Population pharmacokinetics and dosing optimization of vancomycin in infants, children and adolescents with augmented renal clearance

Augmented renal clearance (ARC) can cause underexposure to vancomycin, thereby increasing the risk of treatment failure. Our objective was to evaluate population pharmacokinetics and optimize the dosing regimen of vancomycin in the pediatric population with ARC. Sparse pharmacokinetic sampling and therapeutic drug monitoring (TDM) data were collected from pediatric patients with ARC treated with vancomycin. A pharmacokinetic model was developed using NONMEM 7.2. The dosing regimen was optimized using Monte Carlo dose simulations. A total of 242 vancomycin serum concentrations from 113 patients (age range 0.4 to 14.9 years, 49 females and 64 males) were available. Mean vancomycin dose was 58.8 mg/kg/day (13.6 mg/kg/dose), and mean vancomycin serum trough concentration was 6.5 mg/L. A one-compartment pharmacokinetic model with first order elimination was developed. Body weight and age were the most significant and positive covariates for clearance and volume of distribution. To the pediatric population with ARC, the current recommended vancomycin dose of 60 mg/kg/day was associated with a high risk of underdosing. To reach the target AUC/MIC of 400-700 in these pediatric patients, the vancomycin dose should be increased to 75 mg/kg/day for infants and children between 1 month and 12 years of age, and 70 mg/kg/day for adolescents between 12 and 18 years of age. In conclusion, a one-compartment pharmacokinetic model with first-order elimination was established with body weight and age as significant covariates. An optimal dosing regimen was developed in pediatric patients with ARC aged 1 month -18 years.

Evaluation of traditional initial vancomycin dosing versus utilizing an electronic AUC/MIC dosing program

Background: Area under the curve to minimum inhibitory concentration (AUC/MIC) has been recommended by the 2020 updated vancomycin guidelines for dosing vancomycin for both efficacy and safety. Previously, AUC/MIC has been cumbersome to calculate so surrogate trough concentrations of 15-20 mg/dL were utilized. However, trough-based dosing is not a sufficient surrogate as AUC/MIC targets of 400-600 can usually be reached without achieving troughs of 15-20 mg/dL. Targeting higher trough levels may also lead to adverse events including acute kidney injury (AKI) and nephrotoxicity. Objective: To compare the mean total first day vancomycin dose in traditional trough-based dosing versus dosing recommended by an AUC/MIC dosing program. Methods: Adult inpatients who received at least 24 hours of IV vancomycin treatment were included in this single-center, retrospective cohort study. The primary endpoint was difference in mean total first day vancomycin dose in milligrams (mg) received between patients’ traditional trough-based dosing and recommended dose via AUC/MIC electronic dosing calculator. Patients served as their own control by analyzing both actual dose received and dose recommended by the electronic AUC/MIC program. Rates of vancomycin induced adverse events, including acute kidney injury, elevated steady-state trough concentrations, and Red Man’s syndrome were also compared between patients who received doses consistent with the AUC/MIC dosing recommendation versus those who did not. Results: 264 patients were included in this study. Initial 24-hour vancomycin exposure was significantly lower with the recommended AUC/MIC dose versus the dose received (2380.7; SD 966.6 mg vs 2649.6; SD 831.8 mg, [95% CI 114.7:423.1] p=0.0007). Conclusions: Utilizing an electronic AUC/MIC vancomycin dosing calculator would result in lower total first day vancomycin doses.

1572. Evaluation of Vancomycin Levels Following Weight-Based Pre-operative and Re-warming Vancomycin Dosing in Cardiac Surgery

Background Weight-based dosing of vancomycin in the pre-operative setting is standard practice at our institution based on the 2013 Clinical Practice Guidelines for Antimicrobial Prophylaxis in Surgery. Our antimicrobial subcommittee recommended a weight-based dosing (15 mg/kg/dose) approach to negate the need for a subsequent vancomycin dose during rewarming in cases requiring cardiopulmonary bypass (CPB). However, after discussion with all perioperative stakeholders, administration of vancomycin 1 g intravenously for all patients on CPB at rewarming continued. The aim of this study was to determine whether subsequent rewarming vancomycin doses contributed to the development of postoperative acute kidney injury (AKI). Methods This was a prospective cohort study of all cardiac surgery patients undergoing surgery from April 16, 2018 through April 27, 2018 for the development of AKI as defined by RIFLE criteria. Institutional guidelines recommend vancomycin as perioperative prophylaxis in all cardiac surgery cases with a preoperative 15 mg/kg dose, a 1 g rewarming dose, and nomogram-based post-operative dosing. Vancomycin troughs were obtained prior to the first post-operative dose in the intensive care unit. Serum creatinine was recorded on the post-op day (POD) 0, POD 1, and POD 7. Results Data were collected on 54 patients over a 2-week period. The median age was 64 years of age, with 41 (76%) male patients. Seven patients (13%) had a prior diagnosis of chronic kidney disease (CKD). Post-op AKI developed in 8 patients (15%) by POD 7; two of which had CKD at baseline. All patients received appropriate preoperative and postoperative dosing. Forty-nine (91%) patients had trough levels obtained, with the median trough 7.6 μg/mL (range 2 – 15.9 μg/mL) prior to the first nomogram-based post-operative vancomycin dose. Higher rates of AKI were associated with a longer duration of CPB rather than vancomycin levels obtained. Conclusion The current practice of redosing 1 g vancomycin at rewarming did not appear to contribute higher rates of AKI. In addition, all vancomycin trough levels reviewed were less than 20 μg/mL. Levels observed in this study are lower than previously described in the literature to cause nephrotoxicity. Further evaluation of vancomycin use in this setting is warranted Disclosures All authors: No reported disclosures.