register interest

Professor Ben Cooper

Research Area: Bioinformatics & Stats (inc. Modelling and Computational Biology)
Technology Exchange: Bioinformatics, Computational biology and Medical statistics
Scientific Themes: Tropical Medicine & Global Health and Immunology & Infectious Disease
Web Links:

Ben Cooper holds an MRC senior non-clinical research fellowship and is based at the Mahidol-Oxford Tropical Medicine Research Unit in Bangkok.  

His work uses mathematical modelling and statistical techniques to help understand infectious disease dynamics and evaluate potential control measures.  This involves developing mathematical models to help evaluate the likely impact and cost-effectiveness of control measures,  developing and applying new statistical approaches based on mechanistic  models for the analysis of longitudinal infectious disease data (increasingly making use of whole genome sequence data), and  designing and analysing epidemiological studies.  The major focus of this work is on antibiotic-resistant bacteria in resource-limited hospital settings.

Additional projects include within-host dynamics of Plasmodium vivax, ecological interactions of the nasopharyngeal flora, cost-effectiveness of seasonal influenza vaccination in Thailand, and dynamics and control of Hepatitis E infections in refugee camps.

Name Department Institution Country
Professor Paul Turner Tropical Medicine University of Oxford United Kingdom
Professor Lisa J White Tropical Medicine University of Oxford United Kingdom
Dr Direk Limmathurotsakul Tropical Medicine University of Oxford United Kingdom
Dr Sharon J Peacock Tropical Medicine University of Oxford United Kingdom
Dr Jonathan D Edgeworth Guy’s and St Thomas’ NHS Foundation Trust United Kingdom
Professor Marc Bonten University Medical Center Utrecht Netherlands
Professor Angela McLean Department of Zoology University of Oxford United Kingdom
Dr Craig MacLean Department of Zoology University of Oxford United Kingdom
Professor Nicholas Graves QUT Australia
Dr Aronrag C Meeyai Mahidol University Thailand
Turner P, Pol S, Soeng S, Sar P, Neou L, Chea P, Day NP, Cooper BS, Turner C. 2016. High Prevalence of Antimicrobial-resistant Gram-negative Colonization in Hospitalized Cambodian Infants. Pediatr Infect Dis J, 35 (8), pp. 856-861. | Show Abstract | Read more

BACKGROUND: Antimicrobial-resistant Gram-negative infections are a significant cause of mortality in young infants. We aimed to determine characteristics of, and risk factors for, colonization and invasive infection caused by 3rd generation cephalosporin (3GC) or carbapenem-resistant organisms in outborn infants admitted to a neonatal unit (NU) in Cambodia. METHODS: During the first year of operation, patients admitted to the Angkor Hospital for Children NU, Siem Reap, Cambodia, underwent rectal swabbing on admission and twice weekly until discharge. Swabs were taken also from 7 environmental sites. Swabs were cultured to identify 3GC or carbapenem-resistant Acinetobacter sp., Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. RESULTS: The study included 333 infants with a median age at NU admission of 10 days (range, 0-43). Colonization by ≥1 3GC-resistant organism was detected in 85.9% (286/333). Admission swabs were collected in 289 infants: 61.9% were colonized by a 3GC-resistant organism at the time of admission, and a further 23.2% were colonized during hospitalization, at a median of 4 days [95% confidence interval: 3-5]. Probiotic treatment (hazard ratio: 0.58; 95% confidence interval: 0.35-0.98) was associated with delayed colonization. Colonization by a carbapenem-resistant organism occurred in 25 (7.5%) infants. Six infants had NU-associated K. pneumoniae bacteremia; phenotypically identical colonizing strains were found in 3 infants. Environmental colonization occurred early. CONCLUSIONS: Colonization by antimicrobial-resistant Gram-negative organisms occurred early in hospitalized Cambodian infants and was associated with subsequent invasive infection. Trials of potential interventions such as probiotics are needed.

Sadique Z, Lopman B, Cooper BS, Edmunds WJ. 2016. Cost-effectiveness of Ward Closure to Control Outbreaks of Norovirus Infection in United Kingdom National Health Service Hospitals. J Infect Dis, 213 Suppl 1 (suppl 1), pp. S19-S26. | Show Abstract | Read more

BACKGROUND: Norovirus is the most common cause of outbreaks of acute gastroenteritis in National Health Service hospitals in the United Kingdom. Wards (units) are often closed to new admissions to stop the spread of the virus, but there is limited evidence describing the cost-effectiveness of ward closure. METHODS: An economic analysis based on the results from a large, prospective, active-surveillance study of gastroenteritis outbreaks in hospitals and from an epidemic simulation study compared alternative ward closure options evaluated at different time points since first infection, assuming different efficacies of ward closure. RESULTS: A total of 232 gastroenteritis outbreaks occurring in 14 hospitals over a 1-year period were analyzed. The risk of a new outbreak in a hospital is significantly associated with the number of admission, general medical, and long-stay wards that are concurrently affected but is less affected by the level of community transmission. Ward closure leads to higher costs but reduces the number of new outbreaks by 6%-56% and the number of clinical cases by 1%-55%, depending on the efficacy of the intervention. The incremental cost per outbreak averted varies from £10 000 ($14 000) to £306 000 ($428 000), and the cost per case averted varies from £500 ($700) to £61 000 ($85 000). The cost-effectiveness of ward closure decreases as the efficacy of the intervention increases, and the cost-effectiveness increases with the timing of the intervention. The efficacy of ward closure is critical from a cost-effectiveness perspective. CONCLUSIONS: Ward closure may be cost-effective, particularly if targeted to high-throughput units.

Hetem DJ, Derde LPG, Empel J, Mroczkowska A, Orczykowska-Kotyna M, Kozińska A, Hryniewicz W, Goossens H, Bonten MJM. 2016. Molecular epidemiology of MRSA in 13 ICUs from eight European countries Journal of Antimicrobial Chemotherapy, 71 (1), pp. 45-52. | Read more

Deeny SR, Worby CJ, Tosas Auguet O, Cooper BS, Edgeworth J, Cookson B, Robotham JV. 2015. Impact of mupirocin resistance on the transmission and control of healthcare-associated MRSA. J Antimicrob Chemother, 70 (12), pp. 3366-3378. | Show Abstract | Read more

OBJECTIVES: The objectives of this study were to estimate the relative transmissibility of mupirocin-resistant (MupR) and mupirocin-susceptible (MupS) MRSA strains and evaluate the long-term impact of MupR on MRSA control policies. METHODS: Parameters describing MupR and MupS strains were estimated using Markov chain Monte Carlo methods applied to data from two London teaching hospitals. These estimates parameterized a model used to evaluate the long-term impact of MupR on three mupirocin usage policies: 'clinical cases', 'screen and treat' and 'universal'. Strategies were assessed in terms of colonized and infected patient days and scenario and sensitivity analyses were performed. RESULTS: The transmission probability of a MupS strain was 2.16 (95% CI 1.38-2.94) times that of a MupR strain in the absence of mupirocin usage. The total prevalence of MupR in colonized and infected MRSA patients after 5 years of simulation was 9.1% (95% CI 8.7%-9.6%) with the 'screen and treat' mupirocin policy, increasing to 21.3% (95% CI 20.9%-21.7%) with 'universal' mupirocin use. The prevalence of MupR increased in 50%-75% of simulations with 'universal' usage and >10% of simulations with 'screen and treat' usage in scenarios where MupS had a higher transmission probability than MupR. CONCLUSIONS: Our results provide evidence from a clinical setting of a fitness cost associated with MupR in MRSA strains. This provides a plausible explanation for the low levels of mupirocin resistance seen following 'screen and treat' mupirocin usage. From our simulations, even under conservative estimates of relative transmissibility, we see long-term increases in the prevalence of MupR given 'universal' use.

Meeyai A, Praditsitthikorn N, Kotirum S, Kulpeng W, Putthasri W, Cooper BS, Teerawattananon Y. 2015. Seasonal influenza vaccination for children in Thailand: a cost-effectiveness analysis. PLoS Med, 12 (5), pp. e1001829. | Show Abstract | Read more

BACKGROUND: Seasonal influenza is a major cause of mortality worldwide. Routine immunization of children has the potential to reduce this mortality through both direct and indirect protection, but has not been adopted by any low- or middle-income countries. We developed a framework to evaluate the cost-effectiveness of influenza vaccination policies in developing countries and used it to consider annual vaccination of school- and preschool-aged children with either trivalent inactivated influenza vaccine (TIV) or trivalent live-attenuated influenza vaccine (LAIV) in Thailand. We also compared these approaches with a policy of expanding TIV coverage in the elderly. METHODS AND FINDINGS: We developed an age-structured model to evaluate the cost-effectiveness of eight vaccination policies parameterized using country-level data from Thailand. For policies using LAIV, we considered five different age groups of children to vaccinate. We adopted a Bayesian evidence-synthesis framework, expressing uncertainty in parameters through probability distributions derived by fitting the model to prospectively collected laboratory-confirmed influenza data from 2005-2009, by meta-analysis of clinical trial data, and by using prior probability distributions derived from literature review and elicitation of expert opinion. We performed sensitivity analyses using alternative assumptions about prior immunity, contact patterns between age groups, the proportion of infections that are symptomatic, cost per unit vaccine, and vaccine effectiveness. Vaccination of children with LAIV was found to be highly cost-effective, with incremental cost-effectiveness ratios between about 2,000 and 5,000 international dollars per disability-adjusted life year averted, and was consistently preferred to TIV-based policies. These findings were robust to extensive sensitivity analyses. The optimal age group to vaccinate with LAIV, however, was sensitive both to the willingness to pay for health benefits and to assumptions about contact patterns between age groups. CONCLUSIONS: Vaccinating school-aged children with LAIV is likely to be cost-effective in Thailand in the short term, though the long-term consequences of such a policy cannot be reliably predicted given current knowledge of influenza epidemiology and immunology. Our work provides a coherent framework that can be used for similar analyses in other low- and middle-income countries.

Cooper BS, Kotirum S, Kulpeng W, Praditsitthikorn N, Chittaganpitch M, Limmathurotsakul D, Day NP, Coker R, Teerawattananon Y, Meeyai A. 2015. Mortality attributable to seasonal influenza A and B infections in Thailand, 2005-2009: a longitudinal study. Am J Epidemiol, 181 (11), pp. 898-907. | Show Abstract | Read more

Influenza epidemiology differs substantially in tropical and temperate zones, but estimates of seasonal influenza mortality in developing countries in the tropics are lacking. We aimed to quantify mortality due to seasonal influenza in Thailand, a tropical middle-income country. Time series of polymerase chain reaction-confirmed influenza infections between 2005 and 2009 were constructed from a sentinel surveillance network. These were combined with influenza-like illness data to derive measures of influenza activity and relationships to mortality by using a Bayesian regression framework. We estimated 6.1 (95% credible interval: 0.5, 12.4) annual deaths per 100,000 population attributable to influenza A and B, predominantly in those aged ≥60 years, with the largest contribution from influenza A(H1N1) in 3 out of 4 years. For A(H3N2), the relationship between influenza activity and mortality varied over time. Influenza was associated with increases in deaths classified as resulting from respiratory disease (posterior probability of positive association, 99.8%), cancer (98.6%), renal disease (98.0%), and liver disease (99.2%). No association with circulatory disease mortality was found. Seasonal influenza infections are associated with substantial mortality in Thailand, but evidence for the strong relationship between influenza activity and circulatory disease mortality reported in temperate countries is lacking.

White LJ, Flegg JA, Phyo AP, Wiladpai-ngern JH, Bethell D, Plowe C, Anderson T, Nkhoma S et al. 2015. Defining the in vivo phenotype of artemisinin-resistant falciparum malaria: a modelling approach. PLoS Med, 12 (4), pp. e1001823. | Show Abstract | Read more

BACKGROUND: Artemisinin-resistant falciparum malaria has emerged in Southeast Asia, posing a major threat to malaria control. It is characterised by delayed asexual-stage parasite clearance, which is the reference comparator for the molecular marker 'Kelch 13' and in vitro sensitivity tests. However, current cut-off values denoting slow clearance based on the proportion of individuals remaining parasitaemic on the third day of treatment ('day-3'), or on peripheral blood parasite half-life, are not well supported. We here explore the parasite clearance distributions in an area of artemisinin resistance with the aim refining the in vivo phenotypic definitions. METHODS AND FINDINGS: Data from 1,518 patients on the Thai-Myanmar and Thai-Cambodian borders with parasite half-life assessments after artesunate treatment were analysed. Half-lives followed a bimodal distribution. A statistical approach was developed to infer the characteristics of the component distributions and their relative contribution to the composite mixture. A model representing two parasite subpopulations with geometric mean (IQR) parasite half-lives of 3.0 (2.4-3.9) hours and 6.50 (5.7-7.4) hours was consistent with the data. For individual patients, the parasite half-life provided a predicted likelihood of an artemisinin-resistant infection which depends on the population prevalence of resistance in that area. Consequently, a half-life where the probability is 0.5 varied between 3.5 and 5.5 hours. Using this model, the current 'day-3' cut-off value of 10% predicts the potential presence of artemisinin-resistant infections in most but not all scenarios. These findings are relevant to the low-transmission setting of Southeast Asia. Generalisation to a high transmission setting as in regions of Sub-Saharan Africa will need additional evaluation. CONCLUSIONS: Characterisation of overlapping distributions of parasite half-lives provides quantitative insight into the relationship between parasite clearance and artemisinin resistance, as well as the predictive value of the 10% cut-off in 'day-3' parasitaemia. The findings are important for the interpretation of in vitro sensitivity tests and molecular markers for artemisinin resistance and for contextualising the 'day 3' threshold to account for initial parasitaemia and sample size.

Cooper BS, Boni MF, Pan-ngum W, Day NP, Horby PW, Olliaro P, Lang T, White NJ, White LJ, Whitehead J. 2015. Evaluating clinical trial designs for investigational treatments of Ebola virus disease. PLoS Med, 12 (4), pp. e1001815. | Show Abstract | Read more

BACKGROUND: Experimental treatments for Ebola virus disease (EVD) might reduce EVD mortality. There is uncertainty about the ability of different clinical trial designs to identify effective treatments, and about the feasibility of implementing individually randomised controlled trials during an Ebola epidemic. METHODS AND FINDINGS: A treatment evaluation programme for use in EVD was devised using a multi-stage approach (MSA) with two or three stages, including both non-randomised and randomised elements. The probabilities of rightly or wrongly recommending the experimental treatment, the required sample size, and the consequences for epidemic outcomes over 100 d under two epidemic scenarios were compared for the MSA, a sequential randomised controlled trial (SRCT) with up to 20 interim analyses, and, as a reference case, a conventional randomised controlled trial (RCT) without interim analyses. Assuming 50% 14-d survival in the population treated with the current standard of supportive care, all designs had similar probabilities of identifying effective treatments correctly, while the MSA was less likely to recommend treatments that were ineffective. The MSA led to a smaller number of cases receiving ineffective treatments and faster roll-out of highly effective treatments. For less effective treatments, the MSA had a high probability of including an RCT component, leading to a somewhat longer time to roll-out or rejection. Assuming 100 new EVD cases per day, the MSA led to between 6% and 15% greater reductions in epidemic mortality over the first 100 d for highly effective treatments compared to the SRCT. Both the MSA and SRCT led to substantially fewer deaths than a conventional RCT if the tested interventions were either highly effective or harmful. In the proposed MSA, the major threat to the validity of the results of the non-randomised components is that referral patterns, standard of care, or the virus itself may change during the study period in ways that affect mortality. Adverse events are also harder to quantify without a concurrent control group. CONCLUSIONS: The MSA discards ineffective treatments quickly, while reliably providing evidence concerning effective treatments. The MSA is appropriate for the clinical evaluation of EVD treatments.

Lee AS, Pan A, Harbarth S, Patroni A, Chalfine A, Daikos GL, Garilli S, Martínez JA, Cooper BS, MOSAR-04 Study Team. 2015. Variable performance of models for predicting methicillin-resistant Staphylococcus aureus carriage in European surgical wards. BMC Infect Dis, 15 (1), pp. 105. | Show Abstract | Read more

BACKGROUND: Predictive models to identify unknown methicillin-resistant Staphylococcus aureus (MRSA) carriage on admission may optimise targeted MRSA screening and efficient use of resources. However, common approaches to model selection can result in overconfident estimates and poor predictive performance. We aimed to compare the performance of various models to predict previously unknown MRSA carriage on admission to surgical wards. METHODS: The study analysed data collected during a prospective cohort study which enrolled consecutive adult patients admitted to 13 surgical wards in 4 European hospitals. The participating hospitals were located in Athens (Greece), Barcelona (Spain), Cremona (Italy) and Paris (France). Universal admission MRSA screening was performed in the surgical wards. Data regarding demographic characteristics and potential risk factors for MRSA carriage were prospectively collected during the study period. Four logistic regression models were used to predict probabilities of unknown MRSA carriage using risk factor data: "Stepwise" (variables selected by backward elimination); "Best BMA" (model with highest posterior probability using Bayesian model averaging which accounts for uncertainty in model choice); "BMA" (average of all models selected with BMA); and "Simple" (model including variables selected >50% of the time by both Stepwise and BMA approaches applied to repeated random sub-samples of 50% of the data). To assess model performance, cross-validation against data not used for model fitting was conducted and net reclassification improvement (NRI) was calculated. RESULTS: Of 2,901 patients enrolled, 111 (3.8%) were newly identified MRSA carriers. Recent hospitalisation and presence of a wound/ulcer were significantly associated with MRSA carriage in all models. While all models demonstrated limited predictive ability (mean c-statistics <0.7) the Simple model consistently detected more MRSA-positive individuals despite screening fewer patients than the Stepwise model. Moreover, the Simple model improved reclassification of patients into appropriate risk strata compared with the Stepwise model (NRI 6.6%, P = .07). CONCLUSIONS: Though commonly used, models developed using stepwise variable selection can have relatively poor predictive value. When developing MRSA risk indices, simpler models, which account for uncertainty in model selection, may better stratify patients' risk of unknown MRSA carriage.

Derde LP, Cooper BS, Brun-Buisson C. 2015. Contact precautions for patients with multidrug-resistant pathogens. JAMA, 313 (6), pp. 629-630. | Read more

Fuller C, Savage J, Cookson B, Hayward A, Cooper B, Duckworth G, Michie S, Jeanes A, Teare L, Charlett A, Stone SP. 2015. National observational study to evaluate the "cleanyourhands" campaign (NOSEC): a questionnaire based study of national implementation. Antimicrob Resist Infect Control, 4 (1), pp. 52. | Show Abstract | Read more

INTRODUCTION: The number of national hand-hygiene campaigns has increased recently, following the World Health Organisation's (WHO) "Save Lives: clean your hands" initiative (2009), which offers hospitals a multi-component hand-hygiene intervention. The number of campaigns to be evaluated remains small. Most evaluations focus on consumption of alcohol hand rub (AHR). We are not aware of any evaluation reporting implementation of all campaign components. In a previously published report, we evaluated the effects of the English and Welsh cleanyourhands campaign (2004-8) on procurement of AHR and soap, and on selected healthcare associated infections. We now report on the implementation of each individual campaign component: provision of bedside AHR, ward posters, patient empowerment materials, audit and feedback, and guidance to secure institutional engagement. METHOD: SETTING: all 189 acute National Health Service (NHS) hospitals in England and Wales (December 2005-June 2008). Six postal questionnaires (five voluntary, one mandatory) were distributed to infection control teams six-monthly from 6 to 36 months post roll-out. Selection and attrition bias were measured. RESULTS: Response rates fell from 134 (71 %) at 6 months to 82 (44 %) at 30 months, rising to 167 (90 %) for the final mandatory one (36 months). There was no evidence of attrition or selection bias. Hospitals reported widespread early implementation of bedside AHR and posters and a gradual rise in audit. At 36 months, 90 % of respondents reported the campaign to be a top hospital priority, with implementation of AHR, posters and audit reported by 96 %, 97 % and 91 % respectively. Patient empowerment was less successful. CONCLUSIONS: The study suggests that all campaign components, apart from patient empowerment, were widely implemented and sustained. It supports previous work suggesting that adequate piloting, strong governmental support, refreshment of campaigns, and sufficient time to engage institutions help secure sustained implementation of a campaign's key components. The results should encourage countries wishing to launch coordinated national campaigns for hospitals to participate in the WHO's "Save Lives" initiative, which offers hospitals a similar multi-component intervention.

