Rationale for the 2010 Revised Susceptibility Breakpoints for Cephalosporins, Aztreonam, and Carbapenems for Enterobacteriaceae.

Abstract

β-Lactam antimicrobial agents are mainstays for treatment of infections due to many members of the Enterobacteriaceae. Since the introduction of these agents into clinical use in the 1970s and 1980s, there have been considerable changes in the potency of these drugs against clinical isolates of Enterobacteriaceae, largely due to the evolution and dissemination of extended spectrum β-lactamases (ESBLs) that hydrolyze penicillins, cephalosporins, and monobactams. The worldwide dissemination of these ESBLs played a major role in the first revision of susceptibility breakpoints (minimum inhibitory concentrations [MICs]) for these drugs by the Clinical Laboratory Standards Institute in June 2010. The increasing problem of β-lactamase-mediated resistance has recently extended to the carbapenem class of antimicrobial agents. The serine carbapenemase KPC (for Klebsiella pneumoniae carbapenemase) has been detected in Enterobacteriaceae from several major population regions in the United States, and is problematic in many institutions in Europe. More recently, a metallo β-lactamase (NDM-1) that hydrolyzes carbapenems and most β-lactams has spread rapidly from Asia to the United Kingdom and other regions in the world. The Centers for Disease Control and Prevention has issued alerts for both of these carbapenemases and recommendations for limiting its spread in hospitals [1, 2]. Carbapenemases of the KPC type produced a situation similar to that for ESBLs; strains producing KPC or ESBLs were often classified as susceptible using breakpoints established in the former era. Thus, new lower breakpoints for cephalosporins and carbapenems against Enterobacteriaceae were established to ensure optimal exposures with US Food and Drug Administration (FDA)-approved dosage regimens, and would also classify these isolates as nonsusceptible. Clinical, pharmacokinetic-pharmacodynamic (PKPD), and MIC distribution data were considered in revising the breakpoints [3, 4]. While highly desirable, clinical data were difficult to acquire. Critical information concerning MIC, concomitant drug treatment, site of infection, and cephalosporin dosage regimen was generally not available in studies of ESBL-producing isolates. Thus, other analyses were required. PK-PD analyses were conducted to determine whether usual FDA-approved dosage regimens of the Pediatric ID Consultant