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

Abstract

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, ...

Expression and Purification of an Active Form of the Mycobacterium leprae DNA Gyrase and Its Inhibition by Quinolones

“…The ranking of the activities of these quinolones based on the inhibition of DNA supercoiling and the induction of DNA cleavage was similar to that based on the activities against M. leprae in the mouse footpad system or in in vitro assays (Table 1). For example, moxifloxacin is highly active at inhibiting M. leprae DNA gyrase and is also by far the most active quinolone against M. leprae in the mouse footpad system (8); on the other hand, ofloxacin is less active at inhibiting the DNA gyrase and is also significantly less bactericidal than moxifloxacin in the mouse (8). Despite good in vitro activity against the purified enzyme, ciprofloxacin is poorly active in vivo, probably due to unfavorable pharmacokinetics (15) and the lack of an intracellular killing ability (30).…”

“…Within the last 20 years, a number of newer antimicrobial agents, such as the quinolones (e.g., pefloxacin, ofloxacin, sparfloxacin, and moxifloxacin), the macrolides (e.g., clarithromycin), and the tetracyclines (e.g., minocycline), that possess various degrees of bactericidal activity against M. leprae have been identified in mouse experiments and in human trials (18,19). Among these newer antimicrobial agents, moxifloxacin has been demonstrated to display very powerful bactericidal activity against M. leprae (8) that is virtually identical to that of rifampin (the key component of the current MDT regimens) and has been well tolerated in human trials (26). Therefore, moxifloxacin may become an important component of a future MDT regimen.…”

In Vitro and In Vivo Activities of Rifampin, Streptomycin, Amikacin, Moxifloxacin, R207910, Linezolid, and PA-824 against Mycobacterium ulcerans

“…Recent studies have demonstrated that both moxifloxacin (MXF), a newer fluoroquinolone, and R207910, a diarylquinoline, exhibit powerful bactericidal activity against M. tuberculosis (2,14) and M. leprae (7,15) (3,9,10).…”

Quinolone Antibiotics: The Development of Moxifloxacin

“…In animal experiments, moxifloxacin is highly active against M. leprae, in particular in combination with rifapentine/minocycline [206].…”