Abstract
BackgroundSevere bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application.MethodsA prospective observational single-centre study was performed with critically ill patients with severe infections receiving standard dosing of meropenem. Serial blood samples were drawn over 4 study days to determine meropenem serum concentrations. Renal function was assessed by creatinine clearance according to the Cockcroft and Gault equation (CLCRCG). Variability in meropenem serum concentrations was quantified at the middle and end of each monitored dosing interval. The attainment of two pharmacokinetic/pharmacodynamic targets (100%T>MIC, 50%T>4×MIC) was evaluated for minimum inhibitory concentration (MIC) values of 2 mg/L and 8 mg/L and standard meropenem dosing (1000 mg, 30-minute infusion, every 8 h). Furthermore, we assessed the impact of CLCRCG on meropenem concentrations and target attainment and developed a tool for risk assessment of target non-attainment.ResultsLarge inter- and intra-patient variability in meropenem concentrations was observed in the critically ill population (n = 48). Attainment of the target 100%T>MIC was merely 48.4% and 20.6%, given MIC values of 2 mg/L and 8 mg/L, respectively, and similar for the target 50%T>4×MIC. A hyperbolic relationship between CLCRCG (25–255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C8h) was derived. For infections with pathogens of MIC 2 mg/L, mild renal impairment up to augmented renal function was identified as a risk factor for target non-attainment (for MIC 8 mg/L, additionally, moderate renal impairment).ConclusionsThe investigated standard meropenem dosing regimen appeared to result in insufficient meropenem exposure in a considerable fraction of critically ill patients. An easy- and free-to-use tool (the MeroRisk Calculator) for assessing the risk of target non-attainment for a given renal function and MIC value was developed.Trial registrationClinicaltrials.gov, NCT01793012. Registered on 24 January 2013.
Highlights
Severe bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality
Severe infections remain a major issue in the intensive care unit (ICU) because of their high prevalence and high mortality rates among critically ill patients [1]
The aims of this study were (1) to quantify inter- and intra-individual variability of meropenem serum concentrations in a heterogeneous critically ill population covering the full spectrum of RF classes after meropenem standard dosing, (2) to investigate the attainment of two different PK/PD targets, (3) to assess the impact of RF on meropenem exposure and target attainment and (4) to develop an easy-to-use risk assessment tool allowing identification and quantification of the risk of target non-attainment for a particular patient on the basis of the patient’s RF
Summary
Severe bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. Severe infections remain a major issue in the intensive care unit (ICU) because of their high prevalence and high mortality rates among critically ill patients [1]. Apart from an appropriate activity spectrum and early initiation of antibiotic therapy, a dosing regimen leading to adequate therapeutic antibiotic concentrations and exposure is crucial [2,3,4,5]. Adequate antibiotic exposure has been found to improve clinical success and has been suggested to reduce resistance development [6, 7]. Infections in these patients are often caused by pathogens with lower susceptibility (i.e., higher minimum inhibitory concentration [MIC]) than in other clinical settings [8,9,10,11]
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