Article

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

ABSTRACT

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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    • "The control plasmid without the RFP was not introduced into the WT strain, as the purpose was to determine if the metabolic burden due to the RFP could adversely affect the strain's ability to cause natural pathogenesis. The outbred, immunocompetent Swiss mice were used as they are commonly used for in vivo efficacy testing of lead anti-tubercular molecules [37] and are also used in-house. The mice were given a high dose (1.5 · 10 6 bacilli/mouse) intravenous infection of wild type/ FS of MTB H37Rv. "
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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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