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

AMC data 2014–2018 Abstract This report presents analyses of data on antimicrobial medicines consumption collected for the period 2014–2018 from non- European Union countries/areas in the WHO European Region. The analyses incorporate the substantial changes to defined daily doses introduced in January 2019 and revisions to the WHO Access, Watch and Reserve (AWaRe) classification in 2019. The report includes analyses of trends over time for key metrics of antibiotic consumption and considers new metrics to inform the responsible use of antibiotics. The WHO Regional Office for Europe and its partners remain committed to supporting countries/ areas in these endeavours through the activities of the WHO Europe Antimicrobial Medicines Consumption Network.

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

ISBN: 97-892-890-5556-7

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AMC data 2014–2018 Corrigenda WHO Regional Office for Europe Antimicrobial Medicines Consumption (AMC) Network: AMC data, 2014-2018

ISBN: 97-892-890-5556-7

The following corrections were made in the electronic file on 5 July 2021:

Page ii: ISBN ISBN has been modified. Initially published under ISBN: 97-892-890-5495-9

Page 1: 1.2 The WHO Europe AMC Network ‘One territory’ has been modified as ‘an area’.

Page 2: 1.3 Previous publications of WHO Europe AMC Network data The last reference in the last paragraph has been modified with the correct year.

Page 11: 2.6.6 Drug utilization 75% (DU75%) The reference in the fourth paragraph has been modified with the correct year.

Page 21: Table 3.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use) The last row of the table has been modified as ‘Total consumption of parenteral agents’.

Table 64: 10.2 Estimates of volumes of consumption of antibacterials for systemic use (J01) The last sentence of the third paragraph has been modified with the correct years.

Page 159: 23 Discussion The reference in the first paragraph has been modified with the correct year.

Page 164: References The first reference has been modified with the URL.

Back cover: The ISBN barcode has been replaced. CONTENTS

Acknowledgements ...... vii

Abbreviations ...... viii

Summary ...... ix

1..Introduction...... 1 1.1.Background...... 1 1.2. The WHO Europe AMC Network...... 1 1.3. Previous publications of WHO Europe AMC Network data...... 2 1.4. Scope and aim of this report...... 2

2..Methods ...... 3 2.1. Definition of consumption and use...... 3 2.2. Data sources and data collection...... 3 2.3. Anatomical Chemical Classification (ATC) and Defined Daily Dose (DDD) classification system. . . . 5 2.4. Antibacterial agents included in this report...... 6 2.5. Health sectors monitored...... 7 2.6. Metrics and indicators reported...... 7 2.7. Data interpretation...... 14

3..Albania...... 16 3.1. Data source and years of data collection...... 16 3.2. Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 16 3.3. Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 17 3.4. Consumption at substance level (5th ATC group level)...... 19 3.5. Other monitoring indicators...... 21 3.6.Discussion...... 21

4..Armenia ...... 22 4.1. Data source and years of data collection...... 22 4.2. Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 22 4.3. Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 23 4.4. Consumption at substance level (5th ATC group level)...... 25 4.5. Other monitoring indicators...... 27 4.6.Discussion...... 28

5..Azerbaijan...... 29 5.1. Data source and years of data collection...... 29 5.2. Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 29 5.3. Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 30 5.4. Consumption at substance level (5th ATC group level)...... 32 5.5. Other monitoring indicators...... 35 5.6. Discussion ...... 35

iii 6..Belarus...... 36 6.1. Data source and years of data collection...... 36 6.2. Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 36 6.3. Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 37 6.4. Consumption at substance level (5th ATC group level)...... 39 6.5. Other monitoring indicators...... 41 6.6.Discussion...... 42

7.. Bosnia and Herzegovina ...... 43 7.1. Data source and years of data collection...... 43 7.2. Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 43 7.3. Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 44 7.4. Consumption at substance level (5th ATC group level)...... 46 7.5. Other monitoring indicators...... 48 7.6.Discussion...... 49

8..Georgia...... 50 8.1. Data source and years of data collection...... 50 8.2. Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 50 8.3. Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 51 8.4. Consumption at substance level (5th ATC group level)...... 53 8.5. Other monitoring indicators...... 56 8.6.Discussion...... 56

9..Kazakhstan ...... 57 9.1. Data source and years of data collection...... 57 9.2. Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 57 9.3. Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 58 9.4. Consumption at substance level (5th ATC group level)...... 60 9.5. Other monitoring indicators...... 62 9.6.Discussion...... 63

10..Kyrgyzstan...... 64 10.1.Data source and years of data collection...... 64 10.2.Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 64 10.3.Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 65 10.4.Consumption at substance level (5th ATC group level)...... 67 10.5.Other monitoring indicators...... 69 10.6.Discussion...... 69

11..Montenegro ...... 71 11.1.Data source and years of data collection...... 71 11.2.Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 71 11.3.Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 72 11.4.Consumption at substance level (5th ATC group level)...... 74 11.5.Other monitoring indicators...... 76 11.6.Discussion...... 77

iv 12.. North Macedonia...... 78 12.1.Data source and years of data collection...... 78 12.2.Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 78 12.3.Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 79 12.4.Consumption at substance level (5th ATC group level)...... 81 12.5.Other monitoring indicators...... 82 12.6.Discussion...... 83

13.. Republic of Moldova ...... 84 13.1.Data source and years of data collection...... 84 13.2.Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 84 13.3.Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 85 13.4.Consumption at substance level (5th ATC group level)...... 87 13.5.Other monitoring indicators...... 90 13.6.Discussion...... 90

14.. Russian Federation...... 91 14.1.Data source and years of data collection...... 91 14.2.Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 91 14.3.Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 92 14.4.Consumption at substance level (5th ATC group level)...... 94 14.5.Other monitoring indicators...... 96 14.6.Discussion...... 97

15..Serbia ...... 98 15.1.Data source and years of data collection...... 98 15.2.Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 98 15.3.Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 99 15.4.Consumption at substance level (5th ATC group level)...... 101 15.5.Other monitoring indicators...... 103 15.6.Discussion...... 104

16..Switzerland...... 105 16.1.Data source and years of data collection...... 105 16.2.Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 105 16.3.Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 106 16.4.Consumption at substance level (5th ATC group level)...... 108 16.5.Other monitoring indicators...... 110 16.6.Discussion...... 110

17..Tajikistan...... 111 17.1.Data source and years of data collection...... 111 17.2.Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 111 17.3.Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 112 17.4.Consumption at substance level (5th ATC group level)...... 114 17.5.Other monitoring indicators...... 116 17.6.Discussion...... 117

v 18..Turkey...... 118 18.1.Data source and years of data collection...... 118 18.2.Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 118 18.3.Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 119 18.4.Consumption at substance level (5th ATC group level)...... 121 18.5.Other monitoring indicators...... 123 18.6.Discussion...... 124

19..Ukraine...... 125 19.1.Data source and years of data collection...... 125 19.2.Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 125 19.3.Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 127 19.4.Consumption at substance level (5th ATC group level)...... 128 19.5.Other monitoring indicators...... 131 19.6.Discussion...... 131

20..Uzbekistan ...... 132 20.1.Data source and years of data collection...... 132 20.2.Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 132 20.3.Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 133 20.4.Consumption at substance level (5th ATC group level)...... 135 20.5.Other monitoring indicators...... 137 20.6.Discussion...... 137

21..Kosovo1...... 139 21.1.Data source and years of data collection...... 139 21.2.Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 139 21.3.Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 140 21.4.Consumption at substance level (5th ATC group level)...... 142 21.5.Other monitoring indicators...... 144 21.6.Discussion...... 145

22.. Comparison of 2018 antimicrobial medicines consumption across the AMC Network...... 146 22.1.Background...... 146 22.2.Estimates of volumes of consumption of antibacterials for systemic use (J01)...... 146 22.3.Relative consumption of Access, Watch and Reserve groups of antibiotics ...... 149 22.4.Drug utilization 75% (DU75%)...... 153 22.5.Other monitoring indicators...... 157 22.6.Comparisons with ESAC-Net...... 157

23..Discussion...... 159

24..References ...... 162

Annex 1. Antibiotics included in 2019 WHO Access, Watch, Reserve and Not recommended lists...... 166

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 and Ms Kotoji Iwamoto of Access to Medicines and Health Products, 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) CAGR compound annual growth rate CHMP Committee for Medicinal Products for Human Use DDD defined daily dose DID defined daily doses per 1000 inhabitants per day DU75% drug utilization 75% DU90% drug utilization 90% ECDC European Centre for Disease Prevention and Control EEA European Economic Area EMA European Medicines Agency 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

Abbreviations of country/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 SWI Switzerland TJK Tajikistan TUR Turkey UKR Ukraine UZB Uzbekistan KOS Kosovo2

2 All references to Kosovo in this publication 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/ 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). Albania, Armenia, Azerbaijan, Belarus, Bosnia and Herzegovina, Georgia, Kazakhstan, Kyrgyzstan, Montenegro, North Macedonia, the Republic of Moldova, the Russian Federation, Serbia, Switzerland, Tajikistan, Turkey, Ukraine and Uzbekistan, as well as Kosovo,3 are members of the WHO Europe AMC Network.

This is the third WHO Europe AMC Network report. It sets out and analyses AMC data for 18 of the participating countries as well as for Kosovo3 where the ministry of health and public health authorities approved data-sharing and publication. Data were not available from all countries/areas for all five years of analysis. The report includes analyses of trends over time (2014–2018) for key metrics of antibacterial consumption, applies the 2019 WHO Access, Watch and Reserve (AWaRe) classification of antibiotics and the substantial changes to defined daily doses (DDDs) in 2019, and reports on the WHO national monitoring target of at least 60% of total consumption being Access agents. Data are presented on the drug utilization 75% (DU75%), which represents the antibacterial substances accounting for 75% of the consumption measured in DDD and was calculated for oral and parenteral formulations separately. Results are compared with ESAC-Net estimates for 2018. Analyses are presented for each AMC Network country/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 17 countries in 2018. There was large variability in reported consumption of J01 antibacterials across the AMC Network – ranging from 8.9 defined daily doses per 1000 inhabitants per day (DID) (Azerbaijan) to 30.9 DID (Turkey), with median consumption of 18.8 DID. The population-weighted mean consumption across the 17 datasets was 18.5 DID. This compares to a range of 6.4 DID for Azerbaijan to 34.7 DID for Turkey in 2014. ESAC-Net analyses also show considerable variability in total J01 consumption, ranging from 9.7 DID in the Netherlands to 34.1 DID in Greece in 2018 (ECDC, 2019).

The extent of consumption of parenteral formulations also varied widely – 3% in Turkey up to 40% in Kyrgyzstan. Four other countries reported parenteral consumption more than 20% of total J01 consumption in 2018 – Georgia (32%), Tajikistan (27%), Uzbekistan (23%) and Azerbaijan (22%).

There was considerable variation in the extent of consumption of the pharmacological subgroups of J01. In 2018, consumption of beta-lactam penicillins (J01C) ranged from 14% (Kyrgyzstan, Tajikistan) to 40% (Switzerland, Turkey). Cephalosporin (J01D) consumption varied from 8% (Azerbaijan) to 35% (Georgia, Kyrgyzstan) while quinolone (J01M) consumption varied from 10% (Azerbaijan, Georgia, Turkey) to 37% (Uzbekistan).

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 Access agents comprised between 30% (Uzbekistan) and 66% (Bosnia and Herzegovina) of total antibacterial consumption in 2018. Watch group agents represented between 34% (Bosnia and Herzegovina) and 69% (Uzbekistan) of total consumption. Consumption of Reserve agents remained low across all years of data analysed. Unclassified agents constituted 7% of consumption in Montenegro and Ukraine in 2018.

In 2018, four AMC Network countries met WHO’s suggested national target of 60% of total consumption of antibacterials being derived from the Access list. Bosnia and Herzegovina was the only AMC Network country to achieve this target in each of the five years analysed.

The number of agents constituting the DU75% by oral substance ranged from four to 10 across the AMC Network countries/areas. There were 10 agents in the WHO/AMC population-weighted network DU75% in 2018 – five Access and five Watch agents. The Watch agents ciprofloxacin and azithromycin were ranked three and four in relative consumption across the AMC Network.

Conclusions

The results presented in this report document trends in consumption of antibacterial agents across the WHO Europe AMC Network. The results show wide variability of estimates, both in volumes of consumption and selection of agents. The reasons for such variability require further investigation. Despite some data limitations, the levels of consumption reported and, in some cases, the choices of antimicrobial agents used confirm the need for action. While the quantitative metrics presented have limited application in assessing the appropriateness of prescribing, they illustrate differing patterns of antibacterial consumption over time and point to potential problems in antibiotic use.

Analyses based on the WHO AWaRe classification can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further. As with other measures of consumption, there was considerable variability in the extent of use of Access and Watch group agents across the Network. Few countries/areas met the WHO proposed global monitoring indicator that 60% of all antibiotics consumed should come from Access, the group of antibiotics at lowest risk of resistance. The relatively higher levels of consumption of specific Watch group antibiotics identified in the DU75% analyses suggest some targets for further investigation, interventions and stewardship activities supported by evidence-based guidelines and treatment algorithms.

The analyses focus on total consumption of antibacterials. Disaggregation of data to hospital and community sectors was not possible in most WHO Europe AMC Network countries/areas; this is an important topic for future development as countries/areas strengthen and enhance their surveillance capacity. Disaggregation of data to community and hospital sectors facilitates monitoring using sector- specific metrics for quantifying antibiotic use and assessing the quality of prescribing.

Country/area chapters in this report can be used to inform activities for participating Network members, while comparisons across countries and areas allow benchmarking of activities across the Network. 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.

Reference

European Commission (2017). A European One Health action plan against antimicrobial resistance (AMR). Brussels: European Commission (https://ec.europa.eu/health/sites/health/files/antimicrobial_ resistance/docs/amr_2017_action-plan.pdf, accessed 1 December 2020).

x 1. INTRODUCTION

1.1 Background

The human and financial costs of antimicrobial resistance (AMR) are well recognized. It is estimated that there are 33 000 deaths per year attributable to infections with antibiotic-resistant bacteria in the European Union (EU)/European Economic Area (EEA) (Cassini et al., 2019) and 700 000 globally (Review on Antimicrobial Resistance, 2016). The Organisation for Economic Co-operation and Development predicts that the costs associated with AMR could increase to US$ 3.5 billion per year if not addressed (Hofer, 2019). 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). A review of progress since 2013 suggests that these efforts have been uneven across countries/areas and that political commitment to AMR may be waning (Laxminarayan et al., 2020). Sustained funding and globally harmonized targets to monitor progress are important in addressing AMR.

Ensuring prudent antimicrobial use is a key priority in an effective AMR response. The importance of surveillance of antibiotic consumption to identify potential overuse, underuse and inappropriate use is highlighted in the Global Action Plan on Antimicrobial Resistance (WHO, 2015), the European Strategic Action Plan on Antibiotic Resistance (WHO Regional Office for Europe, 2011) and the European One Health Action Plan against Antimicrobial Resistance (European Commission, 2017).

1.2 The WHO Europe AMC Network

The WHO Regional Office for Europe (WHO Europe) Antimicrobial Medicines Consumption (AMC) Network has been undertaking systematic surveillance of antimicrobial medicines consumption in 18 non-EU Member States and an area, Kosovo,4 since 2011 (WHO Regional Office for Europe, 2020). Data collection is based on the WHO Anatomical Therapeutic Chemical (ATC) classification system and defined daily doses (DDD) methodology (WHO Collaborating Centre for Drug Statistics Methodology, 2020a).

The methods used by the WHO Europe AMC Network mirror those used by the European Surveillance of Antibiotic Consumption Network (ESAC-Net) coordinated by the European Centre for Disease Prevention and Control (ECDC) that collates and analyses data on antibiotic consumption from 30 countries in the EU and EEA (European Centre for Disease Prevention and Control, 2020a).

A description of the two networks is available in the Europe chapter of the WHO report on surveillance of antibiotic consumption 2016–2018: early implementation (WHO, 2018).

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

1 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

1.2.1 Participating countries/areas

Albania, Armenia, Azerbaijan, Belarus, Bosnia and Herzegovina, Georgia, Kazakhstan, Kyrgyzstan, Montenegro, North Macedonia, the Republic of Moldova, the Russian Federation, Serbia, Switzerland, Tajikistan, Turkey, Ukraine and Uzbekistan, as well as Kosovo,5 currently are engaged in the WHO Europe AMC Network. Of these, 18 countries and Kosovo5 gave permission for their data to be published and included in this report.

1.3 Previous publications of WHO Europe AMC Network data

A report of AMC data for 2011–2014 for 11 of the participating Network countries and for Kosovo5 was published in 2017 (WHO Regional Office for Europe, 2017).

A crossnational comparison of 2015 AMC data for 16 members of the WHO Europe AMC Network was published in 2019 (Robertson et al., 2019). This analysis classified consumption data according to the 2017 WHO Core Access, Watch and Reserve (AWaRe) classification of antibiotics (WHO, 2017a) and examined the implications of proposed changes to DDDs for some commonly used antibiotics that were to come into force in January 2019 (WHO Collaborating Centre for Drug Statistics Methodology, 2020a).

An analysis of data for 2011–2017 for 17 Network members was published in 2020 (WHO Regional Office for Europe, 2020).

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 ESAC-Net and the WHO Europe AMC Network data have been presented, giving a pan-European perspective on antibiotic consumption (Versporten et al., 2014; WHO Regional Office for Europe, 2017; WHO, 2018; Robertson et al., 2019). A first joint publication of the ECDC and WHO Regional Office for Europe using AMC data for 2014–2018 will be published in 2021 (Robertson et al., 2021).

1.4 Scope and aim of this report

This report extends the reporting of the WHO Europe AMC Network, covering consumption data for 2014–2018 from 18 Network countries as well as for Kosovo.5 The analyses apply the changes to DDDs implemented in 2019 and the update of the WHO AWaRE classification of antibiotics in 2019 (WHO, 2019a), and assess concordance with the WHO global/national target that 60% of total consumption is Access agents (WHO, 2020). In addition, analyses report on the drug utilization 75% (DU75%), that is, the antibacterials that constitute 75% of total consumption. Country/area chapters can be used to inform activities for participating Network members, while comparisons across countries and areas allow benchmarking of activities across the Network. The report is intended to provide baseline trend data against which AMC data for future years will be compared and to identify possible targets for further investigation, interventions and stewardship activities to ensure that use of commonly consumed antibacterials is in line with approved clinical guidelines.

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

2 2. METHODS

2.1 Definition of consumption and use

As in previous WHO Regional Office for Europe reports (WHO Regional Office for Europe, 2017, 2020) and in line with the WHO global protocol for data collection (WHO, 2017b) and the global WHO report on the surveillance of antimicrobial consumption 2016–2018 early implementation (WHO, 2018), a distinction is made between consumption data and antimicrobial-use data.

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).

The term antimicrobial use refers 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.

Data on consumption and use each serve specific purposes and complement rather than replace each other.

2.2 Data sources and data collection

2.2.1 Data sources

Participating WHO Europe AMC Network countries/areas mostly rely on import data using customs records and declaration forms supplemented with sales records from market authorization holders, local manufacturing estimates, wholesaler records and, in some cases, commercial data sources for deriving estimates of consumption (Table 2.1). Increasingly, data on antimicrobial use are available from health insurance programmes.

Data represent total consumption estimates except for Kazakhstan, where a commercial data source provides coverage of 80% of hospital and community sales. Data are extrapolated to 100% to estimate total consumption.

Switzerland has provided data for each of the five years of data collection (2014–2018), but data collection is partial for some years. Data in the Swiss Antibiotic Resistance Report 2020 of the Swiss Federal Office of Public Health covering 2017 and 2018 have been used for analyses for this report as they represent total consumption estimates. Estimates are obtained from IQVIA6 sales data that cover both outpatient and inpatient consumption of antibacterials.

6 IQVIA is a data, technology and advanced analytics company with an interest in health care and human health.

3 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 2.1 Sources of data used for consumption estimates, 2014–2018, WHO Europe AMC Network

Country/area 2014 2015 2016 2017 2018 Albania I I I I I Armenia I, S I, S I, S I, S I, S Azerbaijan I I I I I Bosnia and Herzegovina S S S S S Belarus I, S I, S I, S I, S I, S Georgia I I I I I Kazakhstana – S S S S Kyrgyzstan – I, S I, S I, S I, S Montenegro S S S S S Republic of Moldova I, M I, M I, M I, M I, M North Macedoniab R R R R – Russian Federation S S S S S Serbia S S S S S Switzerland – – – S S Tajikistan I, C I, C I, C I, C I, C Turkeyc S S S S S Ukraine S S S S S Uzbekistan – – I, S I, S I, S Kosovo1 I, M I, M I, M I, M I, M

S: sales data. I: import records. M: manufacturing records. C: certification records. R: reimbursement data. a Coverage of sales data in Kazakhstan is 80%. b Reimbursement data cover the community sector only. c Turkey uses wholesalers’ records from pharmaceutical track and trace system. 1 All references to Kosovo in this document should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

The main sources of data for Ukraine are a market research company, Proxima Research, and include government tenders for the hospital sector, hospital purchases from wholesalers (tenders and self- procurement) and pharmacy purchases from wholesalers. Retail and hospital estimates are based on extrapolation of representative sample data using cluster analysis and hierarchical models. Tender data are derived from official information from the Prozorro platform.

In some cases, data are not available for all years examined.

2.2.2 Data collection

Data collection is based on a standardized protocol that is aligned with the WHO methodology for a global programme on surveillance of antimicrobial consumption (WHO, 2017b). Data are collected at the product level (proprietary and generic products) and comprise information on the active substance(s) of the product, route of administration, strength per unit, number of units per package and total number of packages consumed. Data collection is facilitated by means of a standard Excel template with functions to calculate volume and consumption for each product. Further details on the template for data collection are available in previous AMC Network reports (WHO Regional Office for Europe 2017, 2020).

4 Methods

2.3 Anatomical Chemical Classification (ATC) and Defined Daily Dose (DDD) classification ystems

Like the WHO global methodology, the WHO Europe AMC Network uses the ATC classification system to distinguish between pharmacological subgroups and substance levels of antimicrobials, and DDDs as the primary measurement metric (WHO Collaborating Centre for Drug Statistics Methodology, 2020a).

The ATC system classifies active pharmacological substances based on the organ or system on which they act, and their therapeutic, pharmacological and chemical properties. The classification allows analyses from the main classes (level 1) to individual medicines (level 5). Data collection only includes medicines with an assigned ATC code.

The DDD is the assumed average maintenance dose per day for a medicine used for its main indication in adults. A DDD is only assigned for medicines that have an ATC code. The DDD, however, is only a technical unit of use and does not necessarily reflect the recommended or average prescribed daily dose. The DDDs for anti-infectives are as a rule based on use in infections of moderate severity, but some anti-infectives are used only in severe infections and their DDDs are assigned accordingly. There are no separate DDDs for children, which makes the DDD estimates for paediatric formulations more difficult to interpret.

Because of continuous revisions, it is important to report the version of the ATC/DDD used to calculate consumption. This report uses the ATC/DDD version for 2019 and includes changes resulting from a comprehensive revision of DDD values for common antimicrobials that took effect in 2019.

2.3.1 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. The changes were requested following emerging evidence that current DDD allocations for commonly used medicines differed substantially from recommended doses and doses used in clinical practice.

The DDD changes were adopted fully in January 2019 and, because they affect some commonly used agents, significantly affect estimates of total AMC and relative use of classes of antibiotics. The main antibacterials affected by the DDD changes are shown in Table 2.2.

In addition to the changes shown in Table 2.2, 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).

In applying 2019 DDD values to all years of data analysed, this report presents baseline data from which future trends over time can be assessed.

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Table 2.2 2019 changes to DDDs for commonly prescribed J01 antibacterials

ATCa code Medicine Previous DDD New DDD J01CA04 Amoxicillin 1 g O 1.5 g O J01CA04 Amoxicillin 1 g Pd 3 g P J01CA17 Temocillin 2 g 3 g P J01CR02 Amoxicillin and beta-lactamase inhibitor 1 g O 1.5 g O J01CA01 Ampicillin 2 g P 6 g P J01DE01 Cefepime 2 g P 4 g P J01DH02 Meropenem 2 g P 3 g P J01MA02 Ciprofloxacin 0.5 g P 0.8 g P J01XB01 Colistin 3 MU P 9 MU P

DDD: defined daily dose. O: oral. P: parenteral. MU: million units. a ATC: Anatomical Therapeutic Chemical. Source: WHO Collaborating Centre for Drug Statistics Methodology (2020b).

2.4 Antibacterial agents included in this report

The main analyses presented here are for the antibacterials for systemic use (ATC group J01) and related pharmacological subgroups. Data on additional antimicrobials are included in the calculation of the WHO AWaRe classification (WHO, 2019a), namely neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04) and metronidazole (P01AB01) (Table 2.3).

Table 2.3 Antibacterials included in the analyses

Class of agents ATC code (medicine) Antibacterials for systemic use J01

Pharmacological subgroups of J01 Tetracyclines J01A Amphenicols J01B Beta-lactam antibacterials, penicillins J01C Other beta-lactam antibacterials J01D Sulfonamides and trimethoprim J01E Macrolides, lincosamides and streptogramins J01F Aminoglycoside antibacterials J01G Quinolone antibacterials J01M Combinations of antibacterials J01R Other antibacterials J01X A07AA01 (neomycin) A07AA04 (streptomycin) A07AA05 (polymyxin B) Antibiotics for intestinal tract A07AA08 (kanamycin) A07AA09 (vancomycin) A07AA10 (colistin) A07AA11 (rifaximin) J04AB02 (rifampicin) Antimycobacterials J04AB03 (rifamycin) J04AB04 (rifabutin) Nitroimidazole derivatives P01AB01 (metronidazole)

6 Methods

While several agents are derived from classes other than J01, their inclusion in the AWaRe classification reflects their use as antibacterials. For example, while rifabutin, rifampicin and rifamycin are used mostly for the treatment of mycobacterial disease (tuberculosis), they are also used as antibiotics for select invasive staphylococcal infections. Similarly, vancomycin and colistin for oral therapy are classified in group A07AA as antibiotics used to treat enterocolitis. Injection forms of these agents are classified elsewhere (for example, vancomycin injection/infusion is classified in J01XA).

The term antibacterial therefore will be applied in this report to describe the agents included in the AWaRe classification.

2.5 Health sectors monitored

In most of the countries/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. Only five countries – Kazakhstan, Montenegro, the Russian Federation, Switzerland and Turkey – currently are able to report disaggregated data.

Disaggregation of data to community and hospital sectors facilitates monitoring using sector-specific metrics for quantifying antibiotic use and assessing the quality of prescribing (Coenen et al., 2007; de Bie et al., 2016; Stanic Benic et al., 2018). Hospital antimicrobial stewardship programmes that generally focus on changes to antimicrobial-use practices have also demonstrated their value in delivering clinical and economic benefits, with reductions in length of stay a key driver of cost savings (Nathwani et al., 2019).

2.6 Metrics and indicators reported

2.6.1 Measures of volume and relative consumption

Total numbers of DDDs for each product are aggregated to give the total number of DDDs at the desired ATC code level. The number of DDDs provides a measure of the extent of use, but for comparative purposes these data are usually adjusted for population size or population group, depending on the medicines of interest and the level of disaggregation of data that is possible. For most antibacterials, DDD per 1000 inhabitants per day (DID) are calculated for the total population, including all age and gender groups.

World Bank population estimates (World Bank, 2020) were applied to most WHO Europe AMC Network countries/areas apart from Turkey, where estimates were adjusted to take account of the large refugee population, and North Macedonia and Switzerland, where national population estimates were used.

Where there is incomplete consumption coverage, data are extrapolated to estimate 100% consumption at country/area level and to facilitate comparisons across countries and areas.

The ATC/DDD index 2019 was applied to all years of data to enable analysis of trends over time (WHO Collaborating Centre for Drug Statistics Methodology, 2020a).

Patterns of consumption in 2018 by ATC level 3 subgroups of J01 antibacterial agents and by route of administration (oral and parenteral) were assessed. Both volumes in DID and measures of relative consumption, expressed as a percentage of total consumption of groups of antimicrobials, were derived for pharmacological subgroups of J01.

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2.6.1.1 Total consumption in DDD per 1000 inhabitants per day (DID) The DID is the primary indicator of antibiotic consumption in countries/areas as defined by the European Commission and WHO (European Centre for Disease Prevention and Control et al., 2017) and is a key indicator reported in the first WHO global report on antimicrobial consumption (WHO, 2018).

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

2.6.1.2 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. It nevertheless 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 consumption of parenteral formulations is comparatively high, there may be opportunities to increase use of oral formulations without loss of clinical efficacy.

2.6.1.3 Consumption of pharmacological subgroups (ATC3 level) Absolute and relative consumption figures for pharmacological subgroups of J01 (ATC3 level) are presented in this report. Of particular interest is the volume and relative consumption of quinolone antibacterials (J01M).

In 2018, the European Medicines Agency (EMA) reviewed medicines containing fluoroquinolone and quinolone antibiotics (European Medicines Agency, 2019). The review found that very rarely, people having treatment with these antibiotics by mouth, injection or inhalation reported long-lasting and disabling side-effects, mainly involving muscles, tendons, joints and the nervous system.

In addition to recommending suspension of the marketing authorization for medicines containing cinoxacin, flumequine, nalidixic acid and pipemidic acid, EMA’s Committee for Medicinal Products for Human Use (CHMP) recommended restricting the use of the remaining fluoroquinolone antibiotics (European Medicines Agency, 2019). The prescribing information for health-care professionals and information for patients should describe the disabling and potentially permanent side-effects and advise patients to stop treatment with a fluoroquinolone antibiotic at the first sign of a side-effect involving muscles, tendons or joints and the nervous system. The CHMP recommended restrictions on the use of fluoroquinolones, advising that they should not be used to treat infections that might get better without treatment or are not severe (such as throat infections), to treat non-bacterial infections (such as non-bacterial (chronic) prostatitis), for preventing traveller’s diarrhoea or recurring lower urinary tract infections (urine infections that do not extend beyond the bladder), or to treat mild or moderate bacterial infections unless other antibacterial medicines commonly recommended for these infections cannot be used.

Given these EMA recommendations, regulatory authorities outside the EU should review the marketing authorization for medicines containing cinoxacin, flumequine, nalidixic acid and pipemidic acid. High levels of consumption of fluoroquinolines such as ciprofloxacin, norfloxacin, levofloxacin, ofloxacin

8 Methods

and moxifloxacin should be examined to ensure consumption is consistent with approved clinical guidelines and treatment protocols. In some cases, clinical guidelines may need to be reassessed and updated considering the EMA advice.

2.6.2 Trends in total consumption over time

To illustrate changes in rates in antimicrobial consumption over time, the compound annual growth rate (CAGR) of total antibiotic consumption was calculated for each participating country/area. This reflects the average annual change as a proportion (%) of the consumption in the starting year. CAGR were estimated for countries/areas that had five years of data available.

Linear regression was used for presenting trends in consumption for each participating country/area and evaluated using ANOVA tests. P values ≤ 0.05 were considered statistically significant.

2.6.3 WHO Access, Watch, Reserve (AWaRe) 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) (Sharland et al., 2018; WHO, 2017a, 2017b). The Committee identified empirical first- and second- choice treatments for several common community-acquired infections, focusing on treatment choices broadly applicable in most countries/areas. The Expert Committee also proposed a categorization of antibiotics into Access, Watch and Reserve groups. 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.

In 2019, the WHO EML and EMLc (WHO, 2019b) were updated and the AWaRe classification was expanded beyond the antibiotics listed on the EML and EMLc. As a result, 180 antibiotics used globally have been assigned to either Access (n = 48), Watch (n = 110) or Reserve (n = 22) groups (see Annex 1). Nineteen of the 48 Access agents, 11 of the 110 Watch agents and seven of the 22 Reserve agents are included individually in the 2019 WHO Model List of Essential Medicines as first- or second -choice empiric treatment options for specified infectious syndromes (WHO, 2019b).

A further five medicines were included in the analyses here following consultation with members of the Expert Committee on the Selection of Essential Medicines. These were Watch group agents neomycin (A07AA01), streptomycin (A07AA04) and kanamycin A07AA08, and Reserve group agents polymyxin B (A07AA05) and colistin (A07AA10).

In addition to classifying 180 antibiotics, WHO created a list of 103 antibiotics that are not recommended – fixed-dose combinations of multiple broad-spectrum antibiotics that lack evidence-based indications for use or recommendations in high-quality international guidelines. WHO suggests that the use of these antibiotics should be actively discouraged.

A detailed description of the origins of the WHO AWaRe classification is available in the WHO global report on AMC (WHO, 2018).

The characteristics of these groups are summarized in Table 2.4.

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Table 2.4 WHO categories of antibiotics – descriptions

Group Definition This group includes antibiotics that have activity against a wide range of commonly Access agents encountered susceptible pathogens while also showing lower resistance potential than antibiotics in the other groups. This group includes antibiotics that have higher resistance potential and includes most of the highest priority agents among the Critically Important Antimicrobials for Human Medicine and/ Watch agents or antibiotics that are at relatively high risk of selection of bacterial resistance. Antibiotics in the Watch group should be prioritized as key targets of stewardship programmes and monitoring. This group includes antibiotics and antibiotic classes that should be reserved for treatment of confirmed or suspected infections due to multidrug-resistant organisms. Antibiotics in the Reserve group should be treated as “last-resort” options; they should be accessible, but their Reserve agents use should be tailored to highly specific patients and settings when all alternatives have failed or are not suitable. These medicines could be protected and prioritized as key targets of national and international stewardship programmes involving monitoring and utilization reporting to preserve their effectiveness. These are medicines not specifically identified in the groups described above. Some unclassified agents are included in WHO’s list of “not recommended antibiotics”. The “not Unclassified recommended” agents are the fixed-dose combinations of multiple broad-spectrum antibiotics whose use is neither evidence-based nor recommended in high-quality international guidelines. WHO does not recommend their use in clinical practice.

The AWaRe classification can be used to inform stewardship activities both in community and hospital sectors. The proportions of consumption (%) according to the AWaRe classification are presented in this report.

It is not possible to assess levels of use of “not recommended” antibiotics, as these combination medicines do not always have an assigned ATC code and therefore are not included in data collection.

2.6.4 WHO global monitoring indicator

In conjunction with the expansion of the list of antibiotics included in the AWaRe classification, WHO has proposed a global monitoring indicator that by 2023, 60% of all antibiotics consumed should come from Access, the group of antibiotics at lowest risk of resistance (WHO, 2020).

The proportion of total consumption that comprised Access agents was calculated for each year of analysis from 2014 to 2018. The number of countries/areas reaching the WHO global monitoring target in 2018 and across each of the years assessed is reported.

2.6.5 Access-to-Watch indicator

This indicator has been used in several published papers (Hsia et al., 2019; Klein et al., 2020). The measure is calculated as the ratio of DDDs of Access medicines to DDDs of Watch medicines.

Highest Access-to-Watch index scores will be reported in countries/areas with the highest proportional consumption of Access antibacterials. If only Access and Watch agents are consumed, then consumption of 60% Access agents and 40% Watch agents would give a ratio of 1.5 : 1.

The index score will also be influenced by the extent of consumption of unclassified agents as shown in the examples in Table 2.5.

10 Methods

Table 2.5 Examples of calculation of the Access : Watch ratio

Percentage of total DDDs Country Access : Watch ratio Access Watch Reserve Unclassified A 62.0 37.4 0.1 0.4 1.7 (62.0 : 37.4) B 60.3 27.8 0.2 11.9 2.2 (60.3 : 27.8) C 59.6 16.1 0.1 24.6 3.7 (59.5 : 16.1) D 59.1 38.8 0.3 1.9 1.5 (59.1 : 38.8)

DDD: daily defined dose.

In each of the four cases, the proportion of consumption that is Access agents is close to 60%, but as the proportion of consumption of unclassified agents increases and Watch agents decreases, the ratio becomes much higher than 1.5.

2.6.6 Drug utilization 75% (DU75%)

In the 2017 and 2020 WHO AMC Network reports, the 10 most consumed oral formulations and 10 most consumed parenteral formulations were presented. These analyses are based on the observations of ESAC-Net and other analyses that consumption tends to be concentrated in a relatively small number of agents.

Estimates of the drug utilization 90% (DU90%) for antibiotics (that is, antibiotics accounting for 90% of all antibiotic consumption) have been reported in published papers for community (de Bie et al., 2016), hospital (Zhang et al., 2008) and total consumption (Abbasian et al., 2019). The DU90% has been suggested as a useful tool for assessing the quality of prescribing (Bergmann, 1998; Wettermark et al., 2003).

In this report, the drug utilization 75% (DU75%) (the antibiotic substances accounting for 75% of the consumption measured in DDD (Zarb et al., 2011)) is calculated. This metric was considered in the WHO global report on surveillance of antibiotic consumption (WHO, 2018), where results were stratified by route of administration (oral and parenteral formulations) and reported by region. All substances that appeared on the DU75% lists in countries/areas within a region were compiled into a region-specific list for oral substances and parenteral substances, respectively.

The DU75% for 2018 was reported by country/area and across networks in the 2021 joint publication on AMC data from ESAC-Net and the WHO Regional Office for Europe (Robertson et al., 2021).

The DU75% is calculated for oral and parenteral formulations separately. Results are shown as the ranking of consumption at substance level (fifth ATC group level), volumes in DID and percentages of total consumption. In addition to reporting the numbers of antibacterial agents in the DU75% segment, the agents in the segment are classified according to the AWaRe classification. This facilitates identification of restricted and special use antibacterials that may be consumed widely and be targets for stewardship activities.

2.6.7 Other monitoring indicators – amoxicillin index

Antibacterial agents can be classified in different ways – according to type of action (bacteriostatic and bactericidal), source (fungal sources, semisynthetic members which are chemically altered natural product and/or synthetic), spectrum of activity (narrow- or broad-spectrum), chemical structure and function (Ullah & Ali, 2017).

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Narrow-spectrum antibacterials are those that can work on a narrow range of microorganisms, such as acting against Gram-positive only or Gram-negative only bacteria. Broad-spectrum antibacterials are active against a wider number of bacteria, including both Gram-positive and Gram-negative bacteria, and can be used to treat a variety of infectious diseases. Broad-spectrum agents are particularly useful when the infecting bacteria is unknown. In general, narrow-spectrum agents are preferred over broad-spectrum as they do not kill as many of the normal microorganisms in the body, have less ability to cause superinfection and will cause less bacterial resistance, as they deal only with specific bacteria. Examples of narrow-spectrum antibiotics are the older penicillins (penicillin V and G), the macrolides and vancomycin, while broad-spectrum antibiotics include the aminoglycosides, the second- and third-generation cephalosporins, the quinolones and some synthetic penicillins (Ullah & Ali, 2017).

Narrow-spectrum penicillins (beta-lactamase sensitive penicillins, J01CE) include oral agents such as phenoxymethylpenicillin (penicillin V), propicillin, pheneticillin and clometocillin and parenteral agents benzylpenicillin (penicillin G), benzathine benzylpenicillin, procaine benzylpenicillin, and combinations of benzylpenicillin and procaine penicillin (WHO Collaborating Centre for Drug Statistics Methodology, 2020a).

European Surveillance of Antimicrobial Consumption (ESAC) quality indicators for antibiotic consumption in the community include a measure of the relative use of narrow- and broad-spectrum antibiotics within J01 antibiotics (European Centre for Disease Prevention and Control, 2020b). The indicator is calculated as the ratio between the consumption of broad-spectrum antibiotics (J01CR, J01DC, J01DD and J01F (without erythromycin)) to narrow-spectrum penicillins, cephalosporins and macrolides (J01CE, J01DB and J01FA01). The broad/narrow ratio gives an estimate of the balance between prescribing of broad- versus narrow-spectrum antibiotics. The smaller the broad/narrow ratio, the more appropriate the prescribing (Coenen et al., 2007).

Narrow-spectrum phenoxymethylpenicillin is the antibiotic of choice for respiratory tract infections in the Scandinavian countries, while broader-spectrum amoxicillin is used in most other European countries/areas (Skarpeid & Høye, 2018). Not all AMC Network countries/areas have marketing authorization for oral phenoxymethylpenicillin. Alternative quality indicators based on amoxicillin consumption have been developed. De Bie et al. (2016) proposed two indicators: the proportion of amoxicillin users (J01CA04) among all antibiotic users (J01) – the amoxicillin index; and the ratio between the number of amoxicillin users (J01CA04) and the number of users of broad-spectrum penicillins, cephalosporins and macrolides (J01CR, J01DC, J01DD and J01F (without erythromycin)) – the amoxicillin-to-broad-spectrum ratio. These measures provide estimates of the consumption of a first-line and relatively narrower-spectrum penicillin antibiotic to that of broader-spectrum penicillins, cephalosporins and macrolides.

The amoxicillin index has been applied to analyses of antibiotic consumption in children (de Bie et al., 2016; Hsia et al., 2019) and analyses of global consumption patterns (Klein et al., 2020). In the latter, the amoxicillin index was defined as the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs.

The amoxicillin index is a useful measure because amoxicillin and phenoxymethylpenicillin are effective treatments for respiratory tract infections, which are the most common indication for antibiotic prescriptions (Shapiro et al., 2014). The WHO EML (WHO, 2019b) identifies amoxicillin as first- choice antibiotic for a range of clinical conditions, including mild-to-moderate community-acquired pneumonia, otitis media, pharyngitis, sinusitis, lower urinary tract infection and exacerbations of chronic obstructive pulmonary disease.

12 Methods

The amoxicillin index (DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) is applied in the analyses reported here.

2.6.8 Measures applied to crossnational comparisons

Crossnational comparisons of 2018 data were conducted for 17 countries of the Network. AMC Network summary data are presented using arithmetic and population-weighted mean estimates.

Arithmetic means for total consumption are derived by summing the national estimates for total consumption and dividing by the number of countries contributing data to the calculation.

Population-weighted estimates for total consumption are calculated by multiplying DDD per 1000 inhabitants per day for each country with the corresponding population, summing the country estimates and dividing the total DDDs by the total population of participating countries for each network (European Centre for Disease Prevention and Control, 2019).

Using similar methods, population-weighted estimates are calculated for the relative consumption of Access, Watch and Reserve group agents and for components of the DU75% in the AMC Network.

2.6.9 Summary of metrics used in analyses

The key metrics used in analyses and included in this report are summarized in Table 2.6.

Joint interpretation of these metrics will help to identify broad areas for national/area antibiotic stewardship and guideline development, even when information about indication is not available.

Table 2.6 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 DID Total consumption of J01 antibacterials by pharmacological subgroup (ATC3): - tetracyclines (J01A) - amphenicols (J01B) - beta-lactam antibacterials, penicillins (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 of WHO Access, Watch, Reserve antibioticsa Relative consumption of Access, Watch and Reserve group agents % Access-to-Watch index Ratio Concordance with WHO global monitoring indicator Proportion of total consumption that is Access agents % Drug utilization 75% (DU75%) DU75% – oral formulation Rank, DID, % DU75% – parenteral formulation Rank, DID, % Other monitoring indicators Amoxicillin index %

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Table 2.6 contd

Category Unit Metrics reported in crossnational comparisons Arithmetic mean estimates of: - total consumption of J01 antibacterials DID - consumption of pharmacological subgroups (ATC3 level) DID, % - consumption of agents according to AWaRe classification DID, % Population-weighted mean estimates of: - total consumption of J01 antibacterials DID - consumption of pharmacological subgroups (ATC3 level) DID, % - consumption of agents according to AWaRe classification % - agents comprising the DU75% Rank

DID: defined daily doses per 1000 inhabitants per day. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04) and metronidazole (P01AB01).

2.7 Data interpretation

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

• incomplete registration of antimicrobial products in circulation in the country/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.

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 number of products in several countries/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.

Several agents that are consumed in the AMC Network are not yet classified to WHO AWaRe categories. The WHO Regional Office for Europe is compiling a list of these agents for consideration at the next meeting of the Expert Committee on the Selection and Use of Essential Medicines in 2021.

14 Methods

2.7.1 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.

The analyses in this report provide annual consumption estimates. The fluctuations in total consumption estimates from several countries/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/areas.

2.7.2 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/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/ 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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3. ALBANIA

3.1 Data source and years of data collection

Albania has provided data for each of the five years of data collection (2014–2018). The main sources of data are import records provided by the drug agency.

3.2 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. 3.1 and Table 3.1).

Parenteral antibacterials represented 7–9% of total J01 consumption between 2014 and 2018 (Table 3.1).

In 2014, the highest levels of consumption were in beta-lactam penicillins (J01C) at 6.8 DID, decreasing to 4.8 DID in 2018. Over the same period, there were increases in consumption of cephalosporins (J01D), from 3.6 DID in 2014 to 6.0 DID in 2018, and quinolones (J01M), from 2.4 DID in 2014 to 3.5 DID in 2018. Consumption of tetracyclines (J01A) decreased from 3.6 DID in 2014 to 2.0 DID in 2018.

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

Fig. 3.1 Total consumption of J01 antibacterials by pharmacological subgroup

25 Other J01 antibacterials (J01G, J01R, J01X)

20 Quinolone antibacterials (J01M)

Macrolides, lincosamides 15 and streptogramins (J01F)

Sulfonamides and trimethoprim (J01E) 10 Other beta-lactams (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day 5 Beta-lactam penicillins (J01C)

Amphenicols (J01B) 0 Tetracyclines (J01A) ALB ALB ALB ALB ALB 2014 2015 2016 2017 2018

DDD: daily defined dose.

16 Albania

The data show fluctuations in consumption of J01 antibacterials over time. The CAGR for the period 2014–2018 was −0.7% per year, although the suggested trend towards reduced consumption over time was not statistically significant (Table 3.1).

Table 3.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2014 2015 2016 2017 2018 Route of administration Oral J01 17.9 (91) 15.1 (93) 15 (91) 17 (91) 17.5 (92) Parenteral J01 1.7 (9) 1.2 (7) 1.5 (9) 1.8 (9) 1.5 (8) Totala 19.6 16.3 16.5 18.7 19.0 Class of antibacterial agents Tetracyclines (J01A) 3.6 (18) 2.6 (16) 2.7 (16) 0.5 (3) 2.0 (11) Amphenicols (J01B) 0.1 (1) < 0.1 (0) 0.1 (1) < 0.1 (0) < 0.1 (0) Beta-lactam penicillins (J01C) 6.8 (35) 3.7 (23) 4.2 (26) 6.7 (36) 4.8 (25) Other beta-lactams (includes 3.6 (18) 3.5 (22) 4.8 (29) 5.9 (32) 6.0 (32) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 0.2 (1) 0.3 (2) 0.3 (2) – 0.3 (2) Macrolides, lincosamides and 2.0 (10) 2.1 (13) 1.6 (10) 2.1 (11) 2.2 (12) streptogramins (J01F) Quinolone antibacterials (J01M) 2.4 (12) 3.2 (20) 2.4 (15) 3.2 (17) 3.5 (18) Other J01 antibacterials (J01G, J01R, J01X) 0.8 (4) 0.8 (5) 0.5 (3) 0.3 (2) 0.2 (1) Totala 19.6 16.3 16.5 18.7 19.0 Analysis of trend over time Trendb P-value 0.8 CAGRc −0.7

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

Beta-lactam penicillin consumption fluctuated across the years analysed, representing 35% of J01 consumption in 2014 and 25% in 2018. There is evidence of increasing relative consumption of cephalosporins (J01D), at 18% in 2014 and 32% in 2018, and quinolones (J01M), at 12% in 2014 and 18% in 2018.

3.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 3.2 and is summarized in Table 3.2.

Both volumes and relative consumption of Access agents decreased over time, from 12.2 DID (61% of total consumption) in 2014 to 7.5 DID (39%) in 2018. Albania therefore would have met the WHO national monitoring target of at least 60% of total consumption being Access agents only in 2014.

17 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Conversely, volumes and relative consumption of Watch agents increased from 7.6 DID (38% of total consumption) in 2014 to 11.4 DID (60%) in 2018.

Consumption of Reserve and unclassified agents remained low across all years of data analysed.

Fig. 3.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 ALB ALB ALB ALB ALB 2014 2015 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 3.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2014 2015 2016 2017 2018 Access 12.2 (61) 7.8 (48) 8.6 (51) 8.4 (44) 7.5 (39) Watch 7.6 (38) 8.5 (52) 8.1 (48) 10.5 (56) 11.4 (60) Reserve < 0.01 < 0.01 – < 0.1 < 0.01 Unclassified 0.1 (1) 0.1 (0) 0.1 (0) – 0.1 (0) Totalb 19.9 16.4 16.8 19.0 19.0

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 3.3.

Table 3.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2014 1.62 2015 0.92 2016 1.06 2017 0.80 2018 0.66 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

18 Albania

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The decrease in the ratio from 1.62 in 2014 to 0.66 in 2018 illustrates the higher relative use of Watch agents over time.

3.4 Consumption at substance level (5th ATC group level)

Table 3.4 and 3.5 (oral agents) and Table 3.6 and 3.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibiotic consumption.

The number of agents constituting the DU75% by oral substance ranged from seven to nine across the years of analysis (Table 3.4).

Oral amoxicillin and beta-lactamase inhibitor (ATC code J01CR02) was the most consumed oral agent in 2017 and 2018, although the volumes and proportion of consumption decreased from 3.5 DID (20%) in 2017 to 2.3 DID (13%) in 2018 (Table 3.4 and 3.5). The second-ranked agent, amoxicillin (J01CA04), also showed decreases in consumption over time, at 3.2 DID (21%) in 2016 and 2.1 DID (12%) in 2018.

Four or five Watch agents appeared in the DU75% for each of the years analysed. Increases in consumption of two second-generation cephalosporins, cefuroxime (J01DC02) and cefaclor (J01DC04) combined, were seen, from 1.0 DID (5%) to 3.4 DID (20%) between 2014 and 2018. Similarly, consumption of two fluoroquinolones, ciprofloxacin (J01MA02) and levofloxacin (J01MA12) combined, increased from 1.7 DID (9%) to 2.8 DID (16%) between 2014 and 2018.

Table 3.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 5 8 6 Tetracycline (J01AA07) 3 3 3 5 Amoxicillin (J01CA04) 1 2 1 2 2 Amoxicillin and beta-lactamase inhibitor 2 4 7 1 1 (J01CR02) Watch Cefuroxime (J01DC02) 7 6 2 3 3 Cefaclor (J01DC04) 6 Cefixime (J01DD08) 7 7 Clarithromycin (J01FA09) 8 9 6 Azithromycin (J01FA10) 6 5 5 5 7 Ciprofloxacin (J01MA02) 4 1 4 4 4 Levofloxacin (J01MA12) 8 8

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

19 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 3.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 1.1 (6) 0.8 (5) 0.9 (6) Tetracycline (J01AA07) 2.1 (11) 1.6 (11) 1.6 (11) 1.8 (10) Amoxicillin (J01CA04) 3.9 (21) 2.1 (14) 3.2 (21) 2.9 (17) 2.1 (12) Amoxicillin and beta-lactamase inhibitor 2.2 (12) 1.4 (9) 0.7 (5) 3.5 (20) 2.3 (13) (J01CR02) Watch Cefuroxime (J01DC02) 1.0 (5) 1.1 (7) 1.9 (13) 2.1 (12) 1.9 (11) Cefaclor (J01DC04) 1.5 (9) Cefixime (J01DD08) 0.8 (5) 0.8 (5) Clarithromycin (J01FA09) 0.8 (4) 0.6 (4) 0.9 (5) Azithromycin (J01FA10) 1.0 (6) 1.3 (8) 1.4 (9) 1.2 (7) 1.3 (7) Ciprofloxacin (J01MA02) 1.7 (9) 2.3 (15) 1.4 (9) 2.1 (12) 1.8 (10) Levofloxacin (J01MA12) 0.6 (4) 1.0 (6) Consumption in DID 13.8 (75) 11.9 (78) 11.8 (77) 13.5 (78) 13.7 (78) (% of total consumption) Total consumption of oral agents 18.2 15.2 15.3 17.2 17.6

Agent not included in DU75% for this year. DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The number of agents constituting the DU75% by parenteral substance ranged from three to four across the years of analysis (Table 3.6).

The Watch agent ceftriaxone (J01DD04) was ranked number one in each year of analysis, constituting 33% of consumption of parenteral agents in 2014 and 54% in 2018 (Table 3.7).

Table 3.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Amoxicillin and beta-lactamase inhibitor 3 (J01CR02) Cefazolin (J01DB04) 2 2 2 2 2 Gentamicin (J01GB03) 3 3 3 3 Amikacin (J01GB06) 4 4 Watch Ceftriaxone (J01DD04) 1 1 1 1 1

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

20 Albania

Table 3.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Amoxicillin and beta-lactamase inhibitor 0.1 (9) (J01CR02) Cefazolin (J01DB04) 0.5 (27) 0.2 (21) 0.3 (22) 0.1 (8) 0.3 (19) Gentamicin (J01GB03) 0.3 (16) 0.2 (14) 0.1 (9) 0.1 (6) Amikacin (J01GB06) 0.1 (10) 0.1 (6) Watch Ceftriaxone (J01DD04) 0.6 (33) 0.4 (34) 0.7 (50) 1.0 (60) 0.8 (54) Consumption in DID 1.3 (76) 0.9 (78) 1.2 (81) 1.4 (80) 1.2 (82) (% of total consumption) Total consumption of parenteral agents 1.7 1.2 1.5 1.8 1.5

Agent not included in DU75% for this year. DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

3.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index decreased from 22% in 2014 to 12% in 2018 (Table 3.8).

Table 3.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2014 2015 2016 2017 2018 Oral amoxicillin 3.9 (22) 2.1 (14) 3.2 (21) 2.9 (17) 2.1 (12) Oral amoxicillin and 3.9 (22) 2.1 (14) 3.2 (21) 2.9 (17) 2.1 (12) phenoxymethylpenicillin Total oral J01 17.9 15.1 15.0 17.0 17.5

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

3.6 Discussion

The analyses presented here document consumption between 2014 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. The five years of data examined provide a platform for future years of data to enable assessment of trends over time. The most notable feature of these data is the increasing and relatively higher levels of consumption of specific Watch group antibiotics between 2014 and 2018, which suggests some targets for further investigation, interventions and stewardship activities.

21 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

4. ARMENIA

4.1 Data source and years of data collection

Armenia has provided data for each of the five years of data collection (2014–2018). 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).

Parenteral antibacterials represented 10–16% of total J01 consumption between 2014 and 2018 (Table 4.1).

The highest levels of consumption were in beta-lactam penicillins (J01C) at 3.9 DID in 2014 and 3.4 DID in 2018. Over the same period, there were small increases in the consumption of macrolides, lincosamides and streptogramins (J01F), from 1.5 DID in 2014 to 1.7 DID in 2018, and quinolones (J01M), from 1.5 DID in 2014 to 1.7 DID in 2018. Consumption of cephalosporins (J01D) decreased from 1.4 DID in 2014 to 1.1 DID in 2018.

Fig. 4.1 Total consumption of J01 antibacterials by pharmacological subgroup

15 Other J01 antibacterials (J01G, J01R, J01X)

Quinolone antibacterials (J01M)

10 Macrolides, lincosamides and streptogramins (J01F)

Sulfonamides and trimethoprim (J01E)

5 Other beta-lactams (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day Beta-lactam penicillins (J01C)

Amphenicols (J01B) 0 Tetracyclines (J01A) ARM ARM ARM ARM ARM 2014 2015 2016 2017 2018

DDD: daily defined dose.

22 Armenia

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

The data show fluctuations in consumption of J01 antibacterials over time. The CAGR for the period 2014–2018 was −1.2% per year, although the suggested trend towards reduced consumption over time was not statistically significant (Table 4.1).

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

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2014 2015 2016 2017 2018 Route of administration Oral J01 11.3 (88) 8.2 (87) 7.8 (84) 10.7 (89) 10.9 (90) Parenteral J01 1.5 (12) 1.2 (13) 1.5 (16) 1.3 (11) 1.2 (10) Totala 12.7 9.4 9.4 12.0 12.1 Class of antibacterial agents Tetracyclines (J01A) 2.0 (15) 0.8 (9) 1.6 (17) 1.5 (13) 1.6 (14) Amphenicols (J01B) 0.4 (3) 0.3 (4) 0.2 (2) 0.4 (3) 0.3 (2) Beta-lactam penicillins (J01C) 3.9 (30) 3.0 (32) 2.0 (21) 3.8 (32) 3.4 (28) Other beta-lactams (includes 1.4 (11) 1.0 (11) 1.3 (14) 1.2 (10) 1.1 (9) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 1.4 (11) 1.1 (12) 0.9 (10) 1.2 (10) 1.4 (11) Macrolides, lincosamides and 1.5 (11) 0.8 (9) 1.4 (15) 1.5 (12) 1.7 (14) streptogramins (J01F) Quinolone antibacterials (J01M) 1.5 (12) 1.3 (14) 1.2 (13) 1.3 (11) 1.7 (15) Other J01 antibacterials (J01G, J01R, J01X) 0.8 (6) 0.9 (10) 0.6 (7) 1.0 (9) 0.9 (8) Totala 12.7 9.4 9.4 12.0 12.1 Analysis of trend over time Trendb P-value 0.83 CAGRc −1.2

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

Beta-lactam penicillin consumption fluctuated across the years analysed, representing 30% of J01 consumption in 2014 and 28% in 2018. There is evidence of increasing relative consumption of macrolides, lincosamides and streptogramins (J01F), at 11% in 2014 and 14% in 2018, and quinolones (J01M), at 12% in 2014 and 15% in 2018. The relative consumption of cephalosporins (J01D) decreased over time, from 11% in 2014 to 9% in 2018.

4.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 4.2 and is summarized in Table 4.2.

23 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Both volumes and relative consumption of Access agents decreased over time, from 8.7 DID (66% of total consumption) in 2014 to 7.8 DID (63%) in 2018. Armenia would have met the WHO national monitoring target of at least 60% of total consumption being Access agents in all years analysed except for 2016 (57%).

Volumes and relative consumption of Watch agents increased from 4.1 DID (32% of total consumption) in 2014 to 4.4 DID (36%) in 2018.

Consumption of Reserve and unclassified agents remained low across all years of data analysed. Few of the medicines classified as Reserve agents are registered in Armenia.

Fig. 4.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 ARM ARM ARM ARM ARM 2014 2015 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 4.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2014 2015 2016 2017 2018 Access 8.7 (66) 6.6 (66) 5.5 (57) 8.1 (66) 7.8 (63) Watch 4.1 (32) 3.1 (31) 3.9 (41) 4.0 (32) 4.4 (36) Reserve 0.01 (0) 0.01 (0) 0.01 (0) 0.02 (0) 0.01 (0) Unclassified 0.3 (2) 0.3 (3) 0.2 (2) 0.3 (2) 0.2 (2) Totalb 13.1 10.0 9.6 12.3 12.4

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 4.3.

24 Armenia

Table 4.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2014 2.10 2015 2.12 2016 1.40 2017 2.04 2018 1.76 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. Apart from 2016, the ratio in Armenia consistently has been above 1.5.

4.4 Consumption at substance level (5th ATC group level)

Table 4.4 and 4.5 (oral agents) and Table 4.6 and 4.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibiotic consumption.

The number of agents constituting the DU75% by oral substance ranged from seven to nine across the years of analysis (Table 4.4).

Table 4.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 2 4 1 3 3 Tetracycline (J01AA07) 7 Amoxicillin (J01CA04) 1 1 5 1 1 Amoxicillin and beta-lactamase inhibitor 4 3 2 2 5 (J01CR02) Sulfamethoxazole and trimethoprim 3 2 3 4 2 (J01EE01) Nitrofurantoin (J01XE01) 8 8 7 7 Metronidazole (P01AB01) 7 Watch Clarithromycin (J01FA09) 7 8 Azithromycin (J01FA10) 6 6 4 5 4 Ciprofloxacin (J01MA02) 5 5 6 6 6 Levofloxacin (J01MA12) 9

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

25 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Oral amoxicillin (J01CA04) was the most consumed oral agent in all years apart from 2016, when doxycycline (J01AA02) was the most consumed oral agent. The volumes and proportion of consumption of amoxicillin were consistent across years except 2016, at 2.3 DID (20%) in 2014 and 2.1 DID (19%) in 2018 (Table 4.5). The second-ranked agent varied across the years, being doxycycline in 2014, amoxicillin and beta-lactamase inhibitor (ATC code J01CR02) in 2016 and 2017, and sulfamethoxazole and trimethoprim (J01EE01) in 2015 and 2018.

Two to four Watch agents appeared in the DU75% for each of the years analysed. Most consistently consumed Watch agents over time were azithromycin (J01FA10), increasing from 0.7 DID (6% of total consumption) in 2014 to 1.2 DID (11%) in 2018, and ciprofloxacin (J01MA02), at 1.0 DID (8%) in 2014 and 0.8 DID (7%) in 2018.

Table 4.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 1.6 (14) 0.8 (9) 1.2 (15) 1.4 (13) 1.2 (11) Tetracycline (J01AA07) 0.4 (5) Amoxicillin (J01CA04) 2.3 (20) 1.9 (21) 0.7 (8) 2.3 (20) 2.1 (19) Amoxicillin and beta-lactamase inhibitor 1.1 (10) 0.8 (10) 1.1 (13) 1.4 (13) 1.2 (11) (J01CR02) Sulfamethoxazole and trimethoprim 1.4 (12) 1.1 (12) 0.9 (11) 1.2 (11) 1.4 (12) (J01EE01) Nitrofurantoin (J01XE01) 0.5 (4) 0.5 (6) 0.6 (6) 0.6 (5) Metronidazole (P01AB01) 0.6 (6) Watch Clarithromycin (J01FA09) 0.5 (4) 0.4 (5) Azithromycin (J01FA10) 0.7 (6) 0.6 (7) 0.8 (10) 1.0 (9) 1.2 (11) Ciprofloxacin (J01MA02) 1.0 (8) 0.7 (8) 0.5 (6) 0.7 (6) 0.8 (7) Levofloxacin (J01MA12) 0.4 (5) Consumption in DID 9.2 (79) 7.0 (79) 6.3 (78) 8.6 (77) 8.5 (75) (% of total consumption) Total consumption of oral agents 11.6 8.8 8.1 11.1 11.2

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The number of agents constituting the DU75% by parenteral substance ranged from three to five across the years of analysis (Table 4.6).

The Watch agent ceftriaxone (J01DD04) was ranked number one in each year of analysis, constituting 62% of consumption of parenteral agents in 2014 and 59% in 2018 (Table 4.7).

26 Armenia

Table 4.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Benzylpenicillin (J01CE01) 3 4 2 4 4 Cefazolin (J01DB04) 2 5 Metronidazole (J01XD01) 3 3 3 2 Watch Ceftriaxone (J01DD04) 1 1 1 1 1 Streptomycin (J01GA01) 2 4 2 3

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

Table 4.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Benzylpenicillin (J01CE01) 0.1 (6) 0.1 (7) 0.1 (8) 0.1 (5) 0.1 (5) Cefazolin (J01DB04) 0.1 (9) 0.1 (5) Metronidazole (J01XD01) 0.1 (7) 0.1 (5) 0.1 (7) 0.1 (7) Watch Ceftriaxone (J01DD04) 0.9 (62) 0.6 (53) 0.9 (59) 0.7 (52) 0.7 (59) Streptomycin (J01GA01) 0.2 (13) 0.1 (5) 0.1 (9) 0.1 (6) Consumption in DID 1.1 (76) 0.9 (80) 1.2 (77) 1.0 (77) 0.9 (77) (% of total consumption) Total consumption of parenteral agents 1.5 1.2 1.5 1.3 1.2

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

4.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index decreased from 21% in 2014 to 19% in 2018 (Table 4.8).

27 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 4.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2014 2015 2016 2017 2018 Oral amoxicillin 2.3 (21) 1.9 (23) 0.7 (9) 2.3 (21) 2.1 (19) Oral amoxicillin and 2.3 (21) 1.9 (23) 0.7 (9) 2.3 (21) 2.1 (19) phenoxymethylpenicillin Total oral J01 11.3 8.2 7.8 10.7 10.9

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

4.6 Discussion

The analyses presented here document consumption between 2014 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. The five years of data examined provide a platform for future years of data to enable assessment of trends over time. Differences in 2016 data may relate to the data source used and the impact of supply cycles for some medicines.

Reasons for the relatively high levels of consumption of sulfamethoxazole and trimethoprim (around 12% of total consumption in each of the years of analysis) could be investigated further. The WHO Model List of Essential Medicines (WHO, 2019b) suggests the combination may be a first-choice agent for lower urinary tract infections and a second-choice agent for acute invasive diarrhoea and bacterial diarrhoea. In addition, it is listed as an antipneumocystosis medicine in the Model List, to prevent or treat Pneumocystis jiroveci pneumonia or Pneumocystis carinii pneumonia. The high level of consumption of sulfamethoxazole and trimethoprim suggests it is being used for other indications in Armenia. This could be assessed through reviews of prescriptions and existing clinical guidelines. Similarly, the relatively higher consumption of tetracyclines, particularly doxycycline, could be investigated further.

Armenia is already achieving the WHO target that by 2023, 60% of all antibiotics consumed should come from Access, the group of antibiotics at lowest risk of resistance.

28 5. AZERBAIJAN

5.1 Data source and years of data collection

Azerbaijan has provided data for each of the five years of data collection (2014–2018). The main sources of data are import records provided by the drug agency.

5.2 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. 5.1 and Table 5.1).

Parenteral antibacterial consumption has decreased substantially over time, from 61% of total J01 consumption in 2014 to 22% in 2018 (Table 5.1).

For all years except 2015, the highest levels of consumption were in beta-lactam penicillins (J01C), at 3.5 DID in 2014 and 3.0 DID in 2018. Tetracyclines (J01A) had the highest level of consumption in 2015 at 1.8 DID. Consumption of cephalosporins (J01D) fluctuated, at 0.5 DID in 2014, 1.6 DID in 2016 and 0.7 DID in 2018. Over the same period, there were increases in consumption of macrolides, lincosamides and streptogramins (J01F), from 0.6 DID in 2014 to 1.4 DID in 2018, and quinolones (J01M), from 0.4 DID in 2014 to 0.9 DID in 2018.

Fig. 5.1 Total consumption of J01 antibacterials by pharmacological subgroup

10 Other J01 antibacterials (J01G, J01R, J01X)

Quinolone antibacterials (J01M)

Macrolides, lincosamides and streptogramins (J01F)

5 Sulfonamides and trimethoprim (J01E)

Other beta-lactams (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day Beta-lactam penicillins (J01C)

Amphenicols (J01B) 0 Tetracyclines (J01A) AZE AZE AZE AZE AZE 2014 2015 2016 2017 2018

DDD: daily defined dose.

29 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

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

The data show fluctuations in consumption of J01 antibacterials over time. The CAGR for the period 2014–2018 was 8.6% per year, although the suggested trend towards increased consumption over time was not statistically significant (Table 5.1).

Table 5.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2014 2015 2016 2017 2018 Route of administration Oral J01 2.5 (39) 5.9 (79) 7.0 (75) 5.9 (75) 6.9 (78) Parenteral J01 3.9 (61) 1.5 (21) 2.4 (25) 2.0 (25) 2.0 (22) Totala 6.4 7.4 9.5 7.8 8.9 Class of antibacterial agents Tetracyclines (J01A) 0.6 (9) 1.8 (24) 1.4 (15) 1.3 (17) 1.5 (17) Amphenicols (J01B) 0.1 (1) 0.2 (2) < 0.1 (0) < 0.1 (0) 0.1 (1) Beta-lactam penicillins (J01C) 3.5 (55) 1.4 (19) 2.1 (22) 1.8 (23) 3.0 (33) Other beta-lactams (includes 0.5 (8) 0.7 (10) 1.6 (17) 1.5 (19) 0.7 (8) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 0.5 (7) 0.7 (9) 0.7 (7) 0.5 (7) 0.6 (7) Macrolides, lincosamides and 0.6 (9) 1.0 (14) 1.2 (12) 1.0 (13) 1.4 (16) streptogramins (J01F) Quinolone antibacterials (J01M) 0.4 (6) 0.8 (11) 1.5 (16) 1.0 (13) 0.9 (10) Other J01 antibacterials (J01G, J01R, J01X) 0.3 (5) 0.8 (10) 1.1 (11) 0.7 (8) 0.8 (10) Totala 6.4 7.4 9.5 7.8 8.9 Analysis of trend over time Trendb P-value 0.19 CAGRc 8.6

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

Beta-lactam penicillin consumption fluctuated across the years analysed, representing 55% of J01 consumption in 2014, 19% in 2015 and 33% in 2018. There is evidence of increasing relative consumption of tetracyclines (J01A), at 9% in 2014 and 17% in 2018, macrolides, lincosamides and streptogramins (J01F), at 9% in 2014 and 16% in 2018, and quinolones (J01M), at 6% in 2014 and 10% in 2018. Relative consumption of cephalosporins (J01D) varied across the years analysed, at 8% in 2014, 19% in 2017 and 8% in 2018.

5.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

30 Azerbaijan

The relative consumption of Access, Watch and Reserve group antibiotics is shown in Fig. 5.2 and is summarized in Table 5.2.

The volumes and relative consumption of Access agents increased over time, from 3.5 DID (54% of total consumption) in 2014 to 5.8 DID (61%) in 2018. Azerbaijan would have met the WHO national monitoring target of at least 60% of total consumption being Access agents only in 2018.

Volumes and relative consumption of Watch agents also increased over time, from 1.5 DID (23% of total consumption) in 2014 to 3.4 DID (36%) in 2018.

Consumption of Reserve agents remained low across all years of data analysed, while consumption of unclassified agents decreased from 23% in 2014 to 4% in 2018.

Fig. 5.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 AZE AZE AZE AZE AZE 2014 2015 2016 2017 2018

a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 5.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2014 2015 2016 2017 2018 Access 3.5 (54) 4.6 (59) 4.8 (49) 5.6 (55) 5.8 (61) Watch 1.5 (23) 2.7 (35) 4.3 (44) 4.1 (40) 3.4 (36) Reserve – – – – – Unclassified 1.5 (23) 0.4 (5) 0.7 (7) 0.5 (5) 0.3 (4) Totalb 6.6 7.7 9.9 10.1 9.6

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 5.3.

31 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 5.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2014 2.31 2015 1.70 2016 1.11 2017 1.37 2018 1.71 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The ratio of 2.31 in 2014 is influenced by the high level of consumption of unclassified agents in that year. The 2018 access-to-watch index score is consistent with meeting the WHO national monitoring target of at least 60% of total consumption being Access agents in 2018.

5.4 Consumption at substance level (5th ATC group level)

Table 5.4 and 5.5 (oral agents) and Table 5.6 and 5.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibacterial consumption.

The number of agents constituting the DU75% by oral substance ranged from eight to 10 across the years of analysis (Table 5.4).

Table 5.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 1 6 6 7 2 Tetracycline (J01AA07) 7 1 1 3 4 Amoxicillin (J01CA04) 4 3 2 2 1 Amoxicillin and beta-lactamase inhibitor 8 10 7 3 (J01CR02) Sulfamethoxazole and trimethoprim 5 2 5 8 7 (J01EE01) Nitrofurantoin (J01XE01) 10 10 Metronidazole (P01AB01) 9 9 9 1 Watch Erythromycin (J01FA01) 8 Clarithromycin (J01FA09) 6 8 Azithromycin (J01FA10) 2 4 3 4 5 Ofloxacin (J01MA01) 7 8 Levofloxacin (J01MA12) 5 4 5 6 Rifampicin (J04AB02) 6 9 Unclassified Sulfadimethoxine (J01ED01) 3

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial. 32 Azerbaijan

The most consumed oral agent varied over time, with doxycycline (J01AA02) first-ranked in 2014 at 0.4 DID (16%), tetracycline (J01AA07) in 2015 and 2016 at 1.5 DID (24%) and 0.9 DID (12%) respectively, metronidazole (P01AB01) in 2017 at 1.8 DID (22%) and amoxicillin (J01CA04) in 2018 at 1.0 DID (13%) (Table 5.4).

Two to four Watch agents appeared in the DU75% for each of the years analysed, although the specific medicines included varied a little. Rifampicin (J04AB02) was included in the DU75% in 2017 and 2018. This represents consumption as part of antituberculosis regimens.

Table 5.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 0.4 (16) 0.3 (5) 0.5 (7) 0.5 (6) 0.9 (12) Tetracycline (J01AA07) 0.2 (6) 1.5 (24) 0.9 (12) 0.8 (10) 0.6 (8) Amoxicillin (J01CA04) 0.2 (7) 0.5 (8) 0.9 (12) 0.8 (10) 1.0 (13) Amoxicillin and beta-lactamase inhibitor 0.1 (5) 0.2 (4) 0.5 (7) 0.7 (9) (J01CR02) Sulfamethoxazole and trimethoprim 0.2 (7) 0.6 (9) 0.5 (7) 0.5 (6) 0.5 (7) (J01EE01) Nitrofurantoin (J01XE01) 0.3 (4) 0.3 (5) Metronidazole (P01AB01) 0.1 (5) 0.3 (4) 0.3 (5) 1.8 (22) Watch Erythromycin (J01FA01) 0.3 (5) Clarithromycin (J01FA09) 0.2 (6) 0.4 (6) Azithromycin (J01FA10) 0.3 (12) 0.5 (8) 0.8 (11) 0.6 (8) 0.6 (8) Ofloxacin (J01MA01) 0.3 (5) 0.4 (5) Levofloxacin (J01MA12) 0.4 (6) 0.7 (9) 0.6 (7) 0.6 (7) Rifampicin (J04AB02) 0.5 (7) 0.4 (5) Unclassified Sulfadimethoxine (J01ED01) 0.3 (11) Consumption in DID 2.0 (76) 4.8 (78) 5.9 (79) 6.1 (75) 6.0 (79) (% of total consumption) Total consumption of oral agents 2.6 6.2 7.5 8.2 7.6

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The number of agents constituting the DU75% by parenteral substance ranged from three to seven across the years of analysis (Table 5.6).

The Access agent ampicillin (J01CA01) was the most consumed parenteral antibacterial in 2014, at 1.4 DID (36%), and 2018, at 1.0 DID (50%) (Table 5.7). The Watch agent ceftriaxone (J01DD04) was ranked number one for consumption in 2015, 2016 and 2017, and was second ranked in 2018.

Combinations of benzathine benzylpenicillin/procaine penicillin/benzylpenicillin (J01CE30) were ranked second for consumption in 2014, 2016 and 2017, but the volumes and relative consumption decreased over time, from 1.1 DID (27%) in 2014 to 0.2 DID (10%) in 2017.

33 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 5.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Ampicillin (J01CA01) 1 7 1 Benzylpenicillin (J01CE01) 3 2 3 Cefazolin (J01DB04) 4 Gentamicin (J01GB03) 3 Amikacin (J01GB06) 4 Metronidazole (J01XD01) 6 Watch Ceftriaxone (J01DD04) 1 1 1 2 Streptomycin (J01GA01) 3 3 Kanamycin (J01GB04) 5 Unclassified Combinations (J01CE30) 2 5 2 2

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

Table 5.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Ampicillin (J01CA01) 1.4 (36) 0.1 (4) 1.0 (50) Benzylpenicillin (J01CE01) 0.5 (12) 0.3 (17) 0.1 (5) Cefazolin (J01DB04) 0.1 (5) Gentamicin (J01GB03) 0.1 (6) Amikacin (J01GB06) 0.1 (5) Metronidazole (J01XD01) 0.1 (4) Watch Ceftriaxone (J01DD04) 0.5 (34) 1.2 (49) 1.2 (62) 0.4 (21) Streptomycin (J01GA01) 0.1 (8) 0.1 (5) Kanamycin (J01GB04) 0.1 (4) Unclassified Combinations (J01CE30) 1.1 (27) 0.1 (5) 0.3 (13) 0.2 (10) Consumption in DID 3.0 (75) 1.2 (78) 1.9 (78) 1.5 (77) 1.5 (76) (% of total consumption) Total consumption of parenteral agents 3.9 1.5 2.4 2.0 2.0

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

34 Azerbaijan

5.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index increased from 7% in 2014 to 14% in 2018 (Table 5.8).

Table 5.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

Components of amoxicillin index DDD/1 000 inhabitants per day (% of total oral J01)a 2014 2015 2016 2017 2018 Oral amoxicillin 0.2 (7) 0.5 (9) 0.9 (12) 0.8 (14) 1.0 (14) Oral amoxicillin and 0.2 (7) 0.5 (9) 0.9 (12) 0.8 (14) 1.0 (14) phenoxymethylpenicillin Total oral J01 2.5 5.9 7.0 5.9 6.9

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

5.6 Discussion

The analyses presented here document consumption between 2014 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. The most notable feature of these data is the substantial reduction in consumption of parenteral antibacterials, from 61% of total consumption in 2014 to 22% in 2018. There is variability in the volumes and relative consumption of different antibacterials between 2014 and 2018 and it is unclear the extent to which these fluctuations reflect the data sources used and the impact of procurement and import cycles on estimates of consumption.

Based on the available data, Azerbaijan met the WHO national monitoring target of at least 60% of total consumption being Access agents in 2018. The DU75% analyses can be used to identify specific Watch group antibiotics that could be targets for further investigation, interventions and stewardship activities. Prescription-based analyses that include the indication for treatment or other analyses of patient-level data will be important to ensure that consumption aligns with approved clinical guidelines and treatment algorithms.

35 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

6. BELARUS

6.1 Data source and years of data collection

Belarus has provided data for each of the five years of data collection (2014–2018). The main sources of data are import records from the drug agency and information provided by local pharmaceutical manufacturers.

6.2 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. 6.1 and Table 6.1).

Parenteral antibacterials represented 12–20% of total J01 consumption between 2014 and 2018 (Table 6.1).

The highest levels of consumption were in beta-lactam penicillins (J01C), at 4.9 DID in 2014 increasing to 7.1 DID in 2018. Over the same period, there were decreases in consumption of tetracyclines (J01A), from 2.7 DID in 2014 to 2.3 DID in 2018, cephalosporins (J01D), from 2.9 DID in 2014 to 2.2 DID in 2018, and quinolones (J01M), from 2.4 DID in 2014 to 2.0 DID in 2018.

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

Fig. 6.1 Total consumption of J01 antibacterials by pharmacological subgroup

25 Other J01 antibacterials (J01G, J01R, J01X)

20 Quinolone antibacterials (J01M)

Macrolides, lincosamides 15 and streptogramins (J01F)

Sulfonamides and trimethoprim (J01E) 10 Other beta-lactams (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day 5 Beta-lactam penicillins (J01C)

Amphenicols (J01B) 0 Tetracyclines (J01A) BLR BLR BLR BLR BLR 2014 2015 2016 2017 2018

DDD: daily defined dose.

36 Belarus

The data show fluctuations in consumption of J01 antibacterials over time. The CAGR for the period 2014–2018 was 0.8% per year, although the suggested trend towards increased consumption over time was not statistically significant (Table 6.1).

Table 6.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2014 2015 2016 2017 2018 Route of administration Oral J01 15.3 (84) 13.6 (80) 14.0 (82) 17.6 (88) 16.7 (88) Parenteral J01 3.0 (16) 3.5 (20) 3.0 (18) 2.3 (12) 2.2 (12) Totala 18.3 17.1 16.9 20.0 18.9 Class of antibacterial agents Tetracyclines (J01A) 2.7 (15) 3.0 (18) 2.5 (15) 2.8 (14) 2.3 (12) Amphenicols (J01B) 0.2 (1) 0.1 (0) 0.1 (0) 0.1 (0) 0.1 (0) Beta-lactam penicillins (J01C) 4.9 (27) 5.1 (30) 5.0 (29) 7.5 (37) 7.1 (38) Other beta-lactams (includes 2.9 (16) 2.9 (17) 2.7 (16) 2.6 (13) 2.2 (12) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 0.2 (1) 0.1 (1) 0.1 (1) 0.1 (1) 0.2 (1) Macrolides, lincosamides and 2.9 (16) 2.4 (14) 3.0 (18) 3.1 (16) 2.9 (16) streptogramins (J01F) Quinolone antibacterials (J01M) 2.4 (13) 1.6 (10) 1.8 (11) 2.0 (10) 2.0 (11) Other J01 antibacterials (J01G, J01R, J01X) 2.0 (11) 1.7 (10) 1.7 (10) 1.7 (9) 2.0 (11) Totala 18.3 17.1 16.9 20.0 18.9 Analysis of trend over time

Trendb

P-value 0.38 CAGRc 0.8

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

Beta-lactam penicillin consumption increased across the years analysed, representing 27% of J01 consumption in 2014 and 38% in 2018. There is evidence of decreasing relative consumption of tetracyclines (J01A), at 15% in 2014 and 12% in 2018, cephalosporins (J01D), at 16% in 2014 and 12% in 2018, and quinolones (J01M), at 13% in 2014 and 11% in 2018.

6.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 6.2 and is summarized in Table 6.2.

37 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Both volumes and relative consumption of Access agents increased over time, from 10.4 DID (55% of total consumption) in 2014 to 11.2 DID (57%) in 2018. Belarus would not have met the WHO national monitoring target of at least 60% of total consumption being Access agents in any of the years analysed.

Conversely, volumes and relative consumption of Watch agents decreased from 7.9 DID (42% of total consumption) in 2014 to 7.2 DID (37%) in 2018.

Consumption of Reserve and unclassified agents remained low across all years of data analysed.

Fig. 6.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 BLR BLR BLR BLR BLR 2014 2015 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 6.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2014 2015 2016 2017 2018 Access 10.4 (55) 10.0 (57) 9.4 (53) 12.2 (59) 11.2 (57) Watch 7.9 (42) 6.9 (39) 7.6 (43) 7.6 (37) 7.2 (37) Reserve 0.01 (0) 0.02 (0) 0.03 (0) 0.07 (0) 0.13 (1) Unclassified 0.7 (4) 0.7 (4) 0.6 (4) 0.7 (3) 1.0 (5) Totalb 19.0 17.6 17.7 20.6 19.5

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 6.3.

38 Belarus

Table 6.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2014 1.32 2015 1.45 2016 1.24 2017 1.60 2018 1.57 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The scores for the Access-to-Watch index are consistent with relative consumption of Access agents falling just short of the 60% WHO global monitoring target.

6.4 Consumption at substance level (5th ATC group level)

Table 6.4 and 6.5 (oral agents) and Table 6.6 and 6.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibiotic consumption.

The number of agents constituting the DU75% by oral substance ranged from seven to eight across the years of analysis (Table 6.4).

Table 6.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 2 2 2 2 3 Amoxicillin (J01CA04) 1 1 1 1 1 Amoxicillin and beta-lactamase inhibitor 3 3 4 3 2 (J01CR02) Nitrofurantoin (J01XE01) 6 6 7 Metronidazole (P01AB01) 8 Watch Cefuroxime (J01DC02) 7 Clarithromycin (J01FA09) 7 5 5 5 5 Azithromycin (J01FA10) 4 4 3 4 4 Ciprofloxacin (J01MA02) 5 6 6 6 Unclassified Furazidin (J01XE03) 7 7

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

39 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Oral amoxicillin (J01CA04) was the most consumed oral agent in all years of analysis, with the volumes and proportion of consumption increasing from 2.8 DID (18%) in 2014 to 4.2 DID (24%) in 2018 (Table 6.4 and 6.5). Volumes and relative consumption of doxycycline, the second-ranked agent for four of the five years analysed, fluctuated a little over time, at 2.5 DID (16%) in 2014, 2.7 DID (15%) in 2017 and 2.3 DID (13%) in 2018. The ranking of amoxicillin and beta-lactamase inhibitor (ATC code J01CR02) changed over time, with both volumes and relative consumption increasing from 1.6 DID (10%) in 2014 to 2.6 DID (15%) in 2018.

Two to four Watch agents appeared in the DU75% for each of the years analysed. Two macrolides, clarithromycin (J01FA09) and azithromycin (J01FA10), together constituted 16% of oral agent consumption in 2018. Consumption of the fluoroquinolone ciprofloxacin (J01MA02) decreased from 1.3 DID (8%) to 0.8 DID (4%) between 2014 and 2018.

The unclassified agent furazidin (J01XE03) was ranked seventh most consumed oral agent in 2015 and 2018. Furazidin is a nitrofuran derivative, an antibacterial medicine with bacteriostatic action, and is used for the treatment of urinary tract infections.

Table 6.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 2.5 (16) 2.9 (20) 2.4 (16) 2.7 (15) 2.3 (13) Amoxicillin (J01CA04) 2.8 (18) 3.0 (21) 3.2 (22) 4.5 (24) 4.2 (24) Amoxicillin and beta-lactamase inhibitor 1.6 (10) 1.9 (13) 1.4 (10) 2.7 (15) 2.6 (15) (J01CR02) Nitrofurantoin (J01XE01) 1.0 (6) 0.6 (5) 0.7 (5) Metronidazole (P01AB01) 0.6 (4) Watch Cefuroxime (J01DC02) 0.7 (4) Clarithromycin (J01FA09) 0.9 (6) 0.7 (5) 1.1 (7) 1.0 (6) 1.2 (7) Azithromycin (J01FA10) 1.5 (10) 1.3 (9) 1.6 (11) 1.7 (10) 1.6 (9) Ciprofloxacin (J01MA02) 1.3 (8) 0.8 (6) 1.0 (5) 0.8 (4) Unclassified Furazidin (J01XE03) 0.5 (4) 0.7 (4) Consumption in DID 12.3 (77) 10.8 (77) 11.3 (77) 14.3 (78) 13.4 (77) (% of total consumption) Total consumption of oral agents 16.0 14.1 14.7 18.3 17.4

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The number of agents constituting the DU75% by parenteral substance ranged from five to seven across the years of analysis (Table 6.6).

The Watch agent ceftriaxone (J01DD04) was ranked number one in each year of analysis, although volumes and relative consumption decreased over time from 1.5 DID (50%) in 2014 to 0.7 DID (33%) in 2018 (Table 6.7).

40 Belarus

Table 6.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Cefazolin (J01DB04) 4 3 4 3 Amikacin (J01GB06) 5 5 Metronidazole (J01XD01) 5 6 4 Watch Cefotaxime (J01DD01) 2 2 2 2 2 Ceftriaxone (J01DD04) 1 1 1 1 1 Cefepime (J01DE01) 3 7 5 Ciprofloxacin (J01MA02) 6 Levofloxacin (J01MA12) 5 4 3 4 3

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

Table 6.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Cefazolin (J01DB04) 0.1 (5) 0.2 (7) 0.2 (6) 0.2 (9) Amikacin (J01GB06) 0.1 (4) 0.1 (6) Metronidazole (J01XD01) 0.1 (4) 0.1 (5) 0.1 (6) Watch Cefotaxime (J01DD01) 0.4 (14) 0.4 (13) 0.4 (12) 0.3 (15) 0.3 (16) Ceftriaxone (J01DD04) 1.5 (50) 1.8 (50) 1.5 (50) 0.8 (34) 0.7 (33) Cefepime (J01DE01) 0.2 (6) 0.1 (4) 0.1 (4) Ciprofloxacin (J01MA02) 0.1 (3) Levofloxacin (J01MA12) 0.1 (4) 0.2 (5) 0.2 (6) 0.1 (6) 0.3 (11) Consumption in DID 2.4 (79) 2.7 (79) 2.4 (79) 1.8 (79) 1.6 (75) (% of total consumption) Total consumption of parenteral agents 3.0 3.5 3.0 2.3 2.2

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

6.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

41 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

The amoxicillin index increased from 19% in 2014 to 25% in 2018, driven by increased consumption of amoxicillin (Table 6.8).

Table 6.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2014 2015 2016 2017 2018 Oral amoxicillin 2.8 (19) 3.0 (22) 3.2 (23) 4.5 (25) 4.2 (25) Oral amoxicillin and 2.8 (19) 3.0 (22) 3.2 (23) 4.5 (25) 4.2 (25) phenoxymethylpenicillin Total oral J01 15.3 13.6 14.0 17.6 16.7

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

6.6 Discussion

The analyses presented here document consumption between 2014 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. The five years of data examined provide a platform for future years of data to enable assessment of trends over time. The most notable features of these data are the increasing and relatively higher levels of consumption of the narrow-spectrum agent amoxicillin and decreased consumption of the Watch group quinolone ciprofloxacin.

The relatively high contribution of macrolides clarithromycin and azithromycin to overall consumption of oral agents (16% of total consumption in 2018) could be reviewed to ensure prescribing is in line with best-practice clinical guidelines. The WHO EML (WHO, 2019b) suggests that clarithromycin is first-choice agent for the treatment of severe community-acquired pneumonia and second-choice treatment for pharyngitis. Azithromycin is recommended as first-choice antibiotic for sexually transmitted infections due to Chlamydia trachomatis, for cholera and gonorrhoea. It is second-choice antibiotic for the treatment of acute invasive diarrhoea and dysentery.

Belarus is close to achieving the 2023 WHO monitoring target of at least 60% of total consumption being Access agents.

42 7. BOSNIA AND HERZEGOVINA

7.1 Data source and years of data collection

Bosnia and Herzegovina has provided data for each of the five years of data collection (2014–2018). The main sources of data are sales records of wholesalers and local manufacturers provided by the drug agency.

7.2 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. 7.1 and Table 7.1).

Parenteral antibacterials represented 4–7% of total J01 consumption between 2014 and 2018 (Table .1).

The highest levels of consumption were in beta-lactam penicillins (J01C) at 5.8 DID in 2014, increasing to 7.6 DID in 2018. Over the same period, there were increases in consumption of cephalosporins (J01D), from 2.2 DID in 2014 to 3.0 DID in 2018, macrolides, lincosamides and streptogramins (J01F), from 1.6 DID in 2014 to 2.4 DID in 2018, and quinolones (J01M), from 2.1 DID in 2014 to 2.5 DID in 2018.

Fig. 7.1 Total consumption of J01 antibacterials by pharmacological subgroup

25 Other J01 antibacterials (J01G, J01R, J01X)

20 Quinolone antibacterials (J01M)

Macrolides, lincosamides 15 and streptogramins (J01F)

Sulfonamides and trimethoprim (J01E) 10 Other beta-lactams (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day 5 Beta-lactam penicillins (J01C)

Amphenicols (J01B) 0 Tetracyclines (J01A) BIH BIH BIH BIH BIH 2014 2015 2016 2017 2018

DDD: daily defined dose.

43 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

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

The CAGR for the period 2014–2018 was 6% per year, and this trend towards increased consumption over time is statistically significant (Table 7.1).

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

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2014 2015 2016 2017 2018 Route of administration Oral J01 14.3 (93) 15.5 (96) 17.1 (95) 16.5 (95) 18.3 (95) Parenteral J01 1.0 (7) 0.7 (4) 0.9 (5) 0.9 (5) 1.0 (5) Totala 15.3 16.3 18.0 17.4 19.3 Class of antibacterial agents Tetracyclines (J01A) 1.2 (8) 1.3 (8) 1.9 (11) 1.4 (8) 1.2 (6) Amphenicols (J01B) – – – – – Beta-lactam penicillins (J01C) 5.8 (38) 6.8 (42) 7.3 (41) 7.1 (41) 7.6 (39) Other beta-lactams (includes 2.2 (14) 2.1 (13) 2.4 (13) 2.4 (14) 3.0 (15) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 1.5 (10) 1.5 (9) 1.5 (8) 1.5 (9) 1.8 (10) Macrolides, lincosamides and 1.6 (11) 2.1 (13) 1.8 (10) 2.0 (12) 2.4 (12) streptogramins (J01F) Quinolone antibacterials (J01M) 2.1 (14) 2.0 (12) 2.4 (14) 2.3 (13) 2.5 (13) Other J01 antibacterials (J01G, J01R, J01X) 0.8 (5) 0.7 (4) 0.7 (4) 0.6 (3) 0.8 (4) Totala 15.3 16.3 18.0 17.4 19.3 Analysis of trend over time Trendb P-value 0.02 CAGRc 6.0

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

Beta-lactam penicillin consumption represented 38% of J01 consumption in 2014 and 39% in 2018. On a pattern of increasing total consumption over the time analysed, the relative consumption of the pharmacological subgroups of J01 was relatively stable.

7.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 7.2 and is summarized in Table 7.2.

44 Bosnia and Herzegovina

Volumes of Access agents consumed increased over time, from 10.7 DID (69% of total consumption) in 2014 to 12.9 DID (66%) in 2018. Bosnia and Herzegovina would have met the WHO national monitoring target of at least 60% of total consumption being Access agents in all five years analysed.

Volumes of Watch agents consumed increased over time from 4.7 DID (30%) in 2014 to 6.6 DID (34%) in 2018.

Consumption of Reserve and unclassified agents remained low across all years of data analysed.

Fig. 7.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 BIH BIH BIH BIH BIH 2014 2015 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 7.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2014 2015 2016 2017 2018 Access 10.7 (69) 11.5 (69) 12.9 (70) 12.1 (68) 12.9 (66) Watch 4.7 (30) 5.0 (30) 5.3 (29) 5.6 (31) 6.6 (34) Reserve < 0.01 < 0.01 < 0.01 < 0.01 < 0.01 Unclassified 0.2 (1) 0.1 (1) 0.1 (1) 0.1 (1) 0.1 (1) Totalb 15.6 16.6 18.4 17.9 19.7

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 7.3.

45 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 7.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2014 2.27 2015 2.27 2016 2.45 2017 2.15 2018 1.96 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The ratio was greater than 1.5 for all years of analysis, consistent with the relatively higher use of Access agents in Bosnia and Herzegovina.

7.4 Consumption at substance level (5th ATC group level)

Table 7.4 and 7.5 (oral agents) and Table 7.6 and 7.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibiotic consumption.

The number of agents constituting the DU75% by oral substance ranged from seven to eight across the years of analysis (Table 7.4).

Table 7.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 5 5 4 5 5 Ampicillin (J01CA01) 7 8 Amoxicillin (J01CA04) 1 1 1 1 2 Amoxicillin and beta-lactamase inhibitor 3 2 2 2 1 (J01CR02) Cefalexin (J01DB01) 6 6 6 7 7 Sulfamethoxazole and trimethoprim 4 4 5 4 4 (J01EE01) Watch Cefuroxime (J01DC02) 8 6 Clarithromycin (J01FA09) 7 7 8 Azithromycin (J01FA10) 6 8 Ciprofloxacin (J01MA02) 2 3 3 3 3

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

46 Bosnia and Herzegovina

Oral amoxicillin (ATC code J01CA04) was the most consumed oral agent in four of the five years analysed, 2014–2017, and was second-ranked agent in 2018. Volumes of consumption increased while relative consumption decreased slightly, at 2.9 DID (20%) in 2014 and 3.1 DID (17%) in 2018 (Table 7.4 and 7.5). Amoxicillin and beta-lactamase inhibitor (ATC code J01CR02) was the second- ranked agent in 2015–2017 and first-ranked in 2018. Sulfamethoxazole and trimethoprim (J01EE01) was consistently ranked fourth or fifth across the years analysed, representing around 10% of total oral consumption.

Two or three Watch agents appeared in the DU75% for each of the years analysed. Consumption of the fluoroquinolone ciprofloxacin (J01MA02) increased from 1.8 DID (12%) to 2.0 DID (11%) between 2014 and 2018.

Table 7.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 1.2 (8) 1.3 (8) 1.9 (11) 1.4 (8) 1.2 (7) Ampicillin (J01CA01) 0.7 (4) 0.8 (5) Amoxicillin (J01CA04) 2.9 (20) 3.1 (20) 3.4 (20) 3.0 (17) 3.1 (17) Amoxicillin and beta-lactamase inhibitor 1.6 (11) 2.5 (15) 2.6 (15) 2.8 (17) 3.2 (17) (J01CR02) Cefalexin (J01DB01) 1.0 (7) 1.0 (6) 1.1 (6) 0.9 (5) 1.1 (6) Sulfamethoxazole and trimethoprim 1.5 (10) 1.5 (9) 1.5 (9) 1.5 (9) 1.8 (10) (J01EE01) Watch Cefuroxime (J01DC02) 0.6 (4) 1.1 (6) Clarithromycin (J01FA09) 0.9 (5) 0.8 (4) 0.8 (5) Azithromycin (J01FA10) 0.9 (5) 1.0 (5) Ciprofloxacin (J01MA02) 1.8 (12) 1.6 (10) 1.9 (11) 1.8 (11) 2.0 (11) Consumption in DID 11.2 (77) 12.5 (78) 13.2 (76) 13.1 (77) 14.5 (78) (% of total consumption) Total consumption of oral agents 14.6 15.9 17.5 16.9 18.7

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The number of agents constituting the DU75% by parenteral substance ranged from four to six across the years of analysis (Table 7.6). The Access agent gentamicin was first-ranked agent in four of the five years analysed, at 0.3 DID (39%) in 2015 and 0.2 DID (25%) in 2018 (Table 7.7).

The Watch agent ceftriaxone (J01DD04) was second-ranked agent over the same period, at 0.1 DID (14%) in 2015 and 0.2 DID (23%) in 2018.

47 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 7.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Amoxicillin and beta-lactamase inhibitor 4 4 (J01CR02) Cefazolin (J01DB04) 3 3 3 3 3 Gentamicin (J01GB03) 2 1 1 1 1 Metronidazole (J01XD01) 1 5 4 Watch Ceftriaxone (J01DD04) 4 2 2 2 2 Imipenem and cilastatin (J01DH51) 6 Unclassified Combinations (J01CE30) 4 5 5

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

Table 7.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Amoxicillin and beta-lactamase inhibitor 0.1 (5) 0.1 (13) (J01CR02) Cefazolin (J01DB04) 0.1 (14) 0.1 (10) 0.2 (17) 0.2 (17) 0.1 (14) Gentamicin (J01GB03) 0.2 (21) 0.3 (39) 0.2 (26) 0.2 (24) 0.2 (25) Metronidazole (J01XD01) 0.3 (32) 0.1 (7) 0.1 (8) Watch Ceftriaxone (J01DD04) 0.1 (12) 0.1 (14) 0.2 (21) 0.2 (23) 0.2 (23) Imipenem and cilastatin (J01DH51) < 0.1 (5) Unclassified Combinations (J01CE30) 0.1 (8) 0.1 (7) < 0.1 (5) Consumption in DID 0.8 (80) 0.6 (78) 0.7 (79) 0.8 (80) 0.7 (75) (% of total consumption) Total consumption of parenteral agents 1.0 0.7 0.9 0.9 1.0

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

7.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

48 Bosnia and Herzegovina

The amoxicillin index decreased from 25% in 2014 to 20% in 2018 (Table 7.8).

Table 7.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2014 2015 2016 2017 2018 Oral amoxicillin 2.9 (20) 3.1 (20) 3.4 (20) 2.9 (18) 3.1 (17) Oral amoxicillin and 3.5 (25) 3.4 (22) 3.9 (23) 3.5 (21) 3.6 (20) phenoxymethylpenicillin Total oral J01 14.3 15.5 17.1 16.5 18.3

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

7.6 Discussion

The analyses presented here document consumption between 2014 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. The five years of data examined provide a platform for future years of data to enable assessment of trends over time. The data show statistically significant increases in the volume of consumption, from 15.3 DID in 2014 to 19.3 DID in 2018. The pattern of consumption of the pharmacological subgroups of J01 was reasonably stable over time.

There was relatively high consumption of Access agents, with Bosnia and Herzegovina meeting the WHO national monitoring target of at least 60% of total consumption being Access agents in each of the five years analysed.

The 2019 WHO EML (WHO, 2019b) suggests the combination of sulfamethoxazole and trimethoprim may be a first-choice agent for lower urinary tract infections and a second-choice agent for acute invasive diarrhoea and bacterial diarrhoea. In addition, it is listed as an antipneumocystosis medicine in the Model List, to prevent or treat Pneumocystis jiroveci pneumonia or Pneumocystis carinii pneumonia. The relatively high level of consumption of sulfamethoxazole and trimethoprim (10% of total consumption of oral agents in 2018) suggests it is being used for other indications. This could be assessed through reviews of prescriptions and existing clinical guidelines.

The Watch agent ciprofloxacin comprised 10–12% of total consumption of oral agents across the years analysed. The 2019 WHO EML (WHO, 2019b) suggests that ciprofloxacin is first-choice agent for acute invasive bacterial diarrhoea/dysentery, low-risk febrile neutropenia, mild-to-moderate pyelonephritis or prostatitis and enteric fever. It is second-choice agent for cholera and complicated mild-to-moderate intra-abdominal infections. The levels of consumption of ciprofloxacin suggest it is being used for other indications and this could be investigated further.

49 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

8. GEORGIA

8.1 Data source and years of data collection

Georgia has provided data for each of the five years of data collection (2014–2018). The main sources of data are import records provided by the drug agency. There is also local production of some products in Georgia, but data on local products sold in pharmacies were not available for inclusion in this report, meaning the total consumption of antibacterials in Georgia is likely to be underestimated in this report.

8.2 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. 8.1 and Table 8.1).

The consumption of parenteral antibacterials varied over time at 25% of total J01 consumption in 2014, 8% in 2016 and 32% in 2018 (Table 8.1).

Cephalosporins (J01D) had the highest levels of consumption in 2014 and 2018, at 4.6 DID in 2014 and 7.2 DID in 2018. Sulfonamides and trimethoprim (J01E) had the highest levels of consumption in 2015, 2016 and 2017, at 6.7 DID in 2015, 9.8 DID in 2016 and 6.8 DID in 2017, then decreasing to 2.2 DID in 2018. Consumption of beta-lactam penicillins (J01C) fluctuated over time at 4.5 DID in 2014,

Fig. 8.1 Total consumption of J01 antibacterials by pharmacological subgroup

30 Other J01 antibacterials (J01G, J01R, J01X)

25 Quinolone antibacterials (J01M)

20 Macrolides, lincosamides and streptogramins (J01F)

15 Sulfonamides and trimethoprim (J01E)

10 Other beta-lactams (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day 5 Beta-lactam penicillins (J01C) Amphenicols (J01B) 0 Tetracyclines (J01A) GEO GEO GEO GEO GEO 2014 2015 2016 2017 2018

DDD: daily defined dose.

50 Georgia

0.6 DID in 2016 and 4.3 DID in 2018. Over the study period, there were decreases in consumption of macrolides, lincosamides and streptogramins (J01F), from 3.4 DID in 2014 to 1.9 DID in 2018, and quinolones (J01M), from 4.0 DID in 2014 to 2.0 DID in 2018.

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

The data show fluctuations in consumption of J01 antibacterials over time. The CAGR for the period 2014–2018 was 3.8% per year, although the suggested trend towards increased consumption over time was not statistically significant (Table 8.1).

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

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2014 2015 2016 2017 2018 Route of administration Oral J01 13.4 (75) 15.2 (63) 20.7 (92) 21.9 (87) 14.3 (68) Parenteral J01 4.5 (25) 9.0 (37) 1.8 (8) 3.2 (13) 6.6 (32) Totala 17.9 24.2 22.5 25.1 20.8 Class of antibacterial agents Tetracyclines (J01A) 0.1 (1) 0.4 (2) 1.2 (5) 1.2 (5) 1.1 (5) Amphenicols (J01B) < 0.1 (0) 0.2 (1) 0.8 (4) 0.7 (3) 0.6 (3) Beta-lactam penicillins (J01C) 4.5 (25) 2.9 (12) 0.6 (7) 5.9 (23) 4.3 (21) Other beta-lactams (includes 4.6 (26) 4.8 (20) 2.2 (9) 3.6 (14) 7.2 (35) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 0.3 (2) 6.7 (28) 9.8 (42) 6.8 (27) 2.2 (11) Macrolides, lincosamides and 3.4 (19) 1.9 (8) 1.9 (8) 2.2 (9) 1.9 (9) streptogramins (J01F) Quinolone antibacterials (J01M) 4.0 (22) 6.3 (26) 3.3 (14) 2.4 (10) 2.0 (10) Other J01 antibacterials (J01G, J01R, J01X) 1.0 (6) 1.0 (4) 2.6 (11) 2.3 (9) 1.6 (8) Totala 17.9 24.2 22.5 25.1 20.8 Analysis of trend over time Trendb P-value 0.54 CAGRc 3.8

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

Beta-lactam penicillin consumption fluctuated across the years analysed, representing 25% of J01 consumption in 2014, 7% in 2016 and 21% in 2018. The relative consumption of cephalosporins (J01D) varied, at 26% in 2014, 9% in 2016 and 35% in 2018. Sulfonamides and trimethoprim (J01E) represented 42% of consumption in 2016 and 11% in 2018. The most consistent patterns were decreases in the relative consumption of macrolides, lincosamides and streptogramins (J01F), from 19% in 2014 to 9% in 2018, and quinolones (J01M), from 22% in 2014 to 10% in 2018.

8.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

51 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

The relative consumption of Access and Watch group antibiotics is shown in Fig. 8.2 and is summarized in Table 8.2.

Consumption of Access agents varied over time, at 5.7 DID (32% of total consumption) in 2014, 16.1 DID (63%) in 2017 and 9.1 DID (43%) in 2018. Georgia would have met the WHO national monitoring target of at least 60% of total consumption being Access agents only in 2016 and 2017.

Volumes and relative consumption of Watch agents varied, at 12.1 DID (67% of total consumption) in 2014, 8.4 DID (33%) in 2017 and 11.4 DID (54%) in 2018.

Consumption of Reserve agents was highest in 2016 at 1.1 DID (5% of total consumption). Unclassified agents constituted 0.9 DID (4%) of consumption in 2017.

Fig. 8.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 GEO GEO GEO GEO GEO 2014 2015 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 8.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2014 2015 2016 2017 2018 Access 5.7 (32) 11.2 (46) 13.6 (60) 16.1 (63) 9.1 (43) Watch 12.1 (67) 13.1 (54) 7.6 (33) 8.4 (33) 11.4 (54) Reserve 0.06 (0) 0.01 (0) 1.14 (5) 0.11 (0) 0.08 (0) Unclassified 0.1 (1) 0.1 (0) 0.4 (2) 0.9 (4) 0.5 (3) Totalb 18.0 24.4 22.7 25.5 21.1

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 8.3.

52 Georgia

Table 8.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2014 0.47 2015 0.85 2016 1.79 2017 1.91 2018 0.80 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The ratio was less than 1.0 in 2014, 2015 and 2018, reflecting the higher consumption of Watch agents in those years.

8.4 Consumption at substance level (5th ATC group level)

Table 8.4 and 8.5 (oral agents) and Table 8.6 and 8.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibacterial consumption.

The number of agents constituting the DU75% by oral substance ranged from five to seven across the years of analysis (Table 8.4).

Oral amoxicillin and beta-lactamase inhibitor (ATC code J01CR02) was the most consumed oral agent in 2014 and 2018, at 3.7 DID (28%) in 2014 and 3.9 DID (27%) in 2018 (Table 8.4 and 8.5). Trimethoprim

Table 8.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 5 5 5 Amoxicillin (J01CA04) 6 Amoxicillin and beta-lactamase inhibitor 1 2 2 1 (J01CR02) Trimethoprim (J01EA01) 1 1 1 2 Nitrofurantoin (J01XE01) 5 7 7 6 Watch Cefuroxime (J01DC02) 4 7 Azithromycin (J01FA10) 2 4 2 3 3 Ofloxacin (J01MA01) 3 Ciprofloxacin (J01MA02) 3 3 6 4 Levofloxacin (J01MA12) 5 4 Reserve Linezolid (J01XX08) 4

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

53 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

(J01EA01) was the most consumed oral agent in 2015, 2016 and 2017, at 6.7 DID (44%) in 2015, 9.8 DID (47%) in 2016 and 6.7 DID (30%) in 2017, decreasing to 2.1 DID (15%) in 2018. Amoxicillin (J01CA04) was included in the DU75% only in 2017, at 1.1 DID (5%) of consumption.

Two to four Watch agents appeared in the DU75% for each of the years analysed. The consumption of azithromycin decreased from 2.9 DID (22%) in 2014 to 1.4 DID (10%) in 2018. Decreases were seen in consumption of three fluoroquinolones, ofloxacin (J01MA01), ciprofloxacin (J01MA02) and levofloxacin (J01MA12) combined, from 3.1 DID (24%) to 1.2 DID (8%) between 2014 and 2018.

The Reserve agent linezolid (J01XX08) was included in the DU75% only in 2017, representing 1.1 DID (5%) of consumption of oral antibacterials.

Table 8.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 1.1 (5) 1.1 (5) 1.0 (7) Amoxicillin (J01CA04) 1.1 (5) Amoxicillin and beta-lactamase inhibitor 3.7 (28) 2.0 (13) 4.3 (19) 3.9 (27) (J01CR02) Trimethoprim (J01EA01) 6.7 (44) 9.8 (47) 6.7 (30) 2.1 (15) Nitrofurantoin (J01XE01) 0.7 (4) 0.9 (4) 1.0 (5) 0.8 (5) Watch Cefuroxime (J01DC02) 1.0 (7) 0.6 (4) Azithromycin (J01FA10) 2.9 (22) 1.0 (6) 1.4 (7) 1.3 (6) 1.4 (10) Ofloxacin (J01MA01) 1.2 (6) Ciprofloxacin (J01MA02) 2.4 (18) 1.4 (9) 1.0 (5) 1.1 (5) Levofloxacin (J01MA12) 0.7 (6) 1.2 (8) Reserve Linezolid (J01XX08) 1.1 (5) Consumption in DID 10.8 (80) 11.8 (76) 16.5 (79) 16.7 (75) 11.1 (77) (% of total consumption) Total consumption of oral agents 13.4 15.4 20.9 22.3 14.4

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The number of agents constituting the DU75% by parenteral substance ranged from one to four across the years of analysis (Table 8.6).

The Watch agent ceftriaxone (J01DD04) was ranked number one in all years, constituting 2.8 DID (62% of consumption of parenteral agents) in 2014, 4.1 DID (45%) in 2015, 1.0 DID (57%) in 2016, 2.0 DID (63%) in 2017 and 5.7 DID (86%) in 2018 (Table 8.6 and 8.7).

54 Georgia

Table 8.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Ampicillin (J01CA01) 4 Benzathine benzylpenicillin (J01CE08) 4 Cefazolin (J01DB04) 2 Amikacin (J01GB06) 2 5 Metronidazole (J01XD01) 3 Watch Piperacillin and beta-lactamase inhibitor 3 3 (J01CR05) Ceftriaxone (J01DD04) 1 1 1 1 1 Streptomycin (J01GA01) 2 Levofloxacin (J01MA12) 2 Vancomycin (J01XA01) 4 5

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

Table 8.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Ampicillin (J01CA01) 0.1 (3) Benzathine benzylpenicillin (J01CE08) 0.1 (3) Cefazolin (J01DB04) 0.1 (4) Amikacin (J01GB06) 0.3 (6) 0.1 (3) Metronidazole (J01XD01) 0.2 (5) Watch Piperacillin and beta-lactamase inhibitor 0.1 (5) 0.1 (4) (J01CR05) Ceftriaxone (J01DD04) 2.8 (62) 4.1 (45) 1.0 (57) 2.0 (63) 5.7 (86) Streptomycin (J01GA01) 0.2 (10) Levofloxacin (J01MA12) 3.6 (40) Vancomycin (J01XA01) 0.2 (4.2) 0.0 (2.7) Consumption in DID 3.5 (78) 7.7 (84.9) 1.4 (77.2) 2.5 (76.8) 5.7 (86.3) (% of total consumption) Total consumption of parenteral agents 4.5 9.0 1.8 3.2 6.6

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

55 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

8.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index decreased from 3% in 2014 to 1% in 2018 (Table 8.8).

Table 8.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2014 2015 2016 2017 2018 Oral amoxicillin 0.4 (3) 0.2 (1) 0.1 (1) 1.1 (5) 0.2 (1) Oral amoxicillin and 0.4 (3) 0.2 (1) 0.1 (1) 1.1 (5) 0.2 (1) phenoxymethylpenicillin Total oral J01 13.4 15.2 20.7 21.9 14.3

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

8.6 Discussion

The analyses presented here document consumption between 2014 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. The most notable feature of these data is the wide variability across the study period, with large shifts in the composition of antibacterials consumed. For example, in 2018, parenteral agents represented 32% of consumption, but this was as high as 37% in 2015 and as low as 8% in 2016. Trimethoprim was the most consumed oral agent in 2015, 2016 and 2017, but consumption in 2018 was much lower.

The large year-to-year variations illustrate the importance of looking at trends over time rather than relying on a single year of data to describe patterns of consumption. Some observations may be the result of relying on import records as a measure of consumption. 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 consumption of antibacterials by patients and health- care facilities. In addition, data on sales of local products in pharmacies were not available. Further investigation and local confirmation of consumption data are required.

56 9. KAZAKHSTAN

9.1 Data source and years of data collection

Kazakhstan has provided data for four years of data collection (2015–2018). The data are obtained from VIORTIS, a commercial data source that provides coverage of 80% of hospital and community sales. Data were extrapolated to estimate 100% consumption and to facilitate crossnational comparisons.

9.2 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. 9.1 and Table 9.1).

Consumption of parenteral antibacterials decreased over time, from 8.4 DID (39% of total J01 consumption) in 2015 to 3.5 DID (19%) in 2018 (Table 9.1).

The medicines with the highest levels of consumption varied across the years analysed. In 2015 and 2016, medicines categorized for these analyses as “Other J01 antibacterials” had the highest levels of consumption, at 5.9 DID in 2015 and 4.1 DID in 2016, decreasing to 1.8 DID in 2018. This category comprises ATC pharmacological subgroup J01G (aminoglycoside antibacterials), ATC subgroup J01R (various combinations of antibacterials) and ATC subgroup J01X. The last includes glycopeptide antibacterials (J01XA), polymyxins (J01XB), imidazole derivatives (J01XD) and nitrofuran derivatives (J01XE).

Fig. 9.1 Total consumption of J01 antibacterials by pharmacological subgroup

25 Other J01 antibacterials (J01G, J01R, J01X)

20 Quinolone antibacterials (J01M)

Macrolides, lincosamides 15 and streptogramins (J01F)

Sulfonamides and trimethoprim (J01E) 10 Other beta-lactams (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day 5 Beta-lactam penicillins (J01C)

Amphenicols (J01B) 0 Tetracyclines (J01A) KAZ KAZ KAZ KAZ 2015 2016 2017 2018

DDD: daily defined dose.

57 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Beta-lactam penicillins (J01C) had the highest levels of use in 2017 and 2018, at 3.8 DID in 2017 and 4.5 DID in 2018. There were increases in consumption of quinolones (J01M), from 3.4 DID in 2015 to 4.8 DID in 2018.

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

The data suggest reductions in the consumption of J01 antibacterials between 2015 and 2018. As only four years of data were available, a formal test of trend over time was not conducted (Table 9.1).

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

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2015 2016 2017 2018 Route of administration Oral J01 13.3 (61) 13.2 (67) 13.0 (72) 15.3 (81) Parenteral J01 8.4 (39) 6.5 (33) 4.9 (28) 3.5 (19) Totala 21.8 19.7 17.9 18.8 Class of antibacterial agents Tetracyclines (J01A) 1.6 (8) 1.2 (6) 1.1 (6) 1.3 (7) Amphenicols (J01B) – – – – Beta-lactam penicillins (J01C) 3.9 (18) 4.1 (21) 3.8 (21) 4.5 (24) Other beta-lactams (includes 3.5 (16) 3.4 (18) 3.8 (21) 3.1 (16) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 0.8 (4) 0.6 (3) 0.6 (4) 0.7 (4) Macrolides, lincosamides and 2.0 (9) 2.1 (11) 2.0 (11) 2.1 (11) streptogramins (J01F) Quinolone antibacterials (J01M) 3.4 (16) 3.5 (18) 3.4 (19) 4.8 (26) Other J01 antibacterials (J01G, J01R, J01X) 5.9 (27) 4.1 (21) 2.1 (12) 1.8 (10) Totala 21.8 19.7 17.9 18.8 Analysis of trend over time Trend Not conducted as less than five years of data available

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

Beta-lactam penicillin consumption fluctuated across the years analysed, representing 18% of J01 consumption in 2015 and 24% in 2018. There is evidence of increasing relative consumption of quinolones (J01M), at 16% in 2015 and 26% in 2018.

9.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access and Watch group antibiotics is shown in Fig. 9.2 and is summarized in Table 9.2.

58 Kazakhstan

Both volumes and relative consumption of Access agents decreased over time, from 13.6 DID (61% of total consumption) in 2015 to 9.9 DID (51%) in 2018. Kazakhstan therefore would have met the WHO national monitoring target of at least 60% of total consumption being Access agents only in 2015.

Conversely, volumes and relative consumption of Watch agents increased from 7.6 DID (34% of total consumption) in 2015 to 8.8 DID (45%) in 2018.

Consumption of Reserve and unclassified agents remained low across all years of data analysed.

Fig. 9.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 KAZ KAZ KAZ KAZ 2015 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 9.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2015 2016 2017 2018 Access 13.6 (61) 11.7 (58) 10 (54) 9.9 (51) Watch 7.6 (34) 7.7 (38) 7.6 (41) 8.8 (45) Reserve < 0.01 < 0.01 < 0.01 < 0.01 Unclassified 1.1 (5) 0.9 (5) 0.8 (5) 0.8 (4) Totalb 22.3 20.3 18.4 19.5

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 9.3.

59 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 9.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2015 1.79 2016 1.53 2017 1.32 2018 1.12 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The decrease in the ratio from 1.79 in 2015 to 1.12 in 2018 is consistent with the increasing consumption of Watch agents.

9.4 Consumption at substance level (5th ATC group level)

Table 9.4 and 9.5 (oral agents) and Table 9.6 and 9.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibacterial consumption.

The number of agents constituting the DU75% by oral substance ranged from nine to 11 across the years of analysis and included three or four Watch agents in each year (Table 9.4).

Table 9.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2015 2016 2017 2018 Access Doxycycline (J01AA02) 3 7 7 6 Chloramphenicol (J01BA01) 9 11 3 Ampicillin (J01CA01) 4 4 8 7 Amoxicillin (J01CA04) 2 2 2 3 Amoxicillin and beta-lactamase inhibitor 5 6 6 4 (J01CR02) Sulfamethoxazole and trimethoprim 8 8 9 9 (J01EE01) Metronidazole (P01AB01) 10 9 8 Watch Clarithromycin (J01FA09) 11 10 10 Azithromycin (J01FA10) 6 5 5 5 Ciprofloxacin (J01MA02) 1 1 1 2 Levofloxacin (J01MA12) 7 3 4 1

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

60 Kazakhstan

The fluoroquinolone ciprofloxacin (J01MA02) was the most consumed oral agent in 2015, 2016 and 2017, and was second-ranked agent in 2018. Both volumes and relative consumption of ciprofloxacin increased over time, from 1.6 DID (11% of total consumption) in 2015 to 1.9 DID (12%) in 2018 (Table 9.5). A second fluoroquinolone, levofloxacin (J01MA12), was the most consumed oral agent in 2018 at 2.5 DID (16%). Together, these two agents comprised 28% of total oral consumption in 2018.

There were small increases in consumption of oral amoxicillin (J01CA04) over time, from 1.5 DID in 2015 to 1.8 DID in 2018. This was the second most consumed agent in 2015, 2016 and 2017 and comprised around 11% of total consumption. Doxycyline was third most consumed oral antibacterial in 2015, but consumption decreased over time, from 1.4 DID (10%) in 2015 to 0.9 DID (6%) in 2018.

Table 9.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2015 2016 2017 2018 Access Doxycycline (J01AA02) 1.4 (10) 0.9 (7) 0.8 (6) 0.9 (6) Chloramphenicol (J01BA01) 0.6 (5) 0.5 (3) 1.0 (7) Ampicillin (J01CA01) 1.0 (7) 1.2 (9) 0.8 (6) 0.8 (5) Amoxicillin (J01CA04) 1.5 (11) 1.6 (11) 1.7 (12) 1.8 (11) Amoxicillin and beta-lactamase inhibitor 0.9 (7) 1.0 (7) 0.9 (7) 1.6 (10) (J01CR02) Sulfamethoxazole and trimethoprim 0.8 (6) 0.6 (5) 0.6 (5) 0.7 (4) (J01EE01) Metronidazole (P01AB01) 0.6 (4) 0.6 (4) 0.7 (4) Watch Clarithromycin (J01FA09) 0.5 (4) 0.5 (4) 0.5 (4) Azithromycin (J01FA10) 0.9 (6) 1.0 (7) 0.9 (7) 1.2 (8) Ciprofloxacin (J01MA02) 1.6 (11) 1.6 (12) 1.8 (13) 1.9 (12) Levofloxacin (J01MA12) 0.8 (6) 1.3 (9) 1.0 (7) 2.5 (16) Consumption in DID 10.5 (76) 10.8 (78) 10.1 (75) 12.1 (76) (% of total consumption) Total consumption of oral agents 13.9 13.8 13.5 16.0

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The number of agents constituting the DU75% by parenteral substance ranged from three to four across the years of analysis (Table 9.6).

The consumption of parenteral antibacterials decreased over time, from 8.4 DID in 2015 to 3.5 DID in 2018 (Table 9.7). The aminoglycoside amikacin (J01GB06) was most consumed parenteral agent in 2015 at 4.0 DID and represented 47% of consumption in 2015 (Table 9.7), but was not included in the DU75% for the other years of analysis. The Watch agent ceftriaxone (J01DD04) was ranked number one in 2017 and 2018, constituting 32% of consumption of parenteral agents in 2017 and 40% in 2018. Metronidazole (J01XD01) was most consumed parenteral antibacterial in 2016, but consumption then decreased from 2.3 DID (35%) in 2016 to 0.3 DID (10%) in 2018.

61 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 9.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2015 2016 2017 2018 Access Cefazolin (J01DB04) 2 2 2 2 Gentamicin (J01GB03) 4 Amikacin (J01GB06) 1 Metronidazole (J01XD01) 1 3 3 Watch Ceftriaxone (J01DD04) 3 3 1 1 Cefoperazone (J01DD12) 4

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

Table 9.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2015 2016 2017 2018 Access Cefazolin (J01DB04) 1.2 (14) 1.5 (23) 1.5 (31) 1.1 (32) Gentamicin (J01GB03) 0.3 (5) Amikacin (J01GB06) 4.0 (47) Metronidazole (J01XD01) 2.3 (35) 0.5 (9) 0.3 (10) Watch Ceftriaxone (J01DD04) 1.0 (12) 1.4 (21) 1.6 (32) 1.4 (40) Cefoperazone (J01DD12) 0.7 (9) Consumption in DID 6.9 (82) 5.1 (79) 3.8 (77) 2.9 (82) (% of total consumption) Total consumption of parenteral agents 8.4 6.5 4.9 3.5

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

9.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index remained reasonably stable at 11% in 2015 and 12% in 2018 (Table 9.8).

62 Kazakhstan

Table 9.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2015 2016 2017 2018 Oral amoxicillin 1.5 (11) 1.6 (12) 1.7 (13) 1.8 (12) Oral amoxicillin and 1.5 (11) 1.6 (12) 1.7 (13) 1.8 (12) phenoxymethylpenicillin Total oral J01 13.3 13.2 13.0 15.3

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

9.6 Discussion

The analyses presented here document consumption between 2015 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. Consumption estimates rely on a commercial data source with coverage of 80% of hospital and community sales. Data were extrapolated to estimate 100% consumption. Few details are available on the methods used by the commercial provider for collating sales data and it is unclear the extent to which the methods used may over- or underestimate consumption in Kazakhstan.

With only four years of data available, it is difficult to assess longer-term trends in consumption, apart from decreased relative reductions in the consumption of parenteral antibacterial formulations from 39% of total J01 consumption in 2015 to 19% in 2018.

The medicines with the highest levels of consumption varied across the years analysed, but consumption of two fluoroquinolones, Watch agents ciprofloxacin and levofloxacin, was consistently high: together, they represented 28% of oral antibacterial consumption in 2018. Levofloxacin consumption increased from 0.8 DID (6% of total oral consumption) in 2015 to 2.5 DID (16%) in 2018. There was increasing use of the Watch parenteral antibacterial ceftriaxone, from 1.0 DID in 2015 to 1.4 DID in 2018. On a pattern of decreasing relative use of parenteral formulations over time, ceftriaxone represented 40% of parenteral antibacterial consumption in 2018. These levels of consumption of Watch agents suggest further investigation is needed to determine if the use of these agents is in line with approved clinical guidelines.

63 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

10. KYRGYZSTAN

10.1 Data source and years of data collection

Kyrgyzstan has provided data for each of four years of data collection (2015–2018). The main sources of data are import records provided by the drug agency.

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 pharmacological subgroup (Fig. 10.1 and Table 10.1).

Consumption of parenteral antibacterials varied over time, representing 26% of total J01 consumption in 2016, 47% in 2017 and 40% in 2018 (Table 10.1).

Beta-lactam penicillins (J01C) had the highest levels of consumption at 7.7 DID in 2015 and 2016 and 5.9 DID in 2017 before a sharp decline to 1.6 DID in 2018. Over the same period, there were increases in consumption of cephalosporins (J01D), from 2.2 DID in 2015 to 3.9 DID in 2018, and macrolides, lincosamides and streptogramins (J01F), from 0.9 DID in 2015 to 1.4 DID in 2018. Consumption of quinolones (J01M) fluctuated, at 2.3 DID in 2016, 0.1 DID in 2017 and 1.8 DID in 2018.

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

Fig. 10.1 Total consumption of J01 antibacterials by pharmacological subgroup

35 Other J01 antibacterials (J01G, J01R, J01X) 30 Quinolone antibacterials (J01M) 25 Macrolides, lincosamides and streptogramins (J01F) 20 Sulfonamides and 15 trimethoprim (J01E) Other beta-lactams 10 (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day Beta-lactam penicillins (J01C) 5 Amphenicols (J01B) 0 Tetracyclines (J01A) KGZ KGZ KGZ KGZ 2015 2016 2017 2018

DDD: daily defined dose.

64 Kyrgyzstan

The data show considerable fluctuations in consumption of J01 antibacterials over time, with total consumption as high as 21.3 DID in 2016 and as low as 11.2 DID in 2018. As only four years of data were available, a formal test of trend over time was not conducted (Table 10.1).

Table 10.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2015 2016 2017 2018 Route of administration Oral J01 9.9 (59) 15.7 (74) 8.9 (53) 6.7 (60) Parenteral J01 6.8 (41) 5.6 (26) 8.0 (47) 4.5 (40) Totala 16.7 21.3 16.9 11.2 Class of antibacterial agents Tetracyclines (J01A) 1.1 (7) 1.7 (8) 2.0 (12) 0.6 (5) Amphenicols (J01B) 0.1 (1) 0.3 (2) 0.4 (2) 0.1 (1) Beta-lactam penicillins (J01C) 7.7 (46) 7.7 (36) 5.9 (35) 1.6 (14) Other beta-lactams (includes 2.2 (13) 2.9 (13) 5.0 (30) 3.9 (35) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 0.8 (5) 0.9 (4) 0.0 (0) < 0.1 (0) Macrolides, lincosamides and 0.9 (5) 2.0 (9) 1.0 (6) 1.4 (13) streptogramins (J01F) Quinolone antibacterials (J01M) 1.8 (11) 2.3 (11) 0.1 (1) 1.8 (17) Other J01 antibacterials (J01G, J01R, J01X) 2.1 (12) 3.5 (16) 2.5 (15) 1.7 (15) Totala 16.7 21.3 16.9 11.2 Analysis of trend over time Trend Not conducted as less than five years of data available

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

Beta-lactam penicillin consumption fluctuated across the years analysed, representing 46% of J01 consumption in 2015 but only 14% in 2018. There is evidence of increasing relative consumption of cephalosporins (J01D), at 13% in 2015 and 35% in 2018, macrolides, lincosamides and streptogramins (J01F), at 5% in 2015 and 13% in 2018, and quinolones (J01M), at 11% in 2015 and 17% in 2018.

10.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 10.2 and is summarized in Table 10.2.

Both volumes and relative consumption of Access agents decreased over time, from 12.6 DID (72% of total consumption) in 2015 to 3.9 DID (33%) in 2018. Kyrgyzstan therefore would have met the WHO national monitoring target of at least 60% of total consumption being Access agents only in 2015.

65 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Conversely, volumes and relative consumption of Watch agents increased from 4.5 DID (26% of total consumption) in 2015 to 7.2 DID (61%) in 2018.

Consumption of Reserve and unclassified agents remained low across all years of data analysed.

Fig. 10.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 KGZ KGZ KGZ KGZ 2015 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 10.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2015 2016 2017 2018 Access 12.6 (72) 12.8 (56) 8.8 (50) 3.9 (33) Watch 4.5 (26) 9.7 (42) 8.6 (49) 7.2 (61) Reserve < 0.01 < 0.01 < 0.01 0.01 Unclassified 0.4 (2) 0.5 (2) 0.8 (4) 0.6 (5) Totalb 17.5 22.9 17.6 11.8

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 10.3.

Table 10.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2015 2.79 2016 1.32 2017 1.01 2018 0.54 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

66 Kyrgyzstan

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The decrease in the ratio from 2.79 in 2015 to 0.54 in 2018 is consistent with the increasing consumption of Watch agents over time.

10.4 Consumption at substance level (5th ATC group level)

Table 10.4 and 10.5 (oral agents) and Table 10.6 and 10.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibacterial consumption.

The number of agents constituting the DU75% by oral substance ranged from four to nine across the years of analysis (Table 10.4).

Oral amoxicillin (J01CA04) was the most consumed oral agent in 2015, 2016 and 2017, falling to seventh ranked agent in 2018. The volumes and proportion of consumption of amoxicillin increased from 3.9 DID (37%) in 2015 to 5.1 DID (53%) in 2017 before falling to 0.5 DID (7%) in 2018 (Table 10.4 and 10.5). The second-ranked agent varied across the years, being sulfamethoxazole and trimethoprim (J01EE01) at 0.8 DID (8%) in 2015, ciprofloxacin (J01MA02) at 1.9 DID (11%) in 2016, doxycycline (J01AA02) at 1.2 DID (12%) in 2017 and nitrofurantoin (J01XE01) at 0.7 DID (10%) in 2018.

Two or three Watch agents appeared in the DU75% for each of the years analysed. Ciprofloxacin was first-ranked agent in 2018 at 1.5 DID and represented 21% of consumption of oral antibacterials. Two macrolides, erythromycin (J01FA01) and azithromycin (J01FA10), together constituted 1.1 DID (15%) in 2018 yet neither agent was included in the DU75% in 2017.

The unclassified agent nitroxoline (J01XX07) was included in the DU75% in 2018.

Table 10.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2015 2016 2017 2018 Access Doxycycline (J01AA02) 2 4 Tetracycline (J01AA07) 7 3 3 Amoxicillin (J01CA04) 1 1 1 7 Amoxicillin and beta-lactamase inhibitor 8 8 (J01CR02) Sulfamethoxazole and trimethoprim 2 5 (J01EE01) Nitrofurantoin (J01XE01) 5 2 Metronidazole (P01AB01) 4 6 5 Watch Erythromycin (J01FA01) 4 6 Azithromycin (J01FA10) 3 Ciprofloxacin (J01MA02) 3 2 1 Levofloxacin (J01MA12) 6 Rifampicin (J04AB02) 7 4 Unclassified Nitroxoline (J01XX07) 9

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial. 67 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 10.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2015 2016 2017 2018 Access Doxycycline (J01AA02) 1.2 (12) 0.5 (8) Tetracycline (J01AA07) 0.6 (5) 1.1 (6) 0.8 (8) Amoxicillin (J01CA04) 3.9 (37) 5.7 (33) 5.1 (53) 0.5 (7) Amoxicillin and beta-lactamase inhibitor 0.7 (4) 0.4 (6) (J01CR02) Sulfamethoxazole and trimethoprim 0.8 (8) 0.9 (5) (J01EE01) Nitrofurantoin (J01XE01) 0.7 (7) 0.7 (10) Metronidazole (P01AB01) 0.7 (7) 0.8 (5) 0.5 (7) Watch Erythromycin (J01FA01) 1.0 (6) 0.5 (7) Azithromycin (J01FA10) 0.6 (8) Ciprofloxacin (J01MA02) 0.8 (8) 1.9 (11) 1.5 (21) Levofloxacin (J01MA12) 0.7 (6) Rifampicin (J04AB02) 0.8 (5) 0.7 (8) Unclassified Nitroxoline (J01XX07) 0.3 (4) Consumption in DID 8.2 (76) 13.0 (75) 7.8 (81) 5.6 (78) (% of total consumption) Total consumption of oral agents 10.8 17.3 9.7 7.2

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The number of agents constituting the DU75% by parenteral substance ranged from one to four across the years of analysis (Table 10.6).

The Watch agent ceftriaxone (J01DD04) was ranked number two in 2015 and 2016, and number one in 2017 and 2018. In 2018, ceftriaxone constituted 78% of consumption of parenteral agents (Table 10.7).

Table 10.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2015 2016 2017 2018 Access Ampicillin (J01CA01) 4 Benzylpenicillin (J01CE01) 1 Cefazolin (J01DB04) 3 3 Watch Ceftriaxone (J01DD04) 2 2 1 1 Kanamycin (J01GB04) 1 2

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

68 Kyrgyzstan

Table 10.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2015 2016 2017 2018 Access Ampicillin (J01CA01) 0.7 (11) Benzylpenicillin (J01CE01) 2.6 (39) Cefazolin (J01DB04) 1.0 (14) 0.6 (10) Watch Ceftriaxone (J01DD04) 1.0 (15) 1.6 (28) 4.1 (47) 3.5 (78) Kanamycin (J01GB04) 2.2 (39) 2.2 (25) Consumption in DID 5.3 (78) 4.4 (77) 6.2 (78) 3.5 (78) (% of total consumption) Total consumption of parenteral agents 6.8 5.6 8.0 4.5

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

10.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index decreased from 40% in 2015 to 7% in 2018 (Table 10.8).

Table 10.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2015 2016 2017 2018 Oral amoxicillin 3.9 (40) 5.7 (36) 5.1 (57) 0.5 (7) Oral amoxicillin and 3.9 (40) 5.8 (37) 5.1 (57) 0.5 (7) phenoxymethylpenicillin Total oral J01 9.9 15.7 8.9 6.7

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

10.6 Discussion

The analyses presented here document consumption between 2015 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. With only four years of data available, it is difficult to assess longer-term trends in consumption. However, the wide variability in estimates for individual agents and total consumption raises some concerns about the validity and reliability of the data. For example, total consumption was 16.7 DID in 2015, 21.3 in 2016, 16.9 in 2017 and only 11.2 DID in 2018. The impact of cycles of procurement and importation on consumption estimates should be investigated further.

69 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

The most notable features of these data are the high levels of consumption of parenteral antibacterials (40% of total J01 consumption in 2018) and the increasing levels of consumption of specific Watch group antibiotics between 2015 and 2018. Ciprofloxacin represented 21% of consumption of oral antibacterials and ceftriaxone 78% of consumption of parenteral agents in 2018. These high levels of consumption suggest some targets for further investigation, interventions and stewardship activities to ensure that use of these agents is in line with approved clinical guidelines.

70 11. MONTENEGRO

11.1 Data source and years of data collection

Montenegro has provided data for each of the five years of data collection (2014–2018). The main sources of data are sales records of wholesalers provided by the drug agency.

11.2 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. 11.1 and Table 11.1).

Parenteral antibacterials represented 4–10% of total J01 consumption between 2014 and 2018 (Table 11.1).

Generally, the pattern of consumption of pharmacological subgroups of J01 was reasonably stable over time. The highest levels of consumption were in beta-lactam penicillins (J01C) at 10.6 DID in 2014 and 9.9 DID in 2018. Over the same period, there were small increases in consumption of cephalosporins (J01D), from 4.5 DID in 2014 to 5.4 DID in 2018, and decreases in consumption of macrolides, lincosamides and streptogramins (J01F), from 5.2 DID in 2014 to 4.8 DID in 2018.

Fig. 11.1 Total consumption of J01 antibacterials by pharmacological subgroup

35 Other J01 antibacterials (J01G, J01R, J01X) 30 Quinolone antibacterials (J01M) 25 Macrolides, lincosamides and streptogramins (J01F) 20 Sulfonamides and 15 trimethoprim (J01E) Other beta-lactams 10 (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day Beta-lactam penicillins (J01C) 5 Amphenicols (J01B) 0 Tetracyclines (J01A) MNE MNE MNE MNE MNE 2014 2015 2016 2017 2018

DDD: daily defined dose.

71 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

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

The CAGR for the period 2014–2018 was 0.3% per year, although the suggested trend towards increased consumption over time was not statistically significant (Table 11.1).

Table 11.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2014 2015 2016 2017 2018 Route of administration Oral J01 25.7 (96) 26.1 (90) 26.5 (92) 24.8 (92) 24.8 (92) Parenteral J01 1.0 (4) 2.9 (10) 2.4 (8) 2.3 (8) 2.3 (8) Totala 26.7 29.0 28.9 27.1 27.0 Class of antibacterial agents Tetracyclines (J01A) 1.1 (4) 1.3 (5) 1.4 (5) 1.4 (5) 1.3 (5) Amphenicols (J01B) – – – – – Beta-lactam penicillins (J01C) 10.6 (40) 10.5 (36) 10.2 (35) 9.6 (35) 9.9 (37) Other beta-lactams (includes 4.5 (17) 6.0 (21) 5.5 (19) 5.3 (20) 5.4 (20) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 1.1 (4) 1.1 (4) 0.9 (3) 0.8 (3) 0.8 (3) Macrolides, lincosamides and 5.2 (19) 5.5 (19) 5.3 (18) 4.8 (18) 4.8 (18) streptogramins (J01F) Quinolone antibacterials (J01M) 3.5 (13) 3.5 (12) 3.4 (12) 3.2 (12) 3.3 (12) Other J01 antibacterials (J01G, J01R, J01X) 0.9 (3) 1.2 (4) 2.3 (8) 2.1 (8) 1.5 (6) Totala 26.7 29.0 28.9 27.1 27.0 Analysis of trend over time

Trendb

P-value 0.76 CAGRc 0.3

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

Beta-lactam penicillin (J01C) consumption represented 40% of J01 consumption in 2014 and 37% in 2018. There was a small increase in the relative consumption of cephalosporins (J01D), at 17% in 2014 and 20% in 2018.

11.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 11.2 and is summarized in Table 11.2.

72 Montenegro

Both volumes and relative consumption of Access agents decreased slightly over time, from 16.7 DID (61% of total consumption) in 2014 to 15.8 DID (57%) in 2018. Montenegro would have met the WHO national monitoring target of at least 60% of total consumption being Access agents only in 2014.

Conversely, volumes and relative consumption of Watch agents increased from 9.0 DID (33% of total consumption) in 2014 to 9.8 DID (36%) in 2018.

Consumption of Reserve agents remained low across all years of data analysed.

Unclassified agents represented 6–7% of total J01 consumption in each of the years analysed. This group included pipemidic acid (J01MB04) and combinations of benzathine benzylpenicillin and procaine benzylpenicillin (J01CE30).

Fig. 11.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 MNE MNE MNE MNE MNE 2014 2015 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 11.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2014 2015 2016 2017 2018 Access 16.7 (61) 16.7 (56) 17.1 (58) 16.3 (59) 15.8 (57) Watch 9.0 (33) 11.0 (37) 10.2 (35) 9.5 (34) 9.8 (36) Reserve < 0.01 < 0.01 < 0.01 < 0.01 < 0.01 Unclassified 1.6 (6) 1.9 (7) 2.2 (7) 2.0 (7) 2.0 (7) Totalb 27.3 29.6 29.5 27.7 27.6

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 11.3.

73 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 11.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2014 1.85 2015 1.52 2016 1.68 2017 1.71 2018 1.61 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The decrease in the ratio from 1.85 in 2014 to 1.61 in 2018 is in line with small increases in the relative consumption of Watch agents over time.

11.4 Consumption at substance level (5th ATC group level)

Table 11.4 and 11.5 (oral agents) and Table 11.6 and 11.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibiotic consumption.

The number of agents constituting the DU75% by oral substance ranged from seven to eight across the years of analysis (Table 11.4).

Oral amoxicillin (J01CA04) was the most consumed oral agent in each year of analysis, representing 6.5 DID (25% of total consumption of oral antibacterials) in 2014 and 6.0 DID (24%) in 2018 (Table 11.4 and 11.5). Amoxicillin and beta-lactamase inhibitor (ATC code J01CR02) was second-ranked agent in three and third-ranked agent in two of the five years, at 2.8 DID (11%) in 2014 and 2.7 DID (11%) in 2018.

Table 11.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 7 7 Amoxicillin (J01CA04) 1 1 1 1 1 Amoxicillin and beta-lactamase inhibitor 3 2 3 2 2 (J01CR02) Cefalexin (J01DB01) 4 4 4 4 3 Watch Cefixime (J01DD08) 6 6 6 6 6 Erythromycin (J01FA01) 7 7 7 8 8 Azithromycin (J01FA10) 2 3 2 3 4 Ciprofloxacin (J01MA02) 5 5 5 5 5 Unclassified Pipemidic acid (J01MB04) 8

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

74 Montenegro

Five Watch agents appeared in the DU75% for each of the years analysed. Azithromycin was the most consumed oral Watch agent at 2.9 DID (11%) in 2014 and 2.4 DID (9%) in 2018.

The unclassified agent pipemidic acid (J01MB04) was ranked eighth most consumed oral antibacterial in 2016, at 1.4 DID (5%).

Table 11.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 1.3 (5) 1.2 (5) Amoxicillin (J01CA04) 6.5 (25) 6.6 (25) 6.3 (23) 5.9 (23) 6.0 (24) Amoxicillin and beta-lactamase inhibitor 2.8 (11) 3.1 (11) 2.8 (10) 2.5 (10) 2.7 (11) (J01CR02) Cefalexin (J01DB01) 2.7 (10) 2.6 (10) 2.6 (10) 2.4 (10) 2.4 (10) Watch Cefixime (J01DD08) 1.6 (6) 2.0 (7) 1.7 (6) 1.7 (7) 1.9 (7) Erythromycin (J01FA01) 1.6 (6) 1.7 (6) 1.5 (6) 1.2 (5) 1.2 (5) Azithromycin (J01FA10) 2.9 (11) 3.0 (11) 2.9 (11) 2.5 (10) 2.4 (9) Ciprofloxacin (J01MA02) 2.0 (8) 2.0 (7) 1.8 (7) 1.8 (7) 1.9 (8) Unclassified Pipemidic acid (J01MB04) 1.4 (5) Consumption in DID (% of total consumption) 20.1 (77) 20.8 (78) 21.0 (77) 19.4 (76) 19.8 (78) Total consumption of oral agents 26.2 26.7 27.1 25.5 25.4

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The number of agents constituting the DU75% by parenteral substance ranged from two to three across the years of analysis (Table 11.6).

Table 11.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Sulfamethoxazole and trimethoprim 3 (J01EE01) Gentamicin (J01GB03) 1 2 2 2 2 Amikacin (J01GB06) 3 Watch Ceftriaxone (J01DD04) 1 1 1 1 Unclassified Combinations (J01CE30) 2 3 3

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

75 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Gentamicin (J01GB03) was most consumed parenteral antibacterial in 2014 and second-ranked agent in 2015–2018. The Watch agent ceftriaxone (J01DD04) was ranked number one in 2015–2018, constituting 40% of consumption of parenteral agents in 2015 and 41% in 2018 (Table 11.7).

Table 11.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Sulfamethoxazole and trimethoprim 0.3 (10) (J01EE01) Gentamicin (J01GB03) 0.7 (67) 0.8 (28) 0.7 (30) 0.7 (32) 0.8 (34) Amikacin (J01GB06) 0.1 (5) Watch Ceftriaxone (J01DD04) 1.2 (40) 1.0 (43) 1.0 (42) 0.9 (41) Unclassified Combinations (J01CE30) 0.2 (18) 0.2 (7) 0.1 (5) Consumption in DID 0.9 (85) 2.3 (79) 1.9 (80) 1.8 (79) 1.8 (80) (% of total consumption) Total consumption of parenteral agents 1.0 2.9 2.4 2.3 2.3

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

11.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index decreased from 28% in 2014 to 24% in 2018 (Table 11.8).

Table 11.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2014 2015 2016 2017 2018 Oral amoxicillin 6.5 (25) 6.6 (25) 6.3 (24) 5.9 (24) 6.0 (24) Oral amoxicillin and 7.1 (28) 6.6 (25) 6.3 (24) 5.9 (24) 6.0 (24) phenoxymethylpenicillin Total oral J01 25.7 26.1 26.5 24.8 24.8

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

76 Montenegro

11.6 Discussion

The analyses presented here document consumption between 2014 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. The five years of data examined provide a platform for future years of data to enable assessment of trends over time. Patterns of consumption of antibacterial subgroups was generally stable over time, but the relative consumption of Access and Watch agents means that Montenegro would have met the WHO national monitoring target of at least 60% of total consumption being Access agents only in 2014.

The 2019 WHO EML (WHO, 2019b) suggests that the Watch agent azithromycin (J01FA10) is recommended as first-choice antibiotic for sexually transmitted infections due to Chlamydia trachomatis, for cholera and gonorrhoea. It is second-choice antibiotic for the treatment of acute invasive diarrhoea and dysentery. Azithromycin nevertheless constituted around 10% of the consumption of oral antibacterials in each of the years analysed, suggesting it is being used for other indications; this could be investigated further.

In 2018, the EMA conducted a review of medicines containing fluoroquinolone and quinolone antibiotics, including cinoxacin, ciprofloxacin, flumequine, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, pefloxacin, pipemidic acid, prulifloxacin and rufloxacin (European Medicines Agency, 2019). EMA’s human medicines committee (CHMP) endorsed the recommendations of EMA’s safety committee and concluded that the marketing authorization of medicines containing cinoxacin, flumequine, nalidixic acid and pipemidic acid should be suspended. A legally binding decision to suspend marketing authorization for pipedimic acid applicable in all EU countries was issued by the European Commission in March 2019. Marketing authorization for pipedimic acid has also been withdrawn in Montenegro.

77 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

12. NORTH MACEDONIA

12.1 Data source and years of data collection

North Macedonia has provided data for four years, 2014–2017. Data for 2018 were not available for inclusion in this report. The main sources of data are reimbursement records provided by the Health Insurance Fund. Only data for community consumption of antibacterials are presented.

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

Community consumption of antibacterials for systemic use (ATC class J01) is examined by route of administration (oral and parenteral formulations) and by pharmacological subgroup (Fig. 12.1 and Table 12.1).

There are no estimates of consumption of parenteral antibacterials, as community consumption relies almost exclusively on oral formulations (Table 12.1).

In 2014, the highest levels of consumption were in beta-lactam penicillins (J01C) at 6.8 DID, increasing to 7.2 DID in 2017. Over the same period, there were increases in consumption of macrolides, lincosamides and streptogramins (J01F), from 2.4 DID in 2014 to 3.4 DID in 2017, and small decreases in consumption of cephalosporins (J01D), from 4.0 DID in 2014 to 3.7 DID in 2017, and quinolones (J01M), from 2.7 DID in 2014 to 2.3 DID in 2017.

Fig. 12.1 Community consumption of J01 antibacterials by pharmacological subgroup

20 Other J01 antibacterials (J01G, J01R, J01X)

Quinolone antibacterials 15 (J01M) Macrolides, lincosamides and streptogramins (J01F)

10 Sulfonamides and trimethoprim (J01E)

Other beta-lactams (includes cephalosporins) (J01D) 5

DDD/1000 inhabitants per day Beta-lactam penicillins (J01C)

Amphenicols (J01B) 0 Tetracyclines (J01A) MKD MKD MKD MKD 2014 2015 2016 2017

DDD: daily defined dose.

78 North Macedonia

Community consumption of J01 antibacterials was reasonably stable over the period 2014–2017, ranging from 16.3 to 17.0 DID. As only four years of data were available, a formal test of trend over time was not conducted (Table 12.1).

Table 12.1 Community consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2014 2015 2016 2017 Route of administration Oral J01 16.3 (100) 16.7 (100) 17.0 (100) 16.9 (100) Parenteral J01 – – – – Totala 16.3 16.7 17.0 16.9 Class of antibacterial agents Tetracyclines (J01A) < 0.1 (0) < 0.1 (0) < 0.1 (0) < 0.1 (0) Amphenicols (J01B) – – – – Beta-lactam penicillins (J01C) 6.8 (42) 7.0 (42) 7.2 (42) 7.2 (42) Other beta-lactams (includes 4.0 (25) 3.8 (23) 3.7 (22) 3.7 (22) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 0.4 (2) 0.4 (2) 0.5 (3) 0.4 (2) Macrolides, lincosamides and 2.4 (15) 3.0 (18) 3.2 (19) 3.4 (20) streptogramins (J01F) Quinolone antibacterials (J01M) 2.7 (16) 2.5 (15) 2.3 (14) 2.3 (14) Other J01 antibacterials (J01G, J01R, J01X) – – – – Totala 16.3 16.7 17.0 16.9 Analysis of trend over time Trendb Not conducted as less than five years of data available

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

Beta-lactam penicillins represented 42% of J01 consumption in all four years analysed, with small changes only in relative consumption of other pharmacological subgroups.

12.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 12.2 and is summarized in Table 12.2.

Both volumes and relative consumption of Access agents decreased a little over time, from 8.7 DID (53% of total consumption) in 2014 to 8.1 DID (48%) in 2017. North Macedonia would not have met the WHO national monitoring target of at least 60% of total consumption being Access agents in any of the four years analysed.

Conversely, volumes and relative consumption of Watch agents increased slightly, from 7.3 DID (44% of total consumption) in 2014 to 7.9 DID (46%) in 2017.

79 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

There was no reported consumption of Reserve agents in the community data. Unclassified agents constituted 2–7% of community consumption across all years of data analysed.

Fig. 12.2 Relative consumption by WHO AWaRe classification as a proportion of community consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 MKD MKD MKD MKD 2014 2015 2016 2017 a Community consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 12.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2014 2015 2016 2017 Access 8.7 (53) 8.2 (49) 8.5 (50) 8.1 (48) Watch 7.3 (44) 7.5 (45) 7.7 (45) 7.9 (46) Reserve – – – – Unclassified 0.4 (2) 1.1 (7) 0.9 (5) 1.0 (6) Totalb 16.4 16.8 17.2 17.1

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Community consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 12.3.

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The ratio decreases from 1.20 in 2014 to 1.02 in 2017, consistent with increasing relative use of Watch agents over time.

80 North Macedonia

Table 12.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2014 1.20 2015 1.08 2016 1.10 2017 1.02 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

12.4 Consumption at substance level (5th ATC group level)

Table 12.4 and 12.5 (oral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of community antibiotic consumption.

Seven agents constituted the DU75% by oral substance in each of the years of analysis (Table 12.4).

Oral amoxicillin and beta-lactamase inhibitor (ATC code J01CR02) was the most consumed oral agent in each year, at 4.6 DID (28% of total antibacterial consumption) in 2014 and 4.9 DID (29%) in 2017 (Table 12.4 and 12.5).

Four or five Watch agents appeared in the DU75% for each of the years analysed. The fluoroquinolone ciprofloxacin (J01MA02) represented 9–11% of oral consumption. The macrolide azithromycin was included in the DU75% in 2016 and 2017, constituting 7% of total antibacterial consumption in 2017.

Table 12.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 Access Amoxicillin (J01CA04) 4 3 2 3 Amoxicillin and beta-lactamase inhibitor 1 1 1 1 (J01CR02) Cefalexin (J01DB01) 6 7 Watch Cefuroxime (J01DC02) 3 5 5 5 Cefixime (J01DD08) 7 6 6 6 Clarithromycin (J01FA09) 5 4 3 2 Azithromycin (J01FA10) 7 7 Ciprofloxacin (J01MA02) 2 2 4 4

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

81 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 12.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 Access Amoxicillin (J01CA04) 1.5 (9) 1.7 (10) 1.8 (10) 1.6 (9) Amoxicillin and beta-lactamase inhibitor 4.6 (28) 4.6 (27) 4.9 (29) 4.9 (29) (J01CR02) Cefalexin (J01DB01) 1.0 (6) 1.0 (6) Watch Cefuroxime (J01DC02) 1.6 (10) 1.5 (9) 1.4 (8) 1.4 (8) Cefixime (J01DD08) 0.9 (6) 1.0 (6) 1.1 (7) 1.3 (7) Clarithromycin (J01FA09) 1.2 (7) 1.5 (9) 1.7 (10) 1.8 (11) Azithromycin (J01FA10) 1.1 (6) 1.1 (7) Ciprofloxacin (J01MA02) 1.9 (11) 1.7 (10) 1.6 (10) 1.6 (9) Consumption in DID 12.7 (78) 13.0 (77) 13.6 (79) 13.7 (80) (% of community consumption) Community consumption of oral agents 16.4 16.9 17.2 17.1

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

12.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index decreased from 13% in 2014 to 10% in 2017 (Table 12.6).

Table 12.6 Consumption of oral amoxicillin and phenoxymethylpenicillin of community oral J01 consumption

DDD/1 000 inhabitants per day (% of community oral J01)a Components of amoxicillin index 2014 2015 2016 2017 Oral amoxicillin 1.5 (9) 1.7 (10) 1.8 (10) 1.6 (10) Oral amoxicillin and 2.2 (13) 1.7 (10) 1.8 (10) 1.6 (10) phenoxymethylpenicillin Community oral J01 16.3 16.7 17.0 16.9

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

82 North Macedonia

12.6 Discussion

The analyses presented here document community consumption between 2014 and 2017, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. The data are reasonably stable in both volumes and relative consumption of pharmacological subgroups over time.

There were small increases in consumption of specific Watch group antibiotics between 2014 and 2017, which suggests some targets for further investigation, interventions and stewardship activities.

83 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

13. REPUBLIC OF MOLDOVA

13.1 Data source and years of data collection

The Republic of Moldova has provided data for each of the five years of data collection (2014–2018). The main sources of data are import records from the drug agency and information provided by local pharmaceutical manufacturers.

13.2 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. 13.1 and Table 13.1).

Consumption of parenteral antibacterials varied from 12–20% of total J01 consumption between 2014 and 2018 (Table 13.1).

The highest levels of consumption were in beta-lactam penicillins (J01C), at 4.4 DID in 2014 and 4.2 DID in 2018. Over the same period, there were decreases in consumption of cephalosporins (J01D), from 3.7 DID in 2014 to 3.0 DID in 2018, and quinolones (J01M), from 3.0 DID in 2014 to 2.0 DID in 2018.

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

Fig. 13.1 Total consumption of J01 antibacterials by pharmacological subgroup

20 Other J01 antibacterials (J01G, J01R, J01X)

Quinolone antibacterials 15 (J01M) Macrolides, lincosamides and streptogramins (J01F)

10 Sulfonamides and trimethoprim (J01E)

Other beta-lactams (includes cephalosporins) (J01D) 5

DDD/1000 inhabitants per day Beta-lactam penicillins (J01C)

Amphenicols (J01B) 0 Tetracyclines (J01A) MDA MDA MDA MDA MDA 2014 2015 2016 2017 2018

DDD: daily defined dose.

84 Republic of Moldova

The data show fluctuations in consumption of J01 antibacterials over time. The CAGR for the period 2014–2018 was −4.0% per year, although the suggested trend towards reduced consumption over time was not statistically significant (Table 13.1).

Table 13.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2014 2015 2016 2017 2018 Route of administration Oral J01 13.6 (81) 11.4 (88) 13.5 (81) 13.7 (80) 12.3 (87) Parenteral J01 3.2 (19) 1.5 (12) 3.2 (19) 3.4 (20) 1.8 (13) Totala 16.7 12.9 16.7 17.1 14.2 Class of antibacterial agents Tetracyclines (J01A) 0.6 (4) 1.1 (8) 0.8 (5) 1.0 (6) 0.6 (4) Amphenicols (J01B) 0.2 (1) 0.1 (1) < 0.1 (0) < 0.1 (0) < 0.1 (0) Beta-lactam penicillins (J01C) 4.4 (26) 3.8 (30) 4.3 (26) 4.6 (27) 4.2 (30) Other beta-lactams (includes 3.7 (22) 2.2 (17) 4.1 (25) 4.3 (25) 3.0 (21) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 1.0 (6) 0.9 (7) 0.9 (5) 0.9 (5) 1.1 (8) Macrolides, lincosamides and 2.0 (12) 1.8 (14) 2.2 (13) 2.2 (13) 2.0 (14) streptogramins (J01F) Quinolone antibacterials (J01M) 3.0 (18) 1.7 (14) 2.6 (16) 2.4 (14) 2.0 (14) Other J01 antibacterials (J01G, J01R, J01X) 1.9 (11) 1.3 (10) 1.9 (11) 1.8 (10) 1.2 (9) Totala 16.7 12.9 16.7 17.1 14.2 Analysis of trend over time Trendb P-value 0.50 CAGRc −4.0

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

Beta-lactam penicillin consumption fluctuated across the years analysed, representing 26% of J01 consumption in 2014 and 30% in 2018. There is evidence of decreasing relative consumption of quinolones (J01M), at 18% in 2014 and 14% in 2018.

13.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 13.2 and is summarized in Table 13.2.

Both volumes and relative consumption of Access agents fluctuated over time, from 7.9 DID (46% of total consumption) in 2014 to 7.4 DID (51%) in 2018. The Republic of Moldova would not have met the WHO national monitoring target of at least 60% of total consumption being Access agents in any of the years analysed.

85 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Similarly, volumes and relative consumption of Watch agents varied from 7.6 DID (44% of total consumption) in 2014 to 6.7 DID (46%) in 2018.

Consumption of Reserve agents remained low across all years of data analysed. The consumption of unclassified agents decreased over time from 1.7 DID (10%) in 2014 to 0.4 DID (3%) in 2018.

Fig. 13.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 MDA MDA MDA MDA MDA 2014 2015 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 13.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2014 2015 2016 2017 2018 Access 7.9 (46) 6.9 (52) 7.3 (43) 8.0 (46) 7.4 (51) Watch 7.6 (44) 5.3 (40) 8.1 (47) 8.4 (48) 6.7 (46) Reserve – – < 0.01 < 0.01 – Unclassified 1.7 (10) 1.1 (8) 1.7 (10) 1.2 (7) 0.4 (3) Totalb 17.2 13.4 17.1 17.5 14.5

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 13.3.

86 Republic of Moldova

Table 13.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2014 1.05 2015 1.30 2016 0.91 2017 0.96 2018 1.12 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. Apart from 2015 when Access agents comprised 52% of total consumption of antibacterials, the ratio was around 1 and was consistent with similar volumes of consumption of Access and Watch agents.

13.4 Consumption at substance level (5th ATC group level)

Table 13.4 and 13.5 (oral agents) and Table 13.6 and 13.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibiotic consumption.

The number of agents constituting the DU75% by oral substance ranged from eight to 12 across the years of analysis (Table 13.4).

Table 13.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 9 3 8 5 Ampicillin (J01CA01) 10 7 Amoxicillin (J01CA04) 1 1 1 2 2 Amoxicillin and beta-lactamase inhibitor 2 2 2 1 1 (J01CR02) Sulfamethoxazole and trimethoprim 5 5 5 6 4 (J01EE01) Nitrofurantoin (J01XE01) 7 Metronidazole (P01AB01) 11 Watch Cefuroxime (J01DC02) 7 6 3 3 3 Clarithromycin (J01FA09) 8 8 6 9 6 Azithromycin (J01FA10) 6 4 10 4 8 Lincomycin (J01FF02) 11 Ciprofloxacin (J01MA02) 4 9 7 8 Levofloxacin (J01MA12) 3 4 7 5 Unclassified Ciprofloxacin and ornidazole (J01RA12) 11 Furazidin (J01XE03) 12 10 9 10

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial. 87 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Oral amoxicillin (J01CA04) or amoxicillin and beta-lactamase inhibitor (ATC code J01CR02) was the most consumed oral agent in each of the years analysed. Amoxicillin consumption decreased from 2.4 DID (17%) in 2014 to 1.3 DID (10%) in 2018 (Table 13.4 and 13.5). Conversely, consumption of amoxicillin and beta-lactamase inhibitor increased over time, from 1.1 DID (8%) in 2014 to 2.6 DID (20%) in 2018.

Four to six Watch agents appeared in the DU75% for each of the years analysed. Increases in consumption of the second-generation cephalosporin cefuroxime (J01DC02) were seen, from 0.7 DID (5%) to 1.3 DID (10%), between 2014 and 2018. Consumption of two fluoroquinolones, ciprofloxacin (J01MA02) and levofloxacin (J01MA12) combined, decreased from 2.0 DID (14%) to 1.0 DID (8%) between 2014 and 2018.

Table 13.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (Oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 0.6 (4) 0.9 (8) 0.7 (5) 0.9 (6) Ampicillin (J01CA01) 0.5 (4) 0.7 (6) Amoxicillin (J01CA04) 2.4 (17) 1.6 (13) 1.8 (13) 1.6 (11) 1.3 (10) Amoxicillin and beta-lactamase inhibitor 1.1 (8) 1.3 (11) 1.7 (12) 2.0 (14) 2.6 (20) (J01CR02) Sulfamethoxazole and trimethoprim 1.0 (7) 0.9 (7) 0.9 (6) 0.9 (6) 1.1 (8) (J01EE01) Nitrofurantoin (J01XE01) 0.9 (7) Metronidazole (P01AB01) 0.4 (4) Watch Cefuroxime (J01DC02) 0.7 (5) 0.8 (7) 1.2 (8) 1.4 (10) 1.3 (10) Clarithromycin (J01FA09) 0.6 (4) 0.7 (5) 0.8 (6) 0.8 (5) 0.9 (7) Azithromycin (J01FA10) 0.9 (7) 0.9 (7) 0.6 (5) 1.1 (8) 0.9 (7) Lincomycin (J01FF02) 0.5 (4) Ciprofloxacin (J01MA02) 1.0 (7) 0.6 (5) 0.8 (5) 0.8 (6) Levofloxacin (J01MA12) 1.0 (7) 1.0 (7) 0.9 (6) 1.0 (8) Unclassified Ciprofloxacin and ornidazole (J01RA12) 0.5 (4) Furazidin (J01XE03) 0.5 (4) 0.6 (5) 0.7 (5) 0.6 (4) Consumption in DID 10.9 (77) 9.2 (78) 10.5 (75) 10.9 (77) 9.9 (78) (% of total consumption) Total consumption of oral agents 14.0 11.9 13.9 14.2 12.6

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The number of agents constituting the DU75% by parenteral substance ranged from three to nine across the years of analysis (Table 13.6).

The Watch agent ceftriaxone (J01DD04) was ranked number one in each year of analysis, constituting 35% of consumption of parenteral agents in 2014 and 42% in 2018 (Table 13.7).

88 Republic of Moldova

Table 13.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Ampicillin (J01CA01) 5 Amoxicillin (J01CA04) 3 3 7 Amoxicillin and beta-lactamase inhibitor 5 (J01CR02) Cefazolin (J01DB04) 2 5 2 4 2 Gentamicin (J01GB03) 4 Metronidazole (J01XD01) 4 3 6 3 Watch Cefuroxime (J01DC02) 6 2 2 4 Cefotaxime (J01DD01) 3 9 5 Ceftazidime (J01DD02) 6 Ceftriaxone (J01DD04) 1 1 1 1 1 Streptomycin (J01GA01) 7 Levofloxacin (J01MA12) 8 6

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

Table 13.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Ampicillin (J01CA01) 0.2 (5) Amoxicillin (J01CA04) 0.3 (9) 0.2 (7) 0.1 (5) Amoxicillin and beta-lactamase inhibitor 0.1 (4) (J01CR02) Cefazolin (J01DB04) 0.7 (22) 0.1 (6) 0.4 (14) 0.2 (5) 0.2 (9) Gentamicin (J01GB03) 0.1 (7) Metronidazole (J01XD01) 0.2 (5) 0.1 (7) 0.1 (3) 0.1 (6) Watch Cefuroxime (J01DC02) 0.1 (5) 0.1 (8) 0.5 (14) 0.1 (6) Cefotaxime (J01DD01) 0.2 (6) 0.1 (5) 0.1 (6) Ceftazidime (J01DD02) 0.1 (6) Ceftriaxone (J01DD04) 1.1 (35) 0.5 (30) 1.7 (53) 1.5 (46) 0.8 (42) Streptomycin (J01GA01) 0.1 (5) Levofloxacin (J01MA12) 0.1 (5) 0.1 (6) Consumption in DID 2.4 (77) 1.2 (80) 2.5 (76) 2.7 (79) 1.5 (79) (% of total consumption) Total consumption of parenteral agents 3.2 1.5 3.2 3.4 1.8

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

89 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

13.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index decreased from 17% in 2014 to 11% in 2018 (Table 13.8).

Table 13.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2014 2015 2016 2017 2018 Oral amoxicillin 2.3 (17) 1.6 (14) 1.8 (13) 1.6 (12) 1.3 (11) Oral amoxicillin and 2.3 (17) 1.6 (14) 1.8 (13) 1.6 (12) 1.3 (11) phenoxymethylpenicillin Total oral J01 13.6 11.4 13.5 13.7 12.3

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

13.6 Discussion

The analyses presented here document consumption between 2014 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. The five years of data examined provide a platform for future years of data to enable assessment of trends over time.

The data are characterized by considerable variability in total consumption between 2014 and 2018 and relatively higher levels of consumption of Watch group antibacterials. The Republic of Moldova would not have met the WHO national monitoring target of at least 60% of total consumption being Access agents in any of the years analysed. The DU75% analyses identify specific Watch group agents that could be targets for further investigation, interventions and stewardship activities.

90 14. RUSSIAN FEDERATION

14.1 Data source and years of data collection

The Russian Federation has provided data for each of the five years of data collection (2014–2018). The main sources of data are IQVIA data and include government tenders for the hospital sector, hospital purchases from wholesalers (tenders and self-procurement) and pharmacy purchases from wholesalers.

14.2 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. 14.1 and Table 14.1).

Parenteral antibacterials represented 13–15% of total J01 consumption between 2014 and 2018 (Table 14.1).

Beta-lactam penicillins had the highest levels of consumption in all five years analysed, increasing from 3.5 DID in 2014 to 4.1 DID in 2018. Over the same period, there was evidence of increases in consumption of quinolones (J01M), from 2.4 DID in 2014 to 2.9 DID in 2018. There were small year- to-year fluctuations in consumption of most other pharmacological subgroups.

Fig. 14.1 Total consumption of J01 antibacterials by pharmacological subgroup

20 Other J01 antibacterials (J01G, J01R, J01X)

Quinolone antibacterials 15 (J01M) Macrolides, lincosamides and streptogramins (J01F)

10 Sulfonamides and trimethoprim (J01E)

Other beta-lactams (includes cephalosporins) (J01D) 5

DDD/1000 inhabitants per day Beta-lactam penicillins (J01C)

Amphenicols (J01B) 0 Tetracyclines (J01A) RUS RUS RUS RUS RUS 2014 2015 2016 2017 2018

DDD: daily defined dose.

91 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

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

The CAGR for the period 2014–2018 was 2.3% per year, although the suggested trend towards increased consumption over time was not statistically significant (Table 14.1).

Table 14.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2014 2015 2016 2017 2018 Route of administration Oral J01 11.4 (85) 12.1 (86) 13 (87) 13.0 (86) 12.7 (86) Parenteral J01 2.0 (15) 2.0 (14) 2.0 (13) 2.0 (14) 2.0 (14) Totala 13.4 14.1 14.9 15.1 14.7 Class of antibacterial agents Tetracyclines (J01A) 1.2 (9) 1.3 (9) 1.3 (9) 1.4 (9) 1.3 (9) Amphenicols (J01B) 0.3 (2) 0.1 (1) 0.1 (1) 0.1 (1) 0.1 (1) Beta-lactam penicillins (J01C) 3.5 (26) 3.8 (27) 4.3 (29) 4.1 (28) 4.1 (28) Other beta-lactams (includes 1.6 (12) 1.7 (12) 1.8 (12) 1.9 (13) 1.8 (12) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 0.5 (4) 0.6 (4) 0.6 (4) 0.5 (4) 0.5 (3) Macrolides, lincosamides and 2.5 (19) 2.6 (18) 2.9 (19) 2.7 (18) 2.6 (18) streptogramins (J01F) Quinolone antibacterials (J01M) 2.4 (18) 2.6 (19) 2.7 (18) 2.9 (19) 2.9 (20) Other J01 antibacterials (J01G, J01R, J01X) 1.4 (10) 1.4 (10) 1.2 (8) 1.4 (9) 1.4 (10) Totala 13.4 14.1 14.9 15.1 14.7 Analysis of trend over time

Trendb

P-value 0.10 CAGRc 2.3

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

Beta-lactam penicillin consumption represented 26% of J01 consumption in 2014 and 28% in 2018. There was a small increase in the relative consumption of quinolones (J01M), at 18% in 2014 and 20% in 2018.

14.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 14.2 and is summarized in Table 14.2.

92 Russian Federation

Volumes of consumption of Access agents fluctuated over time, at 7.0 DID (49% of total consumption) in 2014, 8.1 DID (49%) in 2017 and 7.3 DID (47%) in 2018. The Russian Federation would not have met the WHO national monitoring target of at least 60% of total consumption being Access agents in any of the five years of analysis.

The volumes of consumption of Watch agents increased from 6.6 DID (46% of total consumption) in 2014 to 7.7 DID (46%) in 2017 before decreasing to 7.4 DID (48%) in 2018.

Consumption of Reserve agents remained low across all years of data analysed. Unclassified agents constituted 4–6% of total antibacterial consumption between 2014 and 2018.

Fig. 14.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 RUS RUS RUS RUS RUS 2014 2015 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 14.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2014 2015 2016 2017 2018 Access 7.0 (49) 7.3 (48) 7.7 (49) 8.1 (49) 7.3 (47) Watch 6.6 (46) 7.0 (46) 7.4 (47) 7.7 (46) 7.4 (48) Reserve 0.01 (0) 0.01 (0) 0.01 (0) 0.01 (0) 0.02 (0) Unclassified 0.8 (6) 0.8 (5) 0.7 (4) 0.8 (5) 0.7 (5) Totalb 14.4 15.1 15.8 16.6 15.5

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 14.3.

93 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 14.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2014 1.06 2015 1.04 2016 1.03 2017 1.06 2018 0.99 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The ratio was consistently around 1.0 for all years of analysis, reflecting similar volumes of Access and Watch agents consumed.

14.4 Consumption at substance level (5th ATC group level)

Table 14.4 and 14.5 (oral agents) and Table 14.6 and 14.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibiotic consumption.

The number of agents constituting the DU75% by oral substance ranged from nine to 10 across the years of analysis (Table 14.4).

Oral amoxicillin (J01CA04) was the most consumed oral agent in all years analysed, representing 17% of antibacterial consumption in 2018 (Table 14.4 and 14.5). Amoxicillin and beta-lactamase inhibitor (ATC code J01CR02) was third most consumed antibacterial in 2016, 2017 and 2018 and constituted 12% of total antibacterial consumption in 2018.

Table 14.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 4 5 5 4 4 Amoxicillin (J01CA04) 1 1 1 1 1 Amoxicillin and beta-lactamase inhibitor 5 4 3 3 3 (J01CR02) Sulfamethoxazole and trimethoprim 10 (J01EE01) Nitrofurantoin (J01XE01) 9 9 Metronidazole (P01AB01) 6 7 8 6 8 Watch Clarithromycin (J01FA09) 7 6 6 8 7 Azithromycin (J01FA10) 2 2 2 2 2 Ciprofloxacin (J01MA02) 3 3 4 5 5 Norfloxacin (J01MA06) 8 9 9 9 Levofloxacin (J01MA12) 10 8 7 7 6

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial. 94 Russian Federation

Four or five Watch agents appeared in the DU75% for each of the years analysed. Two macrolides, clarithromycin (J01FA09) and azithromycin (J01FA10) combined, represented 17% of consumption of oral antibacterials in 2018. Two fluoroquinolones, ciprofloxacin (J01MA02) and levofloxacin (J01MA12) combined, constituted 15% of consumption in the same year.

Table 14.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 1.1 (9) 1.2 (9) 1.2 (9) 1.2 (9) 1.2 (9) Amoxicillin (J01CA04) 2.1 (17) 2.3 (17) 2.4 (17) 2.3 (16) 2.3 (17) Amoxicillin and beta-lactamase inhibitor 1.1 (9) 1.2 (9) 1.6 (12) 1.6 (11) 1.6 (12) (J01CR02) Sulfamethoxazole and trimethoprim 0.4 (3) (J01EE01) Nitrofurantoin (J01XE01) 0.4 (4) 0.4 (3) Metronidazole (P01AB01) 0.6 (5) 0.6 (5) 0.6 (4) 1.1 (8) 0.5 (4) Watch Clarithromycin (J01FA09) 0.6 (5) 0.6 (5) 0.6 (5) 0.6 (4) 0.6 (5) Azithromycin (J01FA10) 1.6 (13) 1.6 (12) 1.9 (14) 1.8 (12) 1.6 (12) Ciprofloxacin (J01MA02) 1.2 (9) 1.2 (9) 1.2 (9) 1.2 (8) 1.0 (8) Norfloxacin (J01MA06) 0.5 (4) 0.5 (4) 0.5 (4) 0.5 (3) Levofloxacin (J01MA12) 0.4 (3) 0.5 (4) 0.6 (5) 0.8 (5) 0.9 (7) Consumption in DID 9.4 (76) 10.1 (77) 10.6 (77) 11.1 (76) 10.3 (76) (% of total consumption) Total consumption of oral agents 12.4 13.1 13.8 14.5 13.5

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The number of agents constituting the DU75% by parenteral substance ranged from five to six across the years of analysis (Table 14.6).

The Watch agent ceftriaxone (J01DD04) was ranked number one in each year of analysis, constituting 38% of consumption of parenteral agents in 2014 and 48% in 2018 (Table 14.7). Cefotaxime (J01DD01), a second Watch agent cephalosporin, represented a further 9% of consumption of parenteral antibacterials in 2018.

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Table 14.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Cefazolin (J01DB04) 2 2 2 3 4 Gentamicin (J01GB03) 5 Amikacin (J01GB06) 4 4 4 4 3 Metronidazole (J01XD01) 6 5 5 5 5 Watch Cefotaxime (J01DD01) 3 3 3 2 2 Ceftriaxone (J01DD04) 1 1 1 1 1

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

Table 14.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Cefazolin (J01DB04) 0.2 (12) 0.2 (12) 0.2 (9) 0.2 (9) 0.1 (6) Gentamicin (J01GB03) 0.1 (5) Amikacin (J01GB06) 0.1 (6) 0.1 (6) 0.1 (5) 0.1 (6) 0.1 (7) Metronidazole (J01XD01) 0.1 (5) 0.1 (4) 0.1 (4) 0.1 (5) 0.1 (6) Watch Cefotaxime (J01DD01) 0.2 (11) 0.2 (11) 0.2 (9) 0.2 (10) 0.2 (9) Ceftriaxone (J01DD04) 0.7 (38) 0.9 (42) 0.9 (47) 1.0 (47) 1.0 (48) Consumption in DID 1.5 (77) 1.5 (75) 1.5 (76) 1.6 (77) 1.5 (77) (% of total consumption) Total consumption of parenteral agents 2.0 2.0 2.0 2.1 2.0

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

14.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index remained reasonably constant at around 18% in each year of analysis (Table 14.8).

96 Russian Federation

Table 14.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2014 2015 2016 2017 2018 Oral amoxicillin 2.1 (18) 2.3 (19) 2.4 (18) 2.3 (18) 2.3 (18) Oral amoxicillin and 2.1 (18) 2.3 (19) 2.4 (18) 2.3 (18) 2.3 (18) phenoxymethylpenicillin Total oral J01 11.4 12.1 13.0 13.0 12.7

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

14.6 Discussion

The analyses presented here document antibacterial consumption between 2014 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. As noted in earlier WHO Regional Office for Europe reports from 2017 and 2020 (WHO Regional Office for Europe, 2017, 2020), estimates of total consumption and the consumption of pharmacological subgroups in the Russian Federation have been reasonably stable over time. Estimates are derived from IQVIA, a commercial data source, but there are no details on the nature and extent of any sampling used and the methodology applied to generate total consumption estimates.

Watch group agents (oral and parenteral combined) comprised 48% of total antibacterial consumption in 2018. The relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation. For example, the WHO EML (WHO, 2019b) suggests limited indications for use of azithromycin, clarithromycin, ciprofloxacin, levofloxacin, ceftriaxone and cefotaxime. It could be useful to assess whether use of these agents in practice aligns with approved guidelines and treatment protocols.

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15. SERBIA

15.1 Data source and years of data collection

Serbia has provided data for each of the five years of data collection (2014–2018). The main sources of data are sales records of marketing authorization holders provided by the drug agency.

15.2 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. 15.1 and Table 15.1).

Parenteral antibacterials represented 6–8% of total J01 consumption between 2014 and 2018 (Table 15.1).

Across all years of analysis, highest levels of consumption were in beta-lactam penicillins (J01C) at 9.5 DID in 2014, decreasing to 6.8 DID in 2018. Over the same period, there were decreases in consumption of cephalosporins (J01D), from 4.4 DID in 2014 to 3.6 DID in 2018, and increases in consumption of macrolides, lincosamides and streptogramins (J01F), from 3.9 DID in 2014 to 5.3 DID in 2018, and quinolones (J01M), from 3.3 DID in 2014 to 4.0 DID in 2018.

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

Fig. 15.1 Total consumption of J01 antibacterials by pharmacological subgroup

35 Other J01 antibacterials (J01G, J01R, J01X) 30 Quinolone antibacterials (J01M) 25 Macrolides, lincosamides and streptogramins (J01F) 20 Sulfonamides and 15 trimethoprim (J01E) Other beta-lactams 10 (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day Beta-lactam penicillins (J01C) 5 Amphenicols (J01B) 0 Tetracyclines (J01A) SRB SRB SRB SRB SRB 2014 2015 2016 2017 2018

DDD: daily defined dose.

98 Serbia

The data show fluctuations in consumption of J01 antibacterials over time. The CAGR for the period 2014–2018 was −2.7% per year, although the suggested trend towards reduced consumption over time was not statistically significant (Table 15.1).

Table 15.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2014 2015 2016 2017 2018 Route of administration Oral J01 23.6 (93) 29.2 (94) 24.7 (94) 19.7 (92) 21.2 (93) Parenteral J01 1.6 (7) 1.8 (6) 1.5 (6) 1.6 (8) 1.5 (7) Totala 25.3 31.0 26.2 21.3 22.7 Class of antibacterial agents Tetracyclines (J01A) 2.1 (8) 2.3 (7) 2.2 (8) 1.4 (7) 1.7 (7) Amphenicols (J01B) < 0.1 (0) < 0.1 (0) < 0.1 (0) < 0.1 (0) – Beta-lactam penicillins (J01C) 9.5 (37) 11.6 (38) 8.4 (32) 6.7 (32) 6.8 (30) Other beta-lactams (includes 4.4 (17) 5.3 (17) 5.2 (20) 4.3 (20) 3.6 (16) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 1.1 (4) 1.1 (4) 1.0 (4) 0.8 (4) 0.7 (3) Macrolides, lincosamides and 3.9 (16) 5.9 (19) 5.1 (19) 3.5 (16) 5.3 (23) streptogramins (J01F) Quinolone antibacterials (J01M) 3.3 (13) 3.8 (12) 3.5 (14) 3.8 (18) 4.0 (18) Other J01 antibacterials (J01G, J01R, J01X) 1.0 (4) 1.0 (3) 0.8 (3) 0.9 (4) 0.7 (3) Totala 25.3 31.0 26.2 21.3 22.7 Analysis of trend over time Trendb P-value 0.26 CAGRc –2.7

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

Beta-lactam penicillin (J01C) consumption decreased across the years analysed, representing 37% of J01 consumption in 2014 and 30% in 2018. There is evidence of increasing relative consumption of macrolides, lincosamides and streptogramins (J01F), at 16% in 2014 and 23% in 2018, and quinolones (J01M), at 13% in 2014 and 18% in 2018.

15.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 15.2 and is summarized in Table 15.2.

Both volumes and relative consumption of Access agents decreased over time, from 17.7 DID (68% of total consumption) in 2014 to 11.8 DID (51%) in 2018. Serbia would have met the WHO national

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monitoring target of at least 60% of total consumption being Access agents in all years analysed except 2018.

Conversely, volumes and relative consumption of Watch agents increased from 7.0 DID (27% of total consumption) in 2014 to 10.6 DID (46%) in 2018.

Consumption of Reserve remained low across all years of data analysed. Unclassified agents represented 3–5% of total antibacterial consumption.

Fig. 15.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 SRB SRB SRB SRB SRB 2014 2015 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 15.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2014 2015 2016 2017 2018 Access 17.7 (68) 20.4 (64) 17.0 (63) 13.3 (60) 11.8 (51) Watch 7.0 (27) 10.0 (32) 9.1 (34) 8.1 (36) 10.6 (46) Reserve 0.01 (0) 0.01 (0) 0.01 (0) 0.01 (0) 0.02 (0) Unclassified 1.2 (5) 1.2 (4) 0.8 (3) 0.8 (4) 0.7 (3) Totalb 25.9 31.7 26.8 22.2 23.2

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 15.3.

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Table 15.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2014 2.54 2015 2.04 2016 1.87 2017 1.65 2018 1.11 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The decrease in the ratio from 2.54 in 2014 to 1.11 in 2018 is consistent with the higher relative use of Watch agents over time.

15.4 Consumption at substance level (5th ATC group level)

Table 15.4 and 15.5 (oral agents) and Table 15.6 and 15.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibacterial consumption.

The number of agents constituting the DU75% by oral substance ranged from seven to nine across the years of analysis (Table 15.4).

Table 15.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 3 5 5 5 6 Amoxicillin (J01CA04) 1 1 1 1 1 Amoxicillin and beta-lactamase inhibitor 4 4 4 3 3 (J01CR02) Cefalexin (J01DB01) 2 2 2 2 Sulfamethoxazole and trimethoprim 7 (J01EE01) Watch Cefixime (J01DD08) 9 8 Clarithromycin (J01FA09) 7 7 8 4 Azithromycin (J01FA10) 5 3 3 6 2 Ciprofloxacin (J01MA02) 6 6 6 4 5 Levofloxacin (J01MA12) 7 7 Unclassified Pipemidic acid (J01MB04) 8

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

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Oral amoxicillin (J01CA04) was the most consumed oral agent in all years analysed, although the volumes and proportion of consumption decreased from 6.5 DID (27%) in 2014 to 4.0 DID (18%) in 2018 (Table 15.4 and 15.5). The cephalosporin cefalexin (J01DB01) was second-ranked agent in four of the five years analysed, also showing decreases in consumption over time, at 3.4 DID (14%) in 2014 and 2.4 DID (12%) in 2017.

Two to five Watch agents appeared in the DU75% for each of the years analysed. Increases in consumption of two macrolides, clarithromycin (J01FA09) and azithromycin (J01FA10) combined, were seen, from 1.8 DID (7%) to 4.3 DID (20%) between 2014 and 2018. Similarly, consumption of two fluoroquinolones, ciprofloxacin (J01MA02) and levofloxacin (J01MA12) combined, increased from 1.4 DID (6%) to 3.0 DID (14%) between 2014 and 2018.

The unclassified agent pipemidic acid (J01MB04) was included in the DU75% only in 2014.

Table 15.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 2.1 (8) 2.2 (7) 2.2 (9) 1.4 (7) 1.6 (8) Amoxicillin (J01CA04) 6.5 (27) 7.8 (26) 5.3 (21) 4.3 (21) 4.0 (18) Amoxicillin and beta-lactamase inhibitor 1.8 (8) 3.1 (10) 2.3 (9) 2.0 (10) 2.6 (12) (J01CR02) Cefalexin (J01DB01) 3.4 (14) 3.6 (12) 3.7 (14) 2.4 (12) Sulfamethoxazole and trimethoprim 1.1 (4) (J01EE01) Watch Cefixime (J01DD08) 1.0 (5) 1.3 (6) Clarithromycin (J01FA09) 1.5 (5) 1.4 (5) 1.1 (5) 1.7 (8) Azithromycin (J01FA10) 1.8 (7) 3.2 (11) 2.8 (11) 1.4 (7) 2.6 (12) Ciprofloxacin (J01MA02) 1.4 (6) 1.9 (6) 1.5 (6) 1.6 (8) 1.7 (8) Levofloxacin (J01MA12) 1.2 (6) 1.3 (6) Unclassified Pipemidic acid (J01MB04) 0.9 (4) Consumption in DID 19.0 (78) 23.3 (78) 19.1 (75) 16.2 (79) 16.7 (77) (% of total consumption) Total consumption of oral agents 24.2 29.9 25.4 20.6 21.7

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The number of agents constituting the DU75% by parenteral substance ranged from five to seven across the years of analysis (Table 15.6).

The Access agent gentamicin was ranked number one in four of the five years of analysis, constituting 33% of consumption of parenteral agents in 2014, 27% in 2017 and 17% in 2018 (Table 15.7). The Watch agent ceftriaxone (J01DD04) was ranked second in 2014–2017 and number one, at 27%, in 2018. Unclassified combinations of benzathine benzylpenicillin and procaine benzylpenicillin (J01CE30) constituted 5–7% of parenteral antibacterial consumption in each year of analysis.

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Table 15.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Cefazolin (J01DB04) 5 Gentamicin (J01GB03) 1 1 1 1 2 Amikacin (J01GB06) 4 4 6 Metronidazole (J01XD01) 4 4 5 3 4 Watch Cefuroxime (J01DC02) 5 6 6 7 Ceftriaxone (J01DD04) 2 2 2 2 1 Levofloxacin (J01MA12) 3 Unclassified Combinations (J01CE30) 3 3 3 5 5

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

Table 15.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Cefazolin (J01DB04) 0.1 (4) Gentamicin (J01GB03) 0.6 (33) 0.6 (35) 0.5 (36) 0.4 (27) 0.2 (17) Amikacin (J01GB06) 0.1 (6) 0.1 (5) 0.1 (5) Metronidazole (J01XD01) 0.1 (7) 0.1 (6) 0.1 (6) 0.2 (10) 0.1 (9) Watch Cefuroxime (J01DC02) 0.1 (5) 0.1 (4) 0.1 (4) 0.1 (5) Ceftriaxone (J01DD04) 0.4 (25) 0.4 (24) 0.3 (18) 0.4 (25) 0.4 (27) Levofloxacin (J01MA12) 0.2 (11) Unclassified Combinations (J01CE30) 0.1 (7) 0.1 (7) 0.1 (7) 0.1 (5) 0.1 (5) Consumption in DID 1.3 (78) 1.4 (76) 1.1 (76) 1.2 (75) 1.2 (78) (% of total consumption) Total consumption of parenteral agents 1.6 1.8 1.5 1.6 1.5

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

15.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

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The amoxicillin index decreased from 28% in 2014 to 19% in 2018 (Table 15.8).

Table 15.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2014 2015 2016 2017 2018 Oral amoxicillin 6.5 (28) 7.8 (27) 5.3 (21) 4.2 (22) 4.0 (19) Oral amoxicillin and 6.6 (28) 7.8 (27) 5.3 (21) 4.2 (22) 4.0 (19) phenoxymethylpenicillin Total oral J01 23.6 29.2 24.7 19.7 21.2

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

15.6 Discussion

The analyses presented here document consumption between 2014 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. Volumes and patterns of consumption of antibacterial subgroups varied over time.

The most notable feature of the data was the increasing volumes and relative consumption of Watch agents from 2014 to 2018. Specifically, there were increases in consumption of two macrolides, clarithromycin and azithromycin, and two fluoroquinolones, ciprofloxacin and levofloxacin as well as third generation cephalosporin, cefixime. These medicines could be useful targets for further investigation, interventions and stewardship activities to ensure that consumption of these agents is in accord with approved clinical guidelines and treatment algorithms.

In 2018, the EMA conducted a review of medicines containing fluoroquinolone and quinolone antibiotics, including cinoxacin, ciprofloxacin, flumequine, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, pefloxacin, pipemidic acid, prulifloxacin and rufloxacin (European Medicines Agency, 2019). EMA’s human medicines committee (CHMP) endorsed the recommendations of EMA’s safety committee and concluded that the marketing authorization of medicines containing cinoxacin, flumequine, nalidixic acid and pipemidic acid should be suspended. A legally binding decision to suspend marketing authorization for pipedimic acid applicable in all EU countries was issued by the European Commission in March 2019. Pipemidic acid was withdrawn from the market in Serbia in April 2019.

104 16. SWITZERLAND

16.1 Data source and years of data collection

Switzerland has provided data for each of the five years of data collection (2014–2018), but data collection on consumption of antibacterials is partial for some years. The Swiss Antibiotic Resistance Report 2020 of the Swiss Federal Office of Public Health covers 2017, 2018 and 2019 data (Federal Office of Public Health and Federal Food Safety and Veterinary Office, 2020). Only 2017 and 2018 data have been used for the present analysis, as they represent total consumption estimates.

Estimates are obtained from IQVIA sales data that cover both outpatient and inpatient consumption of antibacterials. Additional information on consumption is available from a sentinel network of acute care hospitals (inpatient) and the database maintained by PharmaSuisse, the Swiss Society of Pharmacists, which covers approximately 53% of all pharmacies in Switzerland (outpatient). Prescription data allow analyses of quantities of antibiotics sold to numbers of individuals per age group. These data sources provide complementary information to better understand how antibiotics are used in Switzerland.

16.2 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. 16.1 and Table 16.1).

Fig. 16.1 Total consumption of J01 antibacterials by pharmacological subgroup

15 Other J01 antibacterials (J01G, J01R, J01X)

Quinolone antibacterials (J01M)

10 Macrolides, lincosamides and streptogramins (J01F)

Sulfonamides and trimethoprim (J01E)

5 Other beta-lactams (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day Beta-lactam penicillins (J01C)

Amphenicols (J01B) 0 Tetracyclines (J01A) SWI SWI 2017 2018

DDD: daily defined dose.

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Parenteral antibacterials represented 6% of total J01 consumption in 2017 and 2018 (Table 16.1).

The highest levels of consumption were in beta-lactam penicillins (J01C) at 4.0 DID (39% of J01 consumption) in 2017 and 4.2 DID (40%) in 2018.

Total consumption estimates and consumption of pharmacological subgroups were similar across the two years of data (Table 16.1). There were too few data for a formal test of any trends over time.

Table 16.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2017 2018 Route of administration Oral J01 9.7 (94) 9.9 (94) Parenteral J01 0.6 (6) 0.7 (6) Totala 10.4 10.5 Class of antibacterial agents Tetracyclines (J01A) 1.3 (13) 1.4 (13) Amphenicols (J01B) < 0.1 (0) < 0.1 (0) Beta-lactam penicillins (J01C) 4.0 (39) 4.2 (40) Other beta-lactams (includes cephalosporins) (J01D) 1.0 (9) 0.9 (9) Sulfonamides and trimethoprim (J01E) 0.5 (5) 0.6 (5) Macrolides, lincosamides and streptogramins (J01F) 1.5 (14) 1.4 (14) Quinolone antibacterials (J01M) 1.4 (14) 1.4 (13) Other J01 antibacterials (J01G, J01R, J01X) 0.6 (6) 0.6 (6) Totala 10.4 10.5 Analysis of trend over time Trendb Not conducted as less than five years of data available

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

16.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 16.2 and is summarized in Table 16.2.

Both volumes and relative consumption of Access agents were similar in 2017 and 2018, at 6.3 DID (59% of total consumption) in 2017 and 6.7 DID (61%) in 2018. These results already align with the WHO monitoring target that by 2023, at least 60% of total consumption should be Access agents, the group of antibiotics at lowest risk of resistance.

Consumption of Watch agents remained steady at 4.3 DID (40% of total consumption) in 2017 and 4.2 DID (38%) in 2018.

106 Switzerland

Consumption of Reserve and unclassified agents remained low across all years of data analysed.

Fig. 16.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 SWI SWI 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 16.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2017 2018 Access 6.3 (59) 6.7 (61) Watch 4.3 (40) 4.2 (38) Reserve 0.04 (0) 0.04 (0) Unclassified < 0.1 < 0.1 Totalb 10.7 10.9

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 16.3.

Table 16.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2017 1.48 2018 1.60 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

107 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The ratio in Switzerland is close to this target in both 2017 and 2018.

16.4 Consumption at substance level (5th ATC group level)

Table 16.4 and 16.5 (oral agents) and Table 16.6 and 16.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibiotic consumption.

There were eight agents constituting the DU75% by oral substance in 2017 and 2018 (Table 16.4).

Oral amoxicillin and beta-lactamase inhibitor (ATC code J01CR02) was the most consumed oral agent at 2.7 DID (26% of total oral antibacterial consumption) in 2017 and 2018 (Table 16.4 and 16.5). The second-ranked agent, doxycycline (J01AA02), represented 1.1 DID (11%) in 2018.

Four Watch agents appeared in the DU75%. The fluoroquinolone ciprofloxacin (J01MA02) was fourth most consumed agent and represented 0.9 DID (9%) of oral antibacterial consumption in 2017 and 2018.

Table 16.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2017 2018 Access Doxycycline (J01AA02) 2 2 Amoxicillin (J01CA04) 3 3 Amoxicillin and beta-lactamase inhibitor (J01CR02) 1 1 Sulfamethoxazole and trimethoprim (J01EE01) 7 7 Watch Cefuroxime (J01DC02) 6 6 Clarithromycin (J01FA09) 5 5 Azithromycin (J01FA10) 8 8 Ciprofloxacin (J01MA02) 4 4 a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

108 Switzerland

Table 16.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2017 2018 Access Doxycycline (J01AA02) 1.0 (10) 1.1 (11) Amoxicillin (J01CA04) 1.0 (10) 1.0 (10) Amoxicillin and beta-lactamase inhibitor (J01CR02) 2.7 (26) 2.7 (26) Sulfamethoxazole and trimethoprim (J01EE01) 0.5 (5) 0.5 (5) Watch Cefuroxime (J01DC02) 0.6 (6) 0.6 (6) Clarithromycin (J01FA09) 0.7 (7) 0.7 (7) Azithromycin (J01FA10) 0.5 (5) 0.5 (5) Ciprofloxacin (J01MA02) 0.9 (9) 0.9 (9) Consumption in DID (% of total consumption) 8.0 (79) 8.1 (79) Total consumption of oral agents 10.1 10.2

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Seven agents constituted the DU75% by parenteral substance in 2017 and 2018 (Table 16.6).

Parenteral amoxicillin and beta-lactamase inhibitor (ATC code J01CR02) was the most consumed parenteral agent at 0.2 DID (31% of total parenteral antibacterial consumption) in 2018 (Table 16.6 and 16.7).

The Watch agent ceftriaxone (J01DD04) was ranked number two, constituting 15% of consumption of parenteral agents in 2018 (Table 16.7).

Table 16.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2017 2018 Access Benzylpenicillin (J01CE01) 7 7 Flucloxacillin (J01CF05) 4 5 Amoxicillin and beta-lactamase inhibitor (J01CR02) 1 1 Cefazolin (J01DB04) 6 6 Watch Piperacillin and beta-lactamase inhibitor (J01CR05) 5 4 Cefuroxime (J01DC02) 3 3 Ceftriaxone (J01DD04) 2 2 a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

109 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 16.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2017 2018 Access Benzylpenicillin (J01CE01) 0.0 (4) 0.0 (3) Flucloxacillin (J01CF05) 0.0 (8) 0.0 (6) Amoxicillin and beta-lactamase inhibitor (J01CR02) 0.2 (28) 0.2 (31) Cefazolin (J01DB04) 0.0 (5) 0.0 (4) Watch Piperacillin and beta-lactamase inhibitor (J01CR05) 0.0 (6) 0.1 (8) Cefuroxime (J01DC02) 0.1 (10) 0.1 (10) Ceftriaxone (J01DD04) 0.1 (16) 0.1 (15) Consumption in DID (% of total consumption) 0.5 (77) 0.5 (78) Total consumption of parenteral agents 0.6 0.7

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

16.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index was 11% in both 2017 and 2018 (Table 16.8).

Table 16.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2017 2018 Oral amoxicillin 1.0 (10) 1.0 (11) Oral amoxicillin and phenoxymethylpenicillin 1.0 (11) 1.1 (11) Total oral J01 9.7 9.9

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

16.6 Discussion

The analyses presented here document consumption in 2017 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. There are too few data to assess trends over time. The most notable feature of these data is the consistency in patterns of consumption across the two years. Swiss data already align with the WHO monitoring target that by 2023, 60% of total consumption should be derived from Access agents. The Access-to- Watch index is close to 1.5 in both years. The levels of consumption of specific Watch group antibiotics could suggest some targets for further investigation, interventions and stewardship activities.

