Evidence Based Review on Optimal Duration of Antibiotic Therapy for Bacterial Infections to Support Antimicrobial Stewardship Recommendations

Home , Duration (philosophy), Empiric therapy

Evidence based review on optimal duration of antibiotic therapy for bacterial infections to support antimicrobial stewardship recommendations

Maria Diletta Pezzani, Giorgia Be, Paolo Cattaneo, Amina Zaffagnini, Federico Gobbi, Paola Rodari, Zeno Bisoffi, Evelina Tacconelli

Infectious Diseases Unit, Department of Diagnostic and Public Health, University of Verona, Italy; Infectious Diseases Unit, IRCCS Sacro Cuore Don Calabria, Negrar, Italy

WHO Secretariat Nicola Magrini, Secretary of the Expert Committee on Selection and Use of Essential Medicines; Innovation, Access and Use, Department of Essential Medicines and Health Products

Abbreviations

AAUS: Asian Association of Urinary Tract Infection and Sexually Transmitted Infection AMC: Amoxicillin-clavulanate AMN: Aminoglicosides AMX: Amoxicillin ASP: Antimicrobial stewardship programmes BLA: Beta lactam agents BLBLI: Beta lactam beta-lactamase inhibitors BSI: Bloodstream infections BZP: Benzylpenicillin CAP: Community acquired pneumonia CEPH: Cephalosporines cUTI: Complicated UTI CYS: Cystitis DOX: Doxicycline EAU: European urological association EML: Essential medicine list EMLc: Essential medicine list children ESBL: Extended spectrum beta-lactamases FOS: Fosfomycin FQL: Fluoroquinolomes HIC: High income countries IDSA: Infectious diseases society of America LIC: Low income countries LMIC: Low-middle income countries MCL: Macrolides MRSA: Methycillin resistant Staphylococcus aureus NTF: Nitrofurantoin PHA: Pharingitis PYN: Pyelonephritis RHI: Rhinosinusitis RTI: Respiratory tract infections SEIMC: Spanish Society of Clinical Microbiology and Infectious Diseases TMP: Trimethoprim TMX: Trimethoprim-sulfamethoxazole UMIC: Upper middle income countries UTI: Urinary tract infections uUTI: Uncomplicated UTI VAP: Ventilator associated pneumonia WHO: World health organization

Background

Duration of antibiotic therapy plays a pivotal role in antimicrobial stewardship programme (ASP) within the global effort to optimize antibiotic use and reduce resistance. An appropriate antibiotic use together with a treatment course as short as possible can positively affects patient care and the health-system by reducing the frequency of adverse events and development of resistance (at patient and ecological levels) and associated healthcare costs. Recommendations of an optimal duration of therapy needs to balance between efficacy (clinical and/or microbiological) and risk of adverse events (tolerability, relapses, emergence and spread of resistance). Historically recommendations on duration of antibiotic therapy were based on fairly arbitrary extension of days of treatment (magic numbers like 7, 10 and 14 days) rather than on reliable evidence with the main aim to minimise failures and avoid undertreatment. The dominant concept, before the progressive worldwide increase in the incidence of antibiotic-resistant infections, was to treat long beyond the clinical improvement, based on the evidence from infections as tuberculosis where resistance can occur spontaneously under treatment with inappropriate dosing or monotherapy. That concept accomplished both the desire to reduce relapses and the belief that antimicrobial resistance could be prevented by a prolonged antibiotic course. For example, recommendations suggested 14 days to treat pyelonephritis, 10-14 days for community acquired pneumonia (CAP), and 21-28 for bloodstream infections (BSI). However, since early 2000s, to reduce the selective pressure driving resistance it has been frequently questioned whether a short course of antibitics could be as effective as a longer one in both in adult and pediatric populations. Now in the time of evidence based medicine, recommendations on duration of antibiotic therapy must to be based on non-inferiority clinical studies focusing on old and new antibiotic classes with the appropriate sample size and design in order to be generalised to different epidemiological settings and inform antibiotic policy and stewardship. In last years, several studies mostly addressing BSI and respiratory tract infections (RTI) have been completed to assess effectiveness of shortened antibiotics course with controversial results.1-5 A recent retrospective multicenter cohort study found no differences in 30-day all cause mortality between 6-10 days and 11-16 days therapy in adults with monomicrobial enterobacteriaceae bacteremia. Important to note that and adequate source control was a pre- requsiite for short treatement and less than 1% of study patients had inadequate source control. 1 () In a multicenter randomized control trial (RCT), hemodynamically stable inpatients with GN bacteremia and controlled focus of infections received 7 versus 14 days of antibiotic therapy. The primary outcome at 90 days including all-cause mortality; relapse, suppurative or distant complications and re-admission or extended hospitalization (>14 days) did not vary significantly between the two trial’s arms. 2 Opposite findings were reported from a retrospective cohort study which assessed the effectiveness of 7–10 days versus >10 days of antibiotic therapy for uncomplicated Gram- negative BSI. Patients were comparable in most demographic and baseline characteristics but risk of treatment failure was higher in patients receiving short compared to long courses of antibiotics. 3 The Community-Acquired Pneumonia Organization (CAPO) International Cohort Study compared patients who were treated with antibiotic therapy for a total duration of 5 days or less (SCT Group) versus longer than 5 days (LCT Group). At 30-day follow-up no deaths occurred in the SCT group while 8 patients (0.7%) in the LCT group died and there was no difference in the rate of rehospitalizations (11%) at 30 days after discharge. After controlling for confounding, a short duration of antibiotic 3 therapy was not associated to adverse outcomes. 5 A multicenter, noninferiority RCT included 312 patients admitted with CAP and compared 5 days of therapy versus longer duration of treatment. In the intent-to-treat analysis, clinical success was 48.6% in the control group and 56.3% in the intervention group at day 10 and 88.6% in the control group and 91.9% in the intervention group at day 30. 6 In pediatric infections McCullan and coworkers recently reviewed the evidence for duration of therapy and for de- escalation from intravenous to oral in 36 paediatric infections.7 The database was used to develop evidence based guidance to duration of therapy without specifying type and classes of antibiotics. With the increasing and spread of antimicrobial resistant infections, strategies optimizing the length of antibiotic therapy may be an essential component of ASP and should evaluate whether different recommendations are needed for antibiotic resistant infections. For example the majority of guidelines on UTI suggest that the choice has to be based on local ecology and provide a threshold for resistance rates. A recent review highlighted how guidelines on empirical antibiotic use did not routinely consider resistance patterns in their recommendations thus rendering the interpretation difficult especially for decison-makers.8 The Section 6 of the Essential Medicines List covers anti-infective medicines and antibacterial medicines in sections 6.2.1 (beta-lactam medicines) and 6.2.2 (other antibacterials) have been recently reviewed and updated. This revision addresses Objective 4 of the WHO’s Global Action Plan on Antimicrobial Resistance to “optimize the use of antimicrobial medicines in human and animal health”. Within this context and increase reports of antibiotic-resistant infections in LMIC, the WHO Expert Committee on Selection and Use of Essential Medicine recommended to explore the evidence-base for duration of antibiotic therapy for the diseases inldued in the EML List and if duration was different in case of etiological agent resistant to antibiotic(s). The specific objective of this study is to perform an evidence-based review on duration of treatment of bacterial infections in adults and children and to assess if recommendations vary in case of infections caused by resistant bacteria. The review will focus on the following four infection syndromes (as currently listed in the EML): pharyngitis (PHA), rhinosinusitis (RHI), community-acquired pneumonia (CAP) and UTI. The results will be used to explore indications to future integration on duration of therapy in the EML report and/or dedicated WHO guidance documents on duration of therapy within antimicrobial stewardship interventions in both high income countries (HIC) and low income countries (LIC). Methods This document is a summary of a rapid systematic literature review and inventory of available relevant evidence- based guidelines and of systematic reviews on treatment of bacterial community-acquired pneumonia (CAP), UTI, pharyngitis (PHA), and rhinosinusitis (RHI) in children and adult population. Design: Existing evidence-based clinical practical guidelines (CPG) were identified by (1) a systematic search in Pubmed/Medline (search strategy reported in point #3) with publication date from 1 January 2013 to 30 November 2018. The 5 year period has been selected in order to include only CPG based on the most recent epidemiological scenario in terms of type and duration of antibiotic therapy. The evidence has been explored in the last 15 years through analysis of systematic reviews and meta-analyses (see following paragraph); (2) a grey literature search using Google, followed by a screening of the reference lists included in the documents identified through the search; (3) consultation of guidelines and guidance documents of most relevant international societies in the field of infectious

