A Bayesian inference method to estimate transmission trees with multiple introductions; applied to SARS-CoV-2 in Dutch mink farms.

Knowledge of who infected whom during an outbreak of an infectious disease is important to determine risk factors for transmission and to design effective control measures. Both whole-genome sequencing of pathogens and epidemiological data provide useful information about the transmission events and underlying processes. Existing models to infer transmission trees usually assume that the pathogen is introduced only once from outside into the population of interest. However, this is not always true. For instance, SARS-CoV-2 is suggested to be introduced multiple times in mink farms in the Netherlands from the SARS-CoV-2 pandemic among humans. Here, we developed a Bayesian inference method combining whole-genome sequencing data and epidemiological data, allowing for multiple introductions of the pathogen in the population. Our method does not a priori split the outbreak into multiple phylogenetic clusters, nor does it break the dependency between the processes of mutation, within-host dynamics, transmission, and observation. We implemented our method as an additional feature in the R-package phybreak. On simulated data, our method correctly identifies the number of introductions, with an accuracy depending on the proportion of all observed cases that are introductions. Moreover, when a single introduction was simulated, our method produced similar estimates of parameters and transmission trees as the existing package. When applied to data from a SARS-CoV-2 outbreak in Dutch mink farms, the method provides strong evidence for independent introductions of the pathogen at 13 farms, infecting a total of 63 farms. Using the new feature of the phybreak package, transmission routes of a more complex class of infectious disease outbreaks can be inferred which will aid infection control in future outbreaks.

The discrete-time Kermack-McKendrick model: A versatile and computationally attractive framework for modeling epidemics.

The COVID-19 pandemic has led to numerous mathematical models for the spread of infection, the majority of which are large compartmental models that implicitly constrain the generation-time distribution. On the other hand, the continuous-time Kermack-McKendrick epidemic model of 1927 (KM27) allows an arbitrary generation-time distribution, but it suffers from the drawback that its numerical implementation is rather cumbersome. Here, we introduce a discrete-time version of KM27 that is as general and flexible, and yet is very easy to implement computationally. Thus, it promises to become a very powerful tool for exploring control scenarios for specific infectious diseases such as COVID-19. To demonstrate this potential, we investigate numerically how the incidence-peak size depends on model ingredients. We find that, with the same reproduction number and the same initial growth rate, compartmental models systematically predict lower peak sizes than models in which the latent and the infectious period have fixed duration.

Genome-wide association reveals host-specific genomic traits in Escherichia coli.

BACKGROUND: Escherichia coli is an opportunistic pathogen which colonizes various host species. However, to what extent genetic lineages of E. coli are adapted or restricted to specific hosts and the genomic determinants of such adaptation or restriction is poorly understood. RESULTS: We randomly sampled E. coli isolates from four countries (Germany, UK, Spain, and Vietnam), obtained from five host species (human, pig, cattle, chicken, and wild boar) over 16 years, from both healthy and diseased hosts, to construct a collection of 1198 whole-genome sequenced E. coli isolates. We identified associations between specific E. coli lineages and the host from which they were isolated. A genome-wide association study (GWAS) identified several E. coli genes that were associated with human, cattle, or chicken hosts, whereas no genes associated with the pig host could be found. In silico characterization of nine contiguous genes (collectively designated as nan-9) associated with the human host indicated that these genes are involved in the metabolism of sialic acids (Sia). In contrast, the previously described sialic acid regulon known as sialoregulon (i.e. nanRATEK-yhcH, nanXY, and nanCMS) was not associated with any host species. In vitro growth experiments with a Δnan-9 E. coli mutant strain, using the sialic acids 5-N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) as sole carbon source, showed impaired growth behaviour compared to the wild-type. CONCLUSIONS: This study provides an extensive analysis of genetic determinants which may contribute to host specificity in E. coli. Our findings should inform risk analysis and epidemiological monitoring of (antimicrobial resistant) E. coli.

Does plasmid-based beta-lactam resistance increase E. coli infections: Modelling addition and replacement mechanisms.

Infections caused by antibiotic-resistant bacteria have become more prevalent during past decades. Yet, it is unknown whether such infections occur in addition to infections with antibiotic-susceptible bacteria, thereby increasing the incidence of infections, or whether they replace such infections, leaving the total incidence unaffected. Observational longitudinal studies cannot separate both mechanisms. Using plasmid-based beta-lactam resistant E. coli as example we applied mathematical modelling to investigate whether seven biological mechanisms would lead to replacement or addition of infections. We use a mathematical neutral null model of individuals colonized with susceptible and/or resistant E. coli, with two mechanisms implying a fitness cost, i.e., increased clearance and decreased growth of resistant strains, and five mechanisms benefitting resistance, i.e., 1) increased virulence, 2) increased transmission, 3) decreased clearance of resistant strains, 4) increased rate of horizontal plasmid transfer, and 5) increased clearance of susceptible E. coli due to antibiotics. Each mechanism is modelled separately to estimate addition to or replacement of antibiotic-susceptible infections. Fitness costs cause resistant strains to die out if other strain characteristics are maintained equal. Under the assumptions tested, increased virulence is the only mechanism that increases the total number of infections. Other benefits of resistance lead to replacement of susceptible infections without changing the total number of infections. As there is no biological evidence that plasmid-based beta-lactam resistance increases virulence, these findings suggest that the burden of disease is determined by attributable effects of resistance rather than by an increase in the number of infections.

Transmission routes of antibiotic resistant bacteria: a systematic review.

BACKGROUND: Quantification of acquisition routes of antibiotic resistant bacteria (ARB) is pivotal for understanding transmission dynamics and designing cost-effective interventions. Different methods have been used to quantify the importance of transmission routes, such as relative risks, odds ratios (OR), genomic comparisons and basic reproduction numbers. We systematically reviewed reported estimates on acquisition routes' contributions of ARB in humans, animals, water and the environment and assessed the methods used to quantify the importance of transmission routes. METHODS: PubMed and EMBASE were searched, resulting in 6054 articles published up until January 1st, 2019. Full text screening was performed on 525 articles and 277 are included. RESULTS: We extracted 718 estimates with S. aureus (n = 273), E. coli (n = 157) and Enterobacteriaceae (n = 99) being studied most frequently. Most estimates were derived from statistical methods (n = 560), mainly expressed as risks (n = 246) and ORs (n = 239), followed by genetic comparisons (n = 85), modelling (n = 62) and dosage of ARB ingested (n = 17). Transmission routes analysed most frequently were occupational exposure (n = 157), travelling (n = 110) and contacts with carriers (n = 83). Studies were mostly performed in the United States (n = 142), the Netherlands (n = 87) and Germany (n = 60). Comparison of methods was not possible as studies using different methods to estimate the same route were lacking. Due to study heterogeneity not all estimates by the same method could be pooled. CONCLUSION: Despite an abundance of published data the relative importance of transmission routes of ARB has not been accurately quantified. Links between exposure and acquisition are often present, but the frequency of exposure is missing, which disables estimation of transmission routes' importance. To create effective policies reducing ARB, estimates of transmission should be weighed by the frequency of exposure occurrence.

Interventions to control nosocomial transmission of SARS-CoV-2: a modelling study.

BACKGROUND: Emergence of more transmissible SARS-CoV-2 variants requires more efficient control measures to limit nosocomial transmission and maintain healthcare capacities during pandemic waves. Yet the relative importance of different strategies is unknown. METHODS: We developed an agent-based model and compared the impact of personal protective equipment (PPE), screening of healthcare workers (HCWs), contact tracing of symptomatic HCWs and restricting HCWs from working in multiple units (HCW cohorting) on nosocomial SARS-CoV-2 transmission. The model was fit on hospital data from the first wave in the Netherlands (February until August 2020) and assumed that HCWs used 90% effective PPE in COVID-19 wards and self-isolated at home for 7 days immediately upon symptom onset. Intervention effects on the effective reproduction number (RE), HCW absenteeism and the proportion of infected individuals among tested individuals (positivity rate) were estimated for a more transmissible variant. RESULTS: Introduction of a variant with 56% higher transmissibility increased - all other variables kept constant - RE from 0.4 to 0.65 (+ 63%) and nosocomial transmissions by 303%, mainly because of more transmissions caused by pre-symptomatic patients and HCWs. Compared to baseline, PPE use in all hospital wards (assuming 90% effectiveness) reduced RE by 85% and absenteeism by 57%. Screening HCWs every 3 days with perfect test sensitivity reduced RE by 67%, yielding a maximum test positivity rate of 5%. Screening HCWs every 3 or 7 days assuming time-varying test sensitivities reduced RE by 9% and 3%, respectively. Contact tracing reduced RE by at least 32% and achieved higher test positivity rates than screening interventions. HCW cohorting reduced RE by 5%. Sensitivity analyses show that our findings do not change significantly for 70% PPE effectiveness. For low PPE effectiveness of 50%, PPE use in all wards is less effective than screening every 3 days with perfect sensitivity but still more effective than all other interventions. CONCLUSIONS: In response to the emergence of more transmissible SARS-CoV-2 variants, PPE use in all hospital wards might still be most effective in preventing nosocomial transmission. Regular screening and contact tracing of HCWs are also effective interventions but critically depend on the sensitivity of the diagnostic test used.

gplas: a comprehensive tool for plasmid analysis using short-read graphs.

