Methods for SARS-CoV-2 hospital disinfection, in vitro observations.

Introduction: Escalation of chemical disinfection during the COVID-19 pandemic has raised occupational hazard concerns. Alternative and potentially safer methods such as ultraviolet-C (UVC) irradiation and ozone have been proposed, notwithstanding the lack of standardized criteria for their use in the healthcare environment. Aim: Compare the virucidal activity of 70% ethanol, sodium dichloroisocyanurate (NaDCC), chlorhexidine, ozonated water, UVC-222 nm, UVC-254 nm against three SARS-CoV-2 variants of concern cultured in vitro. Methods: Inactivation of three SARS-CoV-2 variants (alpha, beta, gamma) by the following chemical methods was tested: ethanol 70%, NaDCC (100 ppm, 500 ppm, 1000 ppm), chlorhexidine (2%, 1% and 0.5%), ozonated water 7 ppm. For irradiation, a je2Care 222nm UVC Lamp was compared to a Sylvania G15 UV254 nm lamp. Results: Viral inactivation by >3 log was achieved with ethanol, NaDCC and chlorhexidine. The minor virucidal effect of ozonated water was <1 log. Virus treatment with UVC-254 nm reduced viral activity by 1-5 logs with higher inactivation after exposure for 3 minutes compared to 6 seconds. For all three variants, under equivalent conditions, exposure to UVC-222 nm did not achieve time-dependent inactivation as was observed with treatment with UVC-254 nm. Conclusion: The virucidal activity on replication-competent SARS-CoV-2 by conventional chemical methods, including chlorhexidine at concentrations as low as 0.5%, was not matched by UVC irradiation, and to an even lesser extent by ozonated water treatment.

Laboratory Surveillance, Quality Management, and Its Role in Addressing Antimicrobial Resistance in Africa: A Narrative Review.

AMR is a major public health concern that calls for extensive work and a multidisciplinary team approach. The high prevalence of infectious diseases in African nations leads to widespread antibiotic usage and eventual antimicrobial resistance, which has significant negative effects on people's health, the economy, and society. Additionally, inadequate or nonexistent antimicrobial drug regulations, inappropriate prescription practices, and restrictions on public health prevention initiatives such as immunization, water and sanitation, and sexual health may all contribute to the emergence of AMR. Despite the need for laboratory quality assurance, many African laboratories confront substantial difficulties in implementing efficient quality assurance programs. AMR surveillance in Africa is hampered by a lack of laboratory capacity, insufficient data collection and analysis, and poor stakeholder collaboration. Several initiatives and programs, including the World Health Organization's Global Antimicrobial Resistance and Use Surveillance System (GLASS), the Africa Centres for Disease Control and Prevention (Africa CDC) Antimicrobial Resistance Surveillance Network (AMRSNET), and the Fleming Fund, a UK government initiative aimed at tackling AMR in low- and middle-income countries, have been established to strengthen AMR surveillance in Africa and globally.

Chlorhexidine Resistance or Cross-Resistance, That Is the Question.

Chlorohexidine (CHX) is a widely used biocide in clinical and household settings. Studies over the last few decades have reported CHX resistance in different bacterial species, but at concentrations well below those used in the clinical setting. Synthesis of these findings is hampered by the inconsistent compliance with standard laboratory procedures for biocide susceptibility testing. Meanwhile, studies of in vitro CHX-adapted bacteria have reported cross-resistance between CHX and other antimicrobials. This could be related to common resistance mechanisms of CHX and other antimicrobials and/or the selective pressure driven by the intensive use of CHX. Importantly, CHX resistance and cross-resistance to antimicrobials should be investigated in clinical as well as environmental isolates to further our understanding of the role of CHX in selection of multidrug resistance. Whilst clinical studies to support the hypothesis of CHX cross-resistance with antibiotics are currently lacking, we recommend raising the awareness of healthcare providers in a range of clinical disciplines regarding the potential adverse impact of the unfettered use of CHX on tackling antimicrobial resistance.

Antimicrobial Synergy Testing: Comparing the Tobramycin and Ceftazidime Gradient Diffusion Methodology Used in Assessing Synergy in Cystic Fibrosis-Derived Multidrug-Resistant Pseudomonas aeruginosa.

The need for synergy testing is driven by the necessity to extend the antimicrobial spectrum, reducing drug dosage/toxicity and the development of resistance. Despite the abundance of synergy testing methods, there is the absence of a gold standard and a lack of synergy correlation among methods. The most popular method (checkerboard) is labor-intensive and is not practical for clinical use. Most clinical laboratories use several gradient synergy methods which are quicker/easier to use. This study sought to evaluate three gradient synergy methods (direct overlay, cross, MIC:MIC ratio) with the checkerboard, and compare two interpretative criteria (the fractional inhibitory concentration index (FICI) and susceptibility breakpoint index (SBPI)) regarding these methods. We tested 70 multidrug-resistant Pseudomonas aeruginosa, using a tobramycin and ceftazidime combination. The agreement between the checkerboard and gradient methods was 60 to 77% for FICI, while agreements for SBPI that ranged between 67 and 82.86% were statistically significant (p ≤ 0.001). High kappa agreements were observed using SBPI (Ƙ > 0.356) compared to FICI (Ƙ < 0.291) criteria, and the MIC:MIC method demonstrated the highest, albeit moderate, intraclass correlation coefficient (ICC = 0.542) estimate. Isolate resistance profiles suggest method-dependent synergism for isolates, with ceftazidime susceptibility after increased exposure. The results show that when interpretative criteria are considered, gradient diffusion (especially MIC:MIC) is a valuable and practical method that can inform the treatment of cystic fibrosis patients who are chronically infected with P. aeruginosa.

Trends of Antimicrobial Resistance and Combination Susceptibility Testing of Multidrug-Resistant Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients: a 10-Year Update.

Antimicrobial combination therapy is a time/resource-intensive procedure commonly employed in the treatment of cystic fibrosis (CF) pulmonary exacerbations caused by Pseudomonas aeruginosa Ten years ago, the most promising antimicrobial combinations were proposed, but there has since been the introduction of new ß-lactam plus ß-lactamase inhibitor antimicrobial combinations. The aims of this study were to (i) compare in vitro activity of these new antimicrobials with other antipseudomonal agents and suggest their most synergistic antimicrobial combinations and (ii) determine antimicrobial resistance rates and study inherent trends of antimicrobials over 10 years. A total of 721 multidrug-resistant P. aeruginosa isolates from 183 patients were collated over the study period. Antimicrobial susceptibility and combination testing were carried out using the Etest method. The results were further assessed using the fractional inhibitory concentration index (FICI) and the susceptible breakpoint index (SBPI). Resistance to almost all antimicrobial agents maintained a similar level during the studied period. Colistin (P < 0.001) and tobramycin (P = 0.001) were the only antimicrobials with significant increasing isolate susceptibility, while an increasing resistance trend was observed for levofloxacin. The most active antimicrobials were colistin, ceftolozane-tazobactam, ceftazidime-avibactam, and gentamicin. All combinations with ß-lactam plus ß-lactamase inhibitors produced some synergistic results. Ciprofloxacin plus ceftolozane-tazobactam (40%) and amikacin plus ceftazidime (36.7%) were the most synergistic combinations, while colistin combinations gave the best median SBPI (50.11). This study suggests that effective fluoroquinolone stewardship should be employed for CF patients. It also presents in vitro data to support the efficacy of novel combinations for use in the treatment of chronic P. aeruginosa infections.

Author Correction: A nonlinear time-series analysis approach to identify thresholds in associations between population antibiotic use and rates of resistance.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Longitudinal Surveillance and Combination Antimicrobial Susceptibility Testing of Multidrug-Resistant Achromobacter Species from Cystic Fibrosis Patients.

Achromobacter spp. are recognized as emerging pathogens in patients with cystic fibrosis (CF). Though recent works have established species-level identification using nrdA sequencing, there is a dearth in knowledge relating to species-level antimicrobial susceptibility patterns and antimicrobial combinations, which hampers the use of optimal antimicrobial combinations for the treatment of chronic infections. The aims of this study were to (i) identify at species-level referred Achromobacter isolates, (ii) describe species-level antimicrobial susceptibility profiles, and (iii) determine the most promising antimicrobial combination for chronic Achromobacter infections. A total of 112 multidrug-resistant (MDR) Achromobacter species isolates from 39 patients were identified using nrdA sequencing. Antimicrobial susceptibility and combination testing were carried out using the Etest method. We detected six species of Achromobacter and found that Achromobacter xylosoxidans was the most prevalent species. Interestingly, sequence analysis showed it was responsible for persistent infection (18/28 patients), followed by Achromobacter ruhlandii (2/3 patients). Piperacillin-tazobactam (70.27%) and co-trimoxazole (69.72%) were the most active antimicrobials. Differences were observed in species-level susceptibility to ceftazidime, carbapenems, ticarcillin-clavulanate, and tetracycline. Antimicrobial combinations with co-trimoxazole or tobramycin demonstrate the best synergy, while co-trimoxazole gave the best susceptibility breakpoint index values. This study enriches the understanding of MDR Achromobacter spp. epidemiology and confirms prevalence and chronic colonization of A. xylosoxidans in CF lungs. It presents in vitro data to support the efficacy of new combinations for use in the treatment of chronic Achromobacter infections.

Genomic Stability of Composite SCCmec ACME and COMER-Like Genetic Elements in Staphylococcus epidermidis Correlates With Rate of Excision.

The epidemiological success of methicillin-resistant Staphylococcus aureus USA300 has been associated with the presence of two mobile elements, the arginine catabolic mobile element (ACME) and the copper and mercury resistance (COMER) element. These two mobile elements are associated with resistance to copper, which has been related to host fitness and survival within macrophages. Several studies found that ACME is more prevalent, and exhibits greater diversity, in Staphylococcus epidermidis while COMER has not been identified in S. epidermidis or any other staphylococcal species. We aimed in this study to evaluate the presence and diversity of ACME and COMER-like elements in our S. epidermidis clinical isolates. The genomes of 58 S. epidermidis clinical isolates, collected between 2009 and 2018 in a Scottish hospital, were sequenced. A core-genome phylogenetic tree and genome based MLST typing showed that more than half of the isolates belong to the clinically predominant sequence type2 (ST2) and these isolates have been found to split into two lineages within the phylogenetic tree. Analysis showed the presence of SCCmec in the majority of isolates. Comparative analysis identified a cluster of ACME-positive isolates with most of them belonging to ST48. ACME showed high variation even between isolates of the same ACME type and ST. COMER-like elements have been identified in one of the two major hospital adapted drug resistant ST2 lineages; and showed high stability. This difference in stability at the genomic level correlates well with the up to one hundred times higher excision frequency found for the SCCmec elements in ACME-containing isolates compared to COMER-like element containing isolates. ACME/COMER-like element positive isolates did not show a significant phenotype of decreased copper susceptibility, while resistance to mercury was over-represented in COMER-like element positive isolates. To the best of our knowledge, this is the first molecular characterization of COMER-like elements in S. epidermidis isolates. The presence of the COMER-like elements is the most prominent accessory genome feature of these successful lineages suggesting that this chromosomal island contributes to the success and wide clinical distribution of ST2 S. epidermidis.

Challenges and opportunities for antimicrobial stewardship in resource-rich and resource-limited countries.

Introduction: Inappropriate prescription practices, patient and provider knowledge and attitudes, variable availability of diagnostic and surveillance systems, and the unrestricted use of antimicrobials in animals and plants are contributory factors to the global crisis of antimicrobial resistance (AMR). Areas covered: Notwithstanding that interventions to revert AMR should be tailored to the socio-politico-economic landscape, there is a global consensus for the implementation and enhancement of antimicrobial stewardship strategies. Yet the implementation of Antimicrobial Stewardship Programs (ASPs) remains relatively limited within healthcare settings and faces complex challenges in resource-limited countries. The current review summarizes the limitations of current ASPs, translation challenges in resource-limited countries, and potential solutions. Expert opinion: Suboptimal ASP implementation in hospitals is multifactorial. Restriction of antimicrobial use should be informed by risk-benefit analyses, including the potential for substitute prescribing, and displacement of selection pressures. Thresholds in population use of antibiotics above which AMR increases may provide quantitative targets for ASPs. Horizontal and vertical collaborations involving policymakers and the general public are of paramount importance. While impactful prescribing changes require sustained engagement of the public and health-care professionals, we warn against over-estimating the benefits of behavioral interventions. We advocate for population-level stewardship interventions in addition to investment in structural factors that will aid ASP implementation.

Antibacterials in the pipeline and perspectives for the near future.

Antimicrobial resistance is a global threat to the management of infections in our patients. Sound stewardship of antibacterial agents at our disposal must be accompanied by a concerted effort to develop new agents to bolster our armamentarium. This review will cover the latest antibiotics that have come through the pipeline and the role they can play in the management of infections that are increasingly difficult to treat due to resistance mechanisms.

