Rare but Severe Lung Toxicity With Trimethoprim-Sulfamethoxazole

Source: Ahmadi F, McArthur E, Garcia-Bournissen F, et al. Trimethoprim-sulfamethoxazole and acute respiratory failure in adolescents and young adults. 2025;8(11):e2545251; doi: 10.1001/jamanetworkopen.2025.45251.Investigators from ICES (Institute for Clinical Evaluative Sciences), Toronto, and Western University, London, Ontario, Canada, conducted a retrospective study to assess the association between trimethoprim-sulfamethoxazole (TMP-SMX) usage and acute respiratory failure in adolescents and young adults. For the study, they used administrative health databases to identify 2 cohorts of individuals 10 to <25 years old in Ontario, Canada. One cohort included individuals who had a new prescription for TMP-SMX or amoxicillin for at least 3 days that was dispensed by an outpatient pharmacy between April 2002 and August 2023. The other cohort included adolescents and young adults who had an outpatient prescription for TMP-SMX or a cephalosporin during the same period. The participants in the 2 cohorts were mutually exclusive. The main study outcome was a hospital visit for acute respiratory failure, defined using ICD-10 diagnostic codes, or treatment with mechanical ventilation, tracheotomy, or extracorporeal membrane oxygenation (ECMO) within 30 days of the prescription date. To compare the risk of acute respiratory failure in patients receiving TMP-SMX or amoxicillin, or TMP-SMX or cephalosporin, propensity-scoring weighting was used to identify comparable participants in each group who received TMP-SMX or the other antibiotic. Using the propensity-scored matched populations, the relative risk (RR) for acute respiratory failure in participants receiving TMP-SMX vs the corresponding antibiotic was calculated.The TMP-SMX vs amoxicillin cohort included 575,218 participants, with 44,801 prescribed TMP-SMX and 530,417 receiving amoxicillin. After weighting, data on 21,579 participants in each antibiotic group, with a median age of 19 years, were compared. Acute respiratory failure occurred in 7 (0.03%) of those in the TMP-SMX weighted group and 2 (0.01%) of those receiving amoxicillin (weighted RR, 2.79; 95% CI, 1.01, 7.71). The median duration from the time of the prescription to meeting criteria for acute respiratory failure was 9 days for those receiving TMP-SMX and 20 days for those in the amoxicillin group. The other cohort included 248,236 adolescents and young adults, with 51,197 prescribed TMP-SMX and 197,039 receiving cephalosporins. In the weighted population, which included 20,538 participants in each antibiotic group, with a median age of 19 years, acute respiratory failure occurred in 8 (0.04%) individuals in the weighted population receiving TMP-SMX and in 3 (0.01%) of those in the cephalosporin group (weighted RR, 2.85; 95% CI, 1.11, 7.31). Median time from prescription to meeting criteria for acute respiratory failure was 9 days for participants receiving TMP-SMX or a cephalosporin.The authors conclude that TMP-SMX usage was associated with an increased risk of acute respiratory failure in adolescents and young adults.Dr Raphael has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.In 2019, following the publication of a case series describing 5 previously healthy adolescents who developed acute respiratory failure related to TMP-SMX, the Food and Drug Administration updated its labeling instructions to include lung injury as a potential serious adverse reaction.1,2,3 Similar concerns also have been raised in pharmacovigilance analyses of global databases that compile spontaneous reports of adverse events.4The current study provides the first population-based assessment of the risk of acute respiratory failure associated with short courses of TMP-SMX. The study had several methodological strengths. By using more than 2 decades of longitudinal data from multiple linked administrative databases and capturing nearly all residents within a single-payor system, the study investigators were able to minimize selection bias and loss to follow-up. Confounding was addressed using propensity scores to create well balanced comparison groups and an active comparator design. The cohort was restricted to healthy adolescents and young adults without acute or chronic lung disease, thus reducing the likelihood that acute respiratory failure was due to an underlying disease. The rigorous sensitivity analysis yielded consistent results, enhancing confidence in the observed associations.There were some limitations to this study. Antibiotic exposure (ie, prescriptions) may not represent the patients who actually took their medications. Additionally, residual confounders, such as smoking/vaping and genetic factors, may have influenced the outcome. Despite the statistically significant RR increase of acute respiratory failure with use of TMP-SMX, the absolute risk increase was very small. The investigators reported that for every 4,000 to 5,000 adolescents or young adults treated with TMP-SMX instead of amoxicillin or a cephalosporin, 1 additional hospitalization for acute respiratory failure would occur. Though rare, prior data indicate that when lung toxicity occurs, it can be severe, with reported fatality rates of 26% to 40%.4,5Knowledge of the potential for acute respiratory failure may enable early detection of this adverse outcome in a young patient exposed to TMP-SMX.