4 diseases. Systematic reviews (SR) were identified through the same process used to identify CPG except for covering a longer review time from 1 January 2003 to 30 November 2018. In addition, we searched the literature for RCT comparing different duration of an antibiotic or a combination of antibiotics for the treatment of CAP, UTI, PHA, and RHI published after the most recent study among those included in the CPG or SR. Inclusion criteria The following PICO were applied for the systematic review and literature search: • P: Patients (adults and children) affected from CAP, UTI (complicated and uncomplicated cystitis and pyelonephritis), PHA, and RHA • I: Recommendation/ intervention on duration of antibiotic therapy (intravenous and/or oral) in community and hospital settings comparing antibiotic treatment or a combination of antibiotics with different duration (any time); • C: Long versus short duration of antibiotic therapy (definitions of short and long duration as reported by the primary authors in the included studies); • O: Clinical and microbiological outcomes as defined by the authors of the studies. Inclusion criteria for the CPG comprise that the guideline was (1) issued by a country, region, or scientific society; and (2) based on a systematic, evidence-based approach. Inclusion criteria for SR, RCT published after the most recent study included in the CPG or SR, and ongoing clinical studies comprise that the studies provided a head-to-head comparison of duration of therapy for the same antibiotic. Exclusion criteria • Observational studies, case series, case reports, expert opinions, training manuals; • SR assessing the effectiveness of biomarkers driving antibiotic therapy; • SR assessing effectiveness of different doses of the same antibiotic and/or of different routes of administrations and/or different combination regimens; • CPG, SR and studies not in English language. Sources • MEDLINE, In-Process and other non-indexed citations, OvidS, and references of retrieved studies or CPG. A WHO existing electronic database on CPG up to Dec 2016 was consulted (courtesy of Nicola Magrini and Christelle Elias). The clinicaltrials.gov was used to search for ongoing clinical trials. Search terms • CAP: ((pneumonia or community acquired pneumonia or low respiratory tract infection)) • UTI: ((urinary infection or kidney infection or cystits or pyelonephritis)) • Sinusitis and pharyngitis: ((upper respiratory infection OR sinusitis OR sinus infection OR pharyngitis OR pharynx infection)) • Outpatient: (community* or outpatient* or clinic or clinics or ambulatory*) • Inpatient: (inpatient or hospitalization or hospitals) • Treatment duration: (treatment or therap* or duration or length or day*) AND (short* or long* or standard* or prolong*) OR ((treatment or therap* or duration or length or day*);

• Antibiotic therapy: (anti-infective or anti-bacterial) OR (antibiotic* or anti-biotic* or antibacterial* or anti-bacterial* or antimicrobial* or anti-microbial* or antinfective* or anti-infective*). Data extraction Information collected: • Author, year, journal, title; • Design and country (stratified according to World Bank Classifications) or scientific society; • Population (setting / age); • Infection type and etiology; • Resistance pattern considered for therapy suggestions (if any); • Therapy: antibiotic, antibiotic class, route of administration, dose, frequency, duration of treatment; to simplify reporting indications have been reported by antibiotic class and not by single antibiotic unless a difference among different antibiotics within the same class was noted. • Data of publishing of the most recent clinical trial included in each CPG and SR. RESULTS Results are reported for each target clinical syndrome in 4 different paragraph and summary: 1. approach of the EML for duration of antibiotic therapy and antibiotic resistant infections; 2. CPG indications and reference to duration of therapy and antibiotic resistant infections; 3. Evidence from SR and meta-analyses and their limitations; 4. Trials published after the most recent evidence included in the CPG and SR and ongoing clinical trials. Our search identified 1409 articles. After deduplication, 966 abstracts (488 on CAP, 189 on UTI and 319 on RHI and PHA) were evaluated. After the first screening, 49 documents or studies were eligible for full text reading; 19 were added from the gray literature and references retrieve. The final review included 19 documents on CAP, 17 on UTI, and 9 on PHA and SIN. Figure 1 shows the flow chart.

1409

996

Reasons for CAP UTI PHA; SIN exclusion 488 189 319

Other topic 191 75 159 Old CPG 99 61 83 Diagnosis 11 4 10 Treatment 123 19 19 AMS 31 9 21 Biomarkers/Case reports 6 / 8/5

27 21 14

2 duplicates; 1 not English language; 5 SR not specifically addressing short vs 4 SR not assessing short vs long-course; 3 evaluating different regimens long treatment duration 2 review of SRs

19 17 9 6

Legend: Other topic: articles on infections not focus of the review; Old CPG: guidelines published before 2013; Diagnosis: articles on efficacy/performace of different diagnostic methods; Treatment: studies/reviews on antibiotic efficacy not addressing duration; AMS: studies on management of infection, implementation of antimicrobial stwedarship programmes or treatment/diagnostic algorithms not including duration of therapy.

COMMUNITY ACQUIRED PNEUMONIA ▪ EML indications for CAP are driven by a summary of evidence of effectiveness of different treatment regimens in both inpatient and outpatient settings. Focus of the review for the indications were differences in main clinical outcomes (clinical cure rate, mortality, relapse) between fluoroquinolones, macrolides, beta- lactams and combination therapies (mainly the additional benefit of atypical coverage). The table 1 summarizes the endorsement of first and second choices for the treatment of CAP. ▪ To minimize the occurrence of antibiotic resistance the EML suggests: the use of amoxicillin, amoxicillin + clavulanic acid, or phenoxymethylpenicillin as first-line empirical (core) therapy for mild to moderate CAP; and to use combination of ampicillin and gentamicin in childen with severe pneumonia\. ▪ No indications on the length of therapy for sensitive or resistant bacteria are reported in the EML reccomendation. Table 1 CAP EML Antibiotic Class Choice Classification Mild to moderate ACCESS Amoxicillin BLA First ACCESS Phenoxymethylpenicillin BLA First ACCESS Amoxicillin-Clavulanate BLA Second ACCESS Doxycycline TETR Second Severe WATCH Ceftriaxone + clarithromycin BLA; MCL First WATCH Cefotaxime + clarithromycin BLA; MCL First ACCESS Amoxicillin-Clavulanate + Clarithromycin BLA; MCL Second Severe in children ACCESS Amoxicillin-Clavulanate BLA First WATCH Ceftriaxone BLA First WATCH Cefotaxime BLA First ACCESS Gentamicin+benzylpenicllin/ampicillin/amoxicillin AMN; BLA First

CPG IN PEDIATRIC POPULATION (N = 8) ▪ Overall 8 CPG were published in English language in the last 5 years providing indications of duration of therapy for CAP in pediatric population: 3 HIC (2 from national Societies), 2 LMIC, 2 LIC, and 1 UMIC. ▪ Recommendations on duration of therapy for mild CAP vary significantly between a minimum of 5 to 10 days while for severe CAP between 5 and 14 days. Recommendations for atypical etiology ranges from 5 to 7 days and for S. aureus from 21 to 28 days. No objective tool is provided in any CPG on how to define length of therapy within these ranges at individual patient´s level. ▪ Notably, only most recent guidelines from HIC underlines the changes in the epidemiology of CAP due to increasing antibiotic resistant respiratory pathogens and after the introduction of pneumococcal vaccination.

Table 2. Recommendation for CAP therapy in children reported by country and year of publication. Guidelines for CAP treatment in children

Year Country, Infection (antibiotic) Min Max Comments on resistance WBC and/or duration of therapy 2013 Kiribati Mild: BLA, MCL 5 7 LMIC 5

Severe: BZP+MCL 7 7 None Atypical: MCL 5 7

2013 Tanzania Mild: AMX 5 5 None LIC 21 Severe: BZPAMX 35 35

2013 Afghanistan Non severe: TMX, AMX 5 5 If etiology is Staphylococcus aureus the recommended duration LIC 1 Severe: BLA, AMN 5 5 is 21-28 days. 2014 South Africa Mild: AMX, MCL 5 5 None UMIC 22 Severe: SD ceftriaxone before referral° 2014 Italian Mild: BLA + MCL 5 7 None Society of Severe: BLA + MCL 8 14 Preventive and Social Pediatrics, Italy HIC 15 2015 Finland At home: AMX+/-MCL 7 7 o After the introduction of pneumococcal immunisation HIC 29 In hospital: NS (PenG+/- NA NA with conjugate vaccines both macrolide and penicillin MCL) resistance decreased among pneumococcal isolates obtained from children. o Almost one-third of paediatric pneumococcal isolates are resistant to macrolides in Finland. 2015 Canadian Mild: AMX, AMP 7 10 o Ceftriaxone or cefotaxime offer better coverage than AMX Paediatric Severe: CEPH 7 10 or AMP for beta-lactamase-producing H influenzae and Society, Atypical: AZT 5 5 may be more efficacious against high-level penicillin- Canada resistant pneumococcus – and possibly provide empirical HIC 12 coverage for the rare methicillin-susceptible S aureus. o Pneumococcal resistance to macrolide is increasingly common and careful follow-up must be ensured. In children ≥8 years of age (minimum), doxycycline is likely to be effective against such strains. 2016 India Mild: AMX, TMX 5 5 If etiology is Staphylococcus aureus the recommended duration LMIC 10 is 21-28 days Severe: AMP+AMN, CEPH 7 10

Legend: °only indication for first dosage provided; NA: not available; AMX: Amoxicillin; AMN: Aminoglycosides; AMP: Ampicillin; BLA: Beta lactam agents; BZP: Benzylpenicillin; CEPH: Cephalosporines; MCL: Macrolides; SD: Single dose; TMX: Trimethoprim-sulphamethoxazole; WBC: 2018 World bank Classification. Duration is expressed in days. HIC: high income country, LIC: low income country, LMIC: low-medium income country, UMIC: upper medium income country.

CPG IN ADULT POPULATION (N = 14) ▪ Overall 14 CPG were published in English language in the last 5 years providing indications of duration of therapy for CAP in the adult population: 4 HIC (one from national scientific society), 4 UMIC, 4 LIC, and 2 LMIC (from national scientific societies). ▪ Recommendations on duration of therapy for mild CAP vary significantly between a minimum of 4 to 7 days while for severe CAP vary between 7 and 21 days. Recommendations for atypical etiology ranges from 5 to 14 days. No objective tool is provided on how to define length of therapy within these ranges at individual patient´s level. The majority of the CPG refers to improved clinical outcome to assess duration of therapy; the recommendation from the Netherlands recommends to stop the therapy after 5 days in case of mild

pneumonia and improved clinical outcome after 3 days. Reccommendation for prolonged duration of therapy is associated to slow patient´s response to therapy and complications (e.g. Chinese guidelines). ▪ Recommendations in adults provide more stratification than those for children by etiological agent and patients´ risk factors (e.g. with and without frailty in the Spanish guidelines for the elderly population). The duration of therapy by P. aeruginosa is recommended from 14 to 21 days, S. anginosus for 21 days, Legionella from 7 to 21 days, S. aureus (sensitive and resistant strains) from 14 to 21 days.

Table 3. Recommendation for CAP therapy in adult reported by country and year of publication. Guidelines for CAP treatment in adults

Year Country, Infection (antibiotic) Min Max Comments on resistance WBC and/or duration of therapy 2013 Tanzania, Mild (BLA, MCL) 5 5 None LIC 21 Severe (CEPH) 7 10 Atypical 7 14 14 14 S. aureus 10 14

K. pneumoniae

2013 Kiribati, Mild/Moderate (BLA, MCL) 7 10 None LMIC 5 If S. anginosus (BZP) 21 21 If P.aeruginosa 14 21 None (AMN + FQL) Severe If S. aureus 21 21 None (Penicillin) If other NA NA (BLA + AMN) None

2013 Afghanistan Mild (TMX, BLA) 5 5 None LIC 1 Severe (BLA) NS NS None 2014 Ethiopia, Mild (MCL, TETR, AMX, AMC) 4 7 o FQL not recommended as first line agent in LIC 14 mild CAP as they should be reserved as second line agents in pulmonary Severe (CEPH,MCL) 7 10 tuberculosis (especially MDR tuberculosis). 2014 Lebanese No differentiation (BLA + MCL) 5 8 o Monotherapy with a macrolide or Society for doxycycline is not recommended because of Infectious the high incidence of S. pneumoniae diseases and resistance in Lebanon. clinical o Recommended to add a respiratory microbiology, fluoroquinolone or vancomycin in septic Lebanon, patients because of the 17% prevalence of UMIC 16 penicillin resistance with MIC > 8 mg/L among the S. pneumoniae isolates in Lebanon. o In inpatient consideration of risk factors for MRSA and P.aeruginosa essential to drive empiric therapy due to resisatnce patterns. 2014 South Africa, Mild (AMC, FQL) 5 5 None UMIC 22 Severe NA NA (Single-dose Ceftriaxone None before referral°) 2014 Spain*, Without frailty 7 10 o Extended considerations on resistance HIC 6 (AMX, FQL, AMC + MCL) among S.pneumoniae, S.aureus, ESBL With frailty 7 10 producing Enterobactieriaceae, H.influenzae (AMX, FQL, AMC + MCL, CAR) and how it should drive the choice of empirical therapy. If P. aeruginosa 14 14 o No specific indications on duration based on resistant bacteria.

2014 NICE, Mild 5 5 o Antibiotic therapy in accordance with local UK, (BLA, MCL, TETR) hospital policy (which should take into HIC 20 account knowledge of local microbial Severe 7 10 pathogens) and clinical circumstances for (BLA + MCL) patients with hospital-acquired pneumonia. o Do not routinely offer patients with low- severity CAP a FQL. 2015 Malawi, Mild/Moderate 5 7 LIC 17 (AMX, MCL, TETR) None Severe (CEPH + MCL, AMC) 7 7 None Atypical 5 5 None (MCL) 2016 India, Mild/Moderate 5 8 UMIC 10 (AMX, AMC, CEPH, if atypical None suspected add DOX) Severe 5 8 (AMC, CEPH, if atypical None suspected add DOX) 2016 Philippines, All but MRSA, P. aeruginosa, 3 7 o Increased dosage for amoxicillin because of LMIC 26 Legionella high level of resistance of S.pneumoniae. (BLA, MCL, CAR) o Consider carbapenem in case of risk for MRSA, P. aeruginosa, 21 21 MDR strains (ESBL producing Legionella Enterobacteriaceae). o FQL not recommended as first line agent in mild CAP as they should be reserved as second line agents in pulmonary tuberculosis (especially MDR tuberculosis). 2016 Chinese Mild 5 7 Thoracic (AMX, AMC) o S.pneumoniae and M.pneumoniae are highly Society, Severe 10 14 resistant to MCL in China so they can be Chinese (BLA +/- MCL/FQL/DOX; BLBLI, used in regions with lower resistance rates Medical CAR for high risk patients) otherwise FQL are recommended. Association, o For hospitalized patients consider the risk China, In case of slow response or 21 21 for ESBL producing Enterobacteriaceae. UMIC 7 complications 2016 Dutch Mild and conditions improved 5 5 Working after 3 days o S.pneumoniae resistant to erythromycin Party on (AMX, DOC) 12% (monotherapy with MCL is Antibiotic If S. aureus 14 14 discouraged), to TMX 7% and to DOX 9%; Policy (SWAB) resistance to fluoroquinolones uncommon; and Dutch If Legionella 7 10 high level penicillin resistance is <1%. Severe Association of o Recommendation to start with BLA (CEPH Chest monotherapy instead combination qith FQL +/- Physicians If M. pneumoniae or 14 14 or MCL is due to the very low incidence of FQL) (NVALT), Chlamydophila atypical pathogens in patients admitted with Netherlands, severe CAP. HIC 19 2016 Sweden, Mild 7 7 o Proportion of pneumococcal isolates has HIC 29 (PenG, AMX) remained stable at 2-6%. o Proportion of H.influenzae isolates that is Severe 7 7 AMX resistant is estimated to be about 20- (BLA + MCL/FQL) 25%. Resistance to TMX has increased to 31%. Atypical 7 7 o No resistant Mycoplasma isolates were (MCL,TETR) observed in Sweden from 1996-2013. o Other If Legionella 10 10 Because of the increasing incidence of ESBL producers, cephalosporines and fluoroquinolones should be reserved in If S. pneumoniae 14 14 severe CAP and in those not responding to bacteremia initial empirical treatment. o In case of slow response or complications duration can be extended. Legend: °only indication for first dosage provided; *CPG for the elderly population; NA: not available; BLA: Beta lactam agents; BLBLI: Beta lactam- beta lactamase inhibitor; CAR: Carbapenem; CEPH: Cephalosporines; FQL: FLuoroquinolones; MCL: Macrolides; MRSA: Methicillin resistant S.aureus; NS: Not specified; TETR: Tetracycline; TMX: Trimetoprim-Sulphametoxazole. Duration in days. WBC: 2018 World Bank Classification. Duration is expressed in days. HIC: high income country, LIC: low income country, LMIC: low-medium income country, UMIC: upper medium income country.

SYSTEMATIC REVIEWS (N = 4)

▪ Overall three systematic reviews were included in this document. ▪ The two most recent Cochrane reviews (Lassi and Lopez-Alcade) did not find any evidence in favour or against shorter duration of out-patients´ therapy for CAP in neonates, adolescent and adults. ▪ There is very limited evidence of good quality that in inpatients therapy can be shorter to 7 or less days. ▪ The SR does not include any stratification analysis by pathogen, age, comorbid, and resistance ecology. ▪ Sutijono et al. included RCTs comparing different antibiotics (thus not satisfying our inclusion criteria); it is reported in Table 4 because it is the only review reporting assessing short vs long-course regimen in developing countries.

Table 4. Systematic reviews assessing comparison of two treatment duration using the same antibiotic at the same dosage to treat bacterial CAP. Author Population Summary/Notes Year Dimopoulos, • All ages (excluding neonates) ➢ No differences between the two groups regarding 20082 • In- and out-patients clinical success at the end of treatment and at follow- • 5 RCTs (1999-2007) up visit. No differences in subset analysis of adults • Short-course (7 days or less) versus and children. extended-course (at least 2 days longer ➢ Overall quality was good than the short course) of same regimens at ➢ Studies included HIC and LMIC same doses Sutijono, • Children (2months-18 years) ➢ Overall short and long treatment s produce similar 2011 12 • 4 included studies (2002-2008) outcomes. Three out of four studies showed no • Short vs long course-antibiotic. Short course significant differences in treatment failure or relapse defined as less than 7 days and shorter than between 3- and 5-day course of antibiotic the comparison (different drugs used). ➢ All double-blinded, all RCT but one. ➢ Methodology unclear. ➢ Studies included from LMIC and LIC Lassi, • Children (2- 59 months) ➢ No RCT assessing short- (two to three days) versus 2017 11 long- (five days) course of intravenous antibiotics (alone or in combination with oral antibiotics) for severe CAP in children aged two months to 59 months. ➢ The effects of antibiotic therapy duration for neonates and children up to 59 months remain unclear. Lopez-Alcade, • Adolescent and adult outpatients ➢ No RCT assessing short- versus longer-course 2018 8 antibiotic therapy (same antibiotic at the same daily dosage) for adolescent and adult outpatients CAP. ➢ The effects of antibiotic therapy duration for adolescent and adult outpatients with CAP remain unclear.

RCT PUBLISHED AFTER REVIEW PERIOD IN SYSTEMATIC REVIEWS AND CPG Last RCT included in Lopez-Alcade is from November 2017 (adult outpatients); Lassi from January 2015 (children); Dimopuolos from 2007 (in-patients). Most recent CPG (Swedish) included clinical studies up to 2015. ▪ According to our inclusion criteria 2 articles were published, both not a RCT.

ONGOING RCT (N= 6) ▪ Six RCTs are registered in clinicaltrials.gov. ▪ Four out six are planned in children and are exploriong short duration of therapy with amoxicillin or amoxicillin clavulanate (normal or high dosages). ▪ Two RCTs in adults assess short versus long treatment with beta-lactams or moxifloxacin. 11

▪ There is no RCT is registered for severe patients or considering antibiotic resistant etiology.

Table 5. Clinical trials on short vs long regimens of the same antibiotics for CAP registered on Clinicaltrial.gov Identifier/ Infection Participants Comparator Experimental Status/ Country NCT02258763 CAP Children Amoxicillin-clavulanate 22.5mg/kg/bd Amoxicillin-clavulanate (Unknown) for 3 days followed by another 7 days of 22.5mg/kg/dose bd for 10 days Malaysia placebo medication given at the same dose and frequency NCT03609099 CAP NS Active treatment woth Moxifloxacin to Moxifloxacin 400 mg / day once a day (Not yet patients treated during the 5 previous oral treatment during 3 days recruiting) days Spain NCT01963442 CAP Adults To investigate the non inferiority of a short lasting antibiotic treatment (3 days) (Recruiting) when compared to a long lasting antibiotic treatment (8 days), at Day 15 after the France beginning of treatment in terms of clinical efficacy, in adults who responded well to 3 days of beta-lactamin treatment (3GC or A/AC)

NCT02678195 Chest- Children 5 days of amoxicillin dispersible tablets 3 days of amoxicillin dispersible tablets (Recruiting) indrawing (DT) (DT) and then 2 days of placebo Malawi pneumon ia NCT02380352 Mild CAP Children 10 days of high-dose amoxicillin 5 days of high-dose amoxicillin (Recruiting) Canada NCT02783859 CAP Children Longer duration of amoxicillin- Shorter duration of amoxicillin- (Recruiting) clavulanic acid clavulanic acid Malawi

URINARY TRACT INFECTIONS ▪ EML indications for UTI are driven by a summary of evidence of effectiveness of different treatment regimens in both inpatient and outpatient settings. ▪ To minimize the occurrence of antibiotic resistance the EML underlines that use of antibiotics for asymptomatic bacteriuria must be avoided since it also increase the risk for subsequent symptomatic UTI (exception in pregnant women and in men about to undergo urological procedures); and oral nitrofurantoin is recommended because of its minimal propensity for resistance. ▪ No indications on the length of therapy for sensitive or resistant bacteria are reported in the reccomendation. Table 6. Classification EML AB Class Choice Classification Lower UTI ACCESS AMX BLA First ACCESS AMX-CLA BLA First ACCESS TMX TMS First ACCESS NTF NTF First PYN mild-moderate WATCH CIP FQL First ACCESS Ceftriaxone BLA Second ACCESS Cefotaxime BLA Second PYN severe WATCH Ceftriaxone BLA First (Possible addition of aminoglicoside) WATCH Cefotaxime BLA First

Legend: AMX: Amoxicillin; AMC: Amoxicillin-clavulanate; CIP: Ciprofloxacin; FQL: Fluoroquinolones; NTF: Nitrofurantoin; TMX: Trimethoprim- sulfamethoxazole.

CPG IN PEDIATRIC POPULATION (N = 10) ▪ Overall 10 CPG were published in English language in the last 5 years providing indications of duration of therapy for UTI in the pediatric population: 5 HIC, 2 LIC, 2 UMIC, and 1 LMIC. ▪ Recommendations on duration of therapy for lower UTI (cystitis) vary significantly between a minimum of 2 to 7 days while for upper UTI (pyelonephritis) between 7 and 14 days. No objective tool is provided on how to define length of therapy within these ranges at individual patient´s level. ▪ Notably, all the CPG from HIC and those from Mexico suggests to choose empiric therapy based on local resistance rates. In particular, they underline the need to consider rate of ESBL producers among gram negatives in urine culture before chosing antimicrobial regimen. The GPG from Croatia provide recommendations by resistance patterns without difference in duration by pathogen. ▪ There is a consensus among the most recent CPG to avoid aminopenicillins (ampicillin and amoxicillin) and TMX for lower UTI due to the high resistance rates in E.coli.

Table 7. Summary of the Guidelines for the treatment of UTI in children reported by country. Guidelines for the UTI treatment in children

Year Country / Infection Min Max Comments on resistance scientific (Antibiotic) and/or duration of therapy society, WBC 2013 Afghanistan, AUC (BLA, TMX) 5 5 None LIC 1 PYN (BLA +/- AMN) 7 10 2013 Tanzania, CYS (BLA) 5 5 None LIC 21 PYN (BLA) 7 7

2013 Mexico, AUC / PYN (NTF, FOS, 7 10 o To consider an antibiotic as an option in empiric therapy UMIC 18 CEPH) in the Mexican population the recommended threshold for the prevalence of resistance must be < 20%. o Ampicillin and TMP are not recommended because of the high resistance in E.coli. 2014 KHA-CARI, CYS 2 4 o Choice must be guided by local microbiological patterns Australia, (Antibiotic not sensitivities. HIC 3 specified) o Amoxicillin should not be used as first line therapy. PYN 7 10 (Antibiotic not specified) 2014 Canada, Febrile UTI 7 10 o Choice of antibiotic must be guided by knowledge of HIC 13 (BLA, AMN, TMX) local resistance patterns. 2014 South Africa, cCYS (BLA) 7 7 None UMIC 22 PYN 7 7 (Antibiotic not specified) 2015 EAU, CYS 3 4 o Increasing reports of UTI caused by ESBL producing HIC 8 (BLA, NTF, TMX) gram negatives. PYN 7 14 o Choice of agent must be based on local antimicrobial (BLA +/- AMN) susceptibility patterns 2015 Korea, Lower UTI 3 5 o For ESBL-producing E.coli aminoglycoside or imipenem HIC 11 (BLA, AMN, TMX) is recommended. Upper UTI >7 >7 o Resistance rates classified as low (0-20%), intermediate (BLA, AMN, TMX) (20-35%), and high (30-85%). 2016 Croatia, CYS 7 10 o Ampicillin and TMP are not recommended because of HIC 4 (BLA, NTF, AMN, FQL) the high resistance in E.coli. 13

PYN 10 14 o Choice of antibiotic must be guided by knowledge of (BLA, NTF, AMN, FQL) local resistance patterns (provided in the document). 2016 India, Uncomplicated UTI 7 10 None LMIC 10 (TMX, BLA) Complicated / severe 10 14 UTI (BLA, AMN)

Legend: AB, antibiotic, AUC: Acute uncomplicated cystitis; AMN: Aminoglycosides; BLA: Beta-lactam agents (including cephalosporines); cCYS: Complicated cystitis; EAU: European Urological Association; FOS: Fosfomycin; ESBL: Extended spectrum beta-lactamase; FQL: Fluroquinolones; NTF: Nitrofurantoin; PYN: Pyelonephritis; TMP: Trimethoprim; TMX: Trimethoprim-Sulfamethoxazole. Duration is expressed in days. WBC: 2018 World Bank Classification. HIC: high income country, LIC: low income country, LMIC: low-medium income country, UMIC: upper medium income country.

CPG IN ADULT POPULATION (N = 12) ▪ Overall 12 CPG were published in English language in the last 5 years providing indications of duration of therapy for UTI in adult population: 3 LIC, 3 LMIC, 2 HIC, and 2 UMIC. Two were published by international Societies. ▪ Recommendations on duration of therapy for lower UTI (cystitis) vary significantly between a minimum of 1 to 10 days while for upper UTI (pyelonephritis) vary between 5 and 14 days. No objective tool is provided on how to define length of therapy within these ranges at individual patient´s level. ▪ Notably, the majority of CPG suggests to choose empiric therapy based on local resistance rates. In particular, they underline the need to consider rate of ESBL producers among gram negatives in urine culture before chosing antimicrobial regimen. The GESITRA and SEIMC (Spain) CPG suggest assessing risk factors for MDR and in particular ESBL producers and healthcare associated infections before choosing empiric antibiotic therapy. ▪ Although the high rate of resistance to ampicillin, amoxicillin, TMP, FQL in E.coli reported in all WHO regions there are still many CPG recommending these drugs for empiric in particular in LIC and LMIC. ▪ Recommendations in adults provide more stratification by patients´ risk factors and complications compared to those in children. The prolongation of therapy up to 14 days is suggested by the CPG from Kiribati in pregnant women and men, by GESITRA (Spain) in transplant patients, and by SEIMC in case of severe case or slow response. ▪ One day therapy recommended in the the treatment of AUC in the CPG from Tanzania (FQL) and in the EAU CPG (FOS). Table 7. Summary of the Guidelines for the treatment of UTI in adults by country. Guidelines for UTI treatment in adults

Year Country, Infection (antibiotic) Min Max Comments on resistance scientific and/or duration of therapy society, WBC 2013 Afghanistan, AUC 5 5 None LIC 1 (NTF, FQL, BLA, TMX)

PYN 7 14 (BLA +/- AMN) 2013 Mexico, For uUTI no specific indications on duration o To consider an antibiotic as an option in empiric therapy in UMIC 18 (BLA, NTF) the Mexican population the recommended threshold for the prevalence of resistance must be < 20%. o Ampicillin, amoxicillin, TMP, FQL not recommended due to high resistance in E.coli. 2013 Kiribati, AUC 3 5 o Amoxicillin not recommended due to high resistance LMIC 5 (NTF, TMX) among urinary pathogens.

PYN 10 14 o AUC: Pregnant women and men should be treated for 10- (BLA+AMN) 14 days. 2013 Philippine, AUC 3 7 o Aminopenicillins and first generation cephalosporines not LMIC 26 (FQL, FOS, NTF, BLA) recommended; TMX to be used only for culture proven PYN 7 14 susceptibility. (BLA, FQL, AMN) o FQL not recommended for high propensity for collateral damage in lower UTI but recommended for outpatient treatment of uncomplicated PYN. o Carbapenem and piperacillin/tazobactam to be reserved for the treatment of infections due to MDR pathogens. 2014 Tanzania, CYS SD 7 None LIC 21 (FQL) PYN 7 10 (FQL +/- 1st SD BLA)° 2014 Ethiopia, AUC 3 7 None LIC 14 (FQL, TMX, NTF, BLA) PYN 7 14 (BLA, TMX, FQL, BLA) 2014 South Africa, uCYS (FQL) 3 7 None UMIC 22 PYN 7 10 (FQL +/- 1st SD BLA) 2015 GESITRA, CYS 5 7 o Antibiotics recommendations stratified according to Spain, (FOS, BLA, CARB) absence/presence of risk factors for MDR. HIC 23 uPYN 10 14 o Kidney transplant recipients might need longer treatment. (CEPH, BLBLI, CARB) 2016 India, AUC 3 7 None LMIC 10 (FQL, NTF, TMX, BLA) PYN 10 14 (BLA, AMN) 2016 AAUS2 AUC 3 7 o Aminopenicillins not recommended, TMP-SMX resistance rates might exceed 20% in some Asian countries. (FQL, FOS, NTF, TMX, BLA)

PYN 14 14 (BLA, FQL) 2016 SEIMC, Spain AUC 3 5 o Regimens distinguished whether patients have risk factors HIC 24 (FOS, NTF, FQL, BLA) for ESBL or PYN is health-care associated. PYN 5 7 o In case of severe or slow response prolong treatment. (BLA) 2017 EAU 9 AUC SD 5 o Local FQL resistance should be <10%; TMS <20%; (NTF, FOS, BLA, TMX) Aminopenicillins are no more suitable for high resistance PYN 5 14 in E.coli. (FQL, BLA, AMN CAR) o Carbapenems to be used if early culture results indicate cPYN MDR; in patients with signs of urosepsis empirical therapy (FQL, BLA +/- AMN) should cover ESBL. Legend: ° only first dose and drug reported with no indication of in-patients therapy AAUS: Asian Association of Urinary Tract Infection and Sexually Transmitted Infection; AUC: Acute uncomplicated cystitis; AMN: Aminoglicosides; BLA: Beta-lactam agents (including cephalosporines); CAR: Carbapenems; cCYS: Complicated cystitis; cPYN: Complicated pyelonephritis; EAU: Europena Urological Association; ESBL: Extended spectrum beta- lactamases; FOS: Fosfomycin; FQL: Fluroquinolones; GESITRA: Group for the Study of Infection in Transplants Recipients; MDR: multi-drug resistant; NS: not specified; NTF: Nitrofurantoin; PYN: Pyelonephritis; SD: Single dose; SEIMC: Spanish Society of Clinical Microbiology and Infectious Diseases; TMP: Trimethoprim; TMX: Trimethoprim-Sulfamethoxazole. Duration expressed in days. WBC: 2018 World Bank Classification. HIC: high income country, LIC: low income country, LMIC: low-medium income country, UMIC: upper medium income country.

SYSTEMATIC REVIEWS (N = 4) ▪ Overall four systematic reviews were included in this document. ▪ All SRs focused on UTI in adult. ▪ Quality of all studies was rated low-moderate and were all conducted in UMIC and HIC. ▪ The available evidence shows no difference in clinical and microbiological response between short and longer treatment in uUTI and PYN. ▪ These results should be carefully interpreted as the majority of reviews included only a few RCT which were of low/moderate quality and mostly conducted in HIC. ▪ The SR does not include any stratification analysis by pathogen, age, comorbid, and resistance ecology.

Table 8. Systematic reviews assessing comparison of two treatment duration using the same antibiotic at the same dosage to treat bacterial UTI. Author Infection Population Summary results Year Katchman uUTI Non pregnant women ➢ For symptomatic failure rates no difference was 2005 4 ▪ 32 studies (1987-1988) found. ▪ Antibiotic therapy for 3 days vs ➢ Three-day treatment was less effective than prolonged treatment regimens prolonged therapy in preventing bacteriological failure. ➢ Overall quality moderate. ➢ Included studies from UMIC and HIC. Kyriakidou PYN Adults ➢ No significant differences were found in terms of 20085 ▪ 2 studies (1987-1988) clinicals success, bacteriologic efficacy, relapse, ▪ Short-course (7- to 14-day) with adverse events, and withdrawals due to adverse long-course (14- to 42-day) events and recurrences. treatment ➢ Overall quality moderate. ➢ Two studies from HIC. Eliakim-Raz, PYN and Adults ➢ No differences regarding clinical failure, even in a 20133* UTI with ▪ 2 studies (1980-2012) small subgroup of bacteraemic patients, and sepsis ▪ ≤7 day treatment course with a microbiological failure, except in a subgroup of longer course (7 days) studies with a high percentage of patients with urogenital abnormalities. ➢ Overall quality low. ➢ Two studies from HIC. Berti, PYN Adults ➢ No significant differences in clinical success 2018 1 ▪ 4 studies (1987-2012) (moderate quality of evidence), microbiological ▪ long-course (at least 2 days success (low quality of evidence), clinical relapse (very longer) vs a short-course low quality of evidence). antibiotic therapy ➢ All the studies were judged at high risk of attrition bias and at low risk of selective outcome reporting. ➢ All studies from HIC. Legend: PYN: Pyelonephritis; uUTI: Uncomplicated UTI.* Subanalysis for five studies included in the review that compared the same antibiotica at the same dosage.

RCT PUBLISHED AFTER REVIEW PERIOD IN SYSTEMATIC REVIEWS AND CPG Last RCT included in Berti is from 2012 (adult, PYN); Katchman from 1988 (UTI, not pregnant women). Most recent CPG (EAU) included clinical studies up to 2017. ▪ According to our inclusion criteria 3 articles were reviewed: one was a protocol, was was not relevant, and one was a RCT comparing 7- versus 14-days of antibtiocs (all possible) (Daneman N et al., Trails 2018).

ONGOING RCT (N= 3) ▪ Three RCT are registered in clinicaltrials.gov. ▪ One out three is planned in children population and is exploriong short duration of therapy with cephalosporin. ▪ Two RCT in adults assess short versus longer treatment with combination (ceftriaxone+ofloxacin, sequential therapy) or TMP/SMX or ciprofloxacin. ▪ There is no trial registered for severe patients or considering antibiotic resistant etiology.

Table 9. Clinical trials comparing short vs long regimens of same antibiotica t the same dosage registered on Clinicaltrial.gov. Identifier/ Infection Participants Comparator Experimental

Status/ Country NCT03221504 Febrile 3 m to 7 y 10-day treatment arm (7 days of 7-day treatment arm (7 days of (Recruiting) UTIs cefuroxime/cefuroxime axetil followed cefuroxime/cefuroxime axetil followed Poland by 3 days of blinded cefuroxime axetil). by 3 days of blinded placebo) NCT0242446 UTI Male 14-day antibiomicrobial treatment 7 day-antibiomicrobial treatment (Recruiting) • Ceftriaxone : 1 injection 1 g per • Ceftriaxone : 1 injection 1 g per France day for 2 days day for 2 days • Ofloxacine : 400 mg/jour (200 mg/ • Ofloxacine : 400 mg/jour (200 mg/ jour in case of renal failure) for 14 jour in case of renal failure) for days seven days • Placebo of ofloxacine for 7 days NCT01994538 UTI Male 14 day 7 day duration antimicrobial treatment (Recruiting) duration antimicrobial treatment • 7 days of ciprofloxacin OR US • 14 days of ciprofloxacin OR trimethoprim/sulfamethoxazole trimethoprim/sulfamethoxazole followed by 7 days of placebo

SINUSITIS ▪ EML addresses the importance of defyining the need for antibiotic therapy given that more than 90% of cases of rhinosinusitis are due to viral infections. When antibitoc therapy is indicated beta lactams, alone or combined to beta lactamase inhibitors, have been shown to be superior to macrolides and cephalosporines so these represent the recommended first choice. ▪ EML does not cover length of treatment neither choice for empiric therapy in areas at high prevalence of penicillin non susceptible (PNS) S. pneumoniae or H. influenzae beta lactamases producers.

Table 10.

EML Classification AB Class Choice Watchful waiting, symptom relief and no antibiotic treatment should be considered as the first-line treatment option

ACCESS Amoxicillin BLA First ACCESS Amoxicillin-clavulanate BLA Second Legend: AMX: Amoxicillin; AMC: Amoxicllin-clavulanate. BLA: Beta-lactam agents

CPG IN PEDIATRIC POPULATION (N = 6) ▪ Overall 6 CPG were published in English language in the last 5 years providing indications of duration of therapy for UTI in pediatric population: 2 HIC (one from a scientific society), 2 LMIC, and one in LIC and UMIC, respectively. ▪ Guidelines strongly recommend to treat sinusitis only in cases of no spontaneous resolution or worsening of symptoms. ▪ Recommendations suggest beta lactam agents (with amoxicillin and amoxicillin-clavualante as first and second choice, respectively). Duration of therapy for sinusitis vary significantly between a minimum of 5 to 28 days. No objective tool is provided on how to define length of therapy within these ranges at individual patient´s level. ▪ Notably, only the CPG from the USA underlines that TMX and MCL are not recommeded because of resistance and that between 10% and 42% of H. influenzae and almost all M. catarrhalis are likely to be resistant to AMX. The same CPG also suggests high dosage of AMX if the prevalence of PNS S. pneumoniae is >10%. ▪ The CPG from USA suggests consideration of risk factors for antibiotic resistance when choosing empiric therapy (attendance at child care, receipt of antimicrobial treatment within the previous 30 days, and age younger than 2 years) ▪ No insights are given for treatment duration in case of resistant infections.

Table 11. Summary of Guidelines for the treatment of sinusitis in children by country. Guidelines for sinusitis treatment in children

Year Country, Antibiotic Min Max Comments on resistance WBC

2013 Kiribati AMX 5 5 None LMIC 5 2013 USA AMX (1st line)* 10 28 o TMX and MCL not recommeded because of resistance HIC 27 from surveillance studies. AMC (2nd line)* 10 28 o Between 10% and 42% of H. influenzae and close to 100% of M. catarrhalis are likely to be β-lactamase positive and non susceptible to amoxicillin. o Where the prevalence of PNS S. pneumoniae is >10% high doses of AMX are recommmeded. o Consider risk factors for the presence of organisms likely to be resistant to amoxicillin (attendance at child care, receipt of antimicrobial treatment within the previous 30 days, and age younger than 2 years) 2014 South Africa AMX 5 5 None UMIC 22 2014 Italian Society AMC, CEPH 10 14 None of Preventive and Social Pediatrics, Italy HIC 15 2014 Ethiopia AMX (1st line) 10 10 None LIC 14 MCL (2nd line) 3 3 AMC (2nd line) 7 7 2016 India AMX 7 10 None LMIC 10 Legend: AMX: Amoxicillin; AMC: Amoxicllin-clavulanate; MCL: Macrolides; PNS: Penicillin non susceptible; TMX: Trimethoprim-sulphamethoxazole. *= Alternative: continue for 7 days after the patient becomes free of signs and symptoms (minimum course of 10 days). Duration are expressed in days. WBC: 2018 World Bank Classification. HIC: high income country, LIC: low income country, LMIC: low-medium income country, UMIC: upper medium income country.

