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.

Fig 1

High-dose aerosol infection models with M. tuberculosis in BALB/c mice using either JHU H37Rv or Erdman for aerosol infection. Bacterial numbers in lungs (A) or spleens (B) of BALB/c mice after a high-dose aerosol infection with M. tuberculosis and 3 months of treatment with H, Z, and R were determined.

Fig 2

High-dose aerosol infection models in BALB/c mice infected with five strains of M. tuberculosis and treated with either the three-drug combination (HRZ) or the two-drug combination (RZ). (A) Erdman; (B) CSU H37Rv; (C) JHU H37Rv; (D) CDC1551; (E) HN878. The x axes show days from experiment start. Drug treatment included 2 months of HZR, followed by HR for 1 month (solid lines) or ZR for 3 months (dashed lines).