Luangasanatip N, Hongsuwan M, Limmathurotsakul D, Lubell Y, Lee AS, Harbarth S, Day NP, Graves N, Cooper BS. 2015. Comparative efficacy of interventions to promote hand hygiene in hospital: systematic review and network meta-analysis. BMJ, 351 pp. h3728. | Show Abstract | Read more

OBJECTIVE: To evaluate the relative efficacy of the World Health Organization 2005 campaign (WHO-5) and other interventions to promote hand hygiene among healthcare workers in hospital settings and to summarize associated information on use of resources. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, Embase, CINAHL, NHS Economic Evaluation Database, NHS Centre for Reviews and Dissemination, Cochrane Library, and the EPOC register (December 2009 to February 2014); studies selected by the same search terms in previous systematic reviews (1980-2009). REVIEW METHODS: Included studies were randomised controlled trials, non-randomised trials, controlled before-after trials, and interrupted time series studies implementing an intervention to improve compliance with hand hygiene among healthcare workers in hospital settings and measuring compliance or appropriate proxies that met predefined quality inclusion criteria. When studies had not used appropriate analytical methods, primary data were re-analysed. Random effects and network meta-analyses were performed on studies reporting directly observed compliance with hand hygiene when they were considered sufficiently homogeneous with regard to interventions and participants. Information on resources required for interventions was extracted and graded into three levels. RESULTS: Of 3639 studies retrieved, 41 met the inclusion criteria (six randomised controlled trials, 32 interrupted time series, one non-randomised trial, and two controlled before-after studies). Meta-analysis of two randomised controlled trials showed the addition of goal setting to WHO-5 was associated with improved compliance (pooled odds ratio 1.35, 95% confidence interval 1.04 to 1.76; I(2)=81%). Of 22 pairwise comparisons from interrupted time series, 18 showed stepwise increases in compliance with hand hygiene, and all but four showed a trend for increasing compliance after the intervention. Network meta-analysis indicated considerable uncertainty in the relative effectiveness of interventions, but nonetheless provided evidence that WHO-5 is effective and that compliance can be further improved by adding interventions including goal setting, reward incentives, and accountability. Nineteen studies reported clinical outcomes; data from these were consistent with clinically important reductions in rates of infection resulting from improved hand hygiene for some but not all important hospital pathogens. Reported costs of interventions ranged from $225 to $4669 (£146-£3035; €204-€4229) per 1000 bed days. CONCLUSION: Promotion of hand hygiene with WHO-5 is effective at increasing compliance in healthcare workers. Addition of goal setting, reward incentives, and accountability strategies can lead to further improvements. Reporting of resources required for such interventions remains inadequate.

Tong SY, Holden MT, Nickerson EK, Cooper BS, Köser CU, Cori A, Jombart T, Cauchemez S et al. 2015. Genome sequencing defines phylogeny and spread of methicillin-resistant Staphylococcus aureus in a high transmission setting. Genome Res, 25 (1), pp. 111-118. | Show Abstract | Read more

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of nosocomial infection. Whole-genome sequencing of MRSA has been used to define phylogeny and transmission in well-resourced healthcare settings, yet the greatest burden of nosocomial infection occurs in resource-restricted settings where barriers to transmission are lower. Here, we study the flux and genetic diversity of MRSA on ward and individual patient levels in a hospital where transmission was common. We repeatedly screened all patients on two intensive care units for MRSA carriage over a 3-mo period. All MRSA belonged to multilocus sequence type 239 (ST 239). We defined the population structure and charted the spread of MRSA by sequencing 79 isolates from 46 patients and five members of staff, including the first MRSA-positive screen isolates and up to two repeat isolates where available. Phylogenetic analysis identified a flux of distinct ST 239 clades over time in each intensive care unit. In total, five main clades were identified, which varied in the carriage of plasmids encoding antiseptic and antimicrobial resistance determinants. Sequence data confirmed intra- and interwards transmission events and identified individual patients who were colonized by more than one clade. One patient on each unit was the source of numerous transmission events, and deep sampling of one of these cases demonstrated colonization with a "cloud" of related MRSA variants. The application of whole-genome sequencing and analysis provides novel insights into the transmission of MRSA in under-resourced healthcare settings and has relevance to wider global health.

Luangasanatip N, Hongsuwan M, Lubell Y, Cooper BS. 2014. Effectiveness of Hand Hygiene Promotion in Relation to Level of Investment: A Systematic Review. Value Health, 17 (7), pp. A803. | Read more

Wolkewitz M, Cooper BS, Bonten MJ, Barnett AG, Schumacher M. 2014. Interpreting and comparing risks in the presence of competing events. BMJ, 349 (aug21 5), pp. g5060. | Read more

Bonten MJ, Brun-Buisson C, Cooper BS, Derde LP, all authors. 2014. Care bundles in intensive care units - authors' reply. Lancet Infect Dis, 14 (5), pp. 372. | Read more

San Millan A, Peña-Miller R, Toll-Riera M, Halbert ZV, McLean AR, Cooper BS, MacLean RC. 2014. Positive selection and compensatory adaptation interact to stabilize non-transmissible plasmids. Nat Commun, 5 pp. 5208. | Show Abstract | Read more

Plasmids are important drivers of bacterial evolution, but it is challenging to understand how plasmids persist over the long term because plasmid carriage is costly. Classical models predict that horizontal transfer is necessary for plasmid persistence, but recent work shows that almost half of plasmids are non-transmissible. Here we use a combination of mathematical modelling and experimental evolution to investigate how a costly, non-transmissible plasmid, pNUK73, can be maintained in populations of Pseudomonas aeruginosa. Compensatory adaptation increases plasmid stability by eliminating the cost of plasmid carriage. However, positive selection for plasmid-encoded antibiotic resistance is required to maintain the plasmid by offsetting reductions in plasmid frequency due to segregational loss. Crucially, we show that compensatory adaptation and positive selection reinforce each other's effects. Our study provides a new understanding of how plasmids persist in bacterial populations, and it helps to explain why resistance can be maintained after antibiotic use is stopped.

Hongsuwan M, Srisamang P, Kanoksil M, Luangasanatip N, Jatapai A, Day NP, Peacock SJ, Cooper BS, Limmathurotsakul D. 2014. Increasing incidence of hospital-acquired and healthcare-associated bacteremia in northeast Thailand: a multicenter surveillance study. PLoS One, 9 (10), pp. e109324. | Show Abstract | Read more

BACKGROUND: Little is known about the epidemiology of nosocomial bloodstream infections in public hospitals in developing countries. We evaluated trends in incidence of hospital-acquired bacteremia (HAB) and healthcare-associated bacteremia (HCAB) and associated mortality in a developing country using routinely available databases. METHODS: Information from the microbiology and hospital databases of 10 provincial hospitals in northeast Thailand was linked with the national death registry for 2004-2010. Bacteremia was considered hospital-acquired if detected after the first two days of hospital admission, and healthcare-associated if detected within two days of hospital admission with a prior inpatient episode in the preceding 30 days. RESULTS: A total of 3,424 patients out of 1,069,443 at risk developed HAB and 2,184 out of 119,286 at risk had HCAB. Of these 1,559 (45.5%) and 913 (41.8%) died within 30 days, respectively. Between 2004 and 2010, the incidence rate of HAB increased from 0.6 to 0.8 per 1,000 patient-days at risk (p<0.001), and the cumulative incidence of HCAB increased from 1.2 to 2.0 per 100 readmissions (p<0.001). The most common causes of HAB were Acinetobacter spp. (16.2%), Klebsiella pneumoniae (13.9%), and Staphylococcus aureus (13.9%), while those of HCAB were Escherichia coli (26.3%), S. aureus (14.0%), and K. pneumoniae (9.7%). There was an overall increase over time in the proportions of ESBL-producing E. coli causing HAB and HCAB. CONCLUSIONS: This study demonstrates a high and increasing incidence of HAB and HCAB in provincial hospitals in northeast Thailand, increasing proportions of ESBL-producing isolates, and very high associated mortality.

Wolkewitz M, Cooper BS, Palomar-Martinez M, Olaechea-Astigarraga P, Alvarez-Lerma F, Schumacher M. 2014. Nested case-control studies in cohorts with competing events. Epidemiology, 25 (1), pp. 122-125. | Show Abstract | Read more

In nested case-control studies, incidence density sampling is the time-dependent matching procedure to approximate hazard ratios. The cumulative incidence function can also be estimated if information from the full cohort is used. In the presence of competing events, however, the cumulative incidence function depends on the hazard of the disease of interest and on the competing events hazard. Using hospital-acquired infection as an example (full cohort), we propose a sampling method for nested case-control studies to estimate subdistribution hazard ratios. With further information on the full cohort, the cumulative incidence function for the event of interest can then be estimated as well.

Cited:

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Derde LPG, Cooper BS, Goossens H, Malhotra-Kumar S, Willems RJL, Gniadkowski M, Hryniewicz W, Empel J et al. 2014. Interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in intensive care units: An interrupted time series study and cluster randomised trial The Lancet Infectious Diseases, 14 (1), pp. 31-39. | Show Abstract | Read more

Background: Intensive care units (ICUs) are high-risk areas for transmission of antimicrobial-resistant bacteria, but no controlled study has tested the effect of rapid screening and isolation of carriers on transmission in settings with best-standard precautions. We assessed interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in European ICUs. Methods: We did this study in three phases at 13 ICUs. After a 6 month baseline period (phase 1), we did an interrupted time series study of universal chlorhexidine body-washing combined with hand hygiene improvement for 6 months (phase 2), followed by a 12-15 month cluster randomised trial (phase 3). ICUs were randomly assigned by computer generated randomisation schedule to either conventional screening (chromogenic screening for meticillin-resistant Staphylococcus aureus [MRSA] and vancomycin-resistant enterococci [VRE]) or rapid screening (PCR testing for MRSA and VRE and chromogenic screening for highly resistant Enterobacteriaceae [HRE]); with contact precautions for identified carriers. The primary outcome was acquisition of resistant bacteria per 100 patient-days at risk, for which we calculated step changes and changes in trends after the introduction of each intervention. We assessed acquisition by microbiological surveillance and analysed it with a multilevel Poisson segmented regression model. We compared screening groups with a likelihood ratio test that combined step changes and changes to trend. This study is registered with ClinicalTrials.gov, number NCT00976638. Findings: Seven ICUs were assigned to rapid screening and six to conventional screening. Mean hand hygiene compliance improved from 52% in phase 1 to 69% in phase 2, and 77% in phase 3. Median proportions of patients receiving chlorhexidine body-washing increased from 0% to 100% at the start of phase 2. For trends in acquisition of antimicrobial-resistant bacteria, weekly incidence rate ratio (IRR) was 0·976 (0·954-0·999) for phase 2 and 1·015 (0·998-1·032) for phase 3. For step changes, weekly IRR was 0·955 (0·676-1·348) for phase 2 and 0·634 (0·349-1·153) for phase 3. The decrease in trend in phase 2 was largely caused by changes in acquisition of MRSA (weekly IRR 0·925, 95% CI 0·890-0·962). Acquisition was lower in the conventional screening group than in the rapid screening group, but did not differ significantly (p=0·06). Interpretation: Improved hand hygiene plus unit-wide chlorhexidine body-washing reduced acquisition of antimicrobial-resistant bacteria, particularly MRSA. In the context of a sustained high level of compliance to hand hygiene and chlorhexidine bathings, screening and isolation of carriers do not reduce acquisition rates of multidrug-resistant bacteria, whether or not screening is done with rapid testing or conventional testing. Funding: European Commission. © 2014 Derde et al. Open Access article distributed under the terms of CC BY-NC-SA.

Lim C, Wannapinij P, White L, Day NPJ, Cooper BS, Peacock SJ, Limmathurotsakul D. 2013. Using a web-based application to define the accuracy of diagnostic tests when the gold standard is imperfect PLoS ONE, 8 (11), | Show Abstract | Read more

Background: Estimates of the sensitivity and specificity for new diagnostic tests based on evaluation against a known gold standard are imprecise when the accuracy of the gold standard is imperfect. Bayesian latent class models (LCMs) can be helpful under these circumstances, but the necessary analysis requires expertise in computational programming. Here, we describe open-access web-based applications that allow non-experts to apply Bayesian LCMs to their own data sets via a user-friendly interface. Methods/Principal Findings: Applications for Bayesian LCMs were constructed on a web server using R and WinBUGS programs. The models provided (http://mice.tropmedres.ac) include two Bayesian LCMs: the two-tests in two-population model (Hui and Walter model) and the three-tests in one-population model (Walter and Irwig model). Both models are available with simplified and advanced interfaces. In the former, all settings for Bayesian statistics are fixed as defaults. Users input their data set into a table provided on the webpage. Disease prevalence and accuracy of diagnostic tests are then estimated using the Bayesian LCM, and provided on the web page within a few minutes. With the advanced interfaces, experienced researchers can modify all settings in the models as needed. These settings include correlation among diagnostic test results and prior distributions for all unknown parameters. The web pages provide worked examples with both models using the original data sets presented by Hui and Walter in 1980, and by Walter and Irwig in 1988. We also illustrate the utility of the advanced interface using the Walter and Irwig model on a data set from a recent melioidosis study. The results obtained from the web-based applications were comparable to those published previously. Conclusions: The newly developed web-based applications are open-access and provide an important new resource for researchers worldwide to evaluate new diagnostic tests. © 2013 Lim et al.

Luangasanatip N, Hongsuwan M, Lubell Y, Limmathurotsakul D, Teparrukkul P, Chaowarat S, Day NP, Graves N, Cooper BS. 2013. Long-term survival after intensive care unit discharge in Thailand: a retrospective study. Crit Care, 17 (5), pp. R219. | Show Abstract | Read more

INTRODUCTION: Economic evaluations of interventions in the hospital setting often rely on the estimated long-term impact on patient survival. Estimates of mortality rates and long-term outcomes among patients discharged alive from the intensive care unit (ICU) are lacking from lower- and middle-income countries. This study aimed to assess the long-term survival and life expectancy (LE) amongst post-ICU patients in Thailand, a middle-income country. METHODS: In this retrospective cohort study, data from a regional tertiary hospital in northeast Thailand and the regional death registry were linked and used to assess patient survival time after ICU discharge. Adult ICU patients aged at least 15 years who had been discharged alive from an ICU between 1 January 2004 and 31 December 2005 were included in the study, and the death registry was used to determine deaths occurring in this cohort up to 31st December 2010. These data were used in conjunction with standard mortality life tables to estimate annual mortality and life expectancy. RESULTS: This analysis included 10,321 ICU patients. During ICU admission, 3,251 patients (31.5%) died. Of 7,070 patients discharged alive, 2,527 (35.7%) were known to have died within the five-year follow-up period, a mortality rate 2.5 times higher than that in the Thai general population (age and sex matched). The mean LE was estimated as 18.3 years compared with 25.2 years in the general population. CONCLUSIONS: Post-ICU patients experienced much higher rates of mortality than members of the general population over the five-year follow-up period, particularly in the first year after discharge. Further work assessing Health Related Quality of Life (HRQOL) in both post-ICU patients and in the general population in developing countries is needed.

Wittekamp BH, Oostdijk EA, Cooper BS, Brun-Buisson C, Bonten MJ. 2013. Studies of selective decontamination. Lancet Infect Dis, 13 (9), pp. 736-737. | Read more

Deeny SR, Cooper BS, Cookson B, Hopkins S, Robotham JV. 2013. Targeted versus universal screening and decolonization to reduce healthcare-associated meticillin-resistant Staphylococcus aureus infection. J Hosp Infect, 85 (1), pp. 33-44. | Show Abstract | Read more

BACKGROUND: The benefits of universal meticillin-resistant Staphylococcus aureus (MRSA) admission screening, compared with screening targeted patient groups and the additional impact of discharge screening, are uncertain. AIMS: To quantify the impact of MRSA screening plus decolonization treatment on MRSA infection rates. To compare universal with targeted screening policies, and to evaluate the additional impact of screening and decolonization on discharge. METHODS: A stochastic, individual-based model of MRSA transmission was developed that included patient movements between general medical and intensive care unit (ICU) wards, and between the hospital and community, informed by 18 months of individual patient data from a 900-bed tertiary care hospital. We simulated the impact of universal and targeted [for ICU, acute care of the elderly (ACE) or readmitted patients] MRSA screening and decolonization policies, both on admission and discharge. FINDINGS: Universal admission screening plus decolonization resulted in 77% (95% confidence interval: 76-78) reduction in MRSA infections over 10 years. Screening only ACE specialty or ICU patients yielded 62% (61-63) and 66% (65-67) reductions, respectively. Targeted policies reduced the number of screens by up to 95% and courses of decolonization by 96%. In addition to screening on admission, screening on discharge had little impact, with a maximum 7% additional reduction in infection. CONCLUSIONS: Compared with universal screening, targeted screening substantially reduced the amount of screening and decolonization required to achieve only 12% lower reduction in infection. Targeted screening and decolonization could lower the risk of resistance emerging as well as offer a more efficient use of resources.

Vlek AL, Cooper BS, Kypraios T, Cox A, Edgeworth JD, Auguet OT. 2013. Clustering of antimicrobial resistance outbreaks across bacterial species in the intensive care unit. Clin Infect Dis, 57 (1), pp. 65-76. | Show Abstract | Read more

BACKGROUND: There are frequent reports of intensive care unit (ICU) outbreaks due to transmission of particular antibiotic-resistant bacteria. Less is known about the burden of outbreaks of resistance due to horizontal transfer of mobile genetic elements between species. Moreover, the potential of existing statistical software as a preliminary means for detecting such events has never been assessed. This study uses a software package to determine the burden of species and resistance outbreaks in 2 adjacent ICUs and to look for evidence of clustering of resistance outbreaks consistent with interspecies transmission of resistance elements. METHODS: A retrospective analysis of data from 2 adjacent 15-bed adult ICUs between 2002 and 2009 was undertaken. Detection of bacterial species-groups and resistance outbreaks was conducted using SaTScan and WHONet-SaTScan software. Resampling and permutation methods were applied to investigate temporal clustering of outbreaks. RESULTS: Outbreaks occurred for 69% of bacterial species-groups (18/26), and resistance outbreaks were detected against 63% of antibiotics (10/16). Resistance outbreaks against 7 of 10 antibiotics were observed in multiple species-groups simultaneously and there was evidence of inter-species-group dependence for 4 of 7 antibiotics; background temporal changes in resistance did not explain the temporal aggregation of outbreaks in 3 of 7 antibiotics. CONCLUSIONS: Species outbreaks occurred for the majority of bacteria commonly identified in the ICU. There was evidence for frequent temporal clustering of resistance outbreaks consistent with interspecies transmission of resistance elements. Wider application of outbreak detection software combined with targeted sequencing of bacterial genomes is needed to understand the contribution of interspecies gene transfer to resistance emergence.

Worby CJ, Jeyaratnam D, Robotham JV, Kypraios T, O'Neill PD, De Angelis D, French G, Cooper BS. 2013. Estimating the effectiveness of isolation and decolonization measures in reducing transmission of methicillin-resistant Staphylococcus aureus in hospital general wards. Am J Epidemiol, 177 (11), pp. 1306-1313. | Show Abstract | Read more

Infection control for hospital pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) often takes the form of a package of interventions, including the use of patient isolation and decolonization treatment. Such interventions, though widely used, have generated controversy because of their significant resource implications and the lack of robust evidence with regard to their effectiveness at reducing transmission. The aim of this study was to estimate the effectiveness of isolation and decolonization measures in reducing MRSA transmission in hospital general wards. Prospectively collected MRSA surveillance data from 10 general wards at Guy's and St. Thomas' hospitals, London, United Kingdom, in 2006-2007 were used, comprising 14,035 patient episodes. Data were analyzed with a Markov chain Monte Carlo algorithm to model transmission dynamics. The combined effect of isolation and decolonization was estimated to reduce transmission by 64% (95% confidence interval: 37, 79). Undetected MRSA-positive patients were estimated to be the source of 75% (95% confidence interval: 67, 86) of total transmission events. Isolation measures combined with decolonization treatment were strongly associated with a reduction in MRSA transmission in hospital general wards. These findings provide support for active methods of MRSA control, but further research is needed to determine the relative importance of isolation and decolonization in preventing transmission.

Liverani M, Waage J, Barnett T, Pfeiffer DU, Rushton J, Rudge JW, Loevinsohn ME, Scoones I et al. 2013. Understanding and managing zoonotic risk in the new livestock industries. Environ Health Perspect, 121 (8), pp. 873-877. | Show Abstract | Read more

BACKGROUND: In many parts of the world, livestock production is undergoing a process of rapid intensification. The health implications of this development are uncertain. Intensification creates cheaper products, allowing more people to access animal-based foods. However, some practices associated with intensification may contribute to zoonotic disease emergence and spread: for example, the sustained use of antibiotics, concentration of animals in confined units, and long distances and frequent movement of livestock. OBJECTIVES: Here we present the diverse range of ecological, biological, and socioeconomic factors likely to enhance or reduce zoonotic risk, and identify ways in which a comprehensive risk analysis may be conducted by using an interdisciplinary approach. We also offer a conceptual framework to guide systematic research on this problem. DISCUSSION: We recommend that interdisciplinary work on zoonotic risk should take into account the complexity of risk environments, rather than limiting studies to simple linear causal relations between risk drivers and disease emergence and/or spread. In addition, interdisciplinary integration is needed at different levels of analysis, from the study of risk environments to the identification of policy options for risk management. CONCLUSION: Given rapid changes in livestock production systems and their potential health implications at the local and global level, the problem we analyze here is of great importance for environmental health and development. Although we offer a systematic interdisciplinary approach to understand and address these implications, we recognize that further research is needed to clarify methodological and practical questions arising from the integration of the natural and social sciences.

Derde LP, Cooper BS, Goossens H, Malhotra-Kumar S, Willems RJ, Gniadkowski M, Hryniewicz W, Empel J et al. 2014. Interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in intensive care units: an interrupted time series study and cluster randomised trial. Lancet Infect Dis, 14 (1), pp. 31-39. | Show Abstract | Read more

BACKGROUND: Intensive care units (ICUs) are high-risk areas for transmission of antimicrobial-resistant bacteria, but no controlled study has tested the effect of rapid screening and isolation of carriers on transmission in settings with best-standard precautions. We assessed interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in European ICUs. METHODS: We did this study in three phases at 13 ICUs. After a 6 month baseline period (phase 1), we did an interrupted time series study of universal chlorhexidine body-washing combined with hand hygiene improvement for 6 months (phase 2), followed by a 12-15 month cluster randomised trial (phase 3). ICUs were randomly assigned by computer generated randomisation schedule to either conventional screening (chromogenic screening for meticillin-resistant Staphylococcus aureus [MRSA] and vancomycin-resistant enterococci [VRE]) or rapid screening (PCR testing for MRSA and VRE and chromogenic screening for highly resistant Enterobacteriaceae [HRE]); with contact precautions for identified carriers. The primary outcome was acquisition of resistant bacteria per 100 patient-days at risk, for which we calculated step changes and changes in trends after the introduction of each intervention. We assessed acquisition by microbiological surveillance and analysed it with a multilevel Poisson segmented regression model. We compared screening groups with a likelihood ratio test that combined step changes and changes to trend. This study is registered with ClinicalTrials.gov, number NCT00976638. FINDINGS: Seven ICUs were assigned to rapid screening and six to conventional screening. Mean hand hygiene compliance improved from 52% in phase 1 to 69% in phase 2, and 77% in phase 3. Median proportions of patients receiving chlorhexidine body-washing increased from 0% to 100% at the start of phase 2. For trends in acquisition of antimicrobial-resistant bacteria, weekly incidence rate ratio (IRR) was 0·976 (0·954-0·999) for phase 2 and 1·015 (0·998-1·032) for phase 3. For step changes, weekly IRR was 0·955 (0·676-1·348) for phase 2 and 0·634 (0·349-1·153) for phase 3. The decrease in trend in phase 2 was largely caused by changes in acquisition of MRSA (weekly IRR 0·925, 95% CI 0·890-0·962). Acquisition was lower in the conventional screening group than in the rapid screening group, but did not differ significantly (p=0·06). INTERPRETATION: Improved hand hygiene plus unit-wide chlorhexidine body-washing reduced acquisition of antimicrobial-resistant bacteria, particularly MRSA. In the context of a sustained high level of compliance to hand hygiene and chlorhexidine bathings, screening and isolation of carriers do not reduce acquisition rates of multidrug-resistant bacteria, whether or not screening is done with rapid testing or conventional testing. FUNDING: European Commission.

Lim C, Wannapinij P, White L, Day NP, Cooper BS, Peacock SJ, Limmathurotsakul D. 2013. Using a web-based application to define the accuracy of diagnostic tests when the gold standard is imperfect. PLoS One, 8 (11), pp. e79489. | Show Abstract | Read more

BACKGROUND: Estimates of the sensitivity and specificity for new diagnostic tests based on evaluation against a known gold standard are imprecise when the accuracy of the gold standard is imperfect. Bayesian latent class models (LCMs) can be helpful under these circumstances, but the necessary analysis requires expertise in computational programming. Here, we describe open-access web-based applications that allow non-experts to apply Bayesian LCMs to their own data sets via a user-friendly interface. METHODS/PRINCIPAL FINDINGS: Applications for Bayesian LCMs were constructed on a web server using R and WinBUGS programs. The models provided (http://mice.tropmedres.ac) include two Bayesian LCMs: the two-tests in two-population model (Hui and Walter model) and the three-tests in one-population model (Walter and Irwig model). Both models are available with simplified and advanced interfaces. In the former, all settings for Bayesian statistics are fixed as defaults. Users input their data set into a table provided on the webpage. Disease prevalence and accuracy of diagnostic tests are then estimated using the Bayesian LCM, and provided on the web page within a few minutes. With the advanced interfaces, experienced researchers can modify all settings in the models as needed. These settings include correlation among diagnostic test results and prior distributions for all unknown parameters. The web pages provide worked examples with both models using the original data sets presented by Hui and Walter in 1980, and by Walter and Irwig in 1988. We also illustrate the utility of the advanced interface using the Walter and Irwig model on a data set from a recent melioidosis study. The results obtained from the web-based applications were comparable to those published previously. CONCLUSIONS: The newly developed web-based applications are open-access and provide an important new resource for researchers worldwide to evaluate new diagnostic tests.

Lee AS, Cooper BS, Malhotra-Kumar S, Chalfine A, Daikos GL, Fankhauser C, Carevic B, Lemmen S et al. 2013. Comparison of strategies to reduce meticillin-resistant Staphylococcus aureus rates in surgical patients: a controlled multicentre intervention trial. BMJ Open, 3 (9), pp. e003126. | Show Abstract | Read more

OBJECTIVE: To compare the effect of two strategies (enhanced hand hygiene vs meticillin-resistant Staphylococcus aureus (MRSA) screening and decolonisation) alone and in combination on MRSA rates in surgical wards. DESIGN: Prospective, controlled, interventional cohort study, with 6-month baseline, 12-month intervention and 6-month washout phases. SETTING: 33 surgical wards of 10 hospitals in nine countries in Europe and Israel. PARTICIPANTS: All patients admitted to the enrolled wards for more than 24 h. INTERVENTIONS: The two strategies compared were (1) enhanced hand hygiene promotion and (2) universal MRSA screening with contact precautions and decolonisation (intranasal mupirocin and chlorhexidine bathing) of MRSA carriers. Four hospitals were assigned to each intervention and two hospitals combined both strategies, using targeted MRSA screening. OUTCOME MEASURES: Monthly rates of MRSA clinical cultures per 100 susceptible patients (primary outcome) and MRSA infections per 100 admissions (secondary outcome). Planned subgroup analysis for clean surgery wards was performed. RESULTS: After adjusting for clustering and potential confounders, neither strategy when used alone was associated with significant changes in MRSA rates. Combining both strategies was associated with a reduction in the rate of MRSA clinical cultures of 12% per month (adjusted incidence rate ratios (aIRR) 0.88, 95% CI 0.79 to 0.98). In clean surgery wards, strategy 2 (MRSA screening, contact precautions and decolonisation) was associated with decreasing rates of MRSA clinical cultures (15% monthly decrease, aIRR 0.85, 95% CI 0.74 to 0.97) and MRSA infections (17% monthly decrease, aIRR 0.83, 95% CI 0.69 to 0.99). CONCLUSIONS: In surgical wards with relatively low MRSA prevalence, a combination of enhanced standard and MRSA-specific infection control approaches was required to reduce MRSA rates. Implementation of single interventions was not effective, except in clean surgery wards where MRSA screening coupled with contact precautions and decolonisation was associated with significant reductions in MRSA clinical culture and infection rates. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00685867.

Harris JP, Lopman BA, Cooper BS, O'Brien SJ. 2013. Does spatial proximity drive norovirus transmission during outbreaks in hospitals? BMJ Open, 3 (7), pp. e003060-e003060. | Show Abstract | Read more

OBJECTIVE: To assess the role of spatial proximity, defined as patients sharing bays, in the spread of norovirus during outbreaks in hospitals. DESIGN: Enhanced surveillance of norovirus outbreaks between November 2009 and November 2011. METHODS: Data were gathered during 149 outbreaks of norovirus in hospital wards from five hospitals in two major cities in England serving a population of two million. We used the time between the first two cases of each outbreak to estimate the serial interval for norovirus in this setting. This distribution and dates of illness onset were used to calculate epidemic trees for each outbreak. We then used a permutation test to assess whether proximity, for all outbreaks, was more extreme than would be expected by chance under the null hypothesis that proximity was not associated with transmission risk. RESULTS: 65 outbreaks contained complete data on both onset dates and ward position. We estimated the serial interval to be 1.86 days (95% CI 1.6 to 2.2 days), and with this value found strong evidence to reject the null hypothesis that proximity was not significant (p<0.001). Sensitivity analysis using different values of the serial interval showed that there was evidence to reject the null hypothesis provided the assumed serial interval was less than 2.5 days. CONCLUSIONS: Our results provide evidence that patients occupying the same bay as patients with symptomatic norovirus infection are at an increased risk of becoming infected by these patients compared with patients elsewhere in the same ward.

Cooper B, Brun-Buisson C, Bonten M. 2013. Daily chlorhexidine bathing and hospital-acquired infection. N Engl J Med, 368 (24), pp. 2330-2331. | Read more

Meeyai A, Cooper BS, Coker R. 2013. Analysis of 2009 pandemic influenza A/H1N1 outcomes in 19 European countries: association with completeness of national strategic plans BMJ OPEN, 3 (3), pp. e002253-e002253. | Show Abstract | Read more

Objective: To describe changes in reported influenza activity associated with the 2009 H1N1 pandemic in European countries and determine whether there is a correlation between these changes and completeness of national strategic pandemic preparedness. Design: A retrospective correlational study. Setting: Countries were included if their national strategic plans had previously been analysed and if weekly influenza-like illness (ILI) data from sentinel networks between week 21, 2006 and week 20, 2010 were more than 50% complete. Outcome measures: For each country we calculated three outcomes: the percentage change in ILI peak height during the pandemic relative to the prepandemic mean; the timing of the ILI peak and the percentage change in total cases relative to the prepandemic mean. Correlations between these outcomes and completeness of a country's national strategic pandemic preparedness plan were assessed using the Pearson product-moment correlation coefficient. Results: Nineteen countries were included. The ILI peak occurred earlier than the mean seasonal peak in 17 countries. In 14 countries the pandemic peak was higher than the seasonal peak, though the difference was large only in Norway, the UK and Greece. Nine countries experienced more total ILI cases during the pandemic compared with the mean for prepandemic years. Five countries experienced two distinct pandemic peaks. There was no clear pattern of correlation between overall completeness of national strategic plans and pandemic influenza outcome measures and no evidence of association between these outcomes and components of pandemic plans that might plausibly affect influenza outcomes ( public health interventions, vaccination, antiviral use, public communication). Amongst the 17 countries with a clear pandemic peak, only the correlation between planning for essential services and change in total ILI cases significantly differed from zero: correlation coefficient (95% CI) 0.50 (0.02, 0.79). Conclusions: The diversity of pandemic influenza outcomes across Europe is not explained by the marked variation in the completeness of pandemic plans.

Pan A, Lee A, Cooper B, Chalfine A, Daikos GL, Garilli S, Goossens H, Malhotra-Kumar S, Martínez JA, Patroni A, Harbarth S. 2013. Risk factors for previously unknown meticillin-resistant Staphylococcus aureus carriage on admission to 13 surgical wards in Europe Journal of Hospital Infection, 83 (2), pp. 107-113. | Show Abstract | Read more

Background: Early identification of meticillin-resistant Staphylococcus aureus (MRSA) carriers may be helpful for clinical and epidemiological reasons. Aim: To identify and compare risk factors of previously unknown MRSA carriage on admission to 13 surgical wards in France, Greece, Italy, and Spain. Methods: The study was a prospective observational cohort study which enrolled consecutive patients screened for MRSA on admission to surgical wards. Sociodemographic data, comorbidities and possible risk factors for MRSA were recorded. A multivariate logistic regression model was used to predict probabilities of previously unknown MRSA colonization on admission based on patient characteristics. Prediction rules for MRSA carriage were developed and evaluated using the c-statistic. Findings: Of 2901 patients enrolled, admission screening identified 111 (3.8%) new MRSA carriers. Independent risk factors for MRSA carriage were urinary catheterization (odds ratio: 4.4; 95% confidence interval: 2.0-9.9), nursing home residency (3.8; 1.9-7.7), chronic skin disease (2.9; 1.5-5.8), wounds/ulcers (2.4; 1.5-4.0), recent hospitalization (2.2; 1.5-3.3), diabetes (1.6, 1.02-2.5), and age >70 years (1.5; 1.03-2.3). However, risk factors varied between centres. The c-statistic for the common prediction rule for all centres was 0.64, indicating limited predictive power. Conclusions: Risk profiles for MRSA carriers vary between surgical wards in European countries. Identifying local risk factors is important, as a common European prediction rule was found to be of limited clinical value. © 2012 The Healthcare Infection Society.

Luangasanatip N, Hongsuwan M, Lubell Y, Limmathurotsakul D, Teparrukkul P, Chaowarat S, Day NPJ, Graves N, Cooper BS. 2013. Long-term survival after intensive care unit discharge in Thailand: a retrospective study CRITICAL CARE, 17 (5), | Read more

Derde L, Cooper B, Buisson CB, Bonten M, Consortium MOSARR. 2012. MASTERING HOSPITAL ANTIBIOTIC RESISTANCE (MOSAR): A EUROPEAN CLUSTER-RANDOMIZED TRIAL ON REDUCING ACQUISITION OF RESISTANT BACTERIA IN INTENSIVE CARE UNITS INTENSIVE CARE MEDICINE, 38 pp. S249-S249.

Luangasanatip N, Hongsuwan M, Lubell Y, Srisamang P, Limmathurotsakul D, Cooper B. 2012. Excess length of stay due to hospital-associated infections in Thailand: 8 years retrospective data INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E378-E379. | Read more

Meeyai A, Cooper B, Coker R, Pan W, Akarasewie P, Iamsirithaworn S. 2012. The effective reproduction number of Pandemic 2009 H1N1 influenza in Thailand: a spatiotemporal analysis INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E353-E354. | Read more

Cooper B. 2012. Transmission dynamics of MRSA in Asia INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E53-E53. | Read more

Limmathurotsakul D, Turner EL, Wuthiekanun V, Thaipadungpanit J, Suputtamongkol Y, Chierakul W, Smythe LD, Day NP, Cooper B, Peacock SJ. 2012. Fool's gold: Why imperfect reference tests are undermining the evaluation of novel diagnostics: a reevaluation of 5 diagnostic tests for leptospirosis. Clin Infect Dis, 55 (3), pp. 322-331. | Show Abstract | Read more

BACKGROUND: We observed that some patients with clinical leptospirosis supported by positive results of rapid tests were negative for leptospirosis on the basis of our diagnostic gold standard, which involves isolation of Leptospira species from blood culture and/or a positive result of a microscopic agglutination test (MAT). We hypothesized that our reference standard was imperfect and used statistical modeling to investigate this hypothesis. METHODS: Data for 1652 patients with suspected leptospirosis recruited during three observational studies and one randomized control trial that described the application of culture, MAT, immunofluorescence assay (IFA), lateral flow (LF) and/or PCR targeting the 16S rRNA gene were reevaluated using Bayesian latent class models and random-effects meta-analysis. RESULTS: The estimated sensitivities of culture alone, MAT alone, and culture plus MAT (for which the result was considered positive if one or both tests had a positive result) were 10.5% (95% credible interval [CrI], 2.7%-27.5%), 49.8% (95% CrI, 37.6%-60.8%), and 55.5% (95% CrI, 42.9%-67.7%), respectively. These low sensitivities were present across all 4 studies. The estimated specificity of MAT alone (and of culture plus MAT) was 98.8% (95% CrI, 92.8%-100.0%). The estimated sensitivities and specificities of PCR (52.7% [95% CrI, 45.2%-60.6%] and 97.2% [95% CrI, 92.0%-99.8%], respectively), lateral flow test (85.6% [95% CrI, 77.5%-93.2%] and 96.2% [95% CrI, 87.7%-99.8%], respectively), and immunofluorescence assay (45.5% [95% CrI, 33.3%-60.9%] and 96.8% [95% CrI, 92.8%-99.8%], respectively) were considerably different from estimates in which culture plus MAT was considered a perfect gold standard test. CONCLUSIONS: Our findings show that culture plus MAT is an imperfect gold standard against which to compare alterative tests for the diagnosis of leptospirosis. Rapid point-of-care tests for this infection would bring an important improvement in patient care, but their future evaluation will require careful consideration of the reference test(s) used and the inclusion of appropriate statistical models.

Cooper BS, Kypraios T, Batra R, Wyncoll D, Tosas O, Edgeworth JD. 2012. Quantifying type-specific reproduction numbers for nosocomial pathogens: evidence for heightened transmission of an Asian sequence type 239 MRSA clone. PLoS Comput Biol, 8 (4), pp. e1002454. | Show Abstract | Read more

An important determinant of a pathogen's success is the rate at which it is transmitted from infected to susceptible hosts. Although there are anecdotal reports that methicillin-resistant Staphylococcus aureus (MRSA) clones vary in their transmissibility in hospital settings, attempts to quantify such variation are lacking for common subtypes, as are methods for addressing this question using routinely-collected MRSA screening data in endemic settings. Here we present a method to quantify the time-varying transmissibility of different subtypes of common bacterial nosocomial pathogens using routine surveillance data. The method adapts approaches for estimating reproduction numbers based on the probabilistic reconstruction of epidemic trees, but uses relative hazards rather than serial intervals to assign probabilities to different sources for observed transmission events. The method is applied to data collected as part of a retrospective observational study of a concurrent MRSA outbreak in the United Kingdom with dominant endemic MRSA clones (ST22 and ST36) and an Asian ST239 MRSA strain (ST239-TW) in two linked adult intensive care units, and compared with an approach based on a fully parametric transmission model. The results provide support for the hypothesis that the clones responded differently to an infection control measure based on the use of topical antiseptics, which was more effective at reducing transmission of endemic clones. They also suggest that in one of the two ICUs patients colonized or infected with the ST239-TW MRSA clone had consistently higher risks of transmitting MRSA to patients free of MRSA. These findings represent some of the first quantitative evidence of enhanced transmissibility of a pandemic MRSA lineage, and highlight the potential value of tailoring hospital infection control measures to specific pathogen subtypes.

Miller CE, Batra R, Cooper BS, Patel AK, Klein J, Otter JA, Kypraios T, French GL, Tosas O, Edgeworth JD. 2012. An association between bacterial genotype combined with a high-vancomycin minimum inhibitory concentration and risk of endocarditis in methicillin-resistant Staphylococcus aureus bloodstream infection. Clin Infect Dis, 54 (5), pp. 591-600. | Show Abstract | Read more

INTRODUCTION: Antimicrobial resistance and bacterial virulence factors may increase the risk of hematogenous complications during methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI). This study reports on the impact of increasing vancomycin minimum inhibitory concentrations (V-MICs) and MRSA clone type on risk of hematogenous complications from MRSA BSI during implementation of an effective MRSA control program. METHODS: In sum, spa typing, staphylococcal cassette chromosome mec allotyping, and vancomycin and teicoplanin MICs were performed on 821 consecutive MRSA bloodstream isolates from 1999 to 2009. Prospectively collected data, including focus of infection, were available for 695 clinically significant cases. Logistic and multinomial logistic regression was used to determine the association between clone type, vancomycin MIC (V-MIC), and focus of infection. RESULTS: MRSA BSIs decreased by ∼90% during the 11 years. Typing placed isolates into 3 clonal complex (CC) groups that had different population median V-MICs (CC30, 0.5 μg/mL [n = 349]; CC22, 0.75 μg/mL [n = 272]; non-CC22/30, 1.5 μg/mL [n = 199]). There was a progressive increase in the proportion of isolates with a V-MIC above baseline median in each clonal group and a disproportionate fall in the clone group with lowest median V-MIC (CC30). In contrast, there were no increases in teicoplanin MICs. High V-MIC CC22 isolates (1.5-2 μg/mL) were strongly associated with endocarditis (odds ratio, 12; 95% confidence interval, 3.72-38.9) and with a septic metastasis after catheter-related BSI (odds ratio, 106; 95% confidence interval, 12.6-883) compared with other clone type/V-MIC combinations. CONCLUSIONS: An interaction between clone type and V-MIC can influence the risk of endocarditis associated with MRSA BSI, implying involvement of both therapeutic and host-pathogen factors.

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Miller CE, Batra R, Cooper BS, Patel AK, Klein J, Otter JA, Kypraios T, French GL, Tosas O, Edgeworth JD. 2012. An association between bacterial genotype combined with a high-vancomycin minimum inhibitory concentration and risk of endocarditis in methicillin-resistant staphylococcus aureus bloodstream infection Clinical Infectious Diseases, 54 (5), pp. 591-600. | Show Abstract | Read more

Introduction. Antimicrobial resistance and bacterial virulence factors may increase the risk of hematogenous complications during methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI). This study reports on the impact of increasing vancomycin minimum inhibitory concentrations (V-MICs) and MRSA clone type on risk of hematogenous complications from MRSA BSI during implementation of an effective MRSA control program. Methods. In sum, spa typing, staphylococcal cassette chromosome mec allotyping, and vancomycin and teicoplanin MICs were performed on 821 consecutive MRSA bloodstream isolates from 1999 to 2009. Prospectively collected data, including focus of infection, were available for 695 clinically significant cases. Logistic and multinomial logistic regression was used to determine the association between clone type, vancomycin MIC (V-MIC), and focus of infection. Results. MRSA BSIs decreased by ∼90% during the 11 years. Typing placed isolates into 3 clonal complex (CC) groups that had different population median V-MICs (CC30, 0.5 μg/mL [n = 349]; CC22, 0.75 μg/mL [n = 272]; non-CC22/30, 1.5 μg/mL [n = 199]). There was a progressive increase in the proportion of isolates with a V-MIC above baseline median in each clonal group and a disproportionate fall in the clone group with lowest median V-MIC (CC30). In contrast, there were no increases in teicoplanin MICs. High V-MIC CC22 isolates (1.5-2 μg/mL) were strongly associated with endocarditis (odds ratio, 12; 95% confidence interval, 3.72-38.9) and with a septic metastasis after catheter-related BSI (odds ratio, 106; 95% confidence interval, 12.6-883) compared with other clone type/V-MIC combinations.Conclusions.An interaction between clone type and V-MIC can influence the risk of endocarditis associated with MRSA BSI, implying involvement of both therapeutic and host-pathogen factors. © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.

Stone SP, Fuller C, Savage J, Cookson B, Hayward A, Cooper B, Duckworth G, Michie S et al. 2012. Evaluation of the national Cleanyourhands campaign to reduce Staphylococcus aureus bacteraemia and Clostridium difficile infection in hospitals in England and Wales by improved hand hygiene: four year, prospective, ecological, interrupted time series study. BMJ, 344 (may03 2), pp. e3005. | Show Abstract | Read more

OBJECTIVE: To evaluate the impact of the Cleanyourhands campaign on rates of hospital procurement of alcohol hand rub and soap, report trends in selected healthcare associated infections, and investigate the association between infections and procurement. DESIGN: Prospective, ecological, interrupted time series study from 1 July 2004 to 30 June 2008. SETTING: 187 acute trusts in England and Wales. INTERVENTION: Installation of bedside alcohol hand rub, materials promoting hand hygiene and institutional engagement, regular hand hygiene audits, rolled out nationally from 1 December 2004. MAIN OUTCOME MEASURES: Quarterly (that is, every three months) rates for each trust of hospital procurement of alcohol hand rub and liquid soap; Staphylococcus aureus bacteraemia (meticillin resistant (MRSA) and meticillin sensitive (MSSA)) and Clostridium difficile infection for each trust. Associations between procurement and infection rates assessed by mixed effect Poisson regression model (which also accounted for effect of bed occupancy, hospital type, and timing of other national interventions targeting these infections). RESULTS: Combined procurement of soap and alcohol hand rub tripled from 21.8 to 59.8 mL per patient bed day; procurement rose in association with each phase of the campaign. Rates fell for MRSA bacteraemia (1.88 to 0.91 cases per 10,000 bed days) and C difficile infection (16.75 to 9.49 cases). MSSA bacteraemia rates did not fall. Increased procurement of soap was independently associated with reduced C difficile infection throughout the study (adjusted incidence rate ratio for 1 mL increase per patient bed day 0.993, 95% confidence interval 0.990 to 0.996; P < 0.0001). Increased procurement of alcohol hand rub was independently associated with reduced MRSA bacteraemia, but only in the last four quarters of the study (0.990, 0.985 to 0.995; P < 0.0001). Publication of the Health Act 2006 was strongly associated with reduced MRSA bacteraemia (0.86, 0.75 to 0.98; P = 0.02) and C difficile infection (0.75, 0.67 to 0.84; P < 0.0001). Trust visits by Department of Health improvement teams were also associated with reduced MRSA bacteraemia (0.91, 0.83 to 0.99; P=0.03) and C difficile infection (0.80, 0.71 to 0.90; P=0.01), for at least two quarters after each visit. CONCLUSIONS: The Cleanyourhands campaign was associated with sustained increases in hospital procurement of alcohol rub and soap, which the results suggest has an important role in reducing rates of some healthcare associated infections. National interventions for infection control undertaken in the context of a high profile political drive can reduce selected healthcare associated infections.

Pan A, Lee A, Cooper B, Chalfine A, Daikos GL, Garilli S, Goossens H, Malhotra-Kumar S et al. 2013. Risk factors for previously unknown meticillin-resistant Staphylococcus aureus carriage on admission to 13 surgical wards in Europe. J Hosp Infect, 83 (2), pp. 107-113. | Show Abstract | Read more

BACKGROUND: Early identification of meticillin-resistant Staphylococcus aureus (MRSA) carriers may be helpful for clinical and epidemiological reasons. AIM: To identify and compare risk factors of previously unknown MRSA carriage on admission to 13 surgical wards in France, Greece, Italy, and Spain. METHODS: The study was a prospective observational cohort study which enrolled consecutive patients screened for MRSA on admission to surgical wards. Sociodemographic data, comorbidities and possible risk factors for MRSA were recorded. A multivariate logistic regression model was used to predict probabilities of previously unknown MRSA colonization on admission based on patient characteristics. Prediction rules for MRSA carriage were developed and evaluated using the c-statistic. FINDINGS: Of 2901 patients enrolled, admission screening identified 111 (3.8%) new MRSA carriers. Independent risk factors for MRSA carriage were urinary catheterization (odds ratio: 4.4; 95% confidence interval: 2.0-9.9), nursing home residency (3.8; 1.9-7.7), chronic skin disease (2.9; 1.5-5.8), wounds/ulcers (2.4; 1.5-4.0), recent hospitalization (2.2; 1.5-3.3), diabetes (1.6, 1.02-2.5), and age >70 years (1.5; 1.03-2.3). However, risk factors varied between centres. The c-statistic for the common prediction rule for all centres was 0.64, indicating limited predictive power. CONCLUSIONS: Risk profiles for MRSA carriers vary between surgical wards in European countries. Identifying local risk factors is important, as a common European prediction rule was found to be of limited clinical value.

Fuller C, Michie S, Savage J, McAteer J, Besser S, Charlett A, Hayward A, Cookson BD et al. 2012. The Feedback Intervention Trial (FIT)--improving hand-hygiene compliance in UK healthcare workers: a stepped wedge cluster randomised controlled trial. PLoS One, 7 (10), pp. e41617. | Show Abstract | Read more

INTRODUCTION: Achieving a sustained improvement in hand-hygiene compliance is the WHO's first global patient safety challenge. There is no RCT evidence showing how to do this. Systematic reviews suggest feedback is most effective and call for long term well designed RCTs, applying behavioural theory to intervention design to optimise effectiveness. METHODS: Three year stepped wedge cluster RCT of a feedback intervention testing hypothesis that the intervention was more effective than routine practice in 16 English/Welsh Hospitals (16 Intensive Therapy Units [ITU]; 44 Acute Care of the Elderly [ACE] wards) routinely implementing a national cleanyourhands campaign). Intervention-based on Goal & Control theories. Repeating 4 week cycle (20 mins/week) of observation, feedback and personalised action planning, recorded on forms. Computer-generated stepwise entry of all hospitals to intervention. Hospitals aware only of own allocation. PRIMARY OUTCOME: direct blinded hand hygiene compliance (%). RESULTS: All 16 trusts (60 wards) randomised, 33 wards implemented intervention (11 ITU, 22 ACE). Mixed effects regression analysis (all wards) accounting for confounders, temporal trends, ward type and fidelity to intervention (forms/month used). INTENTION TO TREAT ANALYSIS: Estimated odds ratio (OR) for hand hygiene compliance rose post randomisation (1.44; 95% CI 1.18, 1.76;p<0.001) in ITUs but not ACE wards, equivalent to 7-9% absolute increase in compliance. PER-PROTOCOL ANALYSIS FOR IMPLEMENTING WARDS: OR for compliance rose for both ACE (1.67 [1.28-2.22]; p<0.001) & ITUs (2.09 [1.55-2.81]; p<0.001) equating to absolute increases of 10-13% and 13-18% respectively. Fidelity to intervention closely related to compliance on ITUs (OR 1.12 [1.04, 1.20]; p = 0.003 per completed form) but not ACE wards. CONCLUSION: Despite difficulties in implementation, intention-to-treat, per-protocol and fidelity to intervention, analyses showed an intervention coupling feedback to personalised action planning produced moderate but significant sustained improvements in hand-hygiene compliance, in wards implementing a national hand-hygiene campaign. Further implementation studies are needed to maximise the intervention's effect in different settings. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN65246961.

Fuller C, Savage J, Besser S, Hayward A, Cookson B, Cooper B, Stone S. 2011. "The dirty hand in the latex glove": a study of hand hygiene compliance when gloves are worn. Infect Control Hosp Epidemiol, 32 (12), pp. 1194-1199. | Show Abstract | Read more

BACKGROUND AND OBJECTIVE: Wearing of gloves reduces transmission of organisms by healthcare workers' hands but is not a substitute for hand hygiene. Results of previous studies have varied as to whether hand hygiene is worse when gloves are worn. Most studies have been small and used nonstandardized assessments of glove use and hand hygiene. We sought to observe whether gloves were worn when appropriate and whether hand hygiene compliance differed when gloves were worn. DESIGN: Observational study. PARTICIPANTS AND SETTING: Healthcare workers in 56 medical or care of the elderly wards and intensive care units in 15 hospitals across England and Wales. METHODS: We observed hand hygiene and glove usage (7,578 moments for hand hygiene) during 249 one-hour sessions. Observers also recorded whether gloves were or were not worn for individual contacts. RESULTS: Gloves were used in 1,983 (26.2%) of the 7,578 moments for hand hygiene and in 551 (16.7%) of 3,292 low-risk contacts; gloves were not used in 141 (21.1%) of 669 high-risk contacts. The rate of hand hygiene compliance with glove use was 41.4% (415 of 1,002 moments), and the rate without glove use was 50.0% (1,344 of 2,686 moments). After adjusting for ward, healthcare worker type, contact risk level, and whether the hand hygiene opportunity occurred before or after a patient contact, glove use was strongly associated with lower levels of hand hygiene (adjusted odds ratio, 0.65 [95% confidence interval, 0.54-0.79]; P < .0001). CONCLUSION: The rate of glove usage is lower than previously reported. Gloves are often worn when not indicated and vice versa. The rate of compliance with hand hygiene was significantly lower when gloves were worn. Hand hygiene campaigns should consider placing greater emphasis on the World Health Organization indications for gloving and associated hand hygiene. TRIAL REGISTRATION: National Research Register N0256159318.

Birrell PJ, Ketsetzis G, Gay NJ, Cooper BS, Presanis AM, Harris RJ, Charlett A, Zhang XS, White PJ, Pebody RG, De Angelis D. 2011. Bayesian modeling to unmask and predict influenza A/H1N1pdm dynamics in London. Proc Natl Acad Sci U S A, 108 (45), pp. 18238-18243. | Show Abstract | Read more

The tracking and projection of emerging epidemics is hindered by the disconnect between apparent epidemic dynamics, discernible from noisy and incomplete surveillance data, and the underlying, imperfectly observed, system. Behavior changes compound this, altering both true dynamics and reporting patterns, particularly for diseases with nonspecific symptoms, such as influenza. We disentangle these effects to unravel the hidden dynamics of the 2009 influenza A/H1N1pdm pandemic in London, where surveillance suggests an unusual dominant peak in the summer. We embed an age-structured model into a bayesian synthesis of multiple evidence sources to reveal substantial changes in contact patterns and health-seeking behavior throughout the epidemic, uncovering two similar infection waves, despite large differences in the reported levels of disease. We show how this approach, which allows for real-time learning about model parameters as the epidemic progresses, is also able to provide a sequence of nested projections that are capable of accurately reflecting the epidemic evolution.

Cited:

35

WOS

Robotham JV, Graves N, Cookson BD, Barnett AG, Wilson JA, Edgeworth JD, Batra R, Cuthbertson BH, Cooper BS. 2011. Screening, isolation, and decolonisation strategies in the control of meticillin resistant Staphylococcus aureus in intensive care units: cost effectiveness evaluation BRITISH MEDICAL JOURNAL, 343 (oct05 3), pp. d5694-d5694. | Read more

Talpaert MJ, Gopal Rao G, Cooper BS, Wade P. 2011. Impact of guidelines and enhanced antibiotic stewardship on reducing broad-spectrum antibiotic usage and its effect on incidence of Clostridium difficile infection. J Antimicrob Chemother, 66 (9), pp. 2168-2174. | Show Abstract | Read more

OBJECTIVES: To evaluate the impact of an 'intervention' consisting of revised antibiotic guidelines for empirical treatment of common infections and enhanced stewardship on reducing broad-spectrum antibiotic usage and its effect on incidence of Clostridium difficile infection (CDI). METHODS: This was a retrospective, quasi-experimental study using interrupted time series (ITS) over 12 months before and after the intervention. The setting was adult medical and surgical wards in University Hospital Lewisham, an acute general hospital in London. The intervention was introduced in April 2006. Revised guidelines avoided broad-spectrum antibiotics, e.g. fluoroquinolones, cephalosporins, clindamycin, amoxicillin and co-amoxiclav, as they were considered to be 'high risk' for CDI. Instead, 'low risk' antibiotics such as penicillin, clarithromycin, doxycycline, gentamicin, vancomycin, trimethoprim and nitrofurantoin were recommended. Changes in antibiotic usage and incidence of CDI before and after the intervention were compared using segmented regression analysis. The negative binomial model was used to analyse the time series to estimate the CDI incidence rate ratio (IRR) following the intervention. RESULTS: The intervention was associated with a significant reduction in the use of fluoroquinolones by 105.33 defined daily doses (DDDs)/1000 occupied bed-days (OBDs) per month [95% confidence interval (CI) 34.18-176.48, P < 0.001] and cephalosporins by 45.93 DDDs/1000 OBDs/month (95% CI 24.11-67.74, P < 0.0001). There was no significant change in total antibiotic, clindamycin, amoxicillin or co-amoxiclav use. There was a significant decrease in CDI following the intervention [IRR 0.34 (0.20-0.58), P < 0.0001]. CONCLUSIONS: Revised antibiotic guidelines and enhanced stewardship was associated with a significant stepwise reduction in the use of cephalosporins and fluoroquinolones and a significant decrease in the incidence of CDI.

Limmathurotsakul D, Chantratita N, Teerawattanasook N, Piriyagitpaiboon K, Thanwisai A, Wuthiekanun V, Day NP, Cooper B, Peacock SJ. 2011. Enzyme-linked immunosorbent assay for the diagnosis of melioidosis: better than we thought. Clin Infect Dis, 52 (8), pp. 1024-1028. | Show Abstract | Read more

We used Bayesian latent-class models to generate receiver operating characteristic curves and to revise the cutoff values for an enzyme-linked immunosorbent assay that has been developed previously for melioidosis. The new cutoff was unbiased towards misclassification caused by an imperfect gold standard and resulted in an increase in both sensitivity (from 66.4% to 80.2%) and specificity (82.1% and 95.0%).

Wilson AP, Smyth D, Moore G, Singleton J, Jackson R, Gant V, Jeanes A, Shaw S et al. 2011. The impact of enhanced cleaning within the intensive care unit on contamination of the near-patient environment with hospital pathogens: a randomized crossover study in critical care units in two hospitals. Crit Care Med, 39 (4), pp. 651-658. | Show Abstract | Read more

OBJECTIVES: To determine the effect of enhanced cleaning of the near-patient environment on the isolation of hospital pathogens from the bed area and staff hands. DESIGN: Prospective randomized crossover study over the course of 1 yr. SETTING: Intensive care units at two teaching hospitals. PATIENTS: There were 1252 patients staying during enhanced cleaning and 1331 staying during standard cleaning. INTERVENTIONS: In each of six 2-month periods, one unit was randomly selected for additional twice-daily enhanced cleaning of hand contact surfaces. MEASUREMENTS AND MAIN RESULTS: Agar contact samples were taken at five sites around randomly selected bed areas, from staff hands, and from communal sites three times daily for 12 bed days per week. Patients admitted in the year commencing April 2007 were analyzed for hospital-acquired colonization and infection. Over the course of 1152 bed days, 20,736 samples were collected. Detection of environmental methicillin-resistant Staphylococcus aureus per bed-area day was reduced during enhanced cleaning phases from 82 of 561 (14.6%) to 51 of 559 (9.1%) (adjusted odds ratio, 0.59; 95% confidence interval, 0.40-0.86; p = .006). Other targeted pathogens (Acinetobacter baumannii, extended-spectrum β-lactamase-producing Gram-negative bacteria, vancomycin-resistant enterococci, and Clostridium difficile) were rarely detected. Subgroup analyses showed reduced methicillin-resistant Staphylococcus aureus contamination on doctors' hands during enhanced cleaning (3 of 425; 0.7% vs. 11 of 423; 2.6%; adjusted odds ratio, 0.26; 95% confidence interval, 0.07-0.95; p = .025) and a trend to reduction on nurses' hands (16 of 1647; 1.0% vs. 28 of 1694; 1.7%; adjusted odds ratio 0.56; 95% confidence interval, 0.29-1.08; p = .077). All 1252 critical care patients staying during enhanced and 1,331 during standard cleaning were included, but no significant effect on patient methicillin-resistant Staphylococcus aureus acquisition was observed (adjusted odds ratio, 0.98; 95% confidence interval, 0.58-1.65; p = .93). CONCLUSIONS: Enhanced cleaning reduced environmental contamination and hand carriage, but no significant effect was observed on patient acquisition of methicillin-resistant Staphylococcus aureus. TRIAL REGISTRY: ISRCTN. Identifier: 06298448. http://www.controlled-trials.com/isrctn/.

Limmathurotsakul D, Cooper B, Peacock SJ, De Stavola B. 2011. Long-term outcome of Q fever endocarditis. Lancet Infect Dis, 11 (2), pp. 81. | Read more

Kypraios T, O'Neill PD, Jones DE, Ware J, Batra R, Edgeworth JD, Cooper BS. 2011. Effect of systemic antibiotics and topical chlorhexidine on meticillin-resistant Staphylococcus aureus carriage in intensive care unit patients Journal of Hospital Infection,

Kypraios T, O'Neill PD, Jones DE, Ware J, Batra R, Edgeworth JD, Cooper BS. 2011. Effect of systemic antibiotics and topical chlorhexidine on meticillin-resistant Staphylococcus aureus carriage in intensive care unit patients. J Hosp Infect, 79 (3), pp. 222-226. | Show Abstract | Read more

Antibiotics and antiseptics have the potential to influence carriage and transmission of meticillin-resistant Staphylococcus aureus (MRSA), although effects are likely to be complex, particularly in a setting where multiple agents are used. Here admission and weekly MRSA screens and daily antibiotic and antiseptic prescribing data from 544 MRSA carriers on an intensive care unit (ICU) are used to determine the effect of these agents on short-term within-host MRSA carriage dynamics. Longitudinal data were analysed using Markov models allowing patients to move between two states: MRSA positive (detectable MRSA carriage) and MRSA negative (no detectable carriage). The effect of concurrent systemic antibiotic and topical chlorhexidine (CHX) on movement between these states was assessed. CHX targeted to MRSA screen carriage sites increased transition from culture positive to negative and there was also weaker evidence that it decreased subsequent transition from negative back to positive. In contrast, there was only weak and inconsistent evidence that any antibiotic influenced transition in either direction. For example, whereas univariate analysis found quinolones to be strongly associated with both increased risk of losing and then reacquiring MRSA carriage over time intervals of one day, no effect was seen with weekly models. Similar studies are required to determine the generalisability of these findings.

Christopher S, Verghis RM, Antonisamy B, Sowmyanarayanan TV, Brahmadathan KN, Kang G, Cooper BS. 2011. Transmission dynamics of methicillin-resistant Staphylococcus aureus in a medical intensive care unit in India PLoS ONE, 6 (7), | Show Abstract | Read more

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a global pathogen and an important but seldom investigated cause of morbidity and mortality in lower and middle-income countries where it can place a major burden on limited resources. Quantifying nosocomial transmission in resource-poor settings is difficult because molecular typing methods are prohibitively expensive. Mechanistic statistical models can overcome this problem with minimal cost. We analyse the transmission dynamics of MRSA in a hospital in south India using one such approach and provide conservative estimates of the organism's economic burden. Methods and Findings: Fifty months of MRSA infection data were collected retrospectively from a Medical Intensive Care Unit (MICU) in a tertiary hospital in Vellore, south India. Data were analysed using a previously described structured hidden Markov model. Seventy-two patients developed MRSA infections and, of these, 49 (68%) died in the MICU. We estimated that 4.2% (95%CI 1.0, 19.0) of patients were MRSA-positive when admitted, that there were 0.39 MRSA infections per colonized patient month (0.06, 0.73), and that the ward-level reproduction number for MRSA was 0.42 (0.08, 2.04). Anti-MRSA antibiotic treatment costs alone averaged $124/patient, over three times the monthly income of more than 40% of the Indian population. Conclusions: Our analysis of routine data provides the first estimate of the nosocomial transmission potential of MRSA in India. The high levels of transmission estimated underline the need for cost-effective interventions to reduce MRSA transmission in hospital settings in low and middle income countries. © 2011 Christopher et al.

Willemsen I, Cooper B, van Buitenen C, Winters M, Andriesse G, Kluytmans J. 2010. Improving quinolone use in hospitals by using a bundle of interventions in an interrupted time series analysis. Antimicrob Agents Chemother, 54 (9), pp. 3763-3769. | Show Abstract | Read more

The objectives of the present study were to determine the effects of multiple targeted interventions on the level of use of quinolones and the observed rates of resistance to quinolones in Escherichia coli isolates from hospitalized patients. A bundle consisting of four interventions to improve the use of quinolones was implemented. The outcome was measured from the monthly levels of use of intravenous (i.v.) and oral quinolones and the susceptibility patterns for E. coli isolates from hospitalized patients. Statistical analyses were performed using segmented regression analysis and segmented Poisson regression models. Before the bundle was implemented, the annual use of quinolones was 2.7 defined daily doses (DDDs)/100 patient days. After the interventions, in 2007, this was reduced to 1.7 DDDs/100 patient days. The first intervention, a switch from i.v. to oral medication, was associated with a stepwise reduction in i.v. quinolone use of 71 prescribed daily doses (PDDs) per month (95% confidence interval [CI] = 47 to 95 PDDs/month, P < 0.001). Intervention 2, introduction of a new antibiotic guideline and education program, was associated with a stepwise reduction in the overall use of quinolones (reduction, 107 PDDs/month [95% CI = 58 to 156 PDDs/month). Before the interventions the quinolone resistance rate was increasing, on average, by 4.6% (95% CI = 2.6 to 6.1%) per year. This increase leveled off, which was associated with intervention 2 and intervention 4, active monitoring of prescriptions and feedback. Trends in resistance to other antimicrobial agents did not change. This study showed that the hospital-wide use of quinolones can be significantly reduced by an active policy consisting of multiple interventions. There was also a stepwise reduction in the rate of quinolone resistance associated with the bundle of interventions.

Batra R, Cooper BS, Whiteley C, Patel AK, Wyncoll D, Edgeworth JD. 2010. Efficacy and limitation of a chlorhexidine-based decolonization strategy in preventing transmission of methicillin-resistant Staphylococcus aureus in an intensive care unit. Clin Infect Dis, 50 (2), pp. 210-217. | Show Abstract | Read more

BACKGROUND: Surface-active antiseptics, such as chlorhexidine, are increasingly being used as part of intervention programs to prevent methicillin-resistant Staphylococcus aureus (MRSA) transmission, despite limited evidence and potential for resistance. We report on the effect of an antiseptic protocol on acquisition of both endemic MRSA and an outbreak strain of MRSA sequence type 239 (designated TW). METHODS: Interrupted time-series data on MRSA acquisitions in two 15-bed intensive care units were analyzed using segmented regression models to estimate the effects of sequential introduction of an educational campaign, cohorting, and a chlorhexidine-based antiseptic protocol on transmission of TW and non-TW MRSA strains. Representative TW and non-TW MRSA strains were assessed for carriage of qacA/B genes and antiseptic susceptibility. RESULTS: The antiseptic protocol was associated with a highly significant, immediate 70% reduction in acquisition of non-TW MRSA strains (estimated model-averaged incidence rate ratio, 0.3; 95% confidence interval, 0.19-0.47) and an increase in acquisition of TW MRSA strains (estimated model-averaged incidence rate ratio, 3.85; 95% confidence interval, 0.80-18.59). There was only weak evidence of an effect of other interventions on MRSA transmission. All TW MRSA strains (21 of 21 isolates) and <5% (1 of 21 isolates) of non-TW MRSA strains tested carried the chlorhexidine resistance loci qacA/B. In vitro chlorhexidine minimum bactericidal concentrations of TW strains were 3-fold higher than those of non-TW MRSA strains, and in vivo, only patients with non-TW MRSA demonstrated a reduction in the number of colonization sites in response to chlorhexidine treatment. CONCLUSION: A chlorhexidine-based surface antiseptic protocol can interrupt transmission of MRSA in the intensive care unit, but strains carrying qacA/B genes may be unaffected or potentially spread more rapidly.

Kypraios T, O'Neill PD, Huang SS, Rifas-Shiman SL, Cooper BS. 2010. Assessing the role of undetected colonization and isolation precautions in reducing methicillin-resistant Staphylococcus aureus transmission in intensive care units. BMC Infect Dis, 10 (1), pp. 29. | Show Abstract | Read more

BACKGROUND: Screening and isolation are central components of hospital methicillin-resistant Staphylococcus aureus (MRSA) control policies. Their prevention of patient-to-patient spread depends on minimizing undetected and unisolated MRSA-positive patient days. Estimating these MRSA-positive patient days and the reduction in transmission due to isolation presents a major methodological challenge, but is essential for assessing both the value of existing control policies and the potential benefit of new rapid MRSA detection technologies. Recent methodological developments have made it possible to estimate these quantities using routine surveillance data. METHODS: Colonization data from admission and weekly nares cultures were collected from eight single-bed adult intensive care units (ICUs) over 17 months. Detected MRSA-positive patients were isolated using single rooms and barrier precautions. Data were analyzed using stochastic transmission models and model fitting was performed within a Bayesian framework using a Markov chain Monte Carlo algorithm, imputing unobserved MRSA carriage events. RESULTS: Models estimated the mean percent of colonized-patient-days attributed to undetected carriers as 14.1% (95% CI (11.7, 16.5)) averaged across ICUs. The percent of colonized-patient-days attributed to patients awaiting results averaged 7.8% (6.2, 9.2). Overall, the ratio of estimated transmission rates from unisolated MRSA-positive patients and those under barrier precautions was 1.34 (0.45, 3.97), but varied widely across ICUs. CONCLUSIONS: Screening consistently detected >80% of colonized-patient-days. Estimates of the effectiveness of barrier precautions showed considerable uncertainty, but in all units except burns/general surgery and one cardiac surgery ICU, the best estimates were consistent with reductions in transmission associated with barrier precautions.

Graves N, Harbarth S, Beyersmann J, Barnett A, Halton K, Cooper B. 2010. Estimating the cost of health care-associated infections: mind your p's and q's. Clin Infect Dis, 50 (7), pp. 1017-1021. | Show Abstract | Read more

Monetary valuations of the economic cost of health care-associated infections (HAIs) are important for decision making and should be estimated accurately. Erroneously high estimates of costs, designed to jolt decision makers into action, may do more harm than good in the struggle to attract funding for infection control. Expectations among policy makers might be raised, and then they are disappointed when the reduction in the number of HAIs does not yield the anticipated cost saving. For this article, we critically review the field and discuss 3 questions. Why measure the cost of an HAI? What outcome should be used to measure the cost of an HAI? What is the best method for making this measurement? The aim is to encourage researchers to collect and then disseminate information that accurately guides decisions about the economic value of expanding or changing current infection control activities.

Maude RJ, Lubell Y, Socheat D, Yeung S, Saralamba S, Pongtavornpinyo W, Cooper BS, Dondorp AM, White NJ, White LJ. 2010. The role of mathematical modelling in guiding the science and economics of malaria elimination. Int Health, 2 (4), pp. 239-246. | Show Abstract | Read more

Unprecedented efforts are now underway to eliminate malaria from many regions. Despite the enormous financial resources committed, if malaria elimination is perceived as failing it is likely that this funding will not be sustained. It is imperative that methods are developed to use the limited data available to design site-specific, cost-effective elimination programmes. Mathematical modelling is a way of including mechanistic understanding to use available data to make predictions. Different strategies can be evaluated much more rapidly than is possible through trial and error in the field. Mathematical modelling has great potential as a tool to guide and inform current elimination efforts. Economic modelling weighs costs against characterised effects or predicted benefits in order to determine the most cost-efficient strategy but has traditionally used static models of disease not suitable for elimination. Dynamic mathematical modelling and economic modelling techniques need to be combined to contribute most effectively to ongoing policy discussions. We review the role of modelling in previous malaria control efforts as well as the unique nature of elimination and the consequent need for its explicit modelling, and emphasise the importance of good disease surveillance. The difficulties and complexities of economic evaluation of malaria control, particularly the end stages of elimination, are discussed.

Presanis AM, De Angelis D, Hagy A, Reed C, Riley S, Cooper BS, Finelli L, Biedrzycki P, Lipsitch M. 2009. The Severity of Pandemic H1N1 Influenza in the United States, from April to July 2009: A Bayesian Analysis PLoS Medicine, 6 (12), pp. e1000207-e1000207. | Read more

de Vlas SJ, Feng D, Cooper BS, Fang LQ, Cao WC, Richardus JH. 2009. The impact of public health control measures during the SARS epidemic in mainland China. Trop Med Int Health, 14 Suppl 1 (SUPPL. 1), pp. 101-104. | Show Abstract | Read more

We tracked the effective reproductive number (Rt) over time to assess the impact of important public health control measures in the five most SARS-affected geographic areas in mainland China. As soon as the Chinese authorities gained full control of all activities to combat SARS, Rt decreased dramatically and consistently below one. Many control measures that seriously affected public life were implemented afterwards, i.e., when the epidemic was already dying down.

Cooper BS, Fang LQ, Zhou JP, Feng D, Lv H, Wei MT, Wang SX, Cao WC, de Vlas SJ. 2009. Transmission of SARS in three Chinese hospitals. Trop Med Int Health, 14 Suppl 1 (SUPPL. 1), pp. 71-78. | Show Abstract | Read more

OBJECTIVE: To quantify the transmissibility of severe acute respiratory syndrome (SARS) in hospitals in mainland China and to assess the effectiveness of control measures. METHODS: We report key epidemiological details of three major hospital outbreaks of SARS in mainland China, and estimate the evolution of the effective reproduction number in each of the three hospitals during the course of the outbreaks. RESULTS: The three successive hospital outbreaks infected 41, 99 and 91 people of whom 37%, 60% and 70% were hospital staff. These cases resulted in 33 deaths, five of which occurred in hospital staff. In a multivariate logistic regression, age and whether or not the case was a healthcare worker (HCW) were found to be significant predictors of mortality. The estimated effective reproduction numbers (95% CI) for the three epidemics peaked at 8 (5, 11), 9 (4, 14) and 12 (7, 17). In all three hospitals the epidemics were rapidly controlled, bringing the reproduction number below one within 25, 10 and 5 days respectively. CONCLUSIONS: This work shows that in three major hospital epidemics in Beijing and Tianjin substantially higher rates of transmission were initially observed than those seen in the community. In all three cases the hospital epidemics were rapidly brought under control, with the time to successful control becoming shorter in each successive outbreak.

Barnett AG, Batra R, Graves N, Edgeworth J, Robotham J, Cooper B. 2009. Using a longitudinal model to estimate the effect of methicillin-resistant Staphylococcus aureus infection on length of stay in an intensive care unit. Am J Epidemiol, 170 (9), pp. 1186-1194. | Show Abstract | Read more

Health-care-associated methicillin-resistant Staphylococcus aureus (MRSA) infection may cause increased hospital stay, or sometimes death. Quantifying this effect is complicated because the exposure is time dependent: infection may prolong hospital stay, while longer stays increase infection risk. In this paper, the authors overcome these problems by using a multinomial longitudinal model to estimate the daily probability of death and discharge. They then extend the basic model to estimate how the effect of MRSA infection varies over time and to quantify number of excess days in the intensive care unit due to infection. They found that infection decreased the relative risk of discharge (relative risk ratio = 0.68, 95% credible interval: 0.54, 0.82). Infection on the first day of admission resulted in a mean extra stay of 0.3 days (95% credible interval: 0.1, 0.5) for a patient with an Acute Physiology and Chronic Health Evaluation II score of 10 and 1.2 days (95% credible interval: 0.5, 2.0) for a patient with a score of 30. The decrease in the relative risk of discharge remained fairly constant with day of MRSA infection but was slightly stronger closer to the start of infection. Results confirm the importance of MRSA infection in increasing stay in an intensive care unit but suggest that previous work may have systematically overestimated the effect size.

Wu JT, Leung GM, Lipsitch M, Cooper BS, Riley S. 2009. Hedging against Antiviral Resistance during the Next Influenza Pandemic Using Small Stockpiles of an Alternative Chemotherapy PLoS Medicine, 6 (5), pp. e1000085-e1000085. | Read more

de Smet AMGA, Kluytmans JAJW, Cooper BS, Mascini EM, Benus RFJ, van der Werf TS, van der Hoeven JG, Pickkers P et al. 2009. Decontamination of the Digestive Tract and Oropharynx in ICU Patients New England Journal of Medicine, 360 (1), pp. 20-31. | Read more

Wu JT, Leung GM, Lipsitch M, Cooper BS, Riley S. 2009. Hedging against antiviral resistance during the next influenza pandemic using small stockpiles of an alternative chemotherapy. PLoS Med, 6 (5), pp. e1000085. | Show Abstract | Read more

BACKGROUND: The effectiveness of single-drug antiviral interventions to reduce morbidity and mortality during the next influenza pandemic will be substantially weakened if transmissible strains emerge which are resistant to the stockpiled antiviral drugs. We developed a mathematical model to test the hypothesis that a small stockpile of a secondary antiviral drug could be used to mitigate the adverse consequences of the emergence of resistant strains. METHODS AND FINDINGS: We used a multistrain stochastic transmission model of influenza to show that the spread of antiviral resistance can be significantly reduced by deploying a small stockpile (1% population coverage) of a secondary drug during the early phase of local epidemics. We considered two strategies for the use of the secondary stockpile: early combination chemotherapy (ECC; individuals are treated with both drugs in combination while both are available); and sequential multidrug chemotherapy (SMC; individuals are treated only with the secondary drug until it is exhausted, then treated with the primary drug). We investigated all potentially important regions of unknown parameter space and found that both ECC and SMC reduced the cumulative attack rate (AR) and the resistant attack rate (RAR) unless the probability of emergence of resistance to the primary drug p(A) was so low (less than 1 in 10,000) that resistance was unlikely to be a problem or so high (more than 1 in 20) that resistance emerged as soon as primary drug monotherapy began. For example, when the basic reproductive number was 1.8 and 40% of symptomatic individuals were treated with antivirals, AR and RAR were 67% and 38% under monotherapy if p(A) = 0.01. If the probability of resistance emergence for the secondary drug was also 0.01, then SMC reduced AR and RAR to 57% and 2%. The effectiveness of ECC was similar if combination chemotherapy reduced the probabilities of resistance emergence by at least ten times. We extended our model using travel data between 105 large cities to investigate the robustness of these resistance-limiting strategies at a global scale. We found that as long as populations that were the main source of resistant strains employed these strategies (SMC or ECC), then those same strategies were also effective for populations far from the source even when some intermediate populations failed to control resistance. In essence, through the existence of many wild-type epidemics, the interconnectedness of the global network dampened the international spread of resistant strains. CONCLUSIONS: Our results indicate that the augmentation of existing stockpiles of a single anti-influenza drug with smaller stockpiles of a second drug could be an effective and inexpensive epidemiological hedge against antiviral resistance if either SMC or ECC were used. Choosing between these strategies will require additional empirical studies. Specifically, the choice will depend on the safety of combination therapy and the synergistic effect of one antiviral in suppressing the emergence of resistance to the other antiviral when both are taken in combination.

