@misc{EhmannZollerMinichmayretal.2018,
  author    = {Ehmann, Lisa and Zoller, Michael and Minichmayr, Iris K. and Schmitt, Maximilian V. and Hartung, Niklas and Huisinga, Wilhelm and Zander, Johannes and Kloft, Charlotte},
  title     = {Development of a tool to identify intensive care patients at risk of meropenem therapy failure},
  series = {International Journal of Clinical Pharmacy},
  volume    = {40},
  journal   = {International Journal of Clinical Pharmacy},
  number    = {1},
  publisher = {Springer},
  address   = {Dordrecht},
  issn      = {2210-7703},
  pages     = {317 -- 317},
  year      = {2018},
  language  = {en}
}
@article{MinichmayrRobertsFreyetal.2018,
  author    = {Minichmayr, Iris K. and Roberts, Jason A. and Frey, Otto R. and Roehr, Anka C. and Kloft, Charlotte and Brinkmann, Alexander},
  title     = {Development of a dosing nomogram for continuous-infusion meropenem in critically ill patients based on a validated population pharmacokinetic model},
  series = {Journal of Antimicrobial Chemotherapy},
  volume    = {73},
  journal   = {Journal of Antimicrobial Chemotherapy},
  number    = {5},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {0305-7453},
  doi       = {10.1093/jac/dkx526},
  pages     = {1330 -- 1339},
  year      = {2018},
  abstract  = {Background: Optimal antibiotic exposure is a vital but challenging prerequisite for achieving clinical success in ICU patients. Objectives: To develop and externally validate a population pharmacokinetic model for continuous-infusion meropenem in critically ill patients and to establish a nomogram based on a routinely available marker of renal function. Methods: A population pharmacokinetic model was developed in NONMEM (R) 7.3 based on steady-state meropenem concentrations (C-ss) collected during therapeutic drug monitoring. Different serum creatinine-based markers of renal function were compared for their influence on meropenem clearance (the Cockcroft-Gault creatinine clearance CLCRcG, the CLCR bedside estimate according to Jelliffe, the Chronic Kidney Disease Epidemiology Collaboration equation and the four-variable Modification of Diet in Renal Disease equation). After validation of the pharmacokinetic model with independent data, a dosing nomogram was developed, relating renal function to the daily doses required to achieve selected target concentrations (4/8/16 mg/L) in 90\% of the patients. Probability of target attainment was determined for efficacy (C-ss >= 8 mg/L) and potentially increased likelihood of adverse drug reactions (C-ss >32 mg/L). Results: In total, 433 plasma concentrations (3.20-48.0 mg/L) from 195 patients (median/P-0.05 - P-0.95 at baseline: weight 77.0/55.0-114 kg, CLCRCG 63.0/19.6-168 mL/min) were used for model building. We found that CLCRCG best described meropenem clearance (CL = 7.71 L/h, CLCRCG = 80 mL/min). The developed model was successfully validated with external data (n = 171, 73 patients). According to the nomogram, daily doses of 910/1480/2050/2800/ 3940 mg were required to reach a target C-ss = 8 mg/L in 90\% of patients with CLCRCG = 20/50/80/120/180 mL/min, respectively. A low probability of adverse drug reactions (<0.5\%) was associated with these doses. Conclusions: A dosing nomogram was developed for continuous-infusion meropenem based on renal function in a critically ill population.},
  language  = {en}
}
@article{EhmannZollerMinichmayretal.2017,
  author    = {Ehmann, Lisa and Zoller, Michael and Minichmayr, Iris K. and Scharf, Christina and Maier, Barbara and Schmitt, Maximilian V. and Hartung, Niklas and Huisinga, Wilhelm and Vogeser, Michael and Frey, Lorenz and Zander, Johannes and Kloft, Charlotte},
  title     = {Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients},
  series = {Critical care},
  volume    = {21},
  journal   = {Critical care},
  publisher = {BioMed Central},
  address   = {London},
  issn      = {1466-609X},
  doi       = {10.1186/s13054-017-1829-4},
  pages     = {14},
  year      = {2017},
  abstract  = {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.},
  language  = {en}
}
@article{EhmannZollerMinichmayretal.2019,
  author    = {Ehmann, Lisa and Zoller, Michael and Minichmayr, Iris K. and Scharf, Christina and Huisinga, Wilhelm and Zander, Johannes and Kloft, Charlotte},
  title     = {Development of a dosing algorithm for meropenem in critically ill patients based on a population pharmacokinetic/pharmacodynamic analysis},
  series = {International journal of antimicrobial agents},
  volume    = {54},
  journal   = {International journal of antimicrobial agents},
  number    = {3},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {0924-8579},
  doi       = {10.1016/j.ijantimicag.2019.06.016},
  pages     = {309 -- 317},
  year      = {2019},
  abstract  = {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.},
  language  = {en}
}
@misc{WichaKeesSolmsetal.2015,
  author    = {Wicha, Sebastian G. and Kees, Martin G. and Solms, Alexander Maximilian and Minichmayr, Iris K. and Kratzer, Alexander and Kloft, Charlotte},
  title     = {TDMx: A novel web-based open-access support tool for optimising antimicrobial dosing regimens in clinical routine},
  series = {International journal of antimicrobial agents},
  volume    = {45},
  journal   = {International journal of antimicrobial agents},
  number    = {4},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {0924-8579},
  doi       = {10.1016/j.ijantimicag.2014.12.010},
  pages     = {442 -- 444},
  year      = {2015},
  language  = {en}
}