SUMMARY: Plasmids can horizontally transmit genetic traits, enabling rapid bacterial adaptation to new environments and hosts. Short-read whole-genome sequencing data are often applied to large-scale bacterial comparative genomics projects but the reconstruction of plasmids from these data is facing severe limitations, such as the inability to distinguish plasmids from each other in a bacterial genome. We developed gplas, a new approach to reliably separate plasmid contigs into discrete components using sequence composition, coverage, assembly graph information and network partitioning based on a pruned network of plasmid unitigs. Gplas facilitates the analysis of large numbers of bacterial isolates and allows a detailed analysis of plasmid epidemiology based solely on short-read sequence data. AVAILABILITY AND IMPLEMENTATION: Gplas is written in R, Bash and uses a Snakemake pipeline as a workflow management system. Gplas is available under the GNU General Public License v3.0 at https://gitlab.com/sirarredondo/gplas.git. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Dynamics of Intestinal Carriage of Extended-Spectrum Beta-lactamase-Producing Enterobacteriaceae in the Dutch General Population, 2014-2016.

BACKGROUND: In the Netherlands, the prevalence of intestinal extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) carriage in community-dwelling subjects is ~5%. Little is known about the dynamics of ESBL-E carriage. METHODS: In a nationwide, population-based study (2014-2016) with 4177 community-dwelling subjects, fecal samples from 656 subjects were collected after 1 (time point [T] = 1) and 6 (T = 2) months. The growth of ESBL-E was quantified and a whole-genome sequence analysis was performed. Subjects were categorized as either an incidental, short-term, or long-term carrier or as a noncarrier. Risk factors were determined by random forest models and logistic regression. The transmissibility and duration of ESBL-E carriage was quantified using a transmission model, which also incorporated previous study data. RESULTS: Out of 656 participants, 96 were ESBL-E carriers at T = 0. Of these, 66 (10.1%) subjects were incidental carriers, 22 (3.3%) were short-term carriers, and 38 (5.8%) were long-term carriers; the remaining 530 (80.8%) were noncarriers. The risk factors for long-term carriage were travelling to Asia, swimming in a sea/ocean, and not changing the kitchen towel daily. The log-transformed colony forming units ratio at T = 0 was predictive for ESBL-E carriage at T = 1 (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.2-1.6) and T = 2 (OR, 1.2; 95% CI, 1.1-1.4). Model simulations revealed a median decolonization rate of 2.83/year, an average duration of carriage of 0.35 years, and an acquisition rate of 0.34/year. The trend of the acquisition rate during the study period was close to 0. CONCLUSIONS: The risk factors for long-term ESBL-E carriage were travel- and hygiene-related. The dynamics of ESBL-E carriage in the general Dutch population are characterized by balancing decolonization and acquisition rates.

Impact of self-imposed prevention measures and short-term government-imposed social distancing on mitigating and delaying a COVID-19 epidemic: A modelling study.

