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