.36 group of agents Total consumption for all 6.52 6.52 6.52 6.52 6.52 6.52 6.52 6.52 6.52 6.52 parenteral J01 agents Proportion (%) of total consumption for parenteral 94.3% 93.3% 91.0% 87.2% 81.6% 75.9% 69.4% 62.8% 54.9% 36.1% J01 antibacterials a DDD: daily defined dose.

17.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 17.3 and Fig. 17.4, and is summarized in Table 17.7.

100

60 Other

40 Core Access group 69 68 66 65 Proportion (%) Proportion 64 62 51 20

0 TJK TJK TJK TJK TJK TJK TJK 2011 2012 2013 2014 2015 2016 2017

Fig. 17.3 Relative consumption of Core Access group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

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100

60 Other Watch group 40 Proportion (%) Proportion

44 20 32 24 24 26 27 31 0 TJK TJK TJK TJK TJK TJK TJK 2011 2012 2013 2014 2015 2016 2017 Fig. 17.4 Relative consumption of Watch group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 17.7 Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

Percentage of total consumptiona Category 2011 2012 2013 2014 2015 2016 2017 Core Access group 68.9 68.5 63.8 65.9 62.1 64.7 50.8 Watch group 23.8 24.3 25.5 27.1 31.6 30.8 44.4 Reserve group 0.03 0.03 0.07 0.03 0.04 0.04 0.06 Ungrouped 7.3 7.2 10.6 6.9 6.2 4.4 4.7 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The relative consumption of Watch agents increased over time, from 23.8% of total consumption in 2011 to 44.4% in 2017. Consumption of Reserve group agents was low.

17.6 Analyses based on DDDs applied in 2019

17.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 17.5 (DDD values relevant to year) and Fig. 17.6 (2019 DDD values), and is summarized in Table 17.8.

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30 30

25 25

20 20 Parenteral Parenteral 15 15 antibacterials antibacterials Oral Oral 10 10 antibacterials antibacterials

5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 TJK TJK TJK TJK TJK TJK 2015 2016 2017 2015 2016 2017

Fig. 17.5 Total consumption of J01 Fig. 17.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values)

Table 17.8 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 15 (58) 18.1 (75) 11.8 (64) 13.5 (62) 15.6 (75) 10.7 (66) Parenteral J01 10.8 (42) 6 (25) 6.5 (36) 8.1 (38) 5.3 (25) 5.6 (34) Total 25.8 24.2 18.3 21.7 20.9 16.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The relative consumption of oral and parenteral formulations does not change substantially with the application of the 2019 DDDs (oral agents 64% applying older values and 66% with the 2019 DDD values).

17.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 17.7 (DDD values relevant to year) and Fig. 17.8 (2019 DDD values), and is summarized in Table 17.9. As noted in section 17.7.1, total DIDs decreased by 10.9% in 2017.

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 6.6 DID in 2017 using the DDD values relevant to the year of data to 4.5 DID applying the 2019 DDD values – a reduction of 31.8% in absolute values. Relative consumption of beta-lactams falls from 36.1% to 27.6% of total J01 consumption when the 2019 DDD values are applied.

As the total DIDs decrease with the application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta-lactams generally increases: tetracyclines, for example, increased from 3.3% to 3.7%, cephalosporins from 18% to 19.6%, the macrolides group from 7.1% to 8% and quinolones from 23% to 25.8% in 2017.

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30 Other J01 30 Other J01 antibacterials antibacterials (J01G, J01R, (J01G, J01R, 25 J01X) 25 J01X) Quinolone Quinolone antibacterials antibacterials 20 (J01M) 20 (J01M) Macrolides, Macrolides, lincosamides and lincosamides and 15 streptogramins 15 streptogramins (J01F) (J01F) Sulfonamides Sulfonamides 10 and trimethoprim 10 and trimethoprim (J01E) (J01E) Other beta-lactams Other beta-lactams DDD/1000 inhabitants per day 5 (includes DDD/1000 inhabitants per day 5 (includes cephalosporins) cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols TJK TJK TJK (J01B) TJK TJK TJK (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 17.7 Total consumption of J01 Fig. 17.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

Table 17.9 Relative consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 1.2 0.8 0.6 1.2 0.8 0.6 Tetracyclines (J01A) (4.7) (3.3) (3.3) (5.5) (3.8) (3.7) 0.3 0.1 0.2 0.3 0.1 0.2 Amphenicols (J01B) (1.2) (0.4) (1.1) (1.4) (0.5) (1.2) 11.3 11.5 6.6 7 8.1 4.5 Beta-lactams (J01C) (43.8) (47.5) (36.1) (32.3) (38.8) (27.6) Other beta-lactams (includes 4.7 2.8 3.3 4.8 2.8 3.2 cephalosporins) (J01D) (18.2) (11.6) (18) (22.1) (13.4) (19.6) Sulfonamides and trimethoprim 1.6 0.8 0.9 1.6 0.8 0.9 (J01E) (6.2) (3.3) (4.9) (7.4) (3.8) (5.5) Macrolides, lincosamides and 0.9 0.8 1.3 0.9 0.8 1.3 streptogramins (J01F) (3.5) (3.3) (7.1) (4.1) (3.8) (8) 3.2 4.4 4.2 3.2 4.3 4.2 Quinolone antibacterials (J01M) (12.4) (18.2) (23) (14.7) (20.6) (25.8) Other J01 antibacterials (J01G, 2.5 3.1 1.4 2.6 3.1 1.4 J01R, J01X) (9.7) (12.8) (7.7) (12) (14.8) (8.6) Total 25.8 24.2 18.3 21.7 20.9 16.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

17.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 17.9 (DDD values relevant to year) and Fig. 17.10 (2019 DDD values) for Core Access antibiotics, Fig. 17.11

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(DDD values relevant to year) and Fig. 17.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 17.10.

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group

Proportion (%) Proportion 62 65 (%) Proportion 59 51 55 20 20 45

0 0 TJK TJK TJK TJK TJK TJK 2015 2016 2017 2015 2016 2017

Fig. 17.9 Relative consumption of Core Fig. 17.10 Relative consumption of Core Access group antibacterials (applying DDD Access group antibacterials (applying 2019 values relevant to year)a DDD values)a

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion

44 50 20 20 38 32 31 36

0 0 TJK TJK TJK TJK TJK TJK 2015 2016 2017 2015 2016 2017

Fig. 17.11 Relative consumption of Watch Fig. 17.12 Relative consumption of Watch group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year)a DDD values)a a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The effect of applying the 2019 DDD values is to decrease slightly the proportion of total use that is Core Access group antibiotics (from 51% to 45% in 2017) and increase slightly the proportion of total use that is Watch group antibiotics (from 44.4% to 50% in 2017).

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Table 17.10 Relative consumption of Core Access, Watch and Reserve group antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 16.3 (62) 15.8 (65) 9.4 (51) 12.1 (55) 12.5 (59) 7.4 (45) Watch group 8.3 (31.6) 7.5 (30.8) 8.3 (44.4) 8.3 (38) 7.5 (36) 8.2 (50) Reserve group 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Ungrouped 1.6 (6) 1.1 (4) 0.9 (5) 1.7 (8) 1.1 (5) 0.9 (5) Total 26.2 24.5 18.6 22.1 21.2 16.5 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

17.7 Discussion

The analyses in this report are based on import and certification records covering imported, locally produced and donated medicines.

Estimates of total consumption of J01 antibacterials fluctuated over the period 2011–2017, with a trend to reductions in total consumption between 2014 and 2017. The estimate of total consumption in 2017 (18.3 DID) was only half that reported in 2011 (36.6 DID).

The relative consumption of parenteral antibacterials varied considerably across the years analysed, constituting 36% of total J01 consumption in 2017.

Relative consumption of beta-lactams decreased, offset by increasing relative consumption of cephalosporins, macrolide and quinolone antibacterials.

Of the top 10 oral agents in the J01 class, five are included in the WHO Watch group of antibacterials – ciprofloxacin, levofloxacin and ofloxacin (quinolones), and azithromycin and erythromycin (macrolides).

Ciprofloxacin alone comprised 29.6% of oral agent consumption in 2017. Together, the five Watch agents comprised around 43.5% of J01 oral agent consumption.

The Watch group third-generation cephalosporins ceftriaxone (36.1%) and cefotaxime (5.6%) together constituted just under 42% (3.58 DID) of the consumption of J01 injection formulations in 2017.

These relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities. For example, the WHO EML (WHO, 2017) suggests limited indications for use of azithromycin, ciprofloxacin, levofloxacin and ceftriaxone.

Ciprofloxacin is listed on the WHO EML as a first-choice agent for acute invasive bacterial diarrhoea/dysentery, low-risk febrile neutropenia and mild-to-moderate pyelonephritis or

198 Tajikistan

prostatitis. It is a second-choice agent for the treatment of cholera and mild-to-moderate complicated intra-abdominal infections.

Levofloxacin is listed on the WHO EML as a reserve second-line drug for the treatment of MDR-TB that should be used in specialized centres adhering to WHO standards for TB control.

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with WHO EML recommendations.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 18.3 DID in 2017 using DDD values relevant to year of data to 16.3 DID applying the 2019 DDD values – a reduction of 10.9%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 6.6 DID in 2017 using the DDD values relevant to the year of data to 4.5 DID applying the 2019 DDD values – a reduction of 31.8% in absolute values.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in Tajikistan and can help to identify areas for further investigation, allowing the development of targeted interventions to address potential problems identified in the consumption of antibacterials. Interventions targeting medicines should be supported by evidence-based guidelines and treatment protocols.

Total DID decreased by 10.9% when the new 2019 DDDs were applied, independent of any intervention by government, agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

Reference

199 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

18. TURKEY

18.1 Data source and years of data collection

Turkey has provided data for each of the seven years of data collection (2011–2017). In 2011 and 2012, data were provided by IMS Health (IQVIA) and covered community consumption of antibacterials only. Since 2013, the main source of data has been sales records of wholesalers provided by the track and trace system of the Turkish drug agency. Only data for the period 2013–2017 are presented in this report. Both total consumption and estimates disaggregated to community and hospital consumption are available.

Elsewhere in this report, World Bank estimates have been used to provide population data for the calculation of medicines consumption. In the case of Turkey, Turkish Statistical Institution estimates were used to take account of the large refugee and displaced persons populations.

18.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

The data show reasonably stable total consumption of J01 antibacterials between 2013 and 2016 (42.4 DID in 2013, 41.5 DID in 2016), with a substantial fall to 36.4 DID in 2017.

The relative consumption of parenteral antibacterials represented around 4% of total J01 consumption.

The highest levels of consumption were in beta-lactams (J01C), at 18.6 DID in 2013 and 17.1 DID in 2017. There have been decreases in consumption of cephalosporins, at 13.6 DID in 2013 and 9.6 DID in 2017, and quinolones, at 3.1 DID in 2013 and 2.6 DID in 2017.

These observations relate to total consumption. Disaggregated data for the hospital and community sectors and presented in section 18.7.

The relative consumption of beta-lactam antibiotics increased slightly over time, at 43.9% in 2013 and 47% in 2017. There is evidence of small increases in relative consumption of macrolides (J01F), at 9.7% in 2013 and 11% in 2017. The relative consumption of cephalosporins decreased over time, at 32.1% in 2013 and 26.4% in 2017.

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45 Other J01 antibacterials 40 (J01G, J01R, J01X) a 35 Quinolone antibacterials (J01M) 30 Macrolides, lincosamides and streptogramins (J01F) 25 Sulfonamides and 20 trimethoprim (J01E)

15 Other beta-lactams (includes cephalosporins) (J01D) 10 Beta-lactams (J01C) DDD/1000 inhabitants per day 5 Amphenicols (J01B) Tetracyclines (J01A) 0 TUR TUR TUR TUR TUR 2013 2014 2015 2016 2017

Fig. 18.1. Total consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose.

Table 18.1. Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2013 2014 2015 2016 2017 Route of administration Oral J01 40.6 (96) 38.7 (96) 39.8 (96) 39.9 (96) 34.9 (96) Parenteral J01 1.8 (4) 1.7 (4) 1.8 (4) 1.6 (4) 1.5 (4) Total 42.4 40.4 41.5 41.5 36.4 Class of antibacterial agents Tetracyclines (J01A) 1.3 (3.1) 1.3 (3.2) 1.3 (3.1) 1.2 (2.9) 1.2 (3.3) Amphenicols (J01B) – – – – – Beta-lactams (J01C) 18.6 (43.9) 18 (44.6) 18.5 (44.6) 19.1 (46) 17.1 (47) Other beta-lactams (includes cephalosporins) 13.6 (32.1) 12.2 (30.2) 12 (28.9) 11.6 (28) 9.6 (26.4) (J01D) Sulfonamides and trimethoprim (J01E) 0.4 (0.9) 0.4 (1) 0.4 (1) 0.3 (0.7) 0.3 (0.8) Macrolides, lincosamides and streptogramins 4.1 (9.7) 4.1 (10.1) 4.8 (11.6) 4.7 (11.3) 4 (11) (J01F) Quinolone antibacterials (J01M) 3.1 (7.3) 3 (7.4) 3.1 (7.5) 3 (7.2) 2.6 (7.1) Other J01 antibacterials (J01G, J01R, J01X) 1.4 (3.3) 1.5 (3.7) 1.5 (3.6) 1.6 (3.9) 1.7 (4.7) Total 42.4 40.4 41.5 41.5 36.4 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The relative consumption of cephalosporins and quinolones combined decreased over time, at 39.4% in 2013 and 33.5% in 2017, mostly driven by reduced consumption of cephalosporins.

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18.3 Relative consumption by choice of agent

18.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2013–2017 is shown in Fig. 18.2 and summarized in Table 18.2. Table 18.3 shows the most consumed agents within each of the generations of cephalosporin agents.

