Part 2: Identifying Research MethodologiesAfter reading each of the four peer-reviewed articles you selected, use the Matrix Worksheet template to analyze the methodologies applied in each of the four

990 www.thelancet.com/infection Vol 17 September 2017 Articles Lancet Infect Dis 2017; 17: 990–1001 Published Online June 16, 2017 http://dx.doi.org/10.1016/ S1473-3099(17)30325-0 See Comment page 892 *Contributed equally Division of Infectious Disease, Department of Internal Medicine I, DZIF Partner site, Tübingen University Hospital, Tübingen, Germany (D Baur MD, B P Gladstone PhD, F Burkert MD, E Carrara MD, F Foschi MD, S Döbele MD, Prof E Tacconelli PhD) Correspondence to:

Prof Evelina Tacconelli, Division of Infectious Disease, Department of Internal Medicine I, DZIF Partner site, Tübingen University Hospital, Tübingen 72076, Germany [email protected] tuebingen.de Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis David Baur*, Beryl Primrose Gladstone*, Francesco Burkert, Elena Carrara, Federico Foschi, Stefanie Döbele, Evelina Tacconelli Summary Background Antibiotic stewardship programmes have been shown to reduce antibiotic u\ se and hospital costs. We aimed to evaluate evidence of the effect of antibiotic stewardship on \ the incidence of infections and colonisation with antibiotic-resistant bacteria.

Methods For this systematic review and meta-analysis, we searched PubMed, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and Web of Science for studies published from Jan 1, 1960, to May 31, 2016, that analysed the effect of antibiotic stewardship programmes on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infections in hospital inpatients. Two authors independently assessed the eligibility of trials and extracted data. Stu\ dies involving long-term care facilities were excluded. The main outcomes were incidence ratios (IRs) of target infe\ ctions and colonisation per 1000 patient-days before and after implementation of antibiotic stewardship. Meta-analyses were done with random-effect models and heterogeneity was calculated with the I² method.

Findings We included 32 studies in the meta-analysis, comprising 9 056 241 patient-days and 159 estimates of IRs. Antibiotic stewardship programmes reduced the incidence of infections an\ d colonisation with multidrug-resistant Gram-negative bacteria (51% reduction; IR 0·49, 95% CI 0·35–0·68; p<0·0001), extended-spectrum β-lactamase- producing Gram-negative bacteria (48%; 0·52, 0·27–0·98; p=0·0428),\ and meticillin-resistant Staphylococcus aureus (37%; 0·63, 0·45–0·88; p=0·0065), as well as the incidence of C difficile infections (32%; 0·68, 0·53–0·88; p=0·0029). Antibiotic stewardship programmes were more effective when implemented with infection control measures (IR 0·69, 0·54–0·88; p=0·0030), especially han\ d-hygiene interventions (0·34, 0·21–0·54; p<0·0001), than when implemented alone. Antibiotic stewardship did not affect the\ IRs of vancomycin-resistant enterococci and quinolone-resistant and aminoglycoside-resistant Gram-negative bacteria. Significant heterogeneity between studies was detected, which was partly explained by the type of interven\ tions and co-resistance patterns of the target bacteria.

Interpretation Antibiotic stewardship programmes significantly reduce the incidence \ of infections and colonisation with antibiotic-resistant bacteria and C difficile infections in hospital inpatients. These results provide stakeholders and policy makers with evidence for implementation of antibiotic steward\ ship interventions to reduce the burden of infections from antibiotic-resistant bacteria.

Funding German Center for Infection Research.

Introduction In view of the increasing number of infections caused by antibiotic-resistant bacteria, restriction of un necessary antibiotic use and optimisation of infection control measures are of the utmost importance. 1,2 Strategies for optimal antibiotic use are highly recommended among measures to limit the increasing expansion of antibiotic- resistant bacterial populations at both hospital and community levels. 2–5 Antibiotic stewardship programmes include heterogeneous inter ventions, such as auditing, restriction of specific antibiotics, restriction of treatment duration, and antibiotic cycling or mixing. 6 The implementation of these measures has been shown to significantly reduce hospital costs and use of antibiotics. 7,8 Four systematic reviews and meta-analyses have summarised the evidence of the effects of antibiotic stewardship programmes in hospital inpatients. 7,9–11 Feazel and colleagues 10 focused on Clostridium difficile infections and showed a reduction of 52% in the incidence of these infections after implementation of antibiotic stewardship, although with significant heterogeneity; the sources of heterogeneity were not explained. Schuts and colleagues 9 analysed the effect of 14 stewardship objectives. Implementation of six of these objectives (use of empirical therapy according to guidelines, de-escalation of therapy, switching from intravenous to oral treatment, therapeutic drug monitoring, restriction of antibiotics, and bedside www.thelancet.com/infection Vol 17 September 2017 991 consultation) was associated with significant benefits in terms of clinical outcomes, adverse events, and costs. In particular, guideline-adherent empirical therapy was associated with a relative risk reduction of 35% for mortality. 9 Karanika and colleagues 7 focused on five antibiotic-resistant bacteria in seven studies and showed significant reductions in the absolute risk differences for meticillin-resistant Staphylococcus aureus (MRSA), imipenem-resistant Pseudomonas aeruginosa, and extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae. That study 7 did not analyse the incidence of infection, and the overall percen tage change in infection rates among studies was not sig - nificant. Davey and colleagues 11 analysed 20 interrupted time-series studies and reported a significant reduction in risk of 49% for C difficile infections and non-significant reductions in risk of 13% for resistant Gram-negative bacteria and 19% for resistant Gram-positive bacteria. Despite the importance of antibiotic resistance, the effect of antibiotic stewardship programmes on the incidence of antibiotic-resistant bacteria has not yet been systematically reviewed. The primary goal of this systematic review and meta-analysis was to determine the effectiveness of antibiotic stewardship in reducing the incidence of infections and colonisation with antibiotic-resistant bacteria and that of C difficile infections in hospital inpatients. Methods Search strategy and selection criteria We did a systematic literature review and meta-analysis of the effectiveness of antibiotic stewardship programmes in reducing the incidence of antibiotic-resistant bacterial infections and colonisation in hospital inpatients, in accordance with PRISMA recommendations. 12 We searched PubMed, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and Web of Science from Jan 1, 1960, to May 31, 2016, with the search terms “antibiotic AND stewardship” OR “antibiotic AND intervention AND resistance” and “meticillin/methicillin OR gram negative OR escherichia coli OR clostridium difficile OR ESBL OR extended spectrum beta-lactamase OR pseudomonas OR acinetobacter OR vancomycin OR enterococcus” (appendix). We also searched the reference lists of retrieved articles. No study type or language restriction was applied. Two authors (DB, FF) independently assessed the eligibility of trials and extracted data. In the case of disagreement, a third author (ET) was consulted.

