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ObjectiveTo examine sociodemographic inequalities in people with SARS-CoV-2 during the second (alpha) and third (delta) waves of the covid-19 pandemic.DesignRetrospective, population based cohort study.SettingResident population of England.Participants39 006 194 people aged 10 years and older who were enumerated in the 2011 census, registered with the NHS, and alive on 1 September 2020.Main outcome measuresAge standardised SARS-CoV-2 case rates (ie, the number of people who received a positive test result per 100 000 person weeks at risk) during the second wave (1 September 2020 to 22 May 2021) or third wave (23 May to 10 December 2021) of the pandemic. Age standardised rates were calculated by sociodemographic characteristics and adjusted rate ratios were estimated using generalised linear regression models with a Poisson distribution (models were adjusted for covariates including sex, age, geographical variables, and sociodemographic characteristics).ResultsDuring the study period, 5 767 584 people (14.8% of the study population) tested positive for SARS-CoV-2. In the second wave, the fully adjusted relative risks of having a positive test were highest for the Bangladeshi and Pakistani ethnic groups compared with the white British group, with rate ratios of 1.75 (95% confidence interval 1.73 to 1.77) and 1.69 (1.68 to 1.70), respectively. Muslim and Sikh religious groups had fully adjusted rate ratios of 1.51 (1.50 to 1.51) and 1.64 (1.63 to 1.66), respectively, compared with the Christian group. Greater area deprivation, disadvantaged socioeconomic position, living in a care home, and low English language proficiency were also associated with higher relative risk of having a positive test. However, the inequalities among groups varied over time. Being Christian, white British, without a disability, and from a more advantaged socioeconomic position were associated with increased relative risk of testing positive during the third wave.ConclusionResearch is urgently needed to understand the large sociodemographic inequalities in SARS-CoV-2 case rates in order to inform policy interventions in future waves or pandemics.

BackgroundTrials have identified antimicrobial stewardship (AMS) strategies that effectively reduce antibiotic use in primary care. However, many are not commonly used in England. The authors co-developed an implementation intervention to improve use of three AMS strategies: enhanced communication strategies, delayed prescriptions, and point-of-care C-reactive protein tests (POC-CRPTs).AimTo investigate the use of the intervention in high-prescribing practices and its effect on antibiotic prescribing.Design and settingNine high-prescribing practices had access to the intervention for 12 months from November 2019. This was primarily delivered remotely via a website with practices required to identify an ‘antibiotic champion’.MethodRoutinely collected prescribing data were compared between the intervention and the control practices. Intervention use was assessed through monitoring. Surveys and interviews were conducted with professionals to capture experiences of using the intervention.ResultsThere was no evidence that the intervention affected prescribing. Engagement with intervention materials differed substantially between practices and depended on individual champions’ preconceptions of strategies and the opportunity to conduct implementation tasks. Champions in five practices initiated changes to encourage use of at least one AMS strategy, mostly POC-CRPTs; one practice chose all three. POC-CRPTs was used more when allocated to one person.ConclusionClinicians need detailed information on exactly how to adopt AMS strategies. Remote, one-sided provision of AMS strategies is unlikely to change prescribing; initial clinician engagement and understanding needs to be monitored to avoid misunderstanding and suboptimal use.

Strategies to reduce antibiotic overuse in hospitals depend on prescribers taking decisions to stop unnecessary antibiotic use. There is scarce evidence for how to support these decisions. We evaluated a multifaceted behaviour change intervention (ie, the antibiotic review kit) designed to reduce antibiotic use among adult acute general medical inpatients by increasing appropriate decisions to stop antibiotics at clinical review.We performed a stepped-wedge, cluster (hospital)-randomised controlled trial using computer-generated sequence randomisation of eligible hospitals in seven calendar-time blocks in the UK. Hospitals were eligible for inclusion if they admitted adult non-elective general or medical inpatients, had a local representative to champion the intervention, and could provide the required study data. Hospital clusters were randomised to an implementation date occurring at 1-2 week intervals, and the date was concealed until 12 weeks before implementation, when local preparations were designed to start. The intervention effect was assessed using data from pseudonymised routine electronic health records, ward-level antibiotic dispensing, Clostridioides difficile tests, prescription audits, and an implementation process evaluation. Co-primary outcomes were monthly antibiotic defined daily doses per adult acute general medical admission (hospital-level, superiority) and all-cause mortality within 30 days of admission (patient level, non-inferiority margin of 5%). Outcomes were assessed in the modified intention-to-treat population (ie, excluding sites that withdrew before implementation). Intervention effects were assessed by use of interrupted time series analyses within each site, estimating overall effects through random-effects meta-analysis, with heterogeneity across prespecified potential modifiers assessed by use of meta-regression. This trial is completed and is registered with ISRCTN, ISRCTN12674243.58 hospital organisations expressed an interest in participating. Three pilot sites implemented the intervention between Sept 25 and Nov 20, 2017. 43 further sites were randomised to implement the intervention between Feb 12, 2018, and July 1, 2019, and seven sites withdrew before implementation. 39 sites were followed up for at least 14 months. Adjusted estimates showed reductions in total antibiotic defined daily doses per acute general medical admission (-4·8% per year, 95% CI -9·1 to -0·2) following the intervention. Among 7 160 421 acute general medical admissions, the ARK intervention was associated with an immediate change of -2·7% (95% CI -5·7 to 0·3) and sustained change of 3·0% (-0·1 to 6·2) in adjusted 30-day mortality.The antibiotic review kit intervention resulted in sustained reductions in antibiotic use among adult acute general medical inpatients. The weak, inconsistent intervention effects on mortality are probably explained by the onset of the COVID-19 pandemic. Hospitals should use the antibiotic review kit to reduce antibiotic overuse.UK National Institute for Health and Care Research.

BackgroundThe SARS-CoV-2 Delta variant has been replaced by the highly transmissible Omicron BA.1 variant, and subsequently by Omicron BA.2. It is important to understand how these changes in dominant variants affect reported symptoms, while also accounting for symptoms arising from other co-circulating respiratory viruses.MethodsIn a nationally representative UK community study, the COVID-19 Infection Survey, we investigated symptoms in PCR-positive infection episodes vs. PCR-negative study visits over calendar time, by age and vaccination status, comparing periods when the Delta, Omicron BA.1 and BA.2 variants were dominant.ResultsBetween October-2020 and April-2022, 120,995 SARS-CoV-2 PCR-positive episodes occurred in 115,886 participants, with 70,683 (58%) reporting symptoms. The comparator comprised 4,766,366 PCR-negative study visits (483,894 participants); 203,422 (4%) reporting symptoms. Symptom reporting in PCR-positives varied over time, with a marked reduction in loss of taste/smell as Omicron BA.1 dominated, maintained with BA.2 (44%/45% 17 October 2021, 16%/13% 2 January 2022, 15%/12% 27 March 2022). Cough, fever, shortness of breath, myalgia, fatigue/weakness and headache also decreased after Omicron BA.1 dominated, but sore throat increased, the latter to a greater degree than concurrent increases in PCR-negatives. Fatigue/weakness increased again after BA.2 dominated, although to a similar degree to concurrent increases in PCR-negatives. Symptoms were consistently more common in adults aged 18-65 years than in children or older adults.ConclusionsIncreases in sore throat (also common in the general community), and a marked reduction in loss of taste/smell, make Omicron harder to detect with symptom-based testing algorithms, with implications for institutional and national testing policies.SummaryIn a UK community study, loss of taste/smell was markedly less commonly reported with Omicron BA.1/BA.2 than Delta SARS-CoV-2 infections, with smaller declines in reported shortness of breath, myalgia and fatigue/weakness, but increases in sore throat, challenging symptom-based testing algorithms.

ObjectiveTo assess the risk of death involving COVID-19 following infection from Omicron (B.1.1.539/BA.1) relative to Delta (B.1.617.2).DesignRetrospective cohort study.SettingEngland, UK, 1 December 2021 to 25 January 2022.Participants1,035,163 people aged 18-100 years who tested positive for SARS-CoV-2 in the national surveillance programme, and had an infection identified as either Omicron- or Delta compatible.Main outcome measuresDeath involving COVID-19 as identified from death certification records. The exposure of interest was the SARS-CoV-2 variant identified from NHS Test and Trace PCR positive tests taken in the community (pillar 2) and analysed by Lighthouse laboratories. Cause-specific Cox proportional hazard regression models were adjusted for sex, age, vaccination status, previous infection, calendar time, ethnicity, Index of Multiple Deprivation rank, household deprivation, university degree, keyworker status, country of birth, main language, region, disability, and comorbidities. Additionally, we tested for interactions between variant and sex, age, vaccination status and comorbidities.ResultsThe risk of death involving COVID-19 was 67% lower for Omicron compared to Delta and the reduction in the risk of death involving COVID-19 for Omicron compared to Delta was more pronounced in males than in females and in people under 70 years old than in people aged 70 years or over. Regardless of age, reduction of the risk of death from Omicron relative to Delta more was more pronounced in people who had received a booster than in those having received only two doses.ConclusionsOur results support early work showing the relative reduction in severity of Omicron compared to Delta in terms of hospitalisation and extends this research to assess COVID-19 mortality. Our work also highlights the importance of the vaccination booster campaign, where the reduction in risk of death involving COVID-19 is most pronounced in individuals who had received a booster.What is already known on this topicThe Omicron variant, which refers to the whole lineage (BA.1, BA.2, BA.3) had already been shown to be more transmissible than the Delta variant, but there is emerging evidence suggests that the risk of hospitalisation and risk of death within 28 days after a SARS-COV-2 test is lower. However, with a highly transmissible infection and high levels of population testing, definition of death within 28 days is more likely to be susceptible to misclassification bias due to asymptomatic or co-incidental infection. There is no study so far comparing the risk of COVID-19 death as identified from death certification records, with the cause of death assessed by the physician who attended the patient in the last illness.What this study addsUsing data from a large cohort of COVID-19 infections that occurred in December 2021, we examined the difference in the risk COVID-19 death, as identified from death certification records, between the Delta and Omicron BA.1 variant. Our study shows that risk of death involving COVID-19 was reduced by 67% following infection with the Omicron BA.1 variant relative to the Delta variant after adjusting for a wide range of potential confounders, including vaccination status and comorbidities. Importantly, we found that the relative risk of COVID-19 mortality following Omicron versus Delta infection varied by age and sex, with lower relative risk in younger individuals and for males than females. The reduction in risk of death involving COVID-19 was also most pronounced in individuals who had received a booster.

ObjectiveTo examine socio-demographic disparities in SARS-CoV-2 case rates during the second (Alpha) and third (Delta) waves of the COVID-19 pandemic.DesignRetrospective, population-based cohort study.SettingResident population of England.Participants39,006,194 people aged 10 years and over who were enumerated at the 2011 Census, registered with the National Health Service (NHS) and alive on 1 September 2020.Main outcome measuresTesting positive for SARS-CoV-2 during the second wave (1 September 2020 to 22 May 2021) or third wave (23 May to 10 December 2021) of the pandemic. We calculated age-standardised case rates by socio-demographic characteristics and used logistic regression models to estimate adjusted odds ratios (ORs).ResultsDuring the study period, 5,767,584 individuals tested positive for SARS-CoV-2. In the second wave, the fully-adjusted odds of having a positive test, relative to the White British group, were highest for the Bangladeshi (OR: 1.88, 95% CI 1.86 to 1.90) and Pakistani (1.81, 1.79 to 1.82) ethnic groups. Relative to the Christian group, Muslim and Sikh religious groups had fully-adjusted ORs of 1.58 (1.57 to 1.59) and 1.74 (1.72 to 1.76), respectively. Greater area deprivation, disadvantaged socio-economic position, living in a care home and low English language proficiency were also associated with higher odds of having a positive test. However, the disparities between groups varied over time. Being Christian, White British, non-disabled, and from a more advantaged socio-economic position were all associated with increased odds of testing positive during the third wave.ConclusionThere are large socio-demographic disparities on SARS-CoV-2 cases which have varied between different waves of the pandemic. Research is now urgently needed to understand why these disparities exist to inform policy interventions in future waves or pandemics.What is already known on this topicPeople with pre-existing health conditions or disability, ethnic minority groups, the elderly, some religious groups, people with low socio-economic status, and those living in deprived areas have been disproportionately affected by the COVID-19 pandemic in terms of risk of infection and adverse outcomes.What this study addsUsing linked data on 39 million people in England, we found that during the second wave, COVID-19 case rates were highest among the Bangladeshi and Pakistani ethnic groups, the Muslim religious group, individuals from deprived areas and of low socio-economic position; during the third wave, being Christian, White British, non-disabled, and from a more advantaged socio-economic position were all associated with increased odds of receiving a positive testAdjusting for geographical factors, socio-demographic characteristics, and pre-pandemic health status explained some, but not all, of the excess riskWhen stratifying the dataset by broad age groups, the odds of receiving a positive test remained higher among the Bangladeshi and Pakistani ethnic groups aged 65 years and over during the third wave, which may partly explain the continued elevated mortality rates in these groups

ObjectiveTo assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis.DesignA single-centre open-label randomised controlled trial.SettingKilifi County Hospital, Kenya.Patients120 neonates aged ≤28 days admitted being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and gentamicin between March 2018 and February 2019.InterventionWe randomly assigned half the participants to receive additional intravenous then oral fosfomycin at 100 mg/kg two times per day for up to 7 days (SOC-F) and followed up for 28 days.Main outcome(s) and measure(s)Serum sodium, AEs and fosfomycin pharmacokinetics.Results61 and 59 infants aged 0–23 days were assigned to SOC-F and SOC, respectively. There was no evidence of impact of fosfomycin on serum sodium or gastrointestinal side effects. We observed 35 AEs among 25 SOC-F participants and 50 AEs among 34 SOC participants during 1560 and 1565 infant-days observation, respectively (2.2 vs 3.2 events/100 infant-days; incidence rate difference −0.95 events/100 infant-days (95% CI −2.1 to 0.20)). Four SOC-F and 3 SOC participants died. From 238 pharmacokinetic samples, modelling suggests an intravenous dose of 150 mg/kg two times per day is required for pharmacodynamic target attainment in most children, reduced to 100 mg/kg two times per day in neonates aged Conclusion and relevanceFosfomycin offers potential as an affordable regimen with a simple dosing schedule for neonatal sepsis. Further research on its safety is needed in larger cohorts of hospitalised neonates, including very preterm neonates or those critically ill. Resistance suppression would only be achieved for the most sensitive of organisms so fosfomycin is recommended to be used in combination with another antimicrobial.Trial registration numberNCT03453177.

BackgroundHealthcare-associated wastewater reservoirs and asymptomatic gastrointestinal patient colonisation by carbapenemase-producing Enterobacterales (CPE) can be important in nosocomial CPE dissemination and infection. We characterised these niches and within-niche diversity in a blaKPC-associated CPE (KPC-E) endemic healthcare setting, to better understand transmission potential.MethodsWe systematically sampled wastewater sites and patients across three units (six wards) over 6-12 months in 2016 in a KPC-E endemic hospital. We used Illumina sequencing to characterise up to five isolates per sample. Recombination-adjusted phylogenies were used to define genetically related strains; assembly and mapping-based typing approaches were used to characterise antimicrobial resistance gene and insertion sequence profiles, and Tn4401 types/target site sequences. The wider accessory genome was evaluated in a subset of the largest clusters, and those crossing niches.FindingsWastewater site KPC-E-positivity was substantial (101/349 sites [28.9%] positive, 319/4,488 [7.1%] sampling events positive); 183/4,425 (4.1%) of patients were CPE culture-positive over the same timeframe. 13 species and 109 KPC-E strains were observed across niches, and 24% of wastewater and 26% of patient KPC-E-positive samples harboured ≥1 strain. Most diversity was explained by the individual niche, suggesting highly localised factors are important in selection and spread. Tn4401+target site sequence (TSS) diversity was greater in wastewater sites (p4401-associated transposition/evolution and dissemination. Shower/bath and sluice/mop-associated sites were more likely to be KPC-E-positive (Adjusted Odds Ratio [95% CI]: 2.69 [1.44-5.01], p=0.0019 and 2.60 [1.04-6.52], p=0.0410, respectively). Different strains had different transmission and blaKPC dissemination dynamics.InterpretationThere may be substantial KPC-E colonisation of wastewater sites and patients in KPC-E-endemic healthcare settings. Niche-specific factors, and different strains with different transmission dynamics influence carbapenemase gene dissemination. New transmission models incorporating complex, multi-level dynamics are needed to better quantify CPE dissemination to inform interventions and reduce transmission.FundingThis study was supported by the National Institute for Health Research, UK.RESEARCH IN CONTEXTEvidence before this studyWe searched PubMed to identify previous studies using whole genome sequencing (WGS) to characterise in-hospital dissemination and persistence of carbapenemase-producing Enterobacterales (CPEs) or the presence of CPEs in hospital wastewater reservoirs. In our search (01/Jan/1996-30/Sep/2021) we used the terms ((((CPE) OR (KPC)) AND (healthcare-associated OR nosocomial OR hospital-associated)) AND (genom*) AND ((environment OR patient))). We had no restrictions on language. We found sixty-six studies, but these were limited by: (i) evaluating single species or lineages only (n=34), (ii) including patients or environmental outbreaks only, and not both (n=23), (iii) sampling only small numbers (nex vivo or in vivo evolution), two studies did not use WGS, and one study was not primary research.Added value of this studyWe provide a comprehensive assessment of healthcare-associated CPE dissemination and persistence in hospital wastewater reservoirs through systematic sampling of a large number of environmental sites (n=349 sites, n=4,488 samples) and patients (n=4,425) over 6-12 months in a single hospital. For all CPE-positive environmental samples (n=319) and a subset of CPE-positive patient samples (n=97/399 [24.3%] samples from 76/183 [41.5%] CPE-positive patients), we sampled up to five CPE isolates per sample to capture within-niche diversity, and used short-read Illumina WGS (n=1,732 isolates successfully sequenced) to characterise within-niche diversity, changes in colonisation over time, and genetic overlap between patient and environmental niches.Implications of all the available evidenceThrough a detailed and resource-intensive study we captured the dynamics of seeding and dissemination of important carbapenemase genes amongst patients and environmental reservoirs within a hospital. We found differential colonisation and dissemination dynamics for different species and lineages within and between niches. Improved approaches incorporating variable within-niche diversity, accessory distances and horizontal gene transfer in transmission evaluations are required to better understand CPE dissemination and persistence, in order to direct interventions limiting transmission.

