Association between use of different antibiotics and trimethoprim resistance: Going beyond the obvious crude association

Objectives: To evaluate the association between use of different antibiotics and trimethoprim resistance at the population level. Methods: Monthly primary care prescribing data were obtained from NHS Digital. Positive Enterobacteriaceae records from urine samples frompatients between April 2014 and January 2016 in England were extracted from PHE's Second Generation Surveillance System (SGSS). Elastic net regularization and generalized boosted regression models were used to evaluate associations between antibiotic prescribing and trimethoprim resistance, both measured at Clinical Commission Group level. Results: In total, 2487635 (99%) of 2513285 urine Enterobacteriaceae samples from 1667839 patients were tested for trimethoprim resistance. Using both elastic net regularization and generalized boosted regression models, geographical variation in trimethoprim resistance among Enterobacteriaceae urinary samples could be partly explained by geographical variation in use of trimethoprim (relative risk=1.14, 95% CI=1.02-1.75; relative influence=4.1) and penicillins with extended spectrum (mainly amoxicillin/ampicillin in England) (relative risk=1.19, 95% CI=1.11-1.30; relative influence=7.4). Nitrofurantoin use was associated with lower trimethoprim resistance levels (relative risk=0.83, 95% CI= 0.57-0.96; relative influence=9.2). Conclusions: Use of amoxicillin/ampicillin explained more of the variance in trimethoprim resistance than trimethoprim use, suggesting that co-selection by these antibiotics is an important driver of trimethoprim resistance levels at the population level. Nitrofurantoin usewas consistently associated with lower trimethoprim resistance levels, indicating that trimethoprim resistance levels could be lowered if trimethoprim use is replaced by nitrofurantoin.