Inclusion and exclusion criteria were established a priori.

Studies reporting (or for which the authors, when contacted, were able to provide) the number of events (ie, resistant infections, colonisation) and patient-days were included in the meta-analysis and systematic review. Studies reporting interventions in the community Research in context Evidence before this study We searched PubMed, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and Web of Science from Jan 1, 1960, to May 31, 2016. We included studies analysing the effect of antibiotic stewardship programmes on the incidence of infection and colonisation due to antibiotic-resistant bacteria and Clostridium difficile infections among hospital inpatients, with the exclusion of long-term care facilities. The search terms used included (“antibiotic AND stewardship” OR “antibiotic AND intervention AND resistance”) and (“meticillin/methicillin OR gram negative OR escherichia coli OR clostridium difficile OR ESBL OR extended-spectrum-beta-lactamase OR pseudomonas OR acinetobacter OR vancomycin OR enterococcus”). Reference lists of included studies were also screened. No restriction on study type was applied. Four systematic reviews analysed the effects of antibiotic stewardship programmes in hospital inpatients. Schuts and colleagues focused on clinical outcomes, adverse events, and costs. Karanika and colleagues analysed antimicrobial consumption and costs. The incidence of antibiotic resistance was analysed in seven studies reporting on both antibiotic consumption and resistance. Feazel and colleagues analysed the effect of antibiotic stewardship programmes on C difficile infections, but neither incidence rates nor incidence ratios were reported. Davey and colleagues focused on 20 interrupted time-series studies and found that antibiotic stewardship was associated with consistent reductions in the incidence of C difficile infections but inconsistent effects on antibiotic-resistant bacteria.

Added value of this study This systematic review and meta-analysis showed, for the first time, the effectiveness of antibiotic stewardship programmes in reducing the incidence of infections and colonisation due to multidrug-resistant Gram-negative bacteria, extended-spectrum β -lactamase (ESBL)-producing Gram-negative bacteria, meticillin-resistant Staphylococcus aureus, and C difficile. The effect was increased in haematology-oncology settings and if antibiotic stewardship was co-implemented with hand-hygiene improvement measures.

Implications of all the available evidence This meta-analysis provides stakeholders and policy makers with evidence for the effectiveness of antibiotic stewardship programmes in reducing the incidence of infection and colonisation with antibiotic-resistant bacteria, in particular ESBL-producing and carbapenem-resistant Gram-negative bacteria. The evidence of increased effect when co-implemented in association with interventions targeting hand hygiene provides important information for new antibiotic stewardship programmes. See Online for appendix Articles 992 www.thelancet.com/infection Vol 17 September 2017 or in long-term care facilities and nursing homes were excluded.

Data analysis Information collected included author, corresponding author, country, year of publication, year of study, study duration, type of study, setting, and population.

Information collected about the intervention included description of the antibiotic stewardship programme (objectives, outcomes, components, and duration); type or class of antibiotics; antibiotic-resistant bacteria targeted; results before and after the intervention, according to the authors’ outcome definitions; incidence of infections and colonisation with the targeted antibiotic- resistant bacteria; and total patient-days. When data for total patient-days of follow-up were not available, total patient-days was calculated from the product of the mean length of follow-up and the number of patients followed up for the specific period. Clinical breakpoints were extracted as reported by the authors of the included studies. Antibiotic class was stratified according to the third level of the WHO Anatomical Therapeutic Chemical Classification System, and resistance to single antibiotics was used as the unit of analysis. 13 Since the definition of resistance has changed over time, we devised criteria to define ESBL-producing bacteria and multidrug-resistant (MDR) bacteria. Criteria to define ESBL-producers were resistance to ceftazidime, ceftriaxone, or both (the two drugs might have had hetero - geneous breakpoints, which might have changed over time); phenotypic confirmation (eg, with β-lactamase inhibitor combination); and gene identification with real- time PCR. Criteria to define MDR bacteria were resistance to carbapenem or resistance to at least three anti- pseudomonal antibiotic classes. When more than one antibiotic for each antibiotic class was tested, we only extracted resistance data for predefined drugs in each class to avoid duplicate counting of single isolates (appendix). Infection and colonisation were classified as defined by the authors of the included studies. Data from each study were recorded with standardised forms, verified for consistency and accuracy, and entered into a computerised database. The researchers were not blinded to study authors or location. If needed, authors were contacted via email to request additional information. The primary outcome was the change in the incidence of infection and colonisation with antibiotic-resistant bacteria and C difficile infections in hospital inpatients after implementation of antibiotic stewardship. The primary outcome was measured as the incidence ratio (IR), calculated as the ratio between the incidence (ie, the number of antibiotic-resistant bacteria isolated per 1000 patient-days) of colonisation or infection with the targeted antibiotic-resistant bacteria or C difficile infection before and after implementation of an antibiotic stewardship programme. Secondary outcomes were the IRs by study settings, type of antibiotic stewardship intervention, and concomitant implementation of infection control measures. Risk of bias was assessed independently by two authors (DB, FB) using the National Institutes of Health’s Quality Assessment Tool for Before–After (Pre–Post) Studies With No Control Group. 14 The tool was adapted to our study by removing the criteria (not applicable to our specific subset of data) regarding blinding (no 8), follow-up (no 9), and individual-level data adjustment (no 12), resulting in nine assessment criteria (appendix). Studies were classified as low quality (fewer than four points), moderate quality (four to six points), or high quality (more than six points).

