Community antibiotic prescribing in patients with COVID-19 across three pandemic waves: a population-based study in Scotland, UK.

OBJECTIVES: This study aims to examine community antibiotic prescribing across a complete geographical area for people with a positive COVID-19 test across three pandemic waves, and to examine health and demographic factors associated with antibiotic prescribing. DESIGN: A population-based study using administrative data. SETTING: A complete geographical region within Scotland, UK. PARTICIPANTS: Residents of two National Health Service Scotland health boards with SARS-CoV-2 virus test results from 1 February 2020 to 31 March 2022 (n=184 954). Individuals with a positive test result (n=16 025) had data linked to prescription and hospital admission data ±28 days of the test, general practice data for high-risk comorbidities and demographic data. OUTCOME MEASURES: The associations between patient factors and the odds of antibiotic prescription in COVID-19 episodes across three pandemic waves from multivariate binary logistic regression. RESULTS: Data included 768 206 tests for 184 954 individuals, identifying 16 240 COVID-19 episodes involving 16 025 individuals. There were 3263 antibiotic prescriptions ±28 days for 2395 episodes. 35.6% of episodes had a prescription only before the test date, 52.3% of episodes after and 12.1% before and after. Antibiotic prescribing reduced over time: 20.4% of episodes in wave 1, 17.7% in wave 2 and 12.0% in wave 3. In multivariate logistic regression, being female (OR 1.31, 95% CI 1.19 to 1.45), older (OR 3.02, 95% CI 2.50 to 3.68 75+ vs <25 years), having a high-risk comorbidity (OR 1.45, 95% CI 1.31 to 1.61), a hospital admission ±28 days of an episode (OR 1.58, 95% CI 1.42 to 1.77) and health board region (OR 1.14, 95% CI 1.03 to 1.25, board B vs A) increased the odds of receiving an antibiotic. CONCLUSION: Community antibiotic prescriptions in COVID-19 episodes were uncommon in this population and likelihood was associated with patient factors. The reduction over pandemic waves may represent increased knowledge regarding COVID-19 treatment and/or evolving symptomatology.

Clinical and Genomic Evolution of Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections over Two Time Periods at a Tertiary Care Hospital in South India: A Prospective Cohort Study.

INTRODUCTION: The objective of this study was to examine the evolution of carbapenem-resistant Klebsiella pneumoniae (CRKp) infections and their impact at a tertiary care hospital in South India. METHODS: A comparative analysis of clinical data from two prospective cohorts of patients with CRKp bacteremia (C1, 2014-2015; C2, 2021-2022) was carried out. Antimicrobial susceptibilities and whole genome sequencing (WGS) data of selected isolates were also analyzed. RESULTS: A total of 181 patients were enrolled in the study, 56 from C1 and 125 from C2. CRKp bacteremia shifted from critically ill patients with neutropenia to others (ICU stay: C1, 73%; C2, 54%; p = 0.02). The overall mortality rate was 50% and the introduction of ceftazidime-avibactam did not change mortality significantly (54% versus 48%; p = 0.49). Oxacillinases (OXA) 232 and 181 were the most common mechanisms of resistance. WGS showed the introduction of New Delhi metallo-ß-lactamase-5 (NDM-5), higher genetic diversity, accessory genome content, and plasmid burden, as well as increased convergence of hypervirulence and carbapenem resistance in C2. CONCLUSIONS: CRKp continues to pose a significant clinical threat, despite the introduction of new antibiotics. The study highlights the evolution of resistance and virulence in this pathogen and the impact on patient outcomes in South India, providing valuable information for clinicians and researchers.

Performance of bedside tools for predicting infection-related mortality and administrative data for sepsis surveillance: An observational cohort study.