Background Pre-Delta, vaccination reduced SARS-CoV-2 transmission from individuals infected despite vaccination, potentially via reducing viral loads. While vaccination still lowers the risk of infection, similar viral loads in vaccinated and unvaccinated individuals infected with Delta question how much vaccination prevents transmission. Methods We performed a retrospective observational cohort study of adult contacts of SARS-CoV-2-infected adult index cases using English contact testing data. We used multivariable Poisson regression to investigate associations between transmission and index case and contact vaccination, and how these vary with Alpha and Delta variants (classified using S-gene detection/calendar trends) and time since second vaccination. Results 54,667/146,243(37.4%) PCR-tested contacts of 108,498 index cases were PCR-positive. Two doses of BNT162b2 or ChAdOx1 vaccines in Alpha index cases were independently associated with reduced PCR-positivity in contacts (aRR, adjusted rate ratio vs. unvaccinated=0.32[95%CI 0.21-0.48] and 0.48[0.30-0.78] respectively). The Delta variant attenuated vaccine-associated reductions in transmission: two BNT162b2 doses reduced Delta transmission (aRR=0.50[0.39-0.65]), more than ChAdOx1 (aRR=0.76[0.70-0.82]). Variation in Ct values (indicative of viral load) explained 7-23% of vaccine-associated transmission reductions. Transmission reductions declined over time post-second vaccination, for Delta reaching similar levels to unvaccinated individuals by 12 weeks for ChAdOx1 and attenuating substantially for BNT162b2. Protection in contacts also declined in the 3 months post-second vaccination. Conclusions Vaccination reduces transmission of Delta, but by less than the Alpha variant. The impact of vaccination decreased over time. Factors other than PCR Ct values at diagnosis are important in understanding vaccine-associated transmission reductions. Booster vaccinations may help control transmission together with preventing infections.

BackgroundSeveral community-based studies have assessed the ability of different symptoms to identify COVID-19 infections, but few have compared symptoms over time (reflecting SARS-CoV-2 variants) and by vaccination status.MethodsUsing data and samples collected by the COVID-19 Infection Survey at regular visits to representative households across the UK, we compared symptoms in new PCR-positives and comparator test-negative controls.ResultsFrom 26/4/2020-7/8/2021, 27,869 SARS-CoV-2 PCR-positive episodes occurred in 27,692 participants (median 42 years (IQR 22-58)); 13,427 (48%) self-reported symptoms (“symptomatic positive episodes”). The comparator group comprised 3,806,692 test-negative visits (457,215 participants); 130,612 (3%) self-reported symptoms (“symptomatic negative visit”). Reporting of any symptoms in positive episodes varied over calendar time, reflecting changes in prevalence of variants, incidental changes (e.g. seasonal pathogens, schools re-opening) and vaccination roll-out. There was a small increase in sore throat reporting in symptomatic positive episodes and negative visits from April-2021. After May-2021 when Delta emerged there were substantial increases in headache and fever in positives, but not in negatives. Although specific symptom reporting in symptomatic positive episodes vs. negative visits varied by age, sex, and ethnicity, only small improvements in symptom-based infection detection were obtained; e.g. adding fatigue/weakness or all eight symptoms to the classic four symptoms (cough, fever, loss of taste/smell) increased sensitivity from 74% to 81% to 90% but tests per positive from 4.6 to 5.3 to 8.7.ConclusionsWhilst SARS-CoV-2-associated symptoms vary by variant, vaccination status and demographics, differences are modest and do not warrant large-scale changes to targeted testing approaches given resource implications.SummaryWithin the COVID-19 Infection Survey, recruiting representative households across the UK general population, SARS-CoV-2-associated symptoms varied by viral variant, vaccination status and demographics. However, differences are modest and do not currently warrant large-scale changes to targeted testing approaches.

Background The incidence of Gram-negative bloodstream infections (BSIs), predominantly caused by Escherichia coli and Klebsiella species, continues to increase; however, the causes of this are unclear and effective interventions are therefore hard to design. Methods In this study, we sequenced 3468 unselected isolates over a decade in Oxfordshire (UK) and linked this data to routinely collected electronic healthcare records and mandatory surveillance reports. We annotated genomes for clinically relevant genes, contrasting the distribution of these within and between species, and compared incidence trends over time using stacked negative binomial regression. Results We demonstrate that the observed increases in E. coli incidence were not driven by the success of one or more sequence types (STs); instead, four STs continue to dominate a stable population structure, with no evidence of adaptation to hospital/community settings. Conversely in Klebsiella spp., most infections are caused by sporadic STs with the exception of a local drug-resistant outbreak strain (ST490). Virulence elements are highly structured by ST in E. coli but not Klebsiella spp. where they occur in a diverse spectrum of STs and equally across healthcare and community settings. Most clinically hypervirulent (i.e. community-onset) Klebsiella BSIs have no known acquired virulence loci. Finally, we demonstrate a diverse but largely genus-restricted mobilome with close associations between antimicrobial resistance (AMR) genes and insertion sequences but not typically specific plasmid replicon types, consistent with the dissemination of AMR genes being highly contingent on smaller mobile genetic elements (MGEs). Conclusions Our large genomic study highlights distinct differences in the molecular epidemiology of E. coli and Klebsiella BSIs and suggests that no single specific pathogen genetic factors (e.g. AMR/virulence genes/sequence type) are likely contributing to the increasing incidence of BSI overall, that association with AMR genes in E. coli is a contributor to the increasing number of E. coli BSIs, and that more attention should be given to AMR gene associations with non-plasmid MGEs to try and understand horizontal gene transfer networks.

Funder: Oxford NIHR Biomedical Research Centre, Antimicrobial resistance (AMR) surveillance in bloodstream infections (BSIs) is challenging in low/middle-income countries (LMICs) given limited laboratory capacity. Other specimens are easier to collect and process and are more likely to be culture-positive. In 8102 E. coli BSIs, 322,087 E. coli urinary tract infections, 6952 S. aureus BSIs and 112,074 S. aureus non-sterile site cultures from Oxfordshire (1998-2018), and other (55,296 isolates) rarer commensal opportunistic pathogens, antibiotic resistance trends over time in blood were strongly associated with those in other specimens (maximum cross-correlation per drug 0.51-0.99). Resistance prevalence was congruent across drug-years for each species (276/312 (88%) species-drug-years with prevalence within �� 10% between blood/other isolates). Results were similar across multiple countries in high/middle/low income-settings in the independent ATLAS dataset (103,559 isolates, 2004-2017) and three further LMIC hospitals/programmes (6154 isolates, 2008-2019). AMR in commensal opportunistic pathogens cultured from BSIs is strongly associated with AMR in commensal opportunistic pathogens cultured from non-sterile sites over calendar time, suggesting the latter could be used as an effective proxy for AMR surveillance in BSIs.

