To identify the most active curative treatment of Buruli ulcer, two regimens incorporating the use of rifampin (RIF) were compared with the use of RIF alone in a mouse footpad model of Mycobacterium ulcerans infection. Treatments began after footpad swelling from infection and continued for 12 weeks with five doses weekly of one of the following regimens: (i) 10 mg of RIF/kg alone; (ii) 10 mg of RIF/kg and 100 mg of amikacin (AMK)/ kg; and (iii) 10 mg of RIF/kg, 100 mg of clarithromycin (CLR)/kg, and 50 mg of sparfloxacin (SPX)/kg. The activity of each regimen was assessed in terms of the reduction of the average lesion index and acid-fast bacillus (AFB) and CFU counts. All three regimens displayed various degrees of bactericidal activity against M. ulcerans. The ranking of bactericidal activity was found to be as follows: RIF-AMK > RIF-CLR-SPX > RIF. RIF-AMK was able to cure M. ulcerans-infected mice and prevent relapse 26 weeks after completion of treatment. To determine the impact of different rhythms of administration of RIF-AMK on the suppression of M.ulcerans growth, mice were given the RIF-AMK combination for 4 weeks but doses were administered either 5 days a week or twice or once weekly. After completion of treatment, the mice were kept under supervision for 30 additional weeks. M. ulcerans was considered to have grown in the footpad if swelling was visually observed and harvests contained more than 5 ؋ 10 5 AFB per footpad. The proportion of mice in which growth of M. ulcerans occurred, irrespective of drug dosage, was compared with the control mice to determine the proportion of M. ulcerans killed. Each dosage of RIF-AMK was bactericidal for M. ulcerans (P < 0.001), but the effect was significantly stronger in mice treated 5 days per week. The promising results of RIF-AMK treatment in M. ulcerans-infected mice support the clinical trial that is currently in progress under World Health Organization auspices in Ghana.Buruli ulcer or Mycobacterium ulcerans infection is the third most common mycobacterial disease after tuberculosis and leprosy. Large surgical excision of necrotic tissue, followed by skin grafting is, at present, the only treatment (21). The search for antimycobacterial drugs able to increase efficacy or substitute for surgical treatment is a priority.Using the kinetic method designed by C. C. Shepard for testing antileprosy drug activity in the mouse footpad (17), the following antimicrobials were assessed against M. ulcerans: clarithromycin (CLR), minocycline, sparfloxacin (SPX), rifampin (RIF), rifabutin, and amikacin (AMK). RIF, rifabutin, and AMK exhibited bactericidal activity, whereas CLR and SPX exhibited bacteriostatic activity; minocycline demonstrated no activity (3).Since the RIF-AMK combination was anticipated to be highly potent against M. ulcerans, we initially studied the curative efficacy of this combination. Treatment was given daily for 3 months after mouse footpad swelling from M. ulcerans infection had occurred. Because combined RIF-AMK requires the injection of AMK, a...

Mice infected in the left hind footpad with 5 log 10 acid-fast bacilli of Mycobacterium ulcerans were divided into an untreated control group and 17 treatment groups that received one of the following regimens for 4 weeks (all doses in milligrams per kilogram): 100 mg of azithromycin (AZM), 100 mg of clarithromycin (CLR), or 50 mg of AZM for a duration of 5 days a week (daily), three times a week, or once weekly. In addition, the following regimens were administered daily: 100 mg of telithromycin (TLM), sparfloxacin (SPX), or moxifloxacin (MOX); 200 mg of levofloxacin (LVX); 100 mg of streptomycin (STR) or amikacin (AMK); 10 mg of rifampin (RIF); and the combination of 10 mg of RIF and 100 mg of AMK (RIF؉AMK). After completion of treatment, mice were observed for 30 weeks. The effectiveness of treatment regimens was assessed in terms of the delay in median time to footpad swelling in treated mice compared with that in the untreated controls. Clear-cut bactericidal activity, i.e., an observed delay in footpad swelling that exceeded the period of treatment, was observed in the STR-, AMK-, and RIF؉AMK-treated mice. However, all mice treated with either AMK or STR alone had swollen footpads before the end of the 30-week observation period, suggesting regrowth of M. ulcerans. In contrast, 50% of the mice treated with the RIF؉AMK combination exhibited no lesion even after 30 weeks, suggesting cure. The remaining regimens could be assigned to one of three groups: (i) no activity (50 mg of AZM, 100 mg of AZM thrice weekly, TLM, and LVX); (ii) bacteriostatic activity, i.e., a delay in footpad swelling shorter than the 4-week treatment duration (100 mg of AZM daily or once weekly, CLR thrice or once weekly, and MOX); or (iii) weak bactericidal activity (CLR daily and SPX). The RIF؉AMK combination and possibly RIF؉STR warrant further study for the treatment of M. ulcerans infection in humans.Mycobacterium ulcerans, the only toxin-producing mycobacterial species (5) is responsible for Buruli ulcer (BU), the third most prevalent mycobacterial disease throughout the world (20). Over the past 10 years, an increasing incidence of BU has been reported in several West African countries (6, 8) and Australia (4) and is now reported in most of sub-Saharan Africa, Central and South America, India, Southeast Asia, and Papua New Guinea (20).In vitro, M. ulcerans is susceptible to several antimicrobials, including rifampin (RIF), clarithromycin (CLR), streptomycin (STR), amikacin (AMK), sparfloxacin (SPX), and clofazimine (1,11,13,14,19). However, the clinical response of humans with BU to various antimicrobial regimens containing these drugs have not confirmed in vitro studies so that, to date, BU treatment still relies on extensive surgical excision of the lesions followed by skin grafting (20).In a previous study, the mouse footpad model of Fenner (3) was used to assess the in vivo activity of several drugs against M. ulcerans (2). CLR, for which in vitro activity against M. ulcerans has been demonstrated (11), exhibited only bacteri...

