Abstract
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). 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. 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/1.73 m2. 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). 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.
Highlights
Ill patients undergoing aggressive fluid resuscitation and treated empirically with hydro-soluble β-lactams piperacillin/tazobactam (PIP/TZB) and meropenem (ME) may be at risk for sub-therapeutic plasma concentrations as a result of non-attainment of PK/PD targets considered crucial for appropriate bactericidal action
Study patients Enrolled in this prospective observational pharmacokinetic study were 18 critically ill patients admitted to the Surgical Intensive Care Unit (ICU) of the University Hospital in Hradec Králové, Czech Republic
The inclusion criteria were a diagnosis of severe sepsis or septic shock or a systemic inflammatory response (SIRS), together with treatment with a broad-spectrum beta-lactam antibiotic meropenem (ME) respectively piperacillin-tazobactam (PIP/TAZ), provided that the patients signed the informed consent
Summary
Ill patients undergoing aggressive fluid resuscitation and treated empirically with hydro-soluble β-lactams piperacillin/tazobactam (PIP/TZB) and meropenem (ME) may be at risk for sub-therapeutic plasma concentrations as a result of non-attainment of PK/PD targets considered crucial for appropriate bactericidal action. The bactericidal effect of these antibiotics is time-dependent, expressed as % of time in the dosing interval (T) when the plasma concentration of the free drug (f) is elevated above the minimum inhibitory concentration (MIC) for the suspected pathogen – (%f T > MIC). Extravascular volume expansion with fluid loading and increased capillary permeability may alter the volume of distribution[2], while changes in renal function can significantly influence drug renal clearance. This covariate might significantly influence hydrophilic drug Vd and could be a key factor for PK/PD target non-attainment. Its value could allow prediction of an individual loading dose compensating for extravascular fluid shift during the first days of therapy
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Schedule a callMore From: Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia
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