Pharmacokinetic and Pharmacodynamic Evaluation of a Weight-Based Dosing Regimen of Cefoxitin for Perioperative Surgical Prophylaxis in Obese and Morbidly Obese Patients

Abstract

The objective of this study was to determine the pharmacokinetics and pharmacodynamics (PK/PD) of a weight-based cefoxitin dosing regimen for surgical prophylaxis in obese patients. Patients received a single dose of cefoxitin at 40 mg/kg based on total body weight. Cefoxitin samples were obtained over 3 h from serum and adipose tissue, and concentrations were determined by validated high-performance liquid chromatography. Noncompartmental pharmacokinetic analysis was performed, followed by Monte Carlo simulations to estimate probability of target attainment (PTA) for Staphylococcus aureus, Escherichia coli, and Bacteroides fragilis over 4-h periods postdose. Thirty patients undergoing bariatric procedures were enrolled. The body mass index (mean ؎ standard deviation [SD])was 45.9 ؎ 8.0 kg/m 2 (range, 35.0 to 76.7 kg/m 2 ); the median cefoxitin dose was 5 g (range, 4.0 to 7.5 g). The mean maximum concentrations were 216.15 ؎ 41.80 g/ml in serum and 12.62 ؎ 5.89 in tissue; the mean tissue/serum ratio was 8% ؎ 3%. In serum, weight-based regimens achieved >90% PTA (goal time during which free [unbound] drug concentrations exceed pathogen MICs [fT>MIC] of 100%) for E. coli and S. aureus over 2 h and for B. fragilis over 1 h; in tissue this regimen failed to achieve goal PTA at any time point. The 40-mg/kg regimens achieved higher PTAs over longer periods in both serum and tissue than did the standard 2-g doses. However, although weight-based cefoxitin regimens were better than fixed doses, achievement of desired pharmacodynamic targets was suboptimal in both serum and tissue. Alternative dosing regimens and agents should be explored in order to achieve more favorable antibiotic performance during surgical prophylaxis in obese patients. Surgical site infections (SSIs) are the leading cause of postoperative morbidity and mortality and add significantly to the cost of care (1). Perioperative antibiotic prophylaxis is therefore a standard of care and a keystone for the prevention of SSIs (2-6). Recommendations regarding the use of specific antibiotics for prophylaxis during surgical procedures have been published since the early 1990s and have been frequently revisited since that time (1, 2, 5-9). More recently, specific recommendations provided by the National Surgical Infection Prevention (SIP) Project have focused on appropriate timing of administration of prophylactic antibiotics, appropriate drug selection, and the discontinuation of prophylactic antibiotics within 24 h after surgery (2, 9). However, the actual recommended drugs and dosing regimens for surgical prophylaxis have been relatively unchanged over the past 20 years. Limited published data exist regarding appropriate dosing of antimicrobials for prophylaxis. It is generally stated that the drug should be given in an adequate dose based on patient weight, adjusted dosing weight, or body mass index (BMI) (2, 6, 9). Furthermore, antibiotic administration should be repeated intraoperatively if the procedure continues beyond one to two pharmacokinetic (PK) hal...

Impact of Obesity on Ceftriaxone Efficacy

“…There are several pharmacokinetic and clinical studies that illustrate that standard dosing of cephalosporins may be inadequate [ 8 , 9 , 10 , 11 , 12 ]. Studies with cefazolin have led to recommendations for increased dosing strategies in patients over 120 kg [ 8 , 9 ], and second-generation cephalosporins have also demonstrated suboptimal target attainment in obese and morbidly obese patients [ 10 ]. Similarly, in a case-control study of critically ill obese patients, ceftazidime and cefepime demonstrated lower serum concentrations in these patients [ 11 ].…”

Competence Mining of Vancomycin (VAN) in the Management of Infections Due to Bacterial Strains With High VAN Minimum Inhibitory Concentrations (MICs): A Novel Dosing Strategy Based on Pharmacokinetic/Pharmacodynamic Modeling

“…Oracle Crystal Ball (version 11.1.2; Decisioneering Inc., Denver, CO, United States), a leading spreadsheet (i.e., Excel)-based application for predictive modeling, forecasting, simulation, and optimization, was used to perform the MCSs to calculate the probability of each dosing regimen to achieve the given combined PK/PD target against isolates with MICs of 0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, and 64 mg/L, which is referred to as the PTA. This method has been well described elsewhere (Moine et al, 2016;Song and Long, 2018). In general, MCSs includes the following five steps: (1) data inputting (i.e., inputting the simulation variables and their representative values into the Excel table cells), (2) distribution pattern settings of simulation variables (i.e., setting the distribution patterns of the simulation variables according to their characteristics), (3) predictive variable settings and calculation (i.e., setting the variable that can reflect the drug efficacy as the predictive variable and calculating its typical value based on the mathematical model of it established on the simulation variables), (4) simulation parameter settings and execution (i.e., setting the number of simulations and the confidence interval), and (5) simulation result analysis (including the sensitivity and trend analysis, report creation and extraction of data).…”

Cefoxitin: A Neglected Intravenous Betalactam with Interesting Perspectives

“…Similarly, Brunetti et al [14] reported that subcutaneous adipose tissue concentrations of cefoxitin at the time of surgical closure were subtherapeutic in six patients undergoing sleeve gastrectomy. Moine showed that a single dose of cefoxitin at 40 mg/kg failed to achieve the desired probability of target attainment in fat tissue for Staphylococcus aureus, Escherichia coli, and Bacteroides fragilis over 4-h periods postdose [15] . In bariatric surgery, a starting dose of 4 g is recommended instead of 2 g for people weighing more than 100 kg [16] .…”