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Am. J. Respir. Crit. Care Med., Volume 157, Number 5, May 1998, 1436-1440

Once-weekly Rifapentine-containing Regimens for Treatment of Tuberculosis in Mice

JACQUES GROSSET, NACER LOUNIS, CHANTAL TRUFFOT-PERNOT, RICHARD J. O'BRIEN, MARIO C. RAVIGLIONE, and BAOHONG JI

Bactériologie et Hygiène, Faculté de Médecine Pitié-Salpêtrière, Paris, France; Research and Evaluation Branch, Centers for Disease Control and Prevention, Atlanta, Georgia; and Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland

The bactericidal activities of several once-weekly rifapentine (P)-containing combination regimens against Mycobacterium tuberculosis, and their ability to prevent the selection of rifampin (R)-resistant mutants, were compared with those of the standard six-times-weekly regimen consisting of R, isoniazid (H), and pyrazinamide (Z) in a mouse experiment. Mice were infected intravenously with 1.3 × 107 cfu of M. tuberculosis strain H37Rv, and 8 wk of treatment began on Day 14 after infection, when mice were randomly allocated to an untreated control group and nine treatment groups of 30 mice each. At the end of 8 wk of treatment, all the tested regimens showed promising bactericidal activities. Once-weekly P alone was less bactericidal than six-times-weekly R alone; likewise, the once-weekly P-containing combined regimens were less bactericidal than the six-times-weekly standard regimen. However, the difference in killing was about 1 log10, which represented only a fraction of the overall 4 log10 to 5 log10 magnitude of killing effects. The addition of streptomycin (S) improved the bactericidal effect of once-weekly PHZ, and the effect of once-weekly PHZS was further enhanced when it was preceded by 2 wk of daily HZS. The latter regimen achieved the same level of activity as the standard six-times-weekly regimen. All of the once-weekly P-containing combined regimens were able to prevent the selection of R-resistant mutants, whereas monotherapy with R or P selected resistant mutants in approximately 50% of animals.




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