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 TUR TUR TUR TUR TUR 2013 2014 2015 2016 2017

Fig. 18.2 Relative consumption of cephalosporins by generation

Table 18.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2013 2014 2015 2016 2017 First-generation (J01DB) 1.1 (8) 1 (8) 0.9 (8) 0.9 (8) 0.9 (9) Second-generation (J01DC) 7.3 (54) 6.5 (54) 6.1 (51) 5.6 (49) 4.9 (51) Third-generation (J01DD) 5.2 (38) 4.6 (38) 4.9 (41) 4.9 (43) 3.8 (39) Fourth-generation (J01DE) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Total 13.5 12.2 11.9 11.5 9.5 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Consumption of first-generation agents, mostly cefalexin and cefazolin, remained stable over time (9% of total cephalosporin consumption in 2017). Second-generation agents represented around a half of all cephalosporin consumption across the years analysed (51% in 2017). Cefuroxime (68%) and cefaclor (30%) were the most consumed second-generation agents in 2017. Consumption of Watch group third-generation agents were reasonably stable over time (38–43% of cephalosporin consumption between 2013 and 2017). Ceftriaxone, cefixime, cefpodoxime and cefdinir comprised 11%, 32%, 21% and 32% respectively of third-generation agent consumption in 2017. Very small volumes of consumption of fourth-generation cephalosporins (Reserve agents) were reported.

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Table 18.3 Most consumed agents within each generation of cephalosporins

DDD/1 000 inhabitants per daya (% of totalb) Agents 2013 2014 2015 2016 2017 First-generation (J01DB) Cefalexin 0.7 (68) 0.7 (69) 0.6 (66) 0.6 (68) 0.6 (71) Cefazolin 0.3 (32) 0.3 (31) 0.3 (34) 0.3 (32) 0.3 (29) Second-generation (J01DC) Cefuroxime 5.2 (72) 4.6 (71) 4.1 (68) 3.9 (69) 3.3 (68) Cefaclor 1 (13) 1.2 (18) 1.5 (24) 1.5 (27) 1.5 (30) Third-generation (J01DD) Ceftriaxone 0.4 (8) 0.4 (9) 0.5 (10) 0.5 (10) 0.4 (11) Cefixime 1 (20) 1.1 (24) 1.1 (23) 1.3 (27) 1.2 (32) Cefpodoxime 0.9 (17) 0.5 (11) 0.7 (14) 0.7 (15) 0.8 (21) Cefdinir 2.2 (42) 2.1 (45) 2.1 (43) 2.1 (43) 1.2 (32) Ceftibuten 0.2 (5) 0.2 (5) 0.1 (3) 0.1 (2) < 0.1 Cefditoren 0.5 (9) 0.3 (6) 0.3 (6) 0.1 (3) < 0.1 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for the nominated generation of cephalosporins.

18.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) represented 2.6 DID (7.1%) of total J01 consumption in 2017, with essentially all fluoroquinolone consumption. Ciprofloxacin (73%), levofloxacin (12%) and moxifloxacin (14%) consumption dominated in 2017 (Table 18.4).

Table 18.4 Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2013 2014 2015 2016 2017 Ofloxacin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Ciprofloxacin 2.3 (73) 2.2 (75) 2.3 (74) 2.2 (75) 1.9 (73) Levofloxacin 0.4 (12) 0.3 (11) 0.4 (12) 0.3 (11) 0.3 (12) Moxifloxacin 0.3 (11) 0.4 (12) 0.4 (13) 0.4 (13) 0.4 (14) Total 3.1 3.0 3.1 3.0 2.6 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for fluoroquinolones.

18.4 The 10 most consumed agents

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18.4.1 The 10 most consumed agents – oral formulation

Table 18.5 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

Table 18.5 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Amoxicillin and enzyme 14.71 14.71 14.71 14.71 14.71 14.71 14.71 14.71 14.71 14.71 inhibitor Cefuroxime 3.26 3.26 3.26 3.26 3.26 3.26 3.26 3.26 3.26 Clarithromycin 2.94 2.94 2.94 2.94 2.94 2.94 2.94 2.94 Ciprofloxacin 1.85 1.85 1.85 1.85 1.85 1.85 1.85 Amoxicillin 1.49 1.49 1.49 1.49 1.49 1.49 Cefaclor 1.46 1.46 1.46 1.46 1.46 Cefixime 1.20 1.20 1.20 1.20 Cefdinir 1.18 1.18 1.18 Doxycycline 1.08 1.08 Cefpodoxime 0.80 Total consumption for this 29.98 29.18 28.09 26.91 25.71 24.25 22.76 20.91 17.97 14.71 group of agents Total consumption for all oral 34.94 34.94 34.94 34.94 34.94 34.94 34.94 34.94 34.94 34.94 J01 agents Proportion (%) of total consumption for oral J01 85.8% 83.5% 80.4% 77.0% 73.6% 69.4% 65.1% 59.9% 51.4% 42.1% antibacterials a DDD: daily defined dose.

The 10 listed oral agents represent almost 86% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, five are included in the WHO Watch group of antibacterials – clarithromycin (macrolides), ciprofloxacin (quinolones), and cefixime, cefdinir and cefpodoxime (third-generation cephalosporins).

The Watch agents clarithromycin (8.5%), ciprofloxacin (5.2%), cefixime (3.4%), cefdinir (3.4%) and cefpodoxime (2.5%) together comprised 23% of J01 oral agent consumption in 2017.

18.4.2 The 10 most consumed agents – parenteral formulation

Table 18.6 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

As shown in Table 18.1, parenteral agents comprised around 4% of total J01 consumption in 2017. Within this, the Watch group third-generation cephalosporin ceftriaxone constituted 28.5% of the consumption of J01 injection formulations.

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Table 18.6 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Ceftriaxone 0.43 0.43 0.43 0.43 0.43 0.43 0.43 0.43 0.43 0.43 Cefazolin 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 Meropenem 0.09 0.09 0.09 0.09 0.09 0.09 0.09 0.09 Cefuroxime 0.08 0.08 0.08 0.08 0.08 0.08 0.08 Ampicillin and enzyme inhibitor 0.07 0.07 0.07 0.07 0.07 0.07 Gentamicin 0.05 0.05 0.05 0.05 0.05 Clindamycin 0.05 0.05 0.05 0.05 Moxifloxacin 0.04 0.04 0.04 Piperacillin and enzyme 0.04 0.04 inhibitor Ciprofloxacin 0.04 Total consumption for this 1.14 1.10 1.06 1.02 0.97 0.92 0.85 0.77 0.68 0.43 group of agents Total consumption for all 1.51 1.51 1.51 1.51 1.51 1.51 1.51 1.51 1.51 1.51 parenteral J01 agents Proportion (%) of total consumption for parenteral 75.5% 72.9% 70.2% 67.5% 64.4% 61.2% 56.3% 51.3% 45.3% 28.5% J01 antibacterials a DDD: daily defined dose.

18.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 18.3 and Fig. 18.4, and is summarized in Table 18.7.

100

60 Other

40 Core Access group Proportion (%) Proportion 49 51 51 53 54 20

0 TUR TUR TUR TUR TUR 2013 2014 2015 2016 2017

Fig. 18.3 Relative consumption of Core Access antibiotics as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

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100

60 Other Watch group 40 Proportion (%) Proportion

20 29 29 30 30 28

0 TUR TUR TUR TUR TUR 2013 2014 2015 2016 2017

Fig. 18.4 Relative consumption of Watch group antibiotics as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 18.7 Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

Percentage of total consumptiona Antibiotic group 2013 2014 2015 2016 2017 Core Access group 49.3 50.8 50.9 52.8 54.0 Watch group 28.8 28.9 30.4 30.1 28.2 Reserve group 0.10 0.11 0.12 0.14 0.18 Ungrouped 21.7 20.2 18.5 17.0 17.6 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The relative consumption of Watch agents remained reasonably consistent at around 28–30% of total antibiotic consumption. Consumption of ungrouped antibiotics represented 17.6% of consumption in 2017.

18.6 Analyses based on DDDs applied in 2019

18.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 18.5 (DDD values relevant to year) and Fig. 18.6 (2019 DDD values), and is summarized in Table 18.8.

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45 45 40 40 35 35 30 30 25 Parenteral 25 Parenteral 20 antibacterials 20 antibacterials Oral Oral 15 15 antibacterials antibacterials 10 10 5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 TUR TUR TUR TUR TUR TUR 2015 2016 2017 2015 2016 2017

Fig. 18.5 Total consumption of J01 Fig. 18.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values)

Table 18.8 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 39.8 (96) 39.9 (96) 34.9 (96) 34 (96) 33.8 (96) 29.5 (95) Parenteral J01 1.8 (4) 1.6 (4) 1.5 (4) 1.5 (4) 1.5 (4) 1.4 (5) Total 41.5 41.5 36.4 35.5 35.3 31.0 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The relative consumption of oral and parenteral formulations does not change with the application of the 2019 DDDs (oral formulations 96% applying older DDDs and 95% with the 2019 DDD values).

18.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 18.7 (DDD values relevant to year) and Fig. 18.8 (2019 DDD values), and is summarized in Table 18.9. As noted in section 18.6.1, total DID decreased by 14.8% in 2017.

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 17.1 DID in 2017 using the DDD values relevant to the year of data to 11.7 DID applying the 2019 DDD values – a reduction of 31.6% in absolute values. Relative consumption of beta-lactams falls from 47% to 37.7% of total J01 consumption when the 2019 DDD values are applied.

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45 Other J01 45 Other J01 antibacterials antibacterials 40 (J01G, J01R, 40 (J01G, J01R, J01X) J01X) 35 Quinolone 35 Quinolone antibacterials antibacterials 30 (J01M) 30 (J01M) Macrolides, Macrolides, 25 lincosamides and 25 lincosamides and streptogramins streptogramins 20 (J01F) 20 (J01F) Sulfonamides Sulfonamides 15 and trimethoprim 15 and trimethoprim (J01E) (J01E) 10 Other beta-lactams 10 Other beta-lactams DDD/1000 inhabitants per day (includes DDD/1000 inhabitants per day (includes cephalosporins) cephalosporins) 5 (J01D) 5 (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols TUR TUR TUR (J01B) TUR TUR TUR (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 18.7 Total consumption of J01 Fig. 18.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

Table 18.9 Absolute and relative consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 1.3 1.2 1.2 1.3 1.2 1.2 Tetracyclines (J01A) (3.1) (2.9) (3.3) (3.7) (3.4) (3.9) Amphenicols (J01B) – – – – – – 18.5 19.1 17.1 12.6 13 11.7 Beta-lactams (J01C) (44.6) (46) (47) (35.5) (36.7) (37.7) Other beta-lactams (includes 12 11.6 9.6 11.9 11.5 9.6 cephalosporins) (J01D) (28.9) (28) (26.4) (33.5) (32.5) (31) Sulfonamides and trimethoprim 0.4 0.3 0.3 0.4 0.3 0.3 (J01E) (1) (0.7) (0.8) (1.1) (0.8) (1) Macrolides, lincosamides and 4.8 4.7 4 4.8 4.7 4 streptogramins (J01F) (11.6) (11.3) (11) (13.5) (13.3) (12.9) 3.1 3 2.6 3.1 3 2.6 Quinolone antibacterials (J01M) (7.5) (7.2) (7.1) (8.7) (8.5) (8.4) Other J01 antibacterials (J01G, 1.5 1.6 1.7 1.5 1.6 1.7 J01R, J01X) (3.6) (3.9) (4.7) (4.2) (4.5) (5.5) Total 41.5 41.5 36.4 35.5 35.4 31 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

As the total DIDs decrease with the application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta- lactams generally increases: cephalosporins, for example, increased from 26.4% to 31%, the macrolides group from 11% to 12.9% and quinolones from 7.1% to 8.4% in 2017.

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18.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 18.9 (DDD values relevant to year) and Fig. 18.10 (2019 DDD values) for Core Access antibiotics, Fig. 18.11 (DDD values relevant to year) and Fig. 18.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 18.10.

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group Proportion (%) Proportion 54 (%) Proportion 51 53 46 20 20 43 45

0 0 TUR TUR TUR TUR TUR TUR 2015 2016 2017 2015 2016 2017

Fig. 18.9 Relative consumption of Core Fig. 18.10 Relative consumption of Core Access group antibacterials (applying DDD Access group antibacterials (applying 2019 values relevant to year)a DDD values)a

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion

20 20 35 35 30 30 28 33

0 0 TUR TUR TUR TUR TUR TUR 2015 2016 2017 2015 2016 2017

Fig. 18.11 Relative consumption of Watch Fig. 18.12 Relative consumption of Watch group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year)a DDD values)a

a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

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Table 18.10 Relative consumption of Core Access and Watch group antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 21.5 (51) 22.2 (53) 20 (54) 15.7 (43) 16.2 (45) 14.6 (46) Watch group 12.8 (30.4) 12.7 (30.1) 10.5 (28.2) 12.8 (35) 12.6 (35) 10.4 (33) Reserve group 0.1 (0) 0.1 (0) 0.1 (0) 0 (0) 0 (0) 0 (0) Ungrouped 7.8 (18) 7.2 (17) 6.5 (18) 7.6 (21) 7.2 (20) 6.5 (21) Total 42.2 42.1 37.1 36.2 36.0 31.6 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

18.7 Analysis by community and hospital sectors

The analyses presented in sections 18.1–18.6 are based on estimates of total consumption. Different patterns of consumption would be expected in the hospital and community sectors; analyses by these sectors can provide more detailed information to support stewardship activities. Disaggregated data for Turkey for the years 2015-2017 are presented in this report.

18.7.1 Consumption of antibacterials for systemic use (J01) in community and hospital sectors by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 18.13 (community consumption) and Fig. 18.14 (hospital consumption), and is summarized in Table 18.11.

45 45 40 40 35 35 30 30 25 Parenteral 25 Parenteral antibacterials antibacterials 20 20 Oral Oral 15 antibacterials 15 antibacterials 10 10

DDD/1000 inhabitants per day 5 DDD/1000 inhabitants per day 5 0 0 TUR TUR TUR TUR TUR TUR 2015 2016 2017 2015 2016 2017

Fig. 18.13 Community consumption of J01 Fig. 18.14 Hospital consumption of J01 antibacterials by route of administration antibacterials by route of administration

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Table 18.11 Community and hospital consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration Community consumption Hospital consumption

2015 2016 2017 2015 2016 2017 Oral J01 39.4 (98) 39.6 (98) 34.7 (99) 0.3 (24) 0.3 (22) 0.2 (19) Parenteral J01 0.7 (2) 0.6 (2) 0.5 (1) 1.1 (76) 1 (78) 1 (81) Total 40.1 40.2 35.2 1.4 1.2 1.2 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Community consumption represented 96.7% of total J01 consumption in 2017, at 35.2 DID in the community sector and 1.2 DID in the hospital sector.

Oral consumption dominated in the community sector, at 99% oral and 1% parenteral consumption in 2017. Hospital consumption was predominantly parenteral forms, at 81% of hospital consumption in 2017.

18.7.2 Consumption of antibacterials for systemic use (J01) in community and hospital sectors by pharmacological subgroup

The consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 18.15 (community consumption) and Fig. 18.16 (hospital consumption), and is summarized in Table 18.12.

45 Other J01 45 Other J01 antibacterials antibacterials 40 (J01G, J01R, 40 (J01G, J01R, J01X) J01X) 35 Quinolone 35 Quinolone antibacterials antibacterials 30 (J01M) 30 (J01M) Macrolides, Macrolides, 25 lincosamides and 25 lincosamides and streptogramins streptogramins 20 (J01F) 20 (J01F) Sulfonamides Sulfonamides 15 and trimethoprim 15 and trimethoprim (J01E) (J01E) 10 Other beta-lactams 10 Other beta-lactams DDD/1000 inhabitants per day DDD/1000 inhabitants per day (includes (includes 5 cephalosporins) 5 cephalosporins) (J01D) (J01D) 0 Beta-lactams 0 Beta-lactams (J01C) (J01C) Amphenicols Amphenicols TUR TUR TUR (J01B) TUR TUR TUR (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 18.15 Community consumption of J01 Fig. 18.16 Hospital consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup

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Table 18.12 Consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup Community consumption Hospital consumption

2015 2016 2017 2015 2016 2017 1.2 1.2 1.2 Tetracyclines (J01A) – – – (3) (3) (3.4) Amphenicols (J01B) – – – – – – 18.1 18.9 16.9 0.4 0.2 0.2 Beta-lactams (J01C) (45.1) (47) (48) (28.6) (16.7) (16.7) Other beta-lactams (includes 11.4 11 9.1 0.6 0.6 0.6 cephalosporins) (J01D) (28.4) (27.4) (25.9) (42.9) (50) (50) Sulfonamides and trimethoprim 0.3 0.3 0.3 – – – (J01E) (0.7) (0.7) (0.9) Macrolides, lincosamides and 4.7 4.6 3.9 0.1 0.1 0.1 streptogramins (J01F) (11.7) (11.4) (11.1) (7.1) (8.3) (8.3) 3 2.8 2.4 0.2 0.2 0.2 Quinolone antibacterials (J01M) (7.5) (7) (6.8) (14.3) (16.7) (16.7) Other J01 antibacterials (J01G, 1.4 1.5 1.5 0.1 0.2 0.2 J01R, J01X) (3.5) (3.7) (4.3) (7.1) (16.7) (16.7) Total 40.1 40.2 35.2 1.4 1.2 1.2 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Patterns of consumption were substantially different in the community and hospital sectors. Beta- lactam (J01C) consumption dominated in the community sector (48% of community consumption compared to 16.7% of hospital consumption in 2017). Cephalosporin consumption dominated in the hospital sector (50% of hospital consumption compared to 25.9% of community consumption).

There are insufficient data to conclude trends in consumption of different pharmacological subgroups in each of the two sectors.

18.7.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics in community and hospital sectors

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 18.17 (community) and Fig. 18.18 (hospital) for Core Access antibiotics, Fig. 18.19 (community) and Fig. 18.20 (hospital) for Watch group antibiotics, and is summarized in Table 18.13.

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group Proportion (%) Proportion (%) Proportion 52 53 55 20 20 31 29 26

0 0 TUR TUR TUR TUR TUR TUR 2015 2016 2017 2015 2016 2017

212 Turkey

Fig. 18.17 Relative consumption of Fig. 18.18 Relative consumption of Core Access group antibacterials – Core Access group antibacterials – community sectora hospital sectora

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion 56 58 47 20 20 30 29 27

0 0 TUR TUR TUR TUR TUR TUR 2015 2016 2017 2015 2016 2017

Fig. 18.19 Relative consumption of Watch Fig. 18.20 Relative consumption of Watch group antibacterials – community sectora group antibacterials – hospital sectora

a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 18.13 Relative consumption of Core Access, Watch and Reserve group antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category Community sector Hospital sector

2015 2016 2017 2015 2016 2017 Core Access group 21.1 (52) 21.9 (53) 19.7 (55) 0.4 (31) 0.4 (29) 0.3 (26) Watch group 12.2 (30) 12 (29) 9.7 (27) 0.7 (47) 0.7 (56) 0.7 (58) Reserve group 0 (0) 0 (0) 0 (0) 0 (4) 0.1 (5) 0.1 (5) Ungrouped 7.6 (19) 7 (17) 6.4 (18) 0.3 (18) 0.1 (11) 0.1 (10) Total 40.8 40.9 35.9 1.4 1.2 1.2 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Consumption of Core Access antibiotics dominated in the community sector (55% community, 26% hospital in 2017), while consumption of Watch agents dominated in the hospital sector (58%, compared to 27% in the community sector).

The Watch agents clarithromycin (2.88 DID, 8.3%), ciprofloxacin (1.82 DID, 5.3%), cefixime (1.20 DID, 3.5%), cefdinir (1.18 DID, 3.4%) and cefpodoxime (0.8 DID, 2.3%) combined constituted 22.8% of community consumption of J01 oral antibacterials in 2017. Levels of consumption of these three agents in the hospital sector were relatively low (clarithromycin 0.06 DID, ciprofloxacin 0.02 DID and cefixime, cefdinir and cefpodoxime were not included in the top 10 oral agents).

As shown in Table 18.1, parenteral agents comprised around 4% of total J01 consumption in 2017, but represented 1% of community consumption and 81% of hospital consumption (Table 18.10). Within this, the Watch group third-generation cephalosporin ceftriaxone represented 0.20 DID (38.6%)

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of community injection consumption and 0.23 DID (23.2%) of hospital injection consumption in 2017. Small volumes of consumption of Reserve agents teicoplanin (0.03 DID) and colistin (0.03 DID) were reported in hospitals in 2017.

18.8 Discussion

The analyses in this report are based on sales records of wholesalers available through the comprehensive track and trace system operated by the Government of Turkey (Turkish Pharmaceuticals and Medical Devices Agency, 2013).

Estimates of total consumption were reasonably stable in the period 2013–2016 (42.4 DID in 2013, 41.5 DID in 2016), with a substantial fall to 36.4 DID in 2017. The most recent falls are consistent with sustained efforts since 2014 to support more appropriate use of antibacterials in Turkey through education and interventions.

The relative consumption of parenteral antibacterials remained stable across the years analysed, constituting 4% of total J01 consumption in 2017.

Relative consumption of beta-lactams increased slightly over time, representing 47% of J01 consumption in 2017. There were small increases in relative consumption of macrolide antibiotics and decreases in consumption of cephalosporins over the period analysed.

Disaggregated data for the years 2015–2017 are presented in this report. The data illustrate that most consumption occured in the community (96.7% of total J01 consumption) and show substantial differences in patterns of consumption of pharmacological subgroups in the two sectors. Beta- lactam (J01C) consumption dominated in the community sector, while cephalosporin consumption dominated in the hospital sector. The relative consumption of Watch group agents dominated in the hospital sector, at 58% compared to 27% in the community sector. These analyses by sector can provide more detailed information to support stewardship activities.

Of the top 10 oral agents, five are included in the WHO Watch group of antibacterials – clarithromycin (macrolides), ciprofloxacin (quinolones), and cefixime, cefdinir and cefpodoxime (third-generation cephalosporins). Clarithromycin (8.5%), ciprofloxacin (5.2%), cefixime (3.4%), cefdinir (3.4%) and cefpodoxime (2.5%) together comprised 23% of J01 oral agent consumption.

The Watch group third-generation cephalosporin ceftriaxone constituted 28.5% of the total consumption of J01 parenteral formulations in 2017.

Watch group agents (oral and parenteral combined) comprised 28.2% of total consumption in 2017.

214 Turkey

Clarithromycin is listed on the EML as a first-choice option for severe community-acquired pneumonia and as a second-choice option for pharyngitis.

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with EML recommendations.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 36.4 DID in 2017 using DDD values relevant to year of data to 31.0 DID applying the 2019 DDD values – a reduction of 14.8%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 17.1 DID in 2017 using the DDD values relevant to the year of data to 11.7 DID applying the 2019 DDD values – a reduction of 31.6% in absolute values.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in Turkey and can help to identify areas for further investigation, allowing the development of targeted interventions to address potential problems identified in the consumption of antibacterials. Interventions targeting medicines should be supported by evidence-based guidelines and treatment protocols.

Total DID decreased by 14.3% when the new 2019 DDDs were applied, independent of any intervention by government, agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

References

Turkish Pharmaceuticals and Medical Devices Agency (2013). Proje Tanıtımı [Project definition]. In: İlaç Takip Sistemi [Drug tracking system] [website]. Ankara: TechN’ Arts (http://its.technarts.com/ content.php?Id=69#.XH-604gzbZn, accessed 1 April 2019) (in Turkish).

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216 Uzbekistan

19. UZBEKISTAN

19.1 Data source and years of data collection

Uzbekistan provided data for each of the seven years of data collection (2011–2017). The main sources were import records provided by the drug agency. Data derived from importation records will be affected by the cycles of procurement and delivery, potentially giving rise to fluctuations in estimates of consumption that do not relate to actual use of antibacterials by patients and health-care facilities.

19.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

The data show fluctuations in total consumption of J01 antibacterials over time on a general trend of increasing consumption.

UZB UZB UZB UZB UZB UZB UZB 2011 2012 2013 2014 2015 2016 2017

Fig. 19.1 Total consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose.

The relative consumption of parenteral antibacterials varied across the years analysed, ranging from 42% in 2011 to 77% in 2013. Parenteral formulations accounted for 50% of total J01 consumption in 2017 (Table 19.1).

217 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

The highest levels of consumption were in beta-lactams (J01C), at 2.8 DID in 2011 and 7.3 DID in 2017. Different patterns of consumption would be expected in the hospital and community sectors.

Table 19.1 Total consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 Route of administration 3.7 1.8 2.3 6 5 7 6.9 Oral J01 (58) (23) (23) (57) (48) (37) (50) 2.7 6 8 4.5 5.5 11.8 6.9 Parenteral J01 (42) (77) (77) (43) (52) (63) (50) Total 6.4 7.9 10.3 10.4 10.5 18.8 13.9 Class of antibacterial agents 0.3 0.2 0.5 0.6 0.6 0.1 Tetracyclines (J01A) – (3.8) (1.9) (4.8) (5.7) (3.2) (0.7) 0.2 0.2 0.7 0.1 0.4 0.4 Amphenicols (J01B) – (2.5) (1.9) (6.7) (1) (2.1) (2.9) 2.8 4.3 5.6 3.9 4.9 8.9 7.3 Beta-lactams (J01C) (43.8) (54.4) (54.4) (37.5) (46.7) (47.3) (52.5) Other beta-lactams (includes cephalosporins) 2.1 2.4 3.7 3.1 2.4 6.8 3.8 (J01D) (32.8) (30.4) (35.9) (29.8) (22.9) (36.2) (27.3) Sulfonamides and trimethoprim (J01E) – – – – – – – Macrolides, lincosamides and streptogramins 1.2 0.3 0.2 1.6 1.4 1.6 1.8 (J01F) (18.8) (3.8) (1.9) (15.4) (13.3) (8.5) (12.9) 0.1 0.1 0.2 Quinolone antibacterials (J01M) – – – – (1.6) (1.3) (1.9) 0.2 0.3 0.3 0.6 1.1 0.4 0.4 Other J01 antibacterials (J01G, J01R, J01X) (3.1) (3.8) (2.9) (5.8) (10.5) (2.1) (2.9) Total 6.4 7.9 10.3 10.4 10.5 18.8 13.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

There is evidence of increasing relative consumption of beta-lactams (J01C), at 43.8% in 2011 and 52.2% in 2017, and some evidence of decreasing consumption of cephalosporins (J01D), at 32.8% in 2011 and 27.3% in 2017, and macrolides (J01F), at 18.8% in 2011 and 12.9% in 2017. Reported consumption of quinolones (J01M), at 1.6% in 2011 and 0% in 2017, requires confirmation at local level.

The relative consumption of cephalosporins and quinolones combined decreased over time (34.4% in 2011, 27.3% in 2017), driven mostly by decreases in consumption of cephalosporins.

19.3 Relative consumption by choice of agent

19.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

218 Uzbekistan

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2011–2017 is shown in Fig. 19.2 and summarized in Table 19.2.

