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Once-weekly rifapentine-containing regimens for treatment of tuberculosis in mice
J Grosset1, N Lounis, C Truffot-Pernot
1Bactériologie et Hygiène, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
Abstract:
The bactericidal activities of several once-weekly rifapentine (P)-containing combination regimens against Mycobacterium tuberculosis, and their ability to prevent the selection of rifampin (R)-resistant mutants, were compared with those of the standard six-times-weekly regimen consisting of R, isoniazid (H), and pyrazinamide (Z) in a mouse experiment. Mice were infected intravenously with 1.3 x 10(7) cfu of M. tuberculosis strain H37Rv, and 8 wk of treatment began on Day 14 after infection, when mice were randomly allocated to an untreated control group and nine treatment groups of 30 mice each. At the end of 8 wk of treatment, all the tested regimens showed promising bactericidal activities. Once-weekly P alone was less bactericidal than six-times-weekly R alone; likewise, the once-weekly P-containing combined regimens were less bactericidal than the six-times-weekly standard regimen. However, the difference in killing was about 1 log10, which represented only a fraction of the overall 4 log10 to 5 log10 magnitude of killing effects. The addition of streptomycin (S) improved the bactericidal effect of once-weekly PHZ, and the effect of once-weekly PHZS was further enhanced when it was preceded by 2 wk of daily HZS. The latter regimen achieved the same level of activity as the standard six-times-weekly regimen. All of the once-weekly P-containing combined regimens were able to prevent the selection of R-resistant mutants, whereas monotherapy with R or P selected resistant mutants in approximately 50% of animals.
Insights
Once-weekly rifapentine regimens show promise against tuberculosis, preventing drug resistance. While less potent than daily treatments, some regimens match standard efficacy and prevent rifampin resistance.
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Tuberculosis remains a global health challenge, necessitating novel treatment strategies.
- Drug resistance, particularly to rifampin, complicates treatment and necessitates new approaches.
- Rifapentine-containing regimens offer potential for improved treatment schedules.
Purpose of the Study:
- To compare the bactericidal activity of once-weekly rifapentine regimens against Mycobacterium tuberculosis.
- To evaluate the ability of these regimens to prevent the selection of rifampin-resistant mutants.
- To compare novel regimens with the standard six-times-weekly rifampin, isoniazid, and pyrazinamide regimen.
Main Methods:
- A mouse model of tuberculosis (M. tuberculosis strain H37Rv) was utilized.
- Mice received 8 weeks of treatment with various once-weekly rifapentine-containing regimens or the standard regimen.
- Bactericidal activity and the selection of rifampin-resistant mutants were assessed post-treatment.
Main Results:
- All tested regimens demonstrated bactericidal activity against M. tuberculosis.
- Once-weekly rifapentine regimens were less bactericidal than the standard regimen, with a difference of approximately 1 log10.
- Once-weekly rifapentine regimens effectively prevented the selection of rifampin-resistant mutants, unlike monotherapy.
- A regimen of once-weekly rifapentine, isoniazid, pyrazinamide, and streptomycin, preceded by daily isoniazid, pyrazinamide, and streptomycin, matched the standard regimen's efficacy.
Conclusions:
- Once-weekly rifapentine-containing regimens exhibit promising bactericidal activity and are effective in preventing drug resistance.
- Optimized rifapentine regimens can achieve efficacy comparable to standard tuberculosis treatment.
- These findings support the development of simplified, less frequent dosing strategies for tuberculosis treatment.