BACKGROUND: The coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to nearly every country in the world since it first emerged in China in December 2019. Many countries have implemented social distancing as a measure to "flatten the curve" of the ongoing epidemics. Evaluation of the impact of government-imposed social distancing and of other measures to control further spread of COVID-19 is urgent, especially because of the large societal and economic impact of the former. The aim of this study was to compare the individual and combined effectiveness of self-imposed prevention measures and of short-term government-imposed social distancing in mitigating, delaying, or preventing a COVID-19 epidemic. METHODS AND FINDINGS: We developed a deterministic compartmental transmission model of SARS-CoV-2 in a population stratified by disease status (susceptible, exposed, infectious with mild or severe disease, diagnosed, and recovered) and disease awareness status (aware and unaware) due to the spread of COVID-19. Self-imposed measures were assumed to be taken by disease-aware individuals and included handwashing, mask-wearing, and social distancing. Government-imposed social distancing reduced the contact rate of individuals irrespective of their disease or awareness status. The model was parameterized using current best estimates of key epidemiological parameters from COVID-19 clinical studies. The model outcomes included the peak number of diagnoses, attack rate, and time until the peak number of diagnoses. For fast awareness spread in the population, self-imposed measures can significantly reduce the attack rate and diminish and postpone the peak number of diagnoses. We estimate that a large epidemic can be prevented if the efficacy of these measures exceeds 50%. For slow awareness spread, self-imposed measures reduce the peak number of diagnoses and attack rate but do not affect the timing of the peak. Early implementation of short-term government-imposed social distancing alone is estimated to delay (by at most 7 months for a 3-month intervention) but not to reduce the peak. The delay can be even longer and the height of the peak can be additionally reduced if this intervention is combined with self-imposed measures that are continued after government-imposed social distancing has been lifted. Our analyses are limited in that they do not account for stochasticity, demographics, heterogeneities in contact patterns or mixing, spatial effects, imperfect isolation of individuals with severe disease, and reinfection with COVID-19. CONCLUSIONS: Our results suggest that information dissemination about COVID-19, which causes individual adoption of handwashing, mask-wearing, and social distancing, can be an effective strategy to mitigate and delay the epidemic. Early initiated short-term government-imposed social distancing can buy time for healthcare systems to prepare for an increasing COVID-19 burden. We stress the importance of disease awareness in controlling the ongoing epidemic and recommend that, in addition to policies on social distancing, governments and public health institutions mobilize people to adopt self-imposed measures with proven efficacy in order to successfully tackle COVID-19.

Tracking Pseudomonas aeruginosa transmissions due to environmental contamination after discharge in ICUs using mathematical models.

Pseudomonas aeruginosa (P. aeruginosa) is an important cause of healthcare-associated infections, particularly in immunocompromised patients. Understanding how this multi-drug resistant pathogen is transmitted within intensive care units (ICUs) is crucial for devising and evaluating successful control strategies. While it is known that moist environments serve as natural reservoirs for P. aeruginosa, there is little quantitative evidence regarding the contribution of environmental contamination to its transmission within ICUs. Previous studies on other nosocomial pathogens rely on deploying specific values for environmental parameters derived from costly and laborious genotyping. Using solely longitudinal surveillance data, we estimated the relative importance of P. aeruginosa transmission routes by exploiting the fact that different routes cause different pattern of fluctuations in the prevalence. We developed a mathematical model including background transmission, cross-transmission and environmental contamination. Patients contribute to a pool of pathogens by shedding bacteria to the environment. Natural decay and cleaning of the environment lead to a reduction of that pool. By assigning the bacterial load shed during an ICU stay to cross-transmission, we were able to disentangle environmental contamination during and after a patient's stay. Based on a data-augmented Markov Chain Monte Carlo method the relative importance of the considered acquisition routes is determined for two ICUs of the University hospital in Besançon (France). We used information about the admission and discharge days, screening days and screening results of the ICU patients. Both background and cross-transmission play a significant role in the transmission process in both ICUs. In contrast, only about 1% of the total transmissions were due to environmental contamination after discharge. Based on longitudinal surveillance data, we conclude that cleaning improvement of the environment after discharge might have only a limited impact regarding the prevention of P.A. infections in the two considered ICUs of the University hospital in Besançon. Our model was developed for P. aeruginosa but can be easily applied to other pathogens as well.

The Transmissibility of Antibiotic-Resistant Enterobacteriaceae in Intensive Care Units.

Background: The global emergence of infections caused by Enterobacteriaceae resistant to expanded-spectrum cephalosporins (ESCs) in intensive care units (ICUs) is, at least partly, driven by cross-transmission. Yet, individual transmission capacities of bacterial species have not been quantified. Methods: In this post hoc analysis of a multicenter study in 13 European ICUs, prospective surveillance data and a mathematical model were used to estimate transmission capacities and single-admission reproduction numbers (RA) of Escherichia coli and non-E. coli Enterobacteriaceae (non-EcE), all being ESC resistant. Surveillance was based on a chromogenic selective medium for ESC-resistant Enterobacteriaceae, allowing identification of E. coli and of Klebsiella, Enterobacter, Serratia, and Citrobacter species, grouped as non-EcE. Results: Among 11420 patients included, the admission prevalence was 3.8% for non-EcE (74% being Klebsiella pneumoniae) and 3.3% for E. coli. Acquisition rates were 7.4 and 2.6 per 100 admissions at risk for non-EcE and E. coli, respectively. The estimated transmission capacity of non-EcE was 3.7 (95% credibility interval [CrI], 1.4-11.3) times higher than that of E. coli, yielding single-admission reproduction numbers (RA) of 0.17 (95% CrI, .094-.29) for non-EcE and 0.047 (95% CrI, .018-.098) for E. coli. Conclusions: In ICUs, non-EcE, mainly K. pneumoniae, are 3.7 times more transmissible than E. coli. Estimated RA values of these bacteria were below the critical threshold of 1, suggesting that in these ICUs outbreaks typically remain small with current infection control policies.

