Trimethoprim-Sulfamethoxazole and Acute Respiratory Failure in Adolescents and Young Adults.

Importance: The US Food and Drug Administration (FDA) has issued a warning and a label change regarding a potential association between trimethoprim-sulfamethoxazole (TMP-SMX) and acute respiratory failure in healthy adolescents and young adults. Objective: To examine the 30-day risk of a hospital visit (ie, hospitalization or emergency department visit) with acute respiratory failure in adolescents and young adults aged 10 to younger than 25 years old newly dispensed oral TMP-SMX compared with new users of amoxicillin or a cephalosporin. Design, Setting, and Participants: This retrospective, population-based, new-user cohort study in Ontario, Canada (2003-2023) used linked administrative health care data. The TMP-SMX vs amoxicillin and TMP-SMX vs cephalosporins cohorts both included adolescents and young adults aged 10 to younger than 25 years who were newly dispensed oral TMP-SMX, amoxicillin, or cephalosporins for 3 or more days from an outpatient pharmacy. Data were analyzed from January 1 to April 30, 2025. Exposure: TMP-SMX for 3 days or more. Main Outcomes and Measures: The primary outcome was a composite outcome of the 30-day risk of a hospital visit with acute respiratory failure (defined as a diagnosis of acute respiratory failure or receipt of mechanical ventilation, tracheotomy, or extracorporeal membrane oxygenation). Secondary outcomes were the individual components of the composite outcome, all-cause hospitalization, and all-cause mortality. Overlap weighting on the propensity score was used to balance comparison groups on 84 indicators of baseline health. Weighted risk ratios were obtained using log-binomial regression and weighted risk differences using binomial regression. Sensitivity analyses using a negative control outcome, and case-crossover analysis were also performed. Results: The TMP-SMX vs amoxicillin cohort included 575 218 individuals (44 801 TMP-SMX users and 530 417 amoxicillin users; median age after weighting, 19 years [IQR, 16-22 years]; 74.3% female). The TMP-SMX vs cephalosporins cohort included 248 236 individuals (51 197 TMP-SMX users and 197 039 cephalosporin users; median age after weighting, 19 years [IQR, 16-22 years]; 72.3% were female). The risk of the composite outcome occurred in 15 of 44 801 patients (0.03%) who started TMP-SMX and in 49 of 530 417 (0.01%) who started amoxicillin (number of weighted events, 7 of 21 579 [0.03%] for TMP-SMX and 2 of 21 579 [0.01%] for amoxicillin; weighted risk ratio, 2.79 [95% CI, 1.01-7.71]; weighted risk difference, 0.02% [95% CI, 0.001%-0.04%]). The risk of the composite outcome occurred in 17 of 51 197 patients (0.03%) who started TMP-SMX and in 21 of 197 039 (0.01%) who started cephalosporins (number of weighted events, 8 of 20 538 [0.04%] for TMP-SMX and 3 of 20 538 [0.01%] for cephalosporins; weighted risk ratio, 2.85 [95% CI, 1.11-7.31]; weighted risk difference, 0.02% [95% CI, 0.005%-0.05%]). Results were consistent in sensitivity analyses. Conclusions and Relevance: These findings suggest that the 30-day risk of a hospital visit with acute respiratory failure was higher among those receiving TMP-SMX compared with those receiving amoxicillin or cephalosporins. These findings supported the FDA warning, and if replicated, the risks should be carefully weighed against the benefits of TMP-SMX use. Regulatory agencies could reinforce the FDA warning, and product monographs and prescribing guidelines should be updated and revised accordingly.