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meropenem coverage pseudomonas

Anahtar Kelimeler: Antibiyotik duyarlılığı, Meropenem, Pseudomonas aeruginosa. analyzed the data. Does NOT cover Pseudomonas aeruginosa or Acinetobacter. Ciofu O(1), Jensen T, Pressler T, Johansen HK, Koch C, Høiby N. Author information: (1)Department of Clinical Microbiology and Institute of Medical Microbiology and Immunology and. 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 Using the model of Du et al.,6 23.8% of observations fell outside the 90% confidence intervals (P < 0.001), whereas models of Ohata et al.8 and Parker et al.9 performed even more unfavorably (56.8% and 86.5%, respectively, P < 0.001 for each comparison with the new model). Additional manual testing of remaining potential covariates failed to identify further significant reduction in the OFV. These results raise concerns for the adequate treatment of pediatric patients over the age of 3 months with serious infections being treated with meropenem. Details of the population PK (PopPK) modeling procedures, the analysis of models, and the validation and qualification of the final model are provided in the Appendix S1. Pseudomonas aeruginosa is intrinsically resistant to many antimicrobial drugs, making carbapenems crucial in clinical management. 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. 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. Of the 10 studies reviewed in depth, six were focused on premature and/or term newborns. The efficacy of meropenem in adults has been established to occur when T > MIC90 meets or exceeds 40–50% of the dosage interval. Antimicrobial Agents and Chemotherapy , 64 (1), [e01679-19]. 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. Please check your email for instructions on resetting your password. Pseudomonas infection can be treated with a combination of an antipseudomonal beta-lactam (eg, penicillin or cephalosporin) and an aminoglycoside. 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. 135, 136 Isolates of S. maltophilia are typically resistant to meropenem and imipenem, in addition to all other available β-lactam antibiotics.. Pseudomonas is a type of bacteria (germ) that is found commonly in the environment, like in soil and in water. Pelvic inflammatory disease caused by Staphylococcus epidermidis (methicillin-susceptible Imipenem is slightly less potent for P. aeruginosa, and ertapenem should not be used for P. aeruginosa because of poor activity. Diagnosis and Treatment of Infectious Diseases. Meropenem-Tobramycin Combination Regimens Combat Carbapenem-Resistant Pseudomonas aeruginosa in the Hollow-Fiber Infection Model Simulating Augmented Renal Clearance in Critically Ill Patients. Covers gram-negatives well (including pseudomonas), but nothing else. Penetrates into CSF (esp meropenem & imipenem) Cover gram-positives & gram-negatives & anaerobes Bactericidal against: B. fragilis , Enterobacteriaceae, Pseudomonas & … Ureidopenicillin We searched for the term “meropenem,” limited the search to human children, and required one of the following terms: “kinetics,” “pharmacokinetics,” or “PK.” Fifty studies were identified, of which 18 reported original research performed exclusively in pediatric subjects. Diagnosis and management of complicated intra‐abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America, Basic pharmacodynamics of antibacterials with clinical applications to the use of beta‐lactams, glycopeptides, and linezolid. Because the study of Smith et al.10 included the largest subject population and was conducted at multiple study sites, as described below, and had complete, available study data, the other neonatal studies20-23 were not included in our modeling efforts. 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). 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). Beware significant rate of resistance of Pseudomonas in most institutions, so empiric double coverage often required. Antibiotics that cover the difficult to kill gram-positive bacteria Dose Rarely, both were used (five isolates). ☑ Alternative dosage regimens that may minimize the likelihood of treatment failures are proposed for further clinical evaluation. When meropenem for injection is indicated in patients with these risk factors, caution is advised. Meropenem in cystic fibrosis patients infected with resistant Pseudomonas aeruginosa or Burkholderia cepacia and with hypersensitivity to beta-lactam antibiotics. Background. 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. 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). 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. 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, SUMMARY. Husson MO, Richet H, Aubert A, et al. If you do not receive an email within 10 minutes, your email address may not be registered, GA, gestational age; PNA, postnatal age; SCR, serum creatinine; WT, weight. and in requiring only once-daily administration.1 It is marketed for use in severe community-acquired infections, where non-fermenters are unlikely, and is licensed for intra-abdominal infections, community-acquired pneumonia and acute pelvic infection. The parameters were estimated with good precision (Table 3). 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. Therefore, the studies of Blumer et al.,1 Parker et al.,9 and Du et al.6 were further analyzed for inclusion in our modeling. H.E.H., V.I., and T.P.G. Imipenem is slightly less potent for P. aeruginosa, and ertapenem should not be used for P. aeruginosa because of poor activity. 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. 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. DOES NOT cover MRSA or VRE 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. 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. or i.v. Meropenem for Injection, like all β-lactam antibiotics, has the potential to cause seizures. 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. In particular, it examines the activity of meropenem against imipenem-resistant strains and vice versa. 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. For the very resistant P. aeruginosa, doripenem and meropenem are highly potent because they require multiple drug resistance pathways. 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. 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). There have been literature reports that some recommended meropenem dosage regimens may fail to meet therapeutic targets in some high‐risk children and adults. 