title: Dose-dependent activity of pyrazinamide in animal models of intracellular and extracellular tuberculosis infections.
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 log(10) in each species. Doubling the human-equivalent dose of pyrazinamide reduced the lung bacillary burden by 1.7 and 3.0 log(10) 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.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Zahoor
authors.initials: Z
authors.lastname: Ahmad
authors.forename: Mostafa M
authors.initials: MM
authors.lastname: Fraig
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Bisson
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Grosset
authors.forename: Petros C
authors.initials: PC
authors.lastname: Karakousis
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use*; D005260:Female; D006168:Guinea Pigs; D008168:Lung / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D051379:Mice; D011718:Pyrazinamide / Q000627:therapeutic use*; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide