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The PNA was also a covariate on the intercompartmental CL. Meropenem for Injection – Product Monograph Page 4 of 39 Gynecologic Gynecologic infections caused by Staphylococcus aureus (methicillin-susceptible strains only), Staphylococcus epidermidis (methicillin-susceptible strains only), Escherichia coli, Prevotella bivia, and Peptostreptococcus species. A 3-h EI of meropenem 1000 mg Q8H achieved fT > 2 µg/mL > 40 on the first and third days, providing activity against sensitive strains of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. Very few pharmacokinetic (PK) studies have been performed in children to support current dosing recommendations and some recent studies suggest undertreatment may occur in non‐infants. Poole K(1), Gilmour C(1), Farha MA(2), Parkins MD(3), Klinoski R(1), Brown ED(2). For infants under 3 months of age, Smith et al.10 have recommended that longer periods of time over the MIC should be targeted. May fail in species that have inducible AmpC beta-lactamases (citrobacter, enterobacter, morganella, proteus, … Substitution of a maturation function (see final model equations below) for the effect of PNA on CL and CL2 produced a further improvement that was enhanced by the inclusion of a Hill coefficient (change in OFV of 236; P < 0.001). This article examines the activity of meropenem and imipenem against Pseudomonas aeruginosa isolates from the Meropenem Yearly Susceptibility Test Information Collection program between 1997 and 2005. Meropenem is a first-line antibiotic for treating Pseudomonas infections in the CF lung. Compared with imipenem, meropenem and doripenem, the spectrum of activity of ertapenem is more limited primarily because it lacks activity against Pseudomonas aeruginosa and Enterococcus spp. Gram positive and gram negative coverage Streptococcus species (incl some Enterococci), Listeria, H. flu, E. coli Proteus mirabilis, Salmonella, Shigella DO NOT USE IF PENICILLINASE PRODUCING Combinations with beta-lactamase inhibitors: Non anti-pseudomonal Amoxicillin plus clavulanate (po - Augmentin) Extends H. flu and Staph coverage If you do not receive an email within 10 minutes, your email address may not be registered, The parameters were estimated with good precision (Table 3). Meropenem is frequently active against isolates of B. cepacia, an organism that is typically resistant to imipenem. In addition, the prediction‐corrected visual predictive check demonstrated that concentrations in our compiled data set (observed and simulated) were concordant with predicted concentrations (i.e., 89.7% were within the 90% prediction interval of 5–95 percentiles) indicating the appropriateness of the final model. FDA, US Food and Drug Administration; GA, gestational age; MIC, minimum inhibitory concentration; PNA, postnatal age; WT, weight. The approach of combining data from several PK studies on subpopulations may increase understanding of drug PKs in children. Biotransformation. 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 GA, gestational age; PNA, postnatal age; SCR, serum creatinine; WT, weight. As depicted in Table 3, all final model parameter estimates were consistent with values obtained using nonparametric bootstrapping. H.E.H., V.I., and T.P.G. 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. Hi, man of 66 years old has Pseudomonas aeruginosa after being in hospital for more than 1 month for surgery after cerebral hemorrhage . Meropenem should be avoided if carbapenemase testing is positive, even if susceptibility to meropenem is demonstrated. Meropenem is metabolised by hydrolysis of the beta-lactam ring generating a microbiologically inactive metabolite. Two case reports, one study of a drug interaction, and three studies reporting PKs in subjects receiving renal replacement therapy or extracorporeal membrane oxygenation were not considered further. 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 Ertapenem is a new carbapenem, differing from imipenem and meropenem in having only weak activity against Pseudomonas and Acinetobacter spp. It is routinely used for HAP/HCAP/VAP as double-coverage for Pseudomonas (note more frequent dosing for PNA – 400 mg IV q8 hours) 2. For targets of 4 mg/L, 80% or less for subjects achieved targets with each of the alternative regimens. Pseudomonas infection is caused by strains of bacteria found widely in the environment. 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. A drug of choice for empiric treatment of nosocomial pneumonia†. Goodness‐of‐fit plots and visual predictive checks all suggested a good fit of the model to the data. This article examines the activity of meropenem and imipenem against Pseudomonas aeruginosa isolates from the Meropenem Yearly Susceptibility Test Information Collection program between 1997 and 2005. ☑ We combined information from studies in the literature to generate a single unified PK model for children of all ages (birth through 17 years) and used simulation studies to examine the possibility of undertreatment of serious infection in children in all age groups. The following descriptive statistics were calculated for demographic variables: mean, SD, coefficient of variation, median, and range. Background. By continuing to browse this site you are agreeing to our use of cookies. In only one case was the isolate imipenem resistant but meropenem sensitive, and deemed carbapenem resistant. 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 … Drs. Two meropenem resistance genes, mpmA and mpmB, were mapped near ilvB/C and proC, respectively, on the P. aeruginosa PAO chromosome. Additional manual testing of remaining potential covariates failed to identify further significant reduction in the OFV. Carbapenems (eg, imipenem, meropenem) with antipseudomonal quinolones may be used in conjunction with an aminoglycoside. ☑ Meropenem is commonly used to treat life‐threatening bacterial infections in infants and children. Imipenem is slightly less potent for P. aeruginosa, and ertapenem should not be used for P. aeruginosa because of poor activity. performed the research. Chest. There are several important limitations to our study. Two genetically distinct classes of meropenem-low-susceptibility Pseudomonas oaeruginosa PA02152 mutants, which arose spontaneously, were isolated. Global spread of carbapenem‐resistant Pseudomonas aeruginosa (CRPsA) and Acinetobacter baumannii (CRAB) is an emerging clinical problem. Meropenem for Injection, like all β-lactam antibiotics, has the potential to cause seizures. Although our studies indicate that safe and effective therapy may be achieved with more frequent dosing and with extended infusion durations, optimal regimens that provide desirable outcomes but avoid overdosing await further clinical trials. References: Bartlett JG, Auwaerter PG, Pham PA (2010): The Johns Hopkins ABX Guide. Serum creatinine was generated from the median, upper, and lower limits of normal assuming uniform distribution.27 Outliers with respect to serum creatinine in the Du et al.6 study were simulated by randomly increasing serum creatinine by 1.2–3.3‐fold in 10% of the population. Husson MO, Richet H, Aubert A, et al. 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. Descriptive statistics for demographic and dosing variables were calculated using the value at the time of first PK sample. Bacteria are constantly finding new ways to avoid the effects of antibiotics. Do polymicrobial intra‐abdominal infections have worse outcomes than monomicrobial intra‐abdominal infections? designed the research. A forward covariate search (P < 0.05 for inclusion, P < 0.005 for removal) was carried out, yielding significant covariates of serum creatinine (SCR), postnatal age (PNA), and gestational age (GA) on clearance (CL), and PNA on CL2 (change in OFV of 185; P < 0.001). ☑ Alternative dosage regimens that may minimize the likelihood of treatment failures are proposed for further clinical evaluation. The results are provided in Table 4 for MIC targets of 2 mg/L and 4 mg/L, and for a wide range of MIC targets in Figure 2. 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. Our simulated data, however, were in close agreement with the reported Du et al.6 data set (Table 2) and balanced in their contribution to our analysis by the size of the total patients studied by Blumer et al.,1 Parker et al.,9 and Du et al.6 Second, the subjects included in our study were selected to have normal renal function and our results cannot be extended to children with abnormal renal function. Each of the tested models performed less favorably than the final model described in this report, for which 10.3% of observations fell outside the 90% confidence limits. 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 … SUMMARY. 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. Ertapenem is a broad-spectrum carbapenem agent that lacks activity against Pseudomonas aeruginosa and has been available in Australia since 2002.1 Given the increasing prevalence of extended-spectrum β-lactamase (ESBL)-producing organisms and AmpC-producing Gram-negative bacteria, the use of carbapenems to treat non-P. aeruginosa infections is increasing.2 The use of the antipseudomonal carbapenems (aPCs), meropenem, doripenem and imipenem, in this situation may place ecological pres… The age range of these subjects ranged from 1 month to 17.3 years and subjects had received initial doses of 10–40 mg/kg infused over 5 or 30 minutes. For patients with suspected VAP or HAP, an empiric antimicrobial regimen that has activity against Staphylococcus aureus and Pseudomonas aeruginosa should be used. Meropenem 2 g q8h with a 3-h infusion in combination with an aminoglycoside provides the greatest likelihood of P. aeruginosa coverage, and may help to prevent development of resistance, although local MIC data are essential to inform therapeutic decisions. Plasma meropenem concentrations in groups 1–4 (preterm and term infants < 3 months) met therapeutic target in 82.9–95.1% and 86.6–95.8% of subjects for MIC > 2 mg/L and 4 mg/L, respectively (Table 4). A literature search was performed to identify previous PK studies of meropenem in infants and children. There have been literature reports that some recommended meropenem dosage regimens may fail to meet therapeutic targets in some high‐risk children and adults. Meropenem exerts its bactericidal action by interfering with vital bacterial cell wall synthesis. Finally, the two data subsets (neonatal data from Smith et al.10 and the simulated data from Du et al.6) were examined separately with the same visual predictive check approach and were both found to be accurately represented by our model (87.9% of the observed Smith et al.10 data falling within the 90% prediction interval, and 92.9% of the simulated Du et al.6 data). Pseudomonas infection can be treated with a combination of an antipseudomonal beta-lactam (eg, penicillin or cephalosporin) and an aminoglycoside. or i.v. See Carbapenem Coverage & Uses. 1998 Dec. 114(6):1594-8. . Learn more. H.E.H., V.I., and T.P.G. 27 Meropenem is a carbapenem β-lactam that targets PBPs within Gram-negative bacteria, causing inhibition of cell wall peptidoglycan synthesis, ultimately leading to osmotic lysis of bacterial cells. Of the 10 studies reviewed in depth, six were focused on premature and/or term newborns. Anaerobic Coverage 1,2 All carbapenems have fairly good coverage against anaerobes. Temocillin & ertapenem do not cover pseudomonas • Pip -tazobactam, co amoxiclav (& meropenem) have anaerobic cover so metronidazole is not needed • Temocillin & aztreonam have : no : anaerobic or gram positive cover • Carbapenemase producing enterobacteriacae (CPE) are resistant to penicillins, The in vitro susceptibility of 102 nosocomial P. aeruginosa isolates to meropenem were evaluated. Number of times cited according to CrossRef: Reappraisal of the Optimal Dose of Meropenem in Critically Ill Infants and Children: a Developmental Pharmacokinetic-Pharmacodynamic Analysis, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/050706s040lbl.pdf.2016, https://www.regulations.gov/document?D=FDA-2011-N-0918-0006, https://www.cdc.gov/growthcharts/cdc_charts.htm, https://www.fda.gov/drugs/development-resources/meropenem-injection-products, Du—Simulated data set combined with Smith. If the target is 4 mg/L, these modified regimens achieve 90% coverage goals in children under 50 kg, however, those over 50 kg may still have inadequate coverage. 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. Isolates of Pseudomonas aeruginosa (n = 208) were collected from an 810‐bed hospital in Connecticut, USA.A model employing the pharmacokinetic properties of meropenem, susceptibility results and Monte Carlo simulation was used to analyse four different dosing regimens of meropenem … We evaluated this observation in children using literature studies conducted in infants and children. For the very resistant P. aeruginosa, doripenem and meropenem are highly potent because they require multiple drug resistance pathways. To begin, the model included both observed data from 188 subjects and simulated data from 100 subjects. 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. Further investigation is needed to develop new dosing strategies in these patients. Studies in adults have demonstrated a similar risk of undertreatment, particularly with shorter intravenous drug infusion times12-17 and more recent studies in children have voiced this same concern.18, 19 Intrigued by these findings, we sought to comprehensively evaluate the current meropenem dosage regimen recommendations in US children using available literature data. 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. We confirmed that data from the NICHD data repository for the PTN (preterm neonates and infants) were best described by a one‐compartment model with covariates, as described by Smith et al.10 Parameter values and variabilities found in our analysis were virtually identical to those described in that report. Some of these include meningitis, intra-abdominal infection, pneumonia, sepsis, and anthrax. 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.

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