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Published on: September 19, 2016
Comparison of the 'Denver regimen' against acute tuberculosis in the mouse and guinea pig
Zahoor Ahmad1, Eric L Nuermberger, Rokeya Tasneen
1Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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.
Insights
The Denver regimen effectively sterilized tuberculosis in guinea pigs but not mice, indicating guinea pigs are a better model for evaluating TB drug efficacy and persistence. Relapse rates were zero in guinea pigs but high in mice.
Area of Science:
- Tuberculosis research
- Pharmacology
- Infectious disease modeling
Background:
- Tuberculosis (TB) remains a global health challenge, necessitating effective drug regimens.
- Animal models are crucial for evaluating the efficacy of anti-TB drugs and understanding M. tuberculosis persistence.
Purpose of the Study:
- To compare the sterilizing activity of the Denver regimen against acute tuberculosis (TB) in mice and guinea pigs.
- To assess the utility of different animal models for TB drug testing.
Main Methods:
- Human-equivalent doses of rifampicin, isoniazid, and pyrazinamide were established via pharmacokinetic studies in guinea pigs.
- Mice and guinea pigs were infected with Mycobacterium tuberculosis and treated with the Denver regimen for up to 6 months, with varied dosing frequencies.
- Relapse rates were evaluated after treatment cessation.
Main Results:
- Guinea pig lungs cleared Mycobacterium tuberculosis cultures within 3 months of treatment.
- No relapses were observed in guinea pigs after 5 or 6 months of treatment.
- Mice remained culture-positive throughout the 6-month treatment, with high relapse rates (93% and 69% after 5 and 6 months, respectively).
Conclusions:
- The Denver regimen demonstrated significantly greater sterilizing potency against acute TB in guinea pigs compared to mice.
- These findings highlight the importance of selecting appropriate animal models for evaluating novel TB drug regimens and M. tuberculosis persistence.
- The study suggests guinea pigs may be a more predictive model for TB treatment outcomes.
