title: Breakpoints for carbapenemase-producing Enterobacteriaceae: is the problem solved?
abstract: The imipenem and meropenem breakpoints for Enterobacteriaceae established by the Clinical and Laboratory Standards Institute (CLSI) are somewhat lower than those established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), but are identical for ertapenem and doripenem. The differences are primarily due to the various pharmacokinetic/pharmacodynamic (PK/PD) approaches used to define these breakpoints. Both approaches use the Monte Carlo simulation with a probability of target attainment (PTA) for reaching the PD target of free drug concentration above the minimum inhibitory concentration (MIC) at least 40% of the time (~40%fT >MIC). EUCAST uses PTA mean values with confidence intervals (CIs) of 95% and 99%, whereas the CI used by CLSI is 90%. In addition, CLSI uses an "inflated variance" that takes into account the variability of PK parameters in various types of patients, particularly those who are critically ill. By employing this approach, the susceptible CLSI breakpoint captures a higher number of carbapenemase-producing Enterobacteriaceae (CPE) than EUCAST. EUCAST, however, has recently defined cut-off values for screening CPE. Both committees recommend reporting carbapenem susceptibility results "as tested," demonstrating carbapenemase production only for epidemiological purposes and infection control. New clinical data could potentially modify this recommendation because carbapenemase production also influences specific treatment guidance concerning carbapenems in combination with other antimicrobials in infections due to CPE. This advice should not be followed when imipenem or meropenem MICs are >8mg/L, which is coincident with the EUCAST resistant breakpoints for these carbapenems.
authors.affiliation: Departamento de Microbiología, Hospital Universitario Ramón y Cajal e Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; Red Española de Investigación en Patología Infecciosa (REIPI), Madrid, Spain. Electronic address: rafael.canton@salud.madrid.org.
authors.forename: Rafael
authors.initials: R
authors.lastname: Cantón
authors.affiliation: Departamento de Microbiología, Hospital Universitario de Álava, Vitoria, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Canut
authors.affiliation: Departamento de Microbiología, Hospital Universitario Ramón y Cajal e Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; Red Española de Investigación en Patología Infecciosa (REIPI), Madrid, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Morosini
authors.affiliation: Red Española de Investigación en Patología Infecciosa (REIPI), Madrid, Spain; Servicio de Microbiología y Unidad de Investigación, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliver
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism*; D015780:Carbapenems / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial; D004755:Enterobacteriaceae / Q000187:drug effects / Q000201:enzymology*; D004756:Enterobacteriaceae Infections / Q000382:microbiology; D006801:Humans; D007390:International Agencies; D008826:Microbial Sensitivity Tests / Q000379:methods / Q000592:standards*; D009010:Monte Carlo Method; D011159:Population Surveillance; D017410:Practice Guidelines as Topic; D058028:Research Report; D013997:Time Factors; D018440:beta-Lactam Resistance; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015780:Carbapenems; D001618:beta-Lactamases; C063912:carbapenemase
keywords: Carbapenemasas; Carbapenemases; Clinical breakpoints; Enterobacteriaceae; Enterobacterias; Farmacocinética/farmacodinamia; PK/PD breakpoints; Pharmacokinetic/pharmacodynamics; Puntos de corte PK/PD; Puntos de corte clínicos