Population Pharmacokinetics and Target Attainment of Meropenem in Plasma and Tissue of Morbidly Obese Patients after Laparoscopic Intraperitoneal Surgery

Abstract

c Meropenem serves as a clinically important, broad-spectrum antibiotic. While meropenem is commonly used in obese patients, its pharmacokinetics in this patient group is not well known. Our aim was to characterize the population pharmacokinetics and target attainment in plasma, subcutaneous tissue, and peritoneal fluid for meropenem in morbidly obese patients. Four doses of 1g meropenem were given as 15-min infusions every 8 h to five morbidly obese patients (body mass index [BMI], 47.6 to 62.3 kg/m 2 ). After the fourth dose, serial meropenem concentrations were determined in plasma and, via microdialysis, in subcutaneous tissue and peritoneal fluid. All concentrations were analyzed simultaneously via population modeling, and target attainment probabilities predicted via Monte Carlo simulations using the target of unbound meropenem concentrations above the MIC for at least 40% of the dosing interval. For patients with 53 kg fat-free mass, total clearance was 18.7 liters/h and volume of distribution at steady state was 27. W hile antimicrobial resistance is one of the greatest threats to human health, the number of new antibiotics against multidrug-resistant bacteria declined drastically over the last 3 decades (1-3). Meropenem continues to serve as an important component of our antibiotic armamentarium and covers a large range of clinically relevant pathogens for antibiotic therapy, including those causing intra-abdominal infections or infections of the subcutaneous tissue. Meropenem is a potent, broad-spectrum ␤-lactam antibiotic that yields relatively rapid bacterial killing and is among the first antibiotic options for treatment of severe infections; it covers most of the pathogens relevant for intra-abdominal infections (4). Meropenem is a hydrophilic molecule, and it is unknown whether meropenem penetrates well into the subcutaneous tissue and peritoneal fluid of obese patients.Obese patients are at a high risk of postoperative and hospitalrelated infections (5), and optimal management of these infections is crucial to improve the outcome of obese patients with severe infections. The selection of the antibiotic and dose are critical to manage those infections (5, 6). Recommended daily doses are based on pharmacokinetic/pharmacodynamic (PK/PD) studies usually conducted in nonobese healthy volunteers (5). However, PK variables may differ in obese and nonobese patients, potentially resulting in inadequate antibiotic plasma and tissue concentrations. Thus, PK studies in obese, noninfected individuals are essential to avoid the risk of over-or underdosing.Only a few studies have assessed the PK of meropenem in obese patients (4-8), and some of these studies found considerably different clearances and volumes of distribution in obese and nonobese patients. These studies did not perform population pharmacokinetic modeling and did not assess the peritoneal fluid and subcutaneous tissue penetration of meropenem in obese patients.As meropenem is a hydrophilic molecule, it is important to determine whether its PK is...

Population Pharmacokinetics and Target Attainment of Ertapenem in Plasma and Tissue Assessed via Microdialysis in Morbidly Obese Patients after Laparoscopic Visceral Surgery

“…In the absence of a healthy volunteer control group, we used FFM instead of WT to describe body size and body composition in our morbidly obese patients, as we did in our previous study (4). Our study was too small to evaluate different measures of body size, such as FFM or lean body mass; FFM has previously been evaluated and found to be suitable for use in the determination of the doses of drugs of other classes to be used for obese patients (19,(31)(32)(33).…”

“…The small volume was chosen to not affect (or only minimally affect) the disposition parameters of ertapenem estimated on the basis of the plasma concentrations. Details about this approach have been previously described (4,38). This approach captured the scenario that an equilibrium between tissue and plasma has not yet been reached at the time of collection of the first tissue sample; this approach is the most flexible, as it allowed the rate of equilibration in subcutaneous tissue and peritoneal fluid to differ from the rate of equilibration in the shallow peripheral and deep peripheral compartment.…”

“…For this approach, the unbound tissue concentration was calculated by multiplying the unbound concentration in the central compartment (i.e., plasma) by a factor (F SC for subcutaneous tissue and F PF for peritoneal fluid). F SC and F PF also represent the area under the concentration-time curve (AUC) for unbound concentrations of ertapenem in subcutaneous tissue or peritoneal fluid, respectively, divided by the AUC for unbound concentrations of ertapenem in plasma, as described previously (4,37).…”

“…The long half-life of ertapenem provides clinicians more flexibility regarding the timing of doses and potential redosing than they have with other ␤-lactams (4)(5)(6)(7)(8). Thus, ertapenem may be attractive for use in this patient population.…”

“…We considered both total body weight (WT) and fat-free mass (FFM) to characterize body size and body composition and to scale clearance and the volume of distribution (4,19). Suboptimal dosing regimens in obese patients may lead to clinical failures, complications with surgery, and the emergence of bacterial resistance.…”