A nonlinear time-series analysis approach to identify thresholds in associations between population antibiotic use and rates of resistance.

Balancing access to antibiotics with the control of antibiotic resistance is a global public health priority. At present, antibiotic stewardship is informed by a 'use it and lose it' principle, in which antibiotic use by the population is linearly related to resistance rates. However, theoretical and mathematical models suggest that use-resistance relationships are nonlinear. One explanation for this is that resistance genes are commonly associated with 'fitness costs' that impair the replication or transmissibility of the pathogen. Therefore, resistant genes and pathogens may only gain a survival advantage where antibiotic selection pressures exceed critical thresholds. These thresholds may provide quantitative targets for stewardship-optimizing the control of resistance while avoiding over-restriction of antibiotics. Here, we evaluated the generalizability of a nonlinear time-series analysis approach for identifying thresholds using historical prescribing and microbiological data from five populations in Europe. We identified minimum thresholds in temporal relationships between the use of selected antibiotics and incidence rates of carbapenem-resistant Acinetobacter baumannii (Hungary), extended-spectrum ß-lactamase-producing Escherichia coli (Spain), cefepime-resistant E. coli (Spain), gentamicin-resistant Pseudomonas aeruginosa (France) and methicillin-resistant Staphylococcus aureus (Northern Ireland) in different epidemiological phases. Using routinely generated data, our approach can identify context-specific quantitative targets for rationalizing population antibiotic use and controlling resistance. Prospective intervention studies that restrict antibiotic consumption are needed to validate these thresholds.

New Drugs for Multidrug-Resistant Gram-Negative Organisms: Time for Stewardship.

A gradual rise in drug-resistant trends among Gram-negative organisms, especially carbapenem-resistant (CR) Enterobacteriaceae (CRE), CR-Pseudomonas aeruginosa, and extensively-drug-resistant (XDR) Acinetobacter baumannii, poses an enormous threat to healthcare systems worldwide. In the last decade, many pharmaceutical companies have devoted enormous resources to the development of new potent antibiotics against XDR Gram-negative pathogens, particularly CRE. Some of these novel antibiotics against CRE strains are ß-lactam/ß-lactamase-inhibitor combination agents, while others belong to the non-ß-lactam class. Most of these antibiotics display good in vitro activity against the producers of Ambler class A, C, and D ß-lactamase, although avibactam and vaborbactam are not active in vitro against metallo-ß-lactamase (MßL) enzymes. Nevertheless, in vitro efficacy against the producers of some or all class B enzymes (New Delhi MßL, Verona integron-encoded MßL, etc) has been shown with cefepime-zidebactam, aztreonam-avibactam, VNRX-5133, cefiderocol, plazomicin, and eravacycline. As of Feburary 2019, drugs approved for treatment of some CRE-related infections by the US Food and Drug Administration included ceftazidime-avibactam, meropenem-vaborbactam, plazomicin, and eravacycline. Although active against extended-spectrum and AmpC ß-lactamase-producing Enterobacteriaceae, delafloxacin does not show in vitro activity against CRE. Murepavadin is shown to be specifically active against CR- and colistin-resistant P. aeruginosa strains. Despite successful development of novel antibiotics, strict implementation of an antibiotic stewardship policy in combination with the use of well-established phenotypic tests and novel multiplex PCR methods for detection of the most commonly encountered ß-lactamases/carbapenemases in hospitals is important for prescribing effective antibiotics against CRE and decreasing the resistance burden due to CRE.

Phylogenetic analysis of resistance to ceftazidime/avibactam, ceftolozane/tazobactam and carbapenems in piperacillin/tazobactam-resistant Pseudomonas aeruginosa from cystic fibrosis patients.

