Updates from the CLSI Subcommittee on Susceptibility Testing

The Clinical Laboratory and Standards Institute (CLSI) Subcommittee on Antimicrobial Susceptibility Testing met in June. Amy Mathers, MD, D(ABMM), IDSA liaison for CLSI, provided the following clinically relevant updates from the meeting. In addition, it should be noted that the CLSI Performance Standards for Antimicrobial Susceptibility Testing (M100) with all the most current breakpoints for common bacteria are available for free in an online searchable version.

The decision-making process at the CLSI is performed by a group of volunteers representing the government, industry, and the professions that research contemporary issues in antimicrobial susceptibility testing and, through a transparent consensus mechanism, construct the recommendations included in CLSI documents. The subcommittee is comprised of microbiologists, infectious diseases physicians, pharmacists, public health specialists, and others. Listed below are some of the topics which were addressed at the June meeting.

   + Change of Breakpoint for Daptomycin and Enterococcus spp.

   +Establishment of Clinical Breakpoints for Azithromycin and Neisseria gonorrhoeae

   +Update and Review of Fosfomycin Resistance for E. coli and other Enterobacteriales  

   +Establishment of Cefidericol Breakpoints for Several Gram Negative Bacilli

Daptomycin and Enterococcus spp

Due to recent reports of daptomycin treatment failures with Enterococcus faecium, established resistance mechanisms, updates in pharmacokinetics/pharmacodynamics due to altered dosing strategies, the committee eliminated the daptomycin Enterococcus spp. term nonsusceptible (≥8ug/mL) and adopted new interpretive criteria.  

Daptomycin Revised Interpretive Criteria for Enterococcus spp.

• Susceptible ≤1µg/mL
• Susceptible dose dependent (S-DD)* =2-4µg/mL
• Resistant ≥8µg/mL

*The S-DD category is based on a dosing regimen of 8-12 mg/kg in adults and is intended for treatment of serious infections. Infectious Diseases consult is suggested.

This decision was reached by a multidisiplinary work group chaired by Mike Satlin, MD and Jim Jorgenson, PhD with review of current literature in conjunction with additional pharmacokinetic/pharmakodynamic data provided by David Nicalou, PharmD, and colleagues.  Although the recommended SDD dosing is outside the current FDA approved package insert, the committee agreed that there was sufficient data to suggest the revised dosing strategy. This was based on published series demonstrating improved outcomes with treatment of serious E. faecium infections when doses >6mg/kg are used. There was also a review of the available literature evaluating adverse outcomes with doses above those originally cleared by the FDA before adopting the revised dosing strategy. This review of safety issues did not demonstrate a signal of increased toxicity.  The committee decided against separate breakpoints for E. faecium and E. faecalis as the wild type distribution even though most of the clinical failures have been described with E. faecium.  The E. faecalis MIC distribution is roughly one dilution below that of E. faecium; therefore, E. faecalis would most frequently test at a lower MIC which would not require higher dosing.  Most importantly, as the data are nuanced and treatment of infections for invasive E. faecium is often complex and frequently in immunocompromised patients we suggest in the document to seek infectious diseases consultation. This recommendation was intended to highlight that complicated enterococcal infections may require dual therapy although there was not clear enough resolution in the data to make a formal recommendation regarding this issue.

Azithromycin and Neisseria gonorrhoeae

With increasing antimicrobial resistance in Neisseria gonorrhoeae in the United States and additional data about successful treatment outcomes, the CLSI adopted a clinical breakpoint for azithromycin and N.gonorrhoeae.  Previously, there had only been an Epidemiologic Cutoff Value (ECV) of ≤ 1 µg/mL established for N. gonorrhoeae.  This decision was largely based on the lack of any reported clinical failures at a breakpoint of ≤ 1 μg/mL, epidemiologic trends of increasing resistance across multiple antimicrobial classes, and the need for clinical labs to monitor for resistance to azithromycin to identify patients at risk for clinical failure.  Since release of the 2015 Sexually Transmitted Diseases Treatment Guidelines which suggests a regimen of Ceftriaxone 250 mg IM plus Azithromycin 1g orally as single dose, there has not been a clinical failure at an azithromycin MIC of ≤1 µg/mL from the multisite Gonococcal Isolate Surveillance Project (GISP) Network run by the Centers for Disease Control and Prevention (CDC).  There are no clear pharmacokinetic/pharmacodynamic targets for N. gonorrheae; however, with the urgency for a clinical breakpoint in an environment of increasing resistance and the lack of clinical failures, the committee adopted a clinical breakpoint for azithromycin and N. gonorrheae of ≤1 µg/mL as susceptible. 

Fosfomycin susceptibility testing for E. coli

Fosfomycin susceptibility testing by disk diffusion for E. coli was also discussed because of new EUCAST methodology as well as recognition of potential resistance mechanisms for non-E. coli Enterobacteriales.   Colonies appearing within a zone of inhibition has been established to occur ~1-5% of the time when performing fosfomycin disk diffusion testing with E. coli. Recently, EUCAST suggested ignoring the colonies within the zone of inhibition as there is increasing data that these isolates tend to be less fit and thus not thought to be clinically relevant.  However, upon review of the data it was determined that the CLSI would not adopt this amended method because 1) colonies within the zone are a rare event, 2) lack of clinical outcome data, and 3) concern that a change to the E. coli method might imply that colonies could be ignored for other organisms.  In addition, data demonstrated that disk diffusion testing for non-E. coli Enterobacteriales, where many of the examined species naturally carry a fosA gene which can hydrolyze fosfomycin.  This fosAgene appears to contribute to colonies within the zone by a different mechanism for other Gram negativespecies compared to the data reviewed for E. coli (E. coli does not naturally carry fