Pseudomonas aeruginosa is intrinsically resistant to many antimicrobial drugs, making carbapenems crucial in clinical management. For the very resistant P. aeruginosa, doripenem and meropenem are highly potent because they require multiple drug resistance pathways. 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. Additional manual testing of remaining potential covariates failed to identify further significant reduction in the OFV. FDA, US Food and Drug Administration; GA, gestational age; PNA, postnatal age. 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. Moreover, for subjects weighing more than 50 kg, only 41.3% and 17% achieved these respective targets. Some of these include meningitis, intra-abdominal infection, pneumonia, sepsis, and anthrax. 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. 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. Imipenem, meropenem and doripenem have in vivo half lives of approximately 1 hour, while ertapenem has a half-life of approximately 4 hours making it suitable for once-daily administration. Meropenem is metabolised by hydrolysis of the beta-lactam ring generating a microbiologically inactive metabolite. For infants under 3 months of age, Smith et al.10 have recommended that longer periods of time over the MIC should be targeted. H.E.H., V.I., J.G., and T.P.G. Two genetically distinct classes of meropenem-low-susceptibility Pseudomonas oaeruginosa PA02152 mutants, which arose spontaneously, were isolated. 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). 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 … 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 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. (1302 isolates) or sometimes meropenem discs were used (303 isolates in the years 2003–2006) to assess carbapenem susceptibility. 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. GA, gestational age; PNA, postnatal age; SCR, serum creatinine; WT, weight. Of the many different types of Pseudomonas, the one that most often causes infections in humans is called Pseudomonas aeruginosa, which can cause infections in the blood, lungs (pneumonia), or other parts of the body after surgery. If you do not receive an email within 10 minutes, your email address may not be registered, 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). Pseudomonas infection is caused by strains of bacteria found widely in the environment. With the exception of the PK modeling, all statistical analyses were performed with R using RStudio. 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. 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. FDA‐approved dosing regimens and three tested alternative regimens are illustrated. Ovid Medline was queried for English language studies published prior to the initiation of our work in February 2016. Abstract. 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. 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. These results raise concerns for the adequate treatment of pediatric patients over the age of 3 months with serious infections being treated with meropenem. 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). 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. •Conclusion: A regimen of 500mg IV q6h is able to achieve a similar probability of target attainment with DOES NOT cover MRSA or VRE Ertapenem is a new carbapenem, differing from imipenem and meropenem in having only weak activity against Pseudomonas and Acinetobacter spp. 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. In only one case was the isolate imipenem resistant but meropenem sensitive, and deemed carbapenem resistant. 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. Therefore, we conducted a prospective observational study in 169 patients who developed Pseudomonas aeruginosa VAP. Use the link below to share a full-text version of this article with your friends and colleagues. H.E.H., V.I., J.G., and T.P.G. © 2020 American Society for Clinical Pharmacology and Therapeutics. The most common type causing infections in humans is called Pseudomonas aeruginosa. A literature search was performed to identify previous PK studies of meropenem in infants and children. Body weights were generated in R based on Centers for Disease Control (CDC) Growth Charts26 with normal distributions for age and sex. When meropenem for injection is indicated in patients with these risk factors, caution is advised. 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 Meropenem has been shown to penetrate well into several body fluids and tissues: including lung, bronchial secretions, bile, cerebrospinal fluid, gynaecological tissues, skin, fascia, muscle, and peritoneal exudates. The approach of combining data from several PK studies on subpopulations may increase understanding of drug PKs in children. The group 2 carbapenems (imipenem, meropenem and, more recently, doripenem) have been a mainstay of treatment for patients with serious hospital infections caused by Pseudomonas aeruginosa, Enterobacteriaceae and other difficult-to-treat Gram-negative pathogens as well as mixed aerobic/anaerobic infections. Observed and, as necessary, simulated data from the literature were combined, yielding a data set of 288 subjects (1 day to ~ 17 years). SUMMARY. It is very likely that impaired clearance of meropenem would occur in these patients and, therefore, the time below MIC would be minimized. Carbapenems (eg, imipenem, meropenem) with antipseudomonal quinolones may be used in conjunction with an aminoglycoside. Global spread of carbapenem‐resistant Pseudomonas aeruginosa (CRPsA) and Acinetobacter baumannii (CRAB) is an emerging clinical problem. ☑ Our results suggest an unacceptable risk of undertreatment in some children beyond infancy, in particular those children over 50 kg in weight. Finally, studies in adults with serious gram‐negative infections have demonstrated the importance of maintaining serum drug concentrations associated with antibiotic killing for substantial portions of the interdose interval in order to achieve infection bacterial eradication. 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). For targets of 4 mg/L, 80% or less for subjects achieved targets with each of the alternative regimens. As the Ohata et al.8 study was the index analysis suggesting that currently recommended therapeutic regimens may be inadequate in some pediatric subjects (> 3 months of age), this study was reserved for comparison and these patient's PK data were not included in our analysis. Poole K(1), Gilmour C(1), Farha MA(2), Parkins MD(3), Klinoski R(1), Brown ED(2). The efficacy of meropenem in adults has been established to occur when T > MIC90 meets or exceeds 40–50% of the dosage interval. Hi, man of 66 years old has Pseudomonas aeruginosa after being in hospital for more than 1 month for surgery after cerebral hemorrhage . Levofloxacin (Levaquin)(PO and IV) Spectrum: “Respiratory Fluoroquinolone” - excellent activity vs. Strep pneumo, slightly less reliable Pseudomonas coverage than Cipro. 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. Carbapenems are a class of antibiotics that were developed to treat bacteria that are resistant to other drugs. Meropenem (Merrem) is an injectable carbapenem and beta-lactam antibiotic that interferes with bacterial cell wall synthesis in sensitive organisms; Has activity versus a wide array of organisms, including multi-drug resistant Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae. The FDA‐recommended dosage of 20 mg/kg every 8 hours infused over 30 minutes was used. 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. {{configCtrl2.info.metaDescription}} This site uses cookies. 2010 2nd Edition. When dosages of 40 mg/kg every 8 hours with 30‐minute infusion times were simulated, the probability only increased to about 75%. Do polymicrobial intra‐abdominal infections have worse outcomes than monomicrobial intra‐abdominal infections? ɣ, the Hill coefficient for the maturation equation for CL and CL2, as described in the. In particular, it examines the activity of meropenem against imipenem-resistant strains and vice versa. 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. wrote the manuscript. Meropenem, sold under the brandname Merrem among others, is a broad-spectrum antibiotic used to treat a variety of bacterial infections. PD studies have indicated that the most predictive PD parameter of efficacy is the percent time above minimum inhibitory concentration that kills 90% (MIC90) of the pathogen, often represented as T > MIC90. ☑ 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. In addition, except in the European Union, it is licensed for skin and soft tissue infections and for complica… Meropenem is a first-line antibiotic for treating Pseudomonas infections in the CF lung. FDA, US Food and Drug Administration; GA, gestational age; MIC, minimum inhibitory concentration; PNA, postnatal age; WT, weight. Good for atypicals. 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. 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. Pelvic inflammatory disease caused by Staphylococcus epidermidis (methicillin-susceptible Contact, Nebraska Med ASP Slides On Meropenem Extended-Infusion, Zoster vaccine recombinant, adjuvanted (Shingrix), An Unofficial Pharmacy Playlist Of Drug Theme Songs, 5 Important Things To Know About Extended Spectrum Beta-Lactamases (ESBL): Insights From A Clinical Microbiologist, Shorter Is Better With Antibiotics: Lessons & Resources, Antimicrobial Stewardship In Bangladesh: A Pharmacist’s Perspective, Meropenem (Merrem) is an injectable carbapenem and beta-lactam antibiotic that interferes with bacterial cell wall synthesis in sensitive organisms, Has activity versus a wide array of organisms, including multi-drug resistant, Carbapenems like meropenem are generally considered the drugs of choice for ESBL-producing organisms (aka ESBL positive organisms), Reserve this “big gun” antibiotic until you absolutely have to use it, Can be used for many infection types – pneumonia, skin & soft tissue infection, bloodstream infection, etc, Most likely to see this drug used as empiric therapy in an ICU setting, but when more information is known, try to de-escalate to more narrow therapy, Doses in normal kidney function can range form 500mg Q8H for UTI to 2gm Q8H for meningitis, Can be given via extended-infusion to prolong the time > MIC, but product stability can be an issue, Patients who are allergic to penicillins or cephalosporins may also be allergic to carbapenems, Generally speaking cross-reactivity is low, be more concerned in patients with a history of severe allergic reaction. Rarely, both were used (five isolates). 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. Notably, meropenem remains a viable option with efficacy against extended-spectrum beta-lactamase (ESBL)-producing organisms and Pseudomonas aeruginosa. Meropenem-Tobramycin Combination Regimens Combat Carbapenem-Resistant Pseudomonas aeruginosa in the Hollow-Fiber Infection Model Simulating Augmented Renal Clearance in Critically Ill Patients. Carbapenem resistance among Pseudomonas spp. Since, quercetin is a well‐known antibacterial agent; it would be relevant to demonstrate synergy between quercetin and meropenem and elucidate molecular basis of effective bactericidal activity of quercetin‐meropenem against CRPsA … 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".]. 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). 1998 Dec. 114(6):1594-8. . {{configCtrl2.info.metaDescription}} This site uses cookies. 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. Dose 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".]. A two‐compartment model best fit the data with weight, postnatal age, gestational age, and serum creatinine as covariates. 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. 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. Three alternative dosing strategies were explored to improve the percent of subjects meeting the target serum concentration for selected patient groups; first, a doubling of the recommended dose given every 8 hours (this dosing, 40 mg/kg every 8 hours (maximum 2 g), coincides with the FDA recommendation for treatment of meningitis in pediatric subjects > 3 months); second, the recommended dose as outlined in Table 111 but given every 6 hours instead of every 8 hours; and third, administration of the recommended dosages with the intravenous infusion duration increased to 3 hours. Meropenem demonstrates time‐dependent killing of susceptible bacteria. 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). To begin, the model included both observed data from 188 subjects and simulated data from 100 subjects. Extrapolation of these findings to children seems to be a minimum threshold and, in circumstances where immune compromise exists, extended periods of adequate serum drug concentrations may be required.10. Two meropenem resistance genes, mpmA and mpmB, were mapped near ilvB/C and proC, respectively, on the P. aeruginosa PAO chromosome. 135, 136 Isolates of S. maltophilia are typically resistant to meropenem and imipenem, in addition to all other available β-lactam antibiotics.. analyzed the data. 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. 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 is commonly used to treat life‐threatening bacterial infections in infants and children. Meropenem belongs to the antibiotic class of carbapenems, which are known to be broad-spectrum antibiotics effective against several drug-resistant organisms. The In vitro Activity of Meropenem to Nosocomial Pseudomonas aeruginosa Isolates. In particular, it examines the activity of meropenem against imipenem-resistant strains and vice versa. Meropenem is a carbapenem that has an excellent activity against many gram-positive and gram-negative aerobic, facultative, and anaerobic bacteria. Options for covering both Pseudomonas and anaerobes: 1) Pip/Tazo (Zosyn), OR 2) Aztreonam + Metronizadole, OR——- This is on DRMC’s guidelines recommend this combination in pts. 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. 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. 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. 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. 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 …