Goodness‐of‐fit plots for the final PopPK model indicated that the model described the data well without bias (provided in Appendix S1). 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".]. Each panel depicts one age/size group of subjects, as defined in Table, By continuing to browse this site, you agree to its use of cookies as described in our, CPT: Pharmacometrics & Systems Pharmacology, orcid.org/https://orcid.org/0000-0002-6433-1154, orcid.org/https://orcid.org/0000-0003-0171-7129, I have read and accept the Wiley Online Library Terms and Conditions of Use, Sequential, single‐dose pharmacokinetic evaluation of meropenem in hospitalized infants and children, Pharmacokinetics of continuous‐infusion meropenem in a pediatric patient receiving extracorporeal life support, Pharmacokinetics of continuous‐infusion meropenem for the treatment of, Pharmacokinetics of continuous infusion meropenem with concurrent extracorporeal life support and continuous renal replacement therapy: a case report, Safety and effectiveness of meropenem in infants with suspected or complicated intra‐abdominal infections, Population pharmacokinetics and pharmacodynamics of meropenem in pediatric patients, Adverse events associated with meropenem versus imipenem/cilastatin therapy in a large retrospective cohort of hospitalized infants, Optimal dosage regimen of meropenem for pediatric patients based on pharmacokinetic/pharmacodynamic considerations, The pharmacokinetics of meropenem in infants and children: a population analysis, Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra‐abdominal infections, Prescribing information for Merrem® IV (meropenem for injection), for intravenous use, Pharmacodynamic evaluation of extending the administration time of meropenem using a Monte Carlo simulation, Pharmacokinetic and pharmacodynamic properties of meropenem, Pharmacodynamics of meropenem in critically ill patients with febrile neutropenia and bacteraemia, Population pharmacokinetic analysis and dosing regimen optimization of meropenem in adult patients, Comparison of the pharmacodynamics of meropenem in patients with ventilator‐associated pneumonia following administration by 3‐hour infusion or bolus injection, Population pharmacokinetics of meropenem during continuous infusion in surgical ICU patients, Population pharmacokinetics and pharmacodynamic target attainment of meropenem in critically Ill young children, Pharmacokinetics and pharmacodynamics of meropenem in children with severe infection, Short versus long infusion of meropenem in very‐low‐birth‐weight neonates, Meropenem pharmacokinetics in the newborn, Meropenem pharmacokinetics, pharmacodynamics, and Monte Carlo simulation in the neonate, Pharmacokinetics of meropenem in preterm neonates, Population pharmacokinetics and pharmacodynamics of meropenem in Japanese pediatric patients, National Institute of Child Health and Human Development (A0009) ‐ Clinical Study Report 2014, National Center for Health Statistics: CDC growth charts 2004, Establishing age/sex related serum creatinine reference intervals from hospital laboratory data based on different statistical methods, Prediction of creatinine clearance from serum creatinine, Clinical and Laboratory Standards Institute (CLSI), Performance Standards for Antimicrobial Susceptibility Testing, The European Committee on Antimicrobial Susceptibility Testing (EUCAST), Breakpoint tables for interpretation of MICs and zone diameters. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. analyzed the data. Because the index study suggesting suboptimal treatment was performed in an exclusively Japanese study population,8 another exclusively Japanese study24 was omitted from further consideration. Of the 10 studies reviewed in depth, six were focused on premature and/or term newborns. Meropenem Antibiotic Class: Carbapenem Antimicrobial Spectrum: Aerobic gram-positive microorganisms: S. aureus including penicillinase-producing strains, Group D streptococcus including Enterococcus spp., Streptococcus pneumoniae, S. pyogenes, S. viridans group Enter your email address below and we will send you your username, If the address matches an existing account you will receive an email with instructions to retrieve your username, Distributions of steady state, intra‐dosage plasma meropenem concentrations in infants and children receiving currently recommended dosage regimens compared with target serum drug concentrations. Target attainment for the tested dosage regimens in group 6 subjects (> 50 kg) was only 64.7% for subjects receiving an increased dosage for targets of 2 mg/L, but over 90% with either the shortened interdosage interval or the extended infusion time. H.E.H., V.I., J.G., and T.P.G. Meropenem exerts its bactericidal action by interfering with vital bacterial cell wall synthesis. Carbapenems (eg, imipenem, meropenem) with antipseudomonal quinolones may be used in conjunction with an aminoglycoside. A two‐compartment model best fit the data and was substantially improved by scaling the PK parameters (elimination clearance, intercompartmental clearance, volume of the central compartment, and volume of peripheral compartment) by body weight (change in objective function value (OFV) of 1,052; P < 0.001). Background. The carbapenems imipenem and meropenem are recommended by the American Thoracic Society and the Infectious Disease Society of America as one of several first-line therapy options for people with late-onset hospital-acquired or ventilator-associated pneumonia, especially when Pseudomonas, Acinetobacter, or extended spectrum beta-lactamase producing Enterobacteriaceae are suspected … Meropenem is a carbapenem antibiotic for parenteral use, that is relatively stable to human dehydropeptidase-1 (DHP-1) and therefore, does not require the addition of an inhibitor of DHP-1. However, for children 3 months to 17 years of age, the plasma concentrations met the therapeutic target period in only 68.4% and 41.3% in groups 5 and 6, respectively, when the target MIC was > 2 mg/L and in only 41.7% and 17% in groups 5 and 6, respectively, when the target MIC was > 4 mg/L (Table 4). The study of Du et al.6 included all 65 subjects from the previous studies of Blumer et al.1 and Parker et al.,9 in addition to their own data from an additional 34 subjects. In addition, except in the European Union, it is licensed for skin and soft tissue infections and for complica… Meropenem/imipenem/doripenem Ertapenem Ertapenem ... Pseudomonas aeruginosa Neisseria meningitidis Neisseria gonorrhea Above the diaphragm (Peptostreptococcus) Below the diaphragm (Bacteroides sp) Metronidazole Cephalosporins have in-vitro activity for SPACE organisms but induce production of beta-lactamases The study of Smith et al.10 included 188 infants of 23–40 weeks estimated gestational age and 1–92 days postnatal age in whom 780 serum meropenem concentrations were obtained. In only one case was the isolate imipenem resistant but meropenem sensitive, and deemed carbapenem resistant. {{configCtrl2.info.metaDescription}} This site uses cookies. and you may need to create a new Wiley Online Library account. On 12 February 2019, the Pan American Health Organization / World Health Organization (PAHO/WHO) received a report regarding surgical site infections caused by antibiotic-resistant Pseudomonas aeruginosa after invasive procedures performed in Tijuana, Mexico. However, ~ 32–58% of children over the age 3 months may fail to achieve the desired targets when the MIC of the infecting organism is 2 mg/L and ~ 58–83% of children > 3 months will not achieve the T > MIC90 target when the MIC is 4 mg/L. The stepwise development of a new PopPK model for all pediatric subjects was conducted. Learn about our remote access options, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA, Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois, USA, Correspondence: Thomas P. Green (tgreen@northwestern.edu). Meropenem Antibiotic Class: Carbapenem Antimicrobial Spectrum: Aerobic gram-positive microorganisms: S. aureus including penicillinase-producing strains, Group D streptococcus including Enterococcus spp., Streptococcus pneumoniae, S. pyogenes, S. viridans group For the very resistant P. aeruginosa, doripenem and meropenem are highly potent because they require multiple drug resistance pathways. Using the entire data set of 1,482 observations in 288 subjects (ages 0.02–17 years), we compared the performance of the new, comprehensive pediatric PopPK model with non‐neonatal models previously reported in literature.6, 8-10 The observations were compared with the predicted quantiles of the respective structural models and the number of observations falling outside the 90% confidence limits (5%–95%) were tabulated. wrote the manuscript. The PK model developed in this study performs well in all pediatric age groups from prematurely born infants, through and into adolescence. The pediatric data set, simulated to replicate the patient population of Du et al.6 (and containing the patients studied by Blumer et al.1 and Parker et al.9) was highly concordant with the reported population characteristics, as depicted in Table 2.6, 10, The infant PK data set of Smith et al.10 (n = 188) and the simulated PK data set from Du et al.9 (n = 100) were, therefore, combined to generate a comprehensive pediatric data set that includes 288 subjects with an age range of 0.00217.3 years (Table 2).6, 10. Although doubling the currently recommended dosage administered every 8 hours in these older children would decrease the number of inadequately treated patients, achievement of > 90% target attainment when the target is 2 mg/L requires administering recommended dosages every 6 hours or extending infusion duration to 3 hours. The pharmacokinetics (PKs) and pharmacodynamics (PDs) of meropenem have been assessed in pediatric patients.1-10 Smith et al.10 reported that meropenem disposition in pediatric patients < 3 months of age can best be described by a one‐compartment model with weight, albumin, serum creatinine, and postmenstrual age being significant covariates. Topical meropenem 50 mg/ml, which is not routinely used in ocular infections, is an effective alternative for management of hospital acquired resistant Pseudomonas corneal infections and may become an additional agent in the armamentarium of treating ophthalmologist and cornea specialist. Body weights were generated in R based on Centers for Disease Control (CDC) Growth Charts26 with normal distributions for age and sex. DOES NOT cover MRSA or VRE There have been literature reports that some recommended meropenem dosage regimens may fail to meet therapeutic targets in some high‐risk children and adults. Chest. Our findings suggest that recommended dosage regimens in infants less than 3 months of age meet therapeutic targets in at least 83% of subjects [Correction added on January 23, 2020, after first online publication: "> 3 months" corrected to "less than 3 months".]