Comparative Studies Evaluating Mouse Models Used for Efficacy Testing of Experimental Drugs against Mycobacterium tuberculosis

Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 12/2010; 55(3):1237-47. DOI: 10.1128/AAC.00595-10
Source: PubMed


Methodologies for preclinical animal model testing of drugs against Mycobacterium tuberculosis vary from laboratory to laboratory; however, it is unknown if these variations result in different outcomes. Thus, a series of head-to-head comparisons of drug regimens in three commonly used mouse models (intravenous, a low-dose aerosol, and a high-dose aerosol infection model) and in two strains of mice are reported here. Treatment with standard tuberculosis (TB) drugs resulted in similar efficacies in two mouse species after a low-dose aerosol infection. When comparing the three different infection models, the efficacies in mice of rifampin and pyrazinamide were similar when administered with either isoniazid or moxifloxacin. Relapse studies revealed that the standard drug regimen showed a significantly higher relapse rate than the moxifloxacin-containing regimen. In fact, 4 months of the moxifloxacin-containing combination regimen showed similar relapse rates as 6 months of the standard regimen. The intravenous model showed slower bactericidal killing kinetics with the combination regimens tested and a higher relapse of infection than either aerosol infection models. All three models showed similar outcomes for in vivo efficacy and relapse of infection for the drug combinations tested, regardless of the mouse infection model used. Efficacy data for the drug combinations used also showed similar results, regardless of the formulation used for rifampin or timing of the drugs administered in combination. In all three infection models, the dual combination of rifampin and pyrazinamide was less sterilizing than the standard three-drug regimen, and therefore the results do not support the previously reported antagonism between standard TB agents.

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Available from: Charles A Peloquin, Nov 05, 2014
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    • "Animal models are critically important in testing the efficacy of new drugs and vaccines against TB [82]. The challenge of animal models of TBM is that TBM in humans is considered to typically occur a certain period of time after a primary infection through the respiratory tract, a condition that would be difficult to mimic in experimental animals. "
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    ABSTRACT: In the search for new anti-tuberculosis drugs, numerous potential drugs are being screened in vitro. In animal models, promising new anti-tuberculosis drugs are assessed in terms of toxic side effects and comparative therapeutic efficacy. Mice are frequently used and experimental infections are established in different ways. To investigate to what extent the route of Mycobacterium tuberculosis inoculation is a determinant in the pathogenesis of tuberculosis (TB) and the therapeutic outcome. Results will contribute to insight into the translational value of TB models used for preclinical studies. TB in mice was established through intratracheal or intravenous mycobacterial inoculation. The efficacy of a 26-week treatment regimen was evaluated, including assessment of relapse of infection 13 weeks post-treatment. It was shown that the course of TB and the therapeutic response, in terms of histopathological characteristics and mycobacterial load, in lungs and extra- pulmonary organs is substantially different and dependent on the route of infection applied and the inoculum size used. When evaluating the comparative therapeutic potential of novel anti-tuberculosis drugs or drug treatment schedules investigated in different studies, it should be noted that the route of infection applied and the inoculum size used influence the course of murine TB and the therapeutic response to the standard first- line anti-tuberculosis drug regimen.
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