Dataset Information

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

ABSTRACT:

Background

The MeroRisk-calculator, an easy-to-use tool to determine the risk of meropenem target non-attainment after standard dosing (1000 mg; q8h), uses a patient's creatinine clearance and the minimum inhibitory concentration (MIC) of the pathogen. In clinical practice, however, the MIC is rarely available. The objectives were to evaluate the MeroRisk-calculator and to extend risk assessment by including general pathogen sensitivity data.

Methods

Using a clinical routine dataset (155 patients, 891 samples), a direct data-based evaluation was not feasible. Thus, in step 1, the performance of a pharmacokinetic model was determined for predicting the measured concentrations. In step 2, the PK model was used for a model-based evaluation of the MeroRisk-calculator: risk of target non-attainment was calculated using the PK model and agreement with the MeroRisk-calculator was determined by a visual and statistical (Lin's concordance correlation coefficient (CCC)) analysis for MIC values 0.125-16 mg/L. The MeroRisk-calculator was extended to include risk assessment based on EUCAST-MIC distributions and cumulative-fraction-of-response analysis.

Results

Step 1 showed a negligible bias of the PK model to underpredict concentrations (-0.84 mg/L). Step 2 revealed a high level of agreement between risk of target non-attainment predictions for creatinine clearances >50 mL/min (CCC = 0.990), but considerable deviations for patients <50 mL/min. For 27% of EUCAST-listed pathogens the median cumulative-fraction-of-response for the observed patients receiving standard dosing was < 90%.

Conclusions

The MeroRisk-calculator was successfully evaluated: For patients with maintained renal function it allows a reliable and user-friendly risk assessment. The integration of pathogen-based risk assessment substantially increases the applicability of the tool.

SUBMITTER: Liebchen U

PROVIDER: S-EPMC8074046 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Liebchen Uwe U Klose Marian M Paal Michael M Vogeser Michael M Zoller Michael M Schroeder Ines I Schmitt Lisa L Huisinga Wilhelm W Michelet Robin R Zander Johannes J Scharf Christina C Weinelt Ferdinand A FA Kloft Charlotte C

Antibiotics (Basel, Switzerland) 20210420 4

<h4>Background</h4>The MeroRisk-calculator, an easy-to-use tool to determine the risk of meropenem target non-attainment after standard dosing (1000 mg; q8h), uses a patient's creatinine clearance and the minimum inhibitory concentration (MIC) of the pathogen. In clinical practice, however, the MIC is rarely available. The objectives were to evaluate the MeroRisk-calculator and to extend risk assessment by including general pathogen sensitivity data.<h4>Methods</h4>Using a clinical routine datas ...[more]

PMID: 33924047

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Project description:PurposeCritically ill patients with preserved or increased renal function have been shown to be at risk of underexposure to meropenem. Although many meropenem population pharmacokinetic (PK) models have been published, there is no large prospective population PK study with rich sampling focusing on patients most at risk of suboptimal pharmacokinetic/pharmacodynamic (PK/PD) target attainment. Therefore, the aim of the present study was to evaluate PK/PD target attainment and to perform a thorough covariate screening using population PK modelling of meropenem in septic patients with preserved or increased renal function.Patients and methodsA single-centre prospective observational PK study was performed in the intensive care unit (ICU) of the University Hospitals Leuven. Patients with severe sepsis or septic shock and treated with meropenem in the ICU were screened for inclusion. Patients were excluded if they received renal replacement therapy or had an estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology collaboration equation <70 mL/min/1.73m2 on the day of PK sampling. Successful PK/PD target attainment was defined as an unbound meropenem trough concentration above 2 mg/L or 8 mg/L. Population PK modelling was performed with NONMEM7.4.ResultsIn total, 58 patients were included, contributing 345 plasma samples over 70 dosing intervals. The 2 mg/L and 8 mg/L targets were successfully attained in 46% and 11% of all dosing intervals, respectively. A two-compartment population PK model with linear elimination and interindividual variability on clearance best described meropenem PK. The estimated creatinine clearance according to the Cockcroft-Gault equation was the only covariate retained during population PK analysis.ConclusionThis study provided detailed insight into meropenem PK in critically ill patients with preserved or increased renal function. We observed poor PK/PD target attainment, for which renal function was the only significant covariate.Trial registrationThis study is registered at ClinicalTrials.gov (NCT03560557).

Project description: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.

Project description:Background and objectivePopulation pharmacokinetic/pharmacodynamic (PK/PD) modelling of antibiotics including C-reactive protein (C-RP) dynamics could be helpful in predicting the efficacy of antimicrobials. We developed a PK/PD model for assessing the impact of continuous infusion (CI) meropenem PK/PD target attainment on C-RP dynamics in critically ill patients with documented Gram-negative hospital- (HAP) or ventilator-acquired pneumonia (VAP).MethodsPatients were grouped according to the type of antibiotic treatment received [meropenem monotherapy; meropenem plus empirical anti-MRSA (methicillin-resistant Staphylococcus aureus) therapy; meropenem in combination with another anti-Gram-negative active agent; meropenem plus a targeted anti-MRSA therapy]. A one-compartment population PK model of CI meropenem was developed by including all patients. A full C-RP production inhibition model was developed for fitting the PD data by including only patients receiving meropenem monotherapy or meropenem plus empirical anti-MRSA therapy. Monte Carlo simulations explored the relationship between the type of PK/PD target attainment of CI meropenem, defined as optimal (steady-state plasma concentration [Css] to minimum inhibitory concentration [MIC] ratio = 4-8), quasi-optimal (Css/MIC = 1-4) and sub-optimal (Css/MIC < 1) and the magnitude of C-RP production inhibition over time.ResultsA total of 64 patients providing 211 meropenem concentrations were included in the PK analysis, whereas 47 patients providing 328 C-RP data were included in the PD model. Simulations showed that optimal PK/PD target attainment was associated with the highest and most rapid C-RP production inhibition (44% and 56% at days 2 and 4, respectively). Conversely, sub-optimal PK/PD target attainment was shown to be almost ineffective (< 5% at day 4 and < 10% at day 10).ConclusionOur PK/PD model predicted that attaining optimal PK/PD target with CI meropenem may grant prompt and intense C-RP decrease among critically ill patients receiving targeted monotherapy for Gram-negative HAP/VAP, thus anticipating efficacy.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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