Population Pharmacokinetics and Probability of Target Attainment Analysis of Vancomycin Following Intermittent and Continuous Infusion in Adults with Cystic Fibrosis

Abstract

Vancomycin is the drug of choice for treating pulmonary infections caused by methicillinresistant Staphylococcus aureus (MRSA) in people with cystic fibrosis (PwCF). This study characterized the pharmacokinetics (PK) of continuous and intermittent vancomycin infusions following a loading dose using population PK (PopPK) modeling to inform dosing in PwCF. The PopPK model was developed using therapeutic drug monitoring (TDM) data from adult PwCF who received a vancomycin loading dose followed by intermittent, continuous, or both infusion types for MRSA-related pulmonary exacerbations. A total of 212 samples were collected following 90 intermittent and 42 continuous infusions in 21 patients. The final model was a two-compartment model with first-order elimination, incorporating creatinine clearance (CrCL) as a covariate on vancomycin clearance (CL). The estimated CL and volume of distribution were 4.05 L/h/70 kg and 22.5 L/70 kg, respectively. The model was used to predict the probability of target attainment (PTA) following a single intermittent loading dose (500-1500 mg) and continuous infusion (500-6000 mg) over 24 hours. PTA was assessed using efficacy and toxicity thresholds defined by Area Under the Curve0-24 (AUC0-24)/Minimum Inhibitory Concentration (MIC) ratios [≥]400 mg{middle dot}h/L and <650 mg{middle dot}h/L, respectively. At a MIC of 1 {micro}g/mL, a loading dose of 500 mg followed by a 3750 mg continuous infusion achieved PTA targets for efficacy (66.7%) and safety (82.7%). These findings support the use of PopPK modeling to guide vancomycin dosing strategies for MRSA pulmonary infections in PwCF.