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Reappraisal of the Optimal Dose of Meropenem in Critically Ill Infants and Children: a Developmental Pharmacokinetic-Pharmacodynamic Analysis.

ABSTRACT: Data of developmental pharmacokinetics (PK) of meropenem in critically ill infants and children with severe infections are limited. We assessed the population PK and defined the appropriate regimen to optimize treatment in this population based on developmental PK-pharmacodynamic (PD) analysis. Blood samples were collected from pediatric intensive care unit patients with severe infection treated with standard dosage regimens for meropenem. Population PK data were analyzed using NONMEM software. Fifty-seven patients (mean age, 2.96?years [range, 0.101 to 14.4]; mean body weight, 15.8?kg [range, 5.0 to 65.0]) were included. A total of 135 meropenem concentrations were obtainable for population PK modeling. The median number of samples per patients was 2 (range, 1 to 4). A two-compartment model with first-order elimination was optimal for PK modeling. Weight and creatinine clearance (estimated by the Schwartz formula) were significantly correlated with the PK parameters of meropenem. The probabilities of target attainment for pathogens with low MICs of 1 and 2??g/ml were 87.5% and 68.6% following administration of 40?mg/kg/dose (every 8?h [q8h]) as a 4-h infusion and 98.0% and 73.3% with high MICs of 4 and 8??g/ml following administration of 110?mg/kg/day as a continuous infusion in critically ill infants and children under 70% fT _>MIC (the free time during which the plasma concentration of meropenem exceeds the MIC), respectively. The standard dosage regimens for meropenem did not meet an appropriate PD target, and an optimal dosing regimen was established in critically ill infants and children. (This study has been registered at ClinicalTrials.gov under identifier NCT03643497.).

SUBMITTER: Wang ZM

PROVIDER: S-EPMC7526843 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Reappraisal of the Optimal Dose of Meropenem in Critically Ill Infants and Children: a Developmental Pharmacokinetic-Pharmacodynamic Analysis.

Wang Ze-Ming ZM Chen Xiao-Yu XY Bi Jing J Wang Mei-Ying MY Xu Bao-Ping BP Tang Bo-Hao BH Li Cen C Zhao Wei W Shen A-Dong AD

Antimicrobial agents and chemotherapy 20200722 8

Data of developmental pharmacokinetics (PK) of meropenem in critically ill infants and children with severe infections are limited. We assessed the population PK and defined the appropriate regimen to optimize treatment in this population based on developmental PK-pharmacodynamic (PD) analysis. Blood samples were collected from pediatric intensive care unit patients with severe infection treated with standard dosage regimens for meropenem. Population PK data were analyzed using NONMEM software. ...[more]

PMID: 32513801

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Project description:Carbapenem-resistant gram-negative pathogens remain an urgent public health threat, and safe, effective treatment options are limited. Although several agents are now available to combat these infections, meropenem-vaborbactam was the first to combine a novel, cyclic, boronic acid-based, ?-lactamase inhibitor with a carbapenem backbone. Vaborbactam emanated from a discovery program specifically designed to identify candidate ?-lactamase inhibitors with biochemical, microbiologic, and pharmacologic properties optimized for use in conjunction with a carbapenem. Meropenem was selected as the ideal carbapenem given its broad-spectrum in vitro activity, well established safety profile, and proven efficacy in the treatment of serious gram-negative infections. The combination has demonstrated potent in vitro activity against resistant gram-negative pathogens, particularly KPC-producing Klebsiella pneumoniae (MIC50 values typically???0.06 mg/l). Importantly, the pharmacokinetic (PK) profiles of the two agents are well matched, and the approved optimized dosing regimen of 4 g every 8 h (Q8h) as a 3-h infusion provides reliable probability of target attainment against the majority of commonly encountered carbapenem-resistant Enterobacteriaceae (CRE). Robust in vitro and in vivo PK/pharmacodynamic (PD) data support the ability of this dosing regimen to achieve specified PK/PD targets for both bactericidal activity and prevention of resistance among pathogens with MICs up to 8 mg/l. This concerted effort into optimizing the PK and PD parameters of both the ?-lactam and ?-lactamase inhibitor alone and in combination contributed to the clinical success of meropenem-vaborbactam demonstrated in phase 3 trials in patients with complicated urinary tract infections (cUTI), including acute pyelonephritis (AP), and serious CRE infections. As the use of meropenem-vaborbactam increases concomitantly with the prevalence of KPC-producing CRE, continued pharmacovigilance and antimicrobial stewardship efforts will be of upmost importance to ensure that these PK/PD efforts translate into improved patient outcomes.

