Showing papers by "Ben S. Cooper published in 2020"
TL;DR: In this paper, the benefits of contact isolation over standard precautions for reducing the incidence density of ESBL-E colonisation and infection in adult medical and surgical wards with an active surveillance culture program were established.
Abstract: Summary Background The effectiveness of contact isolation for decreasing the spread of extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) has been questioned. The aim of this study was to establish the benefits of contact isolation over standard precautions for reducing the incidence density of ESBL-E colonisation and infection in adult medical and surgical wards with an active surveillance culture programme. Methods We did a cluster-randomised crossover trial in adult wards in four European university hospitals. Medical, surgical, or combined medical–surgical wards without critical care were randomised to continue standard precautions alone or implement contact isolation alongside standard precautions for 12 months, followed by a 1 month washout period and 12 months of the alternate strategy. Randomisation was done via a computer-generated sequence, with a block size of two consecutive wards. Only laboratory technicians and data analysts were masked to allocation. Patients were screened for ESBL-E carriage within 3 days of admission, once a week thereafter, and on discharge. The primary outcome was the incidence density of ESBL-E, defined as the acquisition rate per 1000 patient-days at risk at the ward level and assessed in the per-protocol population, which included all patients screened at least twice with a length of stay of more than 1 week for each intervention period. No specific safety measures were assessed given the minimal risk of adverse events. The trial is registered, ISRCTN57648070. Findings We enrolled 20 wards from four hospitals in Germany (eight wards), the Netherlands (four wards), Spain (four wards), and Switzerland (four wards). Between Jan 6, 2014, and Aug 31, 2016, 38 357 patients were admitted to these wards. Among 15 184 patients with a length of stay of more than 1 week, 11 368 patients (75%) were screened at least twice. The incidence density of ward-acquired ESBL-E was 6·0 events per 1000 patient-days at risk (95% CI 5·4–6·7) during periods of contact isolation and 6·1 (5·5–6·7) during periods of standard precautions (p=0·9710). Multivariable analysis adjusted for length of stay, percentage of patients screened, and prevalence in first screening cultures yielded an incidence rate ratio of 0·99 (95% CI 0·80–1·22; p=0·9177) for care under contact isolation compared with standard precautions. Interpretation Contact isolation showed no benefit when added to standard precautions for controlling the spread of ESBL-E on non-critical care wards with extensive surveillance screening. Funding European Commission.
34 citations
TL;DR: The implications of different patterns of non-adherence in non-inferiority trials are discussed and practical recommendations for trial design, alternative analysis strategies, and outcome reporting are offered to reduce bias in treatment estimates and improve transparency in reporting.
Abstract: Non-adherence in non-inferiority trials can affect treatment effect estimates and often increases the chance of claiming non-inferiority under the standard intention-to-treat analysis. This article discusses the implications of different patterns of non-adherence in non-inferiority trials and offers practical recommendations for trial design, alternative analysis strategies, and outcome reporting to reduce bias in treatment estimates and improve transparency in reporting.
29 citations
TL;DR: A data-driven model of the within-host dynamics of extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae predicts that typical antibiotic exposures can have substantial long-term effects on blaCTX-M carriage duration.
Abstract: Antibiotic-induced perturbation of the human gut flora is expected to play an important role in mediating the relationship between antibiotic use and the population prevalence of antibiotic resistance in bacteria, but little is known about how antibiotics affect within-host resistance dynamics. Here we develop a data-driven model of the within-host dynamics of extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae. We use blaCTX-M (the most widespread ESBL gene family) and 16S rRNA (a proxy for bacterial load) abundance data from 833 rectal swabs from 133 ESBL-positive patients followed up in a prospective cohort study in three European hospitals. We find that cefuroxime and ceftriaxone are associated with increased blaCTX-M abundance during treatment (21% and 10% daily increase, respectively), while treatment with meropenem, piperacillin-tazobactam, and oral ciprofloxacin is associated with decreased blaCTX-M (8% daily decrease for all). The model predicts that typical antibiotic exposures can have substantial long-term effects on blaCTX-M carriage duration.
23 citations
TL;DR: Following PCV13 introduction into the Cambodian immunization schedule, there have been declines in VT pneumococcal colonization and disease in children aged <5 years.
Abstract: BACKGROUND Cambodia introduced the 13-valent pneumococcal conjugate vaccine (PCV13) in January 2015 using a 3 + 0 dosing schedule and no catch-up campaign. We investigated the effects of this introduction on pneumococcal colonization and invasive disease in children aged <5 years. METHODS There were 6 colonization surveys done between January 2014 and January 2018 in children attending the outpatient department of a nongovernmental pediatric hospital in Siem Reap. Nasopharyngeal swabs were analyzed by phenotypic and genotypic methods to detect pneumococcal serotypes and antimicrobial resistance. Invasive pneumococcal disease (IPD) data for January 2012-December 2018 were retrieved from hospital databases. Pre-PCV IPD data and pre-/post-PCV colonization data were modelled to estimate vaccine effectiveness (VE). RESULTS Comparing 2014 with 2016-2018, and using adjusted prevalence ratios, VE estimates for colonization were 16.6% (95% confidence interval [CI] 10.6-21.8) for all pneumococci and 39.2% (95% CI 26.7-46.1) for vaccine serotype (VT) pneumococci. There was a 26.0% (95% CI 17.7-33.0) decrease in multidrug-resistant pneumococcal colonization. The IPD incidence was estimated to have declined by 26.4% (95% CI 14.4-35.8) by 2018, with a decrease of 36.3% (95% CI 23.8-46.9) for VT IPD and an increase of 101.4% (95% CI 62.0-145.4) for non-VT IPD. CONCLUSIONS Following PCV13 introduction into the Cambodian immunization schedule, there have been declines in VT pneumococcal colonization and disease in children aged <5 years. Modelling of dominant serotype colonization data produced plausible VE estimates.
19 citations
TL;DR: To determine the duration of carbapenemase-producing Enterobacteriaceae (CPE) carriage, 21 CPE carriers for 1 year were studied, suggesting that CPE-carriers’ status can be reviewed yearly.
Abstract: To determine the duration of carbapenemase-producing Enterobacteriaceae (CPE) carriage, we studied 21 CPE carriers for »1 year. Mean carriage duration was 86 days; probability of decolonization in 1 year was 98.5%, suggesting that CPE-carriers' status can be reviewed yearly. Prolonged carriage was associated with use of antimicrobial drugs.
12 citations
TL;DR: The AutoMated tool for Antimicrobial resistance Surveillance System (AMASS), which can support clinical microbiology laboratories to analyze their microbiology and hospital data files onsite and promptly generate AMR surveillance reports, is developed and tested.
Abstract: Background: Reporting cumulative antimicrobial susceptibility testing data on a regular basis is crucial to inform antimicrobial resistance (AMR) action plans at local, national, and global levels. However, analyzing data and generating a report are time consuming and often require trained personnel.
Objective: This study aimed to develop and test an application that can support a local hospital to analyze routinely collected electronic data independently and generate AMR surveillance reports rapidly.
Methods: An offline application to generate standardized AMR surveillance reports from routinely available microbiology and hospital data files was written in the R programming language (R Project for Statistical Computing). The application can be run by double clicking on the application file without any further user input. The data analysis procedure and report content were developed based on the recommendations of the World Health Organization Global Antimicrobial Resistance Surveillance System (WHO GLASS). The application was tested on Microsoft Windows 10 and 7 using open access example data sets. We then independently tested the application in seven hospitals in Cambodia, Lao People’s Democratic Republic, Myanmar, Nepal, Thailand, the United Kingdom, and Vietnam.
Results: We developed the AutoMated tool for Antimicrobial resistance Surveillance System (AMASS), which can support clinical microbiology laboratories to analyze their microbiology and hospital data files (in CSV or Excel format) onsite and promptly generate AMR surveillance reports (in PDF and CSV formats). The data files could be those exported from WHONET or other laboratory information systems. The automatically generated reports contain only summary data without patient identifiers. The AMASS application is downloadable from https://www.amass.website/. The participating hospitals tested the application and deposited their AMR surveillance reports in an open access data repository.
Conclusions: The AMASS is a useful tool to support the generation and sharing of AMR surveillance reports.
10 citations
TL;DR: The pervasive within-patient transfer of pOXA-48 is uncovered, suggesting that horizontal plasmid transfer occurs in the gut of virtually every colonised patient.
Abstract: Infections caused by carbapenemase-producing enterobacteria (CPE) are a major concern in clinical settings worldwide. Two fundamentally different processes shape the epidemiology of CPE in hospitals: the dissemination of CPE clones from patient to patient (between-patient transfer), and the transfer of carbapenemase-encoding plasmids between enterobacteria in the gut microbiota of individual patients (within-patient transfer). The relative contribution of each process to the overall dissemination of carbapenem resistance in hospitals remains poorly understood. Here, we used mechanistic models combining epidemiological data from more than 9,000 patients with whole genome sequence information from 250 enterobacteria clones to characterise the dissemination routes of the carbapenemase-encoding plasmid pOXA-48 in a hospital setting over a two-year period. Our results revealed frequent between-patient transmission of high-risk pOXA-48-carrying clones, mostly of Klebsiella pneumoniae and sporadically Escherichia coli. The results also identified pOXA-48 dissemination hotspots within the hospital, such as specific wards and individual rooms within wards. Using high-resolution plasmid sequence analysis, we uncovered the pervasive within-patient transfer of pOXA-48, suggesting that horizontal plasmid transfer occurs in the gut of virtually every colonised patient. The complex and multifaceted epidemiological scenario exposed by this study provides new insights for the development of intervention strategies to control the in-hospital spread of CPE.
7 citations
TL;DR: In this paper, the authors report measurements of shifts in the frequencies of positronium atoms while they are inside the open volumes of MgO smoke powder, and attribute these shifts to resonant interactions between Ps atoms and surfaces mediated via spectrally overlapping UV photo-luminescent absorption bands.
Abstract: We report measurements of shifts in the frequencies of $1\phantom{\rule{0.16em}{0ex}}^{3}S_{1}\ensuremath{\rightarrow}2\phantom{\rule{0.16em}{0ex}}^{3}P_{J}$ and $2\phantom{\rule{0.16em}{0ex}}^{3}P_{J}\ensuremath{\rightarrow}n\phantom{\rule{0.16em}{0ex}}^{3}D/n\phantom{\rule{0.16em}{0ex}}^{3}S$ transitions optically driven in positronium atoms while they are inside the open volumes of MgO smoke powder. The observed intervals are larger than the corresponding vacuum excitations, but, surprisingly, the transitions to Rydberg states are less strongly affected, and the energy shifts exhibit no dependence on the principal quantum number $n$ of the final state. We attribute these shifts to resonant interactions between Ps atoms and MgO surfaces, mediated via spectrally overlapping MgO ultra violet (UV) photo-luminescent absorption bands. Since many insulating materials suitable for Ps confinement exhibit similar broadband UV absorption characteristics, the observed phenomena have implications for optical diagnostics and laser cooling schemes of relevance to studies of high-density Ps ensembles in insulating cavities, including the production of a Ps Bose-Einstein condensate.
7 citations
TL;DR: It is shown that the effect of hand hygiene is highly dependent on the duration of viral persistence on hands and that hand washing needs to be performed very frequently or immediately after hand contamination events in order to substantially reduce the probability of infection.
Abstract: Increased hand hygiene amongst the general public has been widely promoted as one of the most important non-pharmaceutical interventions for reducing transmission during the ongoing COVID-19 pandemic and is likely to continue to play a key role in long-term efforts to suppress transmission before a vaccine can be deployed. For other respiratory tract infections community hand hygiene interventions are supported by evidence from randomised trials, but information on how effectiveness in reducing transmission scales with achieved changes in hand hygiene behaviour is lacking. This information is of critical importance when considering the potential value of substantially enhancing community hand hygiene frequency to help suppress COVID-19. Here, we developed a simple model-based framework for understanding the key determinants of the effectiveness of changes in hand hygiene behaviour in reducing transmission and use it to explore the potential impact of interventions aimed at achieving large-scale population-wide changes in hand hygiene behaviour. Our analyses show that the effect of hand hygiene is highly dependent on the duration of viral persistence on hands and that hand washing needs to be performed very frequently or immediately after hand contamination events in order to substantially reduce the probability of infection. Hand washing at a lower frequency, such as every 30 minutes or with a delay of 15 minutes after contamination events, may be adequate to reduce the probability of infection when viral survival on hands is longer, such as when hands are contaminated with mucus. Immediate hand washing after contamination is more effective than hand washing at fixed-time intervals even when the total number of hand washing events is similar. This event-prompted hand washing strategy is consistently more effective than fixed-time strategy regardless of hand contamination rates and should be highlighted in hand hygiene campaigns.
5 citations
TL;DR: Intermittent metagenomics of pooled human samples could represent a powerful pragmatic and economical approach for determining and monitoring AMR in clinical infections, especially in resource-limited settings.
Abstract: Antimicrobial resistance (AMR) is a global health threat, especially in low-/middle-income countries (LMICs), where there is limited surveillance to inform empiric antibiotic treatment guidelines. Enterobacterales are amongst the most important causes of drug-resistant bacterial infections. We developed a novel AMR surveillance approach for Enterobacterales by profiling pooled human faecal metagenomes from three sites (n=563 individuals; Cambodia, Kenya, UK) to derive a taxonomy-adjusted AMR metric (“resistance potential”) which could be used to predict the aggregate percentage of resistant invasive Enterobacterales infections within each setting. Samples were sequenced (Illumina); taxonomic and resistance gene profiling was performed using ResPipe. Data on organisms causing bacteraemia and meningitis and antibiotic susceptibility test results from 2010-2017 were collated for each site. Bayesian generalised linear models with a binomial likelihood were fitted to determine the capacity of the resistance potential to predict AMR in Enterobacterales infections in each setting. The most informative model accurately predicted the numbers of resistant infections in the target populations for 14/14 of antibiotics in the UK, 12/12 in Kenya, and 9/12 in Cambodia. Intermittent metagenomics of pooled human samples could represent a powerful pragmatic and economical approach for determining and monitoring AMR in clinical infections, especially in resource-limited settings.
2 citations
TL;DR: It is found that falls in MRSA incidence over time were associated with decreases in both the number of patients admitted to the ICU colonised with MRSA and in transmission rates, and could be used to direct infection control interventions.
Abstract: Healthcare-associated infection and antimicrobial resistance are major concerns. However, the extent to which antibiotic exposure affects transmission and detection of infections such as MRSA is unclear. Additionally, temporal trends are typically reported in terms of changes in incidence, rather than analysing underling transmission processes. We present a data-augmented Markov chain Monte Carlo approach for inferring changing transmission parameters over time, screening test sensitivity, and the effect of antibiotics on detection and transmission. We expand a basic model to allow use of typing information when inferring sources of infections. Using simulated data, we show that the algorithms are accurate, well-calibrated and able to identify antibiotic effects in sufficiently large datasets. We apply the models to study MRSA transmission in an intensive care unit in Oxford, UK with 7924 admissions over 10 years. We find that falls in MRSA incidence over time were associated with decreases in both the number of patients admitted to the ICU colonised with MRSA and in transmission rates. In our inference model, the data were not informative about the effect of antibiotics on risk of transmission or acquisition of MRSA, a consequence of the limited number of possible transmission events in the data. Our approach has potential to be applied to a range of healthcare-associated infections and settings and could be applied to study the impact of other potential risk factors for transmission. Evidence generated could be used to direct infection control interventions.
TL;DR: Prolonged duration of carriage was associated with exposure to fluoroquinolone or nitrofurantoin during the study, use of any antimicrobial agent in the prior 12 months and travel to endemic regions, and highlights the need for prioritising household focused interventions to control FQR-E spread.
Abstract: Carriage dynamics of drug-resistant bacteria, especially within households, are poorly understood. This limits the ability to develop effective interventions for controlling the spread of antimicrobial resistance in the community. Two groups consisting of: (i) patients with urinary tract infection requiring antimicrobial treatment; and (ii) patients who were not prescribed antimicrobial treatment were prospectively recruited at three European sites: Antwerp (Belgium), Geneva (Switzerland) and Lodz (Poland). Each index patient and up to three additional household members provided faecal samples at baseline, completion of antimicrobial therapy (or 7-10 days after the first sample for the non-exposed) and 28 days after the second sample. We analysed household-level and individual-level fluoroquinolone resistant Enterobacteriaceae (FQR-E) acquisition and carriage data using Bayesian multi-state Markov models. At the individual level, we estimated a median baseline FQR-E acquisition rate of 0.006 (95%CrI = [0.004, 0.01]) per day, and a median duration of carriage of 24.4 days (95% CrI=[15.23,41.38]). Nitrofurantoin exposure was associated with a reduced rate of FQR-E acquisition (HR=0.28, 95%CrI=[0.14,0.56]), while fluoroquinolone exposure had no clear association with rates of FQR-E acquisition (HR=1.43, 95% CrI=[0.81,2.53]) at individual level. There was evidence that rates of FQR-E acquisition varied by site, and coming from Lodz was associated with a higher acquisition rate (HR=3.56, 95% CrI=[1.92, 6.34]). Prolonged duration of carriage was associated with exposure to fluoroquinolone or nitrofurantoin during the study, use of any antimicrobial agent in the prior 12 months and travel to endemic regions. At household level, we found strong evidence of positive association between FQR-E acquisition and fluoroquinolone exposure (HR=3.43, 95% CrI=[1.51,7.74]). There was weak evidence of negative association between FQR-E acquisition and nitrofurantoin exposure (HR=0.42, 95%CrI=[0.12, 1.24]. Similar to the individual level, carriage duration was also associated with antimicrobial exposure at the household level. Our study has identified within household contacts as an important route for FQR-E transmission and highlights the need for prioritising household focused interventions to control FQR-E spread.
TL;DR: The AutoMated tool for Antimicrobial resistance Surveillance System (AMASS), which can support clinical microbiology laboratories to analyse their microbiology and hospital data files onsite and promptly generate AMR surveillance reports, is developed.
Abstract: Background Reporting cumulative antimicrobial susceptibility testing data on a regular basis is crucial to inform antimicrobial resistance (AMR) action plans at local, national and global levels. However, analysing data and generating a report are time-consuming and often require trained personnel. We illustrate the development and utility of an offline, open-access and automated tool that can support the generation of AMR surveillance reports promptly at the local level. Methods An offline application to generate standardized AMR surveillance reports from routinely available microbiology and hospital data files was written in the R programming language. The application can be run by a double-click on the application file without any further user input. The data analysis procedure and report content were developed based on the recommendations of the World Health Organization Global Antimicrobial Resistance Surveillance System (WHO GLASS). The application was tested in Microsoft Windows 10 and 7 using open-access example data sets. We then independently tested the application in seven hospitals in Cambodia, Lao People’s Democratic Republic (PDR), Myanmar, Nepal, Thailand, the United Kingdom, and Vietnam. Findings We developed the AutoMated tool for Antimicrobial resistance Surveillance System (AMASS), which can support clinical microbiology laboratories to analyse their microbiology and hospital data files (in CSV or Excel format) onsite and promptly generate AMR surveillance reports (in PDF and Excel formats). The data files could be those exported from WHONET and/or other laboratory information systems. The automatically generated reports contain only summary data without patient identifiers. The AMASS application is downloadable from www.amass.website. The participating hospitals tested the application and deposited their AMR surveillance reports in an open-access data repository. Interpretation The AMASS application can be a useful tool to support the generation and sharing of AMR surveillance reports. Funding Mahidol Oxford Tropical Medicine Research Unit (MORU) is funded by the Wellcome Trust (Grant no. 106698/Z/14/Z). Oxford University Clinical Research Unit (OUCRU) is funded by the Wellcome Trust (Grant no. 106680/B/14/Z). The investigators are funded by the Wellcome Trust (CL is funded by a Training Research Fellowship [Grant no. 206736] and DL is funded by an Intermediate Training Fellowship [Grant no. 101103]). BSC is funded by the UK Medical Research Council and Department for International Development (Grant no. MR/K006924/1). The funder has no role in the design and conduct of the study, data collection, or analysis and interpretation of the data.
TL;DR: Delays in concordant antibiotic treatment were associated with a 6.6% absolute increase in mortality among patients with hospital-acquired Acinetobacter spp.
Abstract: Delays in treating bacteremias with antibiotics to which the causative organism is susceptible are expected to adversely affect patient outcomes. Quantifying the impact of such delays to concordant treatment is important for decision-making about interventions to reduce the delays and for quantifying the burden of disease due to antimicrobial resistance. There are, however, potentially important biases to be addressed including immortal time bias. Here, we aim to estimate the impact of delays in appropriate antibiotic treatment of patients with Acinetobacter spp. hospital-acquired bacteremia in Thailand on 30-day mortality by emulating a target trial using retrospective cohort data from Sunpasitthiprasong Hospital in 2003 to 2015. For each day, we defined treatment as concordant if the isolated organism was susceptible to at least one antibiotic given. Amongst 1,203 patients with Acinetobacter spp. hospital-acquired bacteremia, 682 had one or more days of delays to concordant treatment. Surprisingly, crude 30-day mortality was lower in patients with delays of ≥3 days compared to those with 1-2 days of delays. Accounting for confounders and immortal time bias resolved this paradox. Emulating a target trial, we found that these delays were associated with an absolute increase in expected 30-day mortality of 6.6% (95% CI: 0.2%, 13.0%), from 33.8% to 40.4%.