3--hydroxy-5--(4-isobutylpiperazinyl)benzoxazinorifamycin and Tuberculosis--Pulmonary

Rifalazil, also known as KRM-1648 or benzoxazinorifamycin, is a new semisynthetic rifamycin with a long half-life of approximately 60 h. Rifalazil has potent bactericidal activity against Mycobacterium tuberculosis in vitro and in animal models of tuberculosis (TB). Prior studies in healthy volunteers showed that once-weekly doses of 25 to 50 mg of rifalazil were well tolerated. In this randomized, open-label, active-controlled phase II clinical trial, 65 subjects with sputum smear-positive pulmonary TB received one of the following regimens for the first 2 weeks of therapy: 16 subjects received isoniazid (INH) (5 mg/kg of body weight) daily; 16 received INH (5 mg/kg) and rifampin (10 mg/kg) daily; 17 received INH (5 mg/kg) daily plus 10 mg of rifalazil once weekly; and 16 received INH (5 mg/kg) daily and 25 mg of rifalazil once weekly. All subjects were then put on 6 months of standard TB therapy. Pretreatment and day 15 sputum CFU of M. tuberculosis were measured to assess the bactericidal activity of each regimen. The number of drug-related adverse experiences was low and not significantly different among treatment arms. A transient decrease in absolute neutrophil count to less than 2,000 cells/mm(3) was detected in 10 to 20% of patients in the rifalazil- and rifampin-containing treatment arms without clinical consequences. Decreases in CFU counts were comparable among the four treatment arms; however, the CFU results were statistically inconclusive due to the variability in the control arms. Acquired drug resistance did not occur in any patient. Studies focused on determining a maximum tolerated dose will help elucidate the full anti-TB effect of rifalazil.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Female; Hematologic Tests; Humans; Isoniazid; Kidney Function Tests; Liver Function Tests; Male; Rifamycins; Tuberculosis, Pulmonary

Rifalazil (formerly known as KRM-1648) in combination with isoniazid has been found to be more active than rifampin/isoniazid. Administration of rifalazil/isoniazid for 12 weeks resulted in continued apparent sterilization of organs 6 months after cessation of therapy. In this study we evaluated the durability of rifalazil/isoniazid treatment. Female CD-1 mice were infected with Mycobacterium tuberculosis ATCC 35801 (strain Erdman). Rifalazil and isoniazid were given in combination for 6 and 12 weeks; no mycobacteria could be cultured from spleens and lungs at both the 6-week and 12-week time points. After completing treatment, groups of mice treated with rifalazil/isoniazid for 6 or 12 weeks were observed without any additional treatment. These observation groups were compared to groups of rifalazil/isoniazid-treated mice (6 and 12 weeks) given dexamethasone for 7 and 8 weeks, respectively. Modest regrowth was noted in the spleens and lungs of the group treated with rifalazil/isoniazid for 6 weeks. Regrowth in the 6-weeks group was enhanced slightly by treatment with dexamethasone. In contrast, no regrowth was noted in the 12-weeks rifalazil/isoniazid group, and treatment with dexamethasone did not result in any regrowth.

Topics: Animals; Antitubercular Agents; Colony Count, Microbial; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Isoniazid; Lung; Mice; Mycobacterium tuberculosis; Rifamycins; Spleen; Treatment Outcome; Tuberculosis, Pulmonary

In this study, profiles of infection due to Mycobacterium avium complex (MAC) in CB-17 SCID mice deficient in T and B cell functions were examined, when mice were given or not given a new benzoxazinorifamycin, KRM-1648 (KRM), during the course of infection. When mice were infected intravenously with MAC, the bacterial loads in their visceral organs were larger than those of their co-isogenic CB-17 counterparts. The incidence and the degree of gross lung lesions were less in SCID mice compared to CB-17 mice. Athymic BALB/c nude mice showed similar profiles of the infection. Beige mice showed more severe gross lesions and larger bacterial loads in the lungs than did SCID and athymic BALB/c nude mice. When MAC was infected subcutaneously into the hind footpads of mice, disseminated growth of organisms in the footpads, blood, and visceral organs was seen in SCID mice, but not in CB-17 or BALB/c mice. KRM exhibited the same level of therapeutic effect on SCID mice infected with MAC via the intravenous route in terms of inhibiting bacterial growth in the lungs and kidneys, as in cases of CB-17 and BALB/c mice with normal T-cell functions. In beige mice, the degree of growth inhibition of MAC due to KRM treatment was significantly greater than that achieved in SCID mice.

Topics: Animals; Antibiotics, Antitubercular; Bacteremia; Disease Models, Animal; Disease Progression; Lung; Mice; Mice, Inbred BALB C; Mice, Nude; Mice, SCID; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Rifamycins; Species Specificity; Time Factors; Tuberculosis, Pulmonary