CPG IN ADULT POPULATION (N = 7) ▪ Overall 7 CPG were published in English language in the last 5 years providing indications of duration of therapy for sinusitis in adult population: 3 LIC, 2 LMIC, and one in UMIC and HIC, respectively. ▪ Guidelines agree in treating sinusitis only in cases of no spontaneous resolution or worsening of symptoms. Recommendations suggest beta lactam agents (with amoxicillin and amoxicillin-clavualante as first and second choice respectively). Duration of therapy for sinusitis vary between a minimum of 3 to 10 days according also to type of antibiotic. A short course of therapy can be recommended based on clinical improvement. No objective tool is provided on how to define length of therapy within these ranges at individual patient´s level. ▪ Notably, only CPG from USA provides a warning on resistance threshold to consider when prescribing empiric antibiotic therapy and possible risk factors for antibiotic resistant etiology. PNS S.pneumoniae need higher doses of amoxicillin and for cases due to H. influenzae beta-lactamases producers the addition of clavulanate is warranted.

Table 12. Summary of Guidelines for the treatment of sinusitis in adults by country. Guidelines for sinusitis treatment in adults

Year Country, Antibiotic Min Max Comments on resistance WBC 2013 Afghanistan AMX (1st line) 10 10 None 1 LIC MCL (2nd line) 5 5 2013 Kiribati AMX (1st line) 5 5 None 5 LMIC DOX (2nd line) 5 5

2014 Ethiopia AMX (1st line) 7 10 None LIC 14 AMC (2nd line) 7 10 MCL (2nd line) 3 3 2014 South Africa AMX (1st line) 5 5 None UMIC 22 MCL (2nd line) 3 5 2015 Malawi 17 AMX (1st line) 7 7 None LIC MCL (2nd line) 7 7 2015 USA AMX (1st line) 5* 10 o The use of high-dose amoxicillin with clavulanate is HIC 28 AMC (1 st line) 5* 10 recommended for adults with at a high risk for penicillin DOX (2nd line) 5* 10 non susceptible. S.pneumoniae (risk exists for areas with FQL (2nd line) 5* 10 >10% of PNS S.pneumoniae) o B-lactamase H.influenzae does not respond to AMX unless clavulanate is added 2016 India AMC (1st line) 5 5 None LMIC 10 FLQ (2nd line) 5 7 Legend: AMX: Amoxicillin; AMC: Amoxicllin-clavulanate; DOX: Doxicycline; FQL: Fluoroquinolones; MCL: Macrolides; PNS: Penicllin non susceptible. *= Alternative: continue for 7 days after the patient becomes free of signs and symptoms (minimum course of 10 days). Duration expressed in days. WBC: 2018 World Bank Classification. HIC: high income country, LIC: low income country, LMIC: low-medium income country, UMIC: upper medium income country.

SYSTEMATIC REVIEW (N = 1) ▪ Only one systematic review was included in this document. ▪ The SR focused on SYN with no age disctinction. ▪ Quality of the 12 studies was rated good-moderate and were all conducted in UMIC and HIC. ▪ The available evidence shows no difference in clinical and microbiological response between short and longer treatment in SYN. ▪ These results should be carefully interpreted as the majority of reviews included only a few RCT which were of low/moderate quality and mostly conducted in HIC. ▪ The SR does not include any stratification analysis by pathogen, age, comorbid, and resistance ecology.

Table 12. Systematic review assessing comparison of two treatment duration using the same antibiotic at the same dosage to treat bacterial sinusitis. Author Population Summary results Year Falagas ▪ Adults ➢ No difference in clinical success, microbiological 2009 7 ▪ 12 studies (1995-2006) efficacy, relapses, adverse events or withdrawals due to ▪ Short-course (up to 7 days) vs. long-course adverse events. therapy (> or =2 days longer than short- ➢ In the sensitivity analysis comparing 5- vs. 10-day course) regimens, clinical success was similar, although adverse events were fewer in short-course treatment. ➢ Overall quality moderate/good. ➢ All studies from UMIC and HIC.

RCT PUBLISHED AFTER REVIEW PERIOD IN SYSTEMATIC REVIEWS AND CPG Last RCT included in Falagas is from 2006. Most recent CPG from India does not report review pweiod, the one from USA included clinical studies up to 2014. ▪ According to our inclusion criteria no RCT was published.

ONGOING RCT (N= 1) One RCT focuses on children comparing same antibiotic (Amoxicillin-Potassium Clavulanate: 5 vs 14 days).

Table 13. Clinical trials comparing short vs long regimens of same antibiotic at the same dosage registered on Clinicaltrial.gov to treat siniusitis. Identifier/ Infection Participants Comparator Experimental Status/ Country NCT01166945 Sinusitis Children Long course (14 days) Short course (5 days) (Unknown) of antimicrobialtherapy of antimicrobialtherapy (Amoxicillin- US (Amoxicillin-Potassium Potassium Clavulanate) and placebo Clavulanate) for next 9 days.

PHARYNGITIS ▪ Considering that most pharyngitis are of viral origin, EML recommendations for pharyngitis are basically limited to Group A Streptococcus pharyngitis (GAS), the most frequent cause of bacterial pharyngitis. The major reason for treating GAS, other than symptomatic relief, has been to reduce complications such as rheumatic fever and post- streptococcal glomerulonephritis. ▪ To minimize the occurrence of antibiotic resistance the EML strongly suggest penicillin or amoxicillin as the first- line antibiotic to spare macrolides and cephalosporins. Clarithromycin can be used where there is a severe allergy to penicillin. ▪ The EML list does not provide insication on treatment duration. Table 14. Classification EML Classification AB Class Choice Pharyngitis Watchful waiting, symptom relief and no antibiotic treatment should be considered as the first- line treatment option ACCESS Phenoxymethylpenicillin BLA First ACCESS Clarithromycin MCL Second Addition ACCESS AMX BLA First ACCESS Cephalexin BLA Second ACCESS Clarithromycin MCL Second (EMLc) Legend: AMX: Amoxicillin; BLA: Beta-lactam agents; MCL: Macrolides

CPG IN PEDIATRIC POPULATION (N = 6) ▪ Overall 6 CPG were published in English language in the last 5 years providing indications of duration of therapy for UTI in pediatric population: 2 LMIC, 2 LIC and 1 in UMIC and HIC, respectively. ▪ Recommendations made for antibiotic treatment are reserved only to Group A streptococcal pharyngitis in order to prevent complications such as rheumatic fever and post-streptococcal glomerulonephritis and suggest as first option a single dose of benzylpenicillin or alternatively 10 days with a beta-lactam and a macrolide in case of penicillin allergy. ▪ Recommendations on duration of therapy for pharyngitis are not provided in range All CPG recommend duration based on type of antibiotic: SD for BZP and 10 days for BLA. The only range provided relates to MCL from 5 to 10 days for ERY and from 3 to 5 days for AZH. The Italian CPG are the only suggesting cephalosporin for 5 days. ▪ No insights are given for duration of therapy in case of resistant infections.

