Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer

Paul J. Converse, Deepak V. Almeida, Rokeya Tasneen, Vikram Saini, Sandeep Tyagi, Nicole C. Ammerman, Si Yang Li, Nicole M. Anders, Michelle A. Rudek, Jacques H. Grosset, Eric L. Nuermberger

Research output: Contribution to journalArticlepeer-review

Abstract

Starting in 2004, the standard regimen for treatment of Buruli ulcer (BU) recommended by the World Health Organization has been daily treatment for eight weeks with rifampin (RIF) and streptomycin. Based on recent clinical trials, treatment with an all-oral regimen of RIF and clarithromycin (CLR) may be an effective alternative. With the achievement of an all-oral regimen, a new goal is to find a regimen that can shorten the duration of treatment without compromising efficacy. We recently observed that increasing the dose of RIF from the standard 10 mg/kg dose to 20 or 40 mg/kg, or replacing RIF with the more potent long-acting rifamycin, rifapentine (RPT) at 10 mg/kg or 20 mg/kg increased the bactericidal activity of the RIF+CLR regimen in a mouse model of BU. We also recently showed that replacing CLR with clofazimine(CFZ) at 25 mg/kg may have greater sterilizing activity than the RIF+CLR regimen. Here, we demonstrate that combining high-dose rifamycins with CFZ at a lower dose of 12.5 mg/kg results in similar reductions in swelling, bacterial burden and mycolactone concentrations in mouse footpads compared to the standard regimens and more rapid sterilization of footpads as determined by the proportions of footpads harboring viable bacteria three months after completion of treatment. The potential of these high-dose rifamycin and CFZ combinations to shorten BU treatment to four weeks warrants evaluation in a clinical trial. Trial registration: ClinicalTrials.gov NCT03474198, NCT01659437.

Original languageEnglish (US)
Article numbere0006728
JournalPLoS neglected tropical diseases
Volume12
Issue number8
DOIs
StatePublished - Aug 2018

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

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