A pilot study on pharmacokinetic/pharmacodynamic target attainment in critically ill patients receiving piperacillin/tazobactam

Background: In critically ill patients, multi-trauma and intensive therapy can influence the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics with time-dependent bacterial killing. Consequently, PK/PD targets (%fT(>MIC)) - crucial for antimicrobial effects - may not be attained. Methods: Two patients admitted to the surgical ICU of the University Hospital in Hradec Kralove for multiple-trauma were given piperacillin/tazobactam by 1-hour IV infusion 4/0.5 g every 8 h. PK variables: total and renal clearance (CLtot, CLR), volume of distribution (V-d), and elimination half-life (T-1/2) were calculated, followed by glomerular filtration rate (MDRD) and cumulative fluid balance (CFB-total fluid volume based on 24-h registered fluid intake minus output). The PK/PD target attainment (100%fT(>MIC)) was defined as free (f) piperacillin plasma concentrations that remain, during the entire dosing interval (T), above the minimum inhibitory concentration (100%fT(>MIC)) within days 4-8 (when CFB culminates and disappears). Piperacillin concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and corrected for unbound fraction (22%). Results: CFB culminated over days 2-5 reaching 15-30 L and was associated with a large V-d (29-42 L). While MDRD in patient 1 was low (0.3-0.4 mL s(-1) 1.7 m(-2)), that of patient 2 was increasing (>3.1 mL s(-1) 1.7 m(-2)), which was associated with augmented CLR. In patient 2, the fT reached only 62, 52, and 44% on days 4, 6, and 8, respectively. In patient 1, the %fT was much higher, attaining values four to fivefold greater than that targeted. Conclusions: Critically ill patients are at risk of drug under-or overdosing without dose up-titration with regard to covariate effects and individual drug pharmacokinetics.