- Design
- Phase 4, double-blind, placebo-controlled randomised trial
- Population
- 1831 patients aged 2–65 with suspected or confirmed uncomplicated typhoid, Nepal, Bangladesh and Pakistan
- Primary outcome
- Composite treatment failure within 28 days
- Effect
- 5.1% vs 5.1%, risk difference 0.00 points (95% CI −2.08 to 2.08); culture-confirmed 11.2% vs 16.0%
ACT-South Asia was a double-blind, placebo-controlled trial in Nepal, Bangladesh and Pakistan. It randomised 1847 patients aged 2 to 65 with suspected or blood culture-confirmed uncomplicated typhoid, after dengue, scrub typhus, malaria and COVID-19 had been excluded. They received 7 days of azithromycin with either cefixime or placebo. The primary outcome was a composite of treatment failure within 28 days. It was published in August 2026.
Treatment failure was 5.1% in both groups. In the 350 culture-confirmed patients, failure was 11.2% with the combination and 16.0% with azithromycin alone, a difference that was not significant. Adverse events were identical at 16%.
For Indian clinicians, where cefixime alone or with azithromycin is widely prescribed for enteric fever, this is directly applicable. It supports the WHO recommendation of oral azithromycin alone for uncomplicated typhoid and gives a clear stewardship reason not to add a second drug. Local resistance patterns still matter, and patients who do not settle need blood cultures and review.
- Use azithromycin 20 mg/kg (maximum 1 g) daily for 7 days for uncomplicated typhoid
- Do not add cefixime routinely
- Exclude dengue, scrub typhus and malaria in acute undifferentiated fever first
- Send blood cultures before starting treatment where possible
- Review patients still febrile at day 7 for complications or resistance
Why it matters
A common two-drug habit for enteric fever adds antibiotic exposure without improving outcomes.
Don't overread it
The culture-confirmed subgroup was small, and its non-significant trend towards fewer failures with the combination is not settled.
The statistics, in plain English
The risk difference of 0.00 percentage points (95% CI −2.08 to 2.08) is narrow, so a meaningful benefit from the combination is unlikely in the overall group. In culture-confirmed patients the interval (−2.52 to 12.21 points) is wide and includes a possible benefit, so the trial cannot rule one out in proven typhoid.
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