TY - JOUR A1 - Ehmann, Lisa A1 - Zoller, Michael A1 - Minichmayr, Iris K. A1 - Scharf, Christina A1 - Maier, Barbara A1 - Schmitt, Maximilian V. A1 - Hartung, Niklas A1 - Huisinga, Wilhelm A1 - Vogeser, Michael A1 - Frey, Lorenz A1 - Zander, Johannes A1 - Kloft, Charlotte T1 - Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients BT - a prospective observational study JF - Critical care N2 - 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->4xMIC) 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->4xMIC. A hyperbolic relationship between CLCRCG (25-255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C-8h) 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. KW - beta-Lactam KW - Intensive care KW - Pharmacokinetics/Pharmacodynamics KW - Target attainment KW - Renal function KW - Risk assessment tool KW - Continuous renal replacement therapy Y1 - 2017 U6 - https://doi.org/10.1186/s13054-017-1829-4 SN - 1466-609X SN - 1364-8535 VL - 21 PB - BioMed Central CY - London ER - TY - JOUR A1 - Ehmann, Lisa A1 - Zoller, Michael A1 - Minichmayr, Iris K. A1 - Scharf, Christina A1 - Huisinga, Wilhelm A1 - Zander, Johannes A1 - Kloft, Charlotte T1 - Development of a dosing algorithm for meropenem in critically ill patients based on a population pharmacokinetic/pharmacodynamic analysis JF - International journal of antimicrobial agents N2 - Effective antibiotic dosing is vital for therapeutic success in critically ill patients. This work aimed to develop an algorithm to identify appropriate meropenem dosing in critically ill patients. Population pharma-cokinetic (PK) modelling was performed in NONMEM (R) 7.3 based on densely sampled meropenem serum samples (n(patients) = 48; n(samples) =1376) and included a systematic analysis of 27 pre-selected covariates to identify factors influencing meropenem exposure. Using Monte Carlo simulations newly considering the uncertainty of PK parameter estimates, standard meropenem dosing was evaluated with respect to attainment of the pharmacokinetic/pharmacodynamic (PK/PD) target and was compared with alternative infusion regimens (short-term, prolonged, continuous; daily dose, 2000-6000 mg). Subsequently, a dosing algorithm was developed to identify appropriate dosing regimens. The two-compartment population PK model included three factors influencing meropenem pharmacokinetics: the Cockcroft-Gault creatinine clearance (CLCRCG ) on meropenem clearance; and body weight and albumin on the central and peripheral volume of distribution, respectively; of these, only CLCRCG was identified as a vital influencing factor on PK/PD target attainment. A three-level dosing algorithm was developed (considering PK parameter uncertainty), suggesting dosing regimens depending on renal function and the level (L) of knowledge about the infecting pathogen (L1, pathogen unknown; L2, pathogen known; L3((-MIC)), pathogen and susceptibility known; L3((+MIC)), MIC known). Whereas patients with higher CLCRCG and lower pathogen susceptibility required mainly intensified dosing regimens, lower than standard doses appeared sufficient for highly susceptible pathogens. In conclusion, a versatile meropenem dosing algorithm for critically ill patients is proposed, indicating appropriate dosing regimens based on patient- and pathogen-specific information. (C) 2019 Published by Elsevier B.V. KW - beta-Lactams KW - Intensive care KW - Pharmacokinetics/pharmacodynamics KW - Renal function KW - Dosing algorithm Y1 - 2019 U6 - https://doi.org/10.1016/j.ijantimicag.2019.06.016 SN - 0924-8579 SN - 1872-7913 VL - 54 IS - 3 SP - 309 EP - 317 PB - Elsevier CY - Amsterdam ER -