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). The FDA‐recommended dosage of 20 mg/kg every 8 hours infused over 30 minutes was used. 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. 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. The following descriptive statistics were calculated for demographic variables: mean, SD, coefficient of variation, median, and range. Meropenem demonstrates time‐dependent killing of susceptible bacteria. Meropenem for injection, like all β-lactam antibiotics, has the potential to cause seizures. Meropenem is metabolised by hydrolysis of the beta-lactam ring generating a microbiologically inactive metabolite. The authors declared no competing interests for this work. 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 On the other hand, Blumer et al.,1 Parker et al.,9 Du et al.,6 and Ohata et al.,8 reported that meropenem disposition in children and older infants follows a two‐compartment model with weight,6, 8, 9 creatinine clearance,6, 9 and postnatal age6, 9 being significant covariates. 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. Good for atypicals. Detailed Meropenem dosage information for adults and children. H.E.H., V.I., and T.P.G. 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. H.E.H., V.I., J.G., and T.P.G. Meropenem exerts its bactericidal action by interfering with vital bacterial cell wall synthesis. Pelvic inflammatory disease caused by Staphylococcus epidermidis (methicillin-susceptible 2010 2nd Edition. The stepwise development of a new PopPK model for all pediatric subjects was conducted. Goodness‐of‐fit plots for the final PopPK model indicated that the model described the data well without bias (provided in Appendix S1). We evaluated this observation in children using literature studies conducted in infants and children. Version 9.0, Clinical characteristics and outcomes of Pseudomonas aeruginosa bacteremia in febrile neutropenic children and adolescents with the impact of antibiotic resistance: a retrospective study. 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 … Carbapenems (eg, imipenem, meropenem) with antipseudomonal quinolones may be used in conjunction with an aminoglycoside. 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. Ertapenem is a new carbapenem, differing from imipenem and meropenem in having only weak activity against Pseudomonas and Acinetobacter spp. The original data were not available from the respective authors, so a representative population of 100 subjects was generated using Monte Carlo simulations mimicking the demographic distribution reported in Du et al.6 In order to do this, four age groups of 25 subjects were created (2–14, 14–38, 38–66, and 66–200 months of age) with random, uniform distribution in each and random, binomial distributions of sex. It is tempting to conclude that therapeutic drug monitoring would be indicated in order to detect inadequately treated patients and adjust therapy. 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). 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. © 2020 American Society for Clinical Pharmacology and Therapeutics. The approach of combining data from several PK studies on subpopulations may increase understanding of drug PKs in children. The data set from this study was obtained from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) data repository for the Pediatric Trials Network (PTN)25 and formatted with R version 3.3.1 (R Foundation for Statistical Computing, Vienna, Austria) using RStudio version 0.99.489 (Boston, MA). A two‐compartment model best fit the data with weight, postnatal age, gestational age, and serum creatinine as covariates. Precision of all parameter estimates was high and nonparametric bootstrap estimates were in close agreement with their parametric counterparts. 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. is a concern; in 2014, 19.1% of P. aeruginosa associated with selected HAI and reported to the NHSN were not susceptible to carbapenems . It is given by injection into a vein. By continuing to browse this site you are agreeing to our use of cookies. Global spread of carbapenem‐resistant Pseudomonas aeruginosa (CRPsA) and Acinetobacter baumannii (CRAB) is an emerging clinical problem. For the very resistant P. aeruginosa, doripenem and meropenem are highly potent because they require multiple drug resistance pathways. Meropenem is a carbapenem that has an excellent activity against many gram-positive and gram-negative aerobic, facultative, and anaerobic bacteria. 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]. It is commonly used for treatment of serious infections, including intra‐abdominal infections and meningitis in both adult and pediatric patients. The PNA was also a covariate on the intercompartmental CL. The most common type causing infections in humans is called Pseudomonas aeruginosa. 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. Chest. Simulations of plasma meropenem concentrations following intravenous doses to subjects in the combined data set were performed using the final PopPK model and dosage regimens based on FDA‐approved dosages for serious infections with organisms requiring high concentrations (e.g., intra‐abdominal infections with pseudomonas; Table 1).11 One thousand simulations were performed for each subject group for each tested dosage regimen. Carbapenems are a class of antibiotics that were developed to treat bacteria that are resistant to other drugs. 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. Two genetically distinct classes of meropenem-low-susceptibility Pseudomonas oaeruginosa PA02152 mutants, which arose spontaneously, were isolated. By continuing to browse this site you are agreeing to our use of cookies. 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. 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. Any queries (other than missing content) should be directed to the corresponding author for the article. ɣ, the Hill coefficient for the maturation equation for CL and CL2, as described in the. Biotransformation. Moreover, for subjects weighing more than 50 kg, only 41.3% and 17% achieved these respective targets. ☑ 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. 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. 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. 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.

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