Meropenem dosing requirements against Enterobacteriaceae in critically ill patients: influence of renal function, geographical area and presence of extended-spectrum β-lactamases
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The aim of this study was the evaluation of the influence of the susceptibility patterns of Escherichia coli and Klebsiella pneumoniae isolates, specifically the presence of extended-spectrum β-lactamases and the geographical area (Europe and USA), on the meropenem dosing requirements in critically ill patients with different degrees of renal function by estimation of the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment. Additionally, estimation of the PK/PD breakpoints according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) approach was also an objective. Six dosing regimens were evaluated: 0.5 g, 1 g and 2 g every 8 h given as 0.5-h or 3-h infusions. Pharmacokinetic data were obtained from the literature, and susceptibility data to meropenem for E. coli and K. pneumoniae were collected from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) surveillance study. For the same dose level, the 3-h infusion provided a probability of target attainment (PTA) ≥90 % for minimum inhibitory concentration (MIC) values up to two-fold dilution higher than those obtained with the 0.5-h infusion. For E. coli, the cumulative fraction of response (CFR) was 100 % in most cases, and neither the dose nor the infusion length nor the geographical area significantly affected the probability to reach the target. With regards to K. pneumoniae, the CFR increased when increasing the dose and decreasing the creatinine clearance (CLCR). The CFR for Spanish and USA strains was higher than that calculated for European strains. Meropenem PK/PD breakpoints are dependent on the dose, infusion length and CLCR, ranging from 2 to 32 mg/L. Based on our results, meropenem administered as a extended infusion is the best option to treat infections due to E. coli and K. pneumoniae.
KeywordsMinimum Inhibitory Concentration Meropenem Susceptibility Pattern Virtual Patient EUCAST
This work was supported by the Department of Education, Universities and Research (IT341-10), Basque Government, Spain. We thank the University of the Basque Country UPV/EHU for the grant awarded to E. Asín-Prieto.
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Conflict of interest
The authors declare that they have no conflict of interest.
- 9.European Committee on Antimicrobial Susceptibility Testing (EUCAST) (2015) Breakpoint tables for interpretation of MICs and zone diameters. Version 5.0. Available online at: http://www.eucast.org
- 14.Roberts JA, Kirkpatrick CM, Roberts MS, Robertson TA, Dalley AJ, Lipman J (2009) Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother 64:142–150CrossRefPubMedGoogle Scholar
- 15.Product Information. Meronem I.V.®, meropenem trihydrate for injection. AstraZeneca, Madrid, Spain. Revised February 2015Google Scholar
- 21.Clinical and Laboratory Standards Institute (CLSI) (2015) Performance standards for antimicrobial susceptibility testing; Twenty-fifth informational supplement. CLSI document M100-S25. CLSI, Wayne, PA, USAGoogle Scholar
- 26.Carlier M, Carrette S, Roberts JA, Stove V, Verstraete A, Hoste E et al (2013) Meropenem and piperacillin/tazobactam prescribing in critically ill patients: does augmented renal clearance affect pharmacokinetic/pharmacodynamic target attainment when extended infusions are used? Crit Care 17:R84PubMedCentralCrossRefPubMedGoogle Scholar
- 27.Glasner C, Albiger B, Buist G, Tambić Andrasević A, Canton R, Carmeli Y et al (2013) Carbapenemase-producing Enterobacteriaceae in Europe: a survey among national experts from 39 countries, February 2013. Euro Surveill 18. pii: 20525Google Scholar
- 28.Oteo J, Ortega A, Bartolomé R, Bou G, Conejo C, Fernández-Martínez M et al (2015) Prospective multicenter study of carbapenemase-producing enterobacteriaceae from 83 hospitals in Spain reveals high in vitro susceptibility to colistin and meropenem. Antimicrob Agents Chemother 59:3406–3412PubMedCentralCrossRefPubMedGoogle Scholar
- 30.Centers for Disease Control and Prevention (CDC) (2013) Antibiotic resistance threats in the United States, 2013. U.S. Department of Health and Human Services, Atlanta, GA, USAGoogle Scholar
- 31.Cefepime breakpoint change for Enterobacteriaceae and introduction of the susceptible-dose dependent (SDD) interpretive category. Available online at: http://community.clsi.org/micro/wp-content/uploads/sites/15/2013/07/Cefepime-BP-Change-for-Enterobacteriaceae_-Intro-of-SDD-For-Labs.pdf
- 34.Ulldemolins M, Soy D, Llaurado-Serra M, Vaquer S, Castro P, Rodríguez AH, Pontes C, Calvo G, Torres A, Martín-Loeches I (2015) Meropenem population pharmacokinetics in critically ill patients with septic shock and continuous renal replacement therapy: influence of residual diuresis on dose requirements. Antimicrob Agent Chemother 59:5520–5528. doi: 10.1128/AAC.00712-15 CrossRefGoogle Scholar