ObjectiveTo examine inequalities in COVID-19 vaccination rates amongst elderly adults in EnglandDesignCohort studySettingPeople living in private households and communal establishments in EnglandParticipants6,829,643 adults aged ≥ 70 years (mean 78.7 years, 55.2% female) who were alive on 15 March 2021.Main outcome measuresHaving received the first dose of a vaccine against COVID-19 by 15 March 2021. We calculated vaccination rates and estimated unadjusted and adjusted odds ratios using logistic regression models.ResultsBy 15 March 2021, 93.2% of people living in England aged 70 years and over had received at least one dose of a COVID-19 vaccine. While vaccination rates differed across all factors considered apart from sex, the greatest disparities were seen between ethnic and religious groups. The lowest rates were in people of Black African and Black Caribbean ethnic backgrounds, where only 67.2% and 73.9% had received a vaccine, with adjusted odds of not being vaccinated at 5.01 (95% CI 4.86 - 5.16) and 4.85 (4.75 - 4.96) times greater than the White British group. The proportion of individuals self-identifying as Muslim and Buddhist who had received a vaccine was 79.1% and 84.1%, respectively. Older age, greater area deprivation, less advantaged socio-economic position (proxied by living in a rented home), being disabled and living either alone or in a multi-generational household were also associated with higher odds of not having received the vaccine.ConclusionPeople disproportionately affected seem most hesitant to COVID-19 vaccinations. Policy Interventions to improve these disparities are urgently needed.Summary BoxWhat is already known on this subject?The UK began an ambitious vaccination programme to combat the COVID-19 pandemic on 8th December 2020. Existing evidence suggests that COVID-19 vaccination rates differ by level of area deprivation, ethnicity and certain underlying health conditions, such as learning disability and mental health problems.What does this study add?Our study shows that first dose vaccination rates in adults aged 70 or over differed markedly by ethnic group and self-reported religious affiliation, even after adjusting for geography, socio-demographic factors and underlying health conditions. Our study also highlights differences in vaccination rates by deprivation, household composition, and disability status, factors disproportionately associated with SARS-CoV-2 infection. Public health policy and community engagement aimed at promoting vaccination uptake is these groups are urgently needed.Strengths and limitations of this studyUsing nationwide linked population-level data from clinical records and the 2011 Census, we examined a wide range of socio-demographic characteristics not available n electronic health recordsMost demographic and socio-economic characteristics are derived from the 2011 Census and therefore are 10 years old. However, we focus primarily on characteristics that are unlikely to change over time, such as ethnicity or religion, or likely to be stable for our populationBecause the data are based on the 2011 Census, it excluded people living in England in 2011 but not taking part in the 2011 Census; respondents who could not be linked to the 2011-2013 NHS patients register; recent migrants. Consequently, we excluded 5.4% of vaccinated people who could not be linked

Background: Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosis . There is currently no WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: A candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 M. tuberculosis isolates with paired whole-genome sequencing and phenotypic drug susceptibility data were amassed from 41 countries. Mutations were graded according to their odds ratio and associated false discovery rate corrected p-value, and their positive predictive value for phenotypic resistance. A series of expert rules were applied for final confidence grading of each mutation. Findings: 15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations’ pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: This first WHO endorsed catalogue of molecular targets for M. tuberculosis drug susceptibility testing provides a global standard for resistance interpretation. It will be expanded as data emerge on phenotypically resistant isolates, including for new and repurposed drugs. Funding: UNITAID, Wellcome, MRC, BMGF. Declaration of Interest: C.U.K. is a consultant Becton Dickinson, the Foundation for Innovative New Diagnostics and the TB Alliance. C.U.K. is collaborating with PZA Innovation and Thermo Fisher Scientific. C.U.K. worked as a consultant for QuantuMDx, the Stop TB Partnership, the World Health Organization (WHO) Global TB Programme and the WHO Regional Office for Europe. C.U.K. gave a paid educational talk for Oxford Immunotec. Hain Lifescience covered C.U.K.’s and accommodation to present at a meeting. C.U.K. is an unpaid advisor to BioVersys and GenoScreen. E.R. is employed by Public Health England and holds an honorary contract with Imperial College London. I.F.L. is Director of the Scottish Mycobacteria Reference Laboratory. S.N. receives funding from German Center for Infection Research, Excellenz Cluster Precision Medicine in Chronic Inflammation, Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG)tion EXC 2167. P.S. is a consultant at Genoscreen. T.R. is funded by NIH and DoD and receives salary support from the non-profit organization FIND. T.R. is a cofounder, board member and shareholder of Verus Diagnostics Inc, a company that was founded with the intent of developing diagnostic assays. Verus Diagnostics was not involved in any way with data collection, analysis or publication of the results. T.R. has not received any financial support from Verus Diagnostics. UCSD Conflict of Interest office has reviewed and approved T.R.’s role in Verus Diagnostics Inc. T.R. is a co-inventor of a provisional patent for a TB diagnostic assay (provisional patent #: 63/048.989). T.R. is a co-inventor on a patent associated with the processing of TB sequencing data (European Patent Application No. 14840432.0 & USSN 14/912,918). T.R. has agreed to “donate all present and future interest in and rights to royalties from this patent” to UCSD to ensure that he does not receive any financial benefits from this patent. S.S. is working and holding ESOPs at HaystackAnalytics Pvt. Ltd. (Product: Using whole genome sequencing for drug susceptibility testing for Mycobacterium tuberculosis). G.F.G. is listed as an inventor on patent applications for RBDdimer- based CoV vaccines. No other authors declare a conflict of interest. Ethical Approval: Approval for CRyPTIC study was obtained by Taiwan Centers for Disease Control IRB No. 106209, University of KwaZulu Natal Biomedical Research Ethics Committee (UKZN BREC) (reference BE022/13) and University of Liverpool Central University Research Ethics Committees (reference 2286), Institutional Research Ethics Committee (IREC) of The Foundation for Medical Research, Mumbai (Ref nos. FMR/IEC/TB/01a/2015 and FMR/IEC/TB/01b/2015), Institutional Review Board of P.D. Hinduja Hospital and Medical Research Centre, Mumbai (Ref no. 915-15-CR [MRC]), scientific committee of the Adolfo Lutz Institute (CTC-IAL 47-J / 2017) and in the Ethics Committee (CAAE: 81452517.1.0000.0059) and Ethics Committee review by Universidad Peruana Cayetano Heredia (Lima, Peru) and LSHTM (London, UK).

