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

Tianyu Zhang, Si Yang Li, Kathy N. Williams, Koen Andries, Eric L. Nuermberger

Research output: Contribution to journalArticle

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 ultra-short 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 1 isoniazid and daily rifapentine 6 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 1 isoniazid, but daily rifapentine 1/2 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.

Original languageEnglish (US)
Pages (from-to)732-737
Number of pages6
JournalAmerican journal of respiratory and critical care medicine
Volume184
Issue number6
DOIs
StatePublished - Sep 15 2011

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Keywords

  • Bacillus Calmette-Guérin
  • Isoniazid
  • Mouse
  • Pyrazinamide
  • Rifampin

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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