BACKGROUND: Measuring sepsis incidence and associated mortality at scale using administrative data is hampered by variation in diagnostic coding. This study aimed first to compare how well bedside severity scores predict 30-day mortality in hospitalised patients with infection, then to assess the ability of combinations of administrative data items to identify patients with sepsis. METHODS: This retrospective case note review examined 958 adult hospital admissions between October 2015 and March 2016. Admissions with blood culture sampling were matched 1:1 to admissions without a blood culture. Case note review data were linked to discharge coding and mortality. For patients with infection the performance characteristics of Sequential Organ Failure Assessment (SOFA), National Early Warning System (NEWS), quick SOFA (qSOFA), and Systemic Inflammatory Response Syndrome (SIRS) were calculated for predicting 30-day mortality. Next, the performance characteristics of administrative data (blood cultures and discharge codes) for identifying patients with sepsis, defined as SOFA ≥2 because of infection, were calculated. RESULTS: Infection was documented in 630 (65.8%) admissions and 347 (55.1%) patients with infection had sepsis. NEWS (Area Under the Receiver Operating Characteristic, AUROC 0.78 95%CI 0.72-0.83) and SOFA (AUROC 0.77, 95%CI 0.72-0.83), performed similarly well for prediction of 30-day mortality. Having an infection and/or sepsis International Classification of Diseases, Tenth Revision (ICD-10) code (AUROC 0.68, 95%CI 0.64-0.71) performed as well in identifying patients with sepsis as having at least one of: an infection code; sepsis code, or; blood culture (AUROC 0.68, 95%CI 0.65-0.71), Sepsis codes (AUROC 0.53, 95%CI 0.49-0.57) and positive blood cultures (AUROC 0.52, 95%CI 0.49-0.56) performed least well. CONCLUSIONS: SOFA and NEWS best predicted 30-day mortality in patients with infection. Sepsis ICD-10 codes lack sensitivity. For health systems without suitable electronic health records, blood culture sampling has potential utility as a clinical component of a proxy marker for sepsis surveillance.

In Vitro Activity of Two Cefepime-Based Novel Combinations, Cefepime/Taniborbactam and Cefepime/Zidebactam, against Carbapenemase-Expressing Enterobacterales Collected in India.

In recent times, discovery efforts for novel antibiotics have mostly targeted carbapenemase-producing Gram-negative organisms. Two different combination approaches are pertinent: ß-lactam-ß-lactamase inhibitor (BL/BLI) or ß-lactam-ß-lactam enhancer (BL/BLE). Cefepime combined with a BLI, taniborbactam, or with a BLE, zidebactam, has been shown to be promising. In this study, we determined the in vitro activity of both these agents along with comparators against multicentric carbapenemase-producing Enterobacterales (CPE). Nonduplicate CPE isolates of Escherichia coli (n = 270) and Klebsiella pneumoniae (n = 300), collected from nine different tertiary-care hospitals across India during 2019 to 2021, were included in the study. Carbapenemases in these isolates were detected by PCR. E. coli isolates were also screened for the presence of the 4-amino-acid insert in penicillin binding protein 3 (PBP3). MICs were determined by reference broth microdilution. Higher MICs of cefepime/taniborbactam (>8 mg/L) were linked to NDM, both in K. pneumoniae and in E. coli. In particular, such higher MICs were observed in 88 to 90% of E. coli isolates producing NDM and OXA-48-like or NDM alone. On the other hand, OXA-48-like-producing E. coli or K. pneumoniae isolates were nearly 100% susceptible to cefepime/taniborbactam. Regardless of the carbapenemase types and the pathogens, cefepime/zidebactam showed potent activity (>99% inhibited at ≤8 mg/L). It seems that the 4-amino-acid insert in PBP3 (present universally in the study E. coli isolates) along with NDM adversely impact the activity of cefepime/taniborbactam. Thus, the limitations of the BL/BLI approach in tackling the complex interplay of enzymatic and nonenzymatic resistance mechanisms were better revealed in whole-cell studies where the activity observed was a net effect of ß-lactamase inhibition, cellular uptake, and target affinity of the combination. IMPORTANCE The study revealed the differential ability of cefepime/taniborbactam and cefepime/zidebactam in tackling carbapenemase-producing Indian clinical isolates that also harbored additional mechanisms of resistance. NDM-expressing E. coli with 4-amino-acid insert in PBP3 are predominately resistant to cefepime/taniborbactam, while the ß-lactam enhancer mechanism-based cefepime/zidebactam showed consistent activity against single- or dual-carbapenemase-producing isolates including E. coli with PBP3 inserts.

Feedback of Antibiotic Prescribing in Primary Care (FAPPC) trial: results of a real-world cluster randomized controlled trial in Scotland, UK.

