INTRODUCTION
Imipenem is a leading antibiotic of the carbapenem family with a broad antibacterial spectrum against gram-positive, gram-negative and anaerobic bacteria[1]. This drug is frequently used in the treatment of critically ill patients with severe infections because of its wide spectrum of antimicrobial activity. Imipenem is a β-lactam and exhibits time-dependent bactericidal activity; the free plasma concentration above the minimum concentration of pathogens (f T>MIC) is the best pharmacokinetic/pharmacodynamic index correlating with clinical efficacy[2].
Early and aggressive antibiotic therapy is very important in the treatment of critically ill patients with serious infections. However, appropriate antibiotic dosing and regimens in critically ill patients are challenging tasks. For critically ill patients, the rapidly changing physiology (e.g., organ dysfunction) might lead to markedly altered antibiotic PK and PD[3]. Augmented renal clearance (ARC), low plasma proteins and hypervolemia distributions affect the metabolism of imipenem in vivo . The susceptibility of bacteria may decrease because of inappropriate PK/PD profiles, and drug resistance may occur[4,5].
Clinicians are increasingly employing therapeutic drug monitoring (TDM) of β-lactam antibiotics to ensure adequate antibiotic exposure[6]. Imipenem is a hydrophilic molecule that is rapidly distributed to most tissues.f T>MIC with a target fractional time greater than 40% is the best PD parameter correlated with clinical efficacy[7,8]. However, for clinically ill patients, the changing physiology might lead to subtherapeutic plasma concentrations, and the targetf T>MIC (greater than 40%) will not be suitable.
In previous studies, a f T>MIC of 100% or a f T>5 MIC to 100% may be necessary[9]. Continuous or prolonged infusions were selected to increase efficacy. However, for dose regimen optimization, the most popular method was using population PK/PD simulation[10]. This approach comprises integrating prior information and evaluating the PK of antibiotic regimens in small numbers. Thef T>MIC was calculated for a specific population, and therapeutic ranges for clinically ill patients have not been established.
In this research, we determined thef T>MIC of imipenem by pharmacokinetic parameters and simulated a mathematical model. The PK model incorporates the limited sampling concentration, and the PK/PD profiles will be verified. We also examined the clinical outcomes of clinically ill patients undergoing imipenem TDM during therapy for bacterial infections and evaluated the bestf T>MIC level for critically ill patients.
METHODS