Optimizing design of research to evaluate antibiotic stewardship interventions: consensus recommendations of a multinational working group

BackgroundAntimicrobial stewardship interventions and programmes aim to ensure effective treatment while minimizing antimicrobial-associated harms including resistance. Practice in this vital area is undermined by the poor quality of research addressing both what specific antimicrobial use interventions are effective and how antimicrobial use improvement strategies can be implemented into practice. In 2016 we established a working party to identify the key design features that limit translation of existing research into practice and then to make recommendations for how future studies in this field should be optimally designed. The first part of this work has been published as a systematic review. Here we present the working group's final recommendations.MethodsAn international working group for design of antimicrobial stewardship intervention evaluations was convened in response to the fourth call for leading expert network proposals by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR). The group comprised clinical and academic specialists in antimicrobial stewardship and clinical trial design from six European countries. Group members completed a structured questionnaire to establish the scope of work and key issues to develop ahead of a first face-to-face meeting that (a) identified the need for a comprehensive systematic review of study designs in the literature and (b) prioritized key areas where research design considerations restrict translation of findings into practice. The working group's initial outputs were reviewed by independent advisors and additional expertise was sought in specific clinical areas. At a second face-to-face meeting the working group developed a theoretical framework and specific recommendations to support optimal study design. These were finalized by the working group co-ordinators and agreed by all working group members.ResultsWe propose a theoretical framework in which consideration of the intervention rationale the intervention setting, intervention features and the intervention aims inform selection and prioritization of outcome measures, whether the research sets out to determine superiority or non-inferiority of the intervention measured by its primary outcome(s), the most appropriate study design (e.g. experimental or quasi- experimental) and the detailed design features. We make 18 specific recommendation in three domains: outcomes, objectives and study design.ConclusionsResearchers, funders and practitioners will be able to draw on our recommendations to most efficiently evaluate antimicrobial stewardship interventions.     

How to start an antimicrobial stewardship programme in a hospital

BackgroundAntimicrobial stewardship (AMS) describes a coherent set of actions that ensure optimal use of antimicrobials to improve patient outcomes, while limiting the risk of adverse events (including antimicrobial resistance (AMR)). Introduction of AMS programmes in hospitals is part of most national action plans to mitigate AMR, yet the optimal components and actions of such a programme remain undetermined.ObjectivesTo describe how health-care professionals can start an AMS programme in their hospital, the components of such a programme and the evidence base for its implementation.SourcesNational and society-led guidelines on AMS, peer-reviewed publications and experience of AMS experts conducting AMS programmes.ContentWe provide a step-by-step pragmatic guide to setting up and implementing a hospital AMS programme in high-income or low-and-middle-income countries.ImplicationsAntimicrobial stewardship programmes in hospitals are a vital component of national action plans for AMR, and have been shown to significantly reduce AMR, particularly when coupled with infection prevention and control interventions. This step-by-step guide of ‘how to’ set up an AMS programme will help health-care professionals involved in AMS to optimally design and implement their actions.     

Rapid microbiological tests for bloodstream infections due to multidrug resistant Gram-negative bacteria: therapeutic implications

BackgroundTreating severe infections due to multidrug-resistant Gram-negative bacteria (MDR-GNB) is one of the most important challenges for clinicians worldwide, partly because resistance may remain unrecognized until identification of the causative agent and/or antimicrobial susceptibility testing (AST). Recently, some novel rapid test for identification and/or AST of MDR-GNB from positive blood cultures or the blood of patients with bloodstream infections (BSIs) have become available.ObjectivesThe objective of this narrative review is to discuss the advantages and limitations of different rapid tests for identification and/or AST of MDR-GNB from positive blood cultures or the blood of patients with BSI, as well as the available evidence on their possible role to improve therapeutic decisions and antimicrobial stewardship.SourcesInductive PubMed search for publications relevant to the topic.ContentThe present review is structured in the following way: (a) rapid tests on positive blood cultures; (b) rapid tests directly on whole blood; (c) therapeutic implications.ImplicationsNovel molecular and phenotypic rapid tests for identification and AST show the potential for favourably influencing patients' outcomes and results of antimicrobial stewardship interventions by reducing both the time to effective treatment and the misuse of antibiotics, although the interpretation about their impact on actual therapeutic decisions and patients' outcomes is still complex. Factors such as feasibility and personnel availability, as well as the detailed knowledge of the local microbiological epidemiology, need to be considered very carefully when implementing novel rapid tests in laboratory workflows and algorithms. Providing high-level, comparable evidence on the clinical impact of rapid identification and AST is becoming of paramount importance for MDR-GNB infections, since in the near future rapid identification of specific resistance mechanisms could be crucial for guiding rapid, effective, and targeted therapy against specific resistance mechanisms.     

Post-discharge oral antimicrobial use among hospitalized patients across an integrated national healthcare network

ObjectivesAntimicrobial stewardship programmes have focused on reducing inappropriate inpatient antimicrobial prescribing, but several small studies have found a large portion of antimicrobial exposure occurs immediately after hospital discharge. In this study, we describe the prescribing of oral antimicrobials at hospital discharge across an integrated national healthcare system. At the hospital level, we also compare total inpatient antimicrobial use and post-discharge oral antimicrobial use.MethodsThis retrospective cross-sectional study used national administrative data to identify all acute-care admissions during 2014–2016 within the Veterans Health Administration (VHA). We evaluated inpatient days of therapy (DOT) and post-discharge DOT, defined as oral outpatient antimicrobials dispensed at the time of hospital discharge. At the hospital level, inpatient DOT/100 admissions were compared with post-discharge DOT/100 admissions using Spearman's rank-order correlation.ResultsThere were 1 681 701 acute-care admissions across 122 hospitals, and 335 369 (19.9%) were prescribed an oral antimicrobial at discharge. Fluoroquinolones (38.3%) were the most common post-discharge antimicrobial. At the hospital level, median inpatient antimicrobial use was 331.3 (interquartile range (IQR) 284.9–367.9) DOT/100 admissions and median post-discharge use was 209.5 (IQR 181.5–239.6) DOT/100 admissions. Thirty-nine per cent of the total duration of antimicrobial exposure occurred after discharge. At the hospital-level, the metrics of inpatient DOT/100 admissions and post-discharge DOT/100 admissions were weakly positively correlated with rho=0.44 (p < 0.001).ConclusionsA large proportion of antimicrobial exposure among hospitalized patients occurred immediately following discharge. Antimicrobial-prescribing at hospital discharge provides an opportunity for antimicrobial stewardship. Hospital-level stewardship metrics need to include both inpatient and post-discharge antimicrobial-prescribing to provide a comprehensive assessment of hospital-associated antimicrobial use.     

Indications for medical antibiotic prophylaxis and potential targets for antimicrobial stewardship intervention: a narrative review

BackgroundMost of the antimicrobial stewardship (AMS) literature has focused on antimicrobial consumption for the treatment of infections, for the prophylaxis of surgical site infection and for the prevention of endocarditis. The role of AMS for medical antibiotic prophylaxis (AP) has not been adequately addressed.AimsTo identify targets for AMS interventions for medical AP in adult patients.SourcesTargeted searches were conducted in PubMed.ContentThe various indications for medical AP and relevant evidence from practice guidelines are outlined. The following were identified as potential targets for AMS interventions: (a) addressing under-utilization of antibiotic-sparing strategies (e.g. for recurrent urinary tract infections, recurrent soft-tissue infections, recurrent exacerbations associated with bronchiectasis or chronic obstructive pulmonary disease), (b) reducing unnecessary AP beyond recommended indications (e.g. for acute pancreatitis, bite wounds, or urinary catheter manipulations), (c) reducing the use of AP with a broader spectrum than necessary, (d) reducing the use of AP for longer than the recommended duration (e.g. AP for prevention of osteomyelitis in open fractures or AP in high-risk neutropenia), (e) evaluating the role of antibiotic cycling to prevent the emergence of resistance during prolonged AP (e.g. in recurrent urinary tract infections or prophylaxis for spontaneous bacterial peritonitis), and (f) addressing research gaps regarding appropriate indications or antibiotic regimens for medical prophylaxis.ImplicationsThis review summarizes current trends in AP and proposes targets for AMS interventions.     

