Pharmacokinetic interaction between rifampicin and clindamycin in staphylococcal osteoarticular infections

• Published in: International journal of antimicrobial agents Vol. 62; no. 2; p. 106885
• Main Authors: Goulenok, T., Seurat, J., Selle, A. de La, Jullien, V., Leflon-Guibout, V., Grall, N., Lescure, F.X., Lepeule, R., Bertrand, J., Fantin, B., Burdet, C., Lefort, A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.08.2023
• Subjects: algorithms; Bone and joint infection; Clindamycin; Drug interaction; Infectious Disease; intravenous injection; patients; pharmacodynamics; Pharmacokinetics; probability; Rifampicin; Staphylococcus aureus; Drug interaction; Rifampicin; Pharmacokinetics; Clindamycin; Bone and joint infection; Bone and joint infections
• ISSN: 0924-8579; 1872-7913; 1872-7913
• DOI: 10.1016/j.ijantimicag.2023.106885

•A strong pharmacokinetic interaction between clindamycin and rifampicin is observed.•In osteoarticular infection (OAI), rifampicin co-administration dramatically increased clindamycin clearance.•Associated with rifampicin, clindamycin concentrations are insufficient for significant antibacterial activity in staphylococcal OAI.•This is observed even at high dose against a fully susceptible strain.•This reinforces the importance of defining the most appropriate PK/PD target for clindamycin. 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. 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. 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. 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.