Determining the Optimal Ceftriaxone MIC for Triggering Extended-Spectrum β-Lactamase Confirmatory Testing

Abstract

As routine testing of clinical isolates for extended-spectrum ␤-lactamase (ESBL) production (screen plus phenotypic confirmatory testing) is no longer required by the Clinical and Laboratory Standards Institute (CLSI), a number of clinical microbiology laboratories use ceftriaxone MICs as a proxy means of identifying bacteria as potential ESBL producers. Data from 1,386 clinical isolates suggest that a ceftriaxone MIC cutoff of 8 g/ml is an excellent predictor of ESBL production, with a positive predictive value and negative predictive value approaching 100% and 99.5%, respectively. In 2010, the Clinical and Laboratory Standards Institute (CLSI) lowered the ceftriaxone (and cefotaxime) breakpoint from 8 g/ml to 1 g/ml, and with that change, the recommendation for screening for extended-spectrum ␤-lactamase (ESBL) production became optional (1). This was in part due to the large workload imposed on clinical microbiology laboratories with phenotypic confirmatory ESBL testing (1). However, identification of organisms producing ESBLs still has important clinical implications. A portion of these organisms retain in vitro susceptibility to piperacillin-tazobactam and cefepime (2), even though these agents are generally considered inferior to carbapenem therapy for the treatment of invasive infections by ESBL-producing organisms (3-5).Without a method of alerting clinicians to the possibility that an agent may be an ESBL producer, potentially suboptimal therapy (e.g., cefepime or piperacillin-tazobactam) may be inadvertently prescribed. In addition, the absence of institutional epidemiological data on ESBLs can hamper efforts to control their spread within health care facilities (6). For these reasons, many clinical microbiology laboratories use ceftriaxone (or other thirdgeneration cephalosporin) MIC thresholds to indicate to clinicians that an organism is a possible ESBL producer or to trigger additional confirmatory phenotypic testing. If the ceftriaxone MIC threshold is lower than necessary, this practice has the potential to lead to the overuse of carbapenems or to needlessly increase the workload of microbiology laboratories (for institutions where confirmatory testing is still performed). If the ceftriaxone MIC threshold for ESBL identification is too high, appropriate infection control and treatment strategies may not be deployed. Our objective was to evaluate the sensitivities and specificities of various ceftriaxone MICs in determining the optimal threshold for identifying an organism as a potential ESBL producer.Microbiology methods. Blood isolates growing Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis obtained from January 2007 to December 2013 were included. These bacteria were selected because the CLSI-recommended method for initial screening and phenotypic confirmatory testing is limited to these organisms (7). Clinical samples were processed at the Johns Hopkins Hospital Microbiology Laboratory according to standard operating procedures. Antimicrobial susceptibility t...

Fluoroquinolone-Resistant and Extended-Spectrum β-Lactamase–ProducingEscherichia coliInfections in Patients with Pyelonephritis, United States1

“…The prevalence of ESBL-producing strains may have been underestimated because we did not use ESBL-selective media and used only ceftriaxone instead of several advanced-generation cephalosporins to screen for presence of ESBL-producing strains. However, this method enabled us to have greater site participation; furthermore, screening isolates with a ceftriaxone MIC >1 µg/mL has been reported to have a sensitivity >98% on the basis of phenotypic testing ( 24 ). In addition, some patients may not have had pyelonephritis if a contaminated specimen was misinterpreted as noncontaminated, although >97% of patients had urine collected by a technique that minimizes contamination (i.e., clean catch, urethral catheterization, or suprapubic aspiration), and the diagnosis of pyelonephritis was further supported by clinical assessment.…”

Point-Counterpoint: Piperacillin-Tazobactam Should Be Used To Treat Infections with Extended-Spectrum-Beta-Lactamase-Positive Organisms

“…Ceftriaxone nonsusceptibility is often used as a proxy for ESBL presence, and when ceftriaxone MICs greater than 1 g/ml are observed, carbapenem therapy is frequently pursued. While it is true that ESBL producers are likely to have ceftriaxone MICs in the nonsusceptible range, not all Enterobacteriaceae with ceftriaxone MICs in the nonsusceptible range are ESBL producers (18). ESBL confirmatory testing can be helpful by taking the guesswork out of deciding if an isolate is ESBL producing, potentially leading to the avoidance of unnecessary carbapenem therapy.…”

Dosing of Ceftriaxone and Metronidazole for Children With Severe Acute Malnutrition

“…By parameterizing the model in terms of free ceftriaxone, simulations of free concentrations were therefore straightforward, and the ft > MIC , which is the index usually found to correlate with antimicrobial activity, was simulated for a range of MIC values ( Figure ). A common target for beta lactam antimicrobials is to achieve a ft > MIC of at least 50% of the dosing interval, and typically Enterobacteriaciae with MICs below 1 mg/L, were considered susceptible, although 2 mg/L is now a more common breakpoint, with MIC >8 mg/L indicating the need to test for the presence of ESBL . Our simulations show that for 50 mg/kg dosing there is a greater than 95% probability of having 50% of the dose interval with concentrations exceeding 2 mg/L and increasing the dose to 80 mg/kg improves this to 95% of patients of patients having greater than 60% of the dose interval exceeding 2 mg/L, and greater than 80% of patients achieving 50% above 8 mg/L (the ESBL breakpoint).…”