Newly developed vancomycin dosing regimens for continuous and intermittent infusion are proposed to better accommodate the pharmacokinetics in overweight and obese patients with renal insufficiency.1
Recently revised guidelineson dosing vancomycin to area-under-curve (AUC) values rather than trough serum levels can improve clinical efficacy and minimize toxicity, but do not adequately account for altered rates of vancomycin clearance (CL) in overweight individuals with renal insufficiency, according to a clinical pharmacy team in the Netherlands.2
Catherijne Knibbe, PharmD, PhD, Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands and colleagues declare that further refinement of dosing for these patients is "urgently needed."
To ascertain the pharmacokinetics of vancomycin in overweight patients with renal insufficiency, the investigators retrieved the timed serum levels (n=1188) that had been determined intherapeutic drug monitoring of 210 overweight and obese patients with varying degrees of renal function insufficiency from general hospital wards (74.8%) and intensive care units (25.2%). These were analyzed along with published data of 207 timed serum level determinations from 20 morbidly obese subjects with normal renal function who had undergone bariatric surgery.
What You Need to Know
Newly developed dosing regimens for continuous and intermittent infusion of vancomycin are proposed to better suit the pharmacokinetics in overweight and obese patients with renal insufficiency.
Total body weight (TBW) was identified as a better correlate with vancomycin clearance (CL) than other bodyweight descriptors.
To achieve the recommended target AUC24 for vancomycin (400 to 600 µg/ml·hr) within the initial 24 to 48 hours, the researchers propose a deviation from current clinical practice for loading doses in overweight and renal insufficient patients.
The investigators analyzed these population pharmacokinetics with potential covariates such as age and sex, and several bodyweight-related descriptors including total body weight (TBW), lean body weight (LBW), adjusted body-weight (ABW), ideal bodyweight (IBW) and body mass index (BMI).They also compared different estimates of renal function with Cockcroft-Gault calculation (CG) using LBW or TBW, the modification of diet in renal disease (MDRD), the chronic kidney disease epidemiology collaboration (CKD-EPI), and the MDRD and CKD-EPI de-indexed for body surface area (BSA).
The investigators determined that TBW was better correlated with CL than other bodyweight descriptors. They also found indexed CKD-EPI superior to CG and other renal function estimates. "In fact," they advised, "the equation of CG, which is commonly used, has been reported to have a low accuracy and high bias in estimating glomerular filtration rate in patients with obesity and should therefore be avoided."
Knibbe and colleagues report finding that vancomycin clearance in overweight and obese individuals increases with total bodyweight and renal function, and is slightly reduced in ICU patients compared with those in general wards. They posit that latter distinction might reflect the rapidly varying disease states of patients in intensive care, which could lead to reduced kidney function and drug elimination.
Knibbe and colleagues then determined serum level-time profiles in the different bodyweight and renal function groups for the recommended target AUC24(serum concentration vs time curve for 0 to 24 hours) of 400 to 600 µg/ml·hr. They note that achieving that target within the initial 24 to 48 hours of the vancomycin course necessitates loading dosage, but found the traditional mg/kg loading dose in a 2-hour infusion before the maintenance regimen inadequate for that target level and time frame in patients who are overweight and have renal insufficiency.
Instead, they determined, and propose that two loading doses be administered for this population. For continuous infusion, a loading dose of 1500mg is administered over 2 hours before the maintenance infusion on day 1, and another loading of 750mg on day 2, after which the maintenance infusion is continued. For intermittent dosing, they propose administering the two loading doses at 12 hour intervals on the first day.
"Even though this is a deviation from current clinical practice, these loading doses are necessary to achieve effective exposure early in the treatment," Knibbe and colleagues state.
"To achieve safe and effective vancomycin exposure for maintenance doses in overweight and obese patients, renal function, total bodyweight and ICU admission status should be taken into account," they advise.
1. Zhang T, Krekels EHJ, SMit C, et al. How to dose vancomycin in overweight and obese patients with varying renal (Dys)function in the novel era of AUC 400-600mg-h/L-targeted dosing. Clin Pharmacokinet 2024; 63:79-91.
2. Rybak MJ, Le J, Lodise TP, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2020;77(11):835–64.