No abstract

Eight weeks of treatment with rifampin-streptomycin sterilizes Mycobacterium ulcerans infection in mice. Because the bactericidal activity against M. ulcerans of the combination rifampin-moxifloxacin, rifampinclarithromycin, or moxifloxacin-clarithromycin was similar to that of rifampin-streptomycin, these combinations might be considered as alternative, orally administered combined regimens for treatment of Buruli ulcer in humans.

The curing activities of various durations of treatment with a combination of rifampin (RIF) and either streptomycin (STR) or amikacin (AMK) in murine Mycobacterium ulcerans infection were compared in two experiments. In the first experiment, treatment was begun 1 week after infection, when the inflammatory footpad lesion had not yet occurred (preventive model), and in the second experiment, treatment was begun 6 weeks after infection, when inflammatory footpad lesions were established (curative model). In the first experiment, 4 weeks of treatment with daily RIF-STR or RIF-AMK was able to postpone the occurrence of footpad lesion by 12 weeks (RIF-STR) or 17 weeks (RIF-AMK), thus demonstrating their promising bactericidal activities, but neither treatment was able to prevent the late occurrence of footpad lesions. In the second experiment, the overall cure rates, as assessed by the lack of rebound of inflammatory lesions or remultiplication of M. ulcerans, were only 62% after 2 weeks of treatment with RIF and an aminoglycoside and 85% after 4 weeks; but the cure rate reached 100% after 8 or 12 weeks of treatment. The cure rates were slightly higher with the AMK-containing combination than with the STR-containing combination, but the difference was at the limit of significance (P ‫؍‬ 0.07). These results show that in the murine model of Buruli ulcer, 8 weeks is the optimal duration of treatment with a combination of RIF and an aminoglycoside.Buruli ulcer, or Mycobacterium ulcerans infection, is a major emerging disease and the third most common mycobacterial disease in humans after tuberculosis and leprosy. It has been reported from over 30 countries in Africa, Southeast Asia, and South America and from Australia (9-11). Until recently, the standard treatment has been wide surgical excision followed by skin grafting (10), but surgical treatment is often not available in rural areas where the disease is endemic. Therefore, development of an effective and affordable drug treatment is a research priority for the control of Buruli ulcer (9). The recent demonstration of the promising therapeutic effects of the combination of rifampin (RIF) and streptomycin (STR) in human clinical trials (5; A. Chauty, 8th Annu. World Health Organization Advisory Group Meet. Buruli ulcer, 2005) is a major breakthrough in the treatment of Buruli ulcer, representing the first evidence that preulcerative or small to moderately sized Buruli ulcers may be cured by chemotherapy without surgery (Chauty, 8th Annu. World Health Organization Advisory Group Meet. Buruli ulcer). Nevertheless, the optimal duration of treatment with RIF-STR remains to be determined. Furthermore, the combination of RIF plus amikacin (AMK), another aminoglycoside, also displays powerful bactericidal activity against M. ulcerans in mice (3, 6), but the optimal duration of treatment with this combination is also unknown.The objectives of the study were to compare the activities of the combinations of RIF-STR and RIF-AMK in a preventive and curative model of M. ulcerans ...