Safety of sulfamethoxazole–trimethoprim for the treatment of bacterial infection in outpatient settings: A systematic review and meta‐analysis with active comparator disproportionality analysis

Abstract

AIMS: Sulfamethoxazole-trimethoprim (SMX-TMP) is a widely used antibiotic for treating bacterial infections, but its safety in adult outpatients remains understudied. This systematic review and meta-analysis evaluated the safety profile of SMX-TMP and identified critical research gaps. The pharmacovigilance study aimed to validate and extend findings from meta-analyses to better understand the real-world safety of SMX-TMP. METHODS: We searched MEDLINE and Embase up to 12 August 2024, to identify studies comparing adverse drug events (ADEs) following SMX-TMP vs. other antibiotics in adult outpatients. Meta-analyses were performed where data allowed. A pharmacovigilance study using the Food and Drug Administration Adverse Event Reporting System was conducted to supplement our findings. RESULTS: = 0%, n = 4458 participants, 24 randomized control trials). Pharmacovigilance data confirmed a higher frequencies of skin disorders and other ADEs compared to various comparator drugs. Compared to azithromycin, SMX-TMP was associated with a 5-fold increase in Stevens-Johnson syndrome, a 3-fold increase in toxic epidermal necrolysis, and a 10-fold increase in drug reaction with eosinophilia and systemic symptoms. Additionally, SMX-TMP showed a 10-fold increase in reports of pancytopenia, a 6-fold increase in neutropenia, a 4-fold increase in both thrombocytopenia and aplastic anaemia, a 56-fold increase in hyperkalaemia, and a 10-fold increase in hyponatraemia. CONCLUSION: Our meta-analyses and pharmacovigilance study suggested SMX-TMP was associated with increased risk of ADEs compared to other antibiotics including amoxicillin/clavulanate, azithromycin and nitrofurantoin. Further robust research is essential to confirm these safety signals and guide clinical practice.

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