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

Objectives: The aim of this study was to develop a pharmacokinetic (PK) interaction model of intravenous (i.v.) 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.

Methods: Five hundred and eighteen plasma samples were prospectively obtained from 124 patients treated for bone and joint infections. Population pharmacokinetic analysis was performed using Monolix software. Monte Carlo simulations were run to determine the probability of achieving a minimal clindamycin plasma concentration equal to at least twice the MIC, or an unbound area under the curve/MIC ≥60.

Results: 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, whereas 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 q12 h, respectively. When administered simultaneously with rifampicin, satisfactory clindamycin concentrations could not be obtained when given orally. i.v. administration of a daily 3600 mg dose would be convenient for more than 80% of the patients, but doses of at least 4800 mg/d would be needed for a MIC equal to the 0.25 mg/L European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoint for Staphylococcus aureus. Intermittent i.v. administration every 6 hours is preferable to q8h regimens for the C_min/MIC criteria, but still performed poorly compared with continuous infusion.

Discussion: 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/d by intermittent or, preferably, continuous infusion, can balance the impact of rifampicin.