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

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

Author information

1
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

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.

PMID:
21659613
PMCID:
PMC3208599
DOI:
10.1164/rccm.201103-0397OC
[Indexed for MEDLINE]
Free PMC Article

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