Table 15. Summary of the Guidelines for the treatment of pharyngitis in children by country. Guidelines for pharingitis treatment in children

Year Country, Infection (antibiotic) Duration Comments on resistance scientific and/or duration of therapy society, WBC 2013 Afghanistan, BZP SD None LIC 1 BLA (PNV) 10 MCL (ERY) 5 2016 India, BZP SD None LMIC 10 BLA (PNV, AMX, CFC, CFA) 10 None MCL (ERY) 10 None MCL (AZT) 5 None 2013 Kiribati, BZP SD None LMIC 5 BLA (PNV) 10 None MCL (ERY) 10 None South Africa, BZP SD None 22 UMIC BLA (PNV) 10 None 2016 MCL (ERY) 10 None MCL (AZT) 3 None Italy AMX 10 HIC 15 2014 BZP SD None CEPH 5 Tanzania, BLA (PNV, AMX, AMC) 10 2013 LIC 21 MCL (ERY) 10 None Legend: AMX: Amoxicillin; AMC: Amoxicillin-clavulanate; BZP: Benzylpenicillin; BLA: Beta-lactam agents; CFA: Cephalexin; CFC: Cefaclor; ERY: Erythromycin; AZT: Azithromycin; MCL: Macrolides; PNV: Penicillin V. Duration is expressed in days. WBC: 2018 World Bank Classification. HIC: high income country, LIC: low income country, LMIC: low-medium income country, UMIC: upper medium income country.

CPG IN ADULT POPULATION (N = 7) ▪ Overall 7 CPG were published in English language in the last 5 years providing indications of duration of therapy for UTI in pediatric population: 2 LMIC, 4 LIC, and 1 UMIC. ▪ Recommendations are reserved to Group A streptococcal pharyngitis in order to prevent complications such as rheumatic fever and post-streptococcal glomerulonephritis and suggest as first option a single dose of benzylpenicillin or alternatively 10 days with a beta-lactam and a macrolide in case of penicillin allergy. ▪ Recommendations on duration of therapy for pharyngitis are not provided in range and are based on type of antibiotic: SD for BZP and 10 day for BLA. The only range is reported for MCL which ranges from 5 to 10 days for ERY and from 3 to 5 days for AZT. ▪ No insights are given for duration of therapy in case of resistant infections.

Table 16. Summary of the Guidelines for the treatment of pharyngitis in adults by country. Guidelines for pharyngitis treatment in adults

Year Country, Antibiotic Min Max Comments on resistance WBC and/or duration of therapy 2013 Afghanistan, BZP SD SD None LIC 1 BLA (PNV) 10 10 MCL (ERY) 5 7 2014 Ethiopia, BLA (AMX, AMP) 7 10 None LIC 14 BLA (AMC) 10 10 2016 India, BZP SD SD None 22

LMIC 10 BLA (PNV, AMX) 10 10 None MCL (AZT) 5 5 None 2013 Kiribati, BZP SD SD None 5 LMIC BLA (PNV) 10 10 None MCL (ERY) 10 10 None Malawi, BLA (AMX) 7 7 None 2015 LIC 17 MCL (ERY) NA NA None South Africa, BZP SD SD None 2016 UMIC 22 BLA (PNV) 10 10 None MCL (AZT) 3 3 None Tanzania, BLA (PNV, AMX, AMC) 10 10 None 2013 LIC 21 MCL (ERY) 10 10 None Legend: AMX: Amoxicillin; AMC: Amoxicillin-clavulanate; BZP: Benzylpenicillin; BLA: Beta-lactam agents; CFA: Cephalexin; CFC: Cefaclor; ERY: Erythromycin; AZT: Azithromycin; MCL: Macrolides; PNV: Penicillin V. Duration is expressed in days. WBC: 2018 World Bank Classification. HIC: high income country, LIC: low income country, LMIC: low-medium income country, UMIC: upper medium income country.

SYSTEMATIC REVIEWS (N = 1) ▪ Only one systematic review from HIC was included in this document. ▪ The SR focused on pharyngitis in patients younger than 25 y.o. ▪ Quality of the 7 studies included was rated moderate. ▪ The available evidence shows that the clinical success was inferior in patients who received short-course treatment. ▪ These results should be carefully interpreted as the majority of studies included are not RCT. ▪ The SR does not include any stratification analysis by pathogen, age, comorbid, and resistance ecology.

Table 17. Systematic review assessing comparison of two treatment duration using the same antibiotic at the same dosage to treat bacterial pharyngitis. Author, Population Summary results Year Falagas ▪ Children and adults ≤25 years old ➢ Microbiological eradication was less likely with 2008 6 ▪ 7 studies (1972-2003) short-course treatment in trials involving primarily ▪ Short-course (< or =7 days) vs long-course (at children and adolescents. least 2 days longer than short-course) ➢ Clinical success was inferior in patients who received treatment. short-course treatment. ➢ Overall quality moderate. ➢ Included studies from HIC.

RCT PUBLISHED REVIEW PERIOD IN SYSTEMATIC REVIEWS AND CPG Last RCT included in Falagas is from 2003. Most recent CPG (South Africa, India) included clinical studies up to 2007. ▪ According to our inclusion criteria no RCT was published after the above documents have been published.

ONGOING RCT (N= 1) ▪ One RCT have been completed in 2018 in Sweden in childen and adolescents with streptococcal faringitis comparing 10 vs 5 days of phenoxymethylpenicillin (PcV) at different dosages (published in BMC Infect Dis Sept 2018, Skoog et al.).

Table 18. Clinical trials comparing short vs long regimens of same antibiotic at the same dosage registered on Clinicaltrial.gov to treat pharingitis. Identifier/ Infection Participants Comparator Experimental Status/

Country NCT02712307 Streptococcal adults, 10 days (1000 mg x 3) with 5 days (800 mg x 4) with (Completed in tonsillitis adolescents and phenoxymethylpenicillin (PcV) phenoxymethylpenicillin 2018) children Sweden

Summary EML and the need for an update

▪ Reduction of duration of antibiotic therapy can play an important role in stewardship interventions and policy. Our review show that there is increasing evidence of moderate, good level mainly from HIC, that reduction of antibiotic treatment duration for CAP, UTI, SYN, and PHA is feasible in adult and children population. Importantly, all included CPG agree on the recommendation that PHA and SYN do not require routine antibiotic treatment unless worsening of symptoms or lack of clinical resolution despite symptomatic therapy and warrant antibiotic prescription for Group A streptococcal PHA to prevent acute rheumatic fever. However, it should be noted that a previous comparison of the recommendations in acute sore throat guidelines underlined some discrepancies with this regard mainly related to different findings from epidemiological studies.11 ▪ The current version of the EML does not address the issue of duration although in some cases, as for the CAP, a reduction of duration of therapy in mild pnemonia can be responsible for a significant reduction in terms of DDDs at country level and of microbiota changes and transmission at patient’s level. ▪ The most recent CPG on the target infections explored from this document address increasingly the importance for stewardship point of view of modelling and calibrating the empiric therapy according to the local resistance rate. For example, the indication of TMX for UTI in some countries could be consider anymore an appropriate therapy. Since the EML has also the improvement of antibiotic policy and stewardship within its scope, the missing information on duration limit the efficacy of the EML in particular in LMIC where the CPG are not always available and updated. ▪ Indications for antibiotic therapy provided by EML are the result of an evidence based systematic literature review, are focused on common infections acquired in the community and are guided by the principle of parsimony and worldwide applicability. Recommendations need to balance between feasibility in most countries and “collateral damages” of prescribed antibiotic, defined as development of resistance and antibiotic related adverse events. At this time, development of guidance document should consider the specific geographical resistance patterns and the existance of local CPG to avoid the risk to provide indications that might be conflicting. The EML should consider that some indications are not consistent with national CPG or some drugs as FOS and AMG included in the CPG to avoid to use wide spectrum antibiotic in UTI, are completely missing. ▪ Our review has limitations. First, the review period is limited to the last five years for the CPG and last 15 years for the SR. Due to the chosen period important international guidelines such as NICE for UTI and IDSA for CAP and UTI were not include. Second, the selection of RCT and SR were targeting trials comparing the same drug at the same dosage with two different duration. Although this could be considered an advantage for the geenralisability of the results, it did not allow us to include trials comparing different dosages which, in some cases as the PHA, could be definitvely interesting for stewardship approaches. ▪ To complete the review data should be extracted for the other EML diseases (in particular HAP, otitis media, sepsis in children, meningitis, complicated intra-abdominal infections, and bone and joint infections) and 25

enlarge the review time. Furthermore, language restriction criteria could be modified for a more comprehensive inclusion. ▪ The data could be use for an accompaying document to the EML focusing on duration and alternatives in case of resistance by bacteria and infection.

REFERENCES

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