The meta-analysis was done following the Cochrane Collaboration recommendations and reported in accordance with the PRISMA guidelines (appendix). 12,15 Studies with no events before and after the intervention were excluded from the analysis. The pooled estimates of IRs and 95% CIs were obtained by combining the logarithms of the IRs by use of the generic inverse-variance method and random-effect models of meta-analysis. The I ² statistic was used to quantify statistical heterogeneity.

The potential sources of heterogeneity studied with meta- regression were bacterial species, resistance pattern, type of intervention and infection control measures, infection, colonisation, length of follow-up, year of study, and geographical location. The overall significance testing was done with Wald’s test adjusted with the Bonferroni correction. Sensitivity analyses were done for study quality Figure 1: Study selection 1113 articles identi ed through search 56 additional articles identi ed through other sources 1169 abstracts screened 817 articles excluded on the basis of abstract screening 352 full-text articles assessed for eligibility 276 full-text articles excluded 202 no data on resistance rate 35 contacted without reply 17 no intervention 12 systematic review 6 author not contactable 2 full text not available 2 case-control studies 76 studies included in qualitative synthesis 32 studies included in quantitative synthesis (meta-analysis) Articles www.thelancet.com/infection Vol 17 September 2017 993 and study design. Reporting and publication bias were examined with a funnel plot and tested with Egger’s test.

All statistical analyses were done using Stata, version 14.0.

The protocol is available online.

Role of the funding source The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication.

Results Our literature search identified 1113 studies, and an additional 56 articles were identified through other sources (figure 1). After applying inclusion and exclusion criteria at the abstract level, 817 of these 1169 studies were excluded.

We retrieved full texts for the remaining 352 articles for further review. We contacted authors of 45 articles by email to request additional information. Ten authors responded, of whom four were able to provide data that were included in the final review. In total, 76 articles were reviewed in further detail (appendix) and 32 were included in the meta- analysis. Two (6%) studies were of high quality, 26 (81%) were of moderate quality, and four (13%) were of low quality (appendix). Overall, we analysed 9 056 241 patient- days and 159 IR estimates. The study characteristics are summarised in the table. The studies were done between 1992 and 2014 in 20 countries. Countries most represented were the USA (five studies), Japan (four studies), and Germany and France (three studies each). The most common study designs were before–after studies (17 [53%] studies), cohort studies (seven [22%] studies), and interrupted time-series studies (six [19%] studies; table).

About half of the interventions were done in the entire hospital (15 [47%] studies), whereas for 17 (53%) studies the interventions were focused on specific wards. The most frequent antibiotic stewardship interventions were audits (19 [59%] studies) and implementation of restrictive policies (15 [47%] studies). In ten (31%) studies, antibiotic stewardship programmes were co-implemented with infection control measures, most frequently hand hygiene For the protocol see www.medizin.uni-tuebingen.

de/uktmedia/EINRICHTUNGEN/ Kliniken/Medizinische+Klinik/ Innere+Medizin+I/PDF_Archiv/ AG+Tacconelli/ASP_ StudyProtocol2015 Years Country Study designSetting Infection or colonisationIntervention Infection control measuresMain objective Results Borde et al 16 2013–14 Germany ITSHospital InfectionAudit, guideline implementation No change Reduction of antibiotic use Reduced RDD per 1000 patient-days; no effect on incidence of Clostridium difficile infection Cruz-Rodriguez et al 17 2012–13 Mexico Before– afterOrthopaedics InfectionAntibiotic restriction, audit Hand hygiene Reduction of clindamycin use and incidence of C difficile infection Reduced DDD per 1000 patient-days and incidence of C difficile infection Apisarnthanarak et al 18 2010–12 Thailand Before– afterMedical ICU Infection and colonisationAudit, feedback Isolation, environmental cleaning, hand hygiene, chlorhexidine bathingReduction of incidence of XDR Acinetobacter baumannii Reduced incidence of XDR A baumannii Lübbert et al 19 2010–12 Germany Before– afterHospital Infection and colonisationGuideline implementation No change Reduction of antibiotic use and incidence of antibiotic resistance and C difficile infection Reduced DDD per 1000 patient-days, VRE rates, and incidence of C difficile infection Zou et al 20 2009–13 China ITSHospital Infection and colonisationAudit No changeReduction of antibiotic use and incidence of antibiotic resistance Reduced DDD per 100 patient-days; decreased or stable incidence of antibiotic resistance Dubrovskaya et al 21 2009–11 USA Before– afterSurgery InfectionGuideline implementation No change Reduction of antibiotic use and incidence of C difficile infections Reduced DDD per 1000 patient-days; no effect on incidence of C difficile infection Leung et al 22 2009–10 Canada Before– afterICU InfectionAudit, education No changeReduction of use of drugs targeting Pseudomonas aeruginosa, costs, and incidence of C difficile infection Reduced antibiotic use and costs; no effect on incidence of C difficile infection Yeo et al 23 2009–10 Singapore ITSHaematology- oncology Infection Audit No changeReduction of antibiotic use and incidence of antibiotic resistance Reduced DDD per 100 patient-days; no effect on incidence of antibiotic resistance Chong et al 24 2008–11 Japan Before– afterHaematology- oncology Infection Antibiotic cycling No changeReduction of incidence of antibiotic-resistant Gram-negative bacteria Reduced incidence of cefepime-resistant Gram-negative bacteria Niwa et al 25 2008–11 Japan Before– afterHospital InfectionAudit, guideline implementation Education, hand hygieneReduction of antibiotic use, costs, and incidence of antibiotic resistance Reduced DDD per 1000 patient-days and incidence of MRSA and antibiotic- resistant Serratia marcescens (Table continues on next page) Articles 994 www.thelancet.com/infection Vol 17 September 2017 Years Country Study designSetting Infection or colonisationIntervention Infection control measuresMain objective Results (Continued from previous page) Malani et al 26 2008–10 USA CohortHospital InfectionAudit No changeReduction of antibiotic use, costs, and incidence of C difficile infection Reduced antibiotic use, cost, and incidence of C difficile infection Price et al 27 2007–09 UK ITSHospital InfectionAntibiotic restriction Patient cohort (dedicated ward), hand hygieneReduction of antibiotic use and incidence of C difficile infection Reduced DDD per 1000 patient-days (cephalosporin, quinolone), increased use of antibiotics targeting P aeruginosa and penicillins, and reduced incidence of C difficile infection Schön et al 28 2007–08 Sweden Point prev - alence surveyHospital InfectionAntibiotic restriction, guideline implementation No change Reduction of antibiotic use and incidence of C difficile infection Reduced antibiotic use; no effect on incidence of C difficile infection Ramirez et al 29 2006–10 Spain CohortHaematology- oncology, neurosurgery, angiology, nephrology Infection and colonisation Audit No changeReduction of incidence of antibiotic-resistant Gram-positive bacteria Reduced DDD per 1000 patient-days (linezolid) and incidence of antibiotic-resistant Gram-positive bacteria Mimica Matanovic et al 30 2006–07 Croatia Before– afterHospital InfectionAntibiotic restriction No change Reduction of use of amoxicillin and clavulanic acid and incidence of Escherichia coli resistant to amoxicillin and clavulanic acid Reduced DDD per 100 bed-days and incidence of E coli resistant to amoxicillin and clavulanic acid Marra et al 31 2006–07 Brazil Before– afterICU InfectionAntibiotic restriction, audit No change Reduction of antibiotic therapy duration (to <14 days) Reduced antibiotic use and imipenem-resistant Klebsiella pneumoniae and A baumannii Takesue et al 32 2005–08 Japan Before– afterHospital InfectionAntibiotic cycling, antibiotic restriction, audit No change Reduction of infection due to MDR Gram-negative bacteria Reduced incidence of MDR Gram-negative bacteria; no effect on incidence of ESBL producers Schultsz et al 33 2004–06 Vietnam Before– afterTetanus ICU ColonisationAntibiotic mixing Hand hygiene, education, barrier precaution, patient screeningReduction of incidence of MDR Gram-negative bacteria and MRSA Reduced incidence of MRSA and ESBL-producing bacteria Meyer et al 34 2002–06 Germany ITSSurgical ICU InfectionRestriction of a single antibiotic, education No change Reduction of antibiotic use (surgical prophylaxis) and incidence of antibiotic resistance Reduced DDD per 1000 patient-days and incidence of MRSA rates; increased incidence of third-generation cephalosporin-resistant E coli Lee et al 35 2002–03 South Korea Case- controlNeurosurgical ICU Colonisation Audit No changeReduction of cephalosporin use and incidence of ESBL-producing K pneumoniae Reduced DDD per 100 patient-days and incidence of ESBL- producing K pneumoniae Arda et al 36 2002–03 Turkey CohortICU InfectionAntibiotic restriction, audit No change Reduction of antibiotic use and costs Reduced DDD per 1000 patient-days, costs, and antibiotic-resistant K pneumoniae; increased incidence of amikacin-resistant A baumannii Cook and Gooch 37 2001–13 USA CohortHospital InfectionAntibiotic restriction, audit, decision support system Screening of patients for MRSA or VRE, isolation of high-risk patientsLong-term benefits of antibiotic stewardship Reduced DDD per 1000 patient-days, MRSA infection, C difficile infection, and incidence of quinolone-resistant and carbapenem-resistant P aeruginosa Grohs et al 38 2001–12 France ITSHospital ColonisationRestriction of a single antibiotic No change Reduction of Enterobacteriaceae harbouring high-level expression of AmpC β-lactamase Reduced antibiotic use; stable incidence of Enterobacteriaceae harbouring high-level expression of AmpC β-lactamase Miyawaki et al 39 2001–07 Japan CohortHospital InfectionAudit No changeReduction of antibiotic use and drugs targeting MRSA Reduced DDD per 1000 patient-days and MRSA infections (Table continues on next page) Articles www.thelancet.com/infection Vol 17 September 2017 995 (eight [25%] studies) and patient screening (four [13%] studies; table). 21 (66%) studies assessed the effect of antibiotic stewardship programmes on infection only, three (9%) on colonisation only, and eight (25%) on both infection and colonisation. Pooled analysis of eligible studies showed that antibiotic stewardship implementation was associated with significant reductions in the incidence of MDR Gram-negative bacteria (51% reduction; IR 0·49, 95% CI 0·35–0·68; p<0·0001; figure 2), ESBL-producing Gram- negative bacteria (48%; 0·52, 0·27–0·98; p=0·0428; appendix), MRSA (37%; 0·63, 0·45–0·88; p=0·0065; figure 3), and C difficile infections (32%; 0·68, 0·53–0·88; p=0·0029; figure 4) in hospital inpatients. The reduction in the incidence of the MDR Gram-negative bacteria was also confirmed in the subgroup of studies focusing on carbapenem resistance (43%; 0·57, 0·40–0·81; p=0·0018; appendix). The incidence of aminoglycoside-resistant (IR 0·82, 95% CI 0·56–1·20; p=0·3028) and quinolone- resistant (0·74, 0·50–1·11; p=0·1435) Gram-negative bacteria was not significantly reduced (appendix). The incidence of aminoglycoside-resistant (1·00, 0·86–1·16; p=0·9701) and quinolone-resistant (1·10, 0·82–1·48; p=0·5416) Gram-positive bacteria was also not significantly changed. Although not significantly changed, after stratification by type of Gram-negative bacteria, the reduction in incidence was greatest for carbapenem-resistant Acinetobacter baumannii (56% reduction; IR 0·44, 95% CI 0·17–1·13; p=0·0864) and P aeruginosa (29%; 0·71, 0·46–1·10; p=0·1254). One study reporting the incidence of carbapenem-resistant K pneumoniae showed a reduction of 48% (IR 0·52, 95% CI 0·13–2·09; p=0·3639).