Small distances can keep bacteria at bay for days.

Transmission of pathogens between spatially separated hosts, i.e., indirect transmission, is a commonly encountered phenomenon important for epidemic pathogen spread. The routes of indirect transmission often remain untraced, making it difficult to develop control strategies. Here we used a tailor-made design to study indirect transmission experimentally, using two different zoonotic bacteria in broilers. Previous experiments using a single bacterial species yielded a delay in the onset of transmission, which we hypothesized to result from the interplay between diffusive motion of infectious material and decay of infectivity in the environment. Indeed, a mathematical model of diffusive pathogen transfer predicts a delay in transmission that depends both on the distance between hosts and on the magnitude of the pathogen decay rate. Our experiments, carried out with two bacterial species with very different decay rates in the environment, confirm the difference in transmission delay predicted by the model. These results imply that for control of an infectious agent, the time between the distant exposure and the infection event is important. To illustrate how this can work we analyzed data observed on the spread of vancomycin-resistant Enterococcus in an intensive care unit. Indeed, a delayed vancomycin-resistant Enterococcus transmission component was identified in these data, and this component disappeared in a study period in which the environment was thoroughly cleaned. Therefore, we suggest that the impact of control strategies against indirect transmission can be assessed using our model by estimating the control measures' effects on the diffusion coefficient and the pathogen decay rate.

Prevention of Surgical Site Infections: Decontamination With Mupirocin Based on Preoperative Screening for Staphylococcus aureus Carriers or Universal Decontamination?

Perioperative decolonization of Staphylococcus aureus nasal carriers with mupirocin together with chlorhexidine body washing reduces the incidence of S. aureus surgical site infection. A targeted strategy, applied in S. aureus carriers only, is costly, and implementation may reduce effectiveness. Universal decolonization is more cost-effective but increases exposure of noncarriers to mupirocin and the risk of resistance to mupirocin in staphylococci. High-level mupirocin resistance in S. aureus can emerge through horizontal gene transfer originating from coagulase-negative staphylococci (CoNS) and through clonal transmission. The current evidence on the occurrence of high-level mupirocin resistance in S. aureus and CoNS, in combination with the results of mathematical modeling, strongly suggests that the increased selection of high-level mupirocin resistance in CoNS does not constitute an important risk for high-level mupirocin resistance in S. aureus. Compared with a targeted strategy, universal decolonization seems associated with an equally low risk of mupirocin resistance in S. aureus.

Prolonged colonisation with Escherichia coli O25:ST131 versus other extended-spectrum beta-lactamase-producing E. coli in a long-term care facility with high endemic level of rectal colonisation, the Netherlands, 2013 to 2014.

The extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli clone ST131 (ESBL-ST131) has spread in healthcare settings worldwide. The reasons for its successful spread are unknown, but might include more effective transmission and/or longer persistence. We evaluated the colonisation dynamics of ESBL-producing E. coli (ESBL-EC), including ESBL-ST131, in a long-term care facility (LTCF) with an unusually high prevalence of rectal ESBL-EC colonisation. During a 14-month period, rectal or faecal samples were obtained from 296 residents during six repetitive prevalence surveys, using ESBL-selective culture. Transmission rates, reproduction numbers, and durations of colonisation were compared for ESBL-ST131 vs other ESBL-EC. Furthermore, the likely time required for ESBL-ST131 to disappear from the LTCF was estimated. Over time, the endemic level of ESBL-ST131 remained elevated whereas other ESBL-EC returned to low-level prevalence, despite comparable transmission rates. Survival analysis showed a half-life of 13 months for ESBL-ST131 carriage, vs two to three months for other ESBL-EC (p < 0.001). Per-admission reproduction numbers were 0.66 for ESBL-ST131 vs 0.56 for other ESBL-EC, predicting a mean time of three to four years for ESBL-ST131 to disappear from the LTCF under current conditions. Transmission rates were comparable for ESBL-ST131 vs other ESBL-EC. Prolonged rectal carriage explained the persistence of ESBL-ST131 in the LTCF.

Cost and effects of different admission screening strategies to control the spread of methicillin-resistant Staphylococcus aureus.

Nosocomial infection rates due to antibiotic-resistant bacteriae, e.g., methicillin-resistant Staphylococcus aureus (MRSA) remain high in most countries. Screening for MRSA carriage followed by barrier precautions for documented carriers (so-called screen and isolate (S&I)) has been successful in some, but not all settings. Moreover, different strategies have been proposed, but comparative studies determining their relative effects and costs are not available. We, therefore, used a mathematical model to evaluate the effect and costs of different S&I strategies and to identify the critical parameters for this outcome. The dynamic stochastic simulation model consists of 3 hospitals with general wards and intensive care units (ICUs) and incorporates readmission of carriers of MRSA. Patient flow between ICUs and wards was based on real observations. Baseline prevalence of MRSA was set at 20% in ICUs and hospital-wide at 5%; ranges of costs and infection rates were based on published data. Four S&I strategies were compared to a do-nothing scenario: S&I of previously documented carriers ("flagged" patients); S&I of flagged patients and ICU admissions; S&I of flagged and group of "frequent" patients; S&I of all hospital admissions (universal screening). Evaluated levels of efficacy of S&I were 10%, 25%, 50% and 100%. Our model predicts that S&I of flagged and S&I of flagged and ICU patients are the most cost-saving strategies with fastest return of investment. For low isolation efficacy universal screening and S&I of flagged and "frequent" patients may never become cost-saving. Universal screening is predicted to prevent hardly more infections than S&I of flagged and "frequent" patients, albeit at higher costs. Whether an intervention becomes cost-saving within 10 years critically depends on costs per infection in ICU, costs of screening and isolation efficacy.

The Carriage Of Multiresistant Bacteria After Travel (COMBAT) prospective cohort study: methodology and design.

BACKGROUND: Antimicrobial resistance (AMR) is one of the major threats to public health around the world. Besides the intense use and misuse of antimicrobial agents as the major force behind the increase in antimicrobial resistance, the exponential increase of international travel may also substantially contribute to the emergence and spread of AMR. However, knowledge on the extent to which international travel contributes to this is still limited. The Carriage Of Multiresistant Bacteria After Travel (COMBAT) study aims to 1. determine the acquisition rate of multiresistant Enterobacteriaceae during foreign travel 2. ascertain the duration of carriage of these micro-organisms 3. determine the transmission rate within households 4. identify risk factors for acquisition, persistence of carriage and transmission of multiresistant Enterobacteriaceae. METHODS/DESIGN: The COMBAT-study is a large-scale multicenter longitudinal cohort study among travellers (n = 2001) and their non-travelling household members (n = 215). Faecal samples are collected before and immediately after travel and 1 month after return from all participants. Follow-up faecal samples are collected 3, 6 and 12 months after return from travellers (and their non-travelling household members) who acquired multiresistant Enterobacteriaceae. Questionnaires are collected from all participants at each time-point. Faecal samples are screened phenotypically for the presence of extended-spectrum beta-lactamase (ESBL) or carbapenemase-producing Enterobacteriaceae. Positive post-travel isolates from travellers with negative pre-travel samples are genotypically analysed for ESBL and carbapenemase genes with microarray and gene sequencing. DISCUSSION: The design and scale of the COMBAT-study will enable us to provide much needed detailed insights into the risks and dynamics of introduction and spread of ESBL- and carbapenemase-producing Enterobacteriaceae by healthy travellers and the potential need and measures to monitor or manage these risks. TRIAL REGISTRATION: The study is registered at clinicaltrials.gov under accession number NCT01676974.

Transmissibility of livestock-associated methicillin-resistant Staphylococcus aureus.

Previous findings have suggested that the nosocomial transmission capacity of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) is lower than that of other MRSA genotypes. We therefore performed a 6-month (June 1-November 30, 2011) nationwide study to quantify the single-admission reproduction number, RA, for LA-MRSA in 62 hospitals in the Netherlands and to compare this transmission capacity to previous estimates. We used spa typing for genotyping. Quantification of RA was based on a mathematical model incorporating outbreak sizes, detection rates, and length of hospital stay. There were 141 index cases, 40 (28%) of which were LA-MRSA. Contact screening of 2,101 patients and 7,260 health care workers identified 18 outbreaks (2 LA-MRSA) and 47 secondary cases (3 LA-MRSA). RA values indicated that transmissibility of LA-MRSA is 4.4 times lower than that of other MRSA (not associated with livestock).

New methodology to assess the excess burden of antibiotic resistance using country-specific parameters: a case study regarding E. coli urinary tract infections.

OBJECTIVES: Antimicrobial resistant (AMR) infections are a major public health problem and the burden on population level is not yet clear. We developed a method to calculate the excess burden of resistance which uses country-specific parameter estimates and surveillance data to compare the mortality and morbidity due to resistant infection against a counterfactual (the expected burden if infection was antimicrobial susceptible). We illustrate this approach by estimating the excess burden for AMR (defined as having tested positive for extended-spectrum beta-lactamases) urinary tract infections (UTIs) caused by E. coli in the Netherlands in 2018, which has a relatively low prevalence of AMR E. coli, and in Italy in 2016, which has a relatively high prevalence. DESIGN: Excess burden was estimated using the incidence-based disability-adjusted life-years (DALYs) measure. Incidence of AMR E. coli UTI in the Netherlands was derived from ISIS-AR, a national surveillance system that includes tested healthcare and community isolates, and the incidence in Italy was estimated using data reported in the literature. A systematic literature review was conducted to find country-specific parameter estimates for disability duration, risks of progression to bacteraemia and mortality. RESULTS: The annual excess burden of AMR E. coli UTI was estimated at 3.89 and 99.27 DALY/100 0000 population and 39 and 2786 excess deaths for the Netherlands and Italy, respectively. CONCLUSIONS: For the first time, we use country-specific and pathogen-specific parameters to estimate the excess burden of resistant infections. Given the large difference in excess burden due to resistance estimated for Italy and for the Netherlands, we emphasise the importance of using country-specific parameters describing the incidence and disease progression following AMR and susceptible infections that are pathogen specific, and unfortunately currently difficult to locate.

Successful Veterans Affairs initiative to prevent methicillin-resistant Staphylococcus aureus infections revisited.

In 2011 Jain et al reported a 62% reduction of healthcare-associated methicillin-resistant Staphylococcus aureus infections that resulted from an intervention bundle. Here we present a mathematical model and prove, using parameters from the study by Jain et al, that the universal screen and isolate strategy can have contributed only marginally to the reduction in infections.

Nosocomial transmission of community-associated methicillin-resistant Staphylococcus aureus in Danish Hospitals.

OBJECTIVES: The emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has changed the epidemiology of MRSA infections worldwide. In contrast to hospital-associated MRSA (HA-MRSA), CA-MRSA more frequently affects healthy individuals, both with and without recent healthcare exposure. Despite obvious epidemiological differences, it is unknown whether differences in nosocomial transmissibility exist. We have, therefore, quantified the transmissibility, expressed by the single admission reproduction number (R(A)), of CA-MRSA and HA-MRSA in hospital settings in Denmark. METHODS: MRSA index cases and secondary cases were investigated in four hospitals in the Copenhagen area. Index cases were defined as non-isolated, non-screened patients with MRSA, and secondary cases were defined as persons carrying MRSA isolates-identical to that of the corresponding index-as identified through contact screening. CA-MRSA and HA-MRSA were categorized upon genotyping [CA-MRSA: t008-ST8, PVL+; t019-ST30, PVL+; t127-ST1, PVL+; t044-ST80, PVL+; and their related spa types; and HA-MRSA: all other (where ST stands for sequence type and PVL stands for Panton-Valentine leucocidin)]. A mathematical model was applied to determine the genotype-specific transmission rate (i.e. R(A)) of CA-MRSA and HA-MRSA strains. RESULTS: During the 7 year study period there were 117 MRSA index cases with subsequent post-contact screening (of 1108 patients and healthcare workers), revealing 22 outbreaks with a total of 52 secondary patients. R(A) values were 0.07 (95% CI 0.00-0.28) and 0.65 (95% CI 0.48-0.84) for CA-MRSA and HA-MRSA, respectively. CONCLUSIONS: In four Danish hospitals the nosocomial transmission rate of CA-MRSA was 9.3 times lower than that of HA-MRSA.