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 UZB UZB UZB UZB UZB UZB UZB 2011 2012 2013 2014 2015 2016 2017

Fig. 19.2 Relative consumption of cephalosporins by generation

Table 19.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) 0.3 (15) 1.4 (61) 1.9 (52) 1 (33) 1 (40) 1 (15) 1.1 (28) Second-generation (J01DC) 0.2 (11) < 0.1 < 0.1 0.1 (4) 0.1 (5) 0.1 (2) < 0.1 Third-generation (J01DD) 1.5 (72) 0.9 (36) 1.7 (45) 1.9 (63) 1.3 (55) 5.6 (82) 2.7 (71) Fourth-generation (J01DE) < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Total 2.1 2.4 3.7 3.1 2.4 6.8 3.8 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The pattern of consumption of cephalosporin agents fluctuated over time. Generally, consumption of first-generation agents, almost all cefazolin, increased (15% of total cephalosporin use in 2011 and 28% in 2017). There was little consumption of second-generation agents. Consumption of Watch group third-generation agents dominated (71% of total cephalosporin consumption in 2017). Ceftriaxone and cefotaxime comprised 66% and 27% of third-generation agent consumption in 2017. Only small volumes of consumption of fourth-generation cephalosporins (Reserve agents) were reported.

19.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Little or no consumption of quinolone antibacterials (J01M) was reported during the years analysed (Table 19.1).

19.4 The 10 most consumed agents

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19.4.1 The 10 most consumed agents – oral formulation

Table 19.3 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

Table 19.3 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Amoxicillin 3.38 3.38 3.38 3.38 3.38 3.38 3.38 3.38 3.38 3.38 Azithromycin 1.28 1.28 1.28 1.28 1.28 1.28 1.28 1.28 1.28 Ampicillin 1.09 1.09 1.09 1.09 1.09 1.09 1.09 1.09 Erythromycin 0.35 0.35 0.35 0.35 0.35 0.35 0.35 Chloramphenicol 0.29 0.29 0.29 0.29 0.29 0.29 Amoxicillin and enzyme 0.12 0.12 0.12 0.12 0.12 inhibitor Cefpodoxime 0.11 0.11 0.11 0.11 Doxycycline 0.11 0.11 0.11 Roxithromycin 0.06 0.06 Clarithromycin 0.06 Total consumption for 6.85 6.79 6.73 6.62 6.51 6.39 6.10 5.75 4.67 3.38 this group of agents Total consumption for 6.95 6.95 6.95 6.95 6.95 6.95 6.95 6.95 6.95 6.95 all oral J01 agents Proportion (%) of total consumption for oral 98.6% 97.7% 96.8% 95.3% 93.7% 92.0% 87.8% 82.8% 67.2% 48.7% J01 antibacterials a DDD: daily defined dose.

The 10 listed oral agents represent just over 96% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, five are included in the WHO Watch group of antibacterials – azithromycin, erythromycin, roxithromycin and clarithromycin (macrolides), and cefpodoxime (third-generation cephalosporin).

Azithromycin alone constituted just over 18.5% of total consumption of J01 oral antibacterials in 2017. Together with azithromycin, erythromycin (5%), roxithromycin (0.9%), clarithromycin (0.9%) and cefpodoxime (1.6%), these Watch agents comprised 26.9% of J01 oral agent consumption.

19.4.2 The 10 most consumed agents – parenteral formulation

Table 19.4 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

As shown in Table 19.1, parenteral agents comprised around 50% of total J01 consumption in 2017. Within this, the Watch group third-generation cephalosporins ceftriaxone (26.1%) and cefotaxime (10.8%) constituted almost 37% of the consumption of J01 injection formulations.

220 Uzbekistan

Table 19.4 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Ceftriaxone 1.80 1.80 1.80 1.80 1.80 1.80 1.80 1.80 1.80 1.80 Benzylpenicillin 1.44 1.44 1.44 1.44 1.44 1.44 1.44 1.44 1.44 Cefazolin 1.07 1.07 1.07 1.07 1.07 1.07 1.07 1.07 Ampicillin 0.96 0.96 0.96 0.96 0.96 0.96 0.96 Cefotaxime 0.75 0.75 0.75 0.75 0.75 0.75 Combinations of penicillins 0.27 0.27 0.27 0.27 0.27 Gentamicin 0.20 0.20 0.20 0.20 Streptomycin 0.11 0.11 0.11 Chloramphenicol 0.08 0.08 Kanamycin 0.07 Total consumption for this 6.75 6.68 6.60 6.49 6.29 6.02 5.27 4.30 3.24 1.80 group of agents Total consumption for all 6.91 6.91 6.91 6.91 6.91 6.91 6.91 6.91 6.91 6.91 parenteral J01 agents Proportion (%) of total consumption for parenteral 97.7% 96.7% 95.6% 94.0% 91.1% 87.1% 76.3% 62.3% 46.9% 26.1% J01 antibacterials a DDD: daily defined dose.

19.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 19.3 and Fig. 19.4, and is summarized in Table 19.5.

100

60 Other Core Access group 40 72

Proportion (%) Proportion 62 61 63 56 53 20 42

0 UZB UZB UZB UZB UZB UZB UZB 2011 2012 2013 2014 2015 2016 2017

Fig. 19.3 Relative consumption of Core Access group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

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100

60 Other Watch group 40 Proportion (%) Proportion

46 20 34 38 33 25 15 20 0 UZB UZB UZB UZB UZB UZB UZB 2011 2012 2013 2014 2015 2016 2017

Fig. 19.4. Relative consumption of Watch group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

Table 19.5 Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

Percentage of total consumptiona Category 2011 2012 2013 2014 2015 2016 2017 Core Access group 41.6 72.3 62.0 56.5 61.1 53.0 63.5 Watch group 45.9 15.2 19.8 33.8 25.3 38.2 32.5 Reserve group 0.55 0.23 0.32 0.16 0.12 0.10 0.07 Ungrouped 11.9 12.2 17.9 9.5 13.5 8.7 3.9 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The relative consumption of Watch agents varied considerably over the years analysed, representing 32.5% of total antibiotic consumption in 2017. Consumption of Reserve group agents was low.

19.6 Analyses based on DDDs applied in 2019

19.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 19.5 (DDD values relevant to year) and Fig. 19.6 (2019 DDD values), and is summarized in Table 19.6.

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20 20

15 15

Parenteral Parenteral 10 10 antibacterials antibacterials Oral Oral antibacterials antibacterials 5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 UZB UZB UZB UZB UZB UZB 2015 2016 2017 2015 2016 2017

Fig. 19.5 Total consumption of J01 Fig. 19.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values)

Table 19.6 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 5 (48) 7 (37) 6.9 (50) 4.3 (50) 6 (37) 5.8 (47) Parenteral J01 5.5 (52) 11.8 (63) 6.9 (50) 4.2 (50) 10.3 (63) 6.5 (53) Total 10.5 18.8 13.9 8.6 16.3 12.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The relative consumption of oral and parenteral formulations does not change substantially with the application of the 2019 DDDs (oral 50% applying older values and 47% with the 2019 DDD values).

19.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 19.7 (DDD values relevant to year) and Fig. 19.8 (2019 DDD values), and is summarized in Table 19.7. As noted in section 19.6.1, total DIDs decreased by 11.5% in 2017.

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 7.3 DID in 2017 using the DDD values relevant to the year of data to 5.5 DID applying the 2019 DDD values – a reduction of 24.6% in absolute values. Relative consumption of beta-lactams falls from 52.2% to 44.7% of total J01 consumption when the 2019 DDD values are applied.

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DDD/1000 inhabitants per day (includes DDD/1000 inhabitants per day (includes cephalosporins) cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols UZB UZB UZB (J01B) UZB UZB UZB (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 19.7 Total consumption of J01 Fig. 19.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values)

Table 19.7 Consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 0.6 0.6 0.1 0.6 0.6 0.1 Tetracyclines (J01A) (5.7) (3.2) (0.7) (7) (3.7) (0.8) 0.1 0.4 0.4 0.1 0.4 0.4 Amphenicols (J01B) (1) (2.1) (2.9) (1.2) (2.5) (3.3) 4.9 8.9 7.3 2.9 6.5 5.5 Beta-lactams (J01C) (46.7) (47.3) (52.5) (33.7) (39.9) (44.7) Other beta-lactams (includes 2.4 6.8 3.8 2.4 6.8 4.1 cephalosporins) (J01D) (22.9) (36.2) (27.3) (27.9) (41.7) (33.3) Sulfonamides and trimethoprim – – – – – – (J01E) Macrolides, lincosamides and 1.4 1.6 1.8 1.4 1.7 1.8 streptogramins (J01F) (13.3) (8.5) (12.9) (16.3) (10.4) (14.6) Quinolone antibacterials (J01M) – – – – – – Other J01 antibacterials (J01G, 1.1 0.4 0.4 1.1 0.4 0.4 J01R, J01X) (10.5) (2.1) (2.9) (12.8) (2.5) (3.3) Total 10.5 18.8 13.9 8.6 16.3 12.3 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

As the total DIDs decrease with the application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta- lactams generally increases: cephalosporins, for example, increased from 27.3% to 33.3% and the macrolides group from 12.9% to 14.6% in 2017.

224 Uzbekistan

19.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 19.9 (DDD values relevant to year) and Fig. 19.10 (2019 DDD values) for Core Access antibiotics, Fig. 19.11 (DDD values relevant to year) and Fig. 19.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 19.8.

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group

Proportion (%) Proportion 61 63 (%) Proportion 53 52 56 20 20 46

0 0 UZB UZB UZB UZB UZB UZB 2015 2016 2017 2015 2016 2017

Fig. 19.9 Relative consumption of Core Fig. 19.10 Relative consumption of Core Access group antibacterials (applying DDD Access group antibacterials (applying 2019 values relevant to year)a DDD values)a

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion

20 20 44 39 38 33 25 31

0 0 UZB UZB UZB UZB UZB UZB 2015 2016 2017 2015 2016 2017

Fig. 19.11 Relative consumption of Watch Fig. 19.12 Relative consumption of Watch group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year)a DDD values)a

a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The effect of applying the 2019 DDD values is to decrease slightly the proportion of total use that is Core Access group antibiotics (from 63% to 56% in 2017) and increase slightly the proportion of total use that is Watch group antibiotics (from 32.5% to 39% in 2017).

225 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 19.8 Relative consumption of Core Access and Watch group antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 6.4 (61) 10 (53) 8.8 (63) 4.5 (52) 7.5 (46) 7 (56) Watch group 2.6 (25.3) 7.2 (38.2) 4.5 (32.5) 2.7 (31) 7.2 (44) 4.8 (39) Reserve group 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Ungrouped 1.4 (13) 1.6 (9) 0.5 (4) 1.4 (16) 1.6 (10) 0.5 (4) Total 10.48 18.81 13.85 8.55 16.35 12.34 a Total percentages may vary slightly owing to rounding. a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

19.7 Discussion

The analyses in this report are based on import records.

Estimates of total consumption of J01 antibacterials fluctuated over the period 2011–2017, with a general trend to increasing consumption (6.4 DID in 2011, 13.9 DID in 2017).

The relative consumption of parenteral antibacterials varied considerably across the years analysed and constituted 50% of total J01 consumption in 2017.

Relative consumption of beta-lactams increased, offset by decreasing relative consumption of cephalosporins and macrolides. The low levels of consumption of quinolone antibacterials reported require local confirmation.

Of the top 10 oral agents in the J01 class, five are included in the WHO Watch group of antibacterials – azithromycin, erythromycin, roxithromycin and clarithromycin (macrolides), and cefpodoxime (third- generation cephalosporin). Azithromycin alone constituted just over 18.5% of total consumption of J01 oral antibacterials in 2017. Together, the five Watch agents comprised 26.9% of J01 oral agent consumption.

The Watch group third-generation cephalosporins ceftriaxone (26.1%) and cefotaxime (10.8%) together constituted almost 37% of the consumption of J01 injection formulations in 2017.

Clarithromycin is listed on the EML as a first-choice option for severe community-acquired pneumonia and as a second-choice option for pharyngitis.

226 Uzbekistan

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with WHO EML recommendations.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 13.9 DID in 2017 using DDD values relevant to year of data to 12.3 DID applying the 2019 DDD values – a reduction of 11.5%. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 7.3 DID in 2017 using the DDD values relevant to the year of data to 5.5 DID applying the 2019 DDD values – a reduction of 24.6% in absolute values.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in Uzbekistan and can help to identify areas for further investigation, allowing the development of targeted interventions to address potential problems identified in the consumption of antibacterials. Interventions targeting medicines should be supported by evidence-based guidelines and treatment protocols.

Total DID decreased by 11.5% when the new 2019 DDDs were applied, independent of any intervention by government, agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

Reference

227 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

20. KOSOVO7

20.1 Data source and years of data collection

Kosovo7 provided data for each of the seven years of data collection (2011–2017). The main sources were import records provided by the drug agency. Data derived from importation records will be affected by the cycles of procurement and delivery, potentially giving rise to fluctuations in estimates of consumption that do not relate to actual use of antibacterials by patients and health-care facilities.

20.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

The data show fluctuations in total consumption of J01 antibacterials over time. The reasons for this fluctuating pattern are unclear and require further investigation. There may be some influence of medicine import cycles.

The relative consumption of parenteral antibacterials remained reasonably stable across the years, analysed at around 9–10% of total J01 consumption in the period 2013–2017 (Table 20.1).

The highest levels of consumption were in beta-lactams (J01C), at 12.8 DID in 2011 and 11.4 DID in 2017 (Table 20.1). There is some evidence of decreasing consumption of cephalosporin antibacterials (J01D), with 4.9 DID in 2011 and 3.4 DID in 2017.

