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BackgroundAntimicrobial resistance is a serious global health concern that emphasizes completing treatment course. Recently, the effectiveness of short versus longer antibiotic courses has been questioned. This study investigated the duration of prescribed antibiotics, their effectiveness, and associated risk of infection-related complications.MethodsClinical Practice Research Datalink identified 4 million acute infection episodes prescribed an antibiotic in primary care between January 2014—June 2014, England. Prescriptions were categorized by duration. Risk of infection-related hospitalizations within 30 days was modelled overall and by infection type. Risk was assessed immediately after or within 30 days follow-up to measure confounders given similar and varying exposure, respectively. An interaction term with follow-up time assessed whether hazard ratios (HRs) remained parallel with different antibiotic durations.ResultsThe duration of antibiotic courses increased over the study period (5.2–19.1%); 6–7 days were most common (66.9%). Most infection-related hospitalizations occurred with prescriptions of 8–15 days (0.21%), accompanied by greater risk of infection-related complications compared to patients who received a short prescription (HR: 1.75 [95% CI: 1.54–2.00]). Comparing HRs in the first 5 days versus remaining follow-up showed longer antibiotic courses were no more effective than shorter courses (1.02 [95% CI: 0.90–1.16] and 0.92 [95% CI: 0.75–1.12]). No variation by infection-type was observed.ConclusionsEqual effectiveness was found between shorter and longer antibiotic courses and the reduction of infection-related hospitalizations. Stewardship programs should recommend shorter courses of antibiotics for acute infections. Further research is required for treating patients with a complex medical history.SummaryPrescribing of longer courses increased over the study period. The majority of hospitalizations occurred for patients receiving longer courses. Risk of developing a complication (immediate vs remaining follow-up) found longer courses were no more effective than shorter courses.

BackgroundThere is a need to reduce antimicrobial uses in humans. Previous studies have found variations in antibiotic (AB) prescribing between practices in primary care. This study assessed variability of AB prescribing between clinicians.MethodsClinical Practice Research Datalink, which collects electronic health records in primary care, was used to select anonymised clinicians providing 500+ consultations during 2012–2017. Eight measures of AB prescribing were assessed, such as overall and incidental AB prescribing, repeat AB courses and extent of risk-based prescribing. Poisson regression models with random effect for clinicians were fitted.Results6111 clinicians from 466 general practices were included. Considerable variability between individual clinicians was found for most AB measures. For example, the rate of AB prescribing varied between 77.4 and 350.3 per 1000 consultations; percentage of repeat AB courses within 30 days ranged from 13.1% to 34.3%; predicted patient risk of hospital admission for infection-related complications in those prescribed AB ranged from 0.03% to 0.32% (5th and 95th percentiles). The adjusted relative rate between clinicians in rates of AB prescribing was 5.23. Weak correlation coefficients (ConclusionsThe wide variation seen in all measures of AB prescribing and weak correlation between them suggests that a single AB measure, such as prescribing rate, is not sufficient to underpin the optimisation of AB prescribing.

Introduction An outbreak of Influenza B occurred at a large United Kingdom (UK) regional adult cystic fibrosis (CF) centre in May 2016. This was late in the UK 2015–2016 influenza season and occurred on a specialist ward with strict infection control procedures. This study investigates the spread of influenza, clinical consequences and potential contributing factors. Methods Patient records, clinical status and pulmonary function data were reviewed for all inpatients during this period. Respiratory viral PCR results, influenza vaccination status of patients and staff, and environmental factors were also recorded. Affected patients were prospectively monitored for the following three months. Results 10 of 21 inpatients developed influenza B between 5th and 12th May 2016, an attack rate of 48%. All those characterised were confirmed as the same strain of influenza B/Victoria-lineage. Influenza infection resulted in a mean FEV1 reduction of 10.5% (SD 11.3, p = 0.012), which persisted at 3 months post infection (p = 0.003). Nine of the affected cases rooms were in close proximity on the ward while patients in the two isolation rooms with enhanced ventilation did not become infected. Ventilation measurements in affected rooms ranged from 1.75 to 2.10 air changes/hour, below national recommendations. Seventy percent of affected inpatients had received the 2015/16 trivalent seasonal influenza vaccine, which did not contain a B/Victoria-lineage influenza B virus. Conclusion This influenza B outbreak in CF adults had a high attack rate and a significant clinical impact. Room ventilation and a limited protection from the seasonal influenza vaccine were possible contributory factors.

Background This study aimed to evaluate the clinical safety of delayed antibiotic prescribing for upper respiratory tract infections (URTIs), which is recommended in treatment guidelines for less severe cases. Methods Two population-based cohort studies used the English Clinical Practice Research Databank and Welsh Secure Anonymized Information Linkage, containing electronic health records from primary care linked to hospital admission records. Patients with URTI and prescriptions of amoxicillin, clarithromycin, doxycycline, erythromycin, or phenoxymethylpenicillin were identified. Patients were stratified according to delayed and immediate prescribing relative to URTI diagnosis. Outcome of interest was infection-related hospital admission after 30 days. Results The population included 1.82 million patients with an URTI and antibiotic prescription; 91.7% had an antibiotic at URTI diagnosis date (immediate) and 8.3% had URTI diagnosis in 1–30 days before (delayed). Delayed antibiotic prescribing was associated with a 52% increased risk of infection-related hospital admissions (adjusted hazard ratio, 1.52; 95% confidence interval, 1.43–1.62). The probability of delayed antibiotic prescribing was unrelated to predicted risks of hospital admission. Analyses of the number needed to harm showed considerable variability across different patient groups (median with delayed antibiotic prescribing, 1357; 2.5% percentile, 295; 97.5% percentile, 3366). Conclusions This is the first large population-based study examining the safety of delayed antibiotic prescribing. Waiting to treat URTI was associated with increased risk of hospital admission, although delayed antibiotic prescribing was used similarly between high- and low-risk patients. There is a need to better target delayed antibiotic prescribing to URTI patients with lower risks of complications., Delayed antibiotic prescribing in patients with upper respiratory tract infections was associated with a 52% increased risk of infection-related hospital admissions in 2 large population-based cohorts. Delayed antibiotic prescribing should be targeted only to patients with lower risks of complications.

In September 2018, monkeypox virus was transmitted from a patient to a healthcare worker in the United Kingdom. Transmission was probably through contact with contaminated bedding. Infection control precautions for contacts (vaccination, daily monitoring, staying home from work) were implemented. Of 134 potential contacts, 4 became ill; all patients survived.

Objectives To examine variations across general practices and factors associated with antibiotic prescribing for common infections in UK primary care to identify potential targets for improvement and optimization of prescribing. Methods Oral antibiotic prescribing for common infections was analysed using anonymized UK primary care electronic health records between 2000 and 2015 using the Clinical Practice Research Datalink (CPRD). The rate of prescribing for each condition was observed over time and mean change points were compared with national guideline updates. Any correlation between the rate of prescribing for each infectious condition was estimated within a practice. Predictors of prescribing were estimated using logistic regression in a matched patient cohort (1:1 by age, sex and calendar time). Results Over 8 million patient records were examined in 587 UK general practices. Practices varied considerably in their propensity to prescribe antibiotics and this variance increased over time. Change points in prescribing did not reflect updates to national guidelines. Prescribing levels within practices were not consistent for different infectious conditions. A history of antibiotic use significantly increased the risk of receiving a subsequent antibiotic (by 22%–48% for patients with three or more antibiotic prescriptions in the past 12 months), as did higher BMI, history of smoking and flu vaccinations. Other drivers for receiving an antibiotic varied considerably for each condition. Conclusions Large variability in antibiotic prescribing between practices and within practices was observed. Prescribing guidelines alone do not positively influence a change in prescribing, suggesting more targeted interventions are required to optimize antibiotic prescribing in the UK.

In August 2015 two community outbreaks of hepatitis A virus (HAV) occurred in sub-urban communities in Northern England. Each was managed by an independent outbreak control team. In outbreak one, mass vaccination was deployed targeting a residential area and two schools, while in outbreak two, vaccination was reserved for household-type contacts of cases. The highest vaccination uptake was achieved in the school settings (82% and 95%). These case studies illustrate the range of approaches that can be used and the factors that influence decision-making in response to a hepatitis A community outbreak. Both outbreaks likely started from importation(s) of HAV by returning travellers and spread through extended social networks and the local community. Vaccination strategies were selected based on hypotheses about transmission pathways, which were informed by evidence from oral fluid (OF) testing of asymptomatic contacts. More evidence about the effectiveness of mass vaccination in community outbreaks of hepatitis A in low endemicity settings is needed. Hepatitis A guidelines should include recommendations for the use of mass vaccination and OF testing in outbreaks.

Objectives To assess whether resistance estimates obtained from sentinel surveillance for antimicrobial resistance (AMR) in community-acquired urinary tract infections (UTIs) differ from routinely collected laboratory community UTI data. Methods All patients aged ≥18 years presenting to four sentinel general practices with a suspected UTI, from 13 November 2017 to 12 February 2018, were asked to provide urine specimens for culture and susceptibility. Specimens were processed at the local diagnostic laboratory. Antibiotic susceptibility testing was conducted using automated methods. We calculated the proportion of Escherichia coli isolates that were non-susceptible (according to contemporaneous EUCAST guidelines) to trimethoprim, nitrofurantoin, cefalexin, ciprofloxacin and amoxicillin/clavulanic acid, overall and by age group and sex, and compared this with routine estimates. Results Sentinel practices submitted 740 eligible specimens. The specimen submission rate had increased by 28 specimens per 1000 population per year (95% CI 21–35). Uropathogens were isolated from 23% (169/740) of specimens; 67% were E. coli (113/169). Non-susceptibility of E. coli to trimethoprim was 28.2% (95% CI 20.2–37.7) on sentinel surveillance (33.4%; 95% CI 29.5–37.6 on routine data) and to nitrofurantoin was 0.9% (95% CI 0–5.7) (1.5%; 95% CI 0.7–3.0 on routine data). Conclusions Routine laboratory data resulted in a small overestimation in resistance (although the difference was not statistically significant) and our findings suggest that it provides an adequate estimate of non-susceptibility to key antimicrobials in community-acquired UTIs in England. This study does not support the need for ongoing local sentinel surveillance.

Background Antimicrobial resistance is driven by the overuse of antibiotics. This study aimed to develop and validate clinical prediction models for the risk of infection-related hospital admission with upper respiratory infection (URTI), lower respiratory infection (LRTI) and urinary tract infection (UTI). These models were used to investigate whether there is an association between the risk of an infection-related complication and the probability of receiving an antibiotic prescription. Methods The study used electronic health record data from general practices contributing to the Clinical Practice Research Datalink (CPRD GOLD) and Welsh Secure Anonymised Information Linkage (SAIL), both linked to hospital records. Patients who visited their general practitioner with an incidental URTI, LRTI or UTI were included and followed for 30 days for hospitalisation due to infection-related complications. Predictors included age, gender, clinical and medication risk factors, ethnicity and socioeconomic status. Cox proportional hazards regression models were used with predicted risks independently validated in SAIL. Results The derivation and validation cohorts included 8.1 and 2.7 million patients in CPRD and SAIL, respectively. A total of 7125 (0.09%) hospital admissions occurred in CPRD and 7685 (0.28%) in SAIL. Important predictors included age and measures of comorbidity. Initial attempts at validating in SAIL (i.e. transporting the models with no adjustment) indicated the need to recalibrate the models for age and underlying incidence of infections; internal bootstrap validation of these updated models yielded C-statistics of 0.63 (LRTI), 0.69 (URTI) and 0.73 (UTI) indicating good calibration. For all three infection types, the rate of antibiotic prescribing was not associated with patients’ risk of infection-related hospital admissions. Conclusion The risk for infection-related hospital admissions varied substantially between patients, but prescribing of antibiotics in primary care was not associated with risk of hospitalisation due to infection-related complications. Our findings highlight the potential role of clinical prediction models to help inform decisions of prescribing of antibiotics in primary care.

