The early bactericidal activities of rifampin and rifapentine in pulmonary tuberculosis.
BACKGROUND
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.


OBJECTIVE
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.
Sirgel
Frik A
FA
Department of Cellular and Molecular Medicine, St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, United Kingdom.
Fourie
P Bernard
PB
Donald
Peter R
PR
Padayatchi
Nesri
N
Rustomjee
Roxana
R
Levin
Jonathan
J
Roscigno
Giorgio
G
Norman
Jennifer
J
McIlleron
Helen
H
Mitchison
Denis A
DA
D000293:Adolescent; D000328:Adult; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D012293:Rifampin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012294:Rifamycins / Q000627:therapeutic use; D055502:Secondary Prevention; D013019:South Africa; D013183:Sputum / Q000382:microbiology; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
D000904:Antibiotics, Antitubercular; D012294:Rifamycins; D012293:Rifampin; C018421:rifapentine