Mice infected with 1.6 x 10(7) CFU of Mycobacterium tuberculosis were treated 14 days later for 6 months with a regimen of once-weekly 10 mg of rifapentine and 75 mg of isoniazid per kg of body weight supplemented with either 150 mg of streptomycin per kg or 100 mg of moxifloxacin per kg during either both the 2-week daily initial and once-weekly continuation phases or only in the daily 2-week initial phase. On completion of treatment, all lung cultures were negative, except for three mice, each with a single colony: two whose rifapentine-isoniazid regimen was supplemented with streptomycin during the whole course of therapy and one whose rifapentine-isoniazid regimen had no initial daily phase, but was supplemented with streptomycin and moxifloxacin during the whole course of therapy. After 3 months of follow-up, positive lung cultures were obtained from 61 and 56% of mice supplemented with streptomycin during either the full course of therapy or only the daily 2-week initial phase, respectively, and 15 and 50% of mice supplemented with moxifloxacin during either the full course of therapy or only the daily 2-week initial phase, respectively. These results suggest that moxifloxacin has sterilizing activity against M. tuberculosis.

Bactericidal activities of HMR 3647 (HMR), moxifloxacin (MXFX), and rifapentine (RPT) againstMycobacterium leprae, measured by the proportional bactericidal technique in the mouse footpad system, were compared with those of the established antileprosy drugs clarithromycin (CLARI), ofloxacin (OFLO), and rifampin (RMP). Administered in five daily doses of 100 mg/kg of body weight, HMR appeared slightly more bactericidal than CLARI. In a single dose, MXFX at 150 mg/kg was more active than the same dose of OFLO and displayed exactly the same level of activity as RMP at 10 mg/kg; the combination MXFX-minocycline (MINO) (MM) was more bactericidal than the combination OFLO-MINO (OM); RPT at 10 mg/kg was more bactericidal than the same dose of RMP and even more active than the combination RMP-OFLO-MINO (ROM); the combination RPT-MXFX-MINO (PMM) killed 99.9% of viable M. leprae and was slightly more bactericidal than RPT alone, indicating that the combination PMM showed an additive effect against M. leprae. Currently, leprosy is treated with multidrug therapy (MDT).Patients with paucibacillary (PB) leprosy are treated for 6 months with two drugs-dapsone (DDS) daily plus rifampin (RMP) monthly, and those with multibacillary (MB) leprosy are treated for 12 or 24 months with a combination of three drugs-DDS and clofazimine (CLO) daily plus RMP and a larger supplemental dose of CLO monthly (18,19). The monthly drug administration is under supervision, whereas the daily drugs are self-administered. Since 1982, more than 10 million leprosy patients in the world have been cured by the treatment (20).Despite the great success of the first MDT regimens, newer regimens are required that are more efficient or operationally less demanding (11). One of the concerns with regard to the current regimens is that it is difficult to persuade patients to comply with the self-administered daily component (3), which is intended to ensure elimination of the spontaneously occurring RMP-resistant mutants before stopping chemotherapy, suggesting that resistance to RMP may still develop among MB patients if the daily DDS-CLO component is not taken regularly. The risk of resistance might be significantly reduced if a fully supervisable, monthly administered MDT regimen were developed, so that all of the components may be administered once monthly under supervision. The recent demonstration of the promising bactericidal activities against Mycobacterium leprae of ofloxacin (OFLO) (6) and minocycline (MINO) (4, 9) led to the development of the monthly administered combined regimen of RMP-OFLO-MINO (ROM) (13). A single dose of ROM exhibited impressive bactericidal activity against M. leprae both in the mouse footpad system and in clinical trial (13); it was only marginally less effective, in terms of clinical improvement, for treatment of single-lesion PB leprosy than the standard 6-month MDT (17,19), and it was well tolerated by the patients (13, 17). The enormous operational advantages of single-dose treatment, especially in a country such as India, ...

Mice were infected intravenously with 3.5 ؋ 10 7 CFU of Mycobacterium xenopi and treated with various clarithromycin-containing regimens or left untreated for 4 weeks. All nine of the clarithromycin-containing regimens reduced the CFU counts to the levels below the pretreatment values, indicating that these regimens had a bactericidal effect on M. xenopi in mice. The rifampin-isoniazid-ethambutol regimen was significantly less bactericidal than clarithromycin alone or clarithromycin-containing combined regimens.