Fluoroquinolone prescribing was associated with antimicrobial resistance (AMR) in multiple major pathogens, in a retrospective cohort study conducted at US Veterans Affairs medical centers (VAMCs).1
"The understanding of the drugs that most strongly drive specific resistance patterns remains incomplete, partly because of methodological challenges in assessing this association," observe Thi Mui Pham, PhD, Department of Epidemiology and Center for Communicable Disease Dynamics, Harvard TH Chan School of Public Health, Boston, MA, and colleagues.
"Few studies have examined how co-selection, where use of one antimicrobial agent promotes the selection and persistence of resistance not only to that agent but also to others, shapes the relationship between antimicrobial use and resistance," the investigators point out.
To assess the influence of antimicrobial prescribing on susceptibility patterns of major pathogens, the investigators analyzed facility-level prescribing and resistance data in 138 VAMCs during the period between 2007 and 2021 for four major hospital-onset isolates (collected on or after 3 days of admission): Staphylococcus aureus, Esherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
In addition to associations of prescribing patterns with AMR, the study sought out temporal relation between prescribing and pathogen-specific AMR profiles.The investigators quantified AMR as number of isolates by categories of susceptible, single class- or multiple drug resistant, per 1000 patient days. The prescribing rates were defined by number inpatient days of therapy per 1000 patient days.
The study analyzed 84,657 of 164,047 (51.6%) hospital-onset isolates across the 4 major pathogens from over 68,000 participants.S aureus comprised 36.2% of isolates, K pneumoniae 63.9%, P aeruginosa 52.1%, and E coli61.1%.The investigators reported that the prevalence of multi-drug resistance, to three antimicrobial classes, declined during the study period for all but E coli, which demonstrated a distinct pattern.
Pham and colleagues found that while the prevalence of third- or fourth-generation cephalosporin-susceptible E coli declined, the prevalence of multiple third- or fourth-generation cephalosporin-resistant profiles increased."Notably, the prevalence of isolates resistant to fluroquinolones and third-generation or fourth-generation cephalosporins but susceptible to ß-lactam-ß-lactamase inhibitor increased," they noted.
The antimicrobial prescription rates remained stable or decreased over the study period, except for third- or fourth-generation cephalosporins, which increased. The greatest decline in prescribing occurred with fluroquinolones.Carbapenem prescribing increased between 2007 and 2011 before declining. ß-lactam-ß-lactamase inhibitor prescribing was stable until 2014, and then declined following shortage of piperacillin-tazobactams in 2015.
What You Needs to Know
In a large VA cohort study of over 84,000 hospital-onset isolates, recent fluoroquinolone exposure was consistently associated with increased odds of fluoroquinolone resistance across all four major pathogens studied (S aureus, E coli, K pneumoniae, and P aeruginosa).
While multidrug resistance declined for most pathogens during 2007–2021, E coli showed a distinct and concerning pattern, with rising co-resistance to fluoroquinolones and third-/fourth-generation cephalosporins even as cephalosporin prescribing increased.
The findings suggest MRSA incidence may be more strongly driven by fluoroquinolone and macrolide use than by anti-staphylococcal β-lactam prescribing, underscoring the need for antimicrobial stewardship strategies that account for cross-class, co-selective resistance dynamics rather than treating each drug class in isolation.
The investigators used multilevel, multinomial logistic regression analysis of antimicrobial exposure and AMR resistance to ascertain relations between prescribing patterns and selective or co-selective AMR pressures.Notably, they found that recent fluroquinolone exposure consistently increased the relative odds of fluroquinolone-resistant profiles across all four target pathogens.
"Specifically, MRSA (methicillin-resistant S aureus) incidence might be driven more by fluoroquinolone and macrolide prescription than by ASBL (anti-staphylococcal ß-lactams) prescription, echoing previous findings2 that linked fluroquinolone but not ß-lactam use to MRSA colonization," they posited.
Pham and colleagues suggest that the emerging co-resistance of E coli to fluroquinolones and third- or fourth- generation cephalsporins highlights the need to monitor multidrug resistance patterns.
"Effective stewardship requires coordinated strategies across antimicrobial classes, informed by pathogen-specific selection dynamics," Pham and colleagues advise.
References
1. Pham TM, Zhang Y, Nevers M, et al. Antimicrobial selection and multidrug resistance in four major pathogens in the US Veterans Affairs health-care system: a multicentre, retrospective, cohort study. Lancet Microbe. 2026 July 31: 101445. doi: 10.1016/j.lanmic.2026.101445. Accessed August 19, 2026.
2. Weber SG, Gold HS, Hooper DC, Karchmer AW, Carmeli Y. Fluoroquinolones and the risk for methicillin-resistant Staphylococcus aureus in hospitalized patients. Emerg Infect Dis. 2003; 9: 1415–22.