Among the Gram-positive bacteria, the IR of vancomycin- resistant enterococci was not significantly changed after implementation of antibiotic stewardship programmes (1·40, 0·81–2·43; p=0·2233; appendix). Substantial heterogeneity (>50%) was noted between the studies (the specific heterogeneity for antibiotic- resistant bacteria is reported in each figure). Heterogeneity assessment, done by meta-regression, showed that the bacterial species ( I² residual 90·2%; adjusted R² 19·2%; p=0·0006) and resistance patterns (94·5%; 10·3%; p=0·0116) were the primary contributors to the high between-study variability. The other study characteristics that contributed to heterogeneity were length of follow-up after an antibiotic stewardship programme (adjusted R ² 7·2%; p=0·0017), presence or absence of hand-hygiene co-implementation (5·5%; p=0·0007), and interventions of audits and feedback (4·5%; p=0·0044). Figure 5 shows the summary forest plot of the pooled estimates of IRs for antibiotic resistance among the various subgroups according to study characteristics.

When stratifying by setting, antibiotic stewardship Years Country Study designSetting Infection or colonisationIntervention Infection control measuresMain objective Results (Continued from previous page) Mach et al 40 2001–04 Czech Republic Cohort Hospital InfectionAntibiotic restriction, guideline implementation No change Reduction of antibiotic use and incidence of antibiotic resistance Reduced RDD per 1000 bed-days; no effect on incidence of resistance Chalfine et al 41 2000–09 France Before– afterHospital Infection and colonisationAntibiotic restriction, audit, education Hand hygiene, isolation, educationReduction of incidence of MRSA Reduced DDD per 1000 patient-days and incidence of MRSA infection Peto et al 42 2000–05 Hungary Before– afterSurgical ICU InfectionAntibiotic restriction, audit No change Reduction of antibiotic use Reduced DDD per 100 patient-days Aubert et al 43 2000–02 France Before– afterICU Infection and colonisationAntibiotic restriction Patient screeningReduction of quinolone use and incidence of resistant bacteria Reduced quinolone use and incidence of resistant P aeruginosa Smith et al 44 1997– 2003 USA Before– afterSurgical ICU InfectionAntibiotic cycling No changeReduction of incidence of MRSA and VRE Reduced incidence of MRSA; no effect on incidence of VRE Leverstein-van Hall et al 45 1996–97 Netherlands CohortNeurology, neurosurgery Infection and colonisationAntibiotic restriction Hand hygiene, patient or staff screeningReduction of MDR Enterobacteriaceae Reduced incidence of MDR Enterobacteriaceae McNulty et al 46 1994–95 UK Before– afterGeriatrics InfectionAntibiotic restriction, audit Hand hygiene, environmental cleaningReduction of incidence of C difficile infection Reduced incidence of C difficile infection Frank et al 47 1992–94 USA Before– afterHospital Infection and colonisationAntibiotic restriction, audit, education No change Reduction of antibiotic use and incidence of resistance Reduced antibiotic use, Gram-negative bacteraemia, and incidence of MRSA; no effect on incidence of C difficile infection ITS=interrupted time series. XDR=extremely drug-resistant. RDD=recommended daily dosage. DDD=defined daily dose. ICU=intensive care unit. VRE=vancomycin-resistant enterococci. MRSA=meticillin-resistant Staphylococcus aureus. MDR=multidrug-resistant. ESBL=extended-spectrum β-lactamase.

Table: Summary of studies included in the meta-analysis (n=32) Articles 996 www.thelancet.com/infection Vol 17 September 2017 interventions were associated with reduced IRs in haematology-oncology departments (59% reduction; IR 0·41, 95% CI 0·20–0·85; p=0·0166), intensive care units (23%; 0·77, 0·66–0·89; p=0·0003), and medical departments (22%; 0·78, 0·66–0·91; p=0·0024).

Antibiotic stewardship programmes implemented with infection control measures had a greater effect on reduction of antibiotic resistance (31%; IR 0·69, 95% CI 0·54–0·88; p=0·0030) than did implementation of antibiotic stewardship programmes alone (19%; 0·81, 0·67–0·97; p=0·0210; figure 5). In particular, interventions that co-implemented hand hygiene together with antibiotic stewardship were associated with a greater reduction in the IR of antibiotic resistance (66%; 0·34, 0·21–0·54; p<0·0001; figure 5) than those without hand-hygiene intervention (17%; 0·83, 0·71–0·98; p=0·0304; appendix). The magnitude of effect was dependent on the type of antibiotic stewardship programme implemented. A significant effect was found for antibiotic cycling (51% reduction in antibiotic resistance; 0·49, 0·34–0·72; p=0·0030), followed by audits and feedback (34% reduction; 0·66, 0·52–0·83; p=0·0006) and antibiotic restriction (23% reduction; 0·77, 0·67–0·89; p=0·0003). Use of implementing guidelines for antibiotic stewardship programmes (IR 1·03, 95% CI 0·85–1·25; p=0·7496) and focusing on one antibiotic class (1·28, 0·68–2·41; p=0·4527) did not lead to significant changes in IRs (appendix). Interventions generally became more effective over time:

10% reduction in antibiotic resistance for 1980–2000 (IR 0·90, 95% CI 0·60–1·36; p=0·6226), 21% reduction for 2001–05 (0·79, 0·69–0·90; p=0·0006), and 32% reducti\ on for 2006–13 (0·68, 0·49–0·95; p=0·0223; figure 5).

Sensitivity analysis based on the quality of the studies revealed no notable difference in IRs, even after exclusion of the low-quality studies. The pooled-effect size estimate based on prospective studies revealed an increased protective effect (IR 0·64, 95% CI 0·49–0·83; p=0·0008\ ).

