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. 2023 Aug;62(2):106885.
doi: 10.1016/j.ijantimicag.2023.106885. Epub 2023 Jun 10.

Pharmacokinetic interaction between rifampicin and clindamycin in staphylococcal osteoarticular infections

T Goulenok  1 , J Seurat  2 , A de La Selle  3 , V Jullien  4 , V Leflon-Guibout  5 , N Grall  6 , F X Lescure  7 , R Lepeule  8 , J Bertrand  2 , B Fantin  2 , C Burdet  9 , A Lefort  10
Affiliations

Pharmacokinetic interaction between rifampicin and clindamycin in staphylococcal osteoarticular infections

T Goulenok et al. Int J Antimicrob Agents. 2023 Aug.

Abstract

Objectives: Oral combination of clindamycin and rifampicin is relevant for the treatment of staphylococcal osteoarticular infection (SOAIs). However, rifampicin induces CYP3A4, suggesting a pharmacokinetic interaction with clindamycin with unknown pharmacokinetic/pharmacodynamic (PK/PD) consequences. This study aimed to quantify clindamycin PK/PD markers before and during rifampicin co-administration in SOAI.

Methods: Patients with SOAI were included. After initial intravenous antistaphylococcal treatment, oral therapy was started with clindamycin (600 or 750 mg t.i.d.), followed by addition of rifampicin 36 h later. Population PK analysis was performed using the SAEM algorithm. PK/PD markers were compared with and without rifampicin co-administration, each patient being his own control.

Results: In 19 patients, clindamycin median (range) trough concentrations were 2.7 (0.3-8.9) mg/L and <0.05 (<0.05-0.3) mg/L before and during rifampicin administration, respectively. Rifampicin co-administration increased clindamycin clearance by a factor 16 and reduced the AUC0-8h/MIC by a factor 15 (P < 0.005). Clindamycin plasma concentrations were simulated for 1000 individuals, without and with rifampicin. Against a susceptible Staphylococcus aureus strain (clindamycin MIC 0.0625 mg/L), >80% of individuals would reach all proposed PK/PD targets without co-administration of rifampicin, even with low clindamycin dose. For the same strain, when rifampicin was co-administered, the probability to reach clindamycin PK/PD targets dropped to 1% for %fT>MIC = 100% and to 6% for AUC0-24h/MIC > 60, even with high clindamycin dose.

Conclusion: Rifampicin co-administration with clindamycin has a high impact on clindamycin exposure and PK/PD targets in SOAI, which could result in clinical failure even for fully susceptible strains.

Keywords: Bone and joint infection; Clindamycin; Drug interaction; Pharmacokinetics; Rifampicin.

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