Project description:BACKGROUND:Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia. METHODS:Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia. RESULTS:The median (IQR) of meropenem AUC0-24 h in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L. CONCLUSIONS:An increase in the dose of meropenem administered by CI achieved a higher exposure in the plasma and ELF. The use of the highest licensed dose of 6 g/day may be necessary to achieve an optimal coverage in ELF for all susceptible isolates (MIC ≤ 2 mg/L) in patients with conserved renal function. An alternative therapy should be considered when the presence of microorganisms with a MIC greater than 2 mg/L is suspected. TRIAL REGISTRATION:The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT-no. 2016-002796-10). Registered on 27 December 2016.

Project description:BackgroundThe primary objective of this study was to develop a population pharmacokinetic model of meropenem, based on the population of critically ill adult patients undergoing CRRT. The secondary one was to examine the relationship between patient characteristics (covariates) and individual PK parameters. Finally, we aimed to perform Monte Carlo simulations to assess the probability of target attainment (PTA) of %T?>?MIC considering the uncertainty of PK parameters.Materials and methodsThe study population included 19 adult critically ill patients on CRRT, receiving 1 g of meropenem in 1-h infusions every 8 h. Blood samples were collected prior to (time zero) and 15, 30, 45, 60, 75, 90, 120, 180, 240 and 480 min after the start of meropenem administration. Population nonlinear mixed-effects modeling was conducted using NONMEM software, Fortran, and Wings for NONMEM.ResultsA two-compartment model was used to describe the available data. Typical values of the central and peripheral volume of distribution, and the CRRT and inter-compartmental clearance for a theoretical patient with 24.6 g/l albumin concertation were V1?=?27.9 l, V2?=?33.7 l, ClCRRT?=?15.1 l/h, and Q?=?21.1 l/h. A significant covariate relationship between V1 and albumin concentration was observed in the data that was described by a power relationship with - 2.87 exponent. Subsequently performed Monte Carlo simulations of the model allowed us to assess the impact of albumin concentration on PTA. The 40%T?>?2 mg/l target was reached in more than 90% of subjects after 1-h infusion of 1000 mg q8h and steady-state conditions. The more stringent 100%T?>?2 mg/l target requires higher doses and/or longer infusion durations that depend on the albumin concentration.ConclusionsThe population PK model was successfully developed to describe the time course of meropenem concentrations. The hypoalbuminemia was found to be associated with higher PTA in the CRRT patients after multiple short-term infusions.

Project description:BackgroundAppropriate antimicrobial dosing is challenging because of changes in pharmacokinetics (PK) parameters and an increase in multidrug-resistant (MDR) organisms in critically ill patients. This study aimed to evaluate the effects of an empirical therapy of high-dose versus standard-dose meropenem in sepsis and septic shock patients.MethodsWe performed a prospective randomized open-label study to compare the changes of modified sequential organ failure assessment (mSOFA) score and other clinical outcomes of the high-dose meropenem (2-g infusion over 3 h every 8 h) versus the standard-dose meropenem (1-g infusion over 3 h every 8 h) in sepsis and septic shock patients. Patients' characteristics, clinical and microbiological outcomes, 14 and 28-day mortality, vasopressor- and ventilator-free days, intensive care unit (ICU) and hospital-free days, percent of the time of antibiotic concentrations above the minimum inhibitory concentration (%T>MIC), and safety were assessed.ResultsSeventy-eight patients were enrolled. Median delta mSOFA was comparable between two groups (- 1 in the high-dose group vs. - 1 in the standard-dose group; P value = 0.75). There was no difference between the two groups regarding clinical and microbiological cure, 14- and 28-day mortality, vasopressor- and ventilator-free days, and ICU- and hospital-free days. In patients admitted from the emergency department (ED) with a mSOFA score ≥ 7, the high-dose group demonstrated significantly better microbiological cure compared with the standard-dose group (75% (9/12 patients) vs. 20% (2/10 patients); P value = 0.03). Likewise, the high-dose group presented higher microbiological cure rate in patients admitted from ED who had either APACHE II score > 20 (83.3% (10/12) vs. 28.6% (2/7); P value = 0.045) or on mechanical ventilator (87.5% (7/8) vs. 23.1% (3/13); P value = 0.008) than the standard-dose group. Adverse events were comparable between the two groups.ConclusionsEmpirical therapy with the high-dose meropenem presented comparable clinical outcomes to the standard-dose meropenem in sepsis and septic shock patients. Besides, subgroup analysis manifested superior microbiological cure rate in sepsis or septic shock patients admitted from ED.Trial registrationClinicalTrials.gov, NCT03344627, registered on November 17, 2017.

Dataset Information

Reappraisal of the Optimal Dose of Meropenem in Critically Ill Infants and Children: a Developmental Pharmacokinetic-Pharmacodynamic Analysis.

Publications

Reappraisal of the Optimal Dose of Meropenem in Critically Ill Infants and Children: a Developmental Pharmacokinetic-Pharmacodynamic Analysis.

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