We did not find any evidence of effects for small studies (Egger’s test p=0·836) or publication bias (appendix). Discussion Our study findings show that implementation of antibiotic stewardship programmes is associated with a reduction in the IRs of infection and colonisation with antibiotic-resistant bacteria and C difficile infections in hospital inpatients. The largest reductions were seen in the incidence of infection or colonisation with MDR Gram-negative bacteria, followed by the incidence of infection or colonisation with ESBL-producing Gram-negative bacteria and MRSA, and the incidence of C difficile infections. Notably, antibiotic stewardship was found to be highly effective in haematology- oncology settings and when implemented alongside infection control measures. Co-implementation of improved hand hygiene had a beneficial effect on the Figure 2: Forest plot of the incidence ratios for studies of the effect of antibiotic stewardship on the incidence of MDR GNB GNB=Gram-negative bacteria. MDR=multidrug-resistant. XDR=extensively drug-resistant.

Apisarnthanarak et\u al 18 Marra et al 31 Apisarnthanarak et\u al 18 Takesue et al 3\f Cook and \booch 37 Peto et al 4\f Takesue et al 3\f Arda et al 36 Leverstein-van Hall\u et al 45 Yeo et al \f3 Arda et al 36 Marra et al 31 Marra et al 31 Arda et al 36 Meyer et al 34 Yeo et al \f3 Zou et al \f0 Niwa et al \f5 Aubert et al 43 Overall I\f=76·\f%, p=0·000 MDR Pseudomonas aeruginosa Imipenem-resistant \uAcinetobacter baumannii XDR A baumannii Metallo- -lactamase \u\bNB Carbapenem-resistan\ut P aeruginosa MDR P aeruginosa MDR \bNB Meropenem-resistant \uAcinetobacter spp MDR Enterobacteriac\ueae Carbapenem-resistan\ut P aeruginosa Meropenem-resistant \uP aeruginosa Imipenem-resistant Klebsiella pneumoniae Imipenem-resistant \uP aeruginosa Meropenem-resistant \uA baumannii Imipenem-resistant \uP aeruginosa Carbapenem-resistan\ut A baumannii Meropenem-resistant \uP aeruginosa Imipenem-resistant \uP aeruginosa Imipenem-resistant \uP aeruginosa Before 13/\f889 \f3/84\f1 33/\f889 \f7/698 794 44/\f\f0 474 \f/4\f80 39/698 794 \f8/\f85 606 9 /19 14\f 17/\f0 469 8/\f85 606 6 /84\f1 15/84\f1 45/\f85 606 34/13 50\f 10/\f0 469 185/834 560 11/1\f8 146 49/5100 After 1/13\f4 \f/8066 \f/13\f4 6/635 794 13/\f61 318 1/4\f17 10/635 794 10/308 85\f 4/\f3 583 8/\f1 798 4/308 85\f 3/8066 8/8066 \f9/308 85\f 33/\f1 4\f0 9/\f1 798 17\f/883 500 15/113 873 44/\f548 0·08 (0·00–1·41) 0·09 (0·0\f–0·39) 0·13 (0·03–0·55) 0·\f4 (0·10–0·59) 0·\f5 (0·13–0·46) 0·\f5 (0·01–5·63) 0·\f8 (0·14–0·56) 0·33 (0·16–0·68) 0·36 (0·11–1·17) 0·44 (0·19–1·0\f) 0·46 (0·14–1·54) 0·5\f (0·13–\f·09) 0·56 (0·\f4–1·31) 0·60 (0·37–0·95) 0·61 (0·38–0·99) 0·85 (0·34–\f·08) 0·88 (0·71–1·08) 1·53 (0·70–3·34) 1·80 (1·\f0–\f·70) 0·49 (0·35–0·68) Events/patient-days MDR GNB Antibiotic stewards\uhipprogramme e ective Antibiotic stewards\uhip programme not e ect\uive 1·0 0 0·5 1·5 \f·0Incidence ratio (95% CI) Articles www.thelancet.com/infection Vol 17 September 2017 997 overall success of the interventions, reducing resistance rates by two-thirds. Among the different types of antibiotic stewardship interventions, antibiotic cycling was found to be the most effective, followed by audits and feedback, and antibiotic restriction. The interventions became more effective over time, ranging from 10% reduction of antibiotic resistance for 1980–2000 to 32% reduction for 2006–13.An effect for antibiotic stewardship on other outcomes (eg, mortality, antibiotic costs) has already been shown. Karanika and colleagues 7 analysed the effect of antibiotic stewardship programmes in seven studies published up to July, 2015, and showed a significant decrease in antibiotic resistance among MRSA, imipenem-resistant P aeruginosa, and ESBL-producing K pneumoniae isolates, with a 4·5% reduction in overall resistance. Because that study 7 reported only absolute risk differences for specific bacteria, comparison of their results with the results of this study is difficult. The 2016 systematic review by Schuts and colleagues 9 analysed stewardship objectives Figure 4: Forest plot of the incidence ratios for studies of the effect of antibiotic stewardship on the incidence of Clostridium difficile infections Cruz-Rodriguez et \nal 17 Leung et al \f\f McNult\b et al 46 Price et al \f7 Malani et al \f6 Borde et al 16 Lübbert et al 19 Dubrovska\ba et al \f1 Cook and Gooch 37 Schön et al \f8 Frank et al 47 Overall I\f=80·\f%, p=0·000 8/70\f6 8/1373 37/\f6 144 353/\f71 538 46/\f976 71/1\f7 596 156/310 857 8/\f551 134/\f\f0 474 18\f/169 886 50/103 573 \f/16 507 1/1\f0\f 16/30 467 \f58/373 913 \f0/\f408 \f0/55 156 115/313 060 7/\f489 149/\f61 318 191/170 541 48/91 965 0·11 (0·0\f–0·50) 0·14 (0·0\f–1·14) 0·37 (0·\f1–0·67) 0·53 (0·45–0·6\f) 0·54 (0·3\f–0·91) 0·65 (0·40–1·07) 0·73 (0·58–0·93) 0·90 (0·33–\f·47) 0·94 (0·74–1·18) 1·05 (0·85–1·\f8) 1·08 (0·73–1·61) 0·68 (0·53–0·88) Before After Events/patient-days Incidence ratio (95% CI) Antibiotic stewards\nhip programme e ective Antibiotic stewards\nhip programme not e ect\nive 1 0 0·5 1·01·5\f·0 Figure 3: Forest plot of the incidence ratios for studies of the effect of antibiotic stewardship on the incidence of meticillin-resistant Staphylococcus aureus Apisarnthanarak et al 18 Chal ne et al 41 Chal ne et al 41 Smith et al 44 Frank et al 47 Schultsz et al 33 Cook and Gooch 37 Yeo et al 23 Miyawaki et al 39 Arda et al 36 Meyer et al 34 Niwa et al 25 Zou et al 20 Aubert et al 43 Marra et al 31 Peto et al 42 Mach et al 40 Overall I2=92·2%, p=0·000 17/2889 17/113 194 123/113 194 105/11 979 68/103 573 44/2708 229/220 474 40/20 469 213/293 655 87/285 606 127/13 502 172/128 146 196/834 560 44/5100 7/8421 1/4280 1/146 886 1/1324 2/153 283 26/153 283 11/6012 18/91 965 19/3384 118/261 318 23/21 798 186/305 149 85/308 852 189/21 420 151/113 873 284/883 500 38/2548 13/8066 4/4217 15/155 870 0·06 (0·00–1·07) 0·09 (0·02–0·38) 0·16 (0·10–0·24) 0·21 (0·11–0·39) 0·30 (0·18–0·50) 0·35 (0·20–0·59) 0·43 (0·35–0·54) 0·54 (0·32–0·90) 0·84 (0·69–1·02) 0·90 (0·67–1·22) 0·94 (0·75–1·17) 0·99 (0·79–1·23) 1·37 (1·14–1·64) 1·73 (1·12–2·67) 1·94 (0·77–4·86) 4·06 (0·45–36·32) 28·27 (1·69–473·17) 0·63 (0·45–0·88) Before After Events/patient-days Incidence ratio (95% CI) Antibiotic stewardship programme e ective Antibiotic stewardship programme not e ective 1 0 0·5 1·01·52·0 Articles 998 www.thelancet.com/infection Vol 17 September 2017 and showed a 56% reduction in mortality with guideline- adherent empirical therapy and a 35% reduction in mortality with de-escalation interventions. Feazel and colleagues, 10 when investigating the effect of antibiotic stewardship programmes on the incidence of C difficile infections, estimated a protective effect of 52%. In this meta-analysis and systematic review, we estimated a protective effect of 32% for C difficile infections, and this difference might be attributed to our more conservative approach, with use of IRs, and also to our inclusion of eight studies that were not analysed in the review by Feazel and colleagues. 10 Our findings clearly show that antibiotic stewardship programmes, when implemented alongside infection control measures, are more effective than implementation of antibiotic stewardship alone. In particular, studies co-implementing a hand-hygiene programme with an antibiotic stewardship programme have reported a reduction of 66% in antibiotic resistance versus 17% in studies without co-implementation of hand-hygiene interventions, thus supporting the so-called butterfly effect of hand hygiene. The hand-hygiene measures implemented in the studies included in our meta-analysis varied from education to replacement of handwashing with alcohol-based hand rubbing and substitution of hand-directed soap dispensers with elbow-directed soap dispensers. 33,41,44,46 It is important to emphasise that the effect of infection control and hand hygiene was observed not only for infections due to MRSA but also for those due to antibiotic-resistant Gram-negative bacteria. This finding seems to support the importance of verifying the level of hand-hygiene compliance and adherence to basic infection control measures, with simultaneous implementation of antibiotic stewardship and integration of infection control experts into the antibiotic stewardship programme teams. In this study, antibiotic stewardship programmes were more effective in the haematology-oncology settings than in other settings. This finding is notable because of the serious outcomes of MDR infections in this setting and the scarcity of information about the effectiveness of antibiotic stewardship programmes in haematology- oncology patients.