Summary Background Decisions about the continued need for control measures to contain the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rely on accurate and up-to-date information about the number of people testing positive for SARS-CoV-2 and risk factors for testing positive. Existing surveillance systems are generally not based on population samples and are not longitudinal in design. Methods Samples were collected from individuals aged 2 years and older living in private households in England that were randomly selected from address lists and previous Office for National Statistics surveys in repeated cross-sectional household surveys with additional serial sampling and longitudinal follow-up. Participants completed a questionnaire and did nose and throat self-swabs. The percentage of individuals testing positive for SARS-CoV-2 RNA was estimated over time by use of dynamic multilevel regression and poststratification, to account for potential residual non-representativeness. Potential changes in risk factors for testing positive over time were also assessed. The study is registered with the ISRCTN Registry, ISRCTN21086382. Findings Between April 26 and Nov 1, 2020, results were available from 1 191 170 samples from 280 327 individuals; 5231 samples were positive overall, from 3923 individuals. The percentage of people testing positive for SARS-CoV-2 changed substantially over time, with an initial decrease between April 26 and June 28, 2020, from 0·40% (95% credible interval 0·29–0·54) to 0·06% (0·04–0·07), followed by low levels during July and August, 2020, before substantial increases at the end of August, 2020, with percentages testing positive above 1% from the end of October, 2020. Having a patient-facing role and working outside your home were important risk factors for testing positive for SARS-CoV-2 at the end of the first wave (April 26 to June 28, 2020), but not in the second wave (from the end of August to Nov 1, 2020). Age (young adults, particularly those aged 17–24 years) was an important initial driver of increased positivity rates in the second wave. For example, the estimated percentage of individuals testing positive was more than six times higher in those aged 17–24 years than in those aged 70 years or older at the end of September, 2020. A substantial proportion of infections were in individuals not reporting symptoms around their positive test (45–68%, dependent on calendar time. Interpretation Important risk factors for testing positive for SARS-CoV-2 varied substantially between the part of the first wave that was captured by the study (April to June, 2020) and the first part of the second wave of increased positivity rates (end of August to Nov 1, 2020), and a substantial proportion of infections were in individuals not reporting symptoms, indicating that continued monitoring for SARS-CoV-2 in the community will be important for managing the COVID-19 pandemic moving forwards. Funding Department of Health and Social Care.

Antibiotic prescribing in England varies considerably between Clinical Commissioning Groups (CCGs) and general practices. We aimed to assess social and contextual factors affecting antibiotic prescribing and engagement with antimicrobial stewardship (AMS) initiatives. Semi-structured telephone interviews were conducted with 22 CCG professionals and 19 general practice professionals. Interviews were audio-recorded, transcribed, and analyzed thematically. Social/contextual influences were grouped into the following four categories: (1) Immediate context, i.e., patients’ social characteristics (e.g., deprivation and culture), clinical factors, and practice and clinician characteristics (e.g., “struggling” with staff shortage/turnover) were linked to higher prescribing. (2) Wider context, i.e., pressures on the healthcare system, limited resources, and competing priorities were seen to reduce engagement with AMS. (3) Collaborative and whole system approaches, i.e., communication, multidisciplinary networks, leadership, and teamwork facilitated prioritizing AMS, learning, and consistency. (4) Relativity of appropriate prescribing, i.e., “high” or “appropriate” prescribing was perceived as relative, depending on comparators, and disregarding different contexts, but social norms around antibiotic use among professionals and patients seemed to be changing. Further optimization of antibiotic prescribing would benefit from addressing social/contextual factors and addressing wider health inequalities, not only targeting individual clinicians. Tailoring and adapting to local contexts and constraints, ensuring adequate time and resources for AMS, and collaborative, whole system approaches to promote consistency may help promote AMS. View Full-Text\udKeywords: antibiotic prescribing; antimicrobial stewardship; primary care; qualitative

Background Lateral flow device (LFD) viral antigen immunoassays have been developed around the world as diagnostic tests for SARS-CoV-2 infection. They have been proposed to deliver an infrastructure-light, cost-economical solution giving results within half an hour. Methods LFDs were initially reviewed by a Department of Health and Social Care team, part of the UK government, from which 64 were selected for further evaluation from 1st August to 15th December 2020. Standardised laboratory evaluations, and for those that met the published criteria, field testing in the Falcon-C19 research study and UK pilots were performed (UK COVID-19 testing centres, hospital, schools, armed forces). Findings 4/64 LFDs so far have desirable performance characteristics (orient Gene, Deepblue, Abbott and Innova SARS-CoV-2 Antigen Rapid Qualitative Test). All these LFDs have a viral antigen detection of >90% at 100,000 RNA copies/ml. 8951 Innova LFD tests were performed with a kit failure rate of 5.6% (502/8951, 95% CI: 5.1–6.1), false positive rate of 0.32% (22/6954, 95% CI: 0.20–0.48). Viral antigen detection/sensitivity across the sampling cohort when performed by laboratory scientists was 78.8% (156/198, 95% CI 72.4–84.3). Interpretation Our results suggest LFDs have promising performance characteristics for mass population testing and can be used to identify infectious positive individuals. The Innova LFD shows good viral antigen detection/sensitivity with excellent specificity, although kit failure rates and the impact of training are potential issues. These results support the expanded evaluation of LFDs, and assessment of greater access to testing on COVID-19 transmission. Funding Department of Health and Social Care. University of Oxford. Public Health England Porton Down, Manchester University NHS Foundation Trust, National Institute of Health Research.

