Importance: Antibiotic resistance is a growing concern due to overuse and misuse of antibiotics. Quantitative assessments of the risk of future resistance caused by different antibiotics are limited, although essential for improved guidelines for responsible antibiotic prescription. Objective: To employ instrumental variable (IV) analysis using reported penicillin allergy to estimate the causal effects of prior penicillin use on the development of antibiotic resistance. Design: Retrospective cohort study spanning from 2013 to 2022, with a follow-up period extending to 12 months. Setting: Primary Care Participants: The study analyzed 36,351 adults who underwent an AMR test prompted by a positive urine culture, representing 2.5% of the initial cohort of eligible adults who purchased antibiotics in primary care. Exclusion criteria included recent antibiotic use, hospitalization, nursing home residence, being homebound, or purchasing multiple antibiotic types. Main Outcome(s) and Measure(s): Binary results of antibiotic susceptibility tests at follow-up times of up to 90, 180, 270, and 365 days. We focused on resistance to ampicillin, amoxicillin/clavulanic acid, piperacillin/tazobactam, and ciprofloxacin, using gentamicin as a negative control outcome. Results: The rate difference (RD) of resistance due to previous penicillin use compared to other antibiotics within 12 months was 15.2% (95% CI: 9.8%, 21.4%) for amoxicillin/clavulanic acid, 11.8% (95% CI: 5.5%, 20.3%) for ampicillin, and 1.0% (95% CI: 0.3%, 1.9%) for piperacillin/tazobactam, with NNH values of 6.6, 8.5, and 98, respectively. Gentamicin, used as a negative control, showed no effect. Direct comparison of penicillins and quinolones within 180 days post-exposure revealed that penicillins increased resistance to amoxicillin/clavulanic acid by an RD of 14.9% (95% CI: 2.9%, 24.6%; NNH: 6.7), while quinolones increased resistance to ciprofloxacin by 34.7% (95% CI: 25.3%, 45.9%; NNH: 2.9). Conclusions and Relevance: The study provides causal estimates of how prior use of penicillins and quinolones in outpatient settings impacts future antibiotic resistance, with implications for treatment guidelines and clinical practice. Additionally, it introduces a novel methodological approach to quantify antibiotic-induced resistance, which can be applied to other antibiotic groups known to cause allergic reactions.

The authors have declared no competing interest.

This work was supported by the Israel Science Foundation (ISF 1286/21)

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