Short-course chemotherapy with TMC207 and rifapentine in a murine model of latent tuberculosis infectionShort-course chemotherapy with TMC207 and rifapentine in a murine model of latent tuberculosis infection
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Laboratory for Microbiology, Parasitology and Hygiene (LMPH)
2011New York, 2011
American journal of respiratory and critical care medicine. - New York, 1994, currens
184(2011):6, p. 732-737
University of Antwerp
Rationale: Multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB) is an emerging global health threat. Proper management of close contacts of infectious patients is increasingly important. However, no evidence-based recommendations for treating latent TB infection (LTBI) after MDR/XDR-TB exposure (DR-LTBI) exist. An ultrashort regimen for LTBI caused by drug-susceptible strains (DS-LTBI) is also desirable. TMC207 has bactericidal and sterilizing activity in animal models of TB and improves the activity of current MDR-TB therapy in patients. Objectives: The objective of this study was to determine whether TMC207 might enable short-course treatment of DR-LTBI and ultrashort treatment of DS-LTBI. Methods: Using an established experimental model of LTBI chemotherapy in which mice are aerosol-immunized with a recombinant bacillus Calmette-Guérin vaccine before low-dose aerosol infection with Mycobacterium tuberculosis, the efficacy of TMC207 alone and in combination with rifapentine was compared with currently recommended control regimens as well as once-weekly rifapentine + isoniazid and daily rifapentine ± isoniazid. Measurements: Outcomes included monthly lung colony-forming unit counts and relapse rates. Main Results: Lung colony-forming unit counts were stable at about 3.75 log10 for up to 7.5 months postinfection in untreated mice. Rifamycin-containing regimens were superior to isoniazid monotherapy. TMC207 exhibited sterilizing activity at least as strong as that of rifampin alone and similar to that of rifampin + isoniazid, but daily rifapentine +/− isoniazid was superior to TMC207. Addition of TMC207 to rifapentine did not improve the sterilizing activity of rifapentine in this model. Conclusions: TMC207 has substantial sterilizing activity and may enable treatment of DR-LTBI in 34 months.