Pseudomonas aeruginosa is one of the most important pathogens in cystic fibrosis. This study was conducted to analyse the genetic basis and phylogenetic profile of resistance to ceftazidime/avibactam, ceftolozane/tazobactam and carbapenems in cystic fibrosis P. aeruginosa isolates. Whole genome sequence analysis was conducted of isolates resistant to piperacillin/tazobactam collected from seven hospitals in Scotland since the introduction of these two cephalosporin/ß-lactamase inhibitor combinations. Ceftazidime resistance was primarily related to AmpC induction, as tested by cloxacillin inhibition assays, while high-level ceftazidime resistance not reversed by cloxacillin was associated with amino acid variations in AmpC. Only isolates resistant to both ceftazidime/avibactam and ceftolozane/tazobactam carried AmpD mutations, likely resulting in ampC overexpression. All isolates resistant to ceftazidime/avibactam and/or ceftolozane/tazobactam were resistant to carbapenems and showed inactivating mutations in the chromosomal oprD gene. None of the isolates bore class A, B, D plasmid-encoded carbapenemases. This study showed that mutational resistance emerged in phylogenetically distant lineages, which indicates the mutations occur independently without conferring a selective advantage to any phylogenetic lineage. These findings confirm the strong contribution of mutation-driven evolution to the population structure of P. aeruginosa.

Decision and cost analysis of empirical antibiotic therapy of acute sinusitis in the era of increasing antimicrobial resistance: do we have an additional tool for antibiotic policy decisions?

OBJECTIVE: No previous analyses have attempted to determine optimal therapy for upper respiratory tract infections on the basis of cost-minimization models and the prevalence of antimicrobial resistance among respiratory pathogens in Slovakia. This investigation compares macrolides and cephalosporines for empirical therapy and look at this new tool from the aspect of potential antibiotic policy decision-making process. METHODS: We employed a decision tree model to determine the threshold level of macrolides and cephalosporines resistance among community respiratory pathogens that would make cephalosporines or macrolides cost-minimising. To obtain information on clinical outcomes and cost of URTIs, a systematic review of the literature was performed. The cost-minimization model of upper respiratory tract infections (URTIs) treatment was derived from the review of literature and published models. RESULTS: We found that the mean cost of empirical treatment with macrolides for an URTIs was €93.27 when the percentage of resistant Streptococcus pneumoniae in the community was 0%; at 5%, the mean cost was €96.45; at 10%, €99.63; at 20%, €105.99, and at 30%, €112.36. Our model demonstrated that when the percentage of macrolide resistant Streptococcus pneumoniae exceeds 13.8%, use of empirical cephalosporines rather than macrolides minimizes the treatment cost of URTIs. CONCLUSIONS: Empirical macrolide therapy is less expensive than cephalosporines therapy for URTIs unless macrolide resistance exceeds 13.8% in the community. Results have important antibiotic policy implications, since presented model can be use as an additional decision-making tool for new guidelines and reimbursement processes by local authorities in the era of continual increase in antibiotic resistance.

Recently approved antibacterials for methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive pathogens: the shock of the new.

A number of novel antimicrobial drugs with activity against Gram-positive bacterial pathogens have been licensed in the past 4 years. These drugs have the potential to enrich the group of intravenous drugs already available that are in common use against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci and other antibiotic-resistant Gram-positive pathogens. The advantages and disadvantages of these drugs are not yet fully appreciated. Here we review the five most promising newly approved compounds, namely ceftaroline, ceftobiprole, oritavancin, dalbavancin and tedizolid. The advantages of their dosing regimens, mechanisms of action and adverse effect profiles as well as evidence for their clinical usefulness and the unique characteristics that distinguish them from one another and from older drugs are reviewed.

Interventions to improve antibiotic prescribing practices for hospital inpatients.

BACKGROUND: Antibiotic resistance is a major public health problem. Infections caused by multidrug-resistant bacteria are associated with prolonged hospital stay and death compared with infections caused by susceptible bacteria. Appropriate antibiotic use in hospitals should ensure effective treatment of patients with infection and reduce unnecessary prescriptions. We updated this systematic review to evaluate the impact of interventions to improve antibiotic prescribing to hospital inpatients. OBJECTIVES: To estimate the effectiveness and safety of interventions to improve antibiotic prescribing to hospital inpatients and to investigate the effect of two intervention functions: restriction and enablement. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library), MEDLINE, and Embase. We searched for additional studies using the bibliographies of included articles and personal files. The last search from which records were evaluated and any studies identified incorporated into the review was January 2015. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and non-randomised studies (NRS). We included three non-randomised study designs to measure behavioural and clinical outcomes and analyse variation in the effects: non- randomised trials (NRT), controlled before-after (CBA) studies and interrupted time series (ITS) studies. For this update we also included three additional NRS designs (case control, cohort, and qualitative studies) to identify unintended consequences. Interventions included any professional or structural interventions as defined by the Cochrane Effective Practice and Organisation of Care Group. We defined restriction as 'using rules to reduce the opportunity to engage in the target behaviour (or increase the target behaviour by reducing the opportunity to engage in competing behaviours)'. We defined enablement as 'increasing means/reducing barriers to increase capability or opportunity'. The main comparison was between intervention and no intervention. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed study risk of bias. We performed meta-analysis and meta-regression of RCTs and meta-regression of ITS studies. We classified behaviour change functions for all interventions in the review, including those studies in the previously published versions. We analysed dichotomous data with a risk difference (RD). We assessed certainty of evidence with GRADE criteria. MAIN RESULTS: This review includes 221 studies (58 RCTs, and 163 NRS). Most studies were from North America (96) or Europe (87). The remaining studies were from Asia (19), South America (8), Australia (8), and the East Asia (3). Although 62% of RCTs were at a high risk of bias, the results for the main review outcomes were similar when we restricted the analysis to studies at low risk of bias.More hospital inpatients were treated according to antibiotic prescribing policy with the intervention compared with no intervention based on 29 RCTs of predominantly enablement interventions (RD 15%, 95% confidence interval (CI) 14% to 16%; 23,394 participants; high-certainty evidence). This represents an increase from 43% to 58% .There were high levels of heterogeneity of effect size but the direction consistently favoured intervention.The duration of antibiotic treatment decreased by 1.95 days (95% CI 2.22 to 1.67; 14 RCTs; 3318 participants; high-certainty evidence) from 11.0 days. Information from non-randomised studies showed interventions to be associated with improvement in prescribing according to antibiotic policy in routine clinical practice, with 70% of interventions being hospital-wide compared with 31% for RCTs. The risk of death was similar between intervention and control groups (11% in both arms), indicating that antibiotic use can likely be reduced without adversely affecting mortality (RD 0%, 95% CI -1% to 0%; 28 RCTs; 15,827 participants; moderate-certainty evidence). Antibiotic stewardship interventions probably reduce length of stay by 1.12 days (95% CI 0.7 to 1.54 days; 15 RCTs; 3834 participants; moderate-certainty evidence). One RCT and six NRS raised concerns that restrictive interventions may lead to delay in treatment and negative professional culture because of breakdown in communication and trust between infection specialists and clinical teams (low-certainty evidence).Both enablement and restriction were independently associated with increased compliance with antibiotic policies, and enablement enhanced the effect of restrictive interventions (high-certainty evidence). Enabling interventions that included feedback were probably more effective than those that did not (moderate-certainty evidence).There was very low-certainty evidence about the effect of the interventions on reducing Clostridium difficile infections (median -48.6%, interquartile range -80.7% to -19.2%; 7 studies). This was also the case for resistant gram-negative bacteria (median -12.9%, interquartile range -35.3% to 25.2%; 11 studies) and resistant gram-positive bacteria (median -19.3%, interquartile range -50.1% to +23.1%; 9 studies). There was too much variance in microbial outcomes to reliably assess the effect of change in antibiotic use. Heterogeneity of intervention effect on prescribing outcomesWe analysed effect modifiers in 29 RCTs and 91 ITS studies. Enablement and restriction were independently associated with a larger effect size (high-certainty evidence). Feedback was included in 4 (17%) of 23 RCTs and 20 (47%) of 43 ITS studies of enabling interventions and was associated with greater intervention effect. Enablement was included in 13 (45%) of 29 ITS studies with restrictive interventions and enhanced intervention effect. AUTHORS' CONCLUSIONS: We found high-certainty evidence that interventions are effective in increasing compliance with antibiotic policy and reducing duration of antibiotic treatment. Lower use of antibiotics probably does not increase mortality and likely reduces length of stay. Additional trials comparing antibiotic stewardship with no intervention are unlikely to change our conclusions. Enablement consistently increased the effect of interventions, including those with a restrictive component. Although feedback further increased intervention effect, it was used in only a minority of enabling interventions. Interventions were successful in safely reducing unnecessary antibiotic use in hospitals, despite the fact that the majority did not use the most effective behaviour change techniques. Consequently, effective dissemination of our findings could have considerable health service and policy impact. Future research should instead focus on targeting treatment and assessing other measures of patient safety, assess different stewardship interventions, and explore the barriers and facilitators to implementation. More research is required on unintended consequences of restrictive interventions.