OBJECTIVES: To evaluate the effect of general practice-level prescribing feedback on antibiotic prescribing in a real-world pragmatic cluster randomized controlled trial. METHODS: Three hundred and forty general practices in four territorial Health Boards in NHS Scotland were randomized in Quarter 1, 2016 to receive four quarterly antibiotic-prescribing feedback reports or not, from Quarter 2, 2016 to Quarter 1, 2017. Reports included different clinical topics, benchmarking against national and health board rates, and behavioural messaging with improvement actions. The primary outcome was total antibiotic prescribing rate. There were 16 secondary prescribing outcomes and 5 hospital admission outcomes (potential adverse effects of reduced prescribing). The main evaluation timepoint was 1 year after the final report (Quarter 1, 2018), with an additional evaluation in the quarter after the final report (Quarter 2, 2017). Routine administrative NHS data were used to generate the feedback reports and analyse the effects. RESULTS: Total antibiotic prescribing rates were lower at the main evaluation timepoint in both intervention (1.83 versus baseline 1.93 prescriptions/1000 patients/day) and control (1.90 versus baseline 1.98) practices, with no evidence of intervention effect [adjusted rate ratio (ARR) 0.98 (95% CI 0.94-1.02; P = 0.35)]. At the additional timepoint, adjusted total antibiotic prescribing rates were 1.67 and 1.73 prescriptions/1000 patients/day, with evidence of a small intervention effect, ARR 0.99 (0.98-1.00; P = 0.03). CONCLUSIONS: This well-designed, practice-level antibiotic-prescribing feedback had limited evidence of additional effects in the context of decreasing antibiotic prescribing and an established national stewardship programme.

Associations between declining antibiotic use in primary care in Scotland and hospitalization with infection and patient satisfaction: longitudinal population study.

BACKGROUND: Reducing antibiotic use is central to antimicrobial stewardship, but may have unintended consequences. OBJECTIVES: To examine associations between size of decline in antibiotic prescriptions in general practices and (i) rate of hospitalization for infection and (ii) patient satisfaction. METHODS: Routine data analysis for all general practices in Scotland, quarter one 2012 (Q1 2012) to quarter one 2018 (Q1 2018). Practices were grouped into quartiles of rate of change in prescribing and changes in rates of hospitalization were compared across groups. For satisfaction analysis, associations between practice-level patient satisfaction in 2017-18 (Scottish Health and Care Experience Survey) and prior change in antibiotic prescription were examined. RESULTS: Antibiotic prescriptions overall fell from 194.1 prescriptions/1000 patients in Q1 2012 to 165.3 in Q1 2018 (14.9% reduction). The first quartile of practices had a non-significant increase in prescriptions [change per quarter = 0.22 (95% CI -0.42 to 0.86) prescriptions/1000 patients], compared with large reductions in the other three groups, largest in quartile four: -2.95 (95% CI -3.66 to -2.24) prescriptions/1000 patients/quarter (29.7% reduction overall). In all quartiles, hospitalizations with infection increased. The increase was smallest in quartile four (the biggest reduction in prescriptions) and highest in quartile one (no significant change in prescriptions): 2.18 (95% CI 1.18 to 3.19) versus 3.68 (95% CI 2.64 to 4.73) admissions/100 000 patients/quarter, respectively [difference = - 1.50 (95% CI -2.91 to -0.10)]. There was no statistically significant association between change in antibiotic prescriptions and patient satisfaction. CONCLUSIONS: Very large reductions in antibiotic prescriptions in Scottish general practices have not been associated with increases in hospitalization with infection or changes in patient satisfaction.

A behavioural approach to specifying interventions: what insights can be gained for the reporting and implementation of interventions to reduce antibiotic use in hospitals?

BACKGROUND: Reducing unnecessary antibiotic exposure is a key strategy in reducing the development and selection of antibiotic-resistant bacteria. Hospital antimicrobial stewardship (AMS) interventions are inherently complex, often requiring multiple healthcare professionals to change multiple behaviours at multiple timepoints along the care pathway. Inaction can arise when roles and responsibilities are unclear. A behavioural perspective can offer insights to maximize the chances of successful implementation. OBJECTIVES: To apply a behavioural framework [the Target Action Context Timing Actors (TACTA) framework] to existing evidence about hospital AMS interventions to specify which key behavioural aspects of interventions are detailed. METHODS: Randomized controlled trials (RCTs) and interrupted time series (ITS) studies with a focus on reducing unnecessary exposure to antibiotics were identified from the most recent Cochrane review of interventions to improve hospital AMS. The TACTA framework was applied to published intervention reports to assess the extent to which key details were reported about what behaviour should be performed, who is responsible for doing it and when, where, how often and with whom it should be performed. RESULTS: The included studies (n = 45; 31 RCTs and 14 ITS studies with 49 outcome measures) reported what should be done, where and to whom. However, key details were missing about who should act (45%) and when (22%). Specification of who should act was missing in 79% of 15 interventions to reduce duration of treatment in continuing-care wards. CONCLUSIONS: The lack of precise specification within AMS interventions limits the generalizability and reproducibility of evidence, hampering efforts to implement AMS interventions in practice.

Changes in resistance among coliform bacteraemia associated with a primary care antimicrobial stewardship intervention: A population-based interrupted time series study.