Carbapenem resistance in Enterobacterales is a public health threat. Klebsiella pneumoniae carbapenemase (encoded by alleles of the bla KPC family) is one of the most common transmissible carbapenem resistance mechanisms worldwide. The dissemination of bla KPC historically has been associated with distinct K. pneumoniae lineages (clonal group 258 [CG258]), a particular plasmid family (pKpQIL), and a composite transposon (Tn4401). In the United Kingdom, bla KPC has represented a large-scale, persistent management challenge for some hospitals, particularly in North West England. The dissemination of bla KPC has evolved to be polyclonal and polyspecies, but the genetic mechanisms underpinning this evolution have not been elucidated in detail; this study used short-read whole-genome sequencing of 604 bla KPC-positive isolates (Illumina) and long-read assembly (PacBio)/polishing (Illumina) of 21 isolates for characterization. We observed the dissemination of bla KPC (predominantly bla KPC-2; 573/604 [95%] isolates) across eight species and more than 100 known sequence types. Although there was some variation at the transposon level (mostly Tn4401a, 584/604 [97%] isolates; predominantly with ATTGA-ATTGA target site duplications, 465/604 [77%] isolates), bla KPC spread appears to have been supported by highly fluid, modular exchange of larger genetic segments among plasmid populations dominated by IncFIB (580/604 isolates), IncFII (545/604 isolates), and IncR (252/604 isolates) replicons. The subset of reconstructed plasmid sequences (21 isolates, 77 plasmids) also highlighted modular exchange among non-bla KPC and bla KPC plasmids and the common presence of multiple replicons within bla KPC plasmid structures (>60%). The substantial genomic plasticity observed has important implications for our understanding of the epidemiology of transmissible carbapenem resistance in Enterobacterales for the implementation of adequate surveillance approaches and for control.

Background Previous research reported that individuals prescribed antibiotics frequently develop antimicrobial resistance. The objective of this study was to evaluate whether frequent antibiotic use is associated with reduced hospital admissions for infection-related complications. Methods Population-based cohort study analysing electronic health records from primary care linked to hospital admission records. The study population included patients prescribed a systemic antibiotic, recent record of selected infections and no history of chronic obstructive pulmonary disease. Propensity-matched cohorts were identified based on quintiles of prior antibiotic use in 3 years before. Results A total of 1.8 million patients were included. Repeated antibiotic use was frequent. The highest rates of hospital admissions for infection-related complications were observed shortly after antibiotic start in all prior exposure quintiles. For patients with limited prior antibiotic use, rates then dropped quickly and substantially. In contrast, reductions over time were substantially less in patients with frequent prior antibiotic use, with rates remaining elevated over the following 6 months. In patients without comorbidity comparing the highest to lowest prior exposure quintiles in the Clinical Practice Research Databank, the IRRs were 1.18 [95% CI 0.90–1.55] in the first 3 days after prescription, 1.44 [95% CI 1.14–1.81] in the days 4–30 after and 3.22 [95% CI 2.29–4.53] in the 3–6 months after. Conclusions Repeated courses of antibiotics, although common practice, may have limited benefit and indicator of adverse outcomes. A potential mechanism is that antibiotics may cause dysbiosis (perturbations of intestinal microbiota), contributing to colonization with resistant bacteria. Antibiotics should be used judiciously and only periodically unless indicated. Antimicrobial stewardship should include activities focusing on the substantive number of patients who repeatedly but intermittently get antibiotics.

Carbapenem resistance in Enterobacterales is a public health threat. Klebsiella pneumoniae carbapenemase (encoded by alleles of the bla(KPC) family) is one of the most common transmissible carbapenem resistance mechanisms worldwide. The dissemination of bla(KPC) historically has been associated with distinct K. pneumoniae lineages (clonal group 258 [CG258]), a particular plasmid family (pKpQIL), and a composite transposon (Tn4401). In the United Kingdom, bla(KPC) has represented a large-scale, persistent management challenge for some hospitals, particularly in North West England. The dissemination of bla(KPC) has evolved to be polyclonal and polyspecies, but the genetic mechanisms underpinning this evolution have not been elucidated in detail; this study used short-read whole-genome sequencing of 604 bla(KPC)-positive isolates (Illumina) and long-read assembly (PacBio)/polishing (Illumina) of 21 isolates for characterization. We observed the dissemination of bla(KPC) (predominantly bla(KPC-2); 573/604 [95%] isolates) across eight species and more than 100 known sequence types. Although there was some variation at the transposon level (mostly Tn4401a, 584/604 [97%] isolates; predominantly with ATTGA-ATTGA target site duplications, 465/604 [77%] isolates), bla(KPC) spread appears to have been supported by highly fluid, modular exchange of larger genetic segments among plasmid populations dominated by IncFIB (580/604 isolates), IncFII (545/604 isolates), and IncR (252/604 isolates) replicons. The subset of reconstructed plasmid sequences (21 isolates, 77 plasmids) also highlighted modular exchange among non-bla(KPC) and bla(KPC) plasmids and the common presence of multiple replicons within bla(KPC) plasmid structures (>60%). The substantial genomic plasticity observed has important implications for our understanding of the epidemiology of transmissible carbapenem resistance in Enterobacterales for the implementation of adequate surveillance approaches and for control.

Summary Background Over the past decade, the prevalence of carbapenemase-producing Enterobacteriaceae (CPE) has increased. Whilst basic infection prevention and control practices reduce the risk of transmission, cases of unrecognized carriage pose a potential risk of transmission. Aim To estimate the prevalence of CPE and explore risk factors associated with colonization within a large teaching hospital with an established CPE outbreak. Methods All inpatients that had not previously tested positive for CPE were offered testing. Demographic and hospital episode data were also collected, together with antibiotic and proton pump inhibitor (PPI) use in the preceding 24h. Findings This study identified 70 CPE-positive cases (26 newly identified and 44 previously known) and 592 CPE-negative cases, giving a combined prevalence of 11% [95% confidence interval (CI) 8–13]. Medication (antibiotic and PPI use), previous admission, ethnicity and length of stay were assessed as risk factors for colonization, and none were found to be independently associated with CPE colonization. Using logistic regression, age [odds ratio (OR) 1.03, 95% CI 1.01–1.07] and antibiotic use (OR 2.55, 95% CI 1.08-6.03) were the only risk factors significantly associated with CPE colonization. Conclusion This study has added to the evidence base by estimating the prevalence of CPE among inpatients in an acute hospital with an established CPE outbreak. A case-finding exercise was feasible and identified a number of new cases. Despite a small sample size, increasing age and prescription of an antibiotic on the day of testing were significantly associated with CPE colonization.

