TY  - JOUR
A1  - Wicha, Sebastian G.
A1  - Huisinga, Wilhelm
A1  - Kloft, Charlotte
T1  - Translational pharmacometric evaluation of typical antibiotic broad-spectrum combination therapies against staphylococcus aureus exploiting in vitro information
JF  - CPT: pharmacometrics & systems pharmacology
N2  - Broad-spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad-spectrum combination therapies consisting of either linezolid (LZD) or vancomycin (VAN) combined with meropenem (MER) against Staphylococcus aureus (S. aureus) as the most frequent causative pathogen of severe infections. A semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model mimicking a simplified bacterial life-cycle of S. aureus was developed upon time-kill curve data to describe the effects of LZD, VAN, and MER alone and in dual combinations. The PK-PD model was successfully (i) evaluated with external data from two clinical S. aureus isolates and further drug combinations and (ii) challenged to predict common clinical PK-PD indices and breakpoints. Finally, clinical trial simulations were performed that revealed that the combination of VAN-MER might be favorable over LZD-MER due to an unfavorable antagonistic interaction between LZD and MER.
Y1  - 2017
U6  - https://doi.org/10.1002/psp4.12197
SN  - 2163-8306
VL  - 6
SP  - 512
EP  - 522
PB  - Wiley
CY  - Hoboken
ER  - 
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  -