BACKGROUND: Primary care antimicrobial stewardship interventions can improve antimicrobial prescribing, but there is less evidence that they reduce rates of resistant infection. This study examined changes in broad-spectrum antimicrobial prescribing in the community and resistance in people admitted to hospital with community-associated coliform bacteraemia associated with a primary care stewardship intervention. METHODS AND FINDINGS: Segmented regression analysis of data on all patients registered with a general practitioner in the National Health Service (NHS) Tayside region in the east of Scotland, UK, from 1 January 2005 to 31 December 2015 was performed, examining associations between a primary care antimicrobial stewardship intervention in 2009 and primary care prescribing of fluoroquinolones, cephalosporins, and co-amoxiclav and resistance to the same three antimicrobials/classes among community-associated coliform bacteraemia. Prescribing outcomes were the rate per 1,000 population prescribed each antimicrobial/class per quarter. Resistance outcomes were proportion of community-associated (first 2 days of hospital admission) coliform (Escherichia coli, Proteus spp., or Klebsiella spp.) bacteraemia among adult (18+ years) patients resistant to each antimicrobial/class. 11.4% of 3,442,205 oral antimicrobial prescriptions dispensed in primary care over the study period were for targeted antimicrobials. There were large, statistically significant reductions in prescribing at 1 year postintervention that were larger by 3 years postintervention when the relative reduction was -68.8% (95% CI -76.3 to -62.1) and the absolute reduction -6.3 (-7.6 to -5.2) people exposed per 1,000 population per quarter for fluoroquinolones; relative -74.0% (-80.3 to -67.9) and absolute reduction -6.1 (-7.2 to -5.2) for cephalosporins; and relative -62.3% (-66.9 to -58.1) and absolute reduction -6.8 (-7.7 to -6.0) for co-amoxiclav, all compared to their prior trends. There were 2,143 eligible bacteraemia episodes involving 2,004 patients over the study period (mean age 73.7 [SD 14.8] years; 51.4% women). There was no increase in community-associated coliform bacteraemia admissions associated with reduced community broad-spectrum antimicrobial use. Resistance to targeted antimicrobials reduced by 3.5 years postintervention compared to prior trends, but this was not statistically significant for co-amoxiclav. Relative and absolute changes were -34.7% (95% CI -52.3 to -10.6) and -63.5 (-131.8 to -12.8) resistant bacteraemia per 1,000 bacteraemia per quarter for fluoroquinolones; -48.3% (-62.7 to -32.3) and -153.1 (-255.7 to -77.0) for cephalosporins; and -17.8% (-47.1 to 20.8) and -63.6 (-206.4 to 42.4) for co-amoxiclav, respectively. Overall, there was reversal of a previously rising rate of fluoroquinolone resistance and flattening of previously rising rates of cephalosporin and co-amoxiclav resistance. The limitations of this study include that associations are not definitive evidence of causation and that potential effects of underlying secular trends in the postintervention period and/or of other interventions occurring simultaneously cannot be definitively excluded. CONCLUSIONS: In this population-based study in Scotland, compared to prior trends, there were very large reductions in community broad-spectrum antimicrobial use associated with the stewardship intervention. In contrast, changes in resistance among coliform bacteraemia were more modest. Prevention of resistance through judicious use of new antimicrobials may be more effective than trying to reverse resistance that has become established.

A Role for Tetracycline Selection in Recent Evolution of Agriculture-Associated Clostridium difficile PCR Ribotype 078.

The increasing clinical importance of human infections (frequently severe) caused by Clostridium difficile PCR ribotype 078 (RT078) was first reported in 2008. The severity of symptoms (mortality of ≤30%) and the higher proportion of infections among community and younger patients raised concerns. Farm animals, especially pigs, have been identified as RT078 reservoirs. We aimed to understand the recent changes in RT078 epidemiology by investigating a possible role for antimicrobial selection in its recent evolutionary history. Phylogenetic analysis of international RT078 genomes (isolates from 2006 to 2014, n = 400), using time-scaled, recombination-corrected, maximum likelihood phylogenies, revealed several recent clonal expansions. A common ancestor of each expansion had independently acquired a different allele of the tetracycline resistance gene tetM Consequently, an unusually high proportion (76.5%) of RT078 genomes were tetM positive. Multiple additional tetracycline resistance determinants were also identified (including efflux pump tet40), frequently sharing a high level of nucleotide sequence identity (up to 100%) with sequences found in the pig pathogen Streptococcus suis and in other zoonotic pathogens such as Campylobacter jejuni and Campylobacter coli Each RT078 tetM clonal expansion lacked geographic structure, indicating rapid, recent international spread. Resistance determinants for C. difficile infection-triggering antimicrobials, including fluoroquinolones and clindamycin, were comparatively rare in RT078. Tetracyclines are used intensively in agriculture; this selective pressure, plus rapid, international spread via the food chain, may explain the increased RT078 prevalence in humans. Our work indicates that the use of antimicrobials outside the health care environment has selected for resistant organisms, and in the case of RT078, has contributed to the emergence of a human pathogen.IMPORTANCEClostridium difficile PCR ribotype 078 (RT078) has multiple reservoirs; many are agricultural. Since 2005, this genotype has been increasingly associated with human infections in both clinical settings and the community. Investigations of RT078 whole-genome sequences revealed that tetracycline resistance had been acquired on multiple independent occasions. Phylogenetic analysis revealed a rapid, recent increase in numbers of closely related tetracycline-resistant RT078 (clonal expansions), suggesting that tetracycline selection has strongly influenced its recent evolutionary history. We demonstrate recent international spread of emergent, tetracycline-resistant RT078. A similar tetracycline-positive clonal expansion was also identified in unrelated nontoxigenic C. difficile, suggesting that this process may be widespread and may be independent of disease-causing ability. Resistance to typical C. difficile infection-associated antimicrobials (e.g., fluoroquinolones, clindamycin) occurred only sporadically within RT078. Selective pressure from tetracycline appears to be a key factor in the emergence of this human pathogen and the rapid international dissemination that followed, plausibly via the food chain.

Risk of acute kidney injury following community prescription of antibiotics: self-controlled case series.

BACKGROUND: Development of acute kidney injury (AKI) following the use of antibiotics such as sulphonamides, trimethoprim and aminoglycosides is a frequently described phenomenon. More recently, an association between fluoroquinolone use and AKI has been suggested. The aim of this study was to evaluate the risk of AKI as an unintended consequence of commonly prescribed antibiotics in a large community cohort using a method that fully adjusts for underlying patient characteristics, including potential unmeasured confounders. METHODS: A self-controlled case study was conducted and included all individuals aged 18 years and over in the Tayside region of Scotland who had a serum creatinine measured between 1 January 2004 and 31 December 2012. AKI episodes were defined using the Kidney Disease: Improving Global Outcomes definition. Data on oral community-prescribed antibiotics (penicillins, cephalosporins, fluoroquinolones, sulphonamides and trimethoprim, macrolides and nitrofurantoin) were collected for all individuals. Incidence rate ratios (IRRs) for AKI associated with antibiotic exposure versus time periods without antibiotic exposure were calculated. RESULTS: Combined use of sulphonamides, trimethoprim and nitrofurantoin rose by 47% and incidence of community-acquired AKI rose by 16% between 2008 and 2012. During the study period 12 777 individuals developed 14 900 episodes of AKI in the community, of which 68% was AKI Stage 1, 16% Stage 2 and 16% Stage 3. The IRR of AKI during any antibiotic use was 1.16 [95% confidence interval (CI) 1.10-1.23], and this was highest during sulphonamides or trimethoprim use; IRR 3.07 (95% CI 2.81-3.35). Fluoroquinolone and nitrofurantoin use was not associated with a significantly increased rate of AKI; IRR 1.13 (95% CI 0.94-1.35) and 1.16 (95% CI 0.91-1.50), respectively. CONCLUSIONS: Incidence of AKI rose by 16% between 2008 and 2012. In the same period the use of sulphonamides, trimethoprim and nitrofurantoin increased by 47%. A significant increased risk of AKI was seen with the use of sulphonamides and trimethoprim, but not with fluoroquinolones or nitrofurantoin.

Identifying care-home residents in routine healthcare datasets: a diagnostic test accuracy study of five methods.

Background: there is no established method to identify care-home residents in routine healthcare datasets. Methods matching patient's addresses to known care-home addresses have been proposed in the UK, but few have been formally evaluated. Study design: prospective diagnostic test accuracy study. Methods: four independent samples of 5,000 addresses from Community Health Index (CHI) population registers were sampled for two NHS Scotland Health Boards on 1 April 2017, with one sample of adults aged ≥65 years and one of all residents. To derive the reference standard, all 20,000 addresses were manually adjudicated as 'care-home address' or not. The performance of five methods (NHS Scotland assigned CHI Institution Flag, exact address matching, postcode matching, Phonics and Markov) was evaluated compared to the reference standard. Results: the CHI Institution Flag had a high PPV 97-99% in all four test sets, but poorer sensitivity 55-89%. Exact address matching failed in every case. Postcode matching had higher sensitivity than the CHI flag 78-90%, but worse PPV 77-85%. Area under the receiver operating curve values for Phonics and Markov scores were 0.86-0.95 and 0.93-0.98, respectively. Phonics score with cut-off ≥13 had PPV 92-97% with sensitivity 72-87%. Markov PPVs were 90-95% with sensitivity 69-90% with cut-off ≥29.6. Conclusions: more complex address matching methods greatly improve identification compared to the existing NHS Scotland flag or postcode matching, although no method achieved both sensitivity and positive predictive value > 95%. Choice of method and cut-offs will be determined by the specific needs of researchers and practitioners.