Objectives To identify the rates of potentially inappropriate antibiotic choice when prescribing for common infections in UK general practices. To examine the predictors of such prescribing and the clustering effects at the practice level. Methods The rates of potentially inappropriate antibiotic choice were estimated using 1 151 105 consultations for sinusitis, otitis media and externa, upper respiratory tract infection (URTI) and lower respiratory tract infection (LRTI) and urinary tract infection (UTI), using the Clinical Practice Research Datalink (CPRD). Multilevel logistic regression was used to identify the predictors of inappropriate prescribing and to quantify the clustering effect at practice level. Results The rates of potentially inappropriate prescriptions were highest for otitis externa (67.3%) and URTI (38.7%) and relatively low for otitis media (3.4%), sinusitis (2.2%), LRTI (1.5%) and UTI in adults (2.3%) and children (0.7%). Amoxicillin was the most commonly prescribed antibiotic for all respiratory tract infections, except URTI. Amoxicillin accounted for 62.3% of prescriptions for otitis externa and 34.5% of prescriptions for URTI, despite not being recommended for these conditions. A small proportion of the variation in the probability of an inappropriate choice was attributed to the clustering effect at practice level (8% for otitis externa and 23% for sinusitis). Patients with comorbidities were more likely to receive a potentially inappropriate antibiotic for URTI, LRTI and UTI in adults. Patients who received any antibiotic in the 12 months before consultation were more likely to receive a potentially inappropriate antibiotic for all conditions except otitis externa. Conclusions Antibiotic prescribing did not always align with prescribing guidelines, especially for URTIs and otitis externa. Future interventions might target optimizing amoxicillin use in primary care.

Background: Hospital sinks, waste traps and drains can harbour carbapenem-resistant Enterobacteriaceae (CRE).Aim: To investigate the dispersal of CRE from sinks in which water delivered from the tap flows directly into the drain and from clinical handwash basins with the drain at the rear. The effect of fast and slow drainage rates was also assessed.Methods: Waste traps, known to be colonized with CRE, were taken from a hospital and installed within a model laboratory system. New waste traps were also installed and artificially inoculated with CRE. The potential for bacteria to be dispersed from sinks was assessed using cyclone air samplers and/or settle plates.Findings: When the waste traps were artificially contaminated and CRE colonization was confined to the waste trap water, significantly fewer bacteria were dispersed from sinks that drained quickly (P = 0.004) and/or from rear-draining sinks (P = 0.002). When the waste traps were naturally contaminated and CRE colonized the trap, pipework and drain, there was significant interaction between sink drainage and position of the drain (P < 0.001). When drainage was slow, dispersal from rear-draining sinks was almost 30-fold less than from sinks with the drain underneath the tap (P < 0.001). When drainage was fast, rear-draining sinks again released comparatively fewer CRE, although, in this case, the difference was not statistically significant (P = 0.7). Contaminated splashes travelled up to 1 m from the sink.Conclusion: Slow drainage rates and sink designs with the drain directly underneath the tap increase the risk of CRE present in waste traps and drains contaminating the ward environment.

Background: In mice models of cancer and human tissues samples, disturbance of the gut microbiota can reduce the effectiveness of chemotherapy and immunotherapy. There is limited evidence in humans whether antibiotics impact on the effectiveness of cancer treatments. We evaluated the associations between antibiotic use before cancer diagnoses and long-term mortality. Methods: Primary care data from general practices contributing to the English Clinical Practice Research Datalink (CPRD) and Welsh Secure Anonymised Information Linkage (SAIL) linked to Cancer Registries (CR) and Office for National Statistics (ONS) mortality records were used. Two cohort studies involving cancer patients (15 types) exposed to antibiotics before cancer diagnosis were identified. Recent, previous and past antibiotic users were compared using Cox regression models. Findings: 129 990 cancer patients from the National Cancer Registration and Analysis Service (NCRAS) linked to CPRD and 131 330 from the Welsh Cancer Intelligence Surveillance Unit (WCISU) were included. In comparison with past antibiotic users, patients who used antibiotics in the recent past before their cancer diagnosis and were mainly treated with chemotherapy or immunotherapy presented increased hazards ratio (HR) for mortality consistently in both cohorts; for leukaemia, the HR in NCRAS was 1·40 (95% CI 1·22-1·60), for lymphoma 1·19 (95% CI 1·06-1·33), for melanoma 1·31 (95% CI 1·12-1·54), and for myeloma 1·19 (95% CI 1·04-1·36). HR for cancer of the uterus, breast, urinary, colorectal, and kidney cancer followed the same trend in both CRs. Sensitivity analyses based on general practice records suggested comparable results to those from CRs. Interpretation: This study supports the hypothesis that prior use of antibiotics may reduce the effectiveness of chemotherapy and immunotherapy, potentially through disruption to the gut microbiota. Although not providing definitive results, the biological plausibility of the findings does support the need for judicious use of antibiotics. Funding: Department of Health and NIHR. Declaration of Interest: We declare no competing interests. Ethical Approval: The protocol was approved by the Independent Scientific Advisory Committee for CPRD research (protocol number 18_198) and SAIL’s Information Governance Protocol Review Panel (protocol number 0855).

BackgroundHigh levels of antibiotic prescribing are a major concern as they drive antimicrobial resistance. It is currently unknown whether practices that prescribe higher levels of antibiotics also prescribe more medicines in general.AimTo evaluate the relationship between antibiotic and general prescribing levels in primary care.Design and settingCross-sectional study in 2014–2015 of 6517 general practices in England using NHS digital practice prescribing data (NHS-DPPD) for the main study, and of 587 general practices in the UK using the Clinical Practice Research Datalink for a replication study.MethodLinear regression to assess determinants of antibiotic prescribing.ResultsNHS-DPPD practices prescribed an average of 576.1 antibiotics per 1000 patients per year (329.9 at the 5th percentile and 808.7 at the 95th percentile). The levels of prescribing of antibiotics and other medicines were strongly correlated. Practices with high levels of prescribing of other medicines (a rate of 27 159.8 at the 95th percentile) prescribed 80% more antibiotics than low-prescribing practices (rate of 8815.9 at the 5th percentile). After adjustment, NHS-DPPD practices with high prescribing of other medicines gave 60% more antibiotic prescriptions than low-prescribing practices (corresponding to higher prescribing of 276.3 antibiotics per 1000 patients per year). Prescribing of non-opioid painkillers and benzodiazepines were also strong indicators of the level of antibiotic prescribing. General prescribing levels were a much stronger driver for antibiotic prescribing than other risk factors, such as deprivation.ConclusionThe propensity of GPs to prescribe medications generally is an important driver for antibiotic prescribing. Interventions that aim to optimise antibiotic prescribing will need to target general prescribing behaviours, in addition to specifically targeting antibiotics.

ObjectiveDetermine the association of incident antibiotic prescribing levels for common infections with infection-related complications and hospitalisations by comparing high with low prescribing general practitioner practices.Design retrospective cohort studyRetrospective cohort study.Data sourceUK primary care records from the Clinical Practice Research Datalink (CPRD GOLD) and SAIL Databank (SAIL) linked with Hospital Episode Statistics (HES) data, including 546 CPRD, 346 CPRD-HES and 338 SAIL-HES practices.ExposuresInitial general practice visit for one of six common infections and the proportion of antibiotic prescribing in each practice.Main outcome measuresIncidence of infection-related complications (as recorded in general practice) or infection-related hospital admission within 30 days after consultation for a common infection.ResultsA practice with 10.4% higher antibiotic prescribing (the IQR) was associated with a 5.7% lower rate of infection-related hospital admissions (adjusted analysis, 95% CI 3.3% to 8.0%). The association varied by infection with larger associations in hospital admissions with lower respiratory tract infection (16.1%; 95% CI 12.4% to 19.7%) and urinary tract infection (14.7%; 95% CI 7.6% to 21.1%) and smaller association in hospital admissions for upper respiratory tract infection (6.5%; 95% CI 3.5% to 9.5%) The association of antibiotic prescribing levels and hospital admission was largest in patients aged 18–39 years (8.6%; 95% CI 4.0% to 13.0%) and smallest in the elderly aged 75+ years (0.3%; 95% CI −3.4% to 3.9%).ConclusionsThere is an association between lower levels of practice level antibiotic prescribing and higher infection-related hospital admissions. Indiscriminately reducing antibiotic prescribing may lead to harm. Greater focus is needed to optimise antibiotic use by reducing inappropriate antibiotic prescribing and better targeting antibiotics to patients at high risk of infection-related complications.

Carbapenem-resistant Enterobacteriaceae (CRE) represent a health threat, but effective control interventions remain unclear. Hospital wastewater sites are increasingly being highlighted as important potential reservoirs. We investigated a large Klebsiella pneumoniae carbapenemase (KPC)-producing Escherichia coli outbreak and wider CRE incidence trends in the Central Manchester University Hospital NHS Foundation Trust (CMFT) (United Kingdom) over 8 years, to determine the impact of infection prevention and control measures. Bacteriology and patient administration data (2009 to 2017) were linked, and a subset of CMFT or regional hospital KPC-producing E. coli isolates (n = 268) were sequenced. Control interventions followed international guidelines and included cohorting, rectal screening (n = 184,539 screens), environmental sampling, enhanced cleaning, and ward closure and plumbing replacement. Segmented regression of time trends for CRE detections was used to evaluate the impact of interventions on CRE incidence. Genomic analysis (n = 268 isolates) identified the spread of a KPC-producing E. coli outbreak clone (strain A, sequence type 216 [ST216]; n = 125) among patients and in the environment, particularly on 2 cardiac wards (wards 3 and 4), despite control measures. ST216 strain A had caused an antecedent outbreak and shared its KPC plasmids with other E. coli lineages and Enterobacteriaceae species. CRE acquisition incidence declined after closure of wards 3 and 4 and plumbing replacement, suggesting an environmental contribution. However, ward 3/ward 4 wastewater sites were rapidly recolonized with CRE and patient CRE acquisitions recurred, albeit at lower rates. Patient relocation and plumbing replacement were associated with control of a clonal KPC-producing E. coli outbreak; however, environmental contamination with CRE and patient CRE acquisitions recurred rapidly following this intervention. The large numbers of cases and the persistence of blaKPC in E. coli, including pathogenic lineages, are of concern.

Antimicrobial resistance is an important public health concern. As most antibiotics are prescribed in primary care, understanding prescribing patterns in General Medical (GP) practices is vital. The aim of this study was a spatial pattern analysis of antibiotic prescribing rates in GP practices in England and to examine the association of potential clusters with area level socio-economic deprivation. The pattern analysis identified a number of hot and cold spots of antibiotic prescribing, with hot spots predominantly in the North of England. Spatial regression showed that patient catchments of hot spot practices were significantly more deprived than patient catchments of cold spot practices, especially in the domains of income, employment, education and health. This study suggests the presence of area level drivers resulting in clusters of high and low prescribing. Consequently, area level strategies may be needed for antimicrobial stewardship rather than national level strategies.

BACKGROUND: Following hospital outbreaks of carbapenemase-producing Enterobacteriaceae (CPE), Public Health England published a toolkit in December 2013 to promote the early detection, management, and control of CPE colonization and infection in acute hospital settings.AIM: To examine awareness, uptake, implementation and usefulness of the CPE toolkit and identify potential barriers and facilitators to its adoption in order to inform future guidance.METHODS: A cross-sectional survey of National Health Service (NHS) acute trusts was conducted in May 2016. Descriptive analysis and multivariable regression models were conducted, and narrative responses were analysed thematically and informed using behaviour change theory.FINDINGS: Most (92%) acute trusts had a written CPE plan. Fewer (75%) reported consistent compliance with screening and isolation of CPE risk patients. Lower prioritization and weaker senior management support for CPE prevention were associated with poorer compliance. Awareness of the CPE toolkit was high and all trusts with patients infected or colonized with CPE had used the toolkit either as provided (32%), or to inform (65%) their own local CPE plan. Despite this, many respondents (80%) did not believe that the CPE toolkit guidance offered an effective means to prevent CPE or was practical to follow.CONCLUSION: CPE prevention and control requires robust IPC measures. Successful implementation can be hindered by a complex set of factors related to their practical execution, insufficient resources and a lack of confidence in the effectiveness of the guidance. Future CPE guidance would benefit from substantive user involvement, processes for ongoing feedback, and regular guidance updates.

