An open-label, randomized, non-inferiority trial of the efficacy and safety of ciprofloxacin versus streptomycin + ciprofloxacin in the treatment of bubonic plague (IMASOY): study protocol for a randomized control trial

Abstract

Background: Bubonic plague is the primary manifestation of infection with Yersinia pestis, accounting for 90% of all plague cases and with 75% of global cases reported in Madagascar. All drugs in use for treating plague are registered based on experimental data and anecdotal evidence, and no regimen currently recommended is supported by a randomized clinical trial. The IMASOY trial intends to fill this knowledge gap by comparing two 10-day regimens included in the national guidelines in Madagascar. The primary objective of the trial is to test the hypothesis that ciprofloxacin monotherapy is non-inferior to streptomycin followed by ciprofloxacin for the treatment of bubonic plague, thus avoiding the need for injectable, potentially toxic, aminoglycosides. Methods: A two-arm parallel-group randomized control trial will be conducted across peripheral health centres in Madagascar in five districts. Males and non-pregnant females of all ages with suspected bubonic or pneumonic plague will be recruited over the course of three plague 'seasons'. The primary endpoint of the trial is to assess the proportion of patients with bubonic plague who have a therapeutic response to treatment (defined as alive, resolution of fever, 25% reduction in the size of measurable buboes, has not received an alternative treatment and no clinical decision to continue antibiotics) as assessed on day 11. Discussion: If successful, the trial has the potential to inform the standard of care guidelines not just in Madagascar but in other countries afflicted by plague. The trial is currently ongoing and expected to complete recruitment in 2022. Trial registration: ClinicalTrials.gov NCT04110340. Registered on

Transmission of Antimicrobial Resistant Yersinia pestis During a Pneumonic Plague Outbreak

“…Given that AMR/MDR Y. pestis strains continue to emerge in Madagascar, all but one of the 5 AMR/MDR strains identified to date in Madagascar have been resistant to streptomycin, the potential toxicity of this class of antimicrobial, and the need for it to be applied intramuscularly, streptomycin monotherapy is contraindicated and an alternative treatment regimen is warranted. To this end, a plague randomized clinical trial is ongoing for the effectiveness of ciprofloxacin monotherapy in the treatment of plague compared to streptomycin followed by ciprofloxacin [ 34 ].…”

Improved Selective BIN Agar for a Better Rate of Yersinia pestis Isolation from Primary Clinical Specimens in Suspected Madagascar Plague Cases

“…Resistant Y. pestis strains may represent a threat to the exposed population if they spread in the environment and when the first-line recommended antibiotic (streptomycin) is no longer available. Fortunately, a clinical study comparing the efficiency of ciprofloxacin alone (an alternative treatment for plague) versus streptomycin-ciprofloxacin (the first-line treatment regimen for bubonic plague in Madagascar) is ongoing in multiple study sites in Madagascar ( 15 ).…”

Antibiotic Therapy of Plague: A Review

“…The clinical data indicate that many classes of antibiotics (i.e., aminoglycosides, tetracyclines, fluoroquinolones, sulfonamides, phenicols, and β-lactams) have been administered to patients with the different forms of plague [ 22 , 75 , 121 , 122 , 123 ]. A review of published case reports found that aminoglycosides, tetracyclines, and fluoroquinolones (but not sulfonamides) were most consistently effective in the treatment of pneumonic plague.…”

“…The data did not indicate that one class of antibiotic was superior to the others. Lastly, in response to Madagascar’s 2017 plague epidemic, a randomized clinical trial of the efficacy of ciprofloxacin alone vs. streptomycin followed by ciprofloxacin is ongoing [ 122 ].…”