The primary measure was a composite outcome of 30-day risk of hospitalization for acute respiratory failure, defined as that diagnosis or receipt of mechanical ventilation, tracheotomy, or extracorporeal membrane oxygenation.The two active comparators with similar bacterial coverage and indications were used to reduce the influence of indication bias. The investigators acknowledge, however, that the cephalosporin class is heterogeneous, and not all may have been suitable comparators to TMP-SMX.
What You Need to Know
TMP-SMX carries a small but significantly higher risk of acute respiratory failure in adolescents and young adults (0.03%) compared with amoxicillin or cephalosporins (0.01%), supporting the 2019 FDA warning.
The risk appears concentrated in a rare, potentially genetically predisposed subgroup, with possible links to immune gene variants (HLA-B07:02, HLA-C07:02) and differences in drug-metabolizing enzymes.
Findings reinforce the need for careful risk–benefit assessment, updates to prescribing guidance, and further research—especially since the study’s limitations mean results cannot be generalized beyond 10–24-year-olds or longer-term TMP-SMX use.
The exposure to TMP-SMX was at least 3 days; and, to ensure a cohort of new users, those prescribed any other antibiotics within 180 days of the studied prescription were excluded. The investigators suggest that the similar baseline characteristics between groups lessened the likelihood that the acute respiratory failure was associated with particular underlying infections rather than the antibiotic comparators. To further lessen this possibility, they excluded individuals with evidence of an active pulmonary infection on the date of their prescription.Their reported 0.02% absolute risk increase of acute respiratory with TMP-SMX relative to either a cephalosporin or amoxicillin was consistent across several sensitivity analyses.
The investigators posit that the rare TMP-SMX user that manifests this adverse outcome may be genetically predisposed. "Variants in immune genes—eg, HLA-B07:02 and HLA-C07:02—and polymorphisms in drug-metabolizing enzymes could impair drug metabolism, leading to toxic intermediates and severe reactions," Muanda and colleagues suggest.
The investigators acknowledged several study limitations, including not having investigated longer durations of TMP-SMX use, such as commonly used in off-label treatment of acne that was the indication in 4 of the 19 adolescents in the original case series. They also emphasize that their findings cannot be generalized to other age groups, or to those at higher risk of respiratory failure such as older adults with prior lung conditions.
"These findings support the FDA warning, warranting replication, careful risk-benefit evaluation, and updates to product monographs and prescribing guidelines," Muanda and colleagues advise.
References
1. Ahmade F, McArthur E, Garcia-Bournissen F, et al. Trimethoprim-Sulfamethoxazole and acute respiratory failure in adolescents and young adults. JAMA Netw Open 2025:8(11). doi:10.1001/jamanetworkopen.2025.4521.
2. New labeling on TMP-SMX products warns of acute respiratory failure. Food and Drug Administration's Office of Pediatric Therapeutics and Center for Drug Evaluation and Research, Division of Pediatric and Maternal Health, Division of Anti-Infectives, and Office of Surveillance and Epidemiology. AAP News. Accessed December 6, 2025. https://www.fda.gov/media/150781/download
3. Miller JO, Taylor J, Goldman JL. Severe acute respiratory failure in healthy adolescents exposed to trimethoprim-sulfamethoxazole. Pediatrics 2019; 143(6): e20183242.
