Short-Course Therapy with Daily Rifapentine in a Murine Model of Latent Tuberculosis Infection

Abstract

Rationale: Regimens recommended to treat latent tuberculosis infection (LTBI) are 3 to 9 months long. A 2-month rifampin1 pyrazinamide regimen is no longer recommended. Shorter regimens are highly desirable. Because substituting rifapentine for rifampin in the standard regimen for active tuberculosis halves the treatment duration needed to prevent relapse in mice, we hypothesized daily rifapentine-based regimens could shorten LTBI treatment to 2 months or less. Objectives: To improve an existing model of LTBI chemotherapy and evaluate the efficacy of daily rifapentine-based regimens. Methods: Mice were immunized with a more immunogenic recombinant Bacille Calmette-Guérin strain (rBCG30) and received very lowdose aerosol infection with Mycobacterium tuberculosis to establish a stable lung bacterial burden below 10 4 CFU without drug treatment. Mice received a control (isoniazid alone, rifampin alone, rifampin1isoniazid, rifampin1pyrazinamide) or test (rifapentine alone, rifapentine1isoniazid, rifapentine1pyrazinamide, rifapentine1 isoniazid1pyrazinamide) regimen for 8 weeks. Rifamycin doses were 10 mg/kg/d, analogous to the same human doses. Outcomes were biweekly lung CFU counts and relapse after 4 to 8 weeks of treatment. Measurements and Main Results: M. tuberculosis CFU counts remained stable around 3.65 log 10 in immunized, untreated mice. Isoniazid or rifampin left all or most mice culture-positive at week 8. Rifampin1 isoniazid cured 0 and 53% of mice and rifampin1pyrazinamide cured 47 and 100% of mice in 4 and 8 weeks, respectively. Rifapentine-based regimens were more active than rifampin1isoniazid and indistinguishable from rifampin1pyrazinamide. Conclusions: In this improved murine model of LTBI chemotherapy with very low lung burden, existing regimens were well represented. Daily rifapentine-based regimens were at least as active as rifampin1pyrazinamide, suggesting they could effectively treat LTBI in 6 to 8 weeks.Keywords: BCG; mouse; isoniazid; rifampin; pyrazinamide Identification and treatment of latent tuberculosis infection (LTBI) is necessary to eliminate tuberculosis (TB) in lowincidence countries (1-4). This strategy may soon be applied more widely now that new diagnostic tests are available to discriminate LTBI from past vaccination with Bacille CalmetteGuérin (BCG) or exposure to nontuberculous mycobacteria (5). Preventive therapy is also effective, though vastly underutilized, in reducing TB risk among HIV-infected persons with LTBI in high-prevalence settings, including persons receiving concomitant highly active antiretroviral therapy (6-9).Current LTBI treatment guidelines generally consider isoniazid (INH) for 6 to 12 months to be the first-line regimen (1, 4, 10). Rifampin (RIF) for 4 months is an alternative in the United States and Canada (1, 4, 11). In the United Kingdom, a 3-month regimen of RIF1INH is used with success (12, 13). The combination of RIF1pyrazinamide (PZA) was first shown to have potent sterilizing activity in a model of LTBI using mice immunized with BCG (14). Aft...

A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

“…A previously described paucibacillary model of latent tuberculosis infection in which BALB/c mice are immunized with the Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine (Pasteur strain) (24) was used, with the BCG being a recombinant strain that overexpresses the 30-kDa major secretory protein (rBCG30) (25) and with minor modifications to the model (26). Quantitative cultures of lung homogenates were performed in parallel on selective agar plates (7H11 supplemented with 10% OADC), with 2-thiophenecarboxylic acid hydrazide (TCH) (40 g/ml; Sigma, St. Louis, MO) used to select for M. tuberculosis or hygromycin (40 g/ml; Roche Diagnostics, Indianapolis, IN) to select for rBCG30.…”

Latent Tuberculosis Infection: Myths, Models, and Molecular Mechanisms

“…In this model, mice are immunized with a recombinant BCG strain overexpressing the 30-kDa major secretory protein (76) via the aerosol route and challenged 6 weeks later with virulent M. tuberculosis (77,78), leading to a stable lung census of ϳ10 4 bacilli, which approximates the bacillary burden in human LTBI (38). Perhaps most importantly, this paucibacillary model accurately recapitulates the hierarchy of sterilizing activities of the various drug regimens used to treat human LTBI (78). Recently, this model has been enhanced by the use of C3Heb/FeJ mice, which develop necrotic lung granulomas, and infection may be reactivated by TNF-␣ neutralization (362).…”

Population Pharmacokinetics of Rifapentine and Desacetyl Rifapentine in Healthy Volunteers: Nonlinearities in Clearance and Bioavailability

“…However, the relapse rate among patients in some patient populations treated with such an intermittent RFP regimen is unacceptably high, indicating that the optimal dosing regimen of RFP for TB treatment has yet to be fully characterized. Recent studies in a well-validated mouse model of TB disease have shown that the replacement of rifampin with RFP can shorten the treatment duration to 3 months or less when RFP is given daily and that RFP's treatment-shortening activity is dose dependent (4,5). Daily dosing of RFP was well tolerated at doses ranging from 5 to 20 mg/kg of body weight in healthy volunteers (6).…”