Human resources required for antimicrobial stewardship teams: a Dutch consensus report

ScopeAntimicrobial stewardship teams are responsible for implementing antimicrobial stewardship programmes (ASP). However, in many countries, lack of funding challenges this obligation. A consensus procedure was performed to investigate which structural activities need to be performed by Dutch stewardship teams and how much time (and thus full-time equivalent (FTE) labor) is needed to perform these activities.MethodsIn 2015, an electronic survey, based on a nonsystematic literature search and interviews with seven experienced stewardship teams, was sent to 21 stewardship teams that performed an ASP. This was followed by a semistructured face-to-face consensus meeting. Fourteen stewardship teams completed the survey (18% of Dutch acute-care hospitals), and 13 participated in the consensus meeting.RecommendationsThe hours needed each year are dependent on hospital size and number of stewardship objectives monitored. If all activities are performed at a minimal base (one stewardship objective; minimal staffing standard), time investment was estimated to be 1393 to 2680 hours annually in the early phase, corresponding with 0.87 (300 beds) to 1.68 FTE (1200 beds), with a further increase to minimally 1.25 to 3.18 FTE in the following years with three stewardship objectives monitored (optimal staffing standards during the first few years of implementing an ASP). This consensus on required human resources provides a directive for structural financial support of stewardship teams in the Dutch context. Some stewardship activities (and related time investments) might be specific to the Dutch context and hospital setting. To develop standards for other settings, our methodology could be applied.     

Outcomes of the PIRASOA programme,an antimicrobial stewardship programme implemented in hospitals of the Public Health System of Andalusia,Spain: an ecologic study of time-trend analysis

ObjectivesInappropriate antimicrobial use favours the spread of resistance, and multidrug-resistant microorganisms (MDR) are currently of major concern. Antimicrobial stewardship programmes (ASPs) are essential for improving antibiotic use in hospitals. However, their impact on entire healthcare systems has not been thoroughly assessed. Our objective was to provide the results of an institutionally supported ASP involving 31 public hospitals in Andalusia, Spain.MethodsWe designed an ecologic time-series study from 1 January 2014 to 31 December 2017. Quarterly, data on indicators were collected prospectively, and feedback reports were provided. PIRASOA is an ongoing clinically based quality-improvement programme whose key intervention is the educational interview, regular peer-to-peer interventions between advisors and prescribers to reinforce the appropriate use of antibiotics. Seventy-two indicators were monitored to measure prescribing quality (inappropriate treatments), antimicrobial consumption (defined daily doses per 1000 occupied bed-days), incidence density of MDR per 1000 occupied bed-days and crude mortality rate associated with bloodstream infections. We used Joinpoint regression software to analyse the trends.ResultsThe quality of antimicrobial prescribing improved markedly, and the inappropriate treatment rate was significantly lower, with quarterly percentage change (QPC) = −3.0%, p < 0.001. Total antimicrobial consumption decreased (QPC = −0.9%, p < 0.001), specifically carbapenems, amoxicillin/clavulanic acid, quinolones and antifungal agents, whereas antipseudomonal cephalosporin use increased. While the incidence of MDR showed a sustained decreasing trend (QPC = −1.8%; p 0.002), the mortality of patients with bloodstream infections remained stable (QPC = −0.2%, p 0.605).ConclusionsTo date, the PIRASOA programme has succeeded in optimizing the use of antimicrobial agents and has had a positive ecologic result on bacterial resistance at level of an entire healthcare system.     

