Dose-dependent activity of pyrazinamide in animal models of intracellular and extracellular tuberculosis infections

Zahoor Ahmad, Mostafa M. Fraig, Gregory P. Bisson, Eric L. Nuermberger, Jacques H. Grosset, Petros C. Karakousis

Research output: Contribution to journalArticle

Abstract

Recent in vitro pharmacokinetic data suggest that the currently recommended dose of pyrazinamide may be suboptimal for killing intracellular bacilli in humans. We evaluated a range of pyrazinamide doses against intracellular and extracellular Mycobacterium tuberculosis in chronically infected mice and guinea pigs, respectively. Antibiotics were given five times weekly for 4 weeks beginning 28 days after infection. Human-equivalent doses of isoniazid reduced lung bacterial counts 10-fold in each species. Pyrazinamide given at 1/4 and 1/2 the human-equivalent dose was minimally active, while human-equivalent doses reduced lung bacterial counts by ∼1.0 log10 in each species. Doubling the human-equivalent dose of pyrazinamide reduced the lung bacillary burden by 1.7 and 3.0 log10 in mice and guinea pigs, respectively. As in humans and mice, pyrazinamide showed significant synergy with rifampin in guinea pigs. Clinical studies are warranted to investigate the sterilizing activity and tolerability of higher doses of pyrazinamide in combination tuberculosis regimens.

Original languageEnglish (US)
Pages (from-to)1527-1532
Number of pages6
JournalAntimicrobial agents and chemotherapy
Volume55
Issue number4
DOIs
StatePublished - Apr 1 2011

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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