48,49 The main limitation of this finding is the low number (three) of included studies. Bradley and colleagues 50 did a prospective three-phase sequential study in which ceftazidime was replaced with piperacillin- tazobactam in patients with febrile neutropenia. The intervention reduced colonisation with glycopeptide- resistant Enterococcus spp (57% without inter vention vs 19% with intervention). 50 Chong and colleagues 24 were able to reduce antibiotic resistance rates, in particular cefepime-resistant Gram-negative bacteria, by implementation of an antibiotic cycling regimen in which four primary antibiotic classes were rotated. Yeo and colleagues 23 implemented an audit and feedback antibiotic stewardship programme targeting ceftazidime-resistant Escherichia coli, ceftazidime-resistant K pneumoniae, carbapenem-resistant Acinetobacter spp, and MRSA, resulting in a significant reduction in MRSA rates only.

In the intensive care unit setting, a significant effect was also detected in our review, consistent with the observation by Karanika and colleagues 7 of a significant reduction in antibiotic consumption in this setting after implementation of an antibiotic stewardship programme. Among the types of antibiotic stewardship programmes implemented, we found antibiotic cycling, audits, and antibiotic restriction to be effective. Studies of guideline implementation and single antibiotic classes did not show any effect for these interventions on resistance rates, perhaps because of short follow-up. A meta-analysis 51 of antibiotic cycling showed a significant reduction in the incidence of antibiotic-resistant bacteria per 1000 patient- days after the intervention (reduction of 7·2, 95% CI 0·44–14·00; p=0·037). However, the low number of studies (three) implementing antibiotic cycling in our review restricts the generalisability of the results. The success of this measure is usually dependent on the setting in which it is implemented and the local epidemiology. 24,44 Auditing, with its components of intense communication and feedback, renders antibiotic steward - ship programmes effective and seems to be promising in Figure 5: Summary forest plot of the incidence ratios for studies investigating the effect of ASPs on antibiotic resistance, according to study characteristics ICM=infection control measure. ASP=antibiotic stewardship programme.

Study setting Intensive care unit Medical ward Surgical ward Haematology-oncology ward Co-implementation of ICMs ASP alone ASP + ICMs ASP + hand-hygiene intervention Type of intervention Antibiotic restriction Audits/feedback Antibiotic cycling Year of study 1980–2000 2001–05 2006–13 Infection and/or colonisation Infection and colonisation Infection Colonisation Study design Interrupted time-series studies Cohort studies Before–after studies 10 27 53 23 95 15 19 3 5 10 17 8 21 3 6 7 18 0·77 (0·66–0·89) 0·78 (0·66–0·91) 0·76 (0·46–1·25) 0·41 (0·20–0·85) 0·81 (0·67–0·97) 0·69 (0·54–0·88) 0·34 (0·21–0·54) 0·77 (0·67–0·89) 0·66 (0·52–0·83) 0·49 (0·34–0·72) 0·90 (0·60–1·36) 0·79 (0·69–0·90) 0·68 (0·49–0·95) 0·91 (0·60–1·37) 0·75 (0·66–0·85) 0·72 (0·41–1·25) 1·20 (0·97–1·50) 0·79 (0·61–1·02) 0·66 (0·54–0·81) Number of studies Incidence ratio (95% CI) ASP e ectiveASP not e ective 1 00 ·5 1·0 1·5 2·0 Articles www.thelancet.com/infection Vol 17 September 2017 999 all settings. 23,41 Across the studies, success was attributed to high compliance among physicians, the additional educational effect of feedback, a closer working relationship between physicians and the antibiotic stewardship team because of audits, control of certain endpoints of infection control by audits in conjunction with antibiotic stewardship programmes, educational effects, and the Hawthorne effect due to putting electronic monitoring systems in place. 23,25,33,39,41 The effectiveness of antibiotic restriction was also shown by Schuts and colleagues 9 who used a restricted antibiotics list targeting specific bacteria. Our study had some limitations. First, although we had a wide range of eligible studies, we were limited to 32 studies because of the scarcity of essential data in the remaining studies. Incomplete data reporting and absent author responses were the main factors restricting our ability to do a more comprehensive meta-analysis of the clinical efficacy of antibiotic stewardship programmes. However, most of the excluded studies also reported a reduction in their antibiotic resistance rates. Second, we could not investigate the effectiveness of single interventions in greater detail because most of the studies reported comprehensive results of composite antibiotic stewardship programmes implemented together with infection control strategies. Third, we included uncontrolled studies with pre–post data, and we cannot entirely ignore that the observed effect could be due to an underlying secular trend. Fourth, we detected significant heterogeneity between studies. However, analysis of the sources of the heterogeneity showed that 20% of the between-study variance could be explained by the multiple pattern of resistance among included antibiotic-resistant bacteria.

The absence of interventions targeting hand hygiene alongside anti biotic stewardship interventions and the type of antibiotic stewardship intervention also contributed to the heterogeneity. Because of the wide array of study designs, different types of antibiotic stewardship programmes, co-implementation of infection control measures, and the focus on different antibiotic-resistant bacteria, the residual heterogeneity in this complex background is, to an extent, understandable. Further investigation of heterogeneity and interactions between contributing factors could not be done because of the small number of studies. Given that antibiotic stewardship programmes are usually implemented in large settings and I² tends to be increased when the number of patients or patient-days is variable, it can also be speculated that the large denominator used in the IR calculations could explain the substantial amount of heterogeneity even between individual antibiotic-resistant bacteria. 52 The principal strength of our study is the analysis of the incidence of infections or colonisation as the primary outcome of the antibiotic stewardship programmes. To the best of our knowledge, this study is the first to use this measure, which takes into account the individual patient-days of follow-up, is easily comprehensible, and is comparable across studies. 20,31,43 When planning future studies of antibiotic stewardship programmes, it would be advisable to use controlled interventional study designs and data-reporting patterns to enable comparison and generalisation of results.

Standards for data reporting are accessible in the literature and include reporting of absolute bacteria numbers, antibiotic consumption represented by defined daily doses, and reporting of patient-days for the study period. 53 Adherence to such reporting policies can provide more reliable and comparable data, an outcome essential in guiding future research and recommendations. An antibiotic stewardship programme should be studied over a sufficiently long period of time to adequately assess its effect. The effects of various types of antibiotic stewardship interventions should be assessed for Gram- negative and Gram-positive bacteria separately. In conclusion, our meta-analysis shows that antibiotic stewardship programmes have an essential role in combating the development of antibiotic resistance, especially for MDR Gram-negative bacteria, and emph - asises the importance of promoting antibiotic stewardship programmes at the hospital level to reduce the spread of antibiotic-resistant bacteria among the inpatient population. Therefore, implementation of these measures should be recommended not only on the basis of the well known cost benefits, but also because of the more relevant, patient-based clinical advantages. Co-implementation of hand-hygiene improvement interventions with antibiotic stewardship programmes has a synergistic effect and is thus recommended for future antibiotic stewardship planning. Good quality intervention studies are needed to help prioritise the various antibiotic stewardship programmes for each specific resistance scenario.

Contributors ET conceived and designed the study. DB, FB, FF, and SD did the literature review and data collection. BPG, EC, FF, DB, and SD reviewed \ the data. BPG and EC did the statistical analysis. DB, BPG, and ET wrote\ the manuscript. All authors contributed to the interpretation of the dat\ a and writing of the Article and agree with its content and conclusions.

Declaration of interests We declare no competing interests.

Acknowledgments This study was funded by the German Center for Infection Research under grant agreement number D.20.07860. We thank Anne McDonough for editorial support, Niklas Mueller for his assistance in data extraction, and Johannes P Borde and Paul P Cook for providing additional data.

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