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

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.

Figures

Figure 1.
Figure 1.
Mean Mycobacterium tuberculosis colony-forming unit counts (± SD) in the lungs of untreated rBCG30-immunized mice.
Figure 2.
Figure 2.
(A and B) Histopathology of mouse lungs 7.5 months after low-dose challenge with Mycobacterium tuberculosis, demonstrating circumscribed, well-organized granuloma-like lesions (original magnification: A, ×40; B, ×200) in a mouse with 3.35 log10 cfu in the lungs. (C) The few evident bacilli (thin arrows) were localized to central areas in such lesions (original magnification, ×1,000). (D and E) Larger zones of chronic inflammation (original magnification: D, ×20) with many foamy macrophages (original magnification: E, ×200) were noted in the mice with greater than 4.5 log10 cfu in the lungs. (F) Acid-fast bacilli (AFB) were more numerous and localized to foamy macrophages (original magnification, ×1,000). (G–I) Airway obstruction with cell debris (original magnification: G, ×200; thick arrow) and evolving necrosis (original magnification: H, ×200) with extracellular AFB (original magnification: I, ×1,000) were visible in the same lesion.
Figure 3.
Figure 3.
Mean Mycobacterium tuberculosis lung colony-forming unit counts (± SD) after 1 month of treatment. Abbreviations: 1/7, drugs administered once weekly; H, isoniazid; J, TMC207; P, rifapentine; R, rifampin; Z, pyrazinamide.

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Source: PubMed

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