Background: To ensure patients continue to get early access to antibiotics at admission, while also safely reducing antibiotic use in hospitals, one needs to target the continued need for antibiotics as more diagnostic information becomes available. UK Department of Health guidance promotes an initiative called ‘Start Smart then Focus’: early effective antibiotics followed by active ‘review and revision’ 24–72 h later. However in 2017, Methods/design: Antibiotic Review Kit for Hospitals (ARK-Hospital) is a complex ‘review and revise’ behavioural intervention targeting healthcare professionals involved in antibiotic prescribing or administration in inpatients admitted to acute/general medicine (the largest consumers of non-prophylactic antibiotics in hospitals). The primary study objective is to evaluate whether ARK-Hospital can safely reduce the total antibiotic burden in acute/general medical inpatients by at least 15%. The primary hypotheses are therefore that the introduction of the behavioural intervention will be non-inferior in terms of 30-day mortality post-admission (relative margin 5%) for an acute/general medical inpatient, and superior in terms of defined daily doses of antibiotics per acute/general medical admission (co-primary outcomes). The unit of observation is a hospital organisation, a single hospital or group of hospitals organised with one executive board and governance framework (National Health Service trusts in England; health boards in Northern Ireland, Wales and Scotland). The study comprises a feasibility study in one organisation (phase I), an internal pilot trial in three organisations (phase II) and a cluster (organisation)-randomised stepped-wedge trial (phase III) targeting a minimum of 36 organisations in total. Randomisation will occur over 18 months from November 2017 with a further 12 months follow-up to assess sustainability. The behavioural intervention will be delivered to healthcare professionals involved in antibiotic prescribing or administration in adult inpatients admitted to acute/general medicine. Outcomes will be assessed in adult inpatients admitted to acute/general medicine, collected through routine electronic health records in all patients.Discussion: ARK-Hospital aims to provide a feasible, sustainable and generalisable mechanism for increasing antibiotic stopping in patients who no longer need to receive them at ‘review and revise’.Trial registration: ISRCTN Current Controlled Trials, ISRCTN12674243. Registered on 10 April 2017.

ObjectiveTo evaluate the duration of prescriptions for antibiotic treatment for common infections in English primary care and to compare this with guideline recommendations.DesignCross sectional study.SettingGeneral practices contributing to The Health Improvement Network database, 2013-15.Participants931 015 consultations that resulted in an antibiotic prescription for one of several indications: acute sinusitis, acute sore throat, acute cough and bronchitis, pneumonia, acute exacerbation of chronic obstructive pulmonary disease (COPD), acute otitis media, acute cystitis, acute prostatitis, pyelonephritis, cellulitis, impetigo, scarlet fever, and gastroenteritis.Main outcome measuresThe main outcomes were the percentage of antibiotic prescriptions with a duration exceeding the guideline recommendation and the total number of days beyond the recommended duration for each indication.ResultsThe most common reasons for antibiotics being prescribed were acute cough and bronchitis (386 972, 41.6% of the included consultations), acute sore throat (239 231, 25.7%), acute otitis media (83 054, 8.9%), and acute sinusitis (76 683, 8.2%). Antibiotic treatments for upper respiratory tract indications and acute cough and bronchitis accounted for more than two thirds of the total prescriptions considered, and 80% or more of these treatment courses exceeded guideline recommendations. Notable exceptions were acute sinusitis, where only 9.6% (95% confidence interval 9.4% to 9.9%) of prescriptions exceeded seven days and acute sore throat where only 2.1% (2.0% to 2.1%) exceeded 10 days (recent guidance recommends five days). More than half of the antibiotic prescriptions were for longer than guidelines recommend for acute cystitis among females (54.6%, 54.1% to 55.0%). The percentage of antibiotic prescriptions exceeding the recommended duration was lower for most non-respiratory infections. For the 931 015 included consultations resulting in antibiotic prescriptions, about 1.3 million days were beyond the durations recommended by guidelines.ConclusionFor most common infections treated in primary care, a substantial proportion of antibiotic prescriptions have durations exceeding those recommended in guidelines. Substantial reductions in antibiotic exposure can be accomplished by aligning antibiotic prescription durations with guidelines.

BackgroundThe WHO has identified the need for a better understanding of which patients can be cured with ultrashort course hepatitis C (HCV) therapyMethods202 individuals with chronic HCV were randomised to fixed-duration shortened therapy (8 weeks) vs variable-duration ultrashort strategies (VUS1/2). Participants not cured following first-line treatment were retreated with 12 weeks’ sofosbuvir/ledipasvir/ribavirin. Primary outcome was sustained virological response 12 weeks (SVR12) after first-line treatment and retreatment. Participants were factorially randomised to receive ribavirin with first-line treatment.ResultsAll evaluable participants achieved SVR12 overall (197/197, 100%[95%CI 98-100]) demonstrating non-inferiority between fixed-duration and variable-duration strategies (difference 0% [95%CI −3.8%,+3.7%], 4% pre-specified non-inferiority margin). First-line SVR12 was 91%[86%-97%] (92/101) for fixed-duration vs 48%[39%-57%] (47/98) for variable-duration, but was significantly higher for VUS2 (72% [56%-87%] (23/32)) than VUS1 (36% [25%-48%] (24/66)). Overall first-line SVR12 was 72%[65%-78%] (70/101) without ribavirin and 68%[61%-76%] (69/98) with ribavirin (p=0.48). At treatment failure, the emergence of viral resistance was lower with ribavirin (12% [2%-30%] (3/26)) than without (38% [21%-58%] (11/29), p=0.01).ConclusionsUnsuccessful first-line short-course therapy did not compromise retreatment with sofosbuvir/ledipasvir/ribavirin (100% SVR12). SVR12 rates were significantly increased when ultrashort treatment varied between 4-7 weeks rather than 4-6 weeks. Ribavirin significantly reduced resistance emergence in those failing first-line therapy.RegistrationISRCTN 37915093.FundingNational Institutes of Health Research.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants.FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005).INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.FUNDING: UK National Institute for Health Research Health Technology Assessment.

