The Combination of Rifampin plus Moxifloxacin Is Synergistic for Suppression of Resistance but Antagonistic for Cell Kill of <italic toggle="yes">Mycobacterium tuberculosis</italic> as Determined in a Hollow-Fiber Infection Model
ABSTRACT Moxifloxacin is under development for expanded use against Mycobacterium tuberculosis. Rifampin is a mainstay of therapy. We examined the interaction of moxifloxacin plus rifampin for log-phase and nonreplicating persister (NRP) organisms. For this evaluation, we employed our hollow-fiber i...
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American Society for Microbiology
2010
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oai:doaj.org-article:346a155c92eb441da601c67a03e408da2021-11-15T15:38:15ZThe Combination of Rifampin plus Moxifloxacin Is Synergistic for Suppression of Resistance but Antagonistic for Cell Kill of <italic toggle="yes">Mycobacterium tuberculosis</italic> as Determined in a Hollow-Fiber Infection Model10.1128/mBio.00139-102150-7511https://doaj.org/article/346a155c92eb441da601c67a03e408da2010-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00139-10https://doaj.org/toc/2150-7511ABSTRACT Moxifloxacin is under development for expanded use against Mycobacterium tuberculosis. Rifampin is a mainstay of therapy. We examined the interaction of moxifloxacin plus rifampin for log-phase and nonreplicating persister (NRP) organisms. For this evaluation, we employed our hollow-fiber infection model, in which organisms are exposed to clinically relevant drug concentration-time profiles and the impact on bacterial cell kill and resistant subpopulation amplification is determined. In log phase, resistance emergence was observed in all monotherapy regimens and in no combination therapy regimen. No difference was seen in time to a 3-log reduction in the bacterial burden; there was a significant difference in time to resistance emergence (P = 0.0006). In the NRP experiment, no resistance emergence was seen. There was a significant difference between the monotherapy and combination therapy regimens in time to a 3-log reduction in the bacterial burden (P = 0.042). The combination is efficacious for suppressing resistant organisms but is antagonistic for cell kill. IMPORTANCE M. tuberculosis infects one-third of the world’s population. Multiresistant organisms have become more frequent, threatening our ability to provide adequate chemotherapy. Moxifloxacin has been seen as an important new agent with the potential to supplant isoniazid or add to the rifampin/isoniazid combination. M. tuberculosis also exists in different physiological states, including the NRP phenotype. We examined the moxifloxacin/rifampin combination in a new in vitro system to allow judgment of how moxifloxacin would interact with rifampin and allow its performance in clinical trials to be placed into perspective. Importantly, the combination suppressed resistance emergence, but at the price of slightly slowing bacterial cell kill. This new combination is a welcome addition to the physician’s armamentarium.G. L. DrusanoNicole SgambatiAdam EichasDavid L. BrownRobert KulawyArnold LouieAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 1, Iss 3 (2010) |
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Microbiology QR1-502 |
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Microbiology QR1-502 G. L. Drusano Nicole Sgambati Adam Eichas David L. Brown Robert Kulawy Arnold Louie The Combination of Rifampin plus Moxifloxacin Is Synergistic for Suppression of Resistance but Antagonistic for Cell Kill of <italic toggle="yes">Mycobacterium tuberculosis</italic> as Determined in a Hollow-Fiber Infection Model |
| description |
ABSTRACT Moxifloxacin is under development for expanded use against Mycobacterium tuberculosis. Rifampin is a mainstay of therapy. We examined the interaction of moxifloxacin plus rifampin for log-phase and nonreplicating persister (NRP) organisms. For this evaluation, we employed our hollow-fiber infection model, in which organisms are exposed to clinically relevant drug concentration-time profiles and the impact on bacterial cell kill and resistant subpopulation amplification is determined. In log phase, resistance emergence was observed in all monotherapy regimens and in no combination therapy regimen. No difference was seen in time to a 3-log reduction in the bacterial burden; there was a significant difference in time to resistance emergence (P = 0.0006). In the NRP experiment, no resistance emergence was seen. There was a significant difference between the monotherapy and combination therapy regimens in time to a 3-log reduction in the bacterial burden (P = 0.042). The combination is efficacious for suppressing resistant organisms but is antagonistic for cell kill. IMPORTANCE M. tuberculosis infects one-third of the world’s population. Multiresistant organisms have become more frequent, threatening our ability to provide adequate chemotherapy. Moxifloxacin has been seen as an important new agent with the potential to supplant isoniazid or add to the rifampin/isoniazid combination. M. tuberculosis also exists in different physiological states, including the NRP phenotype. We examined the moxifloxacin/rifampin combination in a new in vitro system to allow judgment of how moxifloxacin would interact with rifampin and allow its performance in clinical trials to be placed into perspective. Importantly, the combination suppressed resistance emergence, but at the price of slightly slowing bacterial cell kill. This new combination is a welcome addition to the physician’s armamentarium. |
| format |
article |
| author |
G. L. Drusano Nicole Sgambati Adam Eichas David L. Brown Robert Kulawy Arnold Louie |
| author_facet |
G. L. Drusano Nicole Sgambati Adam Eichas David L. Brown Robert Kulawy Arnold Louie |
| author_sort |
G. L. Drusano |
| title |
The Combination of Rifampin plus Moxifloxacin Is Synergistic for Suppression of Resistance but Antagonistic for Cell Kill of <italic toggle="yes">Mycobacterium tuberculosis</italic> as Determined in a Hollow-Fiber Infection Model |
| title_short |
The Combination of Rifampin plus Moxifloxacin Is Synergistic for Suppression of Resistance but Antagonistic for Cell Kill of <italic toggle="yes">Mycobacterium tuberculosis</italic> as Determined in a Hollow-Fiber Infection Model |
| title_full |
The Combination of Rifampin plus Moxifloxacin Is Synergistic for Suppression of Resistance but Antagonistic for Cell Kill of <italic toggle="yes">Mycobacterium tuberculosis</italic> as Determined in a Hollow-Fiber Infection Model |
| title_fullStr |
The Combination of Rifampin plus Moxifloxacin Is Synergistic for Suppression of Resistance but Antagonistic for Cell Kill of <italic toggle="yes">Mycobacterium tuberculosis</italic> as Determined in a Hollow-Fiber Infection Model |
| title_full_unstemmed |
The Combination of Rifampin plus Moxifloxacin Is Synergistic for Suppression of Resistance but Antagonistic for Cell Kill of <italic toggle="yes">Mycobacterium tuberculosis</italic> as Determined in a Hollow-Fiber Infection Model |
| title_sort |
combination of rifampin plus moxifloxacin is synergistic for suppression of resistance but antagonistic for cell kill of <italic toggle="yes">mycobacterium tuberculosis</italic> as determined in a hollow-fiber infection model |
| publisher |
American Society for Microbiology |
| publishDate |
2010 |
| url |
https://doaj.org/article/346a155c92eb441da601c67a03e408da |
| work_keys_str_mv |
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