title: Efficacy of Rifampin Plus Clofazimine in a Murine Model of Mycobacterium ulcerans Disease.
abstract: Treatment of Buruli ulcer, or Mycobacterium ulcerans disease, has shifted from surgical excision and skin grafting to antibiotic therapy usually with 8 weeks of daily rifampin (RIF) and streptomycin (STR). Although the results have been highly favorable, administration of STR requires intramuscular injection and carries the risk of side effects, such as hearing loss. Therefore, an all-oral, potentially less toxic, treatment regimen has been sought and encouraged by the World Health Organization. A combination of RIF plus clarithromycin (CLR) has been successful in patients first administered RIF+STR for 2 or 4 weeks. Based on evidence of efficacy of clofazimine (CFZ) in humans and mice with tuberculosis, we hypothesized that the combination of RIF+CFZ would be effective against M. ulcerans in the mouse footpad model of M. ulcerans disease because CFZ has similar MIC against M. tuberculosis and M. ulcerans. For comparison, mice were also treated with the gold standard of RIF+STR, the proposed RIF+CLR alternative regimen, or CFZ alone. Treatment was initiated after development of footpad swelling, when the bacterial burden was 4.64±0.14log10 CFU. At week 2 of treatment, the CFU counts had increased in untreated mice, remained essentially unchanged in mice treated with CFZ alone, decreased modestly with either RIF+CLR or RIF+CFZ, and decreased substantially with RIF+STR. At week 4, on the basis of footpad CFU counts, the combination regimens were ranked as follows: RIF+STR>RIF+CLR>RIF+CFZ. At weeks 6 and 8, none of the mice treated with these regimens had detectable CFU. Footpad swelling declined comparably with all of the combination regimens, as did the levels of detectable mycolactone A/B. In mice treated for only 6 weeks and followed up for 24 weeks, there were no relapses in RIF+STR treated mice, one (5%) relapse in RIF+CFZ-treated mice, but >50% in RIF+CLR treated mice. On the basis of these results, RIF+CFZ has potential as a continuation phase regimen for treatment of M. ulcerans disease.
authors.affiliation: Johns Hopkins University Center for Tuberculosis Research, Baltimore, Maryland, United States of America.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Converse
authors.affiliation: Johns Hopkins University Center for Tuberculosis Research, Baltimore, Maryland, United States of America.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Tyagi
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Yalan
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Johns Hopkins University Center for Tuberculosis Research, Baltimore, Maryland, United States of America.
authors.forename: Si-Yang
authors.initials: SY
authors.lastname: Li
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kishi
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: John
authors.initials: J
authors.lastname: Adamson
authors.affiliation: Johns Hopkins University Center for Tuberculosis Research, Baltimore, Maryland, United States of America.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
authors.affiliation: Johns Hopkins University Center for Tuberculosis Research, Baltimore, Maryland, United States of America.
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Grosset
mesh_terms: D000818:Animals; D054312:Buruli Ulcer / Q000188:drug therapy*; D017291:Clarithromycin / Q000494:pharmacology; D002991:Clofazimine / Q000493:pharmacokinetics / Q000494:pharmacology*; D015169:Colony Count, Microbial; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination / Q000379:methods*; D005528:Foot / Q000473:pathology; D018942:Macrolides / Q000302:isolation & purification; D051379:Mice; D008826:Microbial Sensitivity Tests; D012293:Rifampin / Q000494:pharmacology*; D013307:Streptomycin / Q000494:pharmacology; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018942:Macrolides; C117218:mycolactone; D002991:Clofazimine; D017291:Clarithromycin; D012293:Rifampin; D013307:Streptomycin