meropenem and Body-Weight

Although survival of children with hematological diseases and cancer has increased dramatically, febrile neutropenia (FN) is a frequently observed complication and is sometimes life-threatening in pediatric cancer patients. A prospective, randomized study was performed to clarify the usefulness of meropenem (MEPM) and piperacillin/tazobactam (PIPC/TAZ) for pediatric patients with FN. Ninety-nine patients with 394 episodes were randomly assigned to receive MEPM or PIPC/TAZ. MEPM was administered at 120 mg/kg/day as a 1-h drip infusion 3 times a day. On the other hand, PIPC/TAZ was administered at 360 mg/kg/day as a 1-h drip infusion 4 times a day. MEPM was effective in 69.5% of the 200 episodes, and PIPC/TAZ was effective in 77.2% of the 193 episodes. Compared with our previous study of MEPM 120 mg/kg/day as a 1-h drip infusion 3 times a day versus PIPC/TAZ 337.5 mg/kg/day as a 1-h drip infusion 3 times a day, the success rate of the MEPM group was not different. However, the success rate of the PIPC/TAZ group was higher than in the previous study (p = 0.001). In particular, the success rate in patients ≥ 15 years of age was improved in the PIPC/TAZ group of the present study compared with the previous study (p = 0.005).

Topics: Adolescent; Adult; Anti-Bacterial Agents; Bacteremia; Body Weight; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Febrile Neutropenia; Historically Controlled Study; Humans; Immunologic Deficiency Syndromes; Infant; Infant, Newborn; Infusions, Intravenous; Maximum Tolerated Dose; Meropenem; Neoplasms; Piperacillin, Tazobactam Drug Combination; Stem Cell Transplantation; Young Adult

To evaluate if a specific pediatric defined daily dose (PeDDD) can be replaced with the defined daily dose (DDD) indicated by World Health Organization (WHO).. The 50th percentile of body weight for age of children admitted from 2016 to 2020 at Istituto Giannina Gaslini, Genoa, Italy, was used to calculate PeDDD for vancomycin at 40mg/kg and meropenem at 60mg/kg. Data obtained were then used to calculate the PeDDD number based on the amount of drugs delivered quarterly from 2012 to 2016. Subsequently the DDD number was calculated for vancomycin at 2g and meropenem at 3g. With these results two curves were generated which were then compared for parallelism and area under the curve (AUC).. PeDDD was found to be 2.6 times DDD for both drugs, but both curves obtained were parallel and the AUCs were identical CONCLUSIONS: DDD according to WHO definition could be adopted in pediatrics to measure antibiotic consumption and therefore no specific PeDDD could be needed.

Topics: Anti-Bacterial Agents; Body Weight; Child; Hospitalization; Humans; Meropenem; Vancomycin

The average body weight is smaller in Asian patients compared with Western patients, but influence of body weight in antibiotic dosing is unknown. This study was to predict the optimal ceftazidime, cefepime, meropenem, piperacillin/tazobactam doses in Asian patients undergoing continuous venovenous hemofiltration (CVVH).. Monte Carlo simulations (MCS) were performed using published Asian demographics and pharmacokinetics parameters in 5000 virtual patients at three CVVH effluent rates (Qeff; 20, 30, 40 mL/kg/h). Various dosing regimens were assessed for the probability of target attainments using 60% fT > 1 × MIC or 4xMIC and neurotoxicity risk at 48-h using suggested neurotoxicity thresholds.. Ceftazidime 1 g q12h, meropenem 1 g q12h, and piperacillin/tazobactam 3.375 g q6h were optimal for all Qeff settings against fT > 1 × MIC. Cefepime 2 g q24h and 2 g q12h were optimal at 20 and 30-40 mL/kg/h respectively. For the aggressive PD target (4 × MIC), optimal ceftazidime regimens were 1.25 g q8h (20-30 mL/kg/h) and 1.5 g q8h (40 mL/kg/h). Cefepime 2 g q8h and meropenem 1 g q8h were optimal at all Qeff settings. No simulated piperacillin doses attained the aggressive PD target. Increased neurotoxicity risk was predicted with ceftazidime and cefepime doses attaining the efficacy.. MCS enabled the prediction of optimal β-lactam dosing regimens for Asian patients receiving CVVH at varying Qeff. Clinical validation is warranted.

Topics: Anti-Bacterial Agents; Body Weight; Cefepime; Ceftazidime; Critical Illness; Humans; Lactams; Meropenem; Microbial Sensitivity Tests; Piperacillin; Piperacillin, Tazobactam Drug Combination

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.

Topics: Anti-Bacterial Agents; Body Weight; Critical Illness; Dose-Response Relationship, Drug; Humans; Infusions, Intravenous; Meropenem; Microbial Sensitivity Tests; Patient Simulation; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections

There have been literature reports that some recommended meropenem dosage regimens may fail to meet therapeutic targets in some high-risk children and adults. We evaluated this observation in children using literature studies conducted in infants and children. Observed and, as necessary, simulated data from the literature were combined, yielding a data set of 288 subjects (1 day to ~ 17 years). A population pharmacokinetic model was fit to the data and then used to simulate the recommended dosing regimens and estimate the proportion of subjects achieving recommended target exposures. A two-compartment model best fit the data with weight, postnatal age, gestational age, and serum creatinine as covariates. The US Food and Drug Administration (FDA)-approved dosing regimens achieved targets in ~ 90% or more of subjects less than 3 months of age for organisms with minimum inhibitory concentration (MIC)'s of 2 and 4 mg/L; however, only 68.4% and 41.7% of subjects older than 3 months and weighing < 50 kg achieved target exposures for organisms with MIC's of 2 and 4 mg/L, respectively [Correction added on January 23, 2020, after first online publication: "> 3 months" corrected to "less than 3 months".]. Moreover, for subjects weighing more than 50 kg, only 41.3% and 17% achieved these respective targets. Simulation studies were used to explore the impact of changing dose, dosing interval, and infusion duration on the likelihood of achieving therapeutic targets in these groups. Our findings illustrate that current dosing recommendations for children over 3 months of age fail to meet therapeutic targets in an unacceptable fraction of patients. Further investigation is needed to develop new dosing strategies in these patients.

Topics: Adolescent; Anti-Bacterial Agents; Body Weight; Child; Child, Preschool; Computer Simulation; Datasets as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Dosage Calculations; Female; Humans; Infant; Infant, Newborn; Male; Meropenem; Microbial Sensitivity Tests; Models, Biological; Monte Carlo Method; Pseudomonas aeruginosa; Pseudomonas Infections

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. 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.

Topics: Acute Kidney Injury; Aged; Anti-Bacterial Agents; Asian People; Body Weight; Continuous Renal Replacement Therapy; Critical Care; Critical Illness; Drug Dosage Calculations; Female; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Models, Theoretical; Monte Carlo Method; Prospective Studies

A conventional nomogram, based on serum creatinine (sCr) and age, was developed in order to determine the correct initial dosage regimen for meropenem (MEPM) infusions in elderly patients with severe community-acquired pneumonia (CAP), using a target minimum inhibitory concentration (MIC) of 2 mg/L. A correlation between age and actual bodyweight (BW) in a development cohort of 44 males and 45 females was performed by linear regression using the least-squares method (male: y=-0.4676x+80.281, R(2)=0.4888; female: y=-0.4373x+77.502, R(2)=0.3194). There were no significant differences between actual BW and the BW (e-BW) estimated using this equation in this cohort (male: e-BW 41.6±3.1 kg, BW 41.7±3.5 kg, p=0.93; female: e-BW 39.5±2.1 kg, BW 39.5±3.7 kg, p=0.20). By integrating these equations using the Monte Carlo simulation method, a dosage regime was calculated which would have an 80% probability of maintaining plasma drug levels above the MIC for more than 40% of the time (>40%TAM), using only the age and sCr of individual patients. This relationship was summarized as a nomogram. The nomogram was validated using an independent validation cohort (n=28) of patients. An optimized dosage regimen could be predicted in 84 patients (94.4%) in the development cohort and 25 patients (89.3%) in the validation cohort. This nomogram may be a useful tool for clinicians and pharmacists in determining an initial MEPM regimen in elderly patients with severe CAP, based only on age and sCr.

Topics: Age Factors; Aged; Aged, 80 and over; Aging; Anti-Bacterial Agents; Body Weight; Community-Acquired Infections; Creatinine; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Linear Models; Male; Meropenem; Monte Carlo Method; Nomograms; Thienamycins

The aims of this study were to develop a population pharmacokinetic model for meropenem in Japanese pediatric patients, and to use this model to assess the pharmacodynamics of meropenem regimens against common bacterial populations. Pharmacokinetic data were pooled from nine separate studies (229 plasma samples and 61 urine samples from 40 infected children), modeled using the NONMEM program, and used for a pharmacodynamic simulation to estimate the probabilities of attaining the bactericidal target (40% of the time above the MIC for the bacterium). In the final population pharmacokinetic model, body weight (BW, kg) was the most significant covariate: Cl(r) (l/h) = 0.254 x BW, Cl(nr) (l/h) = 3.45, V (c) (l) = 0.272 x BW, Q (l/h) = 1.65, and V (p) (l) = 0.228 x BW, where Cl(r) and Cl(nr) are the renal and non-renal clearances, V (p) and V (c) are the volumes of distribution of the central and peripheral compartments, and Q is the intercompartmental (central-peripheral) clearance. In most typical patients (BW = 10, 20, and 30 kg), the approved regimens of 10-40 mg/kg, three times a day (0.5-h infusions), achieved a target attainment probability of >80% against Escherichia coli, Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa isolates. The results of this study provide a better understanding of the pharmacokinetics and pharmacodynamics of meropenem in Japanese pediatric patients.

Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Body Weight; Child; Humans; Japan; Meropenem; Microbial Sensitivity Tests; Models, Biological; Monte Carlo Method; Thienamycins

Meropenem is a highly potent carbapenem antibiotic against gram-positive and gram-negative bacteria. Meropenem plasma concentration data from 99 pediatric patients (aged 0.08-17.3 years) were used to develop a population pharmacokinetic model. Pharmacokinetic analysis was performed using NONMEM with exponential interindividual variability and combinational residual error model. A 2-compartment model was found to fit the data best. Creatinine clearance and body weight were the most significant covariates explaining variabilities in meropenem pharmacokinetics among pediatric patients. The validated final model was used to predict meropenem plasma concentrations in 37 pediatric meningitis patients, receiving 40 mg/kg meropenem, who had minimum inhibitory concentration values of the causative pathogens and outcome available. Since the causative pathogens in all patients were eradicated, no break points for required exposure could be found. The microbiological outcomes indicate that the current clinical dosage regimen provides sufficient drug exposure to eradicate the pathogens commonly involved in pediatric meningitis.

Topics: Adolescent; Anti-Bacterial Agents; Body Weight; Child; Child, Preschool; Clinical Trials as Topic; Creatine; Drug Administration Schedule; Haemophilus influenzae type b; Humans; Infant; Kidney; Meningitis; Meropenem; Microbial Sensitivity Tests; Models, Biological; Multicenter Studies as Topic; Neisseria meningitidis; Streptococcus pneumoniae; Thienamycins

To determine the probability of meropenem (Merrem, AstraZeneca Pharmaceuticals L.P., Wilmington, DE, USA) and cefotaxime (Claforan, Aventis Pharmaceuticals Inc., Bridgewater, NJ, USA) achieving bactericidal exposures in the cerebrospinal fluid against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae.. A 5,000-patient Monte Carlo simulation in a population of 10-year-old children with meningitis was conducted. Pediatric pharmacokinetic data were derived from the literature. Pathogen minimum inhibitory concentrations (MICs) were obtained from common bacteria that had caused meningitis collected during pediatric clinical trials. Time above the MIC exposures in the cerebrospinal fluid was calculated. Bactericidal exposure or probability of target attainment was defined as 40% and 50% time above the MIC for meropenem and cefotaxime, respectively. High cumulative fractions of responses were defined as >90% probability of target attainment against the populations of bacteria.. Meropenem was calculated to achieve 94.7%, 94.3%, and 96.1% cumulative fractions of response against S. pneumoniae, H. influenzae, and N. meningitidis, respectively. Cefotaxime only achieved a high likelihood of bactericidal attainment against N. meningitidis (91.6%). Against S. pneumoniae and H. influenzae, cefotaxime was only calculated to achieve 84.3% and 84.8% cumulative fractions of response, respectively.. In a simulated population of 10-year-old children, meropenem had a high likelihood of attaining bactericidal exposures in the cerebrospinal fluid. Cefotaxime had a >90% cumulative fraction of response against only N. meningitidis. Therefore, at the doses simulated, meropenem may be a more appropriate empiric choice for the treatment of bacterial meningitis in pediatric patients presumed to be caused by these pathogens until culture and susceptibility data are available.

Topics: Anti-Bacterial Agents; Body Weight; Cefotaxime; Child; Computer Simulation; Dose-Response Relationship, Drug; Humans; Meningitis, Bacterial; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Meropenem; Monte Carlo Method; Thienamycins

Plasma meropenem concentration versus time data collected during a single dose, pharmacokinetic study in infants and children were analysed using the population pharmacokinetics program NONMEM. A total of 300 meropenem concentrations was obtained from 65 patients ranging from 2 months to 12 years of age; weighing between 3.7 and 46 kg. A two-compartment open pharmacokinetic model with a zero-order infusion over 30 min was fitted to the data. The most important determinant of meropenem clearance was the creatinine clearance but an additional improvement occurred when a nonlinear dependence upon age was included. The most important determinant of the volume of distribution in the central and peripheral compartments was the body weight. The distributional clearance showed a nonlinear dependence on body weight. Demographic factors other than weight and age were not found to be influential in the model. Both clearance and distributional clearance were markedly different in the younger (< 2 years) or lighter (< 10 kg) patients, respectively. Thereafter the parameter values slowly approached those found in adults. In this study, a mean of 4.6 samples per patient was used to provide information on the pharmacokinetics and the determinants of the pharmacokinetic variability in infants and children. The findings in the younger, lighter patients, if generally applicable, might have significance for the dosage recommendations for drugs with narrow therapeutic indices.

Topics: Age Factors; Analysis of Variance; Bacterial Infections; Body Weight; Carbapenems; Child; Child, Preschool; Creatinine; Humans; Infant; Meropenem; Models, Biological; Thienamycins