Background\ud \ud There are very few options to treat multidrug-resistant bacterial infections in children. A major barrier is the duration and complexity of regulatory trials of new antibiotics. Extrapolation of safety data from adult trials could facilitate drug development for children.\ud Objective\ud \ud We performed a systematic review on the safety of antibiotic clinical trials (CTs) in children (0–18 years) to evaluate the overall quality of safety trials conducted in children and to determine if age-specific adverse events (AEs) could be identified for specific antibiotic classes.\ud Data Sources\ud \ud We searched the MEDLINE, Cochrane CENTRAL, and ClinicalTrials.gov electronic databases for trials conducted between 2000 and 2016.\ud Study Selection\ud \ud All trials in which safety was declared a primary or secondary endpoint were included. Exclusion criteria were (1) topical or inhalational route of administration; (2) non-infectious conditions; (3) administration for prophylaxis rather than treatment; (4) selected population (i.e. cystic fibrosis, malignancies, HIV and tuberculosis); and (5) design other than randomized controlled trials. Trials reporting data on both adults and children were included only if paediatric results were reported separately.\ud Data Extraction and Synthesis\ud \ud Two authors independently extracted the data. To assess the quality of published trials, the Extension for harms for Consolidated Standards of Reporting Trials (CONSORT) Statement 2004 was used.\ud Main Outcome and Measure\ud \ud In order to quantitatively assess the rate of developing AEs by drug class, the numbers of overall and body-system-specific AEs were collected for each study arm, and then calculated per single drug class as median and interquartile range (IQR) of the proportions across CTs. The AEs most frequently reported were compared in the meta-analysis by selecting the CTs on the most represented drug classes.\ud Results\ud \ud Eighty-three CTs were included, accounting for 27,693 children. Overall, 69.7% of CONSORT items were fully reported. The median proportion of children with any AE was 22.5%, but did not exceed 8% in any single body system. Serious drug-related AEs and drug-related discontinuations were very rare (median 0.3 and 0.9%, respectively). Limitations included the inability to stratify by age group, particularly neonates.\ud Conclusions and Relevance\ud \ud Overall, AEs in paediatric antibiotic CTs were predictable and class-specific, and no unexpected (age-specific) side effects were identified. Smaller, open-label, dose-finding, high-quality, single-arm pharmacokinetic trials seem potentially sufficient for certain common antibiotic classes, extrapolating well-established safety profiles determined from large adult efficacy trials. This approach could reduce duration and enhance subsequent registration of urgently needed new antibiotics. This will need to be combined with enhanced methods of pharmacovigilance for monitoring of emerging AEs in routine clinical practice.

With little evidence that failing to complete a prescribed antibiotic course contributes to antibiotic resistance, it’s time for policy makers, educators, and doctors to drop this message, argue Martin Llewelyn and colleagues.

To determine the frequencies of HLA-B alleles in Ugandan patients in the NORA substudy of the DART trial and to compare HLA-B allele frequencies in those with and without clinically diagnosed hypersensitivity reaction (HSR).DNA-based HLA-B genotyping was used to determine HLA alleles in 247 participants who received abacavir, including all six participants ('cases') with clinically diagnosed abacavir HSR.The incidence of clinical abacavir HSR in this double-blinded study was 2.0% (6/300) in the abacavir group. As HLA-B*5701 was absent throughout the entire cohort, including the six HSR 'cases', an association could not be established between HLA-B*5701 and clinically diagnosed abacavir HSR. No other HLA-B*57 alleles were present among the six 'cases'. HLA-B*5703 was the most frequent HLA-B*57 allele among the abacavir-tolerant participants.The rate of clinical HSR was low, which may reflect the expected 2-3% clinical false-positive rate seen in previous double-blind randomized studies. The presumption that these cases may be false-positive abacavir HSR is supported by the fact that no HLA-B*5701 alleles were found in the abacavir group. Implementation of prospective HLA-B*5701 screening must be based on benefit/risk considerations within local practice. Clinical risk management remains paramount.

Background Epidemiological investigations into Mycobacterium tuberculosis outbreaks use 24-locus genotyping (MIRU-VNTR typing). Where no epidemiological link can be found between patients, the importance of shared genotypes remains unclear. This issue is especially problematic and time-consuming when tracing contacts within some social groups at high tuberculosis risk, in which unwillingness to volunteer information is common. We investigated whether whole-genome sequencing (WGS) could delineate outbreaks with greater resolution than MIRU-VNTR typing has done. Methods We sequenced 390 M tuberculosis isolates from 254 patients from the UK Midlands (1994–2011) using Illumina technology (appendix). We estimated the expected genomic diversity between isolates within a transmission chain by measuring pairwise nucleotide differences between genomes within hosts (79 individuals with pulmonary and extrapulmonary disease, or multiple pulmonary episodes) and between hosts within 25 household outbreaks (63 individuals). We then investigated 11 MIRU-VNTR-based community clusters (168 patients, 157 transmission events) to assess whether WGS could delineate outbreaks more effectively. For each cluster we reconstructed the most plausible transmission chain based on epidemiological data collected by tuberculosis nurses, pairwise nucleotide distances, and times of diagnosis, and compared the genomic diversity across these constructed links with that within individuals and within household outbreaks. Findings 109 (96%) of 114 isolates were within five SNPs of another isolate taken from the same individual or from an individual in the same household outbreak. On the basis of longitudinal isolates from individuals or households, we estimated an evolutionary rate of 0·5 SNPs per genome per year, consistent with a maximum of five SNPs between related isolates 3 years or less apart. Using a greater than five SNP threshold to assess 11 MIRU-VNTR-based community clusters, we found that none of 69 epidemiologically related pairs of MIRU-VNTR-matched cases plausibly related by transmission, two of 13 possibly related pairs, and 13 of 75 pairs with no known epidemiological relation were separated by more than five SNPs (p Interpretation WGS can delineate tuberculosis outbreaks with greater resolution than has previously been possible. These findings offer public health teams the potential to limit outbreak investigations to patients who are likely to be linked by recent transmission, irrespective of whether it has been possible to identify epidemiological links, and to save resources where they are not, even in the context of matched MIRU-VNTR genotypes. Uniquely, WGS also provides information about the genetic structure of outbreak clusters, thereby providing the potential to direct public health resources towards individuals most likely to have infected the largest number of secondary cases. As a consequence, the Health Protection Agency is considering introduction of WGS technology for routine tuberculosis public health practice in England. Funding NIHR Oxford Biomedical Research Centre and the UKCRC Modernising Medical Microbiology Consortium (UKCRC Translational Infection Research Initiative supported by MRC, Biotechnology and Biological Sciences Research Council, and NIHR on behalf of the Department of Health [grant G0800778] and the Wellcome Trust [087646/Z/08/Z]).