Potent twice-weekly rifapentine-containing regimens in murine tuberculosis.
BACKGROUND
Recent studies have demonstrated that intermittent administration of rifamycin-based regimens results in higher rates of tuberculosis relapse and treatment failure compared with daily therapy. Twice-weekly treatment with rifampin, isoniazid, and pyrazinamide may be improved by increasing Mycobacterium tuberculosis exposure to rifamycin by substituting rifapentine for rifampin.


METHODS
To test this hypothesis, we compared the activities of standard daily and twice-weekly rifampin plus isoniazid-based regimens to those of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing regimens in the murine model of tuberculosis. Relapse rates were assessed after 4, 5, and 6 mo of treatment to assess stable cure. Single- and multiple-dose pharmacokinetics of rifampin and rifapentine were also determined.


RESULTS
After 2 mo of treatment, twice-weekly therapy with rifapentine (15 or 20 mg/kg), moxifloxacin, and pyrazinamide was significantly more active than standard daily or twice-weekly therapy with rifampin, isoniazid, and pyrazinamide. Stable cure was achieved after 4 mo of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing therapy, but only after 6 mo of standard daily therapy. Twice-weekly rifapentine (15 mg/kg) displayed more favorable pharmacodynamics than did daily rifampin (10 mg/kg).


CONCLUSIONS
By virtue of the enhanced rifamycin exposure, twice-weekly regimens containing rifapentine (15 or 20 mg/kg) may permit shortening the current treatment duration by 2 mo. Such regimens warrant clinical investigation.
Rosenthal
Ian M
IM
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Williams
Kathy
K
Tyagi
Sandeep
S
Peloquin
Charles A
CA
Vernon
Andrew A
AA
Bishai
William R
WR
Grosset
Jacques H
JH
Nuermberger
Eric L
EL
D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001372:Aza Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D024841:Fluoroquinolones; D007538:Isoniazid / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D000077266:Moxifloxacin; D011718:Pyrazinamide / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012293:Rifampin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000378:metabolism
D000995:Antitubercular Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D011718:Pyrazinamide; D000077266:Moxifloxacin; D007538:Isoniazid; D012293:Rifampin; C018421:rifapentine