What clindamycin dose should be administered by continuous infusion during combination therapy with rifampicin? A prospective population pharmacokinetics study

Background: Despite its important drug-drug interaction, combined clindamycin/rifampicin therapy may achieve effective plasma clindamycin concentrations, provided clindamycin is administered by continuous infusion. However, the precise clindamycin dose remains unknown.Objectives: This study was undertaken to determine the daily clindamycin dose to be administered by continuous infusion in combination with rifampicin to achieve effective plasma clindamycin concentrations.Patients and methods: Two plasma clindamycin concentrations were determined prospectively for 124 patients with bone-and-joint infections treated with continuously infused clindamycin. Twenty patients received clindamycin monotherapy, 19 clindamycin combined with rifampicin and 85 received clindamycin successively without and with rifampicin. A population pharmacokinetic model was developed using NONMEM 7.5. Monte Carlo simulations were run to determine which regimens obtained clindamycin concentrations of at least 3 mg/L.Results: A linear one-compartment model with first-order elimination accurately described the data. Clindamycin distribution volume was not estimated. Mean clindamycin clearances with rifampicin and without, respectively, were 33.6 and 10.9 L/h, with 12.8% interindividual variability. The lowest daily clindamycin dose achieving plasma concentrations of at least 3 mg/L in >90% of the patients, when combined with rifampicin, was 4200 mg/24 h.Conclusions: Our results support continuous infusion of 4200 mg of clindamycin/24 h, in combination with rifampicin. This high-dose regimen requires therapeutic drug monitoring-guided dose adaptation.