Ghani A, Baguelin M, Griffin J, Flasche S, van Hoek AJ, Cauchemez S, Donnelly C, Robertson C et al. 2009. The Early Transmission Dynamics of H1N1pdm Influenza in the United Kingdom. PLoS Curr, 1 pp. RRN1130. | Read more

Presanis AM, De Angelis D, New York City Swine Flu Investigation Team, Hagy A, Reed C, Riley S, Cooper BS, Finelli L, Biedrzycki P, Lipsitch M. 2009. The severity of pandemic H1N1 influenza in the United States, from April to July 2009: a Bayesian analysis. PLoS Med, 6 (12), pp. e1000207. | Show Abstract | Read more

BACKGROUND: Accurate measures of the severity of pandemic (H1N1) 2009 influenza (pH1N1) are needed to assess the likely impact of an anticipated resurgence in the autumn in the Northern Hemisphere. Severity has been difficult to measure because jurisdictions with large numbers of deaths and other severe outcomes have had too many cases to assess the total number with confidence. Also, detection of severe cases may be more likely, resulting in overestimation of the severity of an average case. We sought to estimate the probabilities that symptomatic infection would lead to hospitalization, ICU admission, and death by combining data from multiple sources. METHODS AND FINDINGS: We used complementary data from two US cities: Milwaukee attempted to identify cases of medically attended infection whether or not they required hospitalization, while New York City focused on the identification of hospitalizations, intensive care admission or mechanical ventilation (hereafter, ICU), and deaths. New York data were used to estimate numerators for ICU and death, and two sources of data--medically attended cases in Milwaukee or self-reported influenza-like illness (ILI) in New York--were used to estimate ratios of symptomatic cases to hospitalizations. Combining these data with estimates of the fraction detected for each level of severity, we estimated the proportion of symptomatic patients who died (symptomatic case-fatality ratio, sCFR), required ICU (sCIR), and required hospitalization (sCHR), overall and by age category. Evidence, prior information, and associated uncertainty were analyzed in a Bayesian evidence synthesis framework. Using medically attended cases and estimates of the proportion of symptomatic cases medically attended, we estimated an sCFR of 0.048% (95% credible interval [CI] 0.026%-0.096%), sCIR of 0.239% (0.134%-0.458%), and sCHR of 1.44% (0.83%-2.64%). Using self-reported ILI, we obtained estimates approximately 7-9 x lower. sCFR and sCIR appear to be highest in persons aged 18 y and older, and lowest in children aged 5-17 y. sCHR appears to be lowest in persons aged 5-17; our data were too sparse to allow us to determine the group in which it was the highest. CONCLUSIONS: These estimates suggest that an autumn-winter pandemic wave of pH1N1 with comparable severity per case could lead to a number of deaths in the range from considerably below that associated with seasonal influenza to slightly higher, but with the greatest impact in children aged 0-4 and adults 18-64. These estimates of impact depend on assumptions about total incidence of infection and would be larger if incidence of symptomatic infection were higher or shifted toward adults, if viral virulence increased, or if suboptimal treatment resulted from stress on the health care system; numbers would decrease if the total proportion of the population symptomatically infected were lower than assumed.

White LJ, Buttery J, Cooper B, Nokes DJ, Medley GF. 2008. Rotavirus within day care centres in Oxfordshire, UK: characterization of partial immunity. J R Soc Interface, 5 (29), pp. 1481-1490. | Show Abstract | Read more

Repeated measures data for rotavirus infection in children within 14 day care centres (DCCs) in the Oxfordshire area, UK, are used to explore aspects of rotavirus transmission and immunity. A biologically realistic model for the transmission of infection is presented as a set of probability models suitable for application to the data. Two transition events are modelled separately: incidence and recovery. The complexity of the underlying mechanistic model is reflected in the choice of the fixed variables in the probability models. Parameter estimation was carried out using a Bayesian Markov chain Monte Carlo method. We use the parameter estimates obtained to build a profile of the natural history of rotavirus reinfection in an individual child. We infer that rotavirus transmission in children in DCCs is dependent on the DCC prevalence, with symptomatic infection of longer duration, but no more infectious per day of infectious period, than asymptomatic infection. There was evidence that a recent previous infection reduces the risk of disease and, to a lesser extent, reinfection, but not duration of infection. The results provide evidence that partial immunity to rotavirus infection develops over several time scales.

Cooper BS, Medley GF, Bradley SJ, Scott GM. 2008. An augmented data method for the analysis of nosocomial infection data. Am J Epidemiol, 168 (5), pp. 548-557. | Show Abstract | Read more

The analysis of nosocomial infection data for communicable pathogens is complicated by two facts. First, typical pathogens more commonly cause asymptomatic colonization than overt disease, so transmission can be only imperfectly observed through a sequence of surveillance swabs, which themselves have imperfect sensitivity. Any given set of swab results can therefore be consistent with many different patterns of transmission. Second, data are often highly dependent: the colonization status of one patient affects the risk for others, and, in some wards, repeated admissions are common. Here, the authors present a method for analyzing typical nosocomial infection data consisting of results from arbitrarily timed screening swabs that overcomes these problems and enables simultaneous estimation of transmission and importation parameters, duration of colonization, swab sensitivity, and ward- and patient-level covariates. The method accounts for dependencies by using a mechanistic stochastic transmission model, and it allows for uncertainty in the data by imputing the imperfectly observed colonization status of patients over repeated admissions. The approach uses a Markov chain Monte Carlo algorithm, allowing inference within a Bayesian framework. The method is applied to illustrative data from an interrupted time-series study of vancomycin-resistant enterococci transmission in a hematology ward.

Barnett AG, Graves N, Cooper BS, Batra R, Edgeworth JD. 2008. Hospitals are dangerous places. Med J Aust, 189 (11-12), pp. 672. | Show Abstract

OBJECTIVE: To estimate the effect of day of the week on the odds of being discharged alive from an intensive care unit (ICU). DESIGN: A longitudinal analysis of risk of discharge by day of the week. SETTING AND PATIENTS: 4569 patients admitted to the ICU of St Thomas' Hospital, London, from 2002 to 2006. RESULTS: The odds of being discharged alive were lowest on the weekend and literally climbed during the week. CONCLUSION: Our results show a frightening pattern of discharge from an ICU ward, most likely caused by a complex web of specialist availability and patient demand.

Wilson AP, Ostro P, Magnussen M, Cooper B, Keyboard Study Group. 2008. Laboratory and in-use assessment of methicillin-resistant Staphylococcus aureus contamination of ergonomic computer keyboards for ward use. Am J Infect Control, 36 (10), pp. e19-e25. | Show Abstract | Read more

BACKGROUND: An ideal computer keyboard for clinical use would be easily cleanable and cleaned by staff, meet acceptable levels of usability, and not attract hospital bacteria. METHODS: In vitro studies were performed to demonstrate bacterial transfer between keyboard surfaces and gloves. This was followed by a usability study and a controlled trial of keyboard contamination in an intensive care unit both with and without an alarm to indicate the need for cleaning. Eight cleanable keyboards were placed at random beds and compared with standard keyboards. RESULTS: Bacteria were most easily removed from a flat silicone-coated surface. The total viable count on flat keyboards with an alarm was lower than that on standard or other cleanable keyboards (median, 19 colony-forming units [cfu] (interquartile range, 7 to 40 cfu), n = 34; 65 cfu (33 to 140 cfu), n = 50; and 40 cfu (21 to 57 cfu), n = 80). Compliance with hand hygiene before touching the standard keyboard was 27%, but the alarmed keyboard was cleaned on 87% of occasions on which the alarm was triggered. The usability study found the flat profile of the cleanable keyboard did not interfere with routine use, except for touch-typing. CONCLUSION: The flat keyboard with an alarm is easy to clean, and it use is associated with better cleaning compliance.

White RG, Ben SC, Kedhar A, Orroth KK, Biraro S, Baggaley RF, Whitworth J, Korenromp EL, Ghani A, Boily MC, Hayes RJ. 2007. Quantifying HIV-1 transmission due to contaminated injections. Proc Natl Acad Sci U S A, 104 (23), pp. 9794-9799. | Show Abstract | Read more

Assessments of the importance of different routes of HIV-1 (HIV) transmission are vital for prioritization of control efforts. Lack of consistent direct data and large uncertainty in the risk of HIV transmission from HIV-contaminated injections has made quantifying the proportion of transmission caused by contaminated injections in sub-Saharan Africa difficult and unavoidably subjective. Depending on the risk assumed, estimates have ranged from 2.5% to 30% or more. We present a method based on an age-structured transmission model that allows the relative contribution of HIV-contaminated injections, and other routes of HIV transmission, to be robustly estimated, both fully quantifying and substantially reducing the associated uncertainty. To do this, we adopt a Bayesian perspective, and show how prior beliefs regarding the safety of injections and the proportion of HIV incidence due to contaminated injections should, in many cases, be substantially modified in light of age-stratified incidence and injection data, resulting in improved (posterior) estimates. Applying the method to data from rural southwest Uganda, we show that the highest estimates of the proportion of incidence due to injections are reduced from 15.5% (95% credible interval) (0.7%, 44.9%) to 5.2% (0.5%, 17.0%) if random mixing is assumed, and from 14.6% (0.7%, 42.5%) to 11.8% (1.2%, 32.5%) under assortative mixing. Lower, and more widely accepted, estimates remain largely unchanged, between 1% and 3% (0.1-6.3%). Although important uncertainty remains, our analysis shows that in rural Uganda, contaminated injections are unlikely to account for a large proportion of HIV incidence. This result is likely to be generalizable to many other populations in sub-Saharan Africa.

Stone SP, Cooper BS, Kibbler CC, Cookson BD, Roberts JA, Medley GF, Duckworth G, Lai R et al. 2007. The ORION statement: guidelines for transparent reporting of outbreak reports and intervention studies of nosocomial infection. J Antimicrob Chemother, 59 (5), pp. 833-840. | Show Abstract | Read more

The quality of research in hospital epidemiology (infection control) must be improved to be robust enough to influence policy and practice. In order to raise the standards of research and publication, a CONSORT equivalent for these largely quasi-experimental studies has been prepared by the authors of two relevant systematic reviews, following consultation with learned societies, editors of journals and researchers. It consists of a 22 item checklist, and a summary table. The emphasis is on transparency to improve the quality of reporting and on the use of appropriate statistical techniques. The statement has been endorsed by a number of professional special interest groups and societies. Like CONSORT, ORION should be considered a 'work in progress', which requires ongoing dialogue for successful promotion and dissemination. The statement is therefore offered for further public discussion. Journals and research councils are strongly recommended to incorporate it into their submission and reviewing processes. Feedback to the authors is encouraged and the statement will be revised in 2 years.

Stone SP, Cooper BS, Kibbler CC, Cookson BD, Roberts JA, Medley GF, Duckworth G, Lai R et al. 2007. The ORION statement: guidelines for transparent reporting of outbreak reports and intervention studies of nosocomial infection. Lancet Infect Dis, 7 (4), pp. 282-288. | Show Abstract | Read more

The quality of research in hospital epidemiology (infection control) must be improved to be robust enough to influence policy and practice. In order to raise the standards of research and publication, a CONSORT equivalent for these largely quasi-experimental studies has been prepared by the authors of two relevant systematic reviews, following consultation with learned societies, editors of journals, and researchers. The ORION (Outbreak Reports and Intervention Studies Of Nosocomial infection) statement consists of a 22 item checklist, and a summary table. The emphasis is on transparency to improve the quality of reporting and on the use of appropriate statistical techniques. The statement has been endorsed by a number of professional special interest groups and societies. Like CONSORT, ORION should be considered a "work in progress", which requires ongoing dialogue for successful promotion and dissemination. The statement is therefore offered for further public discussion. Journals and research councils are strongly recommended to incorporate it into their submission and reviewing processes. Feedback to the authors is encouraged and the statement will be revised in 2 years.

McBryde ES, Pettitt AN, Cooper BS, McElwain DL. 2007. Characterizing an outbreak of vancomycin-resistant enterococci using hidden Markov models. J R Soc Interface, 4 (15), pp. 745-754. | Show Abstract | Read more

BACKGROUND: Antibiotic-resistant nosocomial pathogens can arise in epidemic clusters or sporadically. Genotyping is commonly used to distinguish epidemic from sporadic vancomycin-resistant enterococci (VRE). We compare this to a statistical method to determine the transmission characteristics of VRE. METHODS AND FINDINGS: A structured continuous-time hidden Markov model (HMM) was developed. The hidden states were the number of VRE-colonized patients (both detected and undetected). The input for this study was weekly point-prevalence data; 157 weeks of VRE prevalence. We estimated two parameters: one to quantify the cross-transmission of VRE and the other to quantify the level of VRE colonization from sporadic sources. We compared the results to those obtained by concomitant genotyping and phenotyping. We estimated that 89% of transmissions were due to ward cross-transmission while 11% were sporadic. Genotyping found that 90% had identical glycopeptide resistance genes and 84% were identical or nearly identical on pulsed-field gel electrophoresis (PFGE). There was some evidence, based on model selection criteria, that the cross-transmission parameter changed throughout the study period. The model that allowed for a change in transmission just prior to the outbreak and again at the peak of the outbreak was superior to other models. This model estimated that cross-transmission increased at week 120 and declined after week 135, coinciding with environmental decontamination. SIGNIFICANCE: We found that HMMs can be applied to serial prevalence data to estimate the characteristics of acquisition of nosocomial pathogens and distinguish between epidemic and sporadic acquisition. This model was able to estimate transmission parameters despite imperfect detection of the organism. The results of this model were validated against PFGE and glycopeptide resistance genotype data and produced very similar results. Additionally, HMMs can provide information about unobserved events such as undetected colonization.

Stone S, Slade R, Fuller C, McAteer J, Cookson B, Teare L, Jeanes A, Cooper B et al. 2007. Cleanyourhands Campaign: a critique of the critique. J Hosp Infect, 66 (3), pp. 288-289. | Read more

Cooper BS. 2007. Confronting models with data. J Hosp Infect, 65 Suppl 2 pp. 88-92. | Show Abstract | Read more

Until now, most of the mathematical modelling work on nosocomial infections has used simple models that have permitted qualitative, but not reliable quantitative predictions about the likely effect of different interventions. Increasingly, researchers would like to use models to provide reliable quantitative answers to both scientific and policy questions. This requires confronting models with data. Here, we discuss the importance of this confrontation with data with reference to previous modelling work, and outline the standard methods for doing this. We then describe a powerful new set of tools that promises to allow us to provide better answers to such questions, making far greater use than current methods of the information content of highly detailed hospital infection datasets. These tools should allow us to address questions that would have been impossible to answer using previous analytical techniques.

Stone S, Slade R, Fuller C, Charlett A, Cookson B, Teare L, Jeanes A, Cooper B et al. 2007. Early communication: does a national campaign to improve hand hygiene in the NHS work? Initial English and Welsh experience from the NOSEC study (National Observational Study to Evaluate the CleanYourHandsCampaign). J Hosp Infect, 66 (3), pp. 293-296. | Read more

Cooper BS, Cookson BD, Davey PG, Stone SP. 2007. Introducing the ORION Statement, a CONSORT equivalent for infection control studies. J Hosp Infect, 65 Suppl 2 (SUPPL. 2), pp. 85-87. | Read more

Fowler S, Webber A, Cooper BS, Phimister A, Price K, Carter Y, Kibbler CC, Simpson AJ, Stone SP. 2007. Successful use of feedback to improve antibiotic prescribing and reduce Clostridium difficile infection: a controlled interrupted time series. J Antimicrob Chemother, 59 (5), pp. 990-995. | Show Abstract | Read more

OBJECTIVES: To investigate the effect of reinforcing a narrow-spectrum antibiotic policy on antibiotic prescription and Clostridium difficile infection (CDI) rates by feedback of antibiotic use to doctors, as part of a departmental audit and feedback programme. DESIGN: A prospective controlled interrupted time-series (ITS) study, with pre-defined pre- and post-intervention periods, each of 21 months. SETTING: Three acute medical wards for elderly people in a teaching hospital. PARTICIPANTS: Six thousand one hundred and twenty-nine consecutive unselected acute medical admissions aged >or=80 years. INTERVENTIONS: A 'narrow-spectrum' antibiotic policy (reinforced by an established programme of audit and feedback of antibiotic usage and CDI rates) was introduced, following an unplanned rise in amoxicillin/clavulanate (Augmentin) use. It targeted broad-spectrum antibiotics for reduction (cephalosporins and amoxicillin/clavulanate) and narrow-spectrum antibiotics for increase (benzyl penicillin, amoxicillin and trimethoprim). Changes in the use of targeted antibiotics (intervention group) were compared with those of untargeted antibiotics (control group) using segmented regression analysis. Changes in CDI rates were examined by the Poisson regression model. Methicillin-resistant Staphylococcus aureus (MRSA) acquisition rates acted as an additional control. RESULTS: There was a reduction in the use of all targeted broad-spectrum antibiotics and an increase in all targeted narrow-spectrum antibiotics, statistically significant for sudden change and/or linear trend. All other antibiotic use remained unchanged. CDI rates fell with incidence rate ratios of 0.35 (0.17, 0.73) (P=0.009). MRSA incidence did not change [0.79 (0.49, 1.28); P=0.32]. CONCLUSIONS: This is the first controlled prospective ITS study to use feedback to reinforce antibiotic policy and reduce CDI. Multicentre ITS or cluster randomized trials of this and other methods need to be undertaken to establish the most effective means of optimizing antibiotic use and reducing CDI.

McAteer J, Stone S, Roberts J, Michie S, FIT study team, Fuller C, Slade R, Charlett A et al. 2007. Use of performance feedback to increase healthcare worker hand-hygiene behaviour. J Hosp Infect, 66 (3), pp. 291-292. | Read more

Cooper B. 2006. Poxy models and rash decisions. Proc Natl Acad Sci U S A, 103 (33), pp. 12221-12222. | Read more

Cooper BS, Pitman RJ, Edmunds WJ, Gay NJ. 2006. Delaying the international spread of pandemic influenza. PLoS Med, 3 (6), pp. e212. | Show Abstract | Read more

BACKGROUND: The recent emergence of hypervirulent subtypes of avian influenza has underlined the potentially devastating effects of pandemic influenza. Were such a virus to acquire the ability to spread efficiently between humans, control would almost certainly be hampered by limited vaccine supplies unless global spread could be substantially delayed. Moreover, the large increases that have occurred in international air travel might be expected to lead to more rapid global dissemination than in previous pandemics. METHODS AND FINDINGS: To evaluate the potential of local control measures and travel restrictions to impede global dissemination, we developed stochastic models of the international spread of influenza based on extensions of coupled epidemic transmission models. These models have been shown to be capable of accurately forecasting local and global spread of epidemic and pandemic influenza. We show that under most scenarios restrictions on air travel are likely to be of surprisingly little value in delaying epidemics, unless almost all travel ceases very soon after epidemics are detected. CONCLUSIONS: Interventions to reduce local transmission of influenza are likely to be more effective at reducing the rate of global spread and less vulnerable to implementation delays than air travel restrictions. Nevertheless, under the most plausible scenarios, achievable delays are small compared with the time needed to accumulate substantial vaccine stocks.

