Published ahead of print on April 1, 2005, doi:10.1164/rccm.200411-1557OC
Am. J. Respir. Crit. Care Med., Volume 172, Number 1, July 2005, 128-135
A more recent version of this article appeared on July 1, 2005
Submitted on November 22, 2004
Accepted on March 23, 2005
The Early Bactericidal Activities of Rifampin and Rifapentine in Pulmonary Tuberculosis
Frik A Sirgel1, P. Bernard Fourie2, Peter R Donald3, Nesri Padayatchi4, Roxana Rustomjee5, Jonathan Levin6, Giorgio Roscigno7, Jennifer Norman8, Helen McIlleron8, and Denis A Mitchison9*
1 Lead Programme for TB Research, Medical Research Council, Tygerberg, South Africa,
2 Lead Programme for TB Research, Medical Research Council, Pretoria, South Africa,
3 Department of Paediatrics and Child Health, University of Stellenbosch, Tygerberg, South Africa,
4 Unit for Clinical and Biomedical TB Research, King George V Hospital and Medical Research Council, Durban, South Africa,
5 Unit for Clinical and Biomedical TB Research, Medical Research Council, Durban, South Africa,
6 Unit for Biostatistics, Medical Research Council, Pretoria, South Africa,
7 FINDdiagnostics, Geneva, Switzerland,
8 Division of Pharmacology, University of Cape Town, Cape Town, South Africa,
9 Department of Medical Microbiology, St George's Hospital Medical School, London, United Kingdom
* To whom correspondence should be addressed. 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 re-growth between doses, leading to rifamycin mono-resistance at relapse. Objectives: Determination of the dose size of rifapentine that gives sufficient drug exposure to prevent re-growth. Methods: EBA study over initial 5 days of treatment of 123 patients, half at Durban and half at Cape Town, who received a single rifapentine doses of 300, 600, 900 or 1200 mg rifapentine or 5 daily doses of 150, 300 or 600 mg rifampin, with a pharmacokinetic study on 58 patients measuring Tmax, Cmax and AUC 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 1136 mg rifapentine. The AUC divided by the MIC agreed well for both rifamycins on the assumption that the only the 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 post-antibiotic lag, a 1200 mg dose of rifapentine seemed necessary to improve response and to prevent re-growth between doses, and hence rifamycin mono-resistance.
Key words: Rifapentine, rifampin, early bactericidal activity, plasma binding, post-antibiotic effect, pharmacokinetics
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