title: Importance of confirming data on the in vivo efficacy of novel antibacterial drug regimens against various strains of Mycobacterium tuberculosis.
abstract: In preclinical testing of antituberculosis drugs, laboratory-adapted strains of Mycobacterium tuberculosis are usually used both for in vitro and in vivo studies. However, it is unknown whether the heterogeneity of M. tuberculosis stocks used by various laboratories can result in different outcomes in tests of antituberculosis drug regimens in animal infection models. In head-to-head studies, we investigated whether bactericidal efficacy results in BALB/c mice infected by inhalation with the laboratory-adapted strains H37Rv and Erdman differ from each other and from those obtained with clinical tuberculosis strains. Treatment of mice consisted of dual and triple drug combinations of isoniazid (H), rifampin (R), and pyrazinamide (Z). The results showed that not all strains gave the same in vivo efficacy results for the drug combinations tested. Moreover, the ranking of HRZ and RZ efficacy results was not the same for the two H37Rv strains evaluated. The magnitude of this strain difference also varied between experiments, emphasizing the risk of drawing firm conclusions for human trials based on single animal studies. The results also confirmed that the antagonism seen within the standard HRZ regimen by some investigators appears to be an M. tuberculosis strain-specific phenomenon. In conclusion, the specific identity of M. tuberculosis strain used was found to be an important variable that can change the apparent outcome of in vivo efficacy studies in mice. We highly recommend confirmation of efficacy results in late preclinical testing against a different M. tuberculosis strain than the one used in the initial mouse efficacy study, thereby increasing confidence to advance potent drug regimens to clinical trials.
authors.affiliation: Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Mary A
authors.initials: MA
authors.lastname: De Groote
authors.forename: Veronica
authors.initials: V
authors.lastname: Gruppo
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Woolhiser
authors.forename: Ian M
authors.initials: IM
authors.lastname: Orme
authors.forename: Janet C
authors.initials: JC
authors.lastname: Gilliland
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Lenaerts
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology / Q000627:therapeutic use*; D008168:Lung / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests / Q000706:statistics & numerical data; D009169:Mycobacterium tuberculosis / Q000145:classification* / Q000187:drug effects* / Q000235:genetics; D011718:Pyrazinamide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin