title: Safety and bactericidal activity of rifalazil in patients with pulmonary tuberculosis.
abstract: 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.
authors.affiliation: Núcleo de Doenças Infecciosas Centro Biomédico, Universidade Federal de Espírito Santo, Vitória, Brazil. rdietze@npd.ufes.br
authors.forename: R
authors.initials: R
authors.lastname: Dietze
authors.forename: L
authors.initials: L
authors.lastname: Teixeira
authors.forename: L M
authors.initials: LM
authors.lastname: Rocha
authors.forename: M
authors.initials: M
authors.lastname: Palaci
authors.forename: J L
authors.initials: JL
authors.lastname: Johnson
authors.forename: C
authors.initials: C
authors.lastname: Wells
authors.forename: L
authors.initials: L
authors.lastname: Rose
authors.forename: K
authors.initials: K
authors.lastname: Eisenach
authors.forename: J J
authors.initials: JJ
authors.lastname: Ellner
mesh_terms: D000293:Adolescent; D000328:Adult; D000904:Antibiotics, Antitubercular / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000627:therapeutic use; D015169:Colony Count, Microbial; D005260:Female; D006403:Hematologic Tests; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D007677:Kidney Function Tests; D008111:Liver Function Tests; D008297:Male; D012294:Rifamycins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology
chemical_list: D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D012294:Rifamycins; C068980:KRM 1648; D007538:Isoniazid