Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients: a prospective observational study.
BACKGROUND
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. 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.


METHODS
A 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.


RESULTS
Large 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).


CONCLUSIONS
The 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 REGISTRATION
Clinicaltrials.gov, NCT01793012 . Registered on 24 January 2013.
['Ehmann|Lisa|L|', 'Zoller|Michael|M|', 'Minichmayr|Iris K|IK|', 'Scharf|Christina|C|', 'Maier|Barbara|B|', 'Schmitt|Maximilian V|MV|', 'Hartung|Niklas|N|', 'Huisinga|Wilhelm|W|', 'Vogeser|Michael|M|', 'Frey|Lorenz|L|', 'Zander|Johannes|J|', 'Kloft|Charlotte|C|']
D018806:APACHE D000328:Adult D000368:Aged D000900:Anti-Bacterial Agents D016470:Bacteremia D016638:Critical Illness D005260:Female D005858:Germany D006801:Humans D007362:Intensive Care Units D007677:Kidney Function Tests D008297:Male D000077731:Meropenem D008657:Metabolic Clearance Rate D008875:Middle Aged D011379:Prognosis D011446:Prospective Studies D018570:Risk Assessment D013845:Thienamycins
Renal function Intensive care Target attainment Pharmacokinetics/Pharmacodynamics Continuous renal replacement therapy Risk assessment tool β-Lactam