Bone Diseases, Infectious Clinical Trial
Official title:
Clindamycin-Rifampin Interactions: Effect of Rifampin's Enzyme-induction (Cytochrome P450 3A4/3A5) on Plasma Clindamycin Concentrations, With Clindamycin Given Intravenously and Orally to Treat Bone-and-joint Infections
Treatment of bone and joint infections remains difficult and variable according to centres and countries. Clindamycin given intravenously and followed by an oral route is recommended for the treatment of staphylococcal, streptococcal and anaerobes bone and joint infections by the French Society for Infectious Diseases. For staphylococcal bone and implant infections, rifampin is a major drug, as it remains active in bacterial biofilm and on quiescent staphylococci. For that reasons, clindamycin-rifampin combination therapy is frequently used in these infections.Clindamycin is metabolized by the P450 3A4 cytochrome, an enzyme strongly inducible by rifampin. A retrospective study published in 2010 on 70 patients treated for bone and joint infections showed that clindamycin serum concentrations were significantly lower when clindamycin was combined with rifampin (5.3 mg/liter vs 8.9 mg/liter; p<0.02). This drug interaction could even be stronger with the oral route, because of hepatic first-past effect, ending up with very low clindamycin serum concentration, a risk of selecting resistant microorganisms and treatment failure. This latter point is an important issue, because clindamycin has an excellent oral bioavailability and is frequently used in oral regimens. In the above study, a wide variability of clindamycin serum concentration was observed in the group of patients treated with combination therapy (1-12mg/l) suggesting interindividual variability. Rifampin induction of CYP 450 3A4/A5 depends on different receptor (PXR, RXR, LXRalpha) submitted to genetic polymorphism. Hypothesis: Plasma clearance of clindamycin (CLclin) combined with rifampicin (CLclinrif) is higher when clindamycin is administered by the oral route (CLclinrif OR) compared with IV administration (CLclinrif IV).
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