Effects of peri-operative nonsteroidal anti-inflammatory drugs on post-operative kidney function for adults with normal kidney function.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) provide effective analgesia during the post-operative period but can cause acute kidney injury (AKI) when used peri-operatively (at or around the time of surgery). This is an update of a Cochrane review published in 2007. OBJECTIVES: This review looked at the effect of NSAIDs used in the peri-operative period on post-operative kidney function in patients with normal kidney function. SEARCH METHODS: We searched Cochrane Kidney and Transplant's Specialised Register to 4 January 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at the use of NSAIDs versus placebo for the treatment of post-operative pain in patients with normal kidney function were included. DATA COLLECTION AND ANALYSIS: Data extraction was carried out independently by two authors as was assessment of risk of bias. Disagreements were resolved by a third author. Dichotomous outcomes are reported as relative risk (RR) and continuous outcomes as mean difference (MD) together with their 95% confidence intervals (CI). Meta-analyses were used to assess the outcomes of AKI, change in serum creatinine (SCr), urine output, renal replacement therapy (RRT), death (all causes) and length of hospital stay. MAIN RESULTS: We identified 26 studies (8835 participants). Risk of bias was high in 17, unclear in 6and low in three studies. There was high risk of attrition bias in six studies.Only two studies measured AKI. The use of NSAIDs had uncertain effects on the incidence of AKI compared to placebo (7066 participants: RR 1.79, 95% CI 0.40 to 7.96; I2 = 59%; very low certainty evidence). One study was stopped early by the data monitoring committee due to increased rates of AKI in the NSAID group. Moreover, both of these studies were examining NSAIDs for indications other than analgesia and therefore utilised relatively low doses.Compared to placebo, NSAIDs may slightly increase serum SCr (15 studies, 794 participants: MD 3.23 µmol/L, 95% CI -0.80 to 7.26; I2 = 63%; low certainty evidence). Studies displayed moderate to high heterogeneity and had multiple exclusion criteria including age and so were not representative of patients undergoing surgery. Three of these studies excluded patients if their creatinine rose post-operatively.NSAIDs may make little or no difference to post-operative urine output compared to placebo (6 studies, 149 participants: SMD -0.02, 95% CI -0.31 to 0.27). No reliable conclusions could be drawn from these studies due to the differing units of measurements and measurement time points.It is uncertain whether NSAIDs leads to the need for RRT because the certainty of this evidence is very low (2 studies, 7056 participants: RR 1.57, 95% CI 0.49 to 5.07; I2 = 26%); there were few events and the results were inconsistent.It is uncertain whether NSAIDs lead to more deaths (2 studies, 312 participants: RR 1.44, 95% CI 0.19 to 11.12; I2 = 38%) or increased the length of hospital stay (3 studies, 410 participants: MD 0.12 days, 95% CI -0.48 to 0.72; I2 = 24%). AUTHORS' CONCLUSIONS: Overall NSAIDs had uncertain effects on the risk of post-operative AKI, may slightly increase post-operative SCr, and it is uncertain whether NSAIDs lead to the need for RRT, death or increases the length of hospital stay. The available data therefore does not confirm the safety of NSAIDs in patients undergoing surgery. Further larger studies using the Kidney Disease Improving Global Outcomes definition for AKI including patients with co-morbidities are required to confirm these findings. .

Impact of antimicrobial stewardship interventions on Clostridium difficile infection and clinical outcomes: segmented regression analyses.

Background: Antimicrobial exposure is associated with increased risk of Clostridium difficile infection (CDI), but the impact of prescribing interventions on CDI and other outcomes is less clear. Objectives: To evaluate the effect of an antimicrobial stewardship intervention targeting high-risk antimicrobials (HRA), implemented in October 2008, and to compare the findings with similar studies from a systematic review. Methods: All patients admitted to Medicine and Surgery in Ninewells Hospital from October 2006 to September 2010 were included. Intervention effects on HRA use (dispensed DDD), CDI cases and mortality rates, per 1000 admissions per month, were analysed separately in Medicine and Surgery using segmented regression of interrupted time series (ITS) data. Data from comparable published studies were reanalysed using the same method. Results: Six months post-intervention, there were relative reductions in HRA use of 33% (95% CI 11-56) in Medicine and 32% (95% CI 19-46) in Surgery. At 12 months, there was an estimated reduction in CDI of 7.0 cases/1000 admissions [relative change -24% (95% CI - 55 to 6)] in Medicine, but no change in Surgery {estimated 0.1 fewer cases/1000 admissions [-2% (95% CI - 116 to 112)]}. Mortality reduced throughout the study period, unaffected by the intervention. In all six comparable studies, HRA use reduced significantly, but reductions in CDI rates were only statistically significant in two and none measured mortality. Pre-intervention CDI rates and trends influenced the intervention effect. Conclusions: Despite large reductions in HRA prescribing and reductions in CDI, demonstrating real-world impact of stewardship interventions remains challenging.

Building a national Infection Intelligence Platform to improve antimicrobial stewardship and drive better patient outcomes: the Scottish experience.

Background: The better use of new and emerging data streams to understand the epidemiology of infectious disease and to inform and evaluate antimicrobial stewardship improvement programmes is paramount in the global fight against antimicrobial resistance. Objectives: To create a national informatics platform that synergizes the wealth of disjointed, infection-related health data, building an intelligence capability that allows rapid enquiry, generation of new knowledge and feedback to clinicians and policy makers. Methods: A multi-stakeholder community, led by the Scottish Antimicrobial Prescribing Group, secured government funding to deliver a national programme of work centred on three key aspects: (i) technical platform development with record linkage capability across multiple datasets; (ii) a proportionate governance approach to enhance responsiveness; and (iii) generation of new evidence to guide clinical practice. Results: The National Health Service Scotland Infection Intelligence Platform (IIP) is now hosted within the national health data repository to assure resilience and sustainability. New technical solutions include simplified 'data views' of complex, linked datasets and embedded statistical programs to enhance capability. These developments have enabled responsiveness, flexibility and robustness in conducting population-based studies including a focus on intended and unintended effects of antimicrobial stewardship interventions and quantification of infection risk factors and clinical outcomes. Conclusions: We have completed the build and test phase of IIP, overcoming the technical and governance challenges, and produced new capability in infection informatics, generating new evidence for improved clinical practice. This provides a foundation for expansion and opportunity for global collaborations.

Has primary care antimicrobial use really been increasing? Comparison of changes in different prescribing measures for a complete geographic population 1995-2014.

Objectives: To elucidate how population trends in total antimicrobials dispensed in the community translate into individual exposure. Methods: Retrospective, population-based observational study of all antimicrobial prescribing in a Scottish region in financial years 1995, 2000 and 2005-14. Analysis of temporal changes in all antimicrobials and specific antimicrobials measured in: WHO DDD per 1000 population; prescriptions per 1000 population; proportion of population with ≥1 prescription; mean number of prescriptions per person receiving any; mean DDD per prescription. Results: Antimicrobial DDD increased between 1995 and 2014, from 5651 to 6987 per 1000 population [difference 1336 (95% CI 1309-1363)]. Prescriptions per 1000 fell (from 821 to 667, difference -154, -151 to -157), as did the proportion prescribed any antimicrobial [from 39.3% to 30.8% (-8.5, -8.4 to -8.6)]. Rising mean DDD per prescription, from 6.88 in 1995 to 10.47 in 2014 (3.59, 3.55-3.63), drove rising total DDD. In the under-5s, every measure fell over time (68.2% fall in DDD per 1000; 60.7% fall in prescriptions per 1000). Among 5-64 year olds, prescriptions per 1000 were lowest in 2014 but among older people, despite a reduction since 2010, the 2014 rate was still higher than in 2000. Trends in individual antimicrobials provide some explanation for overall trends. Conclusions: Rising antimicrobial volumes up to 2011 were mainly due to rising DDD per prescription. Trends in dispensed drug volumes do not readily translate into information on individual exposure, which is more relevant for adverse consequences including emergence of resistance.

A framework for ensuring a balanced accounting of the impact of antimicrobial stewardship interventions.

