Antimicrobial selection for resistance in four major pathogens in the US Veterans Affairs Healthcare System, 2007-2021

Background Systematic evidence on antimicrobial selection for antimicrobial resistance (AMR) is scarce. We estimated the effect of prescribing key antibiotic classes on AMR across U.S. Veterans Affairs Medical Centres (VAMC).

We analysed clinical isolates of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa from 138 VAMC from Feb 1, 2007 to Dec 31, 2021. Antimicrobial prescribing was measured as inpatient days of therapy per 1000 patient-days; multidrug resistance as number of resistant phenotypes per 1,000 admissions. Temporal trends were modelled using generalized estimating equations and average annual percentage changes (AAPC). Multilevel multinomial logistic regression related facility-level antibiotic prescribing (days of therapy per 100 patient-days in the last 14d) to the relative odds of resistant phenotypes. Findings Hospital-onset infection incidence declined for all pathogens, except third-generation cephalosporin (3GC)-resistant E coli. Antimicrobial prescribing remained stable or decreased, except 3GC prescribing, which increased from 2007 until 2019 (AAPC=2·4%, 95% CI 1·3%–3·5%, p-value<0.0001). Fluoroquinolone (FQL) use was associated with resistance across all pathogens. In S aureus, each day of FQL treatment was linked to a 4·6% (95CI: 1·5, 7·7, p-value=0.0127) increase in the relative odds of isolating FQL-resistant, macrolide-susceptible, methicillin-resistant S aureus. Anti-staphylococcal beta-lactams were not linked to MRSA. Each day of 3GC treatment increased the odds of isolating 3GC- and beta-lactam/beta-lactamase-resistant E coli by 5·2% (95%CI: 1·3%, 9·4%, p-value=0.0079) and K pneumoniae by 3·0% (95% CI: −0·1%-6·2%, p-value=0.0600). Each day of carbapenem treatment increased the odds of carbapenem-resistant, FQL- and BL/BLI-susceptible P aeruginosa by 15·7% (95%CI: 9·4%, 22·4%, p-value<0.0001). Interpretation Higher facility-level antimicrobial use increased the odds of corresponding resistant phenotypes, with important exceptions. FQLs selected for resistance across multiple pathogens. Increased 3GC prescribing likely offset reductions in FQLs and was associated with co-resistance in E coli. These findings underscore the need for comprehensive stewardship that coordinates strategies across antimicrobials. Competing Interest Statement Yonatan Grad serves on the Scientific Advisory Boards of Day Zero Diagnostics and of Decoy Therapeutics and received US National Institutes of Health grants (R01AI32606, R01AI53521, and R21AI72369, all not related to this project). Karim Khader received support from Veterans Affairs Health Systems Research (IIR 21-273) and for two studies from BioMerieux Clinical (IRB_00170297, IRB_00140336). All other authors declare no competing interests. Funding Statement This study was funded by the Centers for Disease Control and Prevention ("Modeling and Simulation to Support Epidemiological Decision-Making in Healthcare Settings" (Modeling Infectious Diseases in Healthcare (MInD-Healthcare) Program) award U01CK000585. MS was supported by the Agency for Healthcare Research and Quality (grant number: R01HS025175) and the Department of Veterans Affairs (grant number: 1I50HX002731-01). We thank the Department of Veterans Affairs for the supported infrastructure and data resources. Funding resources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Authors were not precluded from accessing data in the study, and they accept responsibility to submit for publication. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of University of Utah gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Manuscript updated throughout; added fourth generation cephalosporin use/resistance Data Availability All data produced in the present study are available upon reasonable request to the authors.