Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model.
BACKGROUND
Availability of an ultra-short-course drug regimen capable of curing patients with tuberculosis in 2 to 3 mo would significantly improve global control efforts. Because immediate prospects for novel treatment-shortening drugs remain uncertain, we examined whether better use of existing drugs could shorten the duration of treatment. Rifapentine is a long-lived rifamycin derivative currently recommended only in once-weekly continuation-phase regimens. Moxifloxacin is an 8-methoxyfluoroquinolone currently used in second-line regimens.


RESULTS
Using a well-established mouse model with a high bacterial burden and human-equivalent drug dosing, we compared the efficacy of rifapentine- and moxifloxacin-containing regimens with that of the standard daily short-course regimen based on rifampin, isoniazid, and pyrazinamide. Bactericidal activity was assessed by lung colony-forming unit counts, and sterilizing activity was assessed by the proportion of mice with culture-positive relapse after 2, 3, 4, and 6 mo of treatment. Here, we demonstrate that replacing rifampin with rifapentine and isoniazid with moxifloxacin dramatically increased the activity of the standard daily regimen. After just 2 mo of treatment, mice receiving rifapentine- and moxifloxacin-containing regimens were found to have negative lung cultures, while those given the standard regimen still harbored 3.17 log10 colony-forming units in the lungs (p < 0.01). No relapse was observed after just 3 mo of treatment with daily and thrice-weekly administered rifapentine- and moxifloxacin-containing regimens, whereas the standard daily regimen required 6 mo to prevent relapse in all mice.


CONCLUSIONS
Rifapentine should no longer be viewed solely as a rifamycin for once-weekly administration. Our results suggest that treatment regimens based on daily and thrice-weekly administration of rifapentine and moxifloxacin may permit shortening the current 6 mo duration of treatment to 3 mo or less. Such regimens warrant urgent clinical investigation.
Rosenthal
Ian M
IM
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Zhang
Ming
M
Williams
Kathy N
KN
Peloquin
Charles A
CA
Tyagi
Sandeep
S
Vernon
Andrew A
AA
Bishai
William R
WR
Chaisson
Richard E
RE
Grosset
Jacques H
JH
Nuermberger
Eric L
EL
D000818:Animals; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage*; D000995:Antitubercular Agents / Q000008:administration & dosage*; D001372:Aza Compounds / Q000008:administration & dosage*; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D024841:Fluoroquinolones; D007538:Isoniazid / Q000008:administration & dosage; D008168:Lung / Q000187:drug effects* / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D011718:Pyrazinamide / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage*; D012293:Rifampin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D055502:Secondary Prevention; D013997:Time Factors; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D011718:Pyrazinamide; D000077266:Moxifloxacin; D007538:Isoniazid; D012293:Rifampin; C018421:rifapentine