Information on geographical variation in localised transmission of TB can inform targeting of disease control activities. The aim of this study was to estimate the proportion of TB attributable to localised transmission for the period 2010-2012 in northern England and to identify case characteristics associated with spatiotemporal-genotypical clusters.We combined genotyping data with spatiotemporal scan statistics to define an indicator of localised TB transmission and identified factors associated with localised TB transmission thus defined in a multivariable logistics regression model.The estimated proportion of TB cases in northern England attributable to localised transmission was 10% (95% CI 9% to 12%). Clustered cases (cases which were spatiotemporally clustered with others of identical genotype) were on average younger than non-clustered cases (mean age 34 years vs 43 years; p value0.05). Being UK born (adjusted OR (aOR) 3.6, 95% CI 2.9 to 6.0), presenting with pulmonary disease (aOR 2.2, 95% CI 1.3 to 3.6) and history of homelessness (aOR 2.8, 95% CI 1.2 to 6.8) or incarceration (aOR 2.6, 95% CI 1.2 to 5.9) were independently associated with being part of a spatiotemporal-genotypical cluster in a multivariable model. Belonging to an ethnic group other than white or mixed/other was also significantly associated with localised transmission. We identified localised transmission in 103/1958 middle super output areas mostly in urban areas.Incorporating highly discriminatory genotyping data into spatiotemporal analysis of TB incidence is feasible as part of routine surveillance and can provide valuable information on groups at greater risk and areas with localised transmission of TB, which could be used to inform control measures, such as intensified contact tracing.

Objectives: Detection of rarer carbapenemases is challenging, as it requires molecular assays with comprehensive coverage or the use of phenotypic methods for the detection of carbapenemase activity. We describe a new class A carbapenemase, FRI-2, in an Enterobacter cloacae complex isolate following implementation of an in- house multiplex PCR for the detection of ‘rare’ class A carbapenemases.Methods: MICs were determined by agar dilution. A carbapenem-resistant E. cloacae complex isolate was tested by PCR for the class A carbapenemases blaKPC, blaFRI, blaIMI, blaGES and blaSME. Carbapenemase activity was assessed using Carba NP and the carbapenem inactivation method. Whole genome and plasmid analyses of the clinical isolate and the FRI-2 transformant were performed by WGS, respectively. Typing was carried out by PFGE.Results: The E. cloacae complex isolate showed resistance to imipenem (MIC = 16 mg/L), meropenem (MIC = 8 mg/L) and ertapenem (MIC = 8 mg/L), but remained susceptible to piperacillin/tazobactam (MIC = 8 mg/L). Carbapenemase activity was confirmed in the isolate by both phenotypic methods. A blaFRI-1-like gene was detected by PCR and analysis of WGS data of the clinical isolate identified an ORF of 885 bp, which showed 97% nucleotide identity with blaFRI-1 and was named blaFRI-2. WGS of the transformant indicated blaFRI-2 was located on a 108 kb IncF/IncR plasmid. The FRI-2-positive E. cloacae complex isolate belonged to a novel ST (ST829).ConclusionsThe possible circulation of rarer carbapenemases in clinical settings highlights the role of phenotypic tests to detect carbapenemase activity when molecular assays are negative for the ‘big 5’ carbapenemase families.

In summer 2011, two outbreaks of a unique, multidrug-resistant strain of Salmonella enterica serovar Typhimurium phage type 120 (DT120) occurred mainly in the Midlands, England. The first outbreak occurred among guests attending a wedding in July 2011 ('Wedding outbreak'), followed by a more geographically dispersed outbreak in August and September 2011 ('Midlands outbreak'). Fifty-one cases were confirmed. Detailed epidemiological and environmental health investigations suggested that pork was the most likely source of both outbreaks. All human samples and one pork sample showed the specific multiple-locus variable-number tandem-repeat analysis (MLVA) profile 3-11-12-NA-0211, with at most two loci variations. Trace-back investigations suggested a link to a butcher's shop and a pig farm in the East Midlands. The investigations highlight the utility of molecular analysis (MLVA) in supporting epidemiological investigations of outbreaks caused by S. Typhimurium DT120. Safe handling and cooking of pork by food business operators and consumers are key interventions to prevent future outbreaks.

BACKGROUND: The burden of fungal disease in the UK is unknown. Only limited data are systematically collected. We have estimated the annual burden of invasive and serious fungal disease.METHODS: We used several estimation approaches. We searched and assessed published estimates of incidence, prevalence or burden of specific conditions in various high risk groups. Studies with adequate internal and external validity allowed extrapolation to estimate current UK burden. For conditions without adequate published estimates, we sought expert advice.RESULTS: The UK population in 2011 was 63,182,000 with 18% aged under 15 and 16% over 65. The following annual burden estimates were calculated: invasive candidiasis 5142; Candida peritonitis complicating chronic ambulatory peritoneal dialysis 88; Pneumocystis pneumonia 207-587 cases, invasive aspergillosis (IA), excluding critical care patients 2901-2912, and IA in critical care patients 387-1345 patients, CONCLUSIONS: Uncertainty is intrinsic to most burden estimates due to diagnostic limitations, lack of national surveillance systems, few published studies and methodological limitations. The largest uncertainty surrounds IA in critical care patients. Further research is needed to produce a more robust estimate of total burden.

