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Antimicrobial Agents and Chemotherapy, November 2007, p. 3781-3788, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.01533-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Concentration-Dependent Mycobacterium tuberculosis Killing and Prevention of Resistance by Rifampin{triangledown}

Tawanda Gumbo,1* Arnold Louie,2 Mark R. Deziel,2 Weiguo Liu,2 Linda M. Parsons,3 Max Salfinger,3 and George L. Drusano2

Division of Infectious Diseases, University of Texas Southwestern Medical College, Dallas, Texas,1 Emerging Infections and Host Defenses, Ordway Research Institute, Albany, New York,2 Wadsworth Center, The New York State Department of Health, Albany, New York3

Received 6 December 2006/ Returned for modification 26 March 2007/ Accepted 15 August 2007

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 (Cmax)-to-MIC ratio and not the duration that the rifampin concentration was above MIC. Rifampin prevented resistance to itself at a free Cmax/MIC ratio of ≥175. The postantibiotic effect duration was ≥5.2 days and was most closely related to the Cmax/MIC ratio (r2 = 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 Cmax/MIC of >175 that can be tolerated by patients, and (iii) a long postantibiotic effect duration.

* Corresponding author. Mailing address: Division of Infectious Diseases, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9113. Phone: (214) 648-9914. Fax: (214) 648-2741. E-mail: Tawanda.Gumbo{at}UTSouthwestern.edu

{triangledown} Published ahead of print on 27 August 2007.

Antimicrobial Agents and Chemotherapy, November 2007, p. 3781-3788, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.01533-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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