Dosing and route of administration of clindamycin given in combination with rifampicin.

Abstract

Listen

Translate article

The aim of the present study was to develop a PK interaction model of intravenous (IV) and oral clindamycin when combined with rifampicin, and to determine whether appropriate clindamycin concentrations could be achieved for different doses and administration routes (oral, intermittent and continuous infusion) of clindamycin. Five hundred and eighteen plasma samples were prospectively obtained from 124 patients treated for bone and joint infections. Population PK analysis was performed using Monolix software. Monte-Carlo simulations were run to determine the probability to achieve a minimal clindamycin plasma concentration equal to at least twice the MIC, or an unbound AUC/MIC ≥ 60. A linear one-compartment model with first-order absorption and elimination was developed. Concomitant administration of rifampicin increased clindamycin clearance by an average factor of 3, while the impact on clindamycin bioavailability was dose-dependent, with decreases from 56 to 11 and 4 % for rifampicin doses of 600 mg and 900 mg q12h, respectively. When administered simultaneously with rifampicin, satisfactory clindamycin concentrations could not be obtained when given orally. IV administration of a daily 3600 mg dose would be convenient for more than 80 % of the patients, but doses of at least 4800 mg/day would be needed for a MIC equal to the 0.25 mg/L EUCAST clinical Breakpoint for Staphylococcus aureus. Intermittent IV administration every 6h is preferable than q8h regimens for the Cmin/MIC criteria, but still performed poorly compared to continuous infusion. This model satisfyingly described the differential effect of rifampicin on the bioavailability and clearance of clindamycin. As previously described, this combination must not be taken orally. However, administration of clindamycin doses of at least 3600 mg/day by intermittent or, preferably, continuous infusion, can balance the impact of rifampicin.