Activities of New Macrolides and Fluoroquinolones against Mycobacterium ulcerans Infection in Mice

220

212

Mycobacterium ulcerans disease is common in some humid tropical areas, particularly in parts of West Africa, and current management is by surgical excision of skin lesions ranging from early nodules to extensive ulcers (Buruli ulcer). Antibiotic therapy would be more accessible to patients in areas of Buruli ulcer endemicity. We report a study of the efficacy of antibiotics in converting early lesions (nodules and plaques) from culture positive to culture negative. Lesions were excised either immediately or after treatment with rifampin orally at 10 mg/kg of body weight and streptomycin intramuscularly at 15 mg/kg of body weight daily for 2, 4, 8, or 12 weeks and examined by quantitative bacterial culture, PCR, and histopathology for M. ulcerans. Lesions were measured during treatment. Five lesions excised without antibiotic treatment and five lesions treated with antibiotics for 2 weeks were culture positive, whereas three lesions treated for 4 weeks, five treated for 8 weeks, and three treated for 12 weeks were culture negative. No lesions became enlarged during antibiotic treatment, and most became smaller. Treatment with rifampin and streptomycin for 4 weeks or more inhibited growth of M. ulcerans in human tissue, and it provides a basis for proceeding to a trial of antibiotic therapy as an alternative to surgery for early M. ulcerans disease.

mentioning

confidence: 96%

Efficacy of the Combination Rifampin-Streptomycin in Preventing Growth of Mycobacterium ulcerans in Early Lesions of Buruli Ulcer in Humans

Etuaful

Carbonnelle

Grosset

et al. 2005

220

212

“…Traditionally, BU was managed by surgical excision with or without skin grafting. Antimicrobial therapy was thought to be ineffective until experiments in the mouse footpad model demonstrated the efficacy of combinations composed of an aminoglycoside and rifampin (RIF) (2,6,13). Subsequent clinical experience has confirmed that 2 months of streptomycin (STR) and RIF is the treatment of choice for all forms of BU, although adjunctive surgery may be necessary to heal large ulcers (4,7,12,14).…”

mentioning

confidence: 99%

Using Bioluminescence To Monitor Treatment Response in Real Time in Mice with Mycobacterium ulcerans Infection

Zhang

Converse

et al. 2011

Mycobacterium ulcerans causes Buruli ulcer, a potentially disabling ulcerative skin disease. Only recently was antimicrobial therapy proven effective. Treatment for 2 months with rifampin plus streptomycin was first proposed after experiments in the mouse footpad model demonstrated bactericidal activity. This treatment is now considered the treatment of choice, although larger ulcers may require adjunctive surgery. Shorter, oral regimens are desired, but evaluating drug activity in mice is hampered by the very slow growth of M. ulcerans, which takes 3 months to produce countable colonies. We created a recombinant bioluminescent M. ulcerans strain expressing luxAB from Vibrio harveyi for real-time evaluation of antimicrobial effects in vivo. Mouse footpads were injected with wild-type M. ulcerans 1059 (WtMu) or the recombinant bioluminescent strain (rMu). Two weeks later, mice received rifampin plus streptomycin, kanamycin alone (to which rMu is resistant), or streptomycin alone for 4 weeks and were observed for footpad swelling (preventive model). Untreated controls and kanamycin-treated rMu-infected mice received rifampin plus streptomycin for 4 weeks after developing footpad swelling (curative model). Compared to WtMu, rMu exhibited similar growth and virulence in vivo and similar drug susceptibility. A good correlation was observed between luminescence (measured as relative light units) and number of viable bacteria (measured by CFU) in footpad homogenates. Proof of concept was also shown for serial real-time evaluation of drug activity in live mice. These results indicate the potential of bioluminescence as a real-time surrogate marker for viable bacteria in mouse footpads to accelerate the identification of new treatments for Buruli ulcer.

“…In vitro, M. ulcerans has been shown to be susceptible to rifampin (13), aminoglycosides (7), macrolides (21), and quinolones (26). Infection of mouse footpads has been used as a model for susceptibility testing, and after treatment with the same antibiotics, the lesions became smaller and the total number of M. ulcerans organisms in tissue was reduced (2,8,25). The combination of rifampin with amikacin or streptomycin for 8 weeks has been the most effective in reducing the bacterial load in a number of studies, and the low relapse rate after treatment suggested that this combination was bactericidal (2,15).…”

mentioning

confidence: 99%

Clinical Efficacy of Combination of Rifampin and Streptomycin for Treatment ofMycobacterium ulceransDisease

Sarfo

Phillips

Asiedu

et al. 2010

108

137

We have evaluated the clinical efficacy of the combination of oral rifampin at 10 mg/kg of body weight and intramuscular streptomycin at 15 mg/kg for 8 weeks (RS8), as recommended by the WHO, in 160 PCRconfirmed cases of Mycobacterium ulcerans disease. In 152 patients (95%) with all forms of disease from early nodules to large ulcers, with or without edema, the lesions healed without recourse to surgery. Eight patients whose ulcers were healing poorly had skin grafting after completion of antibiotics. There were no recurrences among 158 patients reviewed at the 1-year follow-up. The times to complete healing ranged from 2 to 48 weeks, according to the type and size of the lesion, but the average rate of healing (rate of reduction in ulcer diameter) varied widely. Thirteen subjects had positive cultures for M. ulcerans during or after treatment, but all the lesions healed without further antibiotic treatment. Adverse events were rare. These results confirm the efficacy of RS8 delivered in a community setting.Mycobacterium ulcerans disease, known as Buruli ulcer, is a chronic subcutaneous infection which is common in humid rural tropical areas. The majority of patients are children aged less than 15 years living in rural areas remote from a hospital (29). Infection initially manifests as a painless nodule or plaque which breaks down centrally to form an ulcer with undermined edges (11). In a small proportion of lesions, there is edema around the ulcer which spreads rapidly, resulting in a very large ulcer. Significant morbidity results from Mycobacterium ulcerans disease when there is extensive scarring or functional limitation from contractures at joints, and there is occasionally a need for amputation of a limb. Ulcers or scars rarely undergo malignant transformation (12).Until recently, the mainstay of treatment for Buruli ulcer was excision of lesions with a wide margin to ensure complete removal of infected tissue. Recurrence rates after surgery varied between 6 and 17%, depending on the type and extent of the lesion and on the experience and skill of the surgeon (1,6,22). Recent evidence that antibiotics are effective has shifted the balance between surgery and antibiotics. In vitro, M. ulcerans has been shown to be susceptible to rifampin (13), aminoglycosides (7), macrolides (21), and quinolones (26). Infection of mouse footpads has been used as a model for susceptibility testing, and after treatment with the same antibiotics, the lesions became smaller and the total number of M. ulcerans organisms in tissue was reduced (2,8,25). The combination of rifampin with amikacin or streptomycin for 8 weeks has been the most effective in reducing the bacterial load in a number of studies, and the low relapse rate after treatment suggested that this combination was bactericidal (2, 15). An important reason for using more than one drug is that resistant mutants were found after rifampin monotherapy in mice (16).The bactericidal effect of rifampin at 10 mg/kg of body weight orally combined with streptomycin at 15 mg/k...