Background: Plague is a high-consequence infectious disease with epidemic potential. Current treatment guidelines are based on weak evidence.

Methods: We enrolled persons (excluding pregnant persons) in Madagascar who had clinically suspected bubonic plague during 2020-2024. Using an open-label noninferiority design, we compared two treatments included in the national plague guidelines: oral ciprofloxacin for 10 days (ciprofloxacin monotherapy) or injectable aminoglycoside for 3 days followed by oral ciprofloxacin for 7 days (aminoglycoside-ciprofloxacin). The primary end point was treatment failure on day 11, with treatment failure defined as death, fever, secondary pneumonic plague, or alternative or prolonged plague treatment. To show noninferiority of ciprofloxacin monotherapy among patients with laboratory-confirmed or probable infections, the upper boundary of the 95% confidence interval around the risk difference had to be less than 15 percentage points.

Results: A total of 933 patients underwent screening; 450 patients with suspected bubonic plague were enrolled and underwent randomization. A total of 220 patients (110 per group) had confirmed infection, and 2 (1 per group) had probable infection. Of the patients who underwent randomization, 53.2% were male, and the median age was 14 years (range, 2 to 72). Ciprofloxacin monotherapy was noninferior to aminoglycoside-ciprofloxacin therapy: among the patients with confirmed or probable infection, treatment failure occurred in 9.0% (10 of 111 patients) in the ciprofloxacin monotherapy group and 8.1% (9 of 111 patients) in the aminoglycoside-ciprofloxacin group (difference, 0.9 percentage points; 95% confidence interval, -6.0 to 7.8). Noninferiority was consistent in other prespecified analysis populations. A total of 5 patients in the ciprofloxacin monotherapy group and 4 patients in the aminoglycoside-ciprofloxacin group died, and secondary pneumonic plague developed in 3 patients in each group. The incidence of adverse events among patients with confirmed or probable infections was similar in the two groups - 18.0% in the ciprofloxacin monotherapy group and 18.9% in the aminoglycoside-ciprofloxacin group had adverse events, and 7.2% and 5.4%, respectively, had serious adverse events.

Conclusions: Oral ciprofloxacin monotherapy for 10 days was noninferior to an aminoglycoside-ciprofloxacin sequential combination for the treatment of patients with bubonic plague. (Funded by the U.K. Foreign, Commonwealth, and Development Office and Wellcome; IMASOY ClinicalTrials.gov number, NCT04110340.).