These observations relate to total consumption. Different patterns of consumption would be expected in the hospital and community sectors.

There is some evidence of increasing relative consumption of beta-lactams (J01C), at 48.5% in 2011 and 54.3% in 2017, and decreasing relative consumption of cephalosporins (J01D), at 18.6% in 2011 and 16.2% in 2017 (Table 20.1).

The relative consumption of cephalosporins and quinolones combined decreased slightly over time (31% in 2011, 27% in 2017).

7 All references to Kosovo in this publication should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

228 KOSOVO (in accordance with Security Council resolution 1244 (1999))

30 Other J01 antibacterials (J01G, J01R, J01X) 25 a Quinolone antibacterials (J01M) 20 Macrolides, lincosamides and streptogramins (J01F) 15 Sulfonamides and trimethoprim (J01E)

10 Other beta-lactams (includes cephalosporins) (J01D) Beta-lactams (J01C) DDD/1000 inhabitants per day 5 Amphenicols (J01B) Tetracyclines (J01A) 0

KOSb KOSb KOSb KOSb KOSb KOSb KOSb 2011 2012 2013 2014 2015 2016 2017

Fig. 20.1 Total consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose. b In accordance with Security Council resolution 1244 (1999).

Table 20.1 Total consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 Route of administration 25.1 21.7 17.3 18.8 20.9 17.4 19.1 Oral J01 (95) (84) (91) (91) (91) (90) (91) 1.3 4.2 1.7 2 2.2 1.8 1.9 Parenteral J01 (5) (16) (9) (9) (9) (10) (9) Total 26.4 26.0 19.0 20.8 23.1 19.2 21.0 Class of antibacterial agents 0.7 0.1 0.5 0.9 0.6 0.5 Tetracyclines (J01A) – (2.7) (0.4) (2.6) (4.3) (2.6) (2.4) Amphenicols (J01B) – – – – – – – 12.8 13.1 10.1 10.6 11.2 10 11.4 Beta-lactams (J01C) (48.5) (50.4) (53.2) (51) (48.5) (52.1) (54.3) Other beta-lactams (includes cephalosporins) 4.9 6.9 4.3 3.9 4.4 4.2 3.4 (J01D) (18.6) (26.5) (22.6) (18.8) (19) (21.9) (16.2) 1.8 0.8 0.7 0.8 1 1.5 0.4 Sulfonamides and trimethoprim (J01E) (6.8) (3.1) (3.7) (3.8) (4.3) (7.8) (1.9) Macrolides, lincosamides and streptogramins 2.6 1.7 1.3 1.9 2.7 1.5 2.1 (J01F) (9.8) (6.5) (6.8) (9.1) (11.7) (7.8) (10) 3 2.5 1.9 1.9 2.4 1.6 2.4 Quinolone antibacterials (J01M) (11.4) (9.6) (10) (9.1) (10.4) (8.3) (11.4) 0.5 0.9 0.3 0.7 0.9 0.4 0.7 Other J01 antibacterials (J01G, J01R, J01X) (1.9) (3.5) (1.6) (3.4) (3.9) (2.1) (3.3) Total 26.4 26.0 19.0 20.8 23.1 19.2 21.0 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

229 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

20.3 Relative consumption by choice of agent

20.3.1 Relative consumption of cephalosporins by generation

Third- and fourth-generation cephalosporins have a broader spectrum of activity than first- and second-generation agents, with enhanced coverage of both Gram-positive and Gram-negative organisms. Third-generation cephalosporins are included in the WHO Watch group of antibiotics and fourth-generation agents in the Reserve group.

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2011–2017 is shown in Fig. 20.2 and summarized in Table 20.2. Table 20.3 shows the most consumed agents within each of the generations of cephalosporin agents.

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 KOSa KOSa KOSa KOSa KOSa KOSa KOSa 2011 2012 2013 2014 2015 2016 2017

Fig. 20.2 Relative consumption of cephalosporins by generation a All references to Kosovo in this publication should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

Table 20.2 Relative consumption of cephalosporins by generation

DDD/1 000 inhabitants per daya (% of totalb) Class of antibacterial agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) 2.1 (42) 3.2 (46) 1 (24) 1 (25) 1 (24) 0.7 (17) 0.7 (22) Second-generation (J01DC) 1.5 (31) 1.6 (24) 1.9 (45) 1.3 (34) 1.3 (29) 1.1 (25) 1 (31) Third-generation (J01DD) 1.3 (27) 2.1 (30) 1.3 (31) 1.6 (41) 2 (47) 2.4 (57) 1.6 (47) Fourth-generation (J01DE) < 0.1 < 0.1 < 0.1 – – – – Total 4.9 6.9 4.3 3.9 4.3 4.2 3.4 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Consumption of first-generation agents decreased (42% of total cephalosporin use in 2011 and 22% in 2017), with cefalexin the most consumed first-generation agent. Second-generation agents, mostly cefuroxime and cefaclor, represented 31% of cephalosporin consumption in 2017. Consumption of Watch group third-generation agents increased over time (27% of total cephalosporin use in 2011 and 47% in 2017). Ceftriaxone and cefixime comprised 62% and 29% of third-generation agent consumption in 2017. Only small volumes of consumption of fourth-generation cephalosporins (Reserve agents) were reported.

230 KOSOVO (in accordance with Security Council resolution 1244 (1999))

Table 20.3 Most consumed agents within each generation of cephalosporins

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 First-generation (J01DB) Cefalexin 2 (94) 1.3 (41) 1 (96) 0.8 (84) 0.9 (89) 0.6 (80) 0.5 (70) Cefazolin < 0.1 1.9 (59) < 0.1 0.1 (13) < 0.1 0.1 (18) < 0.1 Second-generation (J01DC) Cefuroxime 0.1 (9) 0.6 (34) 0.6 (33) 0.5 (34) 0.3 (27) 0.3 (25) 0.5 (47) Cefaclor 1.4 (91) 1.1 (66) 1.3 (67) 0.9 (66) 0.9 (73) 0.8 (75) 0.6 (53) Third-generation (J01DD) Ceftriaxone 0.7 (51) 1.5 (72) 1.1 (81) 1.2 (73) 1 (50) 1.3 (56) 1 (62) Cefixime 0.6 (49) 0.6 (28) 0.3 (19) 0.4 (25) 1 (48) 1 (42) 0.5 (29) a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for the nominated generation of cephalosporins.

20.3.2 Relative consumption of agents within fluoroquinolones (J01MA)

Quinolone antibacterials (J01M) represented 2.4 DID (11%) of total J01 consumption in 2017, with fluoroquinolones comprising 2.0 DID – 83.3% of quinolone consumption. Two fluoroquinolones – ciprofloxacin and levofloxacin – dominated, representing 66% and 31% of fluoroquinolone consumption in 2017 (Table 20.4). The overall pattern, however, was of some reductions in levels of consumption of fluoroquinolones.

Table 20.4 Relative consumption of agents within fluoroquinolones (J01MA)

DDD/1 000 inhabitants per daya (% of totalb) Agents 2011 2012 2013 2014 2015 2016 2017 Ofloxacin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Ciprofloxacin 2.6 (97) 2.1 (91) 1.3 (77) 1.3 (74) 1.5 (72) 1.3 (85) 1.3 (66) Norfloxacin < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 Levofloxacin < 0.1 0.1 (6) 0.4 (22) 0.4 (23) 0.5 (26) 0.2 (11) 0.6 (31) Moxifloxacin < 0.1 < 0.1 – < 0.1 < 0.1 – – Total 2.6 2.3 1.7 1.7 2.1 1.5 2.0 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. Note: this table includes only those medicines for which the absolute consumption was 0.1 DID or more in any year, or the medicine constituted more than 10% of the total consumption for fluoroquinolones.

20.4 The 10 most consumed agents

231 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

20.4.1 The 10 most consumed agents – oral formulation

Table 20.5 summarizes consumption of the oral agents that comprise the 10 most consumed in 2017.

Table 20.5 The 10 most consumed agents – oral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Amoxicillin and enzyme 5.80 5.80 5.80 5.80 5.80 5.80 5.80 5.80 5.80 5.80 inhibitor Amoxicillin 3.88 3.88 3.88 3.88 3.88 3.88 3.88 3.88 3.88 Ciprofloxacin 1.32 1.32 1.32 1.32 1.32 1.32 1.32 1.32 Clarithromycin 1.11 1.11 1.11 1.11 1.11 1.11 1.11 Phenoxymethylpenicillin 0.72 0.72 0.72 0.72 0.72 0.72 Azithromycin 0.63 0.63 0.63 0.63 0.63 Levofloxacin 0.62 0.62 0.62 0.62 Ampicillin 0.61 0.61 0.61 Cefaclor 0.55 0.55 Cefalexin 0.52 Total consumption for 15.77 15.25 14.69 14.08 13.46 12.83 12.11 11.00 9.68 5.80 this group of agents Total consumption for 19.13 19.13 19.13 19.13 19.13 19.13 19.13 19.13 19.13 19.13 all oral J01 agents Proportion (%) of total consumption for oral 82.5% 79.7% 76.8% 73.6% 70.4% 67.1% 63.3% 57.5% 50.6% 30.3% J01 antibacterials a DDD: daily defined dose.

The 10 listed oral agents represent just over 82% of total oral antibiotic consumption in 2017. Of the top 10 oral agents, four are included in the WHO Watch group of antibacterials – ciprofloxacin and levofloxacin (quinolones), and clarithromycin and azithromycin (macrolides).

The Watch agents ciprofloxacin (6.9%), clarithromycin (5.8%), azithromycin (3.3%) and levofloxacin (3.2%) together comprised around 19.2% of J01 oral agent consumption in 2017.

20.4.2 The 10 most consumed agents – parenteral formulation

Table 20.6 summarizes consumption of the parenteral agents that comprise the 10 most consumed in 2017.

As shown in Table 20.1, parenteral agents comprised around 9% of total J01 consumption in 2017. Within this, the Watch group third-generation cephalosporin ceftriaxone comprised just over half of all J01 injection consumption (51.5%).

232 KOSOVO (in accordance with Security Council resolution 1244 (1999))

Table 20.6 The 10 most consumed agents – parenteral formulation (2017)

DDD/1 000 inhabitants per daya Agent Top 10 Top 9 Top 8 Top 7 Top 6 Top 5 Top 4 Top 3 Top 2 Top 1 Ceftriaxone 0.98 0.98 0.98 0.98 0.98 0.98 0.98 0.98 0.98 0.98 Gentamicin 0.40 0.40 0.40 0.40 0.40 0.40 0.40 0.40 0.40 Ampicillin 0.18 0.18 0.18 0.18 0.18 0.18 0.18 0.18 Benzylpenicillin 0.10 0.10 0.10 0.10 0.10 0.10 0.10 Cefazolin 0.09 0.09 0.09 0.09 0.09 0.09 Metronidazole 0.04 0.04 0.04 0.04 0.04 Amikacin 0.03 0.03 0.03 0.03 Imipenem and enzyme 0.02 0.02 0.02 inhibitor Piperacillin and enzyme 0.02 0.02 inhibitor Vancomycin 0.01 Total consumption for this 1.87 1.86 1.84 1.81 1.79 1.75 1.66 1.56 1.38 0.98 group of agents Total consumption for all 1.91 1.91 1.91 1.91 1.91 1.91 1.91 1.91 1.91 1.91 parenteral J01 agents Proportion (%) of total consumption for parenteral 98.2% 97.6% 96.4% 95.2% 93.8% 91.9% 86.9% 81.7% 72.5% 51.5% J01 antibacterials a DDD: daily defined dose.

20.5 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 20.3 and Fig. 20.4, and is summarized in Table 20.7.

100

60 Other

40 Core Access group 66 67 65 67 65 65 Proportion (%) Proportion 62 20

0 KOSb KOSb KOSb KOSb KOSb KOSb KOSb 2011 2012 2013 2014 2015 2016 2017

Fig. 20.3 Relative consumption of Core Access group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01). b All references to Kosovo in this publication should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

233 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

100

60 Other Watch group 40 Proportion (%) Proportion

20 28 25 24 26 31 28 29 0 KOSb KOSb KOSb KOSb KOSb KOSb KOSb 2011 2012 2013 2014 2015 2016 2017

Fig. 20.4 Relative consumption of Watch group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01). b All references to Kosovo in this publication should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

Table 20.7 Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

Percentage of total consumptiona Category 2011 2012 2013 2014 2015 2016 2017 Core Access group 65.9 66.7 64.9 66.6 62.3 65.4 64.8 Watch group 27.6 24.6 24.1 26.0 30.5 28.4 28.7 Reserve group 0.00 0.03 0.02 0.00 0.01 0.00 0.00 Ungrouped 6.5 8.7 11.0 7.4 7.1 6.3 6.5 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The relative consumption of Watch agents remained consistent at around 28–30% of total antibiotic consumption in the period 2015–2017.

20.6 Analyses based on DDDs applied in 2019

20.6.1 Total consumption of antibacterials for systemic use (J01) by route of administration

The consumption of oral and parenteral (injectable) formulations of J01 antibacterials is shown in Fig. 20.5 (DDD values relevant to year) and Fig. 20.6 (2019 DDD values), and is summarized in Table 20.8.

234 KOSOVO (in accordance with Security Council resolution 1244 (1999))

25 25

20 20

15 15 Parenteral Parenteral antibacterials antibacterials 10 Oral 10 Oral antibacterials antibacterials 5 5 DDD/1000 inhabitants per day DDD/1000 inhabitants per day 0 0 KOSa KOSa KOSa KOSa KOSa KOSa 2015 2016 2017 2015 2016 2017

Fig. 20.5 Total consumption of J01 Fig. 20.6 Total consumption of J01 antibacterials by route of administration antibacterials by route of administration (applying DDD values relevant to year) (applying 2019 DDD values) a All references to Kosovo in this publication should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

Table 20.8 Total consumption of J01 antibacterials by route of administration

DDD/1 000 inhabitants per daya (% of totalb)

Route of administration DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Oral J01 20.9 (91) 17.4 (90) 19.1 (91) 17.9 (90) 14.5 (89) 15.9 (90) Parenteral J01 2.2 (9) 1.8 (10) 1.9 (9) 2.1 (10) 1.8 (11) 1.8 (10) Total 23.1 19.2 21.0 20.0 16.3 17.7 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

The relative consumption of oral and parenteral formulations does not change substantially with the application of the 2019 DDDs (oral 91% applying older values and 90% with the 2019 DDD values).

20.6.2 Consumption of antibacterials for systemic use (J01) by pharmacological subgroup

The total consumption of the pharmacological subgroups of J01 antibacterials is shown in Fig. 20.7 (DDD values relevant to year) and Fig. 20.8 (2019 DDD values), and is summarized in Table 20.9. As noted in section 20.6.1, total DID decreased by 15.7% in 2017.

235 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

DDD/1000 inhabitants per day 5 (includes DDD/1000 inhabitants per day 5 (includes cephalosporins) cephalosporins) (J01D) (J01D) Beta-lactams Beta-lactams 0 (J01C) 0 (J01C) Amphenicols Amphenicols KOSa KOSa KOSa (J01B) KOSa KOSa KOSa (J01B) 2015 2016 2017 Tetracyclines 2015 2016 2017 Tetracyclines (J01A) (J01A) Fig. 20.7 Total consumption of J01 Fig. 20.8 Total consumption of J01 antibacterials by pharmacological subgroup antibacterials by pharmacological subgroup (applying DDD values relevant to year) (applying 2019 DDD values) a All references to Kosovo in this publication should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

Table 20.9 Absolute and relative consumption of J01 antibacterials by pharmacological subgroup

DDD/1 000 inhabitants per daya (% of totalb)

Pharmacological subgroup DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 0.6 0.5 0.6 0.5 Tetracyclines (J01A) – – (2.6) (2.4) (3) (2.8) Amphenicols (J01B) – – – – – – 11.2 10 11.4 8 7 8.1 Beta-lactams (J01C) (48.5) (52.1) (54.3) (40) (42.9) (45.8) Other beta-lactams (includes 4.4 4.2 3.4 4.4 4.2 3.4 cephalosporins) (J01D) (19) (21.9) (16.2) (22) (25.8) (19.2) Sulfonamides and trimethoprim 1 1.5 0.4 1 1.5 0.4 (J01E) (4.3) (7.8) (1.9) (5) (9.2) (2.3) Macrolides, lincosamides and 2.7 1.5 2.1 2.8 1.5 2.1 streptogramins (J01F) (11.7) (7.8) (10) (14) (9.2) (11.9) 2.4 1.6 2.4 2.4 1.6 2.4 Quinolone antibacterials (J01M) (10.4) (8.3) (11.4) (12) (9.8) (13.6) Other J01 antibacterials (J01G, 0.9 0.4 0.7 0.9 0.4 0.7 J01R, J01X) (3.9) (2.1) (3.3) (4.5) (2.5) (4) Total 23.1 19.2 21 20 16.3 17.7 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding.

Application of the 2019 DDD values has the greatest impact on the estimates of consumption of beta-lactam antibacterials (J01C), reducing from 11.4 DID in 2017 using the DDD values relevant to the year of data to 8.1 DID applying the 2019 DDD values – a reduction of 29% in absolute values. Relative consumption of beta-lactams falls from 54.3% to 45.8% of total J01 consumption when the 2019 DDD values are applied.

236 KOSOVO (in accordance with Security Council resolution 1244 (1999))

As the total DIDs decrease with the application of 2019 DDD values, the denominator for calculations is smaller, meaning that the relative consumption of pharmacological subgroups other than beta-lactams generally increases: cephalosporins, for example, increased from 16.2% to 19.2%, the macrolides group from 10% to 11.9% and quinolones from 11.4% to 13.6% in 2017.

20.6.3 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 20.9 (DDD values relevant to year) and Fig. 20.10 (2019 DDD values) for Core Access antibiotics, Fig. 20.11 (DDD values relevant to year) and Fig. 20.12 (2019 DDD values) for Watch group antibiotics, and is summarized in Table 20.10.

100 100

80 80

60 Other 60 Other Core Access Core Access 40 group 40 group

Proportion (%) Proportion 65 65 (%) Proportion 62 56 59 58 20 20

0 0 KOSb KOSb KOSb KOSb KOSb KOSb 2015 2016 2017 2015 2016 2017

Fig. 20.9 Relative consumption of Core Fig. 20.10 Relative consumption of Core Access group antibacterials (applying DDD Access group antibacterials (applying 2019 values relevant to year)a DDD values)a

100 100

80 80

60 60 Other Other Watch group Watch group 40 40 Proportion (%) Proportion (%) Proportion

20 20 35 31 28 29 33 34

0 0 KOSb KOSb KOSb KOSb KOSb KOSb 2015 2016 2017 2015 2016 2017

Fig. 20.11 Relative consumption of Watch Fig. 20.12 Relative consumption of Watch group antibacterials (applying DDD values group antibacterials (applying 2019 relevant to year)a DDD values)a a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01). b All references to Kosovo in this publication should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

237 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 20.10 Relative consumption of Core Access and Watch group antibacterials

DDD/1 000 inhabitants per daya (% of totalbc)

Category DDD values relevant to year of data DDD values applied from January 2019

2015 2016 2017 2015 2016 2017 Core Access group 14.5 (62) 12.7 (65) 13.8 (65) 11.3 (56) 9.8 (59) 10.4 (58) Watch group 7.1 (30.5) 5.5 (28.4) 6.1 (28.7) 7.1 (35) 5.5 (33) 6.1 (34) Reserve group 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Ungrouped 1.7 (7) 1.2 (6) 1.4 (7) 1.7 (8) 1.2 (7) 1.4 (8) Total 23.3 19.5 21.3 20.2 16.6 17.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

The effect of applying the 2019 DDD values is to decrease slightly the proportion of total use that is Core Access group antibiotics (from 65% to 58% in 2017) and increase slightly the proportion of total use that is Watch group antibiotics (from 28.7% to 34% in 2017).

20.7 Discussion

The analyses in this report are based on import records.

Estimates of total consumption fluctuated over the period 2011–2017, with a general trend of decreasing J01 consumption between 2011 and 2017 (26.4 DID in 2011, 21.0 DID in 2017). Around 9–10% of consumption was parenteral formulations. The reported consumption of J01 antibacterials across the AMC Network ranged from 36.4 DID (Turkey) to 8.5 DID (Azerbaijan). The median consumption was 20.2 DID.

There was increasing relative consumption of beta-lactams, with some evidence of decreasing consumption of cephalosporins.

Of the top 10 oral agents in the J01 class, four are included in the WHO Watch group of antibacterials – ciprofloxacin and levofloxacin (quinolones), and clarithromycin and azithromycin (macrolides). Ciprofloxacin (6.9%), clarithromycin (5.8%), azithromycin (3.3%) and levofloxacin (3.2%) together comprised around 19.2% of J01 oral agent consumption in 2017.

The Watch group agent ceftriaxone constituted just over half (51.5%) of the consumption of J01 injection formulations in 2017.

Watch group agents (oral and parenteral combined) comprised 28.7% of total consumption in 2017. Across the AMC Network countries, Watch group agents represented between 22.9% (Bosnia and Herzegovina) and 44.4% (Tajikistan) of total consumption.

These relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities. For example, the WHO EML (WHO, 2017) suggests limited indications for use of ciprofloxacin, clarithromycin, azithromycin, levofloxacin and ceftriaxone.

238 KOSOVO (in accordance with Security Council resolution 1244 (1999))

Clarithromycin is listed on the EML as a first-choice option for severe community-acquired pneumonia and as a second-choice option for pharyngitis.

Azithromycin is listed on the EML/EMLc as a first-choice option for trachoma, yaws, Chlamydia trachomatis, cholera and Neisseria gonorrhoeae and as a second-choice option for acute invasive bacterial diarrhoea/dysentery and Neisseria gonorrhoeae.

Levofloxacin is listed on the WHO EML as a reserve second-line drug for the treatment of MDR-TB that should be used in specialized centres adhering to WHO standards for TB control.

Given the limited indications for use of these agents, it could be useful to review existing guidelines and treatment protocols to check alignment with WHO EML recommendations.

Application of the 2019 DDD values has a significant impact on the estimates of total consumption of J01 antibacterials, reducing from 21.0 DID in 2017 using DDD values relevant to year of data to 17.7 DID applying the 2019 DDD values – a reduction of 15.7%. Across the AMC Network countries, the percentage reductions in total DIDs ranged from 8.0% (Azerbaijan) to 15.9% (Kyrgyzstan), with mean and median DID reductions of 12.7% and 13.6% respectively. The new DDD values have greatest impact on estimates of consumption of beta-lactam antibacterials (J01C), reducing from 11.4 DID in 2017 using the DDD values relevant to the year of data to 8.1 DID applying the 2019 DDD values – a reduction of 29% in absolute values. Most changes to DIDs across the AMC Network countries also related to the beta-lactams, with reductions in DIDs for beta-lactams of 23.5% in Georgia up to 34.5% in the Republic of Moldova.

The data presented here provide a more detailed understanding of the patterns of antimicrobial consumption in Kosovo8 and can help to identify areas for further investigation, allowing development of targeted interventions to address potential problems identified in the consumption of antibacterials. Interventions targeting medicines should be supported by evidence-based guidelines and treatment protocols.

Not all antibiotics have been classified by WHO into the Access, Watch and Reserve groups. The lists of Watch and Reserve medicines will be modified as evidence emerges and more clinical conditions

8 All references to Kosovo in this publication should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

239 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

are reviewed. The estimates presented here are based on total consumption – the relative use of Watch and Reserve group antibiotics would be substantially higher in a hospital-based analysis.

Total DID decreased by 15.7% when the new 2019 DDDs were applied, independent of any intervention by agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption in Kosovo.8

Reference

8 All references to Kosovo in this publication should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

240 Comparisons of 2017 antimicrobial medicines consumption across the AMC Network

21. COMPARISONS OF 2017 ANTIMICROBIAL MEDICINES CONSUMPTION ACROSS THE AMC NETWORK

21.1 Background

The previous chapters have reviewed data for the years 2011–2017 for each of the AMC Network countries and areas separately, examining trends for several key metrics of antimicrobial medicines consumption. In this chapter, comparisons are conducted across the Network members to develop a broader picture of the extent and variability of antibacterial consumption in non-EU Europe. Where appropriate, comparisons are made with publicly available estimates from ECDC for an extended comparison of patterns of consumption across Europe. Comparisons are conducted using 2017 data.

21.2 Estimates of volumes of consumption of antibacterials for systemic use (J01)

21.2.1 Total consumption of J01 antibacterials by route of administration

Total consumption of J01 antibacterials is examined by route of administration (oral and parenteral formulations) in Fig. 21.1 and Table 21.1.

40 a 35 30 25 Parenteral 20 antibacterials 15 Oral antibacterials 10 5 DDD/1000 inhabitants per day 0 b c R O E B R B Z D A K S Z B M E U E N R L L G IH K D J U A Z R Z T G M S B A K B M M T R K U A A

Fig. 21.1 Total consumption of J01 antibacterials by route of administration a DDD: daily defined dose. b North Macedonia data are community consumption only. c Kazakhstan data represent 80–85% of hospital and community sales.

241 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 21.1 Total consumption of J01 antibacterials by route of administration

a b Route of DDD/1 000 inhabitants per day (% of total ) administration TUR GEO MNE SRB BLR ALB KGZ BIH MKDc MDA TJK RUS KAZd UZB ARM AZE 34.9 24.5 29 22.8 21.2 20.1 11.5 19.3 20 15.5 11.8 14.9 11.4 6.9 12.5 6.4 Oral J01 (96) (78) (93) (93) (89) (91) (55) (95) (100) (79) (64) (88) (73) (50) (90) (75) Parenteral 1.5 7 2.3 1.7 2.5 1.9 9.3 1 4 6.5 2.1 4.3 6.9 1.3 2.1 – J01 (4) (22) (7) (7) (11) (9) (45) (5) (21) (36) (12) (27) (50) (10) (25) Total 36.4 31.5 31.4 24.5 23.7 22.1 20.8 20.3 20.0 19.5 18.3 17.0 15.7 13.9 13.9 8.5 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c North Macedonia data are community consumption only. d Kazakhstan data represent 80–85% of hospital and community sales.

The extent of consumption of parenteral formulations also varies widely – 4% in Turkey and 5% in Bosnia and Herzegovina, up to 45% in Kyrgyzstan and 50% in Uzbekistan (Table 21.1).

21.2.2 Consumption of J01 antibacterials by pharmacological subgroup

The consumption of J01 antibacterials by pharmacological subgroup is shown in Fig. 21.2 and summarized in Table 21.2.

40 Other J01 antibacterials 35 (J01G, J01R, J01X) a Quinolone antibacterials 30 (J01M)

b c R O E B R B Z H A K S B E U E N R L L G I D D J U Z Z M Z T G B A K B K T A R A M S M M R K U A

Fig. 21.2 Consumption of J01 antibacterials by pharmacological subgroup a DDD: daily defined dose. b North Macedonia data are community consumption only. c Kazakhstan data represent 80–85% of hospital and community sales.

242 Comparisons of 2017 antimicrobial medicines consumption across the AMC Network

Table 21.2 Consumption of J01 antibacterials by pharmacological subgroup

Class of DDD/1 000 inhabitants per daya (% of totalb) antibacterial c d agents TUR GEO MNE SRB BLR ALB KGZ BIH MKD MDA TJK RUS KAZ UZB ARM AZE Tetracyclines 1.2 1.2 1.4 1.4 2.8 0.5 2 1.4 1 0.6 1.4 0.9 0.1 1.5 1.3 < 0.1 (J01A) (3.3) (3.8) (4.5) (5.7) (11.8) (2.3) (9.6) (6.9) (5.1) (3.3) (8.2) (5.7) (0.7) (10.8) (15.3) Amphenicols 0.7 0.1 0.4 0.2 0.1 0.8 0.4 0.4 0 – – - – – – – (J01B) (2.2) (0.4) (1.9) (1.1) (0.6) (5.1) (2.9) (2.9) (0) Beta-lactams 17.1 12.3 13.8 9.8 11 10 9.9 10.1 10.4 6.9 6.6 6.1 4.4 7.3 5.6 2.5 (J01C) (47) (39) (43.9) (40) (46.4) (45.2) (47.6) (49.8) (52) (35.4) (36.1) (35.9) (28) (52.5) (40.3) (29.4) Other beta- lactams 9.6 3.6 5.3 4.3 2.7 5.9 5 2.5 3.7 4.3 3.3 1.9 3 3.8 1.3 1.5 (includes (26.4) (11.4) (16.9) (17.6) (11.4) (26.7) (24) (12.3) (18.5) (22.1) (18) (11.2) (19.1) (27.3) (9.4) (17.6) cephalosporins) (J01D) Sulfonamides and 0.3 6.8 0.8 0.8 0.1 1.5 0.4 0.9 0.9 0.5 0.5 1.2 0.5 – – – trimethoprim (0.8) (21.6) (2.5) (3.3) (0.4) (7.4) (2) (4.6) (4.9) (2.9) (3.2) (8.6) (5.9) (J01E) Macrolides, lincosamides 4 2.2 4.8 3.5 3.1 2.1 1 2 3.2 2.2 1.3 2.7 1.5 1.8 1.5 1 and (11) (7) (15.3) (14.3) (13.1) (9.5) (4.8) (9.9) (16) (11.3) (7.1) (15.9) (9.6) (12.9) (10.8) (11.8) streptogramins (J01F) Quinolone 2.6 2.4 3.2 3.8 2.1 3.3 0.1 2.3 2.3 2.4 4.2 2.9 2.8 1.3 0.9 antibacterials – (7.1) (7.6) (10.2) (15.5) (8.9) (14.9) (0.5) (11.3) (11.5) (12.3) (23) (17.1) (17.8) (9.4) (10.6) (J01M) Other J01 antibacterials 1.7 2.3 2.1 0.9 1.7 0.3 2.5 0.6 1.8 1.4 1.4 1.7 0.4 1 0.7 – (J01G, J01R, (4.7) (7.3) (6.7) (3.7) (7.2) (1.4) (12) (3) (9.2) (7.7) (8.2) (10.8) (2.9) (7.2) (8.2) J01X) Total 36.4 31.5 31.4 24.5 23.7 22.1 20.8 20.3 20.0 19.5 18.3 17.0 15.7 13.9 13.9 8.5 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c North Macedonia data are community consumption only. d Kazakhstan data represent 80–85% of hospital and community sales.

There is considerable variation in the extent of consumption of the different pharmacological subgroups across the AMC Network. In 2017, consumption of beta-lactams (J01C) ranged between 28% of total J01 consumption in Kazakhstan to 52.5% of J01 consumption in Uzbekistan (Table 21.2). Cephalosporin (J01D) consumption varied from 9.5% of J01 consumption in Armenia to 27.5% in Uzbekistan. Quinolone (J01M) consumption varied, with low levels in Uzbekistan and Kyrgyzstan, up to 22.9% of total J01 consumption in Tajikistan.

The relative consumption of cephalosporins and quinolones combined ranged from 19% of J01 consumption in Armenia and Georgia to 41% in Tajikistan.

21.3 Relative consumption by choice of agent

21.3.1 Relative consumption of cephalosporins by generation

The relative consumption of first-, second-, third- and fourth-generation cephalosporins in 2017 is shown in Fig. 21.3 and summarized in Table 21.3.

243 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

100

Fourth-generation (J01DE) 60 Third-generation (J01DD)

40 Second-generation (J01DC) First-generation (J01DB)

cephalosporin (%) cephalosporin 20

consumption of of total consumption Proportion 0 a b E Z A E S K B M IH LR O Z D B J R B L R Z B E A G D K N U R T U Z A A A B G K K M M M R S T U

Fig. 21.3 Relative consumption of cephalosporins by generation a Kazakhstan data represent 80–85% of hospital and community sales. b North Macedonia data are community consumption only.

Patterns of consumption of cephalosporin agents varied widely across AMC Network countries and areas. Consumption of first-generation agents ranged from very low levels in Azerbaijan to 59% of cephalosporin consumption in Serbia (Table 21.3). Second-generation agents represented very low levels of cephalosporin consumption in several Network countries (Azerbaijan, Kyrgyzstan, Montenegro, the Russian Federation, Tajikistan and Uzbekistan) up to 51% in Turkey. Third-generation cephalosporins (Watch agents) comprised more than half of the total cephalosporin consumption in nine countries (Armenia 76%, Azerbaijan 88%, Belarus 53%, Georgia 74%, Kyrgyzstan 86%, Montenegro 51%, the Russian Federation 81%, Tajikistan 88% and Uzbekistan 71%). Consumption of fourth-generation cephalosporins (Reserve agents) was low across the Network.

Table 21.3 Relative consumption of cephalosporins by generation

Class of DDD/1 000 inhabitants per daya (% of totalb) antibacterial agents ALB ARM AZE BIH BLR GEO KAZc KGZ MDA MKDd MNE RUS SRB TJK TUR UZB First-generation 0.7 0.2 1.1 0.3 0.1 1.2 0.6 0.4 0.9 2.5 0.2 2.5 0.4 0.9 1.1 < 0.1 (J01DB) (12) (12) (45) (12) (4) (41) (13) (9) (23) (48) (13) (59) (12) (9) (28) Second- 2.9 0.1 0.8 0.7 0.7 0.3 1.9 1.6 0.2 4.9 generation < 0.1 < 0.1 < 0.1 < 0.1 – < 0.1 (50) (10) (33) (29) (21) (11) (44) (43) (4) (51) (J01DC) Third- 2.2 0.9 1.3 0.5 1.4 2.6 1.4 4.3 2 1.3 2.7 1.5 1.5 2.9 3.8 2.7 generation (37) (76) (88) (22) (53) (74) (47) (86) (47) (34) (51) (81) (36) (88) (39) (71) (J01DD) Fourth 0.2 generation < 0.1 < 0.1 – < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 – < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 (7) (J01DE) Total 5.9 1.2 1.5 2.4 2.6 3.6 3.0 5.0 4.3 3.7 5.2 1.9 4.2 3.3 9.5 3.8 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Kazakhstan data represent 80–85% of hospital and community sales. d North Macedonia data are community consumption only.

244 Comparisons of 2017 antimicrobial medicines consumption across the AMC Network

21.4 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Analyses based on the WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

The relative consumption of Core Access and Watch group antibiotics is shown in Fig. 21.4 and Fig. 21.5, and is summarized in Table 21.4.

100

60 Other Core Access 40 group 72 69 Proportion (%) Proportion 65 65 64 63 57 55 55 54 54 53 52 52 51 20 46

0 b c IH M R B E B Z D S Z R E B A K O B R L R N Z A K U G U Z L D J E A B S M U K M R K T A A M T G

Fig. 21.4 Relative consumption of Core Access group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01). b Kazakhstan data represent 80–85% of hospital and community sales c North Macedonia data are community consumption only.

100

60 Other Watch group 40 Proportion (%) Proportion

20 44 39 35 34 33 33 33 33 33 32 28 27 26 26 24 23 0 b c K E Z H J S Z B B E A B D Z R R M O I T U A L R N D Z K U L R G E B R K A S M M U M A T B A K G

Fig. 21.5 Relative consumption of Watch group of antibiotics classes as a proportion of total consumptiona a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01). b Kazakhstan data represent 80–85% of hospital and community sales c North Macedonia data are community consumption only.

245 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 21.4 Relative consumption of antibiotics according to Core Access, Watch and Reserve classification

DDD/1 000 inhabitants per daya (% of totalbc)

ALB ARM AZE BIH BLR GEO KAZd KGZ MDA MKDe MNE RUS SRB TJK TUR UZB Core 11.6 9.8 5.5 15 15.7 14.7 9.1 11.3 10.3 11.1 20.4 9.9 16.3 9.4 20 8.8 Access (51.8) (69.3) (53.2) (72.3) (64.9) (46.4) (56.7) (54.4) (51.7) (55.1) (64) (54.8) (64.6) (50.8) (54) (63.5) Group Watch 7.6 3.7 3.3 4.7 6.6 7.5 5.6 5.4 6.5 6.6 10.6 7.1 8.4 8.3 10.5 4.5 Group (33.9) (26.3) (31.9) (22.9) (27.5) (23.6) (35.1) (25.8) (32.6) (32.5) (33.2) (39) (33.2) (44.4) (28.2) (32.5) Reserve < 0.1 < 0.1 < 0.1 < 0.1 0.3 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 0.1 < 0.1 0.1 < 0.1 – Group (0.1) (0.2) (0) (0) (1.1) (0.4) (0.1) (0.1) (0.1) (0) (0.2) (0.2) (0.1) (0.2) (0.1) 3.1 0.7 1.5 1 1.6 9.5 1.4 4.1 3.1 2.5 0.9 1.2 0.5 0.9 6.5 0.6 Ungrouped (14.2) (4.1) (14.8) (4.8) (6.5) (29.7) (8) (19.7) (15.6) (12.4) (2.8) (6) (1.9) (4.7) (17.6) (3.9) Total 22.3 14.2 10.3 20.7 24.2 31.8 16.1 20.8 19.9 20.2 31.9 18.2 25.3 18.6 37.1 13.9 a DDD: daily defined dose. b Total amounts and percentages may vary slightly owing to rounding. c Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01). d Kazakhstan data represent 80–85% of hospital and community sales. e North Macedonia data are community consumption only.

Consumption of Core Access agents dominated in all AMC Network countries and areas, representing between 46.4% (Georgia) and 72.3% (Bosnia and Herzegovina) of total antibacterial consumption in 2017 (Table 21.4). Watch group agents represented between 22.9% (Bosnia and Herzegovina) and 44.4% (Tajikistan) of total consumption. Consumption of Reserve group agents was uniformly low across the Network. Ungrouped agents represented 2.8% (Montenegro) to 29.7% of total consumption in Georgia.

21.5 Analyses based on DDDs applied in 2019

21.5.1 Consumption of antibacterials for systemic use (J01)

Applying the DDD changes implemented in 2019 to consumption data for 2017 reduced total consumption estimates from a range of 8.5–36.4 DID using 2018 DDD values to 7.8–31.0 DID using 2019 DDD values (Table 21.5). The percentage reductions in total DIDs ranged from 8.0% (Azerbaijan) to 15.9% (Kyrgyzstan), with mean and median DID reductions of 12.8% and 13.6% respectively, mostly due to reduced total DDDs for penicillins. However, there was limited impact on rankings from highest to lowest total consumption in DIDs.

Most changes to DIDs related to the beta-lactams, with reductions in DIDs for beta-lactams of 23.5% in Georgia up to 34.5% in the Republic of Moldova (Table 21.6). Other pharmacological subgroups were affected to a limited extent by the changes.

246 Comparisons of 2017 antimicrobial medicines consumption across the AMC Network

Table 21.5 Impact of 2019 changes in DDDs on estimates of total antibiotic consumption and ranking of countries and areas

2018 DDD values 2019 DDD values AMC Network member Percentage Ranka DIDb Ranka DIDb Change in rank decrease Turkey 1 36.4 1 31.0 15.0 – Georgia 2 31.5 2 28.7 9.0 – Montenegro 3 31.4 3 27.1 13.7 – Serbia 4 24.5 4 21.3 13.1 – Belarus 5 23.7 5 20.0 15.7 – Albania 6 22.1 6 18.7 15.3 – Kyrgyzstan 7 20.8 7 17.5 15.9 – Bosnia and 8 20.3 8 17.4 14.2 – Herzegovina North Macedoniac 9 20.0 10 16.9 15.5 –1 Republic of Moldova 10 19.5 9 17.1 12.3 +1 Tajikistan 11 18.3 11 16.3 11.2 – Russian Federation 12 17.0 12 15.0 11.8 – Kazakhstand 13 15.7 13 14.3 8.6 – Uzbekistan 14 13.9 14 12.3 10.9 – Armenia 15 13.9 15 12.0 13.6 – Azerbaijan 16 8.5 16 7.8 8.0 – Mean 21.1 Mean 18.3 12.7 – Median 20.2 Median 17.3 13.3 – Range 8.5–36.4 Range 7.8–31.0 8.0–15.9 – a Highest to lowest. b DID DDD/1 000 inhabitants per day. c North Macedonia data are community consumption only. d Kazakhstan data represent 80–85% of hospital and community sales.