Antibiotic resistance associated with the COVID-19 pandemic: a systematic review and meta-analysis

BackgroundCOVID-19 and antimicrobial resistance (AMR) are two intersecting global public health crises.ObjectiveWe aimed to describe the impact of the COVID-19 pandemic on AMR across health care settings.Data sourceA search was conducted in December 2021 in WHO COVID-19 Research Database with forward citation searching up to June 2022.Study eligibilityStudies evaluating the impact of COVID-19 on AMR in any population were included and influencing factors were extracted. Reporting of enhanced infection prevention and control and/or antimicrobial stewardship programs was noted.MethodsPooling was done separately for Gram-negative and Gram-positive organisms. Random-effects meta-analysis was performed.ResultsOf 6036 studies screened, 28 were included and 23 provided sufficient data for meta-analysis. The majority of studies focused on hospital settings (n = 25, 89%). The COVID-19 pandemic was not associated with a change in the incidence density (incidence rate ratio 0.99, 95% CI: 0.67–1.47) or proportion (risk ratio 0.91, 95% CI: 0.55–1.49) of methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci cases. A non-statistically significant increase was noted for resistant Gram-negative organisms (i.e. extended-spectrum beta-lactamase, carbapenem-resistant Enterobacterales, carbapenem or multi-drug resistant or carbapenem-resistant Pseudomonas aeruginosa or Acinetobacter baumannii, incidence rate ratio 1.64, 95% CI: 0.92–2.92; risk ratio 1.08, 95% CI: 0.91–1.29). The absence of reported enhanced infection prevention and control and/or antimicrobial stewardship programs initiatives was associated with an increase in gram-negative AMR (risk ratio 1.11, 95% CI: 1.03–1.20). However, a test for subgroup differences showed no statistically significant difference between the presence and absence of these initiatives (p 0.40).ConclusionThe COVID-19 pandemic may have hastened the emergence and transmission of AMR, particularly for Gram-negative organisms in hospital settings. But there is considerable heterogeneity in both the AMR metrics used and the rate of resistance reported across studies. These findings reinforce the need for strengthened infection prevention, antimicrobial stewardship, and AMR surveillance in the context of the COVID-19 pandemic.     

Diagnosis of bloodstream infections from positive blood cultures and directly from blood samples: recent developments in molecular approaches

BackgroundBloodstream infections are a major cause of death with increasing incidence and severity. Blood cultures are still the reference standard for microbiological diagnosis, but are rather slow. Molecular methods can be used as add-on complementary assays. They can be useful to speed up microbial identification and to predict antimicrobial susceptibility, applied to direct blood samples or positive blood cultures.AimTo review recent developments in molecular-based diagnostic platforms used for the identification of bloodstream infections, with a focus on assays performed directly on blood samples and positive blood cultures.SourcesPeer reviewed articles, conference abstracts, and manufacturers' websites.ContentWe give an update on recent developments of molecular methods in diagnosing BSIs. We first describe the currently available molecular methods to be used for positive blood cultures including: a) in situ hybridization-based methods; b) DNA-microarray-based hybridization technology; c) nucleic acid amplification-based methods; and d) combined methods. Subsequently, molecular methods applied directly to whole blood samples are discussed, including the use of nucleic acid amplification-based methods, T2 magnetic resonance-based methods, and metagenomics for diagnosing BSIs.ImplicationsAdvances in molecular-based methods complementary to conventional blood culture diagnostics and antimicrobial stewardship programmes may optimize infection management by allowing rapid identification of pathogens and relevant antimicrobial resistance genes. Rapid diagnosis of the causing microorganism and relevant resistance determinants is important for early administration and modification of appropriate antimicrobial therapy. Ultimately, this may lead to improved quality and cost-effectiveness of health care, as well as reduced antimicrobial resistance selection.     

The quality of studies evaluating antimicrobial stewardship interventions: a systematic review

