title: On being the right size: the impact of population size and stochastic effects on the evolution of drug resistance in hospitals and the community.
abstract: The evolution of drug resistant bacteria is a severe public health problem, both in hospitals and in the community. Currently, some countries aim at concentrating highly specialized services in large hospitals in order to improve patient outcomes. Emergent resistant strains often originate in health care facilities, but it is unknown to what extent hospital size affects resistance evolution and the resulting spillover of hospital-associated pathogens to the community. We used two published datasets from the US and Ireland to investigate the effects of hospital size and controlled for several confounders such as antimicrobial usage, sampling frequency, mortality, disinfection and length of stay. The proportion of patients acquiring both sensitive and resistant infections in a hospital strongly correlated with hospital size. Moreover, we observe the same pattern for both the percentage of resistant infections and the increase of hospital-acquired infections over time. One interpretation of this pattern is that chance effects in small hospitals impede the spread of drug-resistance. To investigate to what extent the size distribution of hospitals can directly affect the prevalence of antibiotic resistance, we use a stochastic epidemiological model describing the spread of drug resistance in a hospital setting as well as the interaction between one or several hospitals and the community. We show that the level of drug resistance typically increases with population size: In small hospitals chance effects cause large fluctuations in pathogen population size or even extinctions, both of which impede the acquisition and spread of drug resistance. Finally, we show that indirect transmission via environmental reservoirs can reduce the effect of hospital size because the slow turnover in the environment can prevent extinction of resistant strains. This implies that reducing environmental transmission is especially important in small hospitals, because such a reduction not only reduces overall transmission but might also facilitate the extinction of resistant strains. Overall, our study shows that the distribution of hospital sizes is a crucial factor for the spread of drug resistance.
authors.affiliation: Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland. rkouyos@princeton.edu
authors.forename: Roger D
authors.initials: RD
authors.lastname: Kouyos
authors.forename: Pia
authors.initials: P
authors.lastname: Abel Zur Wiesch
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bonhoeffer
mesh_terms: D000722:Ancylostoma / Q000235:genetics / Q000378:metabolism*; D000724:Ancylostomiasis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D047630:Depsipeptides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004336:Drug Antagonism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006188:Haemonchiasis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006189:Haemonchus / Q000235:genetics / Q000378:metabolism*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics*; D009154:Mutation; D009183:Mycotoxins / Q000494:pharmacology; D013045:Species Specificity
chemical_list: D000871:Anthelmintics; D029742:Caenorhabditis elegans Proteins; D047630:Depsipeptides; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009183:Mycotoxins; C494845:slo-1 protein, C elegans; C003626:tremortin; C468987:emodepside