Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model

Abstract

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.

Methods and findings: 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.

Conflict of interest statement

Competing Interests. WRB: Pending grant from Schering Plough, which markets moxifloxacin in the United States of America. Past grant from Bayer, which manufactures moxifloxacin. Past advisor for Schering Plough. Past grant from Hoechst Marion Roussel (now Sanofi Aventis), producer of rifapentine. Multiple other past and present pharmaceutical grants from companies whose drugs are not involved in this study. Multiple other past and present pharmaceutical advisory roles for companies whose drugs are not involved in this study. REC: Donations of drugs for federally funded research trials from Bayer (moxifloxacin) and Aventis (rifapentine). Honoraria (US$1,200) from Bayer to chair an independent Data Safety Monitoring Board for an experimental drug for HIV infection. For all other authors, no conflicts of interest are declared.

Figures

Figure 1. Lung Log10 CFU Counts in M. tuberculosis–Infected Mice

CFU counts at treatment initiation (D0) and (A) after 1 mo, (B) after 2 mo, and (C) after 3 mo of treatment. Data are presented as means and standard error (error bars) (n = five mice per time point). H, isoniazid; M, moxifloxacin; Z, pyrazinamide; R, rifampin; P, rifapentine.

Figure 2. Bactericidal Activity of Daily (5/7) R10MZ, P10MZ, and P10HZ in Comparison to Standard Daily Therapy with R10HZ in M. tuberculosis–Infected Mice

Treatment began when the bacillary burden reached 7.45 ± 0.03 log10 CFU per lung. After 10 wk of treatment and 3 mo of follow-up, the proportion of mice that were lung culture–positive was 100% and 53% for the R-containing regimens (R10HZ and R10MZ, respectively) and only 13% and 0% for the P-containing regimens (P10HZ and P10MZ, respectively) (data not shown in Figure). H, isoniazid; M, moxifloxacin; Z, pyrazinamide; R, rifampin; P, rifapentine.

Figure 3. Mean Rifapentine and Rifampin Serum Concentrations versus Time

Mice were administered a single dose of 7.5, 10, 15, and 20 mg/kg of rifapentine or 10 mg/kg of rifampin. P, rifapentine; R, rifampin.

Figure 4. Steady-State Pharmacodynamic Simulations in Mice Treated with Rifapentine Compared with Rifampin

Mice were treated with (A) twice-weekly (2/7) rifapentine 15 mg/kg (dashed line) and 20 mg/kg (solid line); (B) thrice-weekly (3/7) rifapentine 15 mg/kg; (C) daily (5/7) rifapentine 7.5 mg/kg (dashed line) and 10 mg/kg (solid line); (D) daily (7/7) rifapentine 10 mg/kg; and (e) daily (5/7) rifampin 10 mg/kg. Rifamycin concentrations are expressed in terms of free drug (2.5% and 17.5% free drug for rifapentine and rifampin, respectively). The free rifamycin concentration is below the MIC when the curve falls below the solid horizontal line. Pharmacodynamic parameter estimates are shown in Table 3.