BackgroundAntimicrobial stewardship aims to optimize antibiotic use and minimize selection of antimicrobial resistance. The methodological quality of published studies in this field is unknown.AimsOur objective was to perform a comprehensive systematic review of antimicrobial stewardship research design and identify features which limit validity and translation of research findings into clinical practice.SourcesThe following online database was searched: PubMed.Study eligibility criteriaStudies published between January 1950 and January 2017, evaluating any antimicrobial stewardship intervention in the community or hospital setting, without restriction on study design or outcome.ContentWe extracted data on pre-specified design quality features and factors that may influence design choices including (1) clinical setting, (2) age group studied, (3) when the study was conducted, (4) geographical region, and (5) financial support received. The initial search yielded 17 382 articles; 1008 were selected for full-text screening, of which 825 were included. Most studies (675/825, 82%) were non-experimental; 104 (15%) used interrupted time series analysis, 41 (6%) used external controls, and 19 (3%) used both. Studies in the community setting fulfilled a median of five out of 10 quality features (IQR 3–7) and 3 (IQR 2–4) in the hospital setting. Community setting studies (25%, 205/825) were significantly more likely to use randomization (OR 5.9; 95% CI 3.8–9.2), external controls (OR 5.6; 95% CI 3.6–8.5), and multiple centres (OR 10.5; 95% CI 7.1–15.7). From all studies, only 48% (398/825) reported clinical and 23% (190/825) reported microbiological outcomes. Quality did not improve over time.ImplicationsOverall quality of antimicrobial stewardship studies is low and has not improved over time. Most studies do not report clinical and microbiological outcome data. Studies conducted in the community setting were associated with better quality. These limitations should inform the design of future stewardship evaluations so that a robust evidence base can be built to guide clinical practice.     

Global epidemiology of antimicrobial resistance in commensal Neisseria species: A systematic review

BackgroundCommensal Neisseria species (spp). represent an important reservoir of antimicrobial resistance genes for pathogenic Neisseria spp. In this systematic review, we aimed to assess the antimicrobial susceptibility of commensal Neisseria spp. and how this has evolved over time. We also aimed to assess if commensal Neisseria spp. showed intrinsic resistance to four antimicrobials - penicillin, azithromycin, ceftriaxone and ciprofloxacin.MethodsPubmed and Google Scholar were searched following the PRISMA guidelines. Articles reporting MICs of commensal Neisseria spp. were included according to inclusion/exclusion criteria, and the quality of the articles was assessed using a pre-designed tool. Individual and summary measures of penicillin, azithromycin, ceftriaxone and ciprofloxacin MICs were collected. Additional data was sought to perform a comparison between the MICs of pathogenic and commensal Neisseria spp.ResultsA total of 15 studies met our criteria.We found no evidence of intrinsic AMR in commensal Neisseria spp. We did find evidence of an increasing trend in MICs of commensal Neisseria spp. over time for all antimicrobials assessed. These findings were similar in various countries. Eight additional studies were included to compare pathogenic and commensal Neisseria spp.ConclusionThe MICs of commensal Neisseria spp. appear to be increasing in multiple countries. Surveillance of MICs in commensals could be used as an early warning system for antimicrobial resistance emergence in pathogens. Our findings underline the need for antibiotic stewardship interventions, particularly in populations with high antimicrobial consumption.     

The effectiveness of information technology to improve antimicrobial prescribing in hospitals: A systematic review and meta-analysis

ObjectiveTo review evidence of the effectiveness of information technology (IT) interventions to improve antimicrobial prescribing in hospitals.MethodMEDLINE (1950-March 2015), EMBASE (1947-March 2015) and PubMED (1966-March 2015) were searched for studies where an IT intervention involving any device (e.g. computer, mobile phone) was evaluated in practice. All papers were assessed for quality using a 10-point rating scale.ResultsWe identified 45 articles that evaluated an IT intervention to improve antimicrobial prescribing in hospitals. IT interventions took four main forms: (1) stand-alone computerized decision support systems (CDSSs), (2) decision support embedded within a hospital’s electronic medical record (EMR) or computerized provider order entry (CPOE) system, (3) computerized antimicrobial approval systems (cAAS), and (4) surveillance systems (SSs). Results reported allowed us to perform meta-analyses for three outcome measures: appropriate use of antimicrobials, patient mortality and hospital length of stay (LOS). IT interventions increased appropriate use of antimicrobials (pooled RR: 1.49, 95%CI: 1.07–2.08); however no evidence of an effect was found when analysis included only studies with a quality score of five or above on the 10-point quality scale (pooled RR: 1.53, 95%CI: 0.96–2.44). There was little evidence of an effect of IT interventions on patient mortality or LOS. The range of study designs and outcome measures prevented meaningful comparisons between different IT intervention types to be made.ConclusionIT interventions can improve the appropriateness of antimicrobial prescribing. However, high quality, systematic multi-site comparative studies are critically needed to assist organizations in making informed decisions about the most effective IT interventions.     

Enhanced antimicrobial stewardship based on rapid phenotypic antimicrobial susceptibility testing for bacteraemia in patients with haematological malignancies: a randomized controlled trial

ObjectivesRecently, rapid phenotypic antimicrobial susceptibility testing (AST) based on microscopic imaging analysis has been developed. The aim of this study was to determine whether implementation of antimicrobial stewardship programmes (ASP) based on rapid phenotypic AST can increase the proportion of patients with haematological malignancies who receive optimal targeted antibiotics during early periods of bacteraemia.MethodsThis randomized controlled trial enrolled patients with haematological malignancies and at least one positive blood culture. Patients were randomly assigned 1:1 to conventional (n = 60) or rapid phenotypic (n = 56) AST. The primary outcome was the proportion of patients receiving optimal targeted antibiotics 72 hr after blood collection for culture.ResultsThe percentage receiving optimal targeted antibiotics at 72 hr was significantly higher in the rapid phenotypic AST group (45/56, 80.4%) than in conventional AST group (34/60, 56.7%) (relative risk (RR) 1.42, 95% confidence interval (CI) 1.09–1.83). The percentage receiving unnecessary broad-spectrum antibiotics at 72 hr was significantly lower (7/26, 12.5% vs 18/60, 30.0%; RR 0.42, 95% CI 0.19–0.92) and the mean time to optimal targeted antibiotic treatment was significantly shorter (38.1, standard deviation (SD) 38.2 vs 72.8, SD 93.0 hr; p < 0.001) in the rapid phenotypic AST group. The mean time from blood collection to the AST result was significantly shorter in the rapid phenotypic AST group (48.3, SD 17.6 vs 83.1, SD 22.2 hr).DiscussionASP based on rapid phenotypic AST can rapidly optimize antibiotic treatment for bacteraemia in patients with haematological malignancy. Rapid phenotypic AST can improve antimicrobial stewardship in immunocompromised patients.     

Effect of an antimicrobial stewardship programme on antimicrobial utilisation and costs in patients with leukaemia: a retrospective controlled study

ObjectivesTo examine the effectiveness of an antimicrobial stewardship programme on utilization and cost of antimicrobials in leukaemia patients in Canada.MethodsWe conducted a multisite retrospective observational time series study from 2005 to 2013. We implemented academic detailing as the intervention of an antimicrobial stewardship programme in leukaemia units at a hospital, piloted February–July 2010, then fully implemented December 2010–March 2013, with no intervention in August–November 2010. Internal control was the same hospital's allogeneic haematopoietic stem-cell transplantation unit. External control was the combined leukaemia–haematopoietic stem-cell transplantation unit at another hospital. Primary outcome was antimicrobial utilization (antibiotics and antifungals) in defined daily dose per 100 patient-days (PD). Secondary outcomes were antimicrobial cost (Canadian dollars per PD); cost and utilization by drug class; length of stay; 30-day inpatient mortality; and nosocomial Clostridium difficile infection. We used autoregressive integrated moving average models to evaluate the impact of the intervention on outcomes.ResultsThe intervention group included 1006 patients before implementation and 335 during full implementation. Correspondingly, internal control had 723 and 264 patients, external control 1395 and 864 patients. Antimicrobial utilization decreased significantly in the intervention group (p <0.01, 278 vs. 247 defined daily dose per 100 PD), increased in external control (p = 0.02, 237.4 vs. 268.9 defined daily dose per 100 PD) and remained stable in internal control (p = 0.66). Antimicrobial cost decreased in the intervention group (p = 0.03; $154.59 per PD vs. $128.93 per PD), increased in external control (p = 0.01; $109.4 per PD vs. $135.97 per PD) but was stable in internal control (p = 0.27). Mortality, length of stay and nosocomial C. difficile rate in intervention group remained stable.ConclusionsThe antimicrobial stewardship programme reduced antimicrobial use in leukaemia patients without affecting inpatient mortality and length of stay.