Oral Antibiotic Proves Non-Inferior to Injectable and Oral Regimen for Bubonic Plague

Ten days of oral ciprofloxacin proved non-inferior to 3 days of injectable aminoglycoside followed by 7 days of ciprofloxacin for bubonic plague, in an open-label trial¹ conducted over 5 transmission seasons in endemic regions of Madagascar. Both regimens are approved by the WHO, CDC, and FDA for treatment of plague, but the investigators of the current trial indicate that the approval was based on "weak evidence," and that their data confirms effectiveness of a regimen with lower cost and fewer logistical barriers.

"Our trial filled this knowledge gap by generating evidence of the efficacy and safety of two regimens included in the Madagascar and international treatment guidelines for bubonic plague," indicate lead author Rindra Randrermanana, PhD, Institut Pasteur de Madagascar, Antananarivo, and colleagues.

The investigators conducted the trial in 47 remote sites in Madagascar seasonally for 5 years 2020-2024; constituting a cohort of 220 patients with confirmed plague who were assigned 1:1 to the two treatment regimens.The primary efficacy end point was treatment failure, assessed on day 11, with a composite measure of death, fever, development of secondary pneumonic plague, or receipt of alternative or additional treatment. Secondary efficacy end point was treatment failure with a reduction in bubo size of less than 25% at day 11.

The oral only regimen was ciprofloxacin 500mg twice daily in adults, and 15mg/kg body weight twice daily, not exceeding 500mg dose, in children. The combination consisted of streptomycin intramuscularly 1gm twice daily in adults and 15mg/kg twice daily for children for 3 days, followed by 7 days of the oral ciprofloxacin. Streptomycin became unavailable during the 5 year study, and was replaced with gentamycin intravenously 2.5mg/kg twice daily.All patients were hospitalized for the first 3 days of treatment, and then followed daily by community health workers.

The investigators reported that the ciprofloxacin monotherapy was noninferior to the aminoglycoside-ciproflaxcin combination for confirmed or probable infection, with treatment failure of 9.0% compared to 8.1% of those on the combination regimen.The incidence of adverse events was similar in the two groups; 18.0% in the ciprofloxacin group and 18.9% in the aminoglycoside combination group.

Although demonstrating comparable efficacy, the investigators point out the disparity in cost and logistics of administration."A regimen including gentamycin (when streptomycin was unavailable) has practical limitations because it requires twice-daily (intravenous) injections and is substantially more expensive; approximately $14USD for intravenous injections and $6.50 for intramuscular injections as compared with $0.75 for ciprofloxacin alone," Randremanana and colleagues point out, "in addition to indirect costs borne by the patient for accommodation and subsistence in several settings in Madagascar."

In an accompanying editorial,² Paul Mead, MD, MPH, Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Diseases, Centers for Disease Control and Prevention, Fort Collins, CO, praised the study for contributing valuable evidence on the effectiveness of an all oral regimen for plague, as well as supporting use of the Animal Efficacy Rule by the FDA to approve fluoroquinolones for the treatment of plague in absence of a clinical trial

The rule was applied with acknowledgement of the difficulties in conducting a trial in the rural, resource-limited areas where plague occurs most commonly. "This trial was successful, but it is one of very few in more than half a century," Mead pointed out.

References

1. Randrermanana RV, Raberahona M, Borner J, et al. Ciprofloxacin versus aminoglycoside-ciprofloxacin for bubonic plague. N Engl J Med 2025; 393:544-555.

2. Mead P. Chipping away at an old foe. N Engl J Med 2025; 393:603-604.