Effect of Administration of Moxifloxacin plus Rifampin against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> for 7 of 7 Days versus 5 of 7 Days in an <italic toggle="yes">In Vitro</italic> Pharmacodynamic System

ABSTRACT Some trials administered antituberculosis agents for 5 of 7 days (5/7-day regimen) to optimize adherence. Since moxifloxacin has a longer half-life than rifampin, rifampin concentrations are <1% of the maximum concentration in serum (Cmax) on day 6 and nondetectable on day 7, while conce...

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Autores principales:	G. L. Drusano, N. Sgambati, A. Eichas, D. Brown, R. Kulawy, A. Louie
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2011
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1c54c34996e94dfda6cdb8f76184fbad
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spelling	oai:doaj.org-article:1c54c34996e94dfda6cdb8f76184fbad2021-11-15T15:38:44ZEffect of Administration of Moxifloxacin plus Rifampin against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> for 7 of 7 Days versus 5 of 7 Days in an <italic toggle="yes">In Vitro</italic> Pharmacodynamic System10.1128/mBio.00108-112150-7511https://doaj.org/article/1c54c34996e94dfda6cdb8f76184fbad2011-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00108-11https://doaj.org/toc/2150-7511ABSTRACT Some trials administered antituberculosis agents for 5 of 7 days (5/7-day regimen) to optimize adherence. Since moxifloxacin has a longer half-life than rifampin, rifampin concentrations are <1% of the maximum concentration in serum (Cmax) on day 6 and nondetectable on day 7, while concentrations of moxifloxacin remain and are able to induce error-prone replication. We determined if functional moxifloxacin monotherapy for 24 h/week caused resistance. In in vitro pharmacodynamic experiments, Mycobacterium tuberculosis was treated with mean area under the concentration-time curve (AUC) exposures for moxifloxacin and rifampin of 400 and 600 mg/kg/day and exposures equal to 1 standard deviation (SD) above and below the mean values. The drugs were administered on schedules of 7/7 days and 5/7 days. Over the 28-day experiments, bacteria were plated onto antibiotic-free agar to determine the effects of exposure and schedule on the total population. MICs were checked for emergence of resistance. At days 7 and 14, there was a 0.56- to 1.22-log10-CFU/ml greater cell kill with the 7/7-day regimen versus the 5/7-day regimen (low exposure). This difference was not seen for the larger exposures at day 21. At day 23, the low-exposure 5/7-day arm had breakthrough resistance, with the total count increasing to >2 log10 CFU/ml above the low-exposure 7/7-day arm. Pharmacokinetic mismatching of drugs in the therapy of tuberculosis may result in emergence of resistance when a drug holiday is imposed during which there is functional monotherapy and where the remaining agent induces error-prone replication. This is particularly true for the portion of the population where the clearance is higher (1 SD above the mean). IMPORTANCE Directly observed therapy is a cornerstone of treatment of Mycobacterium tuberculosis. Patients are often given a drug holiday to facilitate the direct observation of therapy. With rifampin and moxifloxacin, there is a discordance between the half-lives of these agents (1.9 versus 6.5 h when employed in combination). In addition, moxifloxacin induces error-prone replication in Mycobacterium tuberculosis. In this experiment, we demonstrate that the drug holiday (5 of 7 days of therapy [5/7-day regimen]) allows the emergence of resistance to moxifloxacin, which was not seen with 7/7-day therapy. If drug holidays are used, it is imperative to better match pharmacokinetics to minimize the risk of emergence of resistance.G. L. DrusanoN. SgambatiA. EichasD. BrownR. KulawyA. LouieAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 2, Iss 4 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 G. L. Drusano N. Sgambati A. Eichas D. Brown R. Kulawy A. Louie Effect of Administration of Moxifloxacin plus Rifampin against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> for 7 of 7 Days versus 5 of 7 Days in an <italic toggle="yes">In Vitro</italic> Pharmacodynamic System
description	ABSTRACT Some trials administered antituberculosis agents for 5 of 7 days (5/7-day regimen) to optimize adherence. Since moxifloxacin has a longer half-life than rifampin, rifampin concentrations are <1% of the maximum concentration in serum (Cmax) on day 6 and nondetectable on day 7, while concentrations of moxifloxacin remain and are able to induce error-prone replication. We determined if functional moxifloxacin monotherapy for 24 h/week caused resistance. In in vitro pharmacodynamic experiments, Mycobacterium tuberculosis was treated with mean area under the concentration-time curve (AUC) exposures for moxifloxacin and rifampin of 400 and 600 mg/kg/day and exposures equal to 1 standard deviation (SD) above and below the mean values. The drugs were administered on schedules of 7/7 days and 5/7 days. Over the 28-day experiments, bacteria were plated onto antibiotic-free agar to determine the effects of exposure and schedule on the total population. MICs were checked for emergence of resistance. At days 7 and 14, there was a 0.56- to 1.22-log10-CFU/ml greater cell kill with the 7/7-day regimen versus the 5/7-day regimen (low exposure). This difference was not seen for the larger exposures at day 21. At day 23, the low-exposure 5/7-day arm had breakthrough resistance, with the total count increasing to >2 log10 CFU/ml above the low-exposure 7/7-day arm. Pharmacokinetic mismatching of drugs in the therapy of tuberculosis may result in emergence of resistance when a drug holiday is imposed during which there is functional monotherapy and where the remaining agent induces error-prone replication. This is particularly true for the portion of the population where the clearance is higher (1 SD above the mean). IMPORTANCE Directly observed therapy is a cornerstone of treatment of Mycobacterium tuberculosis. Patients are often given a drug holiday to facilitate the direct observation of therapy. With rifampin and moxifloxacin, there is a discordance between the half-lives of these agents (1.9 versus 6.5 h when employed in combination). In addition, moxifloxacin induces error-prone replication in Mycobacterium tuberculosis. In this experiment, we demonstrate that the drug holiday (5 of 7 days of therapy [5/7-day regimen]) allows the emergence of resistance to moxifloxacin, which was not seen with 7/7-day therapy. If drug holidays are used, it is imperative to better match pharmacokinetics to minimize the risk of emergence of resistance.
format	article
author	G. L. Drusano N. Sgambati A. Eichas D. Brown R. Kulawy A. Louie
author_facet	G. L. Drusano N. Sgambati A. Eichas D. Brown R. Kulawy A. Louie
author_sort	G. L. Drusano
title	Effect of Administration of Moxifloxacin plus Rifampin against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> for 7 of 7 Days versus 5 of 7 Days in an <italic toggle="yes">In Vitro</italic> Pharmacodynamic System
title_short	Effect of Administration of Moxifloxacin plus Rifampin against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> for 7 of 7 Days versus 5 of 7 Days in an <italic toggle="yes">In Vitro</italic> Pharmacodynamic System
title_full	Effect of Administration of Moxifloxacin plus Rifampin against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> for 7 of 7 Days versus 5 of 7 Days in an <italic toggle="yes">In Vitro</italic> Pharmacodynamic System
title_fullStr	Effect of Administration of Moxifloxacin plus Rifampin against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> for 7 of 7 Days versus 5 of 7 Days in an <italic toggle="yes">In Vitro</italic> Pharmacodynamic System
title_full_unstemmed	Effect of Administration of Moxifloxacin plus Rifampin against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> for 7 of 7 Days versus 5 of 7 Days in an <italic toggle="yes">In Vitro</italic> Pharmacodynamic System
title_sort	effect of administration of moxifloxacin plus rifampin against <named-content content-type="genus-species">mycobacterium tuberculosis</named-content> for 7 of 7 days versus 5 of 7 days in an <italic toggle="yes">in vitro</italic> pharmacodynamic system
publisher	American Society for Microbiology
publishDate	2011
url	https://doaj.org/article/1c54c34996e94dfda6cdb8f76184fbad
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Effect of Administration of Moxifloxacin plus Rifampin against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> for 7 of 7 Days versus 5 of 7 Days in an <italic toggle="yes">In Vitro</italic> Pharmacodynamic System

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