Azithromycin with or without cefixime for suspected or culture-confirmed uncomplicated typhoid fever in Nepal, Bangladesh, and Pakistan (ACT-South Asia): a double-blind, parallel-group, randomised, placebo-controlled, phase 4 trial

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BACKGROUND: WHO recommends azithromycin for uncomplicated typhoid fever treatment. Cefixime is also commonly used, but both drugs have reported failure rates of 10% or more. We hypothesised that combining azithromycin's intracellular activity with the extracellular activity of cefixime could overcome each drugs' pharmacokinetic gaps and enhance tissue sterilisation. The study objective was to determine if a combination of azithromycin and cefixime would reduce treatment failure rates compared with azithromycin alone. METHODS: We did a double-blind, parallel-group, randomised, placebo-controlled, phase 4 trial in adults and children in Nepal, Bangladesh, and Pakistan with blood culture-confirmed or clinically suspected uncomplicated typhoid fever. Participants aged 2-65 years attending emergency and outpatient clinics with acute undifferentiated febrile illness lasting 3-14 days, C-reactive protein at least 10 mg/L, and negative tests for dengue, scrub typhus, malaria, and COVID-19, were randomly assigned 1:1 to receive oral azithromycin (20 mg/kg [maximum 1 g] once daily) and cefixime (10 mg/kg [maximum 400mg] twice daily) or oral azithromycin and placebo for 7 days. We used computer-generated block randomisation with blocks of 4 and 6, stratified by site and age; treatment allocation was concealed from all study personnel and participants throughout the study period. The primary outcome was a composite measure of treatment failure (fever clearance time ≥7 days, microbiological failure at day 7, need for rescue treatment, or typhoid fever complication or relapse within 28 days), which was analysed in the modified intention-to-treat population, defined as all randomly assigned participants who received at least one dose of study drug and did not test positive for COVID-19 by PCR at baseline. This trial is registered with ClinicalTrials.gov, NCT04349826, and has completed enrolment. FINDINGS: Between May 9, 2021, and Sept 30, 2025, we screened 46 947 individuals for eligibility, and 1847 were randomly assigned (926 to azithromycin-cefixime and 921 to azithromycin-placebo). 1831 eligible participants (350 with blood culture-confirmed typhoid) were included in the modified intention-to-treat population; 915 were assigned to azithromycin-cefixime and 916 to azithromycin-placebo. 44 (5·1%) participants had treatment failure in each group (absolute risk difference -0·00 percentage points, 95% CI -2·08 to 2·08; p=1·00). 19 (11·2%) of 179 culture-confirmed participants had treatment failure in the azithromycin-cefixime group versus 26 (16·0%) of 171 in the azithromycin-placebo group (absolute risk difference 4·48 percentage points, 95% CI -2·52 to 12·21; p=0·20). Adverse events occurred in 142 (16%) of 918 participants in the azithromycin-cefixime group and 144 (16%) of 917 in the azithromycin-placebo group. Serious adverse events requiring hospitalisation occurred in 21 participants (2%) and 17 participants (2%), respectively. INTERPRETATION: This study supports the WHO recommendation of oral azithromycin alone for treatment of clinically suspected or culture-confirmed uncomplicated typhoid fever,providing no evidence to support addition of cefixime, which has important implications for antimicrobial stewardship. FUNDING: The Department of Health and Social Care, the Foreign, Commonwealth & Development Office, the Medical Research Council, and Wellcome Trust.

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