3--hydroxy-5--(4-isobutylpiperazinyl)benzoxazinorifamycin and sparfloxacin

WQ-3034 is a newly synthesized acidic fluoroquinolone. We assessed its in vitro activity against Mycobacterium tuberculosis and M. avium complex using levofloxacin (LVFX), ciprofloxacin (CPFX), sparfloxacin (SPFX), and KRM-1648 (KRM) as reference drugs. The MICs of these agents were determined by the agar dilution method with 7H11 medium. The MICs at which 50 and 90% of the test strains were inhibited (MIC(50)s, and MIC(90)s, respectively) for the test quinolones for rifampin (RMP)-susceptible M. tuberculosis strains were in the order SPFX < LVFX SPFX >/= LVFX > WQ-3034 > CPFX. The efficacies of all quinolones against intracellular M. tuberculosis organisms were significantly lower in A-549 cells than in MM6-Mphis. WQ-3034 at the MIC caused more marked growth inhibition of intramacrophage M. tuberculosis than did LVFX. These findings indicate that the in vitro anti-M. tuberculosis activity of WQ-3034 is greater than that of CPFX and is comparable to that of LVFX.

Topics: 4-Quinolones; Aminopyridines; Anti-Infective Agents; Antitubercular Agents; Ciprofloxacin; Fluoroquinolones; Humans; Levofloxacin; Microbial Sensitivity Tests; Mycobacterium avium Complex; Mycobacterium tuberculosis; Ofloxacin; Quinolones; Rifamycins

A new benzoxazinorifamycin, KRM-1648 (KRM), was studied for its therapeutic efficacy in combination with other antimicrobials against Mycobacterium avium complex infections in mice. When M. intracellulare-infected (intravenously) mice were given KRM, clarithromycin (CAM), sparfloxacin (SPFX), or ethambutol (EB) each alone or in combination, by gavage, once daily 6 times per week (streptomycin [SM] was given subcutaneously twice per week) from day 1, KRM + CAM exhibited combined efficacy in terms of reducing the incidence of gross lung lesions and the bacterial loads in the lungs and spleens. The addition of either EB or EB + SPFX to KRM + CAM increased the efficacy. Moreover, the multi-drug regimen of KRM + CAM + EB + SPFX or ofloxacin [OFLX]) was more efficacious than rifampicin (RMP) + CAM + EB + SPFX (or OFLX). In M. avium infection, KRM + clofazimine was the most efficacious among two-drug combinations tested followed by KRM + SM. KRM + CAM was considerably less effective against M. avium than against M. intracellulare infection. KRM + EB and KRM+OFLX failed to show such a combined effect.

Topics: Animals; Antitubercular Agents; Clarithromycin; Clofazimine; Drug Synergism; Drug Therapy, Combination; Ethambutol; Fluoroquinolones; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mycobacterium avium-intracellulare Infection; Ofloxacin; Quinolones; Rifamycins; Streptomycin

Inhibition of the multiplication of Mycobacterium leprae in the footpads of nude mice by the oral administration of sparfloxacin, a new quinolone, and 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)benzoxazinorifamycin (KRM-1648), selected from a series of newly synthesized benzoxazinorifamycins, was studied. When the 2 drugs were administered alternately at intervals of 3 or 4 days, (i.e., each drug was administered once weekly), or simultaneously once weekly, between 3 and 5 months after inoculation of nude mice with M. leprae, 10 mg sparfloxacin and 0.6 mg KRM-1648 per kg bodyweight were sufficient to prevent multiplication of the organisms. Only partial inhibition of multiplication was achieved by alternate administration of 5 mg sparfloxacin and 0.3 mg KRM-1648 per kg, as was the case for 20 mg sparfloxacin per kg or 1 mg KRM-1648, each drug administered alone once weekly. The addition to these 2 drugs of dapsone, administered in the diet in a concentration of 0.001 g per 100 g, enhanced their effect. The potential usefulness of multidrug regimens including these compounds is considered.

Topics: Administration, Oral; Animals; Dapsone; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluoroquinolones; Leprostatic Agents; Leprosy; Mice; Mice, Inbred BALB C; Mice, Nude; Mycobacterium leprae; Quinolones; Rifamycins