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Rifapentine is not more active than rifampin against chronic tuberculosis in guinea pigs.

Abstract
Rifamycins are key sterilizing drugs in the current treatment of active tuberculosis (TB). Daily dosing of rifapentine (P), a potent rifamycin with high intracellular accumulation, in place of rifampin (R) in the standard antitubercular regimen significantly shortens the duration of treatment needed to prevent relapse in a murine model of active TB. We undertook the current study to compare directly the activities of human-equivalent doses of P and R in a guinea pig model of chronic TB, in which bacilli are predominantly extracellular within human-like necrotic granulomas. Hartley strain guinea pigs were aerosol infected with ~200 bacilli of Mycobacterium tuberculosis H37Rv, and treatment given 5 days/week was initiated 6 weeks later. R at 100 mg/kg of body weight and P at 100 mg/kg were given orally alone or in combination with isoniazid (H) at 60 mg/kg and pyrazinamide (Z) at 300 mg/kg. Culture-positive relapse was assessed in subgroups of guinea pigs after completion of 1 and 2 months of treatment. Human-equivalent doses of R and P showed equivalent bactericidal activity when used alone and in combination therapy. In guinea pigs treated with rifampin, isoniazid, and pyrazinamide (RHZ) or PHZ, microbiological relapse occurred in the lungs of 8/10 animals treated for 1 month and in 0/10 animals treated for 2 months. Substitution of P for R in the standard antitubercular regimen did not shorten the time to cure in this guinea pig model of chronic TB. Data from ongoing clinical trials comparing the activity of these two drugs are awaited to determine the relevance of the guinea pig TB model in preclinical drug screening.
AuthorsNoton K Dutta, Peter B Illei, Charles A Peloquin, Michael L Pinn, Khisimuzi E Mdluli, Eric L Nuermberger, Jacques H Grosset, Petros C Karakousis
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 56 Issue 7 Pg. 3726-31 (Jul 2012) ISSN: 1098-6596 [Electronic] United States
PMID22547623 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antitubercular Agents
  • Pyrazinamide
  • Isoniazid
  • Rifampin
  • rifapentine
Topics
  • Animals
  • Antitubercular Agents (therapeutic use)
  • Female
  • Guinea Pigs
  • Isoniazid (therapeutic use)
  • Mycobacterium tuberculosis (drug effects, pathogenicity)
  • Pyrazinamide (therapeutic use)
  • Rifampin (analogs & derivatives, therapeutic use)
  • Tuberculosis (drug therapy)

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