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

Abstract

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.

• Authors: Tianyu Zhang, Si-Yang Li, Kathy N Williams, Koen Andries, Eric L Nuermberger
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 184 Issue 6 Pg. 732-7 (Sep 15 2011) ISSN: 1535-4970 [Electronic] United States
• PMID: 21659613 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

• 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, microbiology)
• Female
• Latent Tuberculosis (drug therapy, microbiology)
• Lung (drug effects, microbiology)
• Mice
• Mice, Inbred BALB C
• Mycobacterium tuberculosis (drug effects)
• Quinolines (administration & dosage)
• Rifampin (administration & dosage, analogs & derivatives)
• Stem Cells (drug effects)
• Treatment Outcome