Powerful Bactericidal Activities of Clarithromycin and Minocycline against Mycobacterium leprae in Lepromatous Leprosy

Ji, Baohong; Jamet, P; Perani, Evelyne G.; Bobin, P; Grosset, J

doi:10.1093/infdis/168.1.188

Cited by 80 publications

(54 citation statements)

References 5 publications

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“…The skin smears were taken from the same six sites as before treatment, and the skin biopsy was taken from the pretreatment site that had provided M. leprae for mouse inoculation. Compared with pretreatment manifestations, the clinical responses, on the bases of the amelioration of nasal obstruction, regression of infiltration, and flattening or disappearance of nodules, lepromas, or plaques, were scored as no change, definite improvement, and marked improvement (3,6,7).…”

Section: Methodsmentioning

confidence: 99%

Clinical trial of ofloxacin alone and in combination with dapsone plus clofazimine for treatment of lepromatous leprosy

Perani

Petinom

et al. 1994

Antimicrob Agents Chemother

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Twenty-four patients with newly diagnosed lepromatous leprosy were allocated randomly to three groups and treated for 56 days with 400 mg of ofloxacin daily, 800 mg of ofloxacin daily, or 400 mg of ofloxacin, 100 mg of dapsone, and 50 mg of clofazimine daily plus 300 mg of clofazimine once every 28 days. Development and implementation of multidrug therapy (13) are the most important achievements in the history of leprosy control (12). However, the duration of the treatment is too long, especially the minimal duration for multibacillary leprosy therapy, which is 2 years, which causes serious operational difficulties in certain areas (5). Of the three components of the multidrug regimen for multibacillary leprosy, rifampin is the only drug that displays powerful bactericidal activity against Mycobacterium leprae; the other two drugs, dapsone and clofazimine, show only a modest degree of bactericidal activity. Without the introduction of new, more powerful bactericidal drugs to the regimens, it is unlikely that the duration may be substantially shortened (5).Among the major commercially available fluoroquinolones, ofloxacin is by far the most active compound against M. leprae (2). A clinical trial with patients with lepromatous leprosy demonstrated that 400 mg of ofloxacin daily was highly effective, producing very remarkable clinical improvement and killing an average of 99.99% (4 orders of magnitude) of M. leprae organisms after only 22 doses of treatment (3). This observation represented the first lead to an important new antileprosy drug since the introduction of rifampin more than 20 years ago.The current trial was carried out with several objectives in mind. First, because the number of spontaneously arising rifampin-resistant mutants in an untreated lepromatous patient is estimated to be no more than 104 (3, 5), it was necessary to confirm the killing of 99.99% of M. leprae by a short course of ofloxacin treatment. Second, because the activity of ofloxacin against M. leprae (2) and Mycobacterium tuberculosis (11) in mice is dose related, it was important to compare the therapeutic effects of and adverse reactions to 400 mg of ofloxacin daily with those of 800 mg of ofloxacin daily in the treatment of * Corresponding author.human leprosy. The third objective was to determine the usefulness of combining ofloxacin with dapsone and clofazimine in a new multidrug regimen. The bactericidal activities of the treatments were monitored by inoculation into mouse footpads of organisms recovered from skin biopsy specimens taken before and at intervals during treatment (3, 5). Because we already knew that 22 doses of ofloxacin alone killed about 99.99% of the viable organisms, nearly the limit of sensitivity of the technique even with nude mice (3, 5), the duration of the trial was set at 56 days. MATERIALS AND METHODSPatients. Twenty-four newly diagnosed leprosy patients (19 men and 5 women) with a mean age of 38 years (range, 18 to 60 years) who demonstrated large bacterial populations and active skin lesions were sele...

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Section: Methodsmentioning

confidence: 99%

Clinical trial of ofloxacin alone and in combination with dapsone plus clofazimine for treatment of lepromatous leprosy

Perani

Petinom

et al. 1994

Antimicrob Agents Chemother

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“…It displays significant bactericidal activity against M. leprae in humans (127,173). In patients with lepromatous leprosy, daily administration of 500 mg of clarithromycin kills 99% of viable M. leprae within 28 days and Ͼ99.9% by 56 days.…”

Section: Molecular Mechanisms Of Drug Resistancementioning

confidence: 99%

The Continuing Challenges of Leprosy

et al. 2006

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SUMMARY Leprosy is best understood as two conjoined diseases. The first is a chronic mycobacterial infection that elicits an extraordinary range of cellular immune responses in humans. The second is a peripheral neuropathy that is initiated by the infection and the accompanying immunological events. The infection is curable but not preventable, and leprosy remains a major global health problem, especially in the developing world, publicity to the contrary notwithstanding. Mycobacterium leprae remains noncultivable, and for over a century leprosy has presented major challenges in the fields of microbiology, pathology, immunology, and genetics; it continues to do so today. This review focuses on recent advances in our understanding of M. leprae and the host response to it, especially concerning molecular identification of M. leprae, knowledge of its genome, transcriptome, and proteome, its mechanisms of microbial resistance, and recognition of strains by variable-number tandem repeat analysis. Advances in experimental models include studies in gene knockout mice and the development of molecular techniques to explore the armadillo model. In clinical studies, notable progress has been made concerning the immunology and immunopathology of leprosy, the genetics of human resistance, mechanisms of nerve injury, and chemotherapy. In nearly all of these areas, however, leprosy remains poorly understood compared to other major bacterial diseases.

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“…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).…”

Section: Currently Leprosy Is Treated With Multidrug Therapy (Mdt)mentioning

confidence: 99%

“…Four different regimens, all administered as a single dose, are compared in the trial: 400 mg of OFLO plus 100 mg of MINO (OM); 400 mg of MXFX plus 100 mg of MINO (MM); 600 mg of RMP plus 400 mg of OFLO and 100 mg of MINO (ROM); and 600 mg of RPT plus 400 mg of MXFX and 100 mg of MINO (PMM). The efficacy and side effects of the treatments are monitored by the standardized method (6,9,12,13), and the bactericidal effect of the treatment is measured by the proportional bactericidal technique (2).…”

Section: Currently Leprosy Is Treated With Multidrug Therapy (Mdt)mentioning

confidence: 99%

Bactericidal Activities of HMR 3647, Moxifloxacin, and Rifapentine against Mycobacterium leprae in Mice

Consigny

Bentoucha

Bonnafous

et al. 2000

Antimicrob Agents Chemother

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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, ...

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Powerful Bactericidal Activities of Clarithromycin and Minocycline against Mycobacterium leprae in Lepromatous Leprosy

Cited by 80 publications

References 5 publications

Clinical trial of ofloxacin alone and in combination with dapsone plus clofazimine for treatment of lepromatous leprosy

Clinical trial of ofloxacin alone and in combination with dapsone plus clofazimine for treatment of lepromatous leprosy

The Continuing Challenges of Leprosy

Bactericidal Activities of HMR 3647, Moxifloxacin, and Rifapentine against Mycobacterium leprae in Mice

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