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 8h. PK variables: total and renal clearance (CL tot , CL R ), 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% f T >MIC ) was defined as free ( f ) piperacillin plasma concentrations that remain, during the entire dosing interval (T), above the minimum inhibitory concentration (100% f T >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 f T reached only 62, 52, and 44% on days 4, 6, and 8, respectively. In patient 1, the % f T 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.