Vancomycin Pharmacokinetics in Obese Patients with Sepsis or Septic Shock

Abstract

Study Objectives Obese patients with sepsis or septic shock may have altered vancomycin pharmacokinetics compared with the general population that may result in improper dosing or inadequate drug concentrations. The objective of this study was to characterize vancomycin pharmacokinetics in obese patients with sepsis or septic shock, and to develop a novel pharmacokinetic dosing model based on pharmacokinetic‐pharmacodynamic target requirements. Design Prospective observational pharmacokinetic study. Setting Large quaternary academic medical center. Patients Sixteen obese (body mass index [BMI] 30 kg/m2 or higher) adults with sepsis and either a gram‐positive bacteremia or requiring vasopressor support (septic shock), who were receiving vancomycin between November 2016 and June 2018, were included. Patients were excluded if they were receiving renal replacement therapy or extracorporeal membrane oxygenation, treatment for central nervous system infections, pregnant, or receiving vancomycin for surgical prophylaxis. Intervention Four blood samples per patient were collected following a single dose of vancomycin: one peak serum vancomycin level (within 1–2 hrs of infusion completion), two random levels during the dosing interval, and one trough level (within 30–60 min of the next dose) were measured. Measurements and Main Results A population pharmacokinetic model was developed to describe vancomycin concentrations over time. Simulations to determine optimal dosing were performed using the pharmacokinetic model with different ranges of creatinine clearance (Clcr) and different vancomycin daily doses. Median age of the patients was 62 years; median BMI was 36.1 kg/m2, Acute Physiology and Chronic Health Evaluation II score was 26, and Sequential Organ Failure Assessment score was 11. Eleven patients (69%) had an acute kidney injury. Median initial vancomycin dose was 15 mg/kg; median vancomycin trough concentration was 17 mg/L. A one‐compartment model best characterized the pharmacokinetics of vancomycin in obese patients with sepsis or septic shock. Volume of distribution was slightly increased in this population (0.8 L/kg) compared with the general population (0.7 L/kg). Only Clcr effect on drug clearance was found to be significant (decrease in the objective function value by 16.4 points), confirming that it is a strong predictor of vancomycin clearance. Conclusion To our knowledge, this study provides the first population‐based pharmacokinetic model in obese patients with sepsis or septic shock. The nomograms generated from this pharmacokinetic model provide a simplified approach to vancomycin dosing in this patient population.

Clinical Practice Guidelines for Therapeutic Drug Monitoring of Vancomycin in the Framework of Model-Informed Precision Dosing: A Consensus Review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring

“… Better prior probability was reported in a population PK model based on rich sampling (full data set: e.g., at the end of infusion, at 60, 120, and 300 min following the infusion, and immediately before the next dose) than that based on limited sampling (e.g., trough and peak concentrations) [ 66 , 67 , 68 , 69 , 70 , 71 ]. Population properties (i.e., age, body weight, kidney function, other potential covariates) for establishing a population PK model should be considered to determine the reasonable candidates for the MIPD software to increase the accuracy of dosing [ 53 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ]. The Bayesian prior information has been accumulated in special populations of obesity, paediatrics, and renal replacement therapy (RRT).…”

“…Population properties (i.e., age, body weight, kidney function, other potential covariates) for establishing a population PK model should be considered to determine the reasonable candidates for the MIPD software to increase the accuracy of dosing [ 53 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ].…”

“…Although the majority are used for research purposes, some software programs have been utilized in clinical settings to date. Turner et al evaluated the ratios of Bayesian posterior AUC using peak–trough sampling to AUC REF in five software packages [ 86 ]. The programs produced average accuracy ratios of 0.80 or higher and bias of less than 20% using the trough concentration alone for calculation.…”

“…Recently, Smit et al reported a population PK model based on the largest paediatric population to date (population size = 1892), including overweight (247, 13%) and obese subjects (301, 16%) [ 78 ]. Han et al summarized six programs for estimating Bayesian posterior AUC in paediatric patients [ 86 ]. Whereas the programs can adopt any paediatric model, one of the programs did not adopt a neonatal model.…”

Therapeutic Drug Monitoring of Vancomycin in Patients with Altered Pharmacokinetics: A Narrative Review on Pharmacokinetic Assessments

“…Considering the higher blood volume and cardiac output in obese patients, increased blood flow and increased Cl V would be predictable. Obese patients may have elevated amount of circulatory plasma proteins that can alter the amounts of vancomycin protein binding and the percentage of free drug available in plasma and target sites [64,65]. Taking into account the pharmacokinetic changes in obese and morbidly obese patients, individualized pharmacotherapy and close plasma concentration monitoring during vancomycin administration is strongly recommended.…”