Summary Background Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1 (NDM-1) are potentially a major global health problem. We investigated the prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the UK. Methods Enterobacteriaceae isolates were studied from two major centres in India—Chennai (south India), Haryana (north India)—and those referred to the UK's national reference laboratory. Antibiotic susceptibilities were assessed, and the presence of the carbapenem resistance gene bla NDM-1 was established by PCR. Isolates were typed by pulsed-field gel electrophoresis of XbaI-restricted genomic DNA. Plasmids were analysed by S1 nuclease digestion and PCR typing. Case data for UK patients were reviewed for evidence of travel and recent admission to hospitals in India or Pakistan. Findings We identified 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan. NDM-1 was mostly found among Escherichia coli (36) and Klebsiella pneumoniae (111), which were highly resistant to all antibiotics except to tigecycline and colistin. K pneumoniae isolates from Haryana were clonal but NDM-1 producers from the UK and Chennai were clonally diverse. Most isolates carried the NDM-1 gene on plasmids: those from UK and Chennai were readily transferable whereas those from Haryana were not conjugative. Many of the UK NDM-1 positive patients had travelled to India or Pakistan within the past year, or had links with these countries. Interpretation The potential of NDM-1 to be a worldwide public health problem is great, and co-ordinated international surveillance is needed. Funding European Union, Wellcome Trust, and Wyeth.

Public Health England recommends patient-held cards for those colonized with carbapenemase-producing Enterobacteriaceae (CPE). Alert cards were provided to 104 CPE-positive inpatients, with follow-up at six months. Excluding those who died, the response rate was 39%. Sixteen patients (46%) recalled receiving the card; 13 (81%) of these retained it, most (64%) of whom reported using it. This is the first evaluation of a patient-held alert card for any antimicrobial-resistant (AMR) bacteria in the UK. This study demonstrated that, when retained, CPE alert cards can be an effective communication tool. Further work is required to evaluate effectiveness and improve retention.

Background Swaziland has the highest national incidence of tuberculosis (TB) in the world, with treatment success rates well below the 85 % international target. Treatment support as part of comprehensive TB services is a core component of the Stop TB Strategy. This study investigated the effects of financial incentives for treatment supporters on TB treatment outcomes in Swaziland. Methods This was a controlled study that compared treatment outcomes for patients with a treatment supporter who received or did not receive a financial incentive. Results The intervention group had a higher chance of treatment success as compared with the control group: 73 % (95 % confidence intervals [CIs] 66–80 %) versus 60 % (95 % CIs 57–64 %), respectively, p = 0.003. This improvement remained significant when treatment success rates were adjusted for differences in baseline characteristics, with the effect of incentivised treatment supporters on treatment outcomes having an odds ratio (OR) of 1.8. There was also a significant improvement in the death rate in the intervention group, as compared with the control group (10.6 versus 23.5 %, p =

An estimated 129 million people are infected with urogenital schistosomiasis in sub-Saharan Africa. Current control recommendations endorse mass administration of praziquantel. Health education is an important component of effective schistosomiasis prevention and control, but there has been limited research on its effectiveness. This paper reviews the effectiveness of health education as an intervention in the prevention and control of urogenital schistosomiasis in sub-Saharan Africa. The outcomes of interest were prevalence, incidence or transmission of schistosomiasis, behaviour change associated with infection, or changes in knowledge of the disease. The findings from this review suggest that health education has a beneficial impact on knowledge and understanding of schistosomiasis within the target groups. However, further research is needed due to the poor quality of the included studies.

This paper describes the epidemiology and management of a prolonged outbreak of measles across the 2.7 million conurbation of Greater Manchester in the United Kingdom. Over a period of one year (from October 2012 to September 2013), over a thousand suspected measles cases (n = 1,073) were notified across Greater Manchester; of these, 395 (37%) were laboratory-confirmed, 91 (8%) were classed as probable, 312 (29%) were classed as possible and 275 (26%) excluded. Most confirmed and probable cases occurred in children within two age groups—infants (too young to be eligible for measles-mumps-rubella (MMR) vaccination according to the national immunisation programme) and children aged 10-19 years (low vaccine uptake in this cohort because of unfounded alleged links between the MMR vaccine and autism). During this one year period, there were a series of local outbreaks and many of these occurred within the secondary school setting. A series of public health measures were taken to control this prolonged outbreak: setting up incident management teams to control local outbreaks, a concerted immunisation catch-up campaign (initially local then national) to reduce the pool of children partially or totally unprotected against measles, and the exclusion of close contacts from nurseries and school settings for a period of 10 days following the last exposure to a case of measles.

Studies on the immunoglobulin (Ig)E immune responses to the gastric nematode, Teladorsagia circumcincta, have demonstrated a major high molecular weight allergen (HMWTc). Cross reactive allergens of similar MW were demonstrated for Trichostrongylus colubriformis and Cooperia curticei, but not for Haemonchus contortus. Purification of HMWTc was achieved by gel-filtration chromatography, and nonreducing SDS-PAGE and Western blot analysis revealed two closely associated bands with a molecular weight of approximately 140-150 kDa. Reduction showed four IgE reactive bands of 120, 50, 45 and 30 kDa, and deglycosylation abrogated the immunoreactivity of the 120 and 30 kDa bands. Ultrastructural immunolocalization by electron microscopy revealed that the IgE reactivity was confined to the cuticular surface of the infective (L3) larvae. ELISA studies to determine the IgE anti-HMWTc responses in lambs during their first grazing season, demonstrated significantly higher IgE antibody in lambs with low accumulative faecal egg count (FEC) compared to animals with high accumulative FEC. These studies provide evidence for a protective function of IgE antibody in Teladorsagia infections in lambs.

Contaminated land risk assessments generally focus on the chronic health risks, arising from long-term, low-level exposure to the contaminants, and a number of risk assessment tools are in routine use. Situations where significant acute risks might be present are not commonly encountered, and methods for risk assessment are less well established. We present two recent case studies from the northwest of England, the first an area of public open space, and the second an occupied school site, with the associated risk assessments.

Summary Objective To map sexual health promotion activity and resources across North West England. Study design Survey. Methods A survey of all sexual health promotion activity commissioned by primary care trusts (PCTs) was carried out using a self-completion questionnaire for PCT sexual health commissioners in North West England. Results Sixteen out of 24 PCTs responded. Some PCTs had difficulty in identifying the relevant commissioner. Most activity was focused on young people, especially around the National Chlamydia Screening Programme (NCSP) and teenage pregnancy, and on particular high-risk groups such as lesbian, gay and bisexual people, those living with human immunodeficiency virus and commercial sex workers. All PCTs commissioned education/training and a condom distribution service. Other common activities included outreach work, and producing and disseminating materials. Most services were confined to one PCT. Most PCTs were unable to identify the resources committed to sexual health promotion. The emergent themes in the analysis of service development ideas and comments were all linked to commissioning: commissioning and strategy; funding; needs assessment; service development and provision; contracting and monitoring; evaluation and evidence; and regional perspective. Conclusions A simple tool to map sexual health promotion activities commissioned by PCTs was developed. Many PCTs could not identify a commissioner for sexual health or the resources committed to sexual health promotion. Sexual health promotion activity focused on young people (linked to the NCSP and teenage pregnancy) and particular high-risk groups, with resultant gaps and a mismatch with the epidemiology. The most frequently commissioned activities were education/training and condom provision (despite the limited evidence base). A series of recommendations to PCTs, sexual health networks and providers are made.

Potentially life threatening profound hypokalaemia with metabolic acidosis may not be adequately dealt with by current treatment recommendations Abnormalities of serum potassium are associated with well described clinical features: lassitude when potassium

We describe a recent outbreak of syphilis in young heterosexuals in the north west of England. A cluster of 12 cases of syphilis (7 primary and 5 early latent) was identified in Rochdale in heterosexuals aged 20 or under. Nine were women. Five were asymptomatic at presentation. This outbreak occurred in a group not usually associated with syphilis transmission in the north west. Not all the identified cases could be linked, and so potentially this outbreak is a sentinel of a larger problem.

Objective To implement and evaluate a formal pre-antiretroviral therapy (ART) care service at a district hospital in Swaziland. Design Operational research. Setting District hospital in Southern Africa. Participants 1171 patients with a previous diagnosis of HIV. A baseline patient group consisted of the first 200 patients using the service. Two follow-up groups were defined: group 1 was all patients recruited from April to June 2009 and group 2 was 200 patients recruited in February 2010. Intervention Introduction of pre-ART care—a package of interventions, including counselling; regular review; clinical staging; timely initiation of ART; social and psychological support; and prevention and management of opportunistic infections, such as tuberculosis. Primary and secondary outcome measures Proportion of patients assessed for ART eligibility, proportion of eligible patients who were started on ART and proportion receiving defined evidence-based interventions (including prophylactic co-trimoxazole and tuberculosis screening). Results Following the implementation of the pre-ART service, the proportion of patients receiving defined interventions increased; the proportion of patient being assessed for ART eligibility significantly increased (baseline: 59%, group 1: 64%, group 2: 76%; p=0.001); the proportion of ART-eligible patients starting treatment increased (baseline: 53%, group 1: 81%, group: 2, 81%; p, Article summary Article focus Impact of pre-ART care on the quality of care in a district hospital in Southern Africa. Key messages After introduction of a pre-ART care service, a higher proportion of patients were assessed for ART, a higher proportion of those eligible started on ART and a higher proportion received key interventions. Strengths and limitations of this study This was a pragmatic evaluation in a routine service setting. The intervention was implemented as part of routine health service delivery by existing clinical staff. Routine data collection systems do not link testing and HIV care data, preventing an evaluation from testing to initiation. The evaluation focuses on those with a known status, rather than new testers, those with tuberculosis or those who are pregnant. The evaluation relies on intermediate outcomes, that is, initiation on ART, rather than long-term outcomes, such as mortality. There is a lack of information on those requiring long-term follow-up but not ART.

Background Swaziland has the highest HIV prevalence in the world and the highest estimated tuberculosis incidence rate in the world. An estimated 80% of TB patients are also infected with HIV. TB detection through intensified case finding (ICF) has yet to become a routine aspect of integrated tuberculosis and HIV care. The purpose of this study was to evaluate implementation of ICF for TB into routine integrated tuberculosis and HIV care at 16 community clinics and one district hospital in Swaziland. Methods Nurses and lay counsellors conducted ICF using a TB screening tool and patient pathway at all HIV service entry points in clinics and the hospital. The patient pathway had three-stages; screening, sputum smear diagnosis and TB treatment initiation. Outcomes and losses to follow up were monitored at each stage. Patient demographics, access, and service feasibility and effectiveness were compared at hospital and clinic sites. Results 1467 HIV patients at clinics and the hospital were screened over a 3 month period. Large losses to follow up occurred prior to the sputum diagnosis stage; only 47% (n = 172) of TB suspects provided a specimen. 28 cases of smear positive TB were diagnosed and 24 commenced treatment. People screened at clinics were significantly more likely to be female, older, and from rural or geographically remote areas (p < 0.001). There was no significant difference between the hospital and clinics sites in the proportion of all participants screened who were smear positive (x2 = 1.909; p = 0.16). The number needed to screen to detect one sputum positive TB case was 34 at clinics and 63 at the district hospital. Conclusions ICF was operationally feasible and became established as a routine aspect of tuberculosis and HIV integrated care. ICF in community clinics was potentially more accessible to an underserved, rural population and was as effective as the hospital service in detecting smear positive TB.

Premature infants are at greater risk of infections in part because of impaired functioning of external barriers, innate and adaptive systems. For similar immunological reasons, diminished responses to particular vaccines have also been reported. This study, utilising a prospective, pragmatic case series approach was designed to show non-inferiority of antibody response in premature infants to diphtheria, tetanus, Haemophilus influenzae type b conjugate (Hib), meningococcal C conjugate (MenC) and pneumococcal conjugate (PnC) vaccines between immunization in a routine clinical situation rather than a vaccine trial. A secondary objective was to determine the effect of gestational age on antibody response to these vaccines. The case series comprised 131 infants born at ≤ 32 weeks gestation and managed on the Special Care Baby Unit (SCBU) of a District General Hospital in Stockport, UK. For diphtheria and tetanus, 98.3% and 100% of premature infants respectively developed a minimum protective antibody response; 86.6% were protected against Men C. However, only 67.8% preterm infants achieved anti-polyribosylribitolphosphate (PRP) antibodies >0.15μg against Hib, with only 34.7% having a level ≥1.0μg, and responses to the different pneumococcal serogroups ranged from 67.5% against serotype 6B to 92.5% against serogroup 19F. In comparison to term infants, preterm infants were less likely to achieve protective levels against MenC and Hib: there were no significant differences in the proportions of infants protected against diphtheria and tetanus. Protection was inferior to expected based on published premature infant clinical trial data for Hib and particular pneumococcal serotypes; data for Men C were also lower than expected.