Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Antimicrob Agents Chemother. 2007 Nov;51(11):3781-8. Epub 2007 Aug 27.

Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin.

Author information

  • 1Division of Infectious Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9113, USA. Tawanda.Gumbo@UTSouthwestern.edu

Abstract

Rifampin is a cornerstone of modern antituberculosis therapy. However, rifampin's half-life of 3 h is believed to limit its utility for intermittent therapy, so new congeners with long half-lives are being developed. Using an in vitro pharmacokinetic-pharmacodynamic model of tuberculosis, we examined the relationships between rifampin exposure, microbial killing of log-phase-growth Mycobacterium tuberculosis, and suppression of resistance. Rifampin's microbial killing was linked to the area under the concentration-time curve-to-MIC ratio. The suppression of resistance was associated with the free peak concentration (C(max))-to-MIC ratio and not the duration that the rifampin concentration was above MIC. Rifampin prevented resistance to itself at a free C(max)/MIC ratio of > or =175. The postantibiotic effect duration was > or =5.2 days and was most closely related to the C(max)/MIC ratio (r(2) = 0.96). To explain rifampin's concentration-dependent effect, we examined the kinetics of rifampin entry into M. tuberculosis. Rifampin achieved concentration-dependent intracellular steady-state concentrations within 15 min. Our results suggest that doses of rifampin higher than those currently employed would optimize the effect of rifampin, if patients could tolerate them. Another major implication is that in the design of new rifampin congeners for intermittent therapy, the important properties may include (i) the efficient entry of the rifamycin into M. tuberculosis, (ii) the achievement of a free C(max)/MIC of >175 that can be tolerated by patients, and (iii) a long postantibiotic effect duration.

PMID:
17724157
[PubMed - indexed for MEDLINE]
PMCID:
PMC2151424
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk