Dose-ranging comparison of rifampin and rifapentine in two pathologically distinct murine models of tuberculosis

Abstract

In previous experiments, replacing the 10-mg/kg of body weight daily dose of rifampin with 7.5 to 10 mg/kg of rifapentine in combinations containing isoniazid and pyrazinamide reduced the duration of treatment needed to cure tuberculosis in BALB/c mice by approximately 50% due to rifapentine's more potent activity and greater drug exposures obtained. In the present study, we performed dose-ranging comparisons of the bactericidal and sterilizing activities of rifampin and rifapentine, alone and in combination with isoniazid and pyrazinamide with or without ethambutol, in BALB/c mice and in C3HeB/FeJ mice, which develop necrotic lung granulomas after infection with Mycobacterium tuberculosis. Each rifamycin demonstrated a significant increase in sterilizing activity with increasing dose. Rifapentine was roughly 4 times more potent in both mouse strains. These results reinforce the rationale for ongoing clinical trials to ascertain the highest well-tolerated doses of rifampin and rifapentine. This study also provides an important benchmark for the efficacy of the first-line regimen in C3HeB/FeJ mice, a strain in which the lung lesions observed after M. tuberculosis infection may better represent the pathology of human tuberculosis.

Fig 1

Mean (± SD) serum drug concentrations of rifampin (a) and rifapentine (b) after 2 weeks of daily dosing (5 days per week). Sampling was performed after the 10th (R₁₀), 11th (P₁₀ and P₂₀), or 13th (R₂₀, R₄₀, and P₅) dose.

Fig 2

Mean (± SD) lung log₁₀ CFU counts at treatment initiation (D0) and after 2 weeks (a), 4 weeks (b), 8 weeks (c), or 10 weeks (d) in experiment 1.

Fig 3

Mean (± SD) lung log₁₀ CFU counts in BALB/c (a and b) or C3HeB/FeJ (c and d) mice at treatment initiation (D0) and after 4 weeks (a and c) or 8 weeks (b and d) in experiment 2.

Fig 4

(a and b) Histopathology of a necrotic granuloma (a) in untreated mouse lung 3.5 months after low-dose challenge with M. tuberculosis, demonstrating central caseation with abundant extracellular acid-fast bacilli (b). Magnification, ×20 (a) or ×500 (b, inset). (c, inset) Large numbers of extracellular bacilli were also found at the transition zone between the central necrosis and the cellular cuff, where evidence of more recent cellular necrosis was observed. Magnification, ×500. (d, inset) Intracellular bacilli were found in smaller concentrations at the outer margin of the cellular cuff. Magnification, ×200.

Fig 5

Histopathology of nonnecrotic lung foci in infected BALB/c (a and b) and C3HeB/FeJ (c and d) mice, demonstrating chronic inflammation with foamy macrophages containing acid-fast bacilli (arrows). Magnification, ×500.