. Abstract. The percentage of subjects achieving a therapeutic target improved to over 85% in group 5 subjects (< 50 kg) with each of these alternative regimens for the potential target of 2 mg/L. Goodness‐of‐fit plots and visual predictive checks all suggested a good fit of the model to the data. Penetrates into CSF (esp meropenem & imipenem) Cover gram-positives & gram-negatives & anaerobes Bactericidal against: B. fragilis , Enterobacteriaceae, Pseudomonas & … Meropenem is a broad spectrum carbapenem antibiotic that has potent activity against an array of important gram‐positive and gram‐negative bacteria, such as pseudomonus aeruginosa, enterobacteriaceae, and anaerobes.It is commonly used for treatment of serious infections, including intra‐abdominal infections and meningitis in both adult and pediatric patients. The combined PK data set for this study, therefore, consisted of the merged data from 188 subjects in the Smith et al.10 study and the data from the 100 simulated subjects replicating those subjects studied by Du et al.,6 Blumer et al.,1 and Parker et al.9 Missing clinical data in the combined data set were imputed using the last value carried forward; except for missing gestational age for infants and children > 120 days of age, for which the gestational age of 40 weeks was imputed. Recent studies in adults suggest that treatment with beta‐lactams in critically ill subjects may be associated with shorter T > MIC90 than recommended and possibly inadequate clinical responses.12-17 The report of Ohata et al.8 originally suggested that this may be the case for many children and, since the completion of our studies, two new reports have been published also suggesting an unacceptable risk for undertreatment in this population.18, 19 In order to explore this phenomenon further in pediatrics, we pooled PK data for pediatrics from literature sources, developed a unified PK model for meropenem in pediatrics, and evaluated currently recommended dosage regimens. Meropenem Target Attainment vs. P. aeruginosa •Probability of target attainment is similar for doses of 1g IV q8h and 500mg IV q6h (both at the desired probability of ≥90%), up to an MIC of 2 mg/L. A two‐compartment model best fit the data with weight, postnatal age, gestational age, and serum creatinine as covariates. Notably, meropenem remains a viable option with efficacy against extended-spectrum beta-lactamase (ESBL)-producing organisms and Pseudomonas aeruginosa. It is very likely that impaired clearance of meropenem would occur in these patients and, therefore, the time below MIC would be minimized. 2010 2nd Edition. For example, some Pseudomonas can produce enzymes called carbapenemases that break down antibiotics including carbapenems, making the drugs ineffective.Carbapenem antibiotics are typically reserved to treat multidrug-resistant bacterial infections, so when bacteria develop resistance to them, treatment … Meropenem is frequently active against isolates of B. cepacia, an organism that is typically resistant to imipenem. In order to further explore the shortcomings of currently recommended dosage schedules for children over 3 months of age, we extended our simulation analysis for groups 5 and 6 to evaluate three alternative dosage regimens: increased dose (40 mg/kg, maximum of 2 g, Q8h), decreased dosage interval (20 mg/kg, maximum 1 g, Q6h in lieu of Q8h), and increased dose infusion duration (20 mg/kg, maximum 1 g, Q8h infused over 3 hours instead of 0.5 hours). Pelvic inflammatory disease caused by Staphylococcus epidermidis (methicillin-susceptible Pharmacokinetics: i.m. Detailed Meropenem dosage information for adults and children. Meropenem is a carbapenem that has an excellent activity against many gram-positive and gram-negative aerobic, facultative, and anaerobic bacteria. Scaling of clearance and weight with an estimated single exponential scaling term for both volume terms and another for both elimination and intercompartmental clearance improved the model further. References: Bartlett JG, Auwaerter PG, Pham PA (2010): The Johns Hopkins ABX Guide. The effect of Pseudomonas aeruginosa infection on clinical parameters in steady-state bronchiectasis. 1998 Dec. 114(6):1594-8. . GA, gestational age; PNA, postnatal age; SCR, serum creatinine; WT, weight. There are several important limitations to our study. Meropenem is metabolised by hydrolysis of the beta-lactam ring generating a microbiologically inactive metabolite. with allergies to PCN who can’t take Pip/Tazo 3) Imipenem or Meropenem or Doripenem. Extended-infusion meropenem is a preferred agent against pyelonephritis and cUTI by CRE that remain susceptible to meropenem, since most of these isolates do not produce carbapenemases [44]. Meropenem, sold under the brandname Merrem among others, is a broad-spectrum antibiotic used to treat a variety of bacterial infections. The following descriptive statistics were calculated for demographic variables: mean, SD, coefficient of variation, median, and range. Creatinine clearance was estimated by the method of Cockcroft and Gault.28 Eight simulated plasma meropenem concentrations were generated for each of these 100 subjects (total of 800 serum meropenem concentrations) based on the model PK parameters, variability statistics, and covariates from Du et al.6 using Phoenix NLME version 7.0 (Certara, Princeton, NJ). Moreover, for subjects weighing more than 50 kg, only 41.3% and 17% achieved these respective targets. The FDA recommendations for treatment of serious, deep tissue infections with meropenem have been based on carefully performed PK analyses.1-3, 5 Nevertheless, these infections are still associated with significant morbidity and further improvements in treatment are needed.31-33. For the potential target of 4 mg/L, target attainment was achieved in 68% of virtual subjects receiving an increased dosage, but to over 90% of subjects for the regimens with a shortened interdosage interval or an extended infusion time.
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