Characterizing antimicrobial selection pressure on resistance across four major causes of infections: Insights from the US Veterans Affairs Healthcare System, 2007-2021

BackgroundSystematic 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). MethodsWe 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. FindingsHospital-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{middle dot}4%, 95% CI 1{middle dot}3%-3{middle dot}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{middle dot}6% (95CI: 1{middle dot}5, 7{middle dot}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{middle dot}2% (95%CI: 1{middle dot}3%, 9{middle dot}4%, p-value=0.0079) and K pneumoniae by 3{middle dot}0% (95% CI: -0{middle dot}1%-6{middle dot}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{middle dot}7% (95%CI: 9{middle dot}4%, 22{middle dot}4%, p-value<0.0001). InterpretationHigher 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.