Bactericidal Activity Does Not Predict Sterilizing Activity: The Case of Rifapentine in the Murine Model of Mycobacterium ulcerans Disease.

Background: Since 2004, treatment of Mycobacterium ulcerans disease, or Buruli ulcer, has shifted from surgery to daily treatment with streptomycin (STR) + rifampin (RIF) for 8 weeks. For shortening treatment duration, we tested the potential of daily rifapentine (RPT), a long-acting rifamycin derivative, as a substitute for RIF. Methodology/Principal Findings: BALB/c mice were infected with M. ulcerans in the right hind footpad and treated either daily (7/7) with STR+RIF or five days/week (5/7) with STR+RIF or STR+RPT for 4 weeks, beginning 28 days after infection when CFU counts were 4.88±0.51. The relative efficacy of the drug treatments was compared by footpad CFU counts during treatment and median time to footpad swelling after treatment cessation as measure of sterilizing activity. All drug treatments were bactericidal. After 1 week of treatment, the decline in CFU counts was significantly greater in treated mice but not different between the three treated groups. After 2 weeks of treatment, the decline in CFU was greater in mice treated with STR+RPT 5/7 than in mice treated with STR+RIF 7/7 and STR+RIF 5/7. After 3 and 4 weeks of treatment, CFU counts were nil in mice treated with STR+RPT and reduced by more than 3 and 4 logs in mice treated with STR+RIF 5/7 and STR+RIF 7/7, respectively. In sharp contrast to the bactericidal activity, the sterilizing activity was not different between all drug regimens although it was in proportion to the treatment duration. Conclusions/Significance: The better bactericidal activity of daily STR+RIF and especially of STR+RPT did not translate into better prevention of relapse, possibly because relapse-freecure after treatment of Buruli ulcer is more related to the reversal of mycolactone-induced local immunodeficiency by drug treatment rather than to the bactericidal potency of drugs. Author Summary: Until 2004, the treatment of Buruli ulcer (BU) was surgical excision followed by skin grafting. Now an 8-week daily regimen of streptomycin and rifampin (STR+RIF) is recommended by the World Health Organization, supplemented when necessary by surgical intervention. However, such an antimicrobial treatment is still a heavy burden in settings with limited public health infrastructure. Thus it would be beneficial to shorten the duration of treatment without reducing antibacterial activity. Among the more active drugs having the potential to reduce the duration of treatment is rifapentine (RPT), a rifamycin derivative with a much longer half-life than RIF, which permitted in mice the reduction of treatment duration for tuberculosis from 6 months to 3 months when it is substituted for RIF tuberculosis. We therefore compared in the mouse daily treatment of BU with STR+RIF and with STR+RPT. As expected, treatment with RPT was much more bactericidal than treatment with RIF, but surprisingly the relapse rate and the time to relapse after stopping treatment were not different between treatment groups. Such findings raise numerous issues on the mechanisms involved in the cure of Buruli ulcer and on the impact of bactericidal activities of rifamycin derivatives in this disease. [ABSTRACT FROM AUTHOR]