Table 21.6 Impact of 2019 changes in DDDs on pharmacological subgroups of J01 antibacterials

Percentage reduction in DIDs for J01 pharmacological subgroupsa

AMC Network member (J01F) (J01E) (J01C) (J01B) (J01A) (J01D) (J01M) J01 DIDs Quinolone Other beta- Macrolides, Macrolides, Amphenicols Tetracyclines Tetracyclines Beta-lactams Sulfonamides antibacterials streptogramins streptogramins cephalosporins) Total reduction in reduction Total lincosamides and and trimethoprim lactams (includes

Albania 0.0 0.0 –33.4 –0.2 – 0.1 –0.7 –15.3 Armenia 0.0 0.0 –33.0 –0.9 0.0 0.9 –1.2 –13.6 Azerbaijan 0.0 0.0 –29.6 0.0 0.0 0.0 6.9 –8.0 Bosnia and Herzegovina 0.0 – –29.0 –0.3 0.0 2.3 –0.7 –14.2 Belarus 0.0 0.0 –32.4 –4.3 0.0 1.2 –2.0 –15.7 Georgia 0.0 0.0 –23.5 –1.0 0.0 0.0 0.9 –9.0 Kazakhstan 0.0 0.0 –30.9 –0.4 0.0 3.8 –0.9 –8.6 Kyrgyzstan 0.0 0.0 –34.1 0.3 – 3.4 0.0 –15.9 Montenegro 0.0 – –30.7 –0.4 0.0 0.0 –0.8 –13.7 North Macedonia 0.0 – –31.2 0.0 0.0 5.2 0.0 –15.5 Republic of Moldova 0.0 0.0 –34.5 –0.2 0.0 1.1 –0.8 –12.3 Russian Federation –0.4 0.0 –32.3 –1.7 0.0 1.2 –0.4 –11.8 Serbia 0.0 0.0 –31.8 –0.8 0.0 0.0 –0.7 –13.1 Tajikistan 0.0 0.0 –31.0 –0.2 0.0 0.0 –0.6 –11.2 Turkey 0.0 0.0 –31.7 –0.4 0.0 0.0 –0.6 –15.0 Uzbekistan 0.0 0.0 –24.9 7.8 – 0.9 – –10.9 a Calculated as: (Consumption with 2019 value – Consumption with old value)/Consumption in old value * 100.

247 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

21.5.2 Relative consumption of Core Access, Watch and Reserve groups of antibiotics

Application of the 2019 DDD values has the effect of decreasing the proportion of antibacterial consumption that is Core Access agents and increasing the proportion that is Watch agents (Table 21.7).

Table 21.7 Impact of 2019 changes in DDDs on relative consumption of Core Access, Watch and Reserve groups of antibiotics

Percentage consumption of antibacterialsa

Core Access Watch Reserve Ungrouped AMC Network member 2018 2019 2018 2019 2018 2019 2018 2019 values values values values values values values values Albania 52 43 34 40 0 0 14 17 Armenia 69 65 26 30 0 0 4 5 Azerbaijan 53 49 32 35 0 0 15 16 Bosnia and 72 68 23 27 0 0 5 6 Herzegovina Belarus 65 59 27 32 1 1 6 8 Georgia 46 41 24 26 0 0 30 33 Kazakhstan 57 53 35 39 0 0 8 9 Kyrgyzstan 54 46 26 31 0 0 20 23 Montenegro 64 59 33 38 0 0 3 3 North Macedonia 55 46 33 39 0 0 12 15 Republic of Moldova 52 45 33 37 0 0 16 18 Russian Federation 55 49 39 44 0 0 6 7 Serbia 65 60 33 38 0 0 2 2 Tajikistan 51 45 44 50 0 0 5 5 Turkey 54 46 28 33 0 0 18 21 Uzbekistan 63 56 33 39 0 0 4 4 a Total consumption of antibiotics for this calculation includes J01, vancomycin (A07AA09), colistin (A07AA10), polymyxin B (A07AA05) and metronidazole (P01AB01).

21.6 Comparisons with ESAC-Net antimicrobial quality indicators

ESAC-Net analyses use several metrics referred to as quality indicators.

Results for each measure are shown by country or area, along with the range of values for the WHO AMC Network and ESAC-Net 2017 analyses (Table 21.8).

Both WHO AMC Network and ESAC-Net datasets show considerable variability in these antibiotic quality indicators. It is important to note that the ESAC-Net quality indicator estimates relate to consumption in the community, not total consumption. In 2017, total consumption (hospital and community sectors combined) was available for 22 EU/EEA countries. Reported consumption ranged from 11.0 DID in the Netherlands to 34.1 DID in Spain (ECDC, 2018).

The substantial differences in consumption estimates provide a basis for further investigation to explore patterns of consumption and determine whether these represent most appropriate use of antibacterial agents.

248 Comparisons of 2017 antimicrobial medicines consumption across the AMC Network

Table 21.8 Quality indicators for J01 antibiotic consumption (2017)

DDD/1 000 inhabitants per daya Relative consumption (%)b Country J01 J01C J01D J01F J01M J01DD+DE J01MA Albania 22.1 10.0 5.9 2.1 3.3 10 15 Armenia 13.9 5.6 1.3 1.5 1.3 7 9 Azerbaijan 8.5 2.5 1.5 1.0 0.9 15 10 Bosnia and 20.3 10.1 2.5 2.0 2.3 3 11 Herzegovina Belarus 23.7 11.0 2.7 3.1 2.1 7 9 Georgia 31.5 12.3 3.6 2.2 2.4 9 7 Kazakhstan 15.7 4.4 3.0 1.5 2.8 9 17 Kyrgyzstan 20.8 9.9 5.0 1.0 0.1 21 1 Montenegro 31.4 13.8 5.3 4.8 3.2 9 6 North Macedonia 20.0 10.4 3.7 3.2 2.3 6 10 Republic of Moldova 19.5 6.9 4.3 2.2 2.4 10 11 Russian Federation 17.0 6.1 1.9 2.7 2.9 9 17 Serbia 24.5 9.8 4.3 3.5 3.8 6 13 Tajikistan 18.3 6.6 3.3 1.3 4.2 16 23 Turkey 36.4 17.1 9.6 4.0 2.6 10 7 Uzbekistan 13.9 7.3 3.8 1.8 0.0 20 NR WHO AMC Network results (2017) Range 8.5–36.4 2.5–17.1 1.3–9.6 1–4.8 0–4.2 3–21 1–23 J01: antibacterials for systemic use; J01C: beta-lactams, penicillins; J01D: other beta-lactam antibacterials; J01F: macrolides, lincosamides and streptogramins; J01M: quinolone antibacterials; J01DD+DE: third- and fourth-generation cephalosporins; J01MA: fluoroquinolones. a DDD: daily defined dose. b Denominator for calculations is total consumption of J01 antibacterials for hospital and community combined for AMC Network members except North Macedonia and community consumption of J01 antibacterials for ESAC-Net estimates.

References

ECDC (2019). Quality indicators for antibiotic consumption in the community. In: European Centre for Disease Prevention and Control [website]. Solna: European Centre for Disease Prevention and Control (https://ecdc.europa.eu/en/antimicrobial-consumption/database/quality-indicators, accessed 1 April 2019).

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22. DISCUSSION

This report extends the analyses of data from the WHO Europe AMC Network from the 2017 report of the WHO Regional Office for Europe and the 2019 peer-reviewed manuscript (Robertson et al., 2019). The report includes analyses of trends over time (2011–2017) for key metrics of antibiotic consumption, the WHO Core Access, Watch and Reserve classification of antibiotics is applied, and analyses of data for 2015–2017 conducted using new DDD values that came into effect in January 2019. In addition, where possible, analyses for hospital and community sector consumption are presented separately.

Notwithstanding the incomplete data capture in North Macedonia (community consumption only) and Kazakhstan (commercial data source captures 80–85% of hospital and community sales), the data in this report illustrate the large variability in reported consumption of J01 antibacterials across the AMC Network – ranging from 8.5 DID (Azerbaijan) to 36.4 DID (Turkey) in 2017. The mean consumption was 21.1 DID (median consumption 20.2 DID). These consumption estimates were mostly lower than those reported in 2011 (range 6.4 DID in Uzbekistan to 42.3 DID in Turkey, mean 23.6 DID) and in 2015 (range 8.0 DID for Azerbaijan to 41.5 DID for Turkey, mean 21.2 DID).

ESAC-Net analyses also show considerable variability in consumption estimates. In 2017, total consumption (hospital and community sectors combined) was available for 22 EU/EEA countries. Reported consumption ranged from 11.0 DID in the Netherlands to 34.1 DID in Spain (ECDC, 2018).

A notable change is the substantial reduction in consumption estimates for Turkey over time, which reflects sustained efforts at national level to improve antibiotics use. Turkish health authorities have implemented an electronic prescription system to track prescription data and provide feedback to physicians, and have adopted a rational drug use national action plan for 2014–2017 that prioritizes the appropriate use of antibiotics. Turkey estimates for 2011 (42.3 DID) relied on commercial IQVIA data and reflected community consumption; the comparable community estimate in 2015 was 40.1 DID, derived from the comprehensive pharmaceutical track and trace system that follows medicines from production to consumption. Data for 2017 were disaggregated to community and hospital consumption, with 35.2 DID in the community sector and 1.2 DID in the hospital sector. These 2017 data show the positive impacts of the sustained educational and regulatory interventions undertaken since 2014 in Turkey.

The extent of consumption of parenteral formulations also varied widely – 4% in Turkey and 5% in Bosnia and Herzegovina, up to 45% in Kyrgyzstan and 50% in Uzbekistan (see Table 21.1). The reasons for these substantial differences require investigation at national level. While there may be cultural and medical practice factors that favour injection use in some settings, oral medications have been shown to be associated with fewer complications, lower health-care costs and earlier hospital discharge without loss of clinical efficacy. There may be opportunities to work with clinicians and the general public to reduce the use of injection formulations in some of the AMC Network countries and areas.

There was also considerable variation in the extent of consumption of the different pharmacological subgroups across the AMC Network. In 2017, cephalosporin (J01D) consumption varied from 9% to 27.5% of J01 consumption. Notably, third-generation cephalosporins (Watch agents) comprised

250 Discussion

more than half of the total cephalosporin consumption in nine AMC Network countries. The individual chapters for each AMC network country and area show the extent of use of agents like ceftriaxone. Given the limited indications for this agent, it could be useful to review existing guidelines and treatment protocols to check alignment with WHO EML recommendations (WHO, 2017).

Quinolone (J01M) consumption varied across the Network, with low levels of consumption in Uzbekistan and Kyrgyzstan up to 22.9% of total J01 consumption in Tajikistan.

Watch group agents (oral and parenteral formulations combined) represented between 22.9% and 44.4% of antibacterial consumption across the AMC Network. The relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities. Consumption of Reserve group agents was uniformly low across the Network.

Changes to DDDs implemented in January 2019 impacted on both total and relative consumption estimates, driven mostly by DDD changes for several commonly used beta-lactam penicillins. Total J01 consumption estimates decreased from a range of 8.5–36.4 DID using 2018 DDD values to 7.8–31.0 DID using 2019 DDD values (Table 21.5). The percentage reductions in total DIDs ranged from 8.0–15.9%, with mean DID reductions of 12.7%, but there was limited impact on rankings from highest to lowest total consumption in DIDs. These decreases in total DIDs are a consequence of changes to measurement metrics rather than reflecting the results of any intervention by government, agencies or professional groups. Communication strategies will be required so stakeholders are aware of the impact of the DDD changes, along with re-setting of trend lines and targets for changes in antibiotic consumption at national level.

Data limitations must be acknowledged. The results presented are mostly based on import records and local manufacturer sales records. Importation records will be affected by the cycles of procurement and delivery, potentially giving rise to fluctuations in estimates of consumption that do not relate to actual use of antibacterials by patients and health-care facilities. Local manufacturer records need to be disaggregated to products for local consumption and products exported to other countries and areas.

The completeness, validity and reliability of the data should be considered when interpreting the results of the analyses. A fuller interpretation of the consumption data requires an understanding of the local context, taking account of changes in regulations (including enforcement of prescription-only status), data sources, resistance patterns and the potential impact of interventions to change practices.

The data presented summarize the experience to date of the WHO AMC Network. Despite some data limitations, the levels of consumption reported and, in some cases, the choices of antimicrobial agents used confirm the need for action. The variability between countries and areas suggests that differences in patterns of consumption are not solely related to differences in disease burden. The quantitative data on antimicrobials in this report provide a starting-point for further studies to understand better the use of these medicines in clinical practice – this will require further quantitative and qualitative studies in primary care and hospital sectors.

References

ECDC. Antimicrobial consumption. In: ECDC. Annual epidemiological report 2017. Stockholm: ECDC; 2018 (https://ecdc.europa.eu/sites/portal/files/documents/ESAC-NET-reportAER-2017-updated. pdf, accessed 1 April 2019).

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252

The WHO Regional Office for Europe

The World Health Organization (WHO) is a specialized agency of the United Nations created in 1948 with the primary responsibility for international health matters and public health. The WHO Regional Office for Europe is one of six regional offices throughout the world, each with its own programme geared to the particular health conditions of the countries it serves.

Member States

Albania Andorra

Armenia ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK, AMC DATA 2011–2017 Austria Azerbaijan Belarus Belgium Bosnia and Herzegovina Bulgaria Croatia Cyprus Czechia Denmark Estonia Finland France Georgia Germany Greece Hungary Iceland Ireland Israel Italy Kazakhstan Kyrgyzstan Latvia Lithuania Luxembourg Malta Monaco Montenegro Netherlands North Macedonia Norway Poland Portugal Republic of Moldova Romania Russian Federation San Marino Serbia Slovakia Slovenia Spain Sweden Switzerland World Health Organization Tajikistan Regional Office for Europe Turkey UN City, Marmorvej 51, DK-2100 Copenhagen Ø, Denmark Turkmenistan Ukraine Tel.: +45 45 33 70 00 Fax: +45 45 33 70 01 United Kingdom Email: [email protected] Uzbekistan Website: www.euro.who.int