Trimethoprim-sulfamethoxazole (SXT) versus azithromycin for the treatment of undifferentiated febrile illness in Nepal: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Azithromycin and trimethoprim-sulfamethoxazole (SXT) are widely used to treat undifferentiated febrile illness (UFI). We hypothesized that azithromycin is superior to SXT for UFI treatment, but the drugs are non-inferior to each other for culture-confirmed enteric fever treatment. METHODS: We conducted a double blind, randomized, placebo-controlled trial of azithromycin (20 mg/kg/day) or SXT (trimethoprim 10 mg/kg/day + sulfamethoxazole 50 mg/kg/day) orally for 7 days for UFI treatment in Nepal. We enrolled patients (aged 3-64 years) presenting to two Kathmandu hospitals with temperature ≥ 38.0°C for ≥4 days without localising signs. The primary endpoint was fever clearance time (FCT); secondary endpoints were treatment failure and adverse events. ClinicalTrials.gov number: NCT02773407. RESULTS: From June 2016 to May 2019, we randomized 326 participants (163 in each arm); 87 (26.7%) had blood culture-confirmed enteric fever. In all participants, the median FCT was 2.7 days (95% CI 2.6-3.3) in the SXT arm and 2.1 days (95% CI 1.6-3.2) in the azithromycin arm 1.25 (95% CI 0.99-1.58, P=0.059). The hazard ratio of treatment failures by 28 days between azithromycin and SXT was 0.62 (95% CI 0.37-1.05, p=0.073). Planned sub-group analysis showed azithromycin resulted in faster FCT in those with sterile blood cultures and less relapses in culture-confirmed enteric fever. Nausea, vomiting, constipation, and headache were more common in the SXT arm. CONCLUSIONS: Despite similar FCT and treatment failure in the two arms, significantly fewer complications and relapses make azithromycin a better choice for empirical treatment of UFI in Nepal.