Short-course chemotherapy with TMC207 and rifapentine in a murine model of latent tuberculosis infection

Am J Respir Crit Care Med. 2011 Sep 15;184(6):732-7. doi: 10.1164/rccm.201103-0397OC. Epub 2011 Jun 9.


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 log(10) 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 3-4 months.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibiotics, Antitubercular / administration & dosage*
  • Antitubercular Agents / administration & dosage*
  • Diarylquinolines
  • Disease Models, Animal
  • Drug Administration Schedule
  • Drug Therapy, Combination / methods
  • Extensively Drug-Resistant Tuberculosis / drug therapy
  • Extensively Drug-Resistant Tuberculosis / microbiology
  • Female
  • Latent Tuberculosis / drug therapy*
  • Latent Tuberculosis / microbiology
  • Lung / drug effects
  • Lung / microbiology
  • Mice
  • Mice, Inbred BALB C
  • Mycobacterium tuberculosis / drug effects
  • Quinolines / administration & dosage*
  • Rifampin / administration & dosage
  • Rifampin / analogs & derivatives*
  • Stem Cells / drug effects
  • Treatment Outcome


  • Antibiotics, Antitubercular
  • Antitubercular Agents
  • Diarylquinolines
  • Quinolines
  • bedaquiline
  • Rifampin
  • rifapentine