Biomedical papers - Ahead of Print

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. X:X | 10.5507/bp.2018.011

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

Milan Kaskaa,b, Eduard Havela,b, Iva Selke-Krulichovab, Petr Safraneka, Jan Bezouskab, Jirina Martinkovaa
a Department of Surgery, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic
b Academic Department of Surgery, Faculty of Medicine in Hradec Kralove, Charles University and Department of Surgery, University Hospital, Sokolska 581, 50005 Hradec Kralove, Czech Republic

Aims: Critically ill patients undergoing aggressive fluid resuscitation and treated empirically with hydrosoluble time-dependent beta-lactam antibiotics are at risk for sub-therapeutic plasma concentrations. The aim of this study was to assess the impact of two covariates - creatinine clearance (Clcr) and cumulative fluid balance (CFB) on pharmacokinetics/pharmacodynamics (PK/PD) target attainment within a week of treatment with meropenem (ME) or piperacillin/tazobactam (PIP/TZB).

Methods: In this prospective observational pharmacokinetic (PK) study, 18 critically ill patients admitted to a surgical Intensive Care Unit (ICU) were enrolled. The primary PK/PD target was free antibiotic concentrations above MIC at 100% of the dosing interval (100%fT>MIC) to obtain maximum bactericidal activity. Drug concentration was measured using liquid chromatography-tandem mass spectrometry.

Results: The treatment of both 8 septic patients with IV extended ME dosing 2 g/3 h q8 h and 10 polytraumatized patients with IV intermittent PIP/TZB dosing 4.0/0.5 g q8 h was monitored. 8/18 patients (44%) manifested augmented renal clearence (ARC) where Clcr ≥130 mL/min/1.73m2. Maximum changes were reported on days 2-3: the median positive CFB followed by the large median volume of distribution: Vdme=70.3 L (41.9-101.5), Vdpip = 46.8 L (39.7-60.0). 100%fTme>MIC was achieved in all patients on ME (aged ≥60 years), and only in two patients (non-ARC, aged ≥65 years) out of 10 on PIP/TZB. A mixed model analysis revealed positive relationship of CFBpip with Vdpip (P=0.021).

Conclusion: Assuming that the positive correlation between CFB and Vd exists for piperacillin in the setting of the pathological state, then CFB should predict Vdpip across subjects at each and every time point.

Keywords: beta-lactam antibiotics, meropenem, piperacillin, pharmacokinetics/pharmacodynamics target, critically ill patient

Received: November 20, 2017; Accepted: March 21, 2018; Prepublished online: March 27, 2018


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