Evaluation of the MeroRisk Calculator, A User-Friendly Tool to Predict the Risk of Meropenem Target Non-Attainment in Critically Ill Patients

Liebchen, Uwe; Klose, Marian; Paal, Michael; Vogeser, Michael; Zöller, Michael; Schroeder, Ines; Schmitt, Lisa; Huisinga, Wilhelm; Michelet, Robin; Zander, Johannes; Scharf, Christina; Weinelt, Ferdinand; Kloft, Charlotte

doi:10.3390/antibiotics10040468

Cited by 5 publications

(5 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The relation between CLCR CG_ABW and meropenem CL was consistent with previous studies [8,[47][48][49][50], and the additional impact of body mass on meropenem clearance (CL nonfilt ) was in line with meropenem elimination besides glomerular filtration such as tubular secretion [51]. Importantly, the final pharmacokinetic model did not include simple allometric scaling of total meropenem CL with ABW but rather a fraction of CL (i.e., by the nonfiltered elimination pathway, 47.7% of total CL) was scaled by ABW and the dominant renally filtered elimination pathway by CLCR (see Sect.…”

Section: Discussionsupporting

confidence: 92%

Comparative Plasma and Interstitial Tissue Fluid Pharmacokinetics of Meropenem Demonstrate the Need for Increasing Dose and Infusion Duration in Obese and Non-obese Patients

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background and Objectives A quantitative evaluation of the PK of meropenem, a broad-spectrum β-lactam antibiotic, in plasma and interstitial space fluid (ISF) of subcutaneous adipose tissue of obese patients is lacking as of date. The objective of this study was the characterisation of meropenem population pharmacokinetics in plasma and ISF in obese and non-obese patients for identification of adequate dosing regimens via Monte-Carlo simulations. Methods We obtained plasma and microdialysate concentrations after administration of meropenem 1000 mg to 15 obese and 15 non-obese surgery patients from a prospective clinical trial. After characterizing plasma-and microdialysis-derived ISF pharmacokinetics via population pharmacokinetic analysis, we simulated thrice-daily (TID) meropenem short-term (0.5 h), prolonged (3.0 h), and continuous infusions. Adequacy of therapy was assessed by the probability of pharmacokinetic/ pharmacodynamic (PK/PD) target attainment (PTA) analysis based on time unbound concentrations exceeded minimum inhibitory concentrations (MIC) on treatment day 1 (%fT > MIC ) and the sum of PTA weighted by relative frequency of MIC values for infections by pathogens commonly treated with meropenem. To avoid interstitial tissue fluid concentrations below MIC for the entire dosing interval during continuous infusions, a more conservative PK/PD index was selected (%fT > 4 × MIC ). Results Adjusted body weight (ABW) and calculated creatinine clearance (CLCR CG_ABW ) of all patients (body mass index [BMI] = 20.5-81.5 kg/m 2 ) explained a considerable proportion of the between-patient pharmacokinetic variability (15.1-31.0% relative reduction). The ISF:plasma ratio of %fT > MIC was relatively similar for MIC ≤ 2 mg/L but decreased for MIC = 8 mg/L over ABW = 60-120 kg (0.50-0.20). Steady-state concentrations were 2.68 times (95% confidence interval [CI] = 2.11-3.37) higher in plasma than in ISF, supporting PK/PD targets related to four times the MIC during continuous infusions to avoid suspected ISF concentrations constantly below the MIC. A 3000 mg/24 h continuous infusion was sufficient at MIC = 2 mg/L for patients with CLCR CG_ABW ≤ 100 mL/min and ABW < 90 kg, whereas 2000 mg TID prolonged infusions were adequate for those with CLCR CG_ABW ≤ 100 mL/min and ABW > 90 kg. For MIC = 2 mg/L and %fT > MIC = 95, PTA was adequate in patients over the entire investigated range of body mass and renal function using a 6000 mg continuous infusion. A prolonged infusion of meropenem 2000 mg TID was sufficient for MIC ≤ 8 mg/L and all investigated ABW and CLCR CG_ABW when employing the PK/PD target %fT > MIC = 40. Short-term infusions of 1000 mg TID were sufficient for CLCR CG_ABW ≤ 130 mL/min and distributions of MIC values for Escherichia coli, Citrobacter freundii, and Klebsiella pneumoniae but not for Pseudomonas aeruginosa. Conclusions This analysis indicated a need for higher doses (≥ 2000 mg) and prolonged infusions (≥ 3 h) for obese and nonobese patients at MIC ≥ 2 mg/L. Higher PTA was achieved with prolonged i...

show abstract

Section: Discussionsupporting

confidence: 92%

Comparative Plasma and Interstitial Tissue Fluid Pharmacokinetics of Meropenem Demonstrate the Need for Increasing Dose and Infusion Duration in Obese and Non-obese Patients

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…We postulate that prolonged infusion of meropenem over 3 h or a high-dosage regimen of 6 g/day should be considered, particularly for treating critically ill patients with increased renal clearance and those infected with less susceptible pathogens, to provide appropriate meropenem concentrations to them and those on ECMO support. Real-time therapeutic drug monitoring (TDM)-guided dosing optimization of meropenem using dosing software could further help clinicians to improve clinical outcomes and reduce toxicity in critically ill patients [14][15][16]. Evaluating the influence of TDM of meropenem on clinical outcomes in ECMO patients is warranted, since the use of inappropriate meropenem concentrations is possible, especially when using the standard-dose regimen [17].…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Meropenem in Critically Ill Korean Patients and Effects of Extracorporeal Membrane Oxygenation

et al. 2021

View full text Add to dashboard Cite

Limited studies have investigated population pharmacokinetic (PK) models and optimal dosage regimens of meropenem for critically ill adult patients using the probability of target attainment, including patients receiving extracorporeal membrane oxygenation (ECMO). A population PK analysis was conducted using non-linear mixed-effect modeling. Monte Carlo simulation was used to determine for how long the free drug concentration was above the minimum inhibitory concentration (MIC) at steady state conditions in patients with various degrees of renal function. Meropenem PK in critically ill patients was described using a two-compartment model, in which glomerular filtration rate was identified as a covariate for clearance. ECMO did not affect meropenem PK. The simulation results showed that the current meropenem dosing regimen would be sufficient for attaining 40%fT>MIC for Pseudomonas aeruginosa at MIC ≤ 4 mg/L. Prolonged infusion over 3 h or a high-dosage regimen of 2 g/8 h was needed for MIC > 2 mg/L or in patients with augmented renal clearance, for a target of 100%fT>MIC or 100%fT>4XMIC. Our study suggests that clinicians should consider prolonged infusion or a high-dosage regimen of meropenem, particularly when treating critically ill patients with augmented renal clearance or those infected with pathogens with decreased in vitro susceptibility, regardless of ECMO support.

show abstract

“…sample collection 5 min to late) would lead to massive inaccuracies of the measured concentrations 19 . It should be noted as a strength of this study that the model employed can be considered valid since the model was evaluated externally showing negligible bias 8 . The evaluation of the PK model revealed a negligibly small underestimation of the measured concentrations (− 0.84 mg/L).…”

Section: Discussionmentioning

confidence: 90%

“…A previously published two compartment model with first-order elimination of critically ill patients was employed for simulation 7 . This model was recently successfully evaluated and revealed a neglectable bias 8 . Briefly, this model is based on a prospective observational study in a population of 48 critically ill patients with severe infections and dense PK sampling (n = 1376) over 4 days.…”

Section: Methodsmentioning

confidence: 99%

Optimal loading dose of meropenem before continuous infusion in critically ill patients: a simulation study

Liebchen

Salletmeier

Kallee

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

The aim of this study was to investigate optimal loading doses prior to continuous infusion of meropenem in critically ill patients. A previously published and successfully evaluated pharmacokinetic model of critically ill patients was used for stochastic simulations of virtual patients. Maintenance doses administered as continuous infusion of 1.5–6 g/24 h with preceding loading doses (administered as 30 min infusion) of 0.15–2 g were investigated. In addition to the examination of the influence of individual covariates, a best-case and worst-case scenario were simulated. Dosing regimens were considered adequate if the 5th percentile of the concentration–time profile did not drop at any time below four times the S/I breakpoint (= 2 mg/L) of Pseudomonas aeruginosa according to the EUCAST definition. Low albumin concentrations, high body weight and high creatinine clearances increased the required loading dose. A maximum loading dose of 0.33 g resulted in sufficient plasma concentrations when only one covariate showed extreme values. If all three covariates showed extreme values (= worst-case scenario), a loading dose of 0.5 g was necessary. Higher loading doses did not lead to further improvements of target attainment. We recommend the administration of a loading dose of 0.5 g meropenem over 30 min immediately followed by continuous infusion.

show abstract

Evaluation of the MeroRisk Calculator, A User-Friendly Tool to Predict the Risk of Meropenem Target Non-Attainment in Critically Ill Patients

Cited by 5 publications

References 36 publications

Comparative Plasma and Interstitial Tissue Fluid Pharmacokinetics of Meropenem Demonstrate the Need for Increasing Dose and Infusion Duration in Obese and Non-obese Patients

Comparative Plasma and Interstitial Tissue Fluid Pharmacokinetics of Meropenem Demonstrate the Need for Increasing Dose and Infusion Duration in Obese and Non-obese Patients

Population Pharmacokinetics of Meropenem in Critically Ill Korean Patients and Effects of Extracorporeal Membrane Oxygenation

Optimal loading dose of meropenem before continuous infusion in critically ill patients: a simulation study

Contact Info

Product

Resources

About