Identifying optimal dosing strategies for meropenem in the paediatric intensive care unit through modelling and simulation.

Meropenem, a β-lactam antibiotic commonly prescribed for severe infections, poses dosing challenges in critically ill patients due to highly variable pharmacokinetics. We sought to develop a population pharmacokinetic model of meropenem for critically ill paediatric and young adult patients. Paediatric intensive care unit patients receiving meropenem 20-40 mg/kg every 8 h as a 30 min infusion were prospectively followed for clinical data collection and scavenged opportunistic plasma sampling. Nonlinear mixed effects modelling was conducted using Monolix®. Monte Carlo simulations were performed to provide dosing recommendations against susceptible pathogens (MIC ≤ 2 mg/L). Data from 48 patients, aged 1 month to 30 years, with 296 samples, were described using a two-compartment model with first-order elimination. Allometric body weight scaling accounted for body size differences. Creatinine clearance and percentage of fluid balance were identified as covariates on clearance and central volume of distribution, respectively. A maturation function for renal clearance was included. Monte Carlo simulations suggested that for a target of 40% fT > MIC, the most effective dosing regimen is 20 mg/kg every 8 h with a 3 h infusion. If higher PD targets are considered, only continuous infusion regimens ensure target attainment against susceptible pathogens, ranging from 60 mg/kg/day to 120 mg/kg/day. We successfully developed a population pharmacokinetic model of meropenem using real-world data from critically ill paediatric and young adult patients with an opportunistic sampling strategy and provided dosing recommendations based on the patients' renal function and fluid status.

Morales Junior R ，Mizuno T ，Paice KM ，Pavia KE ，Hambrick HR ，Tang P ，Jones R ，Gibson A ，Stoneman E ，Curry C ，Kaplan J ，Tang Girdwood S ... -  《-》

Population Pharmacokinetics and Pharmacodynamics of Meropenem in Critically Ill Patients: How to Achieve Best Dosage Regimen According to the Clinical Situation.

Meropenem is frequently used for the treatment of severe bacterial infections in critically ill patients. Because critically ill patients are more prone to pharmacokinetic variability than other patients, ensuring an effective blood concentration can be complex. Therefore, describing this variability to ensure a proper use of this antibiotic drug limits the rise and dissemination of antimicrobial resistance, and helps preserve the current antibiotic arsenal. The aims of this study were to describe the pharmacokinetics of meropenem in critically ill patients, to identify and quantify the patients' characteristics responsible for the observed pharmacokinetic variability, and to perform different dosing simulations in order to determine optimal individually adapted dosing regimens. A total of 58 patients hospitalized in the medical intensive care unit and receiving meropenem were enrolled, including 26 patients with renal replacement therapy. A population pharmacokinetic model was developed (using NONMEM software) and Monte Carlo simulations were performed with different dosing scenarios (bolus-like, extended, and continuous infusion) exploring the impact of clinical categories of residual diuresis (anuria, oliguria, and preserved diuresis) on the probability of target attainment (MIC: 1-45 mg/L). The population pharmacokinetic model included five covariates with a significant impact on clearance: glomerular filtration rate, dialysis (continuous and semi-continuous), renal function status, and volume of residual diuresis. The clearance for a typical patient in our population is 4.20 L/h and volume of distribution approximately 44 L. Performed dosing regimen simulations suggested that, for equivalent doses, the continuous infusion mode (with loading dose) allowed the obtaining of the pharmacokinetic/pharmacodynamic target for a larger number of patients (100% for MIC ≤ 20 mg/L). Nevertheless, for the treatment of susceptible bacteria (MIC ≤ 2 mg/L), differences in the probability of target attainment between bolus-like, extended, and continuous infusions were negligible. Identified covariates in the model are easily accessible information in patient health records. The model highlighted the importance of considering the patient's overall condition (renal function and dialysis) and the pathogen's characteristics (MIC target) during the establishment of a patient's dosing regimen.

O'Jeanson A ，Larcher R ，Le Souder C ，Djebli N ，Khier S ... -  《-》

Optimal Dosing of Meropenem in a Small Cohort of Critically Ill Children Receiving Continuous Renal Replacement Therapy.

Severe sepsis is an important cause of mortality and morbidity in critically ill children. Meropenem is a broad-spectrum antibiotic commonly used to treat sepsis. Current meropenem dosage recommendations for children on continuous renal replacement therapy are extrapolated from pharmacokinetic (PK) studies done in adults. Our study aims to determine the optimal dosing in critically ill septic children receiving continuous renal replacement therapy. A prospective single-center PK study was performed in 9 children in the intensive care unit on continuous renal replacement therapy. Meropenem concentrations were measured from blood and effluent fluid samples. A population PK model was developed using nonlinear mixed-effects modeling software (NONMEM, AstraZeneca UK Ltd, Cheshire, UK). Monte Carlo simulations were performed. The PK/pharmacodynamic target aimed for plasma concentrations above minimum inhibitory concentration of 4 mg/L for 100% of dosing interval (100%ƒT>MIC ). A 2-compartment model best characterized meropenem PK. Mean (range) clearance and elimination half-life was 0.091 L/h/kg (0.04-0.157) and 3.9 hours (2.1-7.5), respectively. Dosing of 40 mg/kg/dose every 12 hours over 30 minutes achieved PK/PD target in only 32% while 20 mg/kg every 8 hours over 4 hours or 40 mg/kg every 8 hours over 2 hours achieved 100% ƒT>MIC target for at least 90% of simulated patients.

Tan WW ，Watt KM ，Boakye-Agyeman F ，Cohen-Wolkowiez M ，Mok YH ，Yung CF ，Chan YH ... -  《-》

Development of a dosing algorithm for meropenem in critically ill patients based on a population pharmacokinetic/pharmacodynamic analysis.

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 pharmacokinetic (PK) modelling was performed in NONMEM®7.3 based on densely sampled meropenem serum samples (npatients = 48; nsamples = 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.

Ehmann L ，Zoller M ，Minichmayr IK ，Scharf C ，Huisinga W ，Zander J ，Kloft C ... -  《-》

Meropenem dosing recommendations for critically ill patients receiving continuous renal replacement therapy.

To gather available meropenem pharmacokinetics and define drug dosing regimens for Asian critically ill patients receiving CRRT. All necessary pharmacokinetic and pharmacodynamic data from Asian population were gathered to develop mathematic models with first order elimination. Meropenem concentration-time profiles were calculated to evaluate efficacy based on the probability of target attainment (PTA) of 40%fT>4MIC. A group of 5000 virtual patients was created and tested using Monte Carlo simulations for each dose in the models. The optimal dosing regimens were defined as the doses achieved at least 90% of the PTA. The recommended meropenem dosing regimen for Asian critically ill patients receiving CRRT with standard (20-25 mL/kg/h) and high (35 mL/kg/h) effluent rates was 750 mg q 8 h to manage Gram negative infections with expected MIC < 2 mg/L in virtual Asian patients. Some meropenem dosages from available clinical resources could not achieve the aforementioned target. The volume of distribution, body weights and nonrenal clearance significantly contributed to drug dosing adaptation especially in the specific population. A meropenem regimen of 750 mg q 8 h was recommended for Asian critically ill patients receiving 2 different CRRT modalities with standard and high effluent rates. Clinical validation of these results is needed.

Chaijamorn W ，Rungkitwattanakul D ，Pattharachayakul S ，Singhan W ，Charoensareerat T ，Srisawat N ... -  《-》