Dataset Information

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, β-lactamase inhibitor with a carbapenem backbone. Vaborbactam emanated from a discovery program specifically designed to identify candidate β-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 β-lactam and β-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.

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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