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

Abstract

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 Králove 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 (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%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 CL R . 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.

Simultaneous Determination of Eight β-Lactam Antibiotics, Amoxicillin, Cefazolin, Cefepime, Cefotaxime, Ceftazidime, Cloxacillin, Oxacillin, and Piperacillin, in Human Plasma by Using Ultra-High-Performance Liquid Chromatography with Ultraviolet Detection

“…A standard mix solution containing all antibiotics at 5 mg/ml was then prepared in water and aliquoted, and the aliquots were placed into polypropylene tubes and stored at Ϫ80°C. On the day of analysis, spiking solutions (10,25,50,125,250,375, 500 mg/liter) were prepared by appropriate dilution of the standard mix solution in water. Calibration standards were prepared by adding 20 l of each spiking solution to 80 l of drug-free plasma in order to obtain the following final concentrations: 2, 5, 10, 25, 50, 75, and 100 mg/liter.…”

“…According to many authors, the optimal bactericidal activity in critically ill patients is achieved when plasma concentrations are above the MIC or even greater than 4 to 5 times the MIC for 70% to 100% of the dosing interval (2)(3)(4)(5)(6)(7)(8)(9)(10). The failure of antibiotic treatment and the development of resistant strains of bacteria may occur in patients with insufficient antibiotic exposure.…”

Covariate determinants of effective dosing regimens for time-dependent beta-lactam antibiotics for critically ill patients

“…The influence of Cl cr may be bidirectional: high Cl cr predicts non-achievement of the predefined %f T (ref. 5,22 ) and failure of antibiotic therapy as shown in patients treated with conventional dosing of piperacillin. Reduced Cl cr and consequent low antibiotic Cl ren can result in drug accumulation 22,30 and elevated %f T. Unfortunately, Cl cr was shown to be a covariate not predictive of variations in drug PK/PD target attainment in such setting 33 .…”

“…5,22 ) and failure of antibiotic therapy as shown in patients treated with conventional dosing of piperacillin. Reduced Cl cr and consequent low antibiotic Cl ren can result in drug accumulation 22,30 and elevated %f T. Unfortunately, Cl cr was shown to be a covariate not predictive of variations in drug PK/PD target attainment in such setting 33 . Is CFB next covariate that should be taken into consideration as the predictor of the first (loading) doses and that presented by Cl cr as the predictor of next dosing adaptation?…”

“…The percentage time of the free fraction above the MIC (%f T>MIC) was evaluated by a graphical method 22 or calculated using a mathematical expression 23 .…”