Bubonic Plague Bowled Over by Oral Antibiotics

Researchers in Madagascar have reported the first randomised controlled trial for the treatment of bubonic plague. Published in The New England Journal of Medicine, the study found that “oral ciprofloxacin monotherapy for 10 days was non-inferior to an aminoglycoside-ciprofloxacin sequential combination for the treatment of patients with bubonic plague.”

The bubonic plague remains endemic to Madagascar, the Democratic Republic of Congo, and Peru. In Madagascar, cases occur almost every year during the epidemic season from September to April.

Current treatment guidelines are based on weak evidence, and until now, no randomised controlled trial has directly compared therapeutic options.

According to Madagascar’s national guideline, adults are treated with 3 days of injectable aminoglycosides, such as streptomycin or gentamicin, followed by 7 days of oral ciprofloxacin. Oral ciprofloxacin monotherapy is recommended as the first-line option for children aged less than 15 years.

“The lack of higher-quality evidence supporting treatment regimens and the shortcomings of aminoglycosides (eg, delivery by injection, unacceptable side effects, and poor intracellular penetration) prompted us to design this randomized controlled trial to compare the two treatment options,” wrote lead author Rindra Vatosoa Randremanana, PhD, Institut Pasteur de Madagascar, Antananarivo, Madagascar.

The open label, noninferiority IMASOY study, conducted between 2020 and 2024, enrolled 450 patients with suspected bubonic plague. Of these, 220 were laboratory-confirmed, and two had probable infection. The participants were 2-72 years old, with a median age of 14.

The bubonic plague, known as the “Black Death” in the Middle Ages, has claimed millions of lives over centuries. It is caused by the gram-negative bacterium Yersinia pestis, which circulates mainly among rodents and their fleas. Although rare, the disease persists. In 2018, the World Health Organization reported 248 cases worldwide, mostly in Madagascar and the Democratic Republic of Congo.

Sulfonamides were the first treatment in the 1930s, effective only for bubonic plague and not for pneumonic plague. A major advance was made in 1948 with streptomycin, the first antibiotic effective against severe pneumonic plague. 

Studies in India and Madagascar have confirmed its efficacy, and streptomycin has remained the standard for decades.

In 2015, the US FDA approved ciprofloxacin for plague under the “Animal Rule,” allowing approval based on animal data when human trials are not feasible. There are no comparable regulations in the European Union where ciprofloxacin is used off-label for plague infections.

In 2017, a major outbreak of bubonic plague occurred in Madagascar’s capital, Antananarivo, with over 2400 suspected cases. At the time, the standard treatment was twice-daily streptomycin injections for 7 days, a regimen difficult to implement widely. The outbreak highlighted the challenges of applying this treatment across the population. The new study suggests that a fully oral ciprofloxacin regimen could offer an even simpler and effective alternative.

The study compared the 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 endpoint was treatment failure on day 11, with treatment failure defined as death, fever, secondary pneumonic plague, or alternative or prolonged plague treatment.

Ciprofloxacin monotherapy was non-inferior to aminoglycoside-ciprofloxacin therapy among patients with confirmed or probable infection.

Treatment failure occurred in 9.0% of patients (10 of 111) receiving 10 days of oral ciprofloxacin and 8.1% (9 of 111) in the control group, which received 3 days of injectable streptomycin followed by 7 days of oral ciprofloxacin, confirming non-inferiority.

The mortality rate was approximately 4% in both the groups. Secondary pneumonic plague developed in three patients per group. Subgroup analyses confirmed the non-inferiority of ciprofloxacin monotherapy.

Adverse events were similar between the groups (18.0% vs 18.9%), with serious adverse events in 7.2% and 5.4%. No severe events were classified as drug-related.

The authors concluded, “In patients with confirmed or suspected bubonic plague, 10 days of oral ciprofloxacin was an effective alternative to a regimen involving an injected aminoglycoside.” They noted that this approach can be more practical and cost-effective in resource-limited settings.

This story was translated from Medscape’s German edition.