Drawing on a Cochrane systematic review, this paper examines the relatively limited range of outcomes measured in published evaluations of antimicrobial stewardship interventions (ASIs) in hospitals. We describe a structured framework for considering the range of consequences that ASIs can have, in terms of their desirability and the extent to which they were expected when planning an ASI: expected, desirable consequences (intervention goals); expected, undesirable consequences (intervention trade-offs); unexpected, undesirable consequences (unpleasant surprises); and unexpected, desirable consequences (pleasant surprises). Of 49 randomized controlled trials identified by the Cochrane review, 28 (57%) pre-specified increased length of stay and/or mortality as potential trade-offs of ASI, with measurement intended to provide reassurance about safety. In actuality, some studies found unexpected decreases in length of stay (a pleasant surprise). In contrast, only 11 (10%) of 110 interrupted time series studies included any information about unintended consequences, with 10 examining unexpected, undesirable outcomes (unpleasant surprises) using case-control, qualitative or cohort designs. Overall, a large proportion of the ASIs reported in the literature only assess impact on their targeted process goals-antimicrobial prescribing-with limited examination of other potential outcomes, including microbial and clinical outcomes. Achieving a balanced accounting of the impact of an ASI requires careful consideration of expected undesirable effects (potential trade-offs) from the outset, and more consideration of unexpected effects after implementation (both pleasant and unpleasant surprises, although the latter will often be more important). The proposed framework supports the systematic consideration of all types of consequences of improvement before and after implementation.

Oral and Topical Antibiotics for Clinically Infected Eczema in Children: A Pragmatic Randomized Controlled Trial in Ambulatory Care.

PURPOSE: Eczema may flare because of bacterial infection, but evidence supporting antibiotic treatment is of low quality. We aimed to determine the effect of oral and topical antibiotics in addition to topical emollient and corticosteroids in children with clinically infected eczema. METHODS: We employed a 3-arm, blinded, randomized controlled trial in UK ambulatory care. Children with clinical, non-severely infected eczema were randomized to receive oral and topical placebos (control), oral antibiotic (flucloxacillin) and topical placebo, or topical antibiotic (fusidic acid) and oral placebo, for 1 week. We compared Patient Oriented Eczema Measure (POEM) scores at 2 weeks using analysis of covariance (ANCOVA). RESULTS: We randomized 113 children (40 to control, 36 to oral antibiotic, and 37 to topical antibiotic). Mean (SD) baseline Patient Oriented Eczema Measure scores were 13.4 (5.1) for the control group, 14.6 (5.3) for the oral antibiotic group, and 16.9 (5.5) for the topical antibiotic group. At baseline, 104 children (93%) had 1 or more of the following findings: weeping, crusting, pustules, or painful skin. Mean (SD) POEM scores at 2 weeks were 6.2 (6.0) for control, 8.3 (7.3) for the oral antibiotic group, and 9.3 (6.2) for the topical antibiotic group. Controlling for baseline POEM score, neither oral nor topical antibiotics produced a significant difference in mean (95% CI) POEM scores (1.5 [-1.4 to 4.4] and 1.5 [-1.6 to 4.5] respectively). There were no significant differences in adverse effects and no serious adverse events. CONCLUSIONS: We found rapid resolution in response to topical steroid and emollient treatment and ruled out a clinically meaningful benefit from the addition of either oral or topical antibiotics. Children seen in ambulatory care with mild clinically infected eczema do not need treatment with antibiotics.

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.

The health and economic burden of bloodstream infections caused by antimicrobial-susceptible and non-susceptible Enterobacteriaceae and Staphylococcus aureus in European hospitals, 2010 and 2011: a multicentre retrospective cohort study.

We performed a multicentre retrospective cohort study including 606,649 acute inpatient episodes at 10 European hospitals in 2010 and 2011 to estimate the impact of antimicrobial resistance on hospital mortality, excess length of stay (LOS) and cost. Bloodstream infections (BSI) caused by third-generation cephalosporin-resistant Enterobacteriaceae (3GCRE), meticillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA) increased the daily risk of hospital death (adjusted hazard ratio (HR) = 1.80; 95% confidence interval (CI): 1.34-2.42, HR = 1.81; 95% CI: 1.49-2.20 and HR = 2.42; 95% CI: 1.66-3.51, respectively) and prolonged LOS (9.3 days; 95% CI: 9.2-9.4, 11.5 days; 95% CI: 11.5-11.6 and 13.3 days; 95% CI: 13.2-13.4, respectively). BSI with third-generation cephalosporin-susceptible Enterobacteriaceae (3GCSE) significantly increased LOS (5.9 days; 95% CI: 5.8-5.9) but not hazard of death (1.16; 95% CI: 0.98-1.36). 3GCRE significantly increased the hazard of death (1.63; 95% CI: 1.13-2.35), excess LOS (4.9 days; 95% CI: 1.1-8.7) and cost compared with susceptible strains, whereas meticillin resistance did not. The annual cost of 3GCRE BSI was higher than of MRSA BSI. While BSI with S. aureus had greater impact on mortality, excess LOS and cost than Enterobacteriaceae per infection, the impact of antimicrobial resistance was greater for Enterobacteriaceae.