The time-varying association between previous antibiotic use and antibiotic resistance

Objectives The objective of the study was to estimate how the time elapsed from previous antibiotic use is associated with antibiotic resistance. Methods Data comprised electronic medical records of all patients in an Israeli hospital who had a positive bacterial culture between 2016-19. These included susceptibility testing results, and clinical and demographic data. Mixed-effects time-varying logistic models were fitted to estimate the association between time elapsed since last use of aminoglycosides and gentamicin resistance ( n = 13,095), cephalosporins and ceftazidime resistance ( n = 13,051), and fluoroquinolones and ciprofloxacin resistance ( n = 15,364), while adjusting for multiple covariates. Results For all examined antibiotics, previous antibiotic use had a statistically significant association with resistance ( p < 0.001). These associations exhibited a clear decreasing pattern over time, which we present as a flexible function of time. Nonetheless, previous antibiotic use remained a significant risk factor for resistance for at least 180 days, with adjusted odds ratios of 1.94 (95% CI 1.40-2.69), 1.33 (95% CI 1.10-1.61), and 2.25 (95% CI 1.49-3.41), for gentamicin, ceftazidime and ciprofloxacin, respectively. Conclusions The association between prior antibiotic use and resistance decreases over time. Commonly used cut-offs for prior antibiotic use can either misclassify patients still at higher risk, when too recent; or provide a diluted estimate of the effects of antibiotic use on future resistance, when too distant. Hence, prior antibiotic use should be considered as a time-dependent risk factor for resistance, both in epidemiological research and clinical practice.