110 17. TAJIKISTAN

17.1 Data source and years of data collection

Tajikistan has provided data for each of the five years of data collection (2014–2018). The main sources are import records and certification records provided by the State Surveillance Service for Pharmaceutical Activities. The data cover imported, locally produced and donated medicines.

17.2 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. 17.1 and Table 17.1).

Consumption of parenteral antibacterials varied over the years analysed, representing 25–38% of total J01 consumption between 2014 and 2018 (Table 17.1).

Beta-lactam penicillins (J01C) had the highest levels of consumption in four of the five years analysed, decreasing from 14.8 DID in 2014 to 2.7 DID in 2018. Over the same period, there were decreases in consumption of cephalosporins (J01D), from 7.0 DID in 2014 to 3.4 DID in 2018, and increases in consumption of medicines in the sulfonamides and trimethoprim (J01E) group, from 1.4 DID in 2014 to 2.5 DID in 2018, and quinolones (J01M), from 2.6 DID in 2014 to 6.1 DID in 2018.

Fig. 17.1 Total consumption of J01 antibacterials by pharmacological subgroup

35 Other J01 antibacterials (J01G, J01R, J01X) 30 Quinolone antibacterials (J01M) 25 Macrolides, lincosamides and streptogramins (J01F) 20 Sulfonamides and 15 trimethoprim (J01E) Other beta-lactams 10 (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day Beta-lactam penicillins (J01C) 5 Amphenicols (J01B) 0 Tetracyclines (J01A) TJK TJK TJK TJK TJK 2014 2015 2016 2017 2018

DDD: daily defined dose.

111 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

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

The data show fluctuations in consumption of J01 antibacterials over time. The CAGR for the period 2014–2018 was −11.5% per year, although the suggested trend towards reduced consumption over time was not statistically significant (Table 17.1).

Table 17.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2014 2015 2016 2017 2018 Route of administration Oral J01 20.9 (67) 13.5 (62) 15.6 (75) 10.7 (66) 13.9 (73) Parenteral J01 10.1 (33) 8.1 (38) 5.3 (25) 5.6 (34) 5.1 (27) Totala 31.0 21.7 20.9 16.3 19.0 Class of antibacterial agents Tetracyclines (J01A) 1.4 (5) 1.2 (6) 0.8 (4) 0.6 (4) 0.7 (4) Amphenicols (J01B) 0.5 (2) 0.3 (2) 0.1 (1) 0.2 (1) 0.1 (1) Beta-lactam penicillins (J01C) 14.8 (48) 7.0 (33) 8.2 (39) 4.5 (28) 2.7 (14) Other beta-lactams (includes 7.0 (22) 4.8 (22) 2.8 (13) 3.2 (20) 3.4 (18) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 1.4 (5) 1.6 (7) 0.8 (4) 0.9 (6) 2.5 (13) Macrolides, lincosamides and 0.9 (3) 0.9 (4) 0.8 (4) 1.3 (8) 1.4 (8) streptogramins (J01F) Quinolone antibacterials (J01M) 2.6 (8) 3.2 (15) 4.3 (21) 4.2 (26) 6.1 (32) Other J01 antibacterials (J01G, J01R, J01X) 2.5 (8) 2.6 (12) 3.1 (15) 1.4 (8) 2.1 (11) Totala 31.0 21.7 20.9 16.3 19.0 Analysis of trend over time Trendb P-value 0.08 CAGRc −11.5

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

Beta-lactam penicillin (J01C) consumption decreased across the years analyzed, representing 48% of J01 consumption in 2014 and 14% in 2018. There is evidence of decreasing relative consumption of cephalosporins (J01D), at 22% in 2014 and 18% in 2018. Relative consumption increased for agents in the sulfonamides and trimethoprim (J01E) group, at 5% in 2014 and 13% in 2018, macrolides, lincosamides and streptogramins (J01F), at 3% in 2014 and 8% in 2018, and for quinolones (J01M), at 8% in 2014 and 32% in 2018.

17.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 WHO Access, Watch and Reserve groups of antibiotics can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.

112 Tajikistan

The relative consumption of Access, Watch and Reserve group antibiotics is shown in Fig. 17.2 and is summarized in Table 17.2.

Both volumes and relative consumption of Access agents decreased over time, from 20.4 DID (65% of total consumption) in 2014 to 8.2 DID (42%) in 2018. Tajikistan would have met the WHO national monitoring target of at least 60% of total consumption being Access agents only in 2014 and 2016.

Conversely, volumes and relative consumption of Watch agents increased from 9.3 DID (29% of total consumption) in 2014 to 10.8 DID (56%) in 2018.

Consumption of Reserve agents remained low across all years of data analysed. Unclassified agents constituted 2–6% of consumption.

Fig. 17.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 TJK TJK TJK TJK TJK 2014 2015 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 17.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2014 2015 2016 2017 2018 Access 20.4 (65) 12.8 (58) 13.0 (61) 7.6 (46) 8.2 (42) Watch 9.3 (29) 8.3 (38) 7.5 (36) 8.3 (50) 10.8 (56) Reserve < 0.01 < 0.01 0.01 (0) < 0.01 0.03 (0) Unclassified 1.8 (6) 1.0 (5) 0.6 (3) 0.6 (4) 0.4 (2) Totalb 31.5 22.1 21.2 16.5 19.4

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 17.3.

113 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 17.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2014 2.20 2015 1.54 2016 1.72 2017 0.91 2018 0.76 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The decrease in the ratio from 2.2 in 2014 to 0.76 in 2018 reflects the higher relative use of Watch agents over time.

17.4 Consumption at substance level (5th ATC group level)

Table 17.4 and 17.5 (oral agents) and Table 17.6 and 17.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibacterial consumption.

The number of agents constituting the DU75% by oral substance ranged from four to seven across the years of analysis (Table 17.4).

Oral amoxicillin (J01CA04) was the most consumed oral agent in 2014–2016 and was ranked second in 2017 and third in 2018, with decreasing consumption over time – 9.7 DID (45%) in 2014 and 1.3 DID (9%) in 2018 (Table 17.4 and 17.5). The combination sulfamethoxazole and trimethoprim (J01EE01) was the second most consumed oral antibacterial in 2018, at 2.5 DID (18%).

Table 17.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Tetracycline (J01AA07) 6 Ampicillin (J01CA01) 3 3 3 3 Amoxicillin (J01CA04) 1 1 1 2 3 Phenoxymethylpenicillin (J01CE02) 5 Sulfamethoxazole and trimethoprim 4 4 4 2 (J01EE01) Nitrofurantoin (J01XE01) 6 5 4 5 Watch Erythromycin (J01FA01) 4 Azithromycin (J01FA10) 5 Ciprofloxacin (J01MA02) 2 2 2 1 1 Levofloxacin (J01MA12) 7 6

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

114 Tajikistan

One to three Watch agents appeared in the DU75% for each of the years analysed. Ciprofloxacin (J01MA02) was second most consumed oral agent in 2014–2016 and most consumed agent in 2017– 2018, with consumption increasing from 1.7 DID (8%) in 2014 to 4.8 DID (34%) in 2018. Consumption of ciprofloxacin (J01MA02) and levofloxacin (J01MA12) combined was 5.5 DID (39%) in 2018.

Table 17.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Tetracycline (J01AA07) 0.7 (5) Ampicillin (J01CA01) 1.6 (8) 1.9 (13) 2.2 (14) 1.2 (11) Amoxicillin (J01CA04) 9.7 (45) 3.1 (22) 5.1 (32) 2.2 (20) 1.3 (9) Phenoxymethylpenicillin (J01CE02) 1.2 (6) Sulfamethoxazole and trimethoprim (J01EE01) 1.4 (7) 1.6 (11) 0.9 (9) 2.5 (18) Nitrofurantoin (J01XE01) 1.1 (5) 1.0 (7) 1.1 (7) 0.8 (6) Watch Erythromycin (J01FA01) 0.8 (6) Azithromycin (J01FA10) 0.9 (8) Ciprofloxacin (J01MA02) 1.7 (8) 2.2 (16) 3.8 (24) 3.5 (32) 4.8 (34) Levofloxacin (J01MA12) 0.6 (4) 0.7 (5) Consumption in DID (% of total consumption) 16.8 (78) 11.0 (79) 12.1 (76) 8.7 (79) 10.9 (76) Total consumption of oral agents 21.4 14.0 15.9 11.0 14.3

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The number of agents constituting the DU75% by parenteral substance ranged from three to six across the years of analysis (Table 17.6).

Table 17.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Ampicillin (J01CA01) 2 3 5 2 Cefazolin (J01DB04) 2 6 Gentamicin (J01GB03) 3 Metronidazole (J01XD01) 3 2 2 3 Watch Ceftriaxone (J01DD04) 1 1 1 1 1 Unclassified Combinations (J01CE30) 3 Combinations of penicillins (J01CR50) 4 4

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

115 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

The Watch agent ceftriaxone (J01DD04) was ranked number one in each year of analysis, constituting 54% of consumption of parenteral agents in 2014 and 57% in 2018 (Table 17.7). Combinations of benzathine benzylpenicillin and procaine benzylpenicillin (J01CE30) constituted 10% of parenteral consumption in 2014.

Table 17.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Ampicillin (J01CA01) 1.3 (16) 0.4 (7) 0.4 (7) 0.6 (13) Cefazolin (J01DB04) 1.1 (11) 0.4 (7) Gentamicin (J01GB03) 0.4 (8) Metronidazole (J01XD01) 0.7 (8) 1.5 (28) 0.5 (9) 0.3 (6) Watch Ceftriaxone (J01DD04) 5.5 (54) 4.0 (49) 2.2 (42) 2.4 (42) 2.9 (57) Unclassified Combinations (J01CE30) 1.0 (10) Combinations of penicillins (J01CR50) 0.5 (7) 0.4 (8) Consumption in DID 7.6 (75) 6.5 (80) 4.1 (77) 4.5 (81) 3.9 (76) (% of total consumption) Total consumption of parenteral agents 10.1 8.1 5.3 5.6 5.1

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

17.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index decreased from 52% in 2014 to 9% in 2018 (Table 17.8).

Table 17.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2014 2015 2016 2017 2018 Oral amoxicillin 9.6 (46) 3.1 (23) 5.0 (32) 2.2 (20) 1.3 (9) Oral amoxicillin and 10.9 (52) 3.1 (23) 5.0 (32) 2.2 (20) 1.3 (9) phenoxymethylpenicillin Total oral J01 20.9 13.5 15.6 10.7 13.9

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

116 Tajikistan

17.6 Discussion

The analyses presented here document consumption between 2014 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. The most notable feature of these data is the increasing and relatively higher levels of consumption of Watch group antibiotics between 2014 and 2018. Consumption of two fluoroquinolones, ciprofloxacin and levofloxacin, represented 39% of oral antibacterials consumption in 2018.

In 2018, the EMA reviewed medicines containing fluoroquinolone and quinolone antibiotics. In addition to recommending suspension of the marketing authorization for medicines containing cinoxacin, flumequine, nalidixic acid and pipemidic acid, EMA’s human medicines committee (CHMP) recommended restricting the use of the remaining fluoroquinolone antibiotics (European Medicines Agency, 2019). The prescribing information for health-care professionals and information for patients should describe the disabling and potentially permanent side-effects and advise patients to stop treatment with a fluoroquinolone antibiotic at the first sign of a side-effect involving muscles, tendons or joints, and the nervous system. The CHMP recommended restrictions on the use of fluoroquinolones, stating they should not be used to: treat infections that might get better without treatment or are not severe (such as throat infections); treat non-bacterial infections, such as non-bacterial (chronic) prostatitis; prevent traveller’s diarrhoea or recurring lower urinary tract infections (urine infections that do not extend beyond the bladder); and treat mild or moderate bacterial infections unless other antibacterial medicines commonly recommended for these infections cannot be used.

Given these EMA recommendations, the high levels of consumption of ciprofloxacin and levofloxacin should be reviewed. These agents should be targets for further investigation, interventions and stewardship activities to ensure consumption is consistent with approved clinical guidelines and treatment protocols.

The 2019 WHO EML (WHO, 2019b) suggests that sulfamethoxazole and trimethoprim is a first-choice agent for lower urinary tract infections and second choice for acute invasive diarrhoea and bacterial diarrhoea. It is also used to prevent or treat Pneumocystis jiroveci pneumonia or Pneumocystis carinii pneumonia. The relatively high level of consumption of sulfamethoxazole and trimethoprim (18% of total consumption of oral agents in 2018) suggests it is being used for other indications. This could be assessed through reviews of prescriptions and existing clinical guidelines.

117 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

18. TURKEY

18.1 Data source and years of data collection

Turkey has provided data for each of the five years of data collection (2014–2018). The main sources of data are sales records of wholesalers provided by the track and trace system of the Turkish Medicine and Medical Devices Agency.

18.2 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. 18.1 and Table 18.1).

Parenteral antibacterials represented 3–5% of total J01 consumption between 2014 and 2018 (Table 18.1).

The highest levels of consumption were in beta-lactam penicillins (J01C), at 12.2 DID in 2014 and 12.4 DID in 2018. Over the same period, consumption of cephalosporins (J01D) decreased from 12.2 DID in 2014 to 8.0 DID in 2018 and accounted for most of the reduction in total consumption of J01 antibacterials seen between 2014 and 2018. Consumption of other pharmacological subgroups was reasonably stable over time.

Fig. 18.1 Total consumption of J01 antibacterials by pharmacological subgroup

40 Other J01 antibacterials (J01G, J01R, J01X) 35 Quinolone antibacterials 30 (J01M) Macrolides, lincosamides 25 and streptogramins (J01F)

20 Sulfonamides and trimethoprim (J01E) 15 Other beta-lactams (includes cephalosporins) (J01D) 10

DDD/1000 inhabitants per day Beta-lactam penicillins (J01C) 5 Amphenicols (J01B) 0 Tetracyclines (J01A) TUR TUR TUR TUR TUR 2014 2015 2016 2017 2018

DDD: daily defined dose.

118 Turkey

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

The data show some fluctuations in consumption of J01 antibacterials over time. The CAGR for the period 2014–2018 was −2.9% per year, although the suggested trend towards reduced consumption was not statistically significant (Table 18.1).

Table 18.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2014 2015 2016 2017 2018 Route of administration Oral J01 33.2 (96) 34.0 (96) 33.8 (96) 29.5 (95) 30.0 (97) Parenteral J01 1.5 (4) 1.5 (4) 1.5 (4) 1.4 (5) 0.9 (3) Totala 34.7 35.5 35.3 31.0 30.9 Class of antibacterial agents Tetracyclines (J01A) 1.3 (4) 1.3 (4) 1.2 (3) 1.2 (4) 1.3 (4) Amphenicols (J01B) < 0.1 (0) < 0.1 (0) < 0.1 (0) < 0.1 (0) – Beta-lactam penicillins (J01C) 12.2 (35) 12.6 (35) 13.0 (37) 11.7 (38) 12.4 (40) Other beta-lactams (includes 12.2 (35) 11.9 (34) 11.5 (33) 9.6 (31) 8.0 (26) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 0.4 (1) 0.4 (1) 0.3 (1) 0.3 (1) 0.3 (1) Macrolides, lincosamides and 4.1 (12) 4.8 (14) 4.7 (13) 4.0 (13) 4.4 (14) streptogramins (J01F) Quinolone antibacterials (J01M) 3.1 (9) 3.1 (9) 3.0 (8) 2.6 (8) 3.0 (10) Other J01 antibacterials (J01G, J01R, J01X) 1.5 (4) 1.5 (4) 1.6 (5) 1.7 (5) 1.5 (5) Totala 34.7 35.5 35.4 31.0 30.9 Analysis of trend over time Trendb P-value 0.09 CAGRc −2.9

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

Consumption of beta-lactam penicillins increased from 35% of J01 consumption in 2014 to 40% in 2018. The relative consumption of cephalosporins (J01D) decreased from 35% in 2014 to 26% in 2018.

18.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 18.2 and is summarized in Table 18.2.

Both volumes and relative consumption of Access agents increased slightly over time, from 15.7 DID (44% of total antibacterial consumption) in 2014 to 16.0 DID (50%) in 2018. Turkey would not have

119 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

met the WHO national monitoring target of at least 60% of total consumption being Access agents in any of the years analysed.

Conversely, volumes and relative consumption of Watch agents decreased from 19.0 DID (54% of total consumption) in 2014 to 15.1 DID (47%) in 2018.

Consumption of Reserve and unclassified agents remained low across all years of data analysed.

Fig. 18.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 TUR TUR TUR TUR TUR 2014 2015 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 18.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2014 2015 2016 2017 2018 Access 15.7 (44) 16.3 (44) 16.7 (46) 15.0 (47) 16.0 (50) Watch 19.0 (54) 19.5 (53) 18.9 (52) 16.0 (50) 15.1 (47) Reserve 0.03 (0) 0.03 (0) 0.04 (0) 0.04 (0) 0.02 (0) Unclassified 0.6 (2) 0.6 (2) 0.7 (2) 0.8 (3) 0.7 (2) Totalb 35.3 36.5 36.3 31.9 31.8

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 18.3.

120 Turkey

Table 18.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2014 0.83 2015 0.83 2016 0.88 2017 0.94 2018 1.06 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The increase of the ratio from 0.83 in 2014 to 1.06 in 2018 illustrates the increasing consumption of Access agents over time.

18.4 Consumption at substance level (5th ATC group level)

Table 18.4 and 18.5 (oral agents) and Table 18.6 and 18.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibiotic consumption.

Eight or nine agents constituted the DU75% by oral substance across the years of analysis (Table 18.4).

Oral amoxicillin and beta-lactamase inhibitor (ATC code J01CR02) was the most consumed oral agent across all years, analysed at 10.0 DID (30% of total oral antibacterial consumption) in 2014 and 10.7 DID (35%) in 2018 (Table 18.4 and 18.5).

Five or six Watch agents appeared in the DU75% for each of the years analysed. Decreases in consumption of two second-generation cephalosporins, cefuroxime (J01DC02) and cefaclor (J01DC04), and two third-generation cephalosporins, cefixime (J01DD08) and cefdinir (J01DD15) combined, were seen, from 7.8 DID (23%) in 2014 to 5.2 DID (17%) in 2018.

Table 18.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 8 8 8 8 6 Amoxicillin (J01CA04) 6 7 7 Amoxicillin and beta-lactamase inhibitor (J01CR02) 1 1 1 1 1 Watch Cefuroxime (J01DC02) 2 2 2 2 3 Cefaclor (J01DC04) 7 6 6 5 Cefixime (J01DD08) 9 7 6 8 Cefdinir (J01DD15) 5 5 5 7 5 Clarithromycin (J01FA09) 3 3 3 3 2 Ciprofloxacin (J01MA02) 4 4 4 4 4

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

121 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 18.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 1.2 (3) 1.1 (3) 1.1 (3) 1.1 (4) 1.1 (4) Amoxicillin (J01CA04) 1.2 (4) 1.2 (3) 0.9 (3) Amoxicillin and beta-lactamase inhibitor 10.0 (30) 10.4 (30) 11.0 (32) 9.8 (32) 10.7 (35) (J01CR02) Watch Cefuroxime (J01DC02) 4.5 (13) 4.0 (12) 3.8 (11) 3.3 (11) 3.1 (10) Cefaclor (J01DC04) 1.2 (4) 1.5 (4) 1.5 (4) 1.5 (5) Cefixime (J01DD08) 1.1 (3) 1.3 (4) 1.2 (4) 0.9 (3) Cefdinir (J01DD15) 2.1 (6) 2.1 (6) 2.1 (6) 1.2 (4) 1.2 (4) Clarithromycin (J01FA09) 3.0 (9) 3.5 (10) 3.6 (10) 2.9 (10) 3.3 (11) Ciprofloxacin (J01MA02) 2.2 (7) 2.3 (7) 2.2 (6) 1.8 (6) 2.1 (7) Consumption in DID 25.4 (75) 27.2 (78) 26.7 (77) 22.8 (75) 23.5 (76) (% of total consumption) Total consumption of oral agents 33.7 34.8 34.7 30.4 30.9

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The number of agents constituting the DU75% by parenteral substance ranged from eight to 10 across the years of analysis (Table 18.6).

The Watch agent ceftriaxone (J01DD04) was ranked number one in each year of analysis, constituting 26% of consumption of parenteral agents in 2014 and 32% in 2018 (Table 18.7).

Table 18.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Ampicillin and beta-lactamase inhibitor (J01CR01) 4 5 5 5 8 Cefazolin (J01DB04) 2 2 2 2 2 Clindamycin (J01FF01) 7 7 8 8 5 Gentamicin (J01GB03) 6 6 6 7 6 Watch Piperacillin and beta-lactamase inhibitor (J01CR05) 9 10 Cefuroxime (J01DC02) 3 3 4 4 4 Ceftriaxone (J01DD04) 1 1 1 1 1 Meropenem (J01DH02) 8 8 7 6 7 Levofloxacin (J01MA12) 9 Moxifloxacin (J01MA14) 9 Rifamycin (J04AB03) 5 4 3 3 3

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

122 Turkey

Table 18.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Ampicillin and beta-lactamase inhibitor 0.1 (6) 0.1 (5) 0.1 (5) 0.1 (5) 0.0 (2) (J01CR01) Cefazolin (J01DB04) 0.3 (20) 0.3 (19) 0.3 (18) 0.3 (16) 0.1 (16) Clindamycin (J01FF01) < 0.1 (3) < 0.1 (3) < 0.1 (3) < 0.1 (3) < 0.1 (5) Gentamicin (J01GB03) 0.1 (5) 0.1 (4) 0.1 (3) < 0.1 (3) < 0.1 (4) Watch Piperacillin and beta-lactamase inhibitor < 0.1 (2) < 0.1 (3) (J01CR05) Cefuroxime (J01DC02) 0.1 (7) 0.1 (7) 0.1 (6) 0.1 (5) 0.1 (7) Ceftriaxone (J01DD04) 0.4 (26) 0.5 (29) 0.5 (29) 0.4 (28) 0.3 (32) Meropenem (J01DH02) < 0.1 (2) < 0.1 (3) 0.1 (3) 0.1 (4) < 0.1 (3) Levofloxacin (J01MA12) < 0.1 (2) Moxifloxacin (J01MA14) < 0.1 (3) Rifamycin (J04AB03) 0.1 (6) 0.1 (6) 0.1 (6) 0.1 (7) 0.1 (8) Consumption in DID 1.2 (75) 1.3 (77) 1.2 (76) 1.2 (76) 0.7 (76) (% of total consumption) Total consumption of parenteral agents 1.6 1.6 1.6 1.5 1.0

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

18.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index was consistently around 4% between 2014 and 2018 (Table 18.8).

Table 18.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2014 2015 2016 2017 2018 Oral amoxicillin 1.2 (4) 1.2 (4) 1.0 (3) 1.0 (3) 0.9 (3) Oral amoxicillin and 1.3 (4) 1.3 (4) 1.2 (3) 1.1 (4) 1.1 (4) phenoxymethylpenicillin Total oral J01 33.2 34.0 33.8 29.5 30.0

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

123 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

18.6 Discussion

The analyses presented here document consumption between 2014 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. The five years of data examined provide a platform for future years of data to enable assessment of trends over time. The most notable features of these data are the trend to decreasing total consumption of antibacterials over time, with small increases in consumption of Access agents and decreases in consumption of Watch agents. However, Turkey would not have met the WHO national monitoring target of at least 60% of total consumption being Access agents in any of the years analysed. The relatively higher levels of consumption of specific Watch group antibiotics suggest some targets for further investigation, interventions and stewardship activities.

124 19. UKRAINE

19.1 Data source and years of data collection

Ukraine has provided data for each of the five years of data collection (2014–2018). The main source of data is a market research company, Proxima Research, but government tenders for the hospital sector, hospital purchases from wholesalers (tenders and self-procurement) and pharmacy purchases from wholesalers are also included. Retail and hospital estimates are based on extrapolation of data from a representative sample of facilities using cluster analysis and hierarchical models. Tender data are derived from official information from the Prozorro platform.

19.2 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. 19.1 and Table 19.1).

Parenteral antibacterials represented 17–20% of total J01 consumption between 2014 and 2018 (Table 19.1).

Fig. 19.1 Total consumption of J01 antibacterials by pharmacological subgroup

15 Other J01 antibacterials (J01G, J01R, J01X)

Quinolone antibacterials (J01M)

10 Macrolides, lincosamides and streptogramins (J01F)

Sulfonamides and trimethoprim (J01E)

5 Other beta-lactams (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day Beta-lactam penicillins (J01C)

Amphenicols (J01B) 0 Tetracyclines (J01A) UKR UKR UKR UKR UKR 2014 2015 2016 2017 2018

DDD: daily defined dose.

125 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

The pharmacological subgroups with the highest levels of consumption varied over time. In 2014, the highest level of consumption was in beta-lactam penicillins (J01C), at 1.8 DID. Quinolones (J01M) were the most consumed group in 2015, at 2.9 DID. Macrolides, lincosamides and streptogramins (J01F) were the most consumed pharmacological subgroup in 2016, 2017 and 2018, with consumption increasing from 1.9 DID in 2016 to 2.7 DID in 2018.

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

The data show fluctuations in consumption of J01 antibacterials over time. The CAGR for the period 2014–2018 was 5.3% per year, although the suggested trend towards increased consumption over time was not statistically significant (Table 19.1).

Table 19.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2014 2015 2016 2017 2018 Route of administration Oral J01 7.8 (83) 9.7 (80) 6.8 (81) 8.8 (83) 9.6 (82) Parenteral J01 1.6 (17) 2.4 (20) 1.6 (19) 1.8 (17) 2.1 (18) Totala 9.5 12.1 8.3 10.7 11.7 Class of antibacterial agents Tetracyclines (J01A) 0.7 (7) 0.7 (6) 0.7 (8) 0.7 (7) 0.8 (7) Amphenicols (J01B) 0.3 (3) 0.3 (2) 0.2 (3) 0.2 (2) 0.2 (2) Beta-lactam penicillins (J01C) 1.8 (19) 1.9 (16) 1.5 (18) 2.0 (19) 2.1 (18) Other beta-lactams (includes 1.6 (17) 2.1 (17) 1.0 (12) 1.9 (18) 2.1 (18) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 0.6 (6) 0.5 (4) 0.5 (7) 0.5 (4) 0.5 (4) Macrolides, lincosamides and 1.7 (18) 2.1 (17) 1.9 (23) 2.2 (21) 2.7 (23) streptogramins (J01F) Quinolone antibacterials (J01M) 1.5 (16) 2.9 (24) 0.7 (9) 1.7 (16) 1.8 (15) Other J01 antibacterials (J01G, J01R, J01X) 1.3 (13) 1.6 (13) 1.8 (21) 1.4 (13) 1.6 (14) Totala 9.5 12.1 8.3 10.7 11.7 Analysis of trend over time Trendb P-value 0.6 CAGRc 5.3

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

There is evidence of increasing relative consumption of macrolides, lincosamides and streptogramins (J01F), at 18% in 2014 and 23% in 2018.

126 Ukraine

19.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 19.2 and is summarized in Table 19.2.

Volumes of consumption of Access agents increased and relative consumption decreased over time, from 3.9 DID (40% of total consumption) in 2014 to 4.3 DID (36%) in 2018. Ukraine would not have met the WHO national monitoring target of at least 60% of total consumption being Access agents in any of the years of analysis.

Volumes and relative consumption of Watch agents increased over time, from 4.8 DID (50% of total consumption) in 2014 to 6.6 DID (56%) in 2018.

Consumption of Reserve agents remained low across all years of data analysed. Unclassified agents constituted 7–11% of consumption across the years analysed.

Fig. 19.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 UKR UKR UKR UKR UKR 2014 2015 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 19.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2014 2015 2016 2017 2018 Access 3.9 (40) 4.1 (33) 3.8 (44) 4.0 (37) 4.3 (36) Watch 4.8 (50) 7.2 (59) 4.0 (45) 5.9 (54) 6.6 (56) Reserve < 0.01 0.01 (0) 0.01 (0) 0.01 (0) 0.03 (0) Unclassified 0.9 (9) 1.0 (8) 0.9 (11) 1.0 (9) 0.9 (7) Totalb 9.6 12.2 8.7 10.8 11.8

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

127 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 19.3.

Table 19.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2014 0.80 2015 0.56 2016 0.96 2017 0.68 2018 0.64 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The Access-to-Watch index score was below 1.0 for all years of analysis, consistent with the higher relative use of Watch agents.

19.4 Consumption at substance level (5th ATC group level)

Table 19.4 and 19.5 (oral agents) and Table 19.6 and 19.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibacterial consumption. The number of agents constituting the DU75% by oral substance ranged from 11 to 12 across the years of analysis (Table 19.4).

Oral azithromycin (J01FA10), a Watch agent, was the most consumed oral agent in all years of analysis, increasing from 1.1 DID (14%) in 2014 to 2.0 DID (20%) in 2018 (Table 19.4 and 19.5). The second- ranked agent in 2016–2018 was oral amoxicillin and beta-lactamase inhibitor (ATC code J01CR02), with volumes increasing slightly from 0.7 DID (9%) in 2016 to 1.0 DID (10%) in 2018.

Four to six Watch agents appeared in the DU75% for each of the years analysed. Beyond azithromycin, consumption of two fluoroquinolones, ciprofloxacin (J01MA02) and levofloxacin (J01MA12) combined, increased from 0.7 DID (10%) to 1.2 DID (12%) between 2014 and 2018.

Table 19.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 4 6 4 5 4 Chloramphenicol (J01BA01) 9 Amoxicillin (J01CA04) 2 3 3 3 3 Amoxicillin and beta-lactamase inhibitor 3 5 2 2 2 (J01CR02) Sulfamethoxazole and trimethoprim 7 8 10 10 (J01EE01) Nitrofurantoin (J01XE01) 6 9 7 7 8

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Table 19.4 contd

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Watch Cefuroxime (J01DC02) 11 11 9 9 Clarithromycin (J01FA09) 8 7 9 8 7 Azithromycin (J01FA10) 1 1 1 1 1 Ofloxacin (J01MA01) 8 Ciprofloxacin (J01MA02) 5 4 6 6 Norfloxacin (J01MA06) 11 Levofloxacin (J01MA12) 10 2 4 5 Rifampicin (J04AB02) 5 Unclassified Sulfadimethoxine (J01ED01) 12 10 Furazidin (J01XE03) 6 11 11 Nitroxoline (J01XX07) 10

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

Table 19.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 0.6 (8) 0.6 (6) 0.7 (9) 0.6 (7) 0.7 (7) Chloramphenicol (J01BA01) 0.3 (4) Amoxicillin (J01CA04) 0.9 (12) 1.0 (10) 0.7 (9) 0.8 (9) 0.9 (10) Amoxicillin and beta-lactamase inhibitor 0.7 (9) 0.7 (7) 0.7 (9) 1.1 (12) 1.0 (10) (J01CR02) Sulfamethoxazole and trimethoprim (J01EE01) 0.4 (5) 0.3 (4) 0.3 (3) 0.3 (3) Nitrofurantoin (J01XE01) 0.4 (6) 0.3 (4) 0.3 (4) 0.4 (4) 0.4 (4) Watch Cefuroxime (J01DC02) 0.3 (3) 0.2 (3) 0.3 (3) 0.4 (4) Clarithromycin (J01FA09) 0.3 (4) 0.4 (4) 0.3 (4) 0.4 (4) 0.4 (4) Azithromycin (J01FA10) 1.1 (14) 1.5 (15) 1.4 (19) 1.6 (18) 2.0 (20) Ofloxacin (J01MA01) 0.4 (4) Ciprofloxacin (J01MA02) 0.4 (6) 0.8 (8) 0.4 (5) 0.5 (5) Norfloxacin (J01MA06) 0.2 (3) Levofloxacin (J01MA12) 0.3 (4) 1.2 (12) 0.7 (7) 0.7 (7) Rifampicin (J04AB02) 0.4 (6) Unclassified Sulfadimethoxine (J01ED01) 0.2 (3) 0.2 (3) Furazidin (J01XE03) 0.4 (5) 0.3 (3) 0.3 (3) Nitroxoline (J01XX07) 0.3 (3) Consumption in DID (% of total consumption) 6.0 (75) 7.5 (76) 5.6 (77) 6.8 (76) 7.5 (77) Total consumption of oral agents 7.9 9.8 7.2 9.0 9.8

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). 129 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

The number of agents constituting the DU75% by parenteral substance ranged from three to seven across the years of analysis (Table 19.6).

The most consumed agent varied across the years of analysis. The Watch agent ceftriaxone (J01DD04) was ranked number one in four of the five years analysed, constituting 53% of consumption of parenteral agents in 2014 and 50% in 2018 (Table 19.7).

Table 19.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Gentamicin (J01GB03) 7 Amikacin (J01GB06) 3 4 4 Metronidazole (J01XD01) 4 2 1 4 2 Watch Cefotaxime (J01DD01) 5 Ceftriaxone (J01DD04) 1 1 2 1 1 Lincomycin (J01FF02) 6 Kanamycin (J01GB04) 3 Levofloxacin (J01MA12) 2 3 3 2 3

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

Table 19.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Gentamicin (J01GB03) < 0.1 (3) Amikacin (J01GB06) 0.1 (3) < 0.1 (3) 0.1 (3) Metronidazole (J01XD01) 0.1 (3) 0.4 (15) 0.6 (41) 0.1 (3) 0.3 (14) Watch Cefotaxime (J01DD01) 0.1 (3) Ceftriaxone (J01DD04) 0.9 (53) 1.3 (54) 0.4 (25) 1.0 (55) 1.0 (50) Lincomycin (J01FF02) 0.0 (3) Kanamycin (J01GB04) 0.1 (8) Levofloxacin (J01MA12) 0.1 (9) 0.2 (8) 0.1 (7) 0.2 (10) 0.2 (9) Consumption in DID 1.3 (77) 1.9 (76) 1.2 (77) 1.4 (75) 1.6 (76) (% of total consumption) Total consumption of parenteral agents 1.6 2.4 1.6 1.8 2.1

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

130 Ukraine

19.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index decreased from 12% in 2014 to 10% in 2018 (Table 19.8).

Table 19.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2014 2015 2016 2017 2018 Oral amoxicillin 0.9 (12) 1.0 (10) 0.7 (10) 0.8 (10) 0.9 (10) Oral amoxicillin and 0.9 (12) 1.0 (10) 0.7 (10) 0.8 (10) 0.9 (10) phenoxymethylpenicillin Total oral J01 7.8 9.7 6.8 8.8 9.6

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

19.6 Discussion

The analyses presented here document consumption between 2014 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. Except for the macrolides, lincosamides and streptogramins (J01F), patterns of consumption of other pharmacological subgroups were reasonably stable. It is unclear the extent to which sampling of retail and hospital sectors, modelling and extrapolation of estimates contributes to this effect. High levels of consumption of parenteral metronidazole in 2016 may be a data artefact due to tenders and import cycles, as consumption fell from 0.6 DID (41% of consumption of parenteral antibacterials) in 2016 to 0.3 DID (14%) in 2018.

Consumption of Watch agents increased over time, with azithromycin representing 20% of consumption of oral antibacterials in 2020. The WHO EML (WHO, 2019b) suggests that azithromycin is first-choice agent for sexually transmitted infections due to Chlamydia trachomatis, for cholera and gonorrhoea. It is second-choice antibiotic for the treatment of acute invasive diarrhoea and dysentery. The high levels of consumption of azithromycin suggest it is being used for other indications. This could be assessed through reviews of prescriptions and existing clinical guidelines.

The 2018 EMA review of medicines containing fluoroquinolone and quinolone antibiotics found that use of these agents sometimes resulted in long-lasting and disabling side-effects, mainly involving muscles, tendons, joints and the nervous system (European Medicines Agency, 2019). Restrictions on the use of fluoroquinolones were recommended. The consumption of ciprofloxacin and levofloxacin, representing 12% of oral antibacterial consumption in 2018, should be examined to ensure consumption is consistent with approved clinical guidelines and treatment protocols. In some cases, clinical guidelines may need to be reassessed and updated to reflect the EMA advice.

131 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

20. UZBEKISTAN

20.1 Data source and years of data collection

Uzbekistan has provided data for each of the three years of data collection (2016–2018). The main sources of data are import records provided by the drug agency.

20.2 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. 20.1 and Table 20.1).

Consumption of parenteral antibacterials appears to have decreased substantially, representing 44% of total J01 consumption in 2016 and 23% in 2018 (Table 20.1).

Highest levels of consumption in 2016 and 2018 were in quinolones (J01M), at 8.7 DID in 2016 and 6.7 DID in 2018. Beta-lactam penicillins (J01C) had the highest consumption in 2017, at 5.5 DID, decreasing to 3.9 DID in 2018. It is difficult to discern reliable trends over three years of data, but there appears to be decreasing consumption of cephalosporins (J01D), from 6.8 DID in 2016 to 3.2 DID in 2018, and increasing consumption of macrolides, lincosamides and streptogramins (J01F), at 1.7 DID in 2016 and 3.3 DID in 2018. Somewhat surprisingly, there was no reported consumption of medicines in the sulfonamides and trimethoprim (J01E) group in any of the three years of analysis.

Fig. 20.1 Total consumption of J01 antibacterials by pharmacological subgroup

30 Other J01 antibacterials (J01G, J01R, J01X)

25 Quinolone antibacterials (J01M)

20 Macrolides, lincosamides and streptogramins (J01F)

15 Sulfonamides and trimethoprim (J01E)

10 Other beta-lactams (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day 5 Beta-lactam penicillins (J01C) Amphenicols (J01B) 0 Tetracyclines (J01A) UZB UZB UZB 2016 2017 2018

DDD: daily defined dose.

132 Uzbekistan

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

The data suggest reductions in the consumption of J01 antibacterials between 2016 and 2018. As only three years of data were available, a formal test of trend over time was not conducted.

Table 20.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2016 2017 2018 Route of administration Oral J01 14.0 (56) 9.4 (58) 14.0 (77) Parenteral J01 11.1 (44) 6.9 (42) 4.2 (23) Totala 25.1 16.3 18.2 Class of antibacterial agents Tetracyclines (J01A) 0.6 (3) 0.1 (1) 0.4 (2) Amphenicols (J01B) 0.4 (2) 0.4 (2) 0.1 (1) Beta-lactam penicillins (J01C) 6.5 (26) 5.5 (34) 3.9 (21) Other beta-lactams (includes cephalosporins) (J01D) 6.8 (27) 4.1 (25) 3.2 (18) Sulfonamides and trimethoprim (J01E) – – – Macrolides, lincosamides and streptogramins (J01F) 1.7 (7) 1.8 (11) 3.3 (18) Quinolone antibacterials (J01M) 8.7 (35) 4.0 (24) 6.7 (37) Other J01 antibacterials (J01G, J01R, J01X) 0.5 (2) 0.4 (3) 0.6 (3) Totala 25.1 16.3 18.2 Analysis of trend over time Trendb Not conducted as less than five years of data available

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

Quinolone consumption fluctuated across the years analyzed, representing 35% of J01 consumption in 2016, 24% in 2017 and 37% in 2018. There is evidence of decreasing relative consumption of cephalosporins (J01D), at 27% in 2016 and 18% in 2018, and increasing relative consumption of macrolides, lincosamides and streptogramins (J01F), at 7% in 2016 and 18% in 2018.

20.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 20.2 and is summarized in Table 20.2.

133 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Volumes of Access agents decreased over time, from 7.8 DID (31% of total consumption) in 2016 to 5.4 DID (30%) in 2018. Uzbekistan would not have met the WHO national monitoring target of at least 60% of total consumption being Access agents in any of the years of analysis.

Consumption of Watch agents varied, at 16.5 DID (66% of total consumption) in 2016, 9.0 DID (54%) in 2017 and 12.5 DID (69%) in 2018.

Fig. 20.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 UZB UZB UZB 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Consumption of Reserve agents remained low across all years of data analysed. Unclassified agents constituted 0.9 DID (4%) of consumption in 2016 and 0.3 DID (1%) in 2018.

Table 20.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2016 2017 2018 Access 7.8 (31) 7.0 (42) 5.4 (30) Watch 16.5 (66) 9.0 (54) 12.5 (69) Reserve – 0.01 (0) < 0.01 Unclassified 0.9 (4) 0.6 (4) 0.3 (1) Totalb 25.2 16.6 18.2

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 20.3.

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Table 20.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2016 0.47 2017 0.77 2018 0.43 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The Access-to-Watch index scores reported here are consistent with the higher relative use of Watch agents in all years analysed.

20.4 Consumption at substance level (5th ATC group level)

Table 20.4 and 20.5 (oral agents) and Table 20.6 and 20.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibacterial consumption.

Four agents constituted the DU75% by oral substance, although the composition of the agents varied (Table 20.4). Two or three Watch agents were included in each year analysed.

The fluoroquinolone ciprofloxacin (J01MA02) was the most consumed oral agent in all three years of analysis, although both volumes and relative consumption of ciprofloxacin decreased from 6.4 DID (45% of total consumption) in 2016 to 4.7 DID (34%) in 2018 (Table 20.5). A second fluoroquinolone, levofloxacin (J01MA12), was included in the DU75% in 2018, at 0.9 DID (7%). Together, these two agents comprised 41% of total oral consumption in 2018.

There were increases in volumes and relative consumption of oral azithromycin (J01FA10), from 1.1 DID (7%) in 2016 to 2.9 DID (21%) in 2018.

Table 20.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2016 2017 2018 Access Ampicillin (J01CA01) 3 4 Amoxicillin (J01CA04) 2 2 3 Watch Azithromycin (J01FA10) 4 3 2 Ciprofloxacin (J01MA02) 1 1 1 Levofloxacin (J01MA12) 4

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

135 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 20.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2016 2017 2018 Access Ampicillin (J01CA01) 1.3 (9) 1.1 (11) Amoxicillin (J01CA04) 2.0 (14) 2.3 (23) 2.4 (17) Watch Azithromycin (J01FA10) 1.1 (7) 1.3 (13) 2.9 (21) Ciprofloxacin (J01MA02) 6.4 (45) 2.9 (30) 4.7 (34) Levofloxacin (J01MA12) 0.9 (7) Consumption in DID (% of total consumption) 10.8 (76) 7.5 (77) 10.9 (78) Total consumption of oral agents 14.1 9.7 14.0

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The number of agents constituting the DU75% by parenteral substance ranged from four to five across the years of analysis (Table 20.6).

The Watch agent ceftriaxone (J01DD04) was ranked number one in each year of analysis, constituting 4.1 DID (37%) of consumption of parenteral agents in 2016 and 1.9 DID (46%) in 2018 (Table 20.7).

Table 20.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2016 2017 2018 Access Ampicillin (J01CA01) 5 4 Benzylpenicillin (J01CE01) 2 2 Cefazolin (J01DB04) 4 3 2 Watch Cefotaxime (J01DD01) 3 4 Ceftriaxone (J01DD04) 1 1 1 Levofloxacin (J01MA12) 3 Unclassified Combinations of penicillins (J01CR50) 5

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

136 Uzbekistan

Table 20.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2016 2017 2018 Access Ampicillin (J01CA01) 0.3 (5) 0.3 (7) Benzylpenicillin (J01CE01) 1.4 (13) 1.4 (21) Cefazolin (J01DB04) 1.0 (9) 1.1 (15) 0.7 (16) Watch Cefotaxime (J01DD01) 1.3 (11) 0.7 (11) Ceftriaxone (J01DD04) 4.1 (37) 1.8 (26) 1.9 (46) Levofloxacin (J01MA12) 0.6 (13) Unclassified Combinations of penicillins (J01CR50) 0.8 (7) Consumption in DID (% of total consumption) 8.7 (78) 5.4 (78) 3.5 (81) Total consumption of parenteral agents 11.1 6.9 4.2

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

20.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index increased from 14% in 2016 to 17% in 2018 (Table 20.8).

Table 20.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2016 2017 2018 Oral amoxicillin 2.0 (14) 2.3 (24) 2.4 (17) Oral amoxicillin and phenoxymethylpenicillin 2.0 (14) 2.3 (24) 2.4 (17) Total oral J01 14.0 9.4 14.0

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

20.6 Discussion

The analyses presented here document consumption between 2016 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. With only three years of data, it is difficult to discern reliable trends in volumes and patterns of consumption. The most notable feature of these data, however, is the relatively higher levels of consumption of Watch group antibiotics, which suggests some targets for further investigation, interventions and stewardship activities.

137 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Together, two fluoroquinolones, ciprofloxacin and levofloxacin, represented 41% of oral antibacterial consumption in 2018. In 2018, the European Medicines Agency (EMA) reviewed medicines containing fluoroquinolone and quinolone antibiotics. In addition to recommending suspension of the marketing authorization for medicines containing cinoxacin, flumequine, nalidixic acid and pipemidic acid, EMA’s human medicines committee (CHMP) recommended restricting the use of the remaining fluoroquinolone antibiotics (European Medicines Agency, 2019). The prescribing information for health-care professionals and information for patients should describe the disabling and potentially permanent side-effects and advise patients to stop treatment with a fluoroquinolone antibiotic at the first sign of a side-effect involving muscles, tendons or joints, and the nervous system. The CHMP recommended restrictions on the use of fluoroquinolones, stating they should not be used to: treat infections that might get better without treatment or are not severe (such as throat infections); treat non-bacterial infections, such as non-bacterial (chronic) prostatitis; prevent traveller’s diarrhoea or recurring lower urinary tract infections (urine infections that do not extend beyond the bladder); and treat mild or moderate bacterial infections unless other antibacterial medicines commonly recommended for these infections cannot be used.

Given these EMA recommendations, the high levels of consumption of ciprofloxacin and levofloxacin should be reviewed to ensure consumption is consistent with approved clinical guidelines and treatment protocols.

The WHO EML (WHO, 2019b) suggests that azithromycin is first-choice antibiotic for sexually transmitted infections due to Chlamydia trachomatis, for cholera and gonorrhoea. It is second-choice antibiotic for the treatment of acute invasive diarrhoea and dysentery. The increasing consumption of azithromycin (16% of total oral consumption in 2018) suggests that it is being used beyond these indications. This could be assessed through reviews of prescriptions and existing clinical guidelines.

138 21. KOSOVO7

21.1 Data source and years of data collection

Kosovo7 has provided data for each of the five years of data collection (2014–2018). The main sources were import records provided by the drug agency.

21.2 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. 21.1 and Table 21.1).

Parenteral antibacterials represented 10–11% of total J01 consumption between 2014 and 2018 (Table 21.1).

Beta-lactam penicillins (J01C) had the highest levels of consumption in all years of analysis, at 7.7 DID in 2014 and 9.0 DID in 2018. Over the same period, there were increases in consumption of cephalosporins (J01D), from 3.9 DID in 2014 to 5.4 DID in 2018, macrolides, lincosamides and streptogramins (J01F), from 1.9 DID in 2014 to 2.4 DID in 2018, and quinolones (J01M), from 1.9 DID in 2014 to 2.4 DID in 2018.

Fig. 21.1 Total consumption of J01 antibacterials by pharmacological subgroup

25 Other J01 antibacterials (J01G, J01R, J01X)

20 Quinolone antibacterials (J01M)

Macrolides, lincosamides 15 and streptogramins (J01F)

Sulfonamides and trimethoprim (J01E) 10 Other beta-lactams (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day 5 Beta-lactam penicillins (J01C)

Amphenicols (J01B) 0 Tetracyclines (J01A) KOS1 KOS1 KOS1 KOS1 KOS1 2014 2015 2016 2017 2018

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

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

139 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

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

The data show fluctuations in consumption of J01 antibacterials over time. The CAGR for the period 2014–2018 was 5.1% per year, although the suggested trend towards increased consumption over time was not statistically significant (Table 21.1).

Table 21.1 Total consumption of J01 antibacterials by route of administration and pharmacological subgroup

DDD/1 000 inhabitants per day (%) Class of antibacterial agents 2014 2015 2016 2017 2018 Route of administration Oral J01 15.9 (89) 17.9 (90) 14.5 (89) 15.9 (90) 19.4 (89) Parenteral J01 2.0 (11) 2.1 (10) 1.8 (11) 1.8 (10) 2.4 (11) Totala 17.9 20.0 16.3 17.7 21.8 Class of antibacterial agents Tetracyclines (J01A) 0.9 (5) 0.6 (3) – 0.5 (3) 0.8 (4) Amphenicols (J01B) < 0.1 (0) – – – – Beta-lactam penicillins (J01C) 7.7 (43) 8.0 (40) 7.0 (43) 8.1 (46) 9.0 (41) Other beta-lactams (includes 3.9 (22) 4.4 (22) 4.2 (26) 3.4 (19) 5.4 (25) cephalosporins) (J01D) Sulfonamides and trimethoprim (J01E) 0.8 (5) 1.0 (5) 1.5 (9) 0.4 (3) 0.8 (4) Macrolides, lincosamides and 1.9 (11) 2.8 (14) 1.5 (9) 2.1 (12) 2.4 (11) streptogramins (J01F) Quinolone antibacterials (J01M) 1.9 (11) 2.4 (12) 1.6 (10) 2.4 (14) 2.4 (11) Other J01 antibacterials (J01G, J01R, J01X) 0.7 (4) 0.9 (5) 0.4 (2) 0.7 (4) 0.9 (4) Totala 17.9 20.0 16.3 17.7 21.8 Analysis of trend over time Trendb P-value 0.50 CAGRc 5.1

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Linear regression evaluated using ANOVA test. c Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year.

Beta-lactam penicillin consumption represented 43% of J01 consumption in 2014 and 41% in 2018.

21.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 21.2 and is summarized in Table 21.2.

140 Kosovo 8

Volumes of consumption of Access agents increased over time, from 11.2 DID (62% of total consumption) in 2014 to 12.9 DID (59%) in 2018. The WHO monitoring target of at least 60% of total consumption being Access agents would have been met in 2014, 2016 and 2017.

Volumes of consumption of Watch agents increased from 6.7 DID (37% of total consumption) in 2014 to 8.9 DID (40%) in 2018.

Consumption of Reserve and unclassified agents remained low across all years of data analysed.

Fig. 21.2 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

Reserve 60 Watch group

40 Access

20

Proportion of total consumption (%) 0 KOS1 KOS1 KOS1 KOS1 KOS1 2014 2015 2016 2017 2018 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). 1 All references to Kosovo in this document should be understood to be in the context of United Nations Security Council resolution 1244 (1999).

Table 21.2 Relative consumption of Access, Watch and Reserve classification antibacterials

DDD/1 000 inhabitants per day (%)a Antibiotic group 2014 2015 2016 2017 2018 Access 11.2 (62) 11.6 (58) 9.9 (60) 10.7 (60) 12.9 (59) Watch 6.7 (37) 8.2 (41) 6.5 (39) 6.8 (38) 8.9 (40) Reserve < 0.01 < 0.01 – – < 0.01 Unclassified 0.2 (1) 0.3 (2) 0.2 (1) 0.4 (2) 0.2 (1) Totalb 18.1 20.2 16.6 18.0 22.0

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

The ratio of consumption (DIDs) of Access to Watch agents (Access-to-Watch index) has been reported in published papers examining antibiotic consumption in young children (Hsia et al., 2019) and global consumption patterns (Klein et al., 2020). The results of this analysis are shown in Table 21.3.

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

141 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 21.3 Access-to-Watch index

Year Access-to-Watch index scoreab 2014 1.66 2015 1.42 2016 1.53 2017 1.57 2018 1.46 a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. The Access-to-Watch index score is consistently around 1.5 for each of the five years analysed.

21.4 Consumption at substance level (5th ATC group level)

Table 21.4 and 21.5 (oral agents) and Table 21.6 and 21.7 (parenteral agents) show the ranking and volumes of consumption of antibacterial agents that comprise 75% of total antibiotic consumption.

The number of agents constituting the DU75% by oral substance ranged from seven to 10 across the years of analysis (Table 21.4).

Oral amoxicillin and beta-lactamase inhibitor (ATC code J01CR02) was the most consumed oral agent in 2014, 2017 and 2018, with volumes and proportion of consumption increasing from 3.3 DID (21% of

Table 21.4 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 8 Ampicillin (J01CA01) 5 6 8 Amoxicillin (J01CA04) 2 1 1 2 2 Phenoxymethylpenicillin (J01CE02) 9 5 Amoxicillin and beta-lactamase inhibitor 1 2 2 1 1 (J01CR02) Cefalexin (J01DB01) 7 9 10 5 Sulfamethoxazole and trimethoprim 6 7 3 7 (J01EE01) Watch Cefaclor (J01DC04) 5 8 7 9 Cefixime (J01DD08) 6 5 4 Clarithromycin (J01FA09) 4 4 4 6 Azithromycin (J01FA10) 6 8 Ciprofloxacin (J01MA02) 3 3 4 3 3 Levofloxacin (J01MA12) 7 9

Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

142 Kosovo 9

total oral consumption) in 2014 to 5.2 DID (27%) in 2018 (Table 21.4 and 21.5). Amoxicillin (J01CA04) was the most consumed oral agent in 2015 and 2016. The consumption of these two beta-lactam penicillins together was 6.3 DID (39%) in 2014 and 7.9 DID (41%) in 2018.

Three to five Watch agents appeared in the DU75% for each of the years analysed. There were increases in consumption of two fluoroquinolones, ciprofloxacin (J01MA02) and levofloxacin (J01MA12) combined, from 1.3 DID (8%) to 2.2 DID (11%) between 2014 and 2018.

Table 21.5 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (oral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Doxycycline (J01AA02) 0.8 (5) Ampicillin (J01CA01) 1.1 (6) 0.8 (6) 0.6 (4) Amoxicillin (J01CA04) 3.0 (18) 4.4 (25) 3.9 (27) 2.6 (16) 2.7 (14) Phenoxymethylpenicillin (J01CE02) 0.7 (4) 0.7 (4) Amoxicillin and beta-lactamase inhibitor 3.3 (21) 1.9 (10) 1.9 (13) 3.9 (24) 5.2 (27) (J01CR02) Cefalexin (J01DB01) 0.8 (5) 0.9 (5) 0.5 (3) 1.1 (6) Sulfamethoxazole and trimethoprim 0.8 (5) 1.0 (5) 1.5 (10) 0.8 (4) (J01EE01) Watch Cefaclor (J01DC04) 0.9 (6) 0.9 (5) 0.8 (5) 0.6 (3) Cefixime (J01DD08) 1.0 (5) 1.0 (7) 1.3 (7) Clarithromycin (J01FA09) 1.1 (7) 1.4 (8) 1.1 (7) 1.0 (5) Azithromycin (J01FA10) 0.6 (4) 0.8 (4) Ciprofloxacin (J01MA02) 1.3 (8) 1.5 (8) 1.3 (9) 1.3 (8) 1.4 (7) Levofloxacin (J01MA12) 0.6 (4) 0.8 (4) Consumption in DID 12.7 (79) 14.1 (78) 11.3 (76) 12.6 (78) 15.2 (78) (% of total consumption) Total consumption of oral agents 16.2 18.1 14.8 16.2 19.6

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. Agent not included in DU75% for this year. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Two agents, gentamicin (J01GB03) and ceftriaxone (J01DD04), constituted the DU75% by parenteral substance across the years of analysis (Table 21.6).

The Watch agent ceftriaxone (J01DD04) was ranked number one in each year of analysis, constituting 60% of consumption of parenteral agents in 2014 and 2018 (Table 21.7).

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

143 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 21.6 Ranking of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

Ranking of agents in the DU75%b Agenta (ATC) 2014 2015 2016 2017 2018 Access Gentamicin (J01GB03) 2 2 2 2 2 Watch Ceftriaxone (J01DD04) 1 1 1 1 1 a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01). b Ranking of agents in the DU75%, such as 1 = most often consumed antimicrobial.

Table 21.7 Volumes (percentages) of antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use)

DDD/1 000 inhabitants per day (%) Agenta (ATC) 2014 2015 2016 2017 2018 Access Gentamicin (J01GB03) 0.4 (22) 0.6 (29) 0.3 (15) 0.4 (22) 0.5 (22) Watch Ceftriaxone (J01DD04) 1.2 (60) 1.0 (48) 1.3 (75) 1.0 (55) 1.5 (60) Consumption in DID 1.6 (82) 1.6 (77) 1.6 (89) 1.4 (78) 2.0 (82) (% of total consumption) Total consumption of parenteral agents 2.0 2.1 1.8 1.8 2.4

DDD: daily defined dose. DID: defined daily doses per 1000 inhabitants per day. a Agents included for this calculation are those in J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

21.5 Other monitoring indicators

The amoxicillin index (the DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) has been proposed as a useful indicator of the relative use of narrow-spectrum antibiotics that are common effective treatments for respiratory tract infections, the most common indication for antibiotic prescriptions globally (Klein et al., 2020).

The amoxicillin index decreased from 23% in 2014 to 17% in 2018 (Table 21.8).

Table 21.8 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

DDD/1 000 inhabitants per day (% of total oral J01)a Components of amoxicillin index 2014 2015 2016 2017 2018 Oral amoxicillin 3.0 (19) 4.4 (25) 3.9 (27) 2.6 (16) 2.7 (14) Oral amoxicillin and 3.6 (23) 4.6 (26) 4.2 (29) 3.3 (21) 3.2 (17) phenoxymethylpenicillin Total oral J01 15.9 17.9 14.5 15.9 19.4

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

144 Kosovo 10

21.6 Discussion

The analyses presented here document consumption between 2014 and 2018, applying the most recent substantive changes to DDD values in 2019 and the 2019 AWaRe classification of antibiotics. The five years of data examined provide a platform for future years of data to enable assessment of trends over time.

While there were increases in total consumption of J01 antibacterials over time, the patterns of relative consumption were reasonably stable. Increases in volumes of consumption of several Watch agents, namely the oral fluoroquinolones ciprofloxacin and levofloxacin and parenteral ceftriaxone, suggest some targets for further investigation, interventions and stewardship activities.

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

145 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

22. COMPARISON OF 2018 ANTIMICROBIAL MEDICINES CONSUMPTION ACROSS THE AMC NETWORK

22.1 Background

The previous chapters have reviewed data for the years 2014–2018 for each of the AMC Network countries/areas separately, examining trends for several key metrics of antimicrobial medicines consumption. In this chapter, comparisons are conducted across 17 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 2018 data.

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

22.2.1 Total consumption

Total consumption of antibacterials for systemic use (ATC class J01) is examined by route of administration (oral and parenteral formulations) (Fig. 22.1 and Table 22.1).

Fig. 22.1 Total consumption of J01 antibacterials by route of administration

35

30 Parenteral 25 antibacterials 20 Oral antibacterials 15

10

DDD/1000 inhabitants per day 5

0

TUR MNE SRB GEO BIH TJK ALB BLR KAZ UZB RUS MDA ARM UKR KGZ SWI AZE

DDD: daily defined dose.

146 Comparison of 2018 antimicrobial medicines consumption across the AMC Network

These data illustrate the large variability in reported consumption of J01 antibacterials across the AMC Network – ranging from 30.9 DID (Turkey) to 8.9 DID (Azerbaijan). The median consumption was 18.8 DID. The arithmetic and population-weighted mean totals of J01 consumption in 2018 were 17.5 and 18.5 DID, respectively.

22.2.2 Route of administration

The extent of consumption of parenteral formulations varied widely, from 3% in Turkey up to 40% in Kyrgyzstan (Table 22.1).

Table 22.1 Total consumption of J01 antibacterials by route of administration, 2018

a Route of DDD/1 000 inhabitants per day (% of total ) administration TUR MNE SRB GEO BIH TJK ALB BLR KAZ UZB RUS MDA ARM UKR KGZ SWI AZE 30.0 24.8 21.2 14.3 18.3 13.9 17.5 16.7 15.3 14.0 12.7 12.3 10.9 9.6 6.7 9.9 6.9 Oral J01 (97) (92) (93) (68) (95) (73) (92) (88) (81) (77) (86) (87) (90) (82) (60) (94) (78) 0.9 2.3 1.5 6.6 1.0 5.1 1.5 2.2 3.5 4.2 2.0 1.8 1.2 2.1 4.5 0.7 2.0 Parenteral J01 (3) (8) (7) (32) (5) (27) (8) (12) (19) (23) (14) (13) (10) (18) (40) (6) (22) Total 30.9 27.0 22.7 20.8 19.3 19.0 19.0 18.9 18.8 18.2 14.7 14.2 12.1 11.7 11.2 10.5 8.9

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

22.2.3 Pharmacological subgroups

Total consumption of antibacterials for systemic use (ATC class J01) is examined by pharmacological subgroup (Fig. 22.2 and Table 22.2).

Fig. 22.2 Total consumption of J01 antibacterials by pharmacological subgroup, 2018

35 Other J01 antibacterials (J01G, J01R, J01X) 30 Quinolone antibacterials (J01M) 25 Macrolides, lincosamides and streptogramins (J01F) 20 Sulfonamides and 15 trimethoprim (J01E) Other beta-lactams 10 (includes cephalosporins) (J01D)

DDD/1000 inhabitants per day Beta-lactam penicillins (J01C) 5 Amphenicols (J01B)

0 Tetracyclines (J01A)

BIH TUR MNE SRB GEO TJK ALB BLR KAZ UZB RUS MDA ARM UKR KGZ SWI

DDD: daily defined dose.

147 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

There is considerable variation in the extent of consumption of the different pharmacological subgroups across the AMC Network. In 2018, consumption of beta-lactam penicillins (J01C) ranged from 14% of total J01 consumption in Kyrgyzstan and Tajikistan to 40% of J01 consumption in Switzerland and Turkey (Table 22.2). Cephalosporin (J01D) consumption varied from 8% of J01 consumption in Azerbaijan to 35% in Georgia and Kyrgyzstan. Quinolone (J01M) consumption varied from 10% in Azerbaijan, Georgia and Turkey to 37% in Uzbekistan.

Table 22.2 Total consumption of J01 antibacterials by pharmacological subgroup, 2018

Class of DDD/1 000 inhabitants per day (% of totala) antibacterial agents TUR MNE SRB GEO BIH TJK ALB BLR KAZ UZB RUS MDA ARM UKR KGZ SWI AZE Tetracyclines 1.3 1.3 1.7 1.1 1.2 0.7 2.0 2.3 1.3 0.4 1.3 0.6 1.6 0.8 0.6 1.4 1.5 (J01A) (4) (5) (7) (5) (6) (4) (11) (12) (7) (2) (9) (4) (14) (7) (5) (13) (17) Amphenicols 0.6 0.1 < 0.1 0.1 0.6 0.1 0.1 < 0.1 0.3 0.2 0.1 < 0.1 0.1 – – – – (J01B) (3) (1) (0) (0) (3) (1) (1) (2) (2) (1) (1) Beta-lactam 12.4 9.9 6.8 4.3 7.6 2.7 4.8 7.1 4.5 3.9 4.1 4.2 3.4 2.1 1.6 4.2 3.0 penicillins (40) (37) (30) (21) (39) (14) (25) (38) (24) (21) (28) (30) (28) (18) (14) (40) (33) (J01C) Other beta- lactams 8.0 5.4 3.6 7.2 3.0 3.4 6.0 2.2 3.1 3.2 1.8 3.0 1.1 2.1 3.9 0.9 0.7 (includes (26) (20) (16) (35) (15) (18) (31) (12) (16) (18) (12) (21) (9) (18) (35) (9) (8) cephalosporins) (J01D) Sulfonamides and 0.3 0.8 0.7 2.2 1.8 2.5 0.3 0.2 0.7 0.5 1.1 1.4 0.5 < 0.1 0.6 0.6 – trimethoprim (1) (3) (3) (11) (10) (13) (2) (1) (4) (3) (8) (11) (4) (5) (7) (J01E) Macrolides, lincosamides 4.4 4.8 5.3 1.9 2.4 1.4 2.2 2.9 2.1 3.3 2.6 2.0 1.7 2.7 1.4 1.4 1.4 and (14) (18) (23) (9) (12) (8) (12) (16) (11) (18) (18) (14) (14) (23) (13) (14) (16) streptogramins (J01F) Quinolone 3.0 3.3 4.0 2.0 2.5 6.1 3.5 2.0 4.8 6.7 2.9 2.0 1.7 1.8 1.8 1.4 0.9 antibacterials (10) (12) (18) (10) (13) (32) (18) (11) (26) (37) (20) (14) (15) (15) (17) (13) (10) (J01M) Other J01 antibacterials 1.5 1.5 0.7 1.6 0.8 2.1 0.2 2.0 1.8 0.6 1.4 1.2 0.9 1.6 1.7 0.6 0.8 (J01G, J01R, (5) (6) (3) (8) (4) (11) (1) (11) (10) (3) (10) (9) (8) (14) (15) (6) (10) J01X) Total 30.9 27.0 22.7 20.8 19.3 19.0 19.0 18.9 18.8 18.2 14.7 14.2 12.1 11.7 11.2 10.5 8.9

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

22.2.4 Trends, 2014–2018

Table 22.3 shows the trends in total consumption of antibacterials for systemic use (ATC J01) for the years 2014–2018. The CAGR of total antibiotic consumption was calculated for each participating country. This reflects the average annual change as a proportion (%) of the consumption in the starting year. The CAGR was estimated for countries that had five years of data available. Linear regression was used for presenting trends in consumption and evaluated using ANOVA tests. P values ≤ 0.05 were considered statistically significant.

There was only one statistically significant increase or decrease in total consumption over the study period in the WHO Europe AMC Network countries, namely in Bosnia and Herzegovina (+6.0%).

148 Comparison of 2018 antimicrobial medicines consumption across the AMC Network

Table 22.3 Trends in consumption of J01 antibacterials, 2014–2018

Total consumption of J01 antibacterials Country in DDD/1 000 inhabitants per day CAGRa Trend line, 2014–2018 Trendb 2014 2015 2016 2017 2018 ALB 19.6 16.3 16.5 18.7 19.0 –0.7

ARM 12.7 9.4 9.4 12.0 12.1 –1.3

AZE 6.4 7.4 9.5 7.8 8.9 8.5

BIH 15.3 16.3 18.0 17.4 19.3 6.0 ↑ BLR 18.3 17.1 16.9 20.0 18.9 0.8

GEO 17.9 24.2 23.6 25.1 20.8 3.8

KAZ – 21.8 19.7 17.9 18.8 – –

KGZ – 16.7 21.3 16.9 11.2 – –

MDA 16.7 12.9 16.7 17.1 14.2 –4.1

MNE 26.7 29.0 28.9 27.1 27.0 0.3

RUS 13.4 14.1 14.9 15.1 14.7 2.3

SRB 25.3 31.0 26.2 21.3 22.7 –2.6

SWI – – – 10.4 10.6 – –

TJK 31.0 21.7 20.9 16.3 19.0 –11.5

TUR 34.7 35.5 35.3 31.0 30.9 –2.9

UKR 9.5 12.1 8.3 10.7 11.7 5.3

UZB – – 25.1 16.3 18.2 – – a Compound annual growth rate (CAGR) shows the average annual change as a proportion (%) of the consumption in the starting year. The CAGR was only calculated where there was five years of data (2014–2018) available for the country.b Linear regression analysis. ↑↓ indicate statistically significant change.

22.3 Relative consumption of Access, Watch and Reserve groups of antibiotics

Analyses based on the 2019 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 Access, Watch and Reserve group antibiotics is shown in Fig. 22.3 and is summarized in Table 22.4.

Consumption of Access agents represented between 30% (Uzbekistan) and 66% (Bosnia and Herzegovina) of total antibacterial consumption in 2018 (Table 22.4). In 10 of 17 countries (59%), Access agents comprised ≥ 50% of total antibacterial consumption in 2018.

Watch group agents represented between 34% (Bosnia and Herzegovina) and 69% (Uzbekistan) of total consumption. Consumption of Reserve agents remained low across all years of data analysed. Unclassified agents constituted 7% of consumption in Montenegro and Ukraine.

The population-weighted estimates across the WHO Europe AMC Network were Access agents 46.9%, Watch agents 49.5%, Reserve agents 0.1% and unclassified agents 3.5%.

149 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Fig. 22.3 Relative consumption by WHO AWaRe classification as a proportion of total consumptiona

100

80 Unclassified

60 Reserve Watch group

40 Access

Proportion consumption 20

0

BIH ARM SWI AZE BLR MNE MDA SRB KAZ TUR RUS GEO TJK ALB UKR KGZ UZB a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

Table 22.4 Relative consumption of Access, Watch and Reserve classification antibacterials

Group of Consumption according to 2019 WHO AWaRe classificationa antibacterial agents BIH ARM SWI AZE BLR MNE MDA SRB KAZ TUR RUS GEO TJK ALB UKR KGZ UZB 12.9 7.8 6.7 5.8 11.2 15.8 7.4 11.8 9.9 16.0 7.3 9.1 8.2 7.5 4.3 3.9 5.4 Access (66) (63) (61) (61) (57) (57) (51) (51) (51) (50) (47) (43) (42) (39) (36) (33) (30) 6.6 4.4 4.2 3.4 7.2 9.8 6.7 10.6 8.8 15.1 7.4 11.4 10.8 11.4 6.7 7.2 12.5 Watch (34) (36) (38) (36) (37) (36) (46) (46) (45) (47) (48) (54) (56) (60) (56) (61) (69) 0.1 Reserve < 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 < 0.1 (1) 0.1 0.2 0.0 0.3 1.0 2.0 0.4 0.7 0.8 0.7 0.7 0.5 0.4 0.1 0.9 0.6 0.3 Unclassified (1) (2) (0) (4) (5) (7) (3) (3) (4) (2) (5) (3) (2) (0) (7) (5) (1) Total 19.6 12.4 10.9 9.6 19.5 27.6 14.5 23.2 19.5 31.8 15.5 21.0 19.4 19.0 11.8 11.8 18.2 a Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

22.3.1 WHO global monitoring indicator

In conjunction with the expansion of the list of antibiotics included in the AWaRe classification in 2019, WHO has proposed a global monitoring indicator that by 2023, 60% of all antibiotics consumed should come from Access, the group of antibiotics at lowest risk of resistance (WHO, 2020).

Only four countries, Azerbaijan, Armenia, Bosnia and Herzegovina and Switzerland, would have met the WHO target of at least 60% of total consumption being Access agents in 2018.

Trends in the relative consumption of Access agents between 2014 and 2018 are shown in Table 22.5. Only one country in the WHO Europe AMC Network would have met the global monitoring indicator in each of the five years examined – Bosnia and Herzegovina.

150 Comparison of 2018 antimicrobial medicines consumption across the AMC Network

Table 22.5 Countries achieving target of 60% of total consumption is Access agents, 2014–2018 (highlighted)

Access agents as proportion (%) of total consumptionb Countrya 2014 2015 2016 2017 2018 ALB 61 48 51 44 39 ARM 66 66 57 66 63 AZE 54 59 49 55 61 BIH 69 69 70 68 66 BLR 55 57 53 59 57 GEO 32 46 62 63 43 KAZ – 61 58 54 51 KGZ – 72 56 50 33 KOS 62 58 60 60 59 MDA 46 52 43 46 51 MKD 53 49 50 48 47 MNE 61 56 58 59 57 RUS 49 48 49 49 47 SRB 68 64 63 60 51 SWI – – – 59 61 TJK 65 58 61 46 42 TUR 44 45 46 47 50 UKR 40 33 44 37 36 UZB – – 31 42 30 a Country estimates are rounded up. b Total consumption of antibiotics for this calculation includes J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

22.3.2 Unclassified agents

In 2019, the AWaRe classification was expanded beyond the antibiotics listed on the WHO EML and EMLc (WHO, 2019b). As a result, 180 antibiotics used globally were assigned to either Access (n = 48), Watch (n = 110) and Reserve (n = 22) groups (see Annex 1). Several agents that are consumed in the AMC Network nevertheless are yet to be classified. Table 22.6 summarizes the unclassified agents and their consumption volumes in 2018.

The most widely consumed unclassified agents in the AMC Network in 2018 were combinations of benzylpenicillin and procaine penicillin (J01CE30), consumed in 12 of the 17 countries, pipemidic acid (J01MB04, 11 countries), nitroxoline (J01XX07, 11 countries) and furazidin (J01XE03, 10 countries). Pipemidic acid is a quinolone antibacterial agent used in the treatment of urinary tract infections. Nitroxoline is a urinary antibacterial agent active against susceptible gram-positive and gram-negative organisms. Furazidin is a nitrofuran derivative anti-infective agent used for urinary tract infections.

151 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK UZB UKR TUR TJK SWI SRB RUS MNE MDA KGZ DDD/1 000 inhabitants/day DDD/1 000 inhabitants/day AZE BIH BLR GEO KAZ ARM – 0.02 0.01 0.03 0.03 0.04 – – 0.01 0.06 0.01 0.07 – 0.01 0.01 0.01 – – – – – – – – – – 0.72 – – 0.03 – 0.31 – – – – – – 0.01 < 0.01 – – 0.01 – – – – – – 0.02 – – – 0.04 – – – – – – – < 0.01 – – – – < 0.01 – – – 0.04 – – – – – – – 0.12 – – – – 0.18 – – – – – – – – – – – – 0.03 – – – – – – 0.09 0.02 0.09 0.01 0.06 0.09 – 0.16 1.16 0.05 0.54 – – – 0.04 – – < 0.01 – – – – – 0.02 – – < 0.01 – – – – – 0.02 – – – – – – 0.01 – – – – – – – – – – – – – – 0.09 – 0.01 0.09 – – 0.13 – – 0.03 – < 0.01 0.02 – – – – 0.07 0.23 0.03 0.02 0.12 – – – – 0.04 0.01 0.04 0.02 – – – – – – < 0.01 0.01 – – < 0.01 – < 0.01 – 0.01 0.02 – – – – – – – – – – – – – – – 0.38 – – – 0.03 0.2 – 0.13 0.19 0.16 0.26 – 0.02 0.17 0.08 – 0.21 – 0.2 – 0.09 0.08 0.02 – 0.7 0.03 0.35 0.07 – – 0.22 – – 0.12 – 0.26 – ALB a Agent Benzathine phenoxymethyl-penicillin Cefoperazone and beta- Cefoperazone lactamase inhibitor Azithromycin, fluconazole Azithromycin, and secnidazole Ciprofloxacin and Ciprofloxacin metronidazole Ciprofloxacin and tinidazole Ciprofloxacin Ciprofloxacin and Ciprofloxacin ornidazole ATC J01CE10 J01CR50 Combinations of penicillins – – 0.02 – – – – – – – < 0.01 – – – – – – J01CE30 Combinations J01DD62 J01EB03 Sulfadimidine J01ED01 Sulfadimethoxine J01FA11 Miocamycin J01MB04 Pipemidic acid J01RA07 J01RA09 and ornidazole Ofloxacin – – – – – – – 0.08 0.06 – 0.01 – – 0.03 – 0.12 0.16 J01RA10 J01RA11 J01RA12 J01RA13 and tinidazole Norfloxacin – – – – – – – 0.02 – – – – – – – 0.04 J01XD03 Ornidazole J01XE03 Furazidin J01XX05 Methenamine J01XX07 Nitroxoline Combinations of benzylpenicillin and procaine penicillin. penicillin. and procaine Combinations of benzylpenicillin Table 22.6 Unclassified agents consumed in AMC Network, 2018 22.6 Unclassified agents consumed in AMC Network, Table defined dose. DDD: daily a

152 Comparison of 2018 antimicrobial medicines consumption across the AMC Network

Several unclassified combinations of antibacterials were consumed in AMC Network countries in 2018, including ciprofloxacin and ornidazole (J01RA12, nine countries), ciprofloxacin and tinidazole (J01RA11, seven countries), ofloxacin and ornidazole (J01RA09, six countries), azithromycin, fluconazole and secnidazole (J01RA07, four countries), norfloxacin and tinidazole (two countries), and ciprofloxacin and metronidazole (J01RA10, one country). Notably, these combination agents are included in WHO’s list of “not recommended antibiotics” (Annex 1). The “not recommended” agents are fixed-dose combinations of multiple broad-spectrum antibiotics whose use is neither evidence-based nor recommended in high-quality international guidelines. WHO therefore does not recommend their use in clinical practice. These combination products are potential targets for further investigation and local interventions to discourage their use in clinical practice.

In 2018, the EMA conducted a review of medicines containing fluoroquinolone and quinolone antibiotics, including cinoxacin, ciprofloxacin, flumequine, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, pefloxacin, pipemidic acid, prulifloxacin and rufloxacin (European Medicines Agency, 2019). EMA’s human medicines committee (CHMP) endorsed the recommendations of EMA’s safety committee and concluded that the marketing authorization of medicines containing cinoxacin, flumequine, nalidixic acid and pipemidic acid should be suspended. A legally binding decision to suspend marketing authorization for pipedimic acid applicable in all EU countries was issued by the European Commission in March 2019. Pipemidic acid has been withdrawn from the market in several AMC Network countries, including Montenegro and Serbia.

22.3.3 Access-to-Watch index

This indicator has been used in several published papers (Hsia et al., 2019; Klein et al., 2020). The measure is calculated as the ratio of DDDs of Access medicines to DDDs of Watch medicines. The results of this analysis are shown in Table 22.7.

Table 22.7 Access-to-Watch index

Country BIH ARM SWI AZE BLR MNE MDA SRB KAZ TUR RUS GEO TJK ALB UKR KGZ UZB Access-to- Watch index 1.96 1.76 1.59 1.71 1.57 1.61 1.12 1.11 1.12 1.06 0.99 0.80 0.76 0.66 0.64 0.54 0.43 scoreab a Ratio of the consumption of Access to Watch antibiotics. b Antibiotics for this calculation include J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifabutin (J04AB04), metronidazole (P01AB01).

A ratio of 1.5 would be consistent with a distribution of Access to Watch agents of 60% to 40%. Only six countries had ratios ≥ 1.5. Lower ratios (< 1.5) reflect higher relative consumption of Watch agents.

22.4 Drug utilization 75% (DU75%)

The DU75% represents the antibacterial substances accounting for 75% of the consumption measured in DDD (Zarb et al., 2011). The DU75% is calculated for oral and parenteral formulations separately. Results are shown as the ranking of consumption at substance level (5th ATC group level). In addition to reporting the numbers of antibacterial agents in the DU75% segment, the agents are classified according to the AWaRe classification. This facilitates identification of restricted and special use antibacterials that may be widely consumed and be targets for stewardship activities.

153 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 22.8 (oral agents) and Table 22.9 (parenteral agents) show the ranking of consumption of antibacterial agents that comprise the DU75%.

In 2018, the number of agents constituting the DU75% by oral substance ranged from four to 10 across the AMC Network countries (Table 22.8). There were 10 agents in the WHO/AMC population- weighted network DU75%.

Oral amoxicillin (J01CA04) was included in the DU75% in 16 of 17 Network countries and ranked second in the WHO/AMC population-weighted network DU75%. Oral amoxicillin and beta-lactamase inhibitor (ATC code J01CR02) appeared in the DU75% for 15 countries and was the most consumed oral agent across the Network.

Two to five Watch agents appeared in the DU75% for each of the AMC Network countries and there were five Watch agents in the population-weighted Network estimate. The most consumed oral Watch agents across the Network were azithromycin (J01FA10), which was included in the DU75% for 15 countries, ciprofloxacin (J01MA02, 14 countries) and levofloxacin (J01MA12, 10 countries).

Two unclassified agents, furazidin (J01XE03) and nitroxoline (J01XX07), were each included in the DU75% for one Network country. These agents were not included in the population-weighted WHO/AMC DU75%.

In 2018, the number of agents constituting the DU75% by parenteral substance ranged from one to eight across the AMC Network countries (Table 22.8). There were five agents in the WHO/AMC population-weighted Network DU75%.

The Watch agent ceftriaxone (J01DD04) was ranked number one in 14 countries and ranked second in the remaining three countries.

22.5 Other monitoring indicators

European Surveillance of Antimicrobial Consumption quality indicators for antibiotic consumption in the community include a measure of the relative use of narrow- and broad-spectrum antibiotics within J01 antibiotics (ECDC, 2020b). The indicator is calculated as the ratio between the consumption of broad-spectrum antibiotics (J01CR, J01DC, J01DD and J01F (without erythromycin)) to narrow- spectrum penicillins, cephalosporins and macrolides (J01CE, J01DB and J01FA01).

Narrow-spectrum phenoxymethylpenicillin is the antibiotic of choice for respiratory tract infections in Scandinavian countries, while broader-spectrum amoxicillin is used in most other European countries (Skarpeid & Høye, 2018). Similarly, not all AMC Network countries have marketing authorization for oral phenoxymethylpenicillin.

An alternative measure based on amoxicillin and phenoxymethylpenicillin consumption has been applied to global estimates of antibacterial consumption (Klein et al., 2020). The amoxicillin index (DIDs of amoxicillin and phenoxymethylpenicillin divided by the total DIDs) is applied in the analyses reported here. This metric provides a measure of the consumption of first-line and relatively narrower- spectrum penicillin antibiotics to that of broader-spectrum penicillins, cephalosporins and macrolides. The volumes of consumption in DID and percentage of total consumption of J01 antibacterials that is amoxicillin and phenoxymethylpenicillin are shown in Table 22.10.

154 Comparison of 2018 antimicrobial medicines consumption across the AMC Network c 6 9 7 3 4 8 5 1 2 WHO/AMC b 1 1 1 1 1 2 9 7 3 2 1 1 8 3 2 9 10 13 15 countries Number of 5 4 10 1 2 15 8 10 5 2 7 3 9 6 4 1 2 TUR UKR UZB 4 6 5 TJK 6 7 2 SWI 8 5 5 4 1 4 6 1 14 8 4 6 2 RUS SRB 3 6 7 4 5 5 6 7 4 7 9 MDA 6 3 MNE 9 6 8 10 KGZ WHO/AMC population-weighted mean for countries of the WHO Europe AMC Network. WHO Europe countries of the mean for WHO/AMC population-weighted c 2 1 5 7 9 8 5 3 7 1 2 1 1 3 3 7 3 3 16 7 4 1 2 6 10 2 7 5 6 3 6 7 9 8 6 4 2 7 4 7 10 3 2 5 3 5 6 4 7 Numbers of countries that have this agent in DU75%. this agent in DU75%. of countries that have Numbers b ear. 6 1531214821331 ALB ARM AZE BIH BLR GEO KAZ a Agent not included in DU75% for this y Agent not included in DU75% for Cefdinir (J01DD15) Rifampicin (J04AB02) Furazidin (J01XE03) Furazidin (J01XX07) Nitroxoline Cefaclor (J01DC04) Cefuroxime (J01DC02)Cefuroxime 3 Erythromycin (J01FA01) Erythromycin Cefixime (J01DD08) Clarithromycin (J01FA09) Clarithromycin Levofloxacin (J01MA12)Levofloxacin 8 Ciprofloxacin (J01MA02)Ciprofloxacin 4 6 Ampicillin (J01CA01) Ampicillin (J01EA01) Trimethoprim (J01FA10)Azithromycin 7 4 5 8 4 3 5 3 4 8 2 2 8 Metronidazole (P01AB01) Metronidazole (J01AA07)Tetracycline 5 Cefalexin (J01DB01) Cefalexin Sulfamethoxazole/tri- methoprim (J01EE01) Nitrofurantoin (J01XE01) Nitrofurantoin Doxycycline (J01AA02) Doxycycline Amoxicillin/enzyme Amoxicillin/enzyme inhibitor (J01CR02) Antibacterial agent (ATC Antibacterial agent (ATC code) (J01CA04)Amoxicillin 2 1 1 2 1

Agents included in this analysis: J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifamycin rifampicin (J04AB02), rifamixin (A07AA11), colistin (A07AA10), (A07AA09), vancomycin (A07AA08), kanamycin B (A07AA05), polymyxin (A07AA04), streptomycin (A07AA01), neomycin J01, Agents included in this analysis: Table 22.8 Antibacterials at substance level (5th ATC group level) that compose DU75% (oral use), 2018 use), that compose DU75% (oral level) group (5th ATC 22.8 Antibacterials at substance level Table rifabutin (J04AB04), metronidazole (P01AB01). (P01AB01). metronidazole rifabutin (J04AB04), a

155 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK c 1 3 5 2 4 WHO/AMC a 1 1 1 1 1 1 1 3 4 1 1 3 2 2 1 8 4 4 1 Number of countries 4 3 2 8 3 3 5 2 4 Combinations of benzylpenicillin and procaine and procaine Combinations of benzylpenicillin d 8 3 7 4 8 5 2 6 TUR UKR UZB 2 3 TJK 4 1 5 6 7 SWI 3 7 3 2 5 3 6 RUS SRB 6 4 5 2 7 2 4 3 5 4 MDA 2 3 MNE KGZ WHO/AMC population-weighted mean for countries of the WHO Europe AMC Network. AMC Network. WHO Europe countries of the mean for WHO/AMC population-weighted c 2 3 6 5 3 2 4 4 3 1 1 3 4 3 2 Numbers of countries that have this agent in DU75%. this agent in DU75%. of countries that have Numbers b ear. 3 ALB ARM AZE BIH BLR GEO KAZ d a Agent not included in DU75% for this y Agent not included in DU75% for Teicoplanin (J01XA02) Teicoplanin (J04AB03) Rifamycin Combinations (J01CE30) Meropenem (J01DH02) Meropenem (J01GA01) Streptomycin (J01MA02) Ciprofloxacin Cefepime (J01DE01) Cefepime Piperacillin/enzyme Piperacillin/enzyme inhibitor (J01CR05) Levofloxacin (J01MA12) Levofloxacin (J01DC02) Cefuroxime (J01DD01) Cefotaxime Amoxicillin (J01CA04) Amoxicillin (J01DD04)Ceftriaxone 1 1 2 2 1 1 1 1 1 1 1 1 2 1 1 1 1 17 Ampicillin (J01CA01) Ampicillin Amoxicillin/enzyme inhibitor (J01CR02) Ampicillin/enzyme inhibitor (J01CR01) Clindamycin (J01FF01) Clindamycin (J01CF05) Flucloxacillin Cefazolin (J01DB04) 2 Gentamicin (J01GB03) (J01GB06) Amikacin Benzylpenicillin (J01CE01) Benzylpenicillin Antibacterial agent (ATC Antibacterial agent (ATC code) (J01XD01) Metronidazole Agents included in this analysis: J01, neomycin (A07AA01), streptomycin (A07AA04), polymyxin B (A07AA05), kanamycin (A07AA08), vancomycin (A07AA09), colistin (A07AA10), rifamixin (A07AA11), rifampicin (J04AB02), rifamycin (J04AB03), rifamycin rifampicin (J04AB02), rifamixin (A07AA11), colistin (A07AA10), (A07AA09), vancomycin (A07AA08), kanamycin B (A07AA05), polymyxin (A07AA04), streptomycin (A07AA01), neomycin J01, Agents included in this analysis: rifabutin (J04AB04), metronidazole (P01AB01). (P01AB01). metronidazole rifabutin (J04AB04), Table 22.9 Antibacterials at substance level (5th ATC group level) that compose DU75% (parenteral use), 2018 use), that compose DU75% (parenteral level) group (5th ATC 22.9 Antibacterials at substance level Table a penicillin. penicillin.

156 Comparison of 2018 antimicrobial medicines consumption across the AMC Network

Table 22.10 Consumption of oral amoxicillin and phenoxymethylpenicillin of total oral J01 consumption

Group of DDD/1 000 inhabitants per day (% of total oral J01a) antibacterial agents ALB ARM AZE BIH BLR GEO KAZ KGZ MDA MNE RUS SRB SWI TJK TUR UKR UZB 2.1 2.1 1.0 3.1 4.2 0.2 1.8 0.5 1.3 6.0 2.3 4.0 1.0 1.3 0.9 0.9 2.4 Oral amoxicillin (12) (19) (14) (17) (25) (1) (12) (7) (11) (24) (18) (19) (11) (9) (3) (10) (17) Oral amoxicillin + 2.1 2.1 1.0 3.6 4.2 0.2 1.8 0.5 1.3 6.0 2.3 4.0 1.1 1.3 1.1 0.9 2.4 phenoxymethyl­ (12) (19) (14) (20) (25) (1) (12) (7) (11) (24) (18) (19) (11) (9) (4) (10) (17) penicillin Total oral J01 17.5 10.9 6.9 18.3 16.7 14.3 15.3 6.7 12.3 24.8 12.7 21.2 9.9 13.9 30.0 9.6 14.0

DDD: daily defined dose. a Total amounts and percentages may vary slightly owing to rounding.

The amoxicillin index ranges from 1% in Georgia to 25% in Belarus. For almost all AMC Network countries there is little or no consumption of phenoxymethypenicillin reported in 2018.

22.6 Comparisons with ESAC-Net

ESAC-Net analyses apply similar methods to those used in the WHO Europe AMC Network. Results for individual AMC Network countries are shown along with population-weighted estimates for ESAC- Net (EU/EEA) and the WHO Europe AMC Network in Table 22.11.

The population-weighted means for total consumption of J01 antibacterials in 2018 were similar in the two networks – 20.0 DID for ESAC-Net compared to 18.5 DID for the WHO Europe AMC Network (ECDC, 2019). Large intercountry variations nevertheless were seen among both the 30 ESAC-Net countries (9.7 to 34.1 DID) and the 17 WHO Europe AMC Network countries (8.9 to 30.9 DID).

The population-weighted consumption of beta-lactam penicillins (ATC J01C) differed in the two networks – 8.7 versus 5.7 DDD per 1000 inhabitants per day and representing 44% and 31% of total consumption of antibacterials for systemic use for ESAC-Net and WHO Europe AMC Network countries, respectively.

In ESAC-Net countries, there was a greater consumption of tetracyclines (J01A: population-weighted consumption 2.2 versus 1.2 DDD per 1000 inhabitants per day), less consumption of other beta-lactam penicillins, predominantly cephalosporins (J01D: 2.3 versus 3.5 DDD per 1000 inhabitants per day) and less consumption of quinolone antibiotics (J01M: 1.7 versus 3.1 DDD per 1000 inhabitants per day) than in WHO Europe AMC Network countries. There was no or very little reported consumption of amphenicols (J01B) in ESAC-Net countries and low levels of consumption in the WHO Europe AMC Network: Armenia (0.3 DID, 2.2% total consumption), Kazakhstan (0.6 DID, 3.1%) and Georgia (0.6 DID, 2.7%).

157 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Table 22.11 Total consumption of antibacterials for systemic use (ATC J01) expressed in DDD per 1000 per day, by pharmacological subgroup, 2018

Country Tetracyclines Tetracyclines (J01A) Amphenicols (J01B) Beta-lactam (J01C) penicillins Other beta- (includes lactams cephalosporins) (J01D) Sulfonamides trimethoprim and (J01E) Macrolides, lincosamides and streptogramins (J01F) Quinolone antibacterials (J01M) Other J01 antibacterials J01R, (J01G, J01X) Total DDD per 1 000 inhabitants per day (% of totala) TUR 1.3 (4) – 12.4 (40) 8.0 (26) 0.3 (1) 4.4 (14) 3.0 (10) 1.5 (5) 30.9 MNE 1.3 (5) – 9.9 (37) 5.4 (20) 0.8 (3) 4.8 (18) 3.3 (12) 1.5 (6) 27.0 SRB 1.7 (7) 0.0 (0) 6.8 (30) 3.6 (16) 0.7 (3) 5.3 (23) 4.0 (18) 0.7 (3) 22.7 GEO 1.1 (5) 0.6 (3) 4.3 (21) 7.2 (35) 2.2 (11) 1.9 (9) 2.0 (10) 1.6 (8) 20.8 BIH 1.2 (6) – 7.6 (39) 3.0 (15) 1.8 (10) 2.4 (12) 2.5 (13) 0.8 (4) 19.3 TJK 0.7 (4) 0.1 (1) 2.7 (14) 3.4 (18) 2.5 (13) 1.4 (8) 6.1 (32) 2.1 (11) 19.0 ALB 2.0 (11) 0.0 (0) 4.8 (25) 6.0 (31) 0.3 (2) 2.2 (12) 3.5 (18) 0.2 (1) 19.0 BLR 2.3 (12) 0.1 (0) 7.1 (38) 2.2 (12) 0.2 (1) 2.9 (16) 2.0 (11) 2.0 (11) 18.9 KAZ 1.3 (7) 0.6 (3) 4.5 (24) 3.1 (16) 0.7 (4) 2.1 (11) 4.8 (26) 1.8 (10) 18.8 UZB 0.4 (2) 0.1 (1) 3.9 (21) 3.2 (18) – 3.3 (18) 6.7 (37) 0.6 (3) 18.2 RUS 1.3 (9) 0.1 (1) 4.1 (28) 1.8 (12) 0.5 (3) 2.6 (18) 2.9 (20) 1.4 (10) 14.7 MDA 0.6 (4) < 0.1 4.2 (30) 3.0 (21) 1.1 (8) 2.0 (14) 2.0 (14) 1.2 (9) 14.2 ARM 1.6 (14) 0.3 (2) 3.4 (28) 1.1 (9) 1.4 (11) 1.7 (14) 1.7 (15) 0.9 (8) 12.1 UKR 0.8 (7) 0.2 (2) 2.1 (18) 2.1 (18) 0.5 (4) 2.7 (23) 1.8 (15) 1.6 (14) 11.7 KGZ 0.6 (5) 0.1 (1) 1.6 (14) 3.9 (35) 0.0 (0) 1.4 (13) 1.8 (17) 1.7 (15) 11.2 SWI 1.4 (13) < 0.1 4.2 (40) 0.9 (9) 0.6 (5) 1.4 (14) 1.4 (13) 0.6 (6) 10.6 AZE 1.5 (17) 0.1 (1) 3.0 (33) 0.7 (8) 0.6 (7) 1.4 (16) 0.9 (10) 0.8 (10) 8.9 Population-weighted estimates EU/EEA 2.2 (11) – 8.7 (44) 2.3 (12) 0.6 (3) 3.2 (16) 1.7 (9) 1.2 (6) 20.0 WHO/AMC 1.2 (6) 0.1 (1) 5.7 (31) 3.5 (19) 0.5 (3) 3.0 (16) 3.1 (17) 1.4 (7) 18.5

DDD: daily defined dose. EU/EEA: European Union/European Economic Area. a Total amounts and percentages may vary slightly owing to rounding.

158 23. DISCUSSION

This report extends the analyses of data from the WHO Europe AMC Network from the 2020 report of the WHO Regional Office for Europe and the 2019 and 2020 peer-reviewed manuscripts (Robertson et al., 2019, 2021). The analyses cover consumption data for 2014–2018 from 18 AMC Network countries as well as for Kosovo.11 For the first time, this report includes consumption data from Switzerland and Ukraine.

The report includes analyses of trends over time (2014–2018) for key metrics of antibiotic consumption, applying the changes to DDDs implemented in 2019, and the update of the WHO Access, Watch and Reserve (AWaRe) classification of antibiotics in 2019 (WHO, 2019a). Concordance with the WHO global/ national target that 60% of total consumption is Access agents is assessed (WHO, 2020). In addition, analyses report on the drug utilization 75% (DU75%) – that is, the antibacterials that constitute 75% of total consumption.

In 2018, total consumption of antibacterials for systemic use (ATC J01) ranged from 8.9 DID for Azerbaijan to 30.9 DID for Turkey. The median consumption was 18.8 DID. The arithmetic and population-weighted mean totals of J01 consumption in 2018 were 17.5 and 18.5 DID, respectively. These consumption estimates were mostly lower than those reported in 2014, where the range of estimates was 6.4 DID for Azerbaijan to 34.7 DID for Turkey. The continuing reduction in consumption estimates for Turkey reflects the sustained efforts at national level to improve antibiotic use. The low starting baseline of consumption estimates for Azerbaijan in 2014 and variability over the study period could suggest poor access to antibiotics, incomplete capture of import and local manufacturing information, the impact of medicines-import cycles, or combinations of these factors. In formal analyses of trends over time, only Bosnia and Herzegovina data showed a statistically significant trend towards increased consumption of J01 antibacterials over the period 2014–2018 (CAGR +6% per year).

There were large variations in the extent of consumption of parenteral antibacterials across the Network, ranging from 3% of J01 consumption in Turkey up to 40% in Kyrgyzstan. Four other countries reported parenteral consumption of more than 20% of total J01 consumption in 2018 – Georgia (32%), Tajikistan (27%), Uzbekistan (23%) and Azerbaijan (22%). The wide range of parenteral consumption is likely to reflect, in part, prescribing practices and cultural preferences. As oral administration generally is regarded as the most acceptable and economical method of administration of antimicrobials, high levels of consumption of parenteral formulations remain a potential target for interventions and behaviour change.

There was considerable variation in the extent of consumption of the pharmacological subgroups of J01. For example, in 2018, consumption of beta-lactam penicillins (J01C) ranged from 14% (Kyrgyzstan, Tajikistan) to 40% (Switzerland, Turkey). Cephalosporin (J01D) consumption varied from 8% (Azerbaijan) to 35% (Georgia, Kyrgyzstan), while quinolone (J01M) consumption varied from 10% (Azerbaijan, Georgia, Turkey) to 37% (Uzbekistan). Reasons for these large variations across the Network require further investigation, including review of prescribing practices, clinical guidelines and treatment algorithms.

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

159 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

High levels of consumption of quinolone antibacterials are of particular concern considering the 2019 EMA recommendations for suspension of marketing authorization of medicines containing cinoxacin, flumequine, nalidixic acid and pipemidic acid, and restrictions on the circumstances in which quinolone medicines should be prescribed (European Medicines Agency, 2019). National/area authorities should review the marketing authorizations for fluoroquinolone and quinolone medicines and promote the appropriate use of these antibiotics. Several AMC Network countries have already withdrawn medicines containing pipemidic acid from their markets.

Analyses based on the WHO AWaRe classification can support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further. As with other measures of consumption, there was considerable variability in the extent of use of Access and Watch group agents across the Network.

In 2018, consumption of Access agents comprised between 30% (Uzbekistan) and 66% (Bosnia and Herzegovina) of total antibacterial consumption. Watch group agents represented between 34% (Bosnia and Herzegovina) and 69% (Uzbekistan) of total consumption. High levels of consumption of Watch group antibacterials suggest targets for further investigation, interventions and stewardship activities.

Consumption of Reserve agents remained low across all years of data analysed. The low levels reflect the analysis of data on total consumption combining community and hospital sectors; different consumption patterns would be expected in analyses of hospital data alone.

Unclassified agents constituted 7% of consumption in Montenegro and Ukraine in 2018. Further analysis showed that the most widely consumed unclassified agents in the AMC Network in 2018 were combinations of benzylpenicillin and procaine penicillin (J01CE30, consumed in 12 countries), pipemidic acid (J01MB04, 11 countries), nitroxoline (J01XX07, 11 countries) and furazidin (J01XE03, 10 countries). As noted above, marketing authorization for pipemidic acid was suspended by the EMA in 2019 and subsequently in some AMC Network countries. A request will be made to the 2021 WHO Expert Committee on Selection of Essential Medicines to address limitations in the current list and expand the AWaRe classification to include antimicrobials that are used in some countries.

Several unclassified combinations of antibacterials were consumed in AMC Network countries in 2018, including ciprofloxacin and ornidazole (J01RA12, nine countries), ciprofloxacin and tinidazole (J01RA11, seven countries), ofloxacin and ornidazole (J01RA09, six countries), azithromycin, fluconazole and secnidazole (J01RA07, four countries), norfloxacin and tinidazole (two countries), and ciprofloxacin and metronidazole (J01RA10, one country). Notably, these combination agents are included in WHO’s list of “not recommended antibiotics” (Annex 1). The “not recommended” agents are fixed-dose combinations of multiple broad-spectrum antibiotics whose use is neither evidence-based nor recommended in high-quality international guidelines. WHO therefore does not recommend their use in clinical practice. These combination products are potential targets for further investigation and local interventions to discourage their use in clinical practice.

The DU75% represents the antibacterial substances accounting for 75% of the consumption measured in DDD and was calculated for oral and parenteral formulations separately. At country level, results are shown as the ranking of consumption at substance level, volumes of consumption in DID and assignment according to the AWaRe classification.

In 2018, the number of agents constituting the DU75% by oral substance ranged from four to 10 across the AMC Network countries. There were 10 agents in the WHO/AMC population-weighted network DU75% – five Access and five Watch agents. The Watch agents ciprofloxacin and azithromycin were ranked three and four in relative consumption across the AMC Network. Relatively higher levels

160 Discussion

of consumption of specific Watch group antibiotics can suggest targets for further investigation, interventions and stewardship activities, including review of clinical guidelines and prescribing algorithms.

In 2018, four AMC Network countries met WHO’s suggested national target of 60% of total consumption of antibacterials being derived from the Access list. Bosnia and Herzegovina was the only AMC Network country to achieve this target in each of the five years analysed.

Comparisons of 2018 data for ESAC-Net and the WHO Europe AMC Network showed similar ranges of estimates of total consumption of J01 antibacterials. The range for ESAC-Net was 9.7 DID (Netherlands) to 34.1 DID (Greece), compared to 8.9 DID (Azerbaijan) to 30.9 DID (Turkey) in the AMC Network. There nevertheless were considerable differences in the absolute and relative consumption of 3rd ATC level groups, with greater consumption of penicillins and tetracyclines and less consumption of cephalosporins and quinolones in ESAC-Net than in WHO Europe AMC Network countries. These observations of similar estimates of total consumption rates in conjunction with substantially different patterns of consumption suggest that relying on indicators measuring total consumption alone is inadequate to assess national performance. More detailed analyses at formulation, group and individual-agent levels are needed to identify useful targets for national interventions to improve the use of antibiotics and promote alignment of clinical practices with international guidance on their responsible use.

The analyses in this report focus on total consumption of antibacterials. Disaggregation of data to hospital and community sectors was not possible in most WHO Europe AMC Network countries and areas, but this is an important area for future development as countries strengthen and enhance their surveillance capacity. Disaggregation of data to community and hospital sectors facilitates monitoring through using sector-specific metrics for quantifying antibiotic use and assessing the quality of prescribing. Community interventions can be developed, building on existing evidence that communication skills training and changing patient expectations to receive antibiotics can lead to significant reductions in antibiotic prescriptions for viral upper respiratory tract infections (Ritchie et al., 2019; Strumann et al., 2020). Hospital antimicrobial stewardship programmes have also demonstrated their value in delivering clinical and economic benefits, with reductions in length of stay a key driver of cost savings (Nathwani et al., 2019).

The limitations of some of the data have implications for interpretation of results. Only medicines with an assigned ATC code and DDD are included in the analyses. Where there are medicines without codes consumed by the population, DID estimates will be underestimated. While import records have limitations, they will include the over-the-counter supply of antibacterials without prescription that occurs in some countries and areas. Aggregate data are used in the analyses presented here. Without information on indication for treatment, some results are difficult to interpret. For example, rifampicin may be used as an antituberculosis treatment or for its antibacterial actions for invasive staphylococcal infections. A fuller interpretation of the consumption data requires an understanding of the local context.

Despite some data limitations, the levels of consumption reported and, in some cases, the choices of antimicrobial agents used confirm the need for action. Country and area chapters can be used to inform national/area activities for participating Network members, while comparisons across countries and areas allow benchmarking of activities across the Network. 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.

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ANNEX 1. ANTIBIOTICS INCLUDED IN 2019 WHO ACCESS, WATCH, RESERVE AND NOT RECOMMENDED LISTS

Access agents (N = 48)

Antibiotic Class ATC code Amikacin Aminoglycosides J01GB06 Amoxicillin Penicillins J01CA04 Amoxicillin/clavulanic acid Beta lactam – beta lactamase inhibitor J01CR02 Ampicillin Penicillins J01CA01 Ampicillin/sulbactam Beta lactam – beta lactamase inhibitor J01CR01 Bacampicillin Penicillins J01CA06 Benzathine benzylpenicillin Penicillins J01CE08 Benzylpenicillin Penicillins J01CE01 Cefacetrile First-generation cephalosporins J01DB10 Cefadroxil First-generation cephalosporins J01DB05 Cefalexin First-generation cephalosporins J01DB01 Cefalotin First-generation cephalosporins J01DB03 Cefapirin First-generation cephalosporins J01DB08 Cefatrizine First-generation cephalosporins J01DB07 Cefazedone First-generation cephalosporins J01DB06 Cefazolin First-generation cephalosporins J01DB04 Cefradine First-generation cephalosporins J01DB09 Cefroxadine First-generation cephalosporins J01DB11 Ceftezole First-generation cephalosporins J01DB12 Chloramphenicol Amphenicols J01BA01 Clindamycin Lincosamides J01FF01 Clometocillin Penicillins J01CE07 Cloxacillin Penicillins J01CF02 Dicloxacillin Penicillins J01CF01 Doxycycline Tetracyclines J01AA02 Flucloxacillin Penicillins J01CF05 Gentamicin Aminoglycosides J01GB03 Mecillinam Penicillins J01CA11 Metronidazole (intravenous) Imidazoles J01XD01 Metronidazole (oral) Imidazoles P01AB01 Nafcillin Penicillins J01CF06 Nitrofurantoin Nitrofurantoin J01XE01

166 Annexes

Antibiotic Class ATC code Oxacillin Penicillins J01CF04 Penamecillin Penicillins J01CE06 Phenoxymethylpenicillin Penicillins J01CE02 Pivampicillin Penicillins J01CA02 Pivmecillinam Penicillins J01CA08 Procaine benzylpenicillin Penicillins J01CE09 Spectinomycin Aminocyclitols J01XX04 Sulfadiazine/trimethoprim Trimethoprim – sulfonamide combinations J01EE02 Sulfamethizole/trimethoprim Trimethoprim – sulfonamide combinations J01EB02 Sulfamethoxazole/trimethoprim Trimethoprim – sulfonamide combinations J01EE01 Sulfametrole/trimethoprim Trimethoprim – sulfonamide combinations J01EE03 Sulfamoxole/trimethoprim Trimethoprim – sulfonamide combinations J01EE04 Sultamicillin Beta lactam – beta lactamase inhibitor J01CR04 Tetracycline Tetracyclines J01AA07 Thiamphenicol Amphenicols J01BA02 Trimethoprim Trimethoprim J01EA01

Watch agents (N = 110)

Antibiotic Class ATC code Arbekacin Aminoglycosides J01GB12 Azithromycin Macrolides J01FA10 Azlocillin Penicillins J01CA09 Biapenem Carbapenems J01DH05 Carbenicillin Carboxypenicillins J01CA03 Cefaclor Second-generation cephalosporins J01DC04 Cefamandole Second-generation cephalosporins J01DC03 Cefbuperazone Second-generation cephalosporins J01DC13 Cefcapene pivoxil Third-generation cephalosporins J01DD17 Cefdinir Third-generation cephalosporins J01DD15 Cefditoren pivoxil Third-generation cephalosporins J01DD16 Cefepime Fourth-generation cephalosporins J01DE01 Cefetamet pivoxil Third-generation cephalosporins J01DD10 Cefixime Third-generation cephalosporins J01DD08 Cefmenoxime Third-generation cephalosporins J01DD05 Cefmetazole Second-generation cephalosporins J01DC09 Cefminox Second-generation cephalosporins J01DC12 Cefodizime Third-generation cephalosporins J01DD09 Cefonicid Second-generation cephalosporins J01DC06 Cefoperazone Third-generation cephalosporins J01DD12 Ceforanide Second-generation cephalosporins J01DC11 Cefoselis Fourth-generation cephalosporins To be assigned Cefotaxime Third-generation cephalosporins J01DD01 Cefotetan Second-generation cephalosporins J01DC05 Cefotiam Second-generation cephalosporins J01DC07 Cefotiam hexetil Second-generation cephalosporins J01DC07 Cefoxitin Second-generation cephalosporins J01DC01 Cefozopran Fourth-generation cephalosporins J01DE03 Cefpiramide Third-generation cephalosporins J01DD11

167 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Antibiotic Class ATC code Cefpirome Fourth-generation cephalosporins J01DE02 Cefpodoxime proxetil Third-generation cephalosporins J01DD13 Cefprozil Second-generation cephalosporins J01DC10 Ceftazidime Third-generation cephalosporins J01DD02 Cefteram pivoxil Third-generation cephalosporins J01DD18 Ceftibuten Third-generation cephalosporins J01DD14 Ceftizoxime Third-generation cephalosporins J01DD07 Ceftriaxone Third-generation cephalosporins J01DD04 Cefuroxime Second-generation cephalosporins J01DC02 Chlortetracycline Tetracyclines J01AA03 Ciprofloxacin Fluoroquinolones J01MA02 Clarithromycin Macrolides J01FA09 Clofoctol Phenol derivatives J01XX03 Delafloxacin Fluoroquinolones J01MA23 Dibekacin Aminoglycosides J01GB09 Dirithromycin Macrolides J01FA13 Doripenem Carbapenems J01DH04 Enoxacin Fluoroquinolones J01MA04 Ertapenem Carbapenems J01DH03 Erythromycin Macrolides J01FA01 Fleroxacin Fluoroquinolones J01MA08 Flomoxef Second-generation cephalosporins J01DC14 Flumequine Fluoroquinolones J01MB07 Fosfomycin (oral) Phosphonics J01XX01 Fusidic acid Steroid antibacterials J01XC01 Garenoxacin Fluoroquinolones J01MA19 Gatifloxacin Fluoroquinolones J01MA16 Gemifloxacin Fluoroquinolones J01MA15 Imipenem/cilastatin Carbapenems J01DH51 Isepamicin Aminoglycosides J01GB11 Josamycin Macrolides J01FA07 Kanamycin Aminoglycosides J01GB04 Latamoxef Third-generation cephalosporins J01DD06 Levofloxacin Fluoroquinolones J01MA12 Lincomycin Macrolides J01FF02 Lomefloxacin Fluoroquinolones J01MA07 Lymecycline Tetracyclines J01AA04 Meropenem Carbapenems J01DH02 Metacycline Tetracyclines J01AA05 Mezlocillin Penicillins J01CA10 Micronomicin Aminoglycosides To be assigned Midecamycin Macrolides J01FA03 Minocycline (oral) Tetracyclines J01AA08 Moxifloxacin Fluoroquinolones J01MA14 Neomycin Aminoglycosides J01GB05 Netilmicin Aminoglycosides J01GB07 Norfloxacin Fluoroquinolones J01MA06 Ofloxacin Fluoroquinolones J01MA01 Oleandomycin Macrolides J01FA05 Oxytetracycline Tetracyclines J01AA06

168 Annexes

Antibiotic Class ATC code Panipenem Carbapenems To be assigned Pazufloxacin Fluoroquinolones J01MA18 Pefloxacin Fluoroquinolones J01MA03 Pheneticillin Penicillins J01CE05 Piperacillin Penicillins J01CA12 Piperacillin/tazobactam Beta lactam – beta lactamase inhibitor (anti-pseudomonal) J01CR05 Pristinamycin Streptogramins J01FG01 Prulifloxacin Fluoroquinolones J01MA17 Ribostamycin Aminoglycosides J01GB10 Rifabutin Rifamycins J04AB04 Rifampicin Rifamycins J04AB02 Rifamycin Rifamycins J04AB03 Rifaximin Rifamycins A07AA11 Roxithromycin Macrolides J01FA06 Rufloxacin Fluoroquinolones J01MA10 Sisomicin Aminoglycosides J01GB08 Sitafloxacin Fluoroquinolones J01MA21 Sparfloxacin Fluoroquinolones J01MA09 Spiramycin Macrolides J01FA02 Spiramycin/metronidazole Combination of antibiotics J01RA04 Streptomycin Aminoglycosides J01GA01 Sulbenicillin Penicillins J01CA16 Tebipenem Carbapenems J01DH06 Teicoplanin Glycopeptides J01XA02 Telithromycin Macrolides J01FA15 Temocillin Carboxypenicillins J01CA17 Ticarcillin Carboxypenicillins J01CA13 Tobramycin Aminoglycosides J01GB01 Tosufloxacin Fluoroquinolones J01MA22 Vancomycin (intravenous) Glycopeptides J01XA01 Vancomycin (oral) Glycopeptides A07AA09

Reserve agents (N = 22)

Antibiotic Class ATC code Aztreonam Monobactams J01DF01 Ceftaroline fosamil Fifth-generation cephalosporins J01DI02 Ceftazidime-avibactam Third-generation cephalosporins J01DD52 Ceftobiprole medocaril Fifth-generation cephalosporins J01DI01 Ceftolozane-tazobactam Fifth-generation cephalosporins J01DI54 Colistin Polymyxins J01XB01 Dalbavancin Glycopeptides J01XA04 Dalfopristin-quinupristin Streptogramins J01FG02 Daptomycin Lipopeptides J01XX09 Eravacycline Tetracyclines J01AA13 Faropenem Penems J01DI03 Fosfomycin (intravenous) Phosphonics J01XX01 Linezolid Oxazolidinones J01XX08 Meropenem-vaborbactam Carbapenems J01DH52

169 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Antibiotic Class ATC code Minocycline (intravenous) Tetracyclines J01AA08 Omadacycline Tetracyclines To be assigned Oritavancin Glycopeptides J01XA05 Plazomicin Aminoglycosides To be assigned Polymyxin B Polymyxins J01XB02 Tedizolid Oxazolidinones J01XX11 Telavancin Glycopeptides J01XA03 Tigecycline Glycylcyclines J01AA12

Antibiotics not recommended (N = 103)

Antibiotics not recommended Acetylspiramycin/metronidazole Amikacin/cefepime Amoxicillin/bacillus coagulans/cloxacillin Amoxicillin/bacillus coagulans/dicloxacillin Amoxicillin/clavulanic acid/lactic ferments Amoxicillin/clavulanic acid/lactobacillus acidophilus Amoxicillin/clavulanic acid/nimesulide Amoxicillin/cloxacillin Amoxicillin/cloxacillin/lactic acid Amoxicillin/cloxacillin/lactobacillus acidophilus/serrapeptase Amoxicillin/cloxacillin/lactobacillus lactis Amoxicillin/cloxacillin/serrapeptase Amoxicillin/dicloxacillin Amoxicillin/dicloxacillin/saccharomyces boulardii Amoxicillin/flucloxacillin Amoxicillin/flucloxacillin/lactobacillus acidophilus Amoxicillin/metronidazole Amoxicillin/pivsulbactam Amoxicillin/sulbactam Ampicillin/bacillus coagulans/cloxacillin Ampicillin/cloxacillin Ampicillin/cloxacillin/lactobacillus acidophilus Ampicillin/cloxacillin/saccharomyces boulardii Ampicillin/dicloxacillin Ampicillin/dicloxacillin/lactobacillus acidophilus Ampicillin/flucloxacillin Ampicillin/lidocaine/sulbactam Ampicillin/oxacillin Ampicillin/sultamicillin Ascorbic acid/metamizole sodium/penicillin G/streptomycin Azithromycin/cefixime Azithromycin/cefixime/lactobacillus acidophilus Azithromycin/cefpodoxime proxetil Azithromycin/fluconazole/secnidazole Azithromycin/levofloxacin Azithromycin/ofloxacin

170 Annexes

Antibiotics not recommended Benzyl penicillin/streptomycin Bromelains/doxycycline/lactobacillus reuteri/lactobacillus rhamnosus/ornidazole Bromhexine/sulfamethoxazole/trimethoprim Cefaclor/clavulanic acid Cefadroxil/clavulanic acid Cefadroxil/trimethoprim Cefalexin/trimethoprim Cefdinir/clavulanic acid Cefepime/sulbactam Cefepime/tazobactam Cefixime/cefpodoxime proxetil Cefixime/clavulanic acid Cefixime/clavulanic acid/lactobacillus acidophilus Cefixime/cloxacillin Cefixime/cloxacillin/lactobacillus acidophilus Cefixime/dicloxacillin Cefixime/lactobacillus acidophilus/ofloxacin Cefixime/levofloxacin Cefixime/linezolid Cefixime/moxifloxacin Cefixime/ofloxacin Cefixime/ornidazole Cefoperazone/sulbactam Cefoperazone/tazobactam Cefotaxime/sulbactam Cefpodoxime proxetil/clavulanic acid Cefpodoxime proxetil/cloxacillin/lactobacillus acidophilus Cefpodoxime proxetil/dicloxacillin Cefpodoxime proxetil/dicloxacillin/lactobacillus acidophilus Cefpodoxime proxetil/levofloxacin Cefpodoxime proxetil/ofloxacin Cefpodoxime proxetil/sulbactam Ceftazidime/sulbactam Ceftazidime/tazobactam Ceftazidime/tobramycin Ceftibuten/clavulanic acid Ceftriaxone/sulbactam Ceftriaxone/tazobactam Ceftriaxone/vancomycin Cefuroxime axetil/clavulanic acid Cefuroxime axetil/linezolid Cefuroxime axetil/sulbactam Cefuroxime/clavulanic acid Cefuroxime/sulbactam Chloramphenicol/tetracycline Ciprofloxacin/metronidazole Ciprofloxacin/ornidazole Ciprofloxacin/tinidazole Doxycycline/tinidazole Erythromycin/sulfamethoxazole/trimethoprim

171 ANTIMICROBIAL MEDICINES CONSUMPTION (AMC) NETWORK

Antibiotics not recommended Erythromycin/trimethoprim Fosfomycin/trimethoprim Gatifloxacin/ornidazole Kanamycin/penicillin G Levofloxacin/metronidazole Levofloxacin/ornidazole Meropenem/sodium/sulbactam Meropenem/sulbactam Metronidazole/norfloxacin Metronidazole/spiramycin Metronidazole/tetracycline Mezlocillin/sulbactam Ofloxacin/ornidazole Oleandomycin/tetracycline Piperacillin/sulbactam Rifampicin/trimethoprim Sulfadiazine/sulfamethoxazole/trimethoprim

Source: WHO (2019). WHO releases the 2019 AWaRe Classification Antibiotics. In: World Health Organization [website]. Geneva: World Health Organization (https://www.who.int/medicines/news/2019/WHO_releases2019AWaRe_classification_antibiotics/en/, accessed 10 February 2021).

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