This Article Full Text Full Text (PDF) All Versions of this Article: 200411-1557OCv1 172/1/128    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sirgel, F. A. Search for Related Content PubMed PubMed Citation Articles by Sirgel, F. A.

The Early Bactericidal Activities of Rifampin and Rifapentine in Pulmonary Tuberculosis

Lead Programme for TB Research, Medical Research Council; Department of Pediatrics and Child Health, Tygerberg; Lead Programme for TB Research, Medical Research Council, Pretoria; King George V Hospital and Unit for Clinical and Biomedical TB Research, Medical Research Council, Durban; Unit for Biostatistics, Medical Research Council, Pretoria; Division of Pharmacology, University of Cape Town, Cape Town, South Africa; FINDdiagnostics, Geneva, Switzerland; and St. George's Hospital Medical School, London, United Kingdom

Correspondence and requests for reprints should be addressed to Prof. Denis A. Mitchison, M.B., F.R.C.P., F.R.C. Path., Department of Cellular and Molecular Medicine, St. George's Hospital Medical School, Cranmer Terrace, London, SW17 0RE, United Kingdom. E-mail: dmitchis{at}sghms.ac.uk

Rationale: Comparison of the early bactericidal activity (EBA) of rifapentine and its pharmacokinetics with those of rifampin to determine the cause of poor clinical response and regrowth between doses, leading to rifamycin monoresistance at relapse. Objectives: Determination of the dose size of rifapentine that gives sufficient drug exposure to prevent regrowth. Methods: EBA study over initial 5 days of treatment of 123 patients, half at Durban and half at Cape Town, who received single rifapentine doses of 300, 600, 900, or 1,200 mg rifapentine or five daily doses of 150, 300, or 600 mg rifampin, with a pharmacokinetic study on 58 patients measuring standard parameters for each dose size of rifamycin and their desacetyl metabolites. Results: The EBAs for both rifamycins were similar, with a linear relationship to log dose at lower doses and a curvilinear response at higher doses giving a plateau at 1,136 mg rifapentine. The area under the concentration–time curve (AUC) divided by the minimal inhibitory concentration (MIC) agreed well for both rifamycins on the assumption that the only free 2% of free rifapentine and the 14% of free rifampin after plasma binding were active in the lesions. Conclusions: Only the free proportions of the rifamycins were active in lesions. From consideration of the pulse size and the duration of the postantibiotic lag, a 1,200-mg dose of rifapentine seemed necessary to improve response and to prevent regrowth between doses, and hence rifamycin monoresistance.

Key Words: early bactericidal activity • pharmacokinetics • plasma binding • postantibiotic effect • rifapentine

This article has been cited by other articles:

				T. Gumbo, A. Louie, M. R. Deziel, W. Liu, L. M. Parsons, M. Salfinger, and G. L. Drusano Concentration-Dependent Mycobacterium tuberculosis Killing and Prevention of Resistance by Rifampin Antimicrob. Agents Chemother., November 1, 2007; 51(11): 3781 - 3788. [Abstract] [Full Text] [PDF]

				A. H. Diacon, R. F. Patientia, A. Venter, P. D. van Helden, P. J. Smith, H. McIlleron, J. S. Maritz, and P. R. Donald Early Bactericidal Activity of High-Dose Rifampin in Patients with Pulmonary Tuberculosis Evidenced by Positive Sputum Smears Antimicrob. Agents Chemother., August 1, 2007; 51(8): 2994 - 2996. [Abstract] [Full Text] [PDF]

				D. C. Perlman, C. C. Leung, and W. W. Yew Treatment of Tuberculosis in HIV-infected Patients: We Need to Know More Am. J. Respir. Crit. Care Med., June 1, 2007; 175(11): 1102 - 1103. [Full Text] [PDF]

				D. A. Mitchison Clinical development of anti-tuberculosis drugs J. Antimicrob. Chemother., September 1, 2006; 58(3): 494 - 495. [Abstract] [Full Text] [PDF]

				H. McIlleron, P. Wash, A. Burger, J. Norman, P. I. Folb, and P. Smith Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients. Antimicrob. Agents Chemother., April 1, 2006; 50(4): 1170 - 1177. [Abstract] [Full Text] [PDF]

				W. W. Yew and C. C. Leung Update in tuberculosis 2005. Am. J. Respir. Crit. Care Med., March 1, 2006; 173(5): 491 - 498. [Full Text] [PDF]

				I. M. Rosenthal, K. Williams, S. Tyagi, A. A. Vernon, C. A. Peloquin, W. R. Bishai, J. H. Grosset, and E. L. Nuermberger Weekly Moxifloxacin and Rifapentine Is More Active Than the Denver Regimen in Murine Tuberculosis Am. J. Respir. Crit. Care Med., December 1, 2005; 172(11): 1457 - 1462. [Abstract] [Full Text] [PDF]

				R. S. Wallis Can Studies of the Early Bactericidal Activity of Rifapentine Tell Us How to Prevent Acquired Rifamycin-Resistant Relapse? Am. J. Respir. Crit. Care Med., July 1, 2005; 172(1): 4 - 5. [Full Text] [PDF]