Pharmacokinetic Drug-drug Interaction of Antibiotics Used in Sepsis Care in China

Many antibiotics have a high potential for interactions with drugs, as a perpetrator and/or victim, in critically ill patients, and particularly in sepsis patients.The aim of this review is to summarize the pharmacokinetic drug-drug interaction (DDI) of 45 antibiotics commonly used in sepsis care in China. Literature search was conducted to obtain human pharmacokinetics/ dispositions of the antibiotics, their interactions with drug-metabolizing enzymes or transporters, and their associated clinical drug interactions. Potential DDI is indicated by a DDI index ≥ 0.1 for inhibition or a treatedcell/ untreated-cell ratio of enzyme activity being ≥ 2 for induction.The literature-mined information on human pharmacokinetics of the identified antibiotics and their potential drug interactions is summarized.Antibiotic-perpetrated drug interactions, involving P450 enzyme inhibition, have been reported for four lipophilic antibacterials (ciprofloxacin, erythromycin, trimethoprim, and trimethoprim-sulfamethoxazole) and three antifungals (fluconazole, itraconazole, and voriconazole). In addition, seven hydrophilic antibacterials (ceftriaxone, cefamandole, piperacillin, penicillin G, amikacin, metronidazole, and linezolid) inhibit drug transporters in vitro. Despite no clinical PK drug interactions with the transporters, caution is advised in the use of these antibacterials. Eight hydrophilic antibiotics (all β-lactams; meropenem, cefotaxime, cefazolin, piperacillin, ticarcillin, penicillin G, ampicillin, and flucloxacillin), are potential victims of drug interactions due to transporter inhibition. Rifampin is reported to perpetrate drug interactions by inducing CYP3A or inhibiting OATP1B; it is also reported to be a victim of drug interactions, due to the dual inhibition of CYP3A4 and OATP1B by indinavir. In addition, three antifungals (caspofungin, itraconazole, and voriconazole) are reported to be victims of drug interactions because of P450 enzyme induction. Reports for other antibiotics acting as victims in drug interactions are scarce.