Comparison of the 'Denver regimen' against acute tuberculosis in the mouse and guinea pig

Abstract

Objectives: In this study, we sought to compare the sterilizing activity of human-equivalent doses of the 'Denver regimen' against acute tuberculosis (TB) infection in the standard mouse model and in the guinea pig.

Methods: Pharmacokinetic studies in guinea pigs were used to establish human-equivalent doses for rifampicin, isoniazid and pyrazinamide. Guinea pigs and mice were aerosol-infected with Mycobacterium tuberculosis CDC1551 and treatment was started 2 weeks later with rifampicin/isoniazid/pyrazinamide for up to 6 months. For the first 2 weeks of therapy, the dosing frequency was 5 days/week, and for the remaining period, twice weekly. Treatment was discontinued in groups of 30 mice and 10 guinea pigs at 5 months and at 6 months, and these animals were held for a further 3 months in order to assess relapse rates.

Results: Guinea pig lungs became culture-negative after 3 months of predominantly twice-weekly treatment and relapse rates were 0% (0/10) both after 5 months and after 6 months of treatment. In contrast, all mice remained culture-positive despite 6 months of the same treatment, and 93% (28/30) and 69% (20/29) of mice relapsed after treatment for 5 and 6 months, respectively.

Conclusions: Treatment with rifampicin/isoniazid/pyrazinamide administered at human-equivalent doses is much more potent against acute TB infection in guinea pigs than in mice. Our findings have important implications for the use of alternative animal models in testing novel TB drug regimens and for modelling M. tuberculosis persistence.

Figure 1

Human-equivalent dosing of rifampicin/isoniazid/pyrazinamide given predominantly twice weekly has greater bactericidal activity against M. tuberculosis in guinea pig lungs relative to mouse lungs. Chemotherapy with the combination regimen was initiated on Day 14 after aerosol infection in each species, and was administered daily (5 days/week) for the first 14 days of treatment, and then twice weekly for the remainder of treatment. Animals received human-equivalent doses of rifampicin and isoniazid during the continuation phase of chemotherapy. In guinea pigs, the following doses were used: 100 mg/kg rifampicin; 60 mg/kg isoniazid; and 300 mg/kg pyrazinamide. In mice, the following doses were used: 10 mg/kg rifampicin; 25 mg/kg isoniazid; and 150 mg/kg pyrazinamide.