Pitman RJ, Cooper BS, Trotter CL, Gay NJ, Edmunds WJ. 2005. Entry screening for severe acute respiratory syndrome (SARS) or influenza: policy evaluation. BMJ, 331 (7527), pp. 1242-1243. | Read more

Cepeda JA, Whitehouse T, Cooper B, Hails J, Jones K, Kwaku F, Taylor L, Hayman S et al. 2005. Isolation of patients in single rooms or cohorts to reduce spread of MRSA in intensive-care units: prospective two-centre study. Lancet, 365 (9456), pp. 295-304. | Show Abstract | Read more

BACKGROUND: Hospital-acquired infection due to meticillin-resistant Staphylococcus aureus (MRSA) is common within intensive-care units. Single room or cohort isolation of infected or colonised patients is used to reduce spread, but its benefit over and above other contact precautions is not known. We aimed to assess the effectiveness of moving versus not moving infected or colonised patients in intensive-care units to prevent transmission of MRSA. METHODS: We undertook a prospective 1-year study in the intensive-care units of two teaching hospitals. Admission and weekly screens were used to ascertain the incidence of MRSA colonisation. In the middle 6 months, MRSA-positive patients were not moved to a single room or cohort nursed unless they were carrying other multiresistant or notifiable pathogens. Standard precautions were practised throughout. Hand hygiene was encouraged and compliance audited. FINDINGS: Patients' characteristics and MRSA acquisition rates were similar in the periods when patients were moved and not moved. The crude (unadjusted) Cox proportional-hazards model showed no evidence of increased transmission during the non-move phase (0.73 [95% CI 0.49-1.10], p=0.94 one-sided). There were no changes in transmission of any particular strain of MRSA nor in handwashing frequency between management phases. INTERPRETATION: Moving MRSA-positive patients into single rooms or cohorted bays does not reduce crossinfection. Because transfer and isolation of critically ill patients in single rooms carries potential risks, our findings suggest that re-evaluation of isolation policies is required in intensive-care units where MRSA is endemic, and that more effective means of preventing spread of MRSA in such settings need to be found.

Cooper BS, Medley GF, Stone SP, Kibbler CC, Cookson BD, Roberts JA, Duckworth G, Lai R, Ebrahim S. 2004. Methicillin-resistant Staphylococcus aureus in hospitals and the community: stealth dynamics and control catastrophes. Proc Natl Acad Sci U S A, 101 (27), pp. 10223-10228. | Show Abstract | Read more

Methicillin-resistant Staphylococcus aureus (MRSA) represents a serious threat to the health of hospitalized patients. Attempts to reduce the spread of MRSA have largely depended on hospital hygiene and patient isolation. These measures have met with mixed success: although some countries have almost eliminated MRSA or remained largely free of the organism, others have seen substantial increases despite rigorous control policies. We use a mathematical model to show how these increases can be explained by considering both hospital and community reservoirs of MRSA colonization. We show how the timing of the intervention, the level of resource provision, and chance combine to determine whether control measures succeed or fail. We find that even control measures able to repeatedly prevent sustained outbreaks in the short-term can result in long-term control failure resulting from gradual increases in the community reservoir. If resources do not scale with MRSA prevalence, isolation policies can fail "catastrophically."

Cooper B, Lipsitch M. 2004. The analysis of hospital infection data using hidden Markov models. Biostatistics, 5 (2), pp. 223-237. | Show Abstract | Read more

Surveillance data for communicable nosocomial pathogens usually consist of short time series of low-numbered counts of infected patients. These often show overdispersion and autocorrelation. To date, almost all analyses of such data have ignored the communicable nature of the organisms and have used methods appropriate only for independent outcomes. Inferences that depend on such analyses cannot be considered reliable when patient-to-patient transmission is important. We propose a new method for analysing these data based on a mechanistic model of the epidemic process. Since important nosocomial pathogens are often carried asymptomatically with overt infection developing in only a proportion of patients, the epidemic process is usually only partially observed by routine surveillance data. We therefore develop a 'structured' hidden Markov model where the underlying Markov chain is generated by a simple transmission model. We apply both structured and standard (unstructured) hidden Markov models to time series for three important pathogens. We find that both methods can offer marked improvements over currently used approaches when nosocomial spread is important. Compared to the standard hidden Markov model, the new approach is more parsimonious, is more biologically plausible, and allows key epidemiological parameters to be estimated.

Cooper BS, Stone SP, Kibbler CC, Cookson BD, Roberts JA, Medley GF, Duckworth G, Lai R, Ebrahim S. 2004. Isolation measures in the hospital management of methicillin resistant Staphylococcus aureus (MRSA): systematic review of the literature. BMJ, 329 (7465), pp. 533. | Show Abstract | Read more

OBJECTIVE: To evaluate the evidence for the effectiveness of isolation measures in reducing the incidence of methicillin resistant Staphylococcus aureus (MRSA) colonisation and infection in hospital inpatients. DESIGN: Systematic review of published articles. DATA SOURCES: Medline, Embase, CINAHL, Cochrane Library, System for Information on Grey Literature in Europe (SIGLE), and citation lists (1966-2000). REVIEW METHODS: Articles reporting MRSA related outcomes and describing an isolation policy were selected. No quality restrictions were imposed on studies using isolation wards or nurse cohorting. Other studies were included if they were prospective or employed planned comparisons of retrospective data. RESULTS: 46 studies were accepted; 18 used isolation wards, nine used nurse cohorting, and 19 used other isolation policies. Most were interrupted time series, with few planned formal prospective studies. All but one reported multiple interventions. Consideration of potential confounders, measures to prevent bias, and appropriate statistical analysis were mostly lacking. No conclusions could be drawn in a third of studies. Most others provided evidence consistent with a reduction of MRSA acquisition. Six long interrupted time series provided the strongest evidence. Four of these provided evidence that intensive control measures including patient isolation were effective in controlling MRSA. In two others, isolation wards failed to prevent endemic MRSA. CONCLUSION: Major methodological weaknesses and inadequate reporting in published research mean that many plausible alternative explanations for reductions in MRSA acquisition associated with interventions cannot be excluded. No well designed studies exist that allow the role of isolation measures alone to be assessed. None the less, there is evidence that concerted efforts that include isolation can reduce MRSA even in endemic settings. Current isolation measures recommended in national guidelines should continue to be applied until further research establishes otherwise.

Lipsitch M, Cohen T, Cooper B, Robins JM, Ma S, James L, Gopalakrishna G, Chew SK et al. 2003. Transmission dynamics and control of severe acute respiratory syndrome. Science, 300 (5627), pp. 1966-1970. | Show Abstract | Read more

Severe acute respiratory syndrome (SARS) is a recently described illness of humans that has spread widely over the past 6 months. With the use of detailed epidemiologic data from Singapore and epidemic curves from other settings, we estimated the reproductive number for SARS in the absence of interventions and in the presence of control efforts. We estimate that a single infectious case of SARS will infect about three secondary cases in a population that has not yet instituted control measures. Public-health efforts to reduce transmission are expected to have a substantial impact on reducing the size of the epidemic.

Cooper BS, Stone SR, Kibbler CC, Cookson BD, Roberts JA, Medley GF, Duckworth GJ, Lai R, Ebrahim S. 2005. Systematic review of isolation policies in the hospital management of methicillin-resistant Staphylococcus aureus: A review of the literature with epidemiological and economic modeling INTERNATIONAL JOURNAL OF TECHNOLOGY ASSESSMENT IN HEALTH CARE, 21 (1), pp. 146-146.

Trzcinski K, Cooper BS, Hryniewicz W, Dowson CG. 2000. Expression of resistance to tetracyclines in strains of methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother, 45 (6), pp. 763-770. | Show Abstract | Read more

A diverse collection of methicillin-resistant Staphylococcus aureus (MRSA) isolates resistant to tetracycline was screened by PCR for the presence of the resistance determinants tetK, tetL, tetM or tetO. Twenty-four of 66 isolates had tetM alone, 21 had tetK alone and 21 had both tetK and tetM (tetKM). All isolates were tetL- and tetO-negative. MICs of tetracycline, doxycycline and minocycline were evaluated for all isolates with or without preincubation in the presence of subinhibitory concentrations of tetracycline or minocycline. All isolates with one or more tetracycline resistance determinants were resistant to tetracycline 8 mg/L without induction of resistance. Some MRSA isolates of each of these three genotypes showed an unexpected lack of resistance to tetracyclines when the disc diffusion or agar dilution method was applied to uninduced cells. Resistance to tetracycline and doxycycline was greater (two- to four-fold) in tetK cells preincubated with tetracycline (tetK MRSA isolates were susceptible to minocycline </=0.25 mg/L under all conditions tested). For isolates with tetM alone, preincubation with tetracycline or minocycline gave up to a four-fold increase in the level of resistance to doxycycline and minocycline. Induction of doxycycline and minocycline resistance was clearly observed for tetKM isolates when cells were preincubated with minocycline. This study suggests that, despite the results of susceptibility testing, all tetracycline-resistant S. aureus isolates should be treated as resistant to doxycycline, and all tetM-positive isolates should be treated as resistant to all tetracyclines. A double disc diffusion method has been developed to identify inducible resistance to minocycline and to distinguish between tetK, tetM and tetKM isolates.

Cooper BS, Medley GF, Scott GM. 1999. Preliminary analysis of the transmission dynamics of nosocomial infections: stochastic and management effects. J Hosp Infect, 43 (2), pp. 131-147. | Show Abstract | Read more

A simple mathematical model is developed for the spread of hand-borne nosocomial pathogens such as Staphylococcus aureus within a general medical-surgical ward. In contrast to previous models a stochastic approach is used. Computer simulations are used to explore the properties of the model, and the results are presented in terms of the pathogen's successful introduction rate, ward-level prevalence, and colonized patient-days, emphasizing the general effects of changes in management of patients and carers. Small changes in the transmissibility of the organism resulted in large changes in all three measures. Even small increases in the frequency of effective handwashes were enough to bring endemic organisms under control. Reducing the number of colonized patients admitted to the ward was also an effective control measure across a wide range of different situations. Increasing surveillance activities had little effect on the successful introduction rate but gave an almost linear reduction in colonized patient-days and ward-level prevalence. Shorter lengths of patient stay were accompanied by higher successful introduction rates, but had little effect on the other measures unless the mean time before detection of a colonized individual was large compared to the mean length of stay. We conclude that chance effects are likely to be amongst the most important factors in determining the course of an outbreak. Mathematical models can provide valuable insights into the non-linear interactions between a small number of processes, but for the very small populations found in hospital wards, a stochastic approach is essential.

Wei Y, Kypraios T, O'Neill PD, Huang SS, Rifas-Shiman SL, Cooper BS. 2016. Evaluating hospital infection control measures for antimicrobial-resistant pathogens using stochastic transmission models: Application to vancomycin-resistant enterococci in intensive care units. Stat Methods Med Res, | Show Abstract | Read more

Nosocomial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) are the cause of significant morbidity and mortality among hospital patients. It is important to be able to assess the efficacy of control measures using data on patient outcomes. In this paper, we describe methods for analysing such data using patient-level stochastic models which seek to describe the underlying unobserved process of transmission. The methods are applied to detailed longitudinal patient-level data on vancomycin-resistant Enterococci from a study in a US hospital with eight intensive care units (ICUs). The data comprise admission and discharge dates, dates and results of screening tests, and dates during which precautionary measures were in place for each patient during the study period. Results include estimates of the efficacy of the control measures, the proportion of unobserved patients colonized with vancomycin-resistant Enterococci, and the proportion of patients colonized on admission.

Tosas Auguet O, Betley JR, Stabler RA, Patel A, Ioannou A, Marbach H, Hearn P, Aryee A et al. 2016. Evidence for Community Transmission of Community-Associated but Not Health-Care-Associated Methicillin-Resistant Staphylococcus Aureus Strains Linked to Social and Material Deprivation: Spatial Analysis of Cross-sectional Data. PLoS Med, 13 (1), pp. e1001944. | Show Abstract | Read more

BACKGROUND: Identifying and tackling the social determinants of infectious diseases has become a public health priority following the recognition that individuals with lower socioeconomic status are disproportionately affected by infectious diseases. In many parts of the world, epidemiologically and genotypically defined community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) strains have emerged to become frequent causes of hospital infection. The aim of this study was to use spatial models with adjustment for area-level hospital attendance to determine the transmission niche of genotypically defined CA- and health-care-associated (HA)-MRSA strains across a diverse region of South East London and to explore a potential link between MRSA carriage and markers of social and material deprivation. METHODS AND FINDINGS: This study involved spatial analysis of cross-sectional data linked with all MRSA isolates identified by three National Health Service (NHS) microbiology laboratories between 1 November 2011 and 29 February 2012. The cohort of hospital-based NHS microbiology diagnostic services serves 867,254 usual residents in the Lambeth, Southwark, and Lewisham boroughs in South East London, United Kingdom (UK). Isolates were classified as HA- or CA-MRSA based on whole genome sequencing. All MRSA cases identified over 4 mo within the three-borough catchment area (n = 471) were mapped to small geographies and linked to area-level aggregated socioeconomic and demographic data. Disease mapping and ecological regression models were used to infer the most likely transmission niches for each MRSA genetic classification and to describe the spatial epidemiology of MRSA in relation to social determinants. Specifically, we aimed to identify demographic and socioeconomic population traits that explain cross-area extra variation in HA- and CA-MRSA relative risks following adjustment for hospital attendance data. We explored the potential for associations with the English Indices of Deprivation 2010 (including the Index of Multiple Deprivation and several deprivation domains and subdomains) and the 2011 England and Wales census demographic and socioeconomic indicators (including numbers of households by deprivation dimension) and indicators of population health. Both CA-and HA-MRSA were associated with household deprivation (CA-MRSA relative risk [RR]: 1.72 [1.03-2.94]; HA-MRSA RR: 1.57 [1.06-2.33]), which was correlated with hospital attendance (Pearson correlation coefficient [PCC] = 0.76). HA-MRSA was also associated with poor health (RR: 1.10 [1.01-1.19]) and residence in communal care homes (RR: 1.24 [1.12-1.37]), whereas CA-MRSA was linked with household overcrowding (RR: 1.58 [1.04-2.41]) and wider barriers, which represent a combined score for household overcrowding, low income, and homelessness (RR: 1.76 [1.16-2.70]). CA-MRSA was also associated with recent immigration to the UK (RR: 1.77 [1.19-2.66]). For the area-level variation in RR for CA-MRSA, 28.67% was attributable to the spatial arrangement of target geographies, compared with only 0.09% for HA-MRSA. An advantage to our study is that it provided a representative sample of usual residents receiving care in the catchment areas. A limitation is that relationships apparent in aggregated data analyses cannot be assumed to operate at the individual level. CONCLUSIONS: There was no evidence of community transmission of HA-MRSA strains, implying that HA-MRSA cases identified in the community originate from the hospital reservoir and are maintained by frequent attendance at health care facilities. In contrast, there was a high risk of CA-MRSA in deprived areas linked with overcrowding, homelessness, low income, and recent immigration to the UK, which was not explainable by health care exposure. Furthermore, areas adjacent to these deprived areas were themselves at greater risk of CA-MRSA, indicating community transmission of CA-MRSA. This ongoing community transmission could lead to CA-MRSA becoming the dominant strain types carried by patients admitted to hospital, particularly if successful hospital-based MRSA infection control programmes are maintained. These results suggest that community infection control programmes targeting transmission of CA-MRSA will be required to control MRSA in both the community and hospital. These epidemiological changes will also have implications for effectiveness of risk-factor-based hospital admission MRSA screening programmes.

Worby CJ, O'Neill PD, Kypraios T, Robotham JV, De Angelis D, Cartwright EJ, Peacock SJ, Cooper BS. 2016. Reconstructing transmission trees for communicable diseases using densely sampled genetic data. Ann Appl Stat, 10 (1), pp. 395-417. | Show Abstract | Read more

Whole genome sequencing of pathogens from multiple hosts in an epidemic offers the potential to investigate who infected whom with unparalleled resolution, potentially yielding important insights into disease dynamics and the impact of control measures. We considered disease outbreaks in a setting with dense genomic sampling, and formulated stochastic epidemic models to investigate person-to-person transmission, based on observed genomic and epidemiological data. We constructed models in which the genetic distance between sampled genotypes depends on the epidemiological relationship between the hosts. A data augmented Markov chain Monte Carlo algorithm was used to sample over the transmission trees, providing a posterior probability for any given transmission route. We investigated the predictive performance of our methodology using simulated data, demonstrating high sensitivity and specificity, particularly for rapidly mutating pathogens with low transmissibility. We then analyzed data collected during an outbreak of methicillin-resistant Staphylococcus aureus in a hospital, identifying probable transmission routes and estimating epidemiological parameters. Our approach overcomes limitations of previous methods, providing a framework with the flexibility to allow for unobserved infection times, multiple independent introductions of the pathogen, and within-host genetic diversity, as well as allowing forward simulation.

Lim C, Paris DH, Blacksell SD, Laongnualpanich A, Kantipong P, Chierakul W, Wuthiekanun V, Day NP, Cooper BS, Limmathurotsakul D. 2015. How to Determine the Accuracy of an Alternative Diagnostic Test when It Is Actually Better than the Reference Tests: A Re-Evaluation of Diagnostic Tests for Scrub Typhus Using Bayesian LCMs. PLoS One, 10 (5), pp. e0114930. | Show Abstract | Read more

BACKGROUND: The indirect immunofluorescence assay (IFA) is considered a reference test for scrub typhus. Recently, the Scrub Typhus Infection Criteria (STIC; a combination of culture, PCR assays and IFA IgM) were proposed as a reference standard for evaluating alternative diagnostic tests. Here, we use Bayesian latent class models (LCMs) to estimate the true accuracy of each diagnostic test, and of STIC, for diagnosing scrub typhus. METHODS/PRINCIPAL FINDINGS: Data from 161 patients with undifferentiated fever were re-evaluated using Bayesian LCMs. Every patient was evaluated for the presence of an eschar, and tested with blood culture for Orientia tsutsugamushi, three different PCR assays, IFA IgM, and the Panbio IgM immunochromatographic test (ICT). True sensitivity and specificity of culture (24.4% and 100%), 56kDa PCR assay (56.8% and 98.4%), 47kDa PCR assay (63.2% and 96.1%), groEL PCR assay (71.4% and 93.0%), IFA IgM (70.0% and 83.8%), PanBio IgM ICT (72.8% and 96.8%), presence of eschar (42.7% and 98.9%) and STIC (90.5% and 82.5%) estimated by Bayesian LCM were considerably different from those obtained when using STIC as a reference standard. The IgM ICT had comparable sensitivity and significantly higher specificity compared to IFA (p=0.34 and p<0.001, respectively). CONCLUSIONS: The low specificity of STIC was caused by the low specificity of IFA IgM. Neither STIC nor IFA IgM can be used as reference standards against which to evaluate alternative diagnostic tests. Further evaluation of new diagnostic tests should be done with a carefully selected set of diagnostic tests and appropriate statistical models.

Meeyai A, Praditsitthikorn N, Kotirum S, Kulpeng W, Putthasri W, Cooper BS, Teerawattananon Y. 2015. Seasonal influenza vaccination for children in Thailand: a cost-effectiveness analysis. PLoS Med, 12 (5), pp. e1001829. | Show Abstract | Read more

BACKGROUND: Seasonal influenza is a major cause of mortality worldwide. Routine immunization of children has the potential to reduce this mortality through both direct and indirect protection, but has not been adopted by any low- or middle-income countries. We developed a framework to evaluate the cost-effectiveness of influenza vaccination policies in developing countries and used it to consider annual vaccination of school- and preschool-aged children with either trivalent inactivated influenza vaccine (TIV) or trivalent live-attenuated influenza vaccine (LAIV) in Thailand. We also compared these approaches with a policy of expanding TIV coverage in the elderly. METHODS AND FINDINGS: We developed an age-structured model to evaluate the cost-effectiveness of eight vaccination policies parameterized using country-level data from Thailand. For policies using LAIV, we considered five different age groups of children to vaccinate. We adopted a Bayesian evidence-synthesis framework, expressing uncertainty in parameters through probability distributions derived by fitting the model to prospectively collected laboratory-confirmed influenza data from 2005-2009, by meta-analysis of clinical trial data, and by using prior probability distributions derived from literature review and elicitation of expert opinion. We performed sensitivity analyses using alternative assumptions about prior immunity, contact patterns between age groups, the proportion of infections that are symptomatic, cost per unit vaccine, and vaccine effectiveness. Vaccination of children with LAIV was found to be highly cost-effective, with incremental cost-effectiveness ratios between about 2,000 and 5,000 international dollars per disability-adjusted life year averted, and was consistently preferred to TIV-based policies. These findings were robust to extensive sensitivity analyses. The optimal age group to vaccinate with LAIV, however, was sensitive both to the willingness to pay for health benefits and to assumptions about contact patterns between age groups. CONCLUSIONS: Vaccinating school-aged children with LAIV is likely to be cost-effective in Thailand in the short term, though the long-term consequences of such a policy cannot be reliably predicted given current knowledge of influenza epidemiology and immunology. Our work provides a coherent framework that can be used for similar analyses in other low- and middle-income countries.

Cooper BS, Kotirum S, Kulpeng W, Praditsitthikorn N, Chittaganpitch M, Limmathurotsakul D, Day NP, Coker R, Teerawattananon Y, Meeyai A. 2015. Mortality attributable to seasonal influenza A and B infections in Thailand, 2005-2009: a longitudinal study. Am J Epidemiol, 181 (11), pp. 898-907. | Show Abstract | Read more

Influenza epidemiology differs substantially in tropical and temperate zones, but estimates of seasonal influenza mortality in developing countries in the tropics are lacking. We aimed to quantify mortality due to seasonal influenza in Thailand, a tropical middle-income country. Time series of polymerase chain reaction-confirmed influenza infections between 2005 and 2009 were constructed from a sentinel surveillance network. These were combined with influenza-like illness data to derive measures of influenza activity and relationships to mortality by using a Bayesian regression framework. We estimated 6.1 (95% credible interval: 0.5, 12.4) annual deaths per 100,000 population attributable to influenza A and B, predominantly in those aged ≥60 years, with the largest contribution from influenza A(H1N1) in 3 out of 4 years. For A(H3N2), the relationship between influenza activity and mortality varied over time. Influenza was associated with increases in deaths classified as resulting from respiratory disease (posterior probability of positive association, 99.8%), cancer (98.6%), renal disease (98.0%), and liver disease (99.2%). No association with circulatory disease mortality was found. Seasonal influenza infections are associated with substantial mortality in Thailand, but evidence for the strong relationship between influenza activity and circulatory disease mortality reported in temperate countries is lacking.

Cooper BS, Boni MF, Pan-ngum W, Day NP, Horby PW, Olliaro P, Lang T, White NJ, White LJ, Whitehead J. 2015. Evaluating clinical trial designs for investigational treatments of Ebola virus disease. PLoS Med, 12 (4), pp. e1001815. | Show Abstract | Read more

BACKGROUND: Experimental treatments for Ebola virus disease (EVD) might reduce EVD mortality. There is uncertainty about the ability of different clinical trial designs to identify effective treatments, and about the feasibility of implementing individually randomised controlled trials during an Ebola epidemic. METHODS AND FINDINGS: A treatment evaluation programme for use in EVD was devised using a multi-stage approach (MSA) with two or three stages, including both non-randomised and randomised elements. The probabilities of rightly or wrongly recommending the experimental treatment, the required sample size, and the consequences for epidemic outcomes over 100 d under two epidemic scenarios were compared for the MSA, a sequential randomised controlled trial (SRCT) with up to 20 interim analyses, and, as a reference case, a conventional randomised controlled trial (RCT) without interim analyses. Assuming 50% 14-d survival in the population treated with the current standard of supportive care, all designs had similar probabilities of identifying effective treatments correctly, while the MSA was less likely to recommend treatments that were ineffective. The MSA led to a smaller number of cases receiving ineffective treatments and faster roll-out of highly effective treatments. For less effective treatments, the MSA had a high probability of including an RCT component, leading to a somewhat longer time to roll-out or rejection. Assuming 100 new EVD cases per day, the MSA led to between 6% and 15% greater reductions in epidemic mortality over the first 100 d for highly effective treatments compared to the SRCT. Both the MSA and SRCT led to substantially fewer deaths than a conventional RCT if the tested interventions were either highly effective or harmful. In the proposed MSA, the major threat to the validity of the results of the non-randomised components is that referral patterns, standard of care, or the virus itself may change during the study period in ways that affect mortality. Adverse events are also harder to quantify without a concurrent control group. CONCLUSIONS: The MSA discards ineffective treatments quickly, while reliably providing evidence concerning effective treatments. The MSA is appropriate for the clinical evaluation of EVD treatments.

Lee AS, Pan A, Harbarth S, Patroni A, Chalfine A, Daikos GL, Garilli S, Martínez JA, Cooper BS, MOSAR-04 Study Team. 2015. Variable performance of models for predicting methicillin-resistant Staphylococcus aureus carriage in European surgical wards. BMC Infect Dis, 15 (1), pp. 105. | Show Abstract | Read more

BACKGROUND: Predictive models to identify unknown methicillin-resistant Staphylococcus aureus (MRSA) carriage on admission may optimise targeted MRSA screening and efficient use of resources. However, common approaches to model selection can result in overconfident estimates and poor predictive performance. We aimed to compare the performance of various models to predict previously unknown MRSA carriage on admission to surgical wards. METHODS: The study analysed data collected during a prospective cohort study which enrolled consecutive adult patients admitted to 13 surgical wards in 4 European hospitals. The participating hospitals were located in Athens (Greece), Barcelona (Spain), Cremona (Italy) and Paris (France). Universal admission MRSA screening was performed in the surgical wards. Data regarding demographic characteristics and potential risk factors for MRSA carriage were prospectively collected during the study period. Four logistic regression models were used to predict probabilities of unknown MRSA carriage using risk factor data: "Stepwise" (variables selected by backward elimination); "Best BMA" (model with highest posterior probability using Bayesian model averaging which accounts for uncertainty in model choice); "BMA" (average of all models selected with BMA); and "Simple" (model including variables selected >50% of the time by both Stepwise and BMA approaches applied to repeated random sub-samples of 50% of the data). To assess model performance, cross-validation against data not used for model fitting was conducted and net reclassification improvement (NRI) was calculated. RESULTS: Of 2,901 patients enrolled, 111 (3.8%) were newly identified MRSA carriers. Recent hospitalisation and presence of a wound/ulcer were significantly associated with MRSA carriage in all models. While all models demonstrated limited predictive ability (mean c-statistics <0.7) the Simple model consistently detected more MRSA-positive individuals despite screening fewer patients than the Stepwise model. Moreover, the Simple model improved reclassification of patients into appropriate risk strata compared with the Stepwise model (NRI 6.6%, P = .07). CONCLUSIONS: Though commonly used, models developed using stepwise variable selection can have relatively poor predictive value. When developing MRSA risk indices, simpler models, which account for uncertainty in model selection, may better stratify patients' risk of unknown MRSA carriage.

Luangasanatip N, Hongsuwan M, Limmathurotsakul D, Lubell Y, Lee AS, Harbarth S, Day NP, Graves N, Cooper BS. 2015. Comparative efficacy of interventions to promote hand hygiene in hospital: systematic review and network meta-analysis. BMJ, 351 pp. h3728. | Show Abstract | Read more

OBJECTIVE: To evaluate the relative efficacy of the World Health Organization 2005 campaign (WHO-5) and other interventions to promote hand hygiene among healthcare workers in hospital settings and to summarize associated information on use of resources. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, Embase, CINAHL, NHS Economic Evaluation Database, NHS Centre for Reviews and Dissemination, Cochrane Library, and the EPOC register (December 2009 to February 2014); studies selected by the same search terms in previous systematic reviews (1980-2009). REVIEW METHODS: Included studies were randomised controlled trials, non-randomised trials, controlled before-after trials, and interrupted time series studies implementing an intervention to improve compliance with hand hygiene among healthcare workers in hospital settings and measuring compliance or appropriate proxies that met predefined quality inclusion criteria. When studies had not used appropriate analytical methods, primary data were re-analysed. Random effects and network meta-analyses were performed on studies reporting directly observed compliance with hand hygiene when they were considered sufficiently homogeneous with regard to interventions and participants. Information on resources required for interventions was extracted and graded into three levels. RESULTS: Of 3639 studies retrieved, 41 met the inclusion criteria (six randomised controlled trials, 32 interrupted time series, one non-randomised trial, and two controlled before-after studies). Meta-analysis of two randomised controlled trials showed the addition of goal setting to WHO-5 was associated with improved compliance (pooled odds ratio 1.35, 95% confidence interval 1.04 to 1.76; I(2)=81%). Of 22 pairwise comparisons from interrupted time series, 18 showed stepwise increases in compliance with hand hygiene, and all but four showed a trend for increasing compliance after the intervention. Network meta-analysis indicated considerable uncertainty in the relative effectiveness of interventions, but nonetheless provided evidence that WHO-5 is effective and that compliance can be further improved by adding interventions including goal setting, reward incentives, and accountability. Nineteen studies reported clinical outcomes; data from these were consistent with clinically important reductions in rates of infection resulting from improved hand hygiene for some but not all important hospital pathogens. Reported costs of interventions ranged from $225 to $4669 (£146-£3035; €204-€4229) per 1000 bed days. CONCLUSION: Promotion of hand hygiene with WHO-5 is effective at increasing compliance in healthcare workers. Addition of goal setting, reward incentives, and accountability strategies can lead to further improvements. Reporting of resources required for such interventions remains inadequate.

Tong SY, Holden MT, Nickerson EK, Cooper BS, Köser CU, Cori A, Jombart T, Cauchemez S et al. 2015. Genome sequencing defines phylogeny and spread of methicillin-resistant Staphylococcus aureus in a high transmission setting. Genome Res, 25 (1), pp. 111-118. | Show Abstract | Read more

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of nosocomial infection. Whole-genome sequencing of MRSA has been used to define phylogeny and transmission in well-resourced healthcare settings, yet the greatest burden of nosocomial infection occurs in resource-restricted settings where barriers to transmission are lower. Here, we study the flux and genetic diversity of MRSA on ward and individual patient levels in a hospital where transmission was common. We repeatedly screened all patients on two intensive care units for MRSA carriage over a 3-mo period. All MRSA belonged to multilocus sequence type 239 (ST 239). We defined the population structure and charted the spread of MRSA by sequencing 79 isolates from 46 patients and five members of staff, including the first MRSA-positive screen isolates and up to two repeat isolates where available. Phylogenetic analysis identified a flux of distinct ST 239 clades over time in each intensive care unit. In total, five main clades were identified, which varied in the carriage of plasmids encoding antiseptic and antimicrobial resistance determinants. Sequence data confirmed intra- and interwards transmission events and identified individual patients who were colonized by more than one clade. One patient on each unit was the source of numerous transmission events, and deep sampling of one of these cases demonstrated colonization with a "cloud" of related MRSA variants. The application of whole-genome sequencing and analysis provides novel insights into the transmission of MRSA in under-resourced healthcare settings and has relevance to wider global health.

Wolkewitz M, Cooper BS, Bonten MJ, Barnett AG, Schumacher M. 2014. Interpreting and comparing risks in the presence of competing events. BMJ, 349 (aug21 5), pp. g5060. | Read more

San Millan A, Peña-Miller R, Toll-Riera M, Halbert ZV, McLean AR, Cooper BS, MacLean RC. 2014. Positive selection and compensatory adaptation interact to stabilize non-transmissible plasmids. Nat Commun, 5 pp. 5208. | Show Abstract | Read more

Plasmids are important drivers of bacterial evolution, but it is challenging to understand how plasmids persist over the long term because plasmid carriage is costly. Classical models predict that horizontal transfer is necessary for plasmid persistence, but recent work shows that almost half of plasmids are non-transmissible. Here we use a combination of mathematical modelling and experimental evolution to investigate how a costly, non-transmissible plasmid, pNUK73, can be maintained in populations of Pseudomonas aeruginosa. Compensatory adaptation increases plasmid stability by eliminating the cost of plasmid carriage. However, positive selection for plasmid-encoded antibiotic resistance is required to maintain the plasmid by offsetting reductions in plasmid frequency due to segregational loss. Crucially, we show that compensatory adaptation and positive selection reinforce each other's effects. Our study provides a new understanding of how plasmids persist in bacterial populations, and it helps to explain why resistance can be maintained after antibiotic use is stopped.

Hongsuwan M, Srisamang P, Kanoksil M, Luangasanatip N, Jatapai A, Day NP, Peacock SJ, Cooper BS, Limmathurotsakul D. 2014. Increasing incidence of hospital-acquired and healthcare-associated bacteremia in northeast Thailand: a multicenter surveillance study. PLoS One, 9 (10), pp. e109324. | Show Abstract | Read more

BACKGROUND: Little is known about the epidemiology of nosocomial bloodstream infections in public hospitals in developing countries. We evaluated trends in incidence of hospital-acquired bacteremia (HAB) and healthcare-associated bacteremia (HCAB) and associated mortality in a developing country using routinely available databases. METHODS: Information from the microbiology and hospital databases of 10 provincial hospitals in northeast Thailand was linked with the national death registry for 2004-2010. Bacteremia was considered hospital-acquired if detected after the first two days of hospital admission, and healthcare-associated if detected within two days of hospital admission with a prior inpatient episode in the preceding 30 days. RESULTS: A total of 3,424 patients out of 1,069,443 at risk developed HAB and 2,184 out of 119,286 at risk had HCAB. Of these 1,559 (45.5%) and 913 (41.8%) died within 30 days, respectively. Between 2004 and 2010, the incidence rate of HAB increased from 0.6 to 0.8 per 1,000 patient-days at risk (p<0.001), and the cumulative incidence of HCAB increased from 1.2 to 2.0 per 100 readmissions (p<0.001). The most common causes of HAB were Acinetobacter spp. (16.2%), Klebsiella pneumoniae (13.9%), and Staphylococcus aureus (13.9%), while those of HCAB were Escherichia coli (26.3%), S. aureus (14.0%), and K. pneumoniae (9.7%). There was an overall increase over time in the proportions of ESBL-producing E. coli causing HAB and HCAB. CONCLUSIONS: This study demonstrates a high and increasing incidence of HAB and HCAB in provincial hospitals in northeast Thailand, increasing proportions of ESBL-producing isolates, and very high associated mortality.

Wolkewitz M, Cooper BS, Palomar-Martinez M, Olaechea-Astigarraga P, Alvarez-Lerma F, Schumacher M. 2014. Nested case-control studies in cohorts with competing events. Epidemiology, 25 (1), pp. 122-125. | Show Abstract | Read more

In nested case-control studies, incidence density sampling is the time-dependent matching procedure to approximate hazard ratios. The cumulative incidence function can also be estimated if information from the full cohort is used. In the presence of competing events, however, the cumulative incidence function depends on the hazard of the disease of interest and on the competing events hazard. Using hospital-acquired infection as an example (full cohort), we propose a sampling method for nested case-control studies to estimate subdistribution hazard ratios. With further information on the full cohort, the cumulative incidence function for the event of interest can then be estimated as well.

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Derde LPG, Cooper BS, Goossens H, Malhotra-Kumar S, Willems RJL, Gniadkowski M, Hryniewicz W, Empel J et al. 2014. Interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in intensive care units: An interrupted time series study and cluster randomised trial The Lancet Infectious Diseases, 14 (1), pp. 31-39. | Show Abstract | Read more

Background: Intensive care units (ICUs) are high-risk areas for transmission of antimicrobial-resistant bacteria, but no controlled study has tested the effect of rapid screening and isolation of carriers on transmission in settings with best-standard precautions. We assessed interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in European ICUs. Methods: We did this study in three phases at 13 ICUs. After a 6 month baseline period (phase 1), we did an interrupted time series study of universal chlorhexidine body-washing combined with hand hygiene improvement for 6 months (phase 2), followed by a 12-15 month cluster randomised trial (phase 3). ICUs were randomly assigned by computer generated randomisation schedule to either conventional screening (chromogenic screening for meticillin-resistant Staphylococcus aureus [MRSA] and vancomycin-resistant enterococci [VRE]) or rapid screening (PCR testing for MRSA and VRE and chromogenic screening for highly resistant Enterobacteriaceae [HRE]); with contact precautions for identified carriers. The primary outcome was acquisition of resistant bacteria per 100 patient-days at risk, for which we calculated step changes and changes in trends after the introduction of each intervention. We assessed acquisition by microbiological surveillance and analysed it with a multilevel Poisson segmented regression model. We compared screening groups with a likelihood ratio test that combined step changes and changes to trend. This study is registered with ClinicalTrials.gov, number NCT00976638. Findings: Seven ICUs were assigned to rapid screening and six to conventional screening. Mean hand hygiene compliance improved from 52% in phase 1 to 69% in phase 2, and 77% in phase 3. Median proportions of patients receiving chlorhexidine body-washing increased from 0% to 100% at the start of phase 2. For trends in acquisition of antimicrobial-resistant bacteria, weekly incidence rate ratio (IRR) was 0·976 (0·954-0·999) for phase 2 and 1·015 (0·998-1·032) for phase 3. For step changes, weekly IRR was 0·955 (0·676-1·348) for phase 2 and 0·634 (0·349-1·153) for phase 3. The decrease in trend in phase 2 was largely caused by changes in acquisition of MRSA (weekly IRR 0·925, 95% CI 0·890-0·962). Acquisition was lower in the conventional screening group than in the rapid screening group, but did not differ significantly (p=0·06). Interpretation: Improved hand hygiene plus unit-wide chlorhexidine body-washing reduced acquisition of antimicrobial-resistant bacteria, particularly MRSA. In the context of a sustained high level of compliance to hand hygiene and chlorhexidine bathings, screening and isolation of carriers do not reduce acquisition rates of multidrug-resistant bacteria, whether or not screening is done with rapid testing or conventional testing. Funding: European Commission. © 2014 Derde et al. Open Access article distributed under the terms of CC BY-NC-SA.

Luangasanatip N, Hongsuwan M, Lubell Y, Limmathurotsakul D, Teparrukkul P, Chaowarat S, Day NP, Graves N, Cooper BS. 2013. Long-term survival after intensive care unit discharge in Thailand: a retrospective study. Crit Care, 17 (5), pp. R219. | Show Abstract | Read more

INTRODUCTION: Economic evaluations of interventions in the hospital setting often rely on the estimated long-term impact on patient survival. Estimates of mortality rates and long-term outcomes among patients discharged alive from the intensive care unit (ICU) are lacking from lower- and middle-income countries. This study aimed to assess the long-term survival and life expectancy (LE) amongst post-ICU patients in Thailand, a middle-income country. METHODS: In this retrospective cohort study, data from a regional tertiary hospital in northeast Thailand and the regional death registry were linked and used to assess patient survival time after ICU discharge. Adult ICU patients aged at least 15 years who had been discharged alive from an ICU between 1 January 2004 and 31 December 2005 were included in the study, and the death registry was used to determine deaths occurring in this cohort up to 31st December 2010. These data were used in conjunction with standard mortality life tables to estimate annual mortality and life expectancy. RESULTS: This analysis included 10,321 ICU patients. During ICU admission, 3,251 patients (31.5%) died. Of 7,070 patients discharged alive, 2,527 (35.7%) were known to have died within the five-year follow-up period, a mortality rate 2.5 times higher than that in the Thai general population (age and sex matched). The mean LE was estimated as 18.3 years compared with 25.2 years in the general population. CONCLUSIONS: Post-ICU patients experienced much higher rates of mortality than members of the general population over the five-year follow-up period, particularly in the first year after discharge. Further work assessing Health Related Quality of Life (HRQOL) in both post-ICU patients and in the general population in developing countries is needed.

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