Importance of Confirming Data on the In Vivo Efficacy of Novel Antibacterial Drug Regimens against Various Strains of Mycobacterium tuberculosis
- 1 February 2012
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 56 (2), 731-738
- https://doi.org/10.1128/aac.05701-11
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.Keywords
This publication has 50 references indexed in Scilit:
- Increased Foxp3 expression in guinea pigs infected with W-Beijing strains of M. tuberculosisTuberculosis, 2011
- T lymphocyte surface expression of exhaustion markers as biomarkers of the efficacy of chemotherapy for tuberculosisTuberculosis, 2011
- Strain diversity, epistasis and the evolution of drug resistance in Mycobacterium tuberculosisClinical Microbiology & Infection, 2011
- Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation studyThe Lancet, 2011
- Comparative Studies Evaluating Mouse Models Used for Efficacy Testing of Experimental Drugs against Mycobacterium tuberculosisAntimicrobial Agents and Chemotherapy, 2011
- Bactericidal Potencies of New Regimens Are Not Predictive of Their Sterilizing Potencies in a Murine Model of TuberculosisAntimicrobial Agents and Chemotherapy, 2010
- Paradoxical Effect of Isoniazid on the Activity of Rifampin-Pyrazinamide Combination in a Mouse Model of TuberculosisAntimicrobial Agents and Chemotherapy, 2009
- Disseminated disease severity as a measure of virulence of Mycobacterium tuberculosis in the guinea pig modelTuberculosis, 2008
- Synergistic Activity of R207910 Combined with Pyrazinamide against Murine TuberculosisAntimicrobial Agents and Chemotherapy, 2007
- Rapid Microbiologic and Pharmacologic Evaluation of Experimental Compounds against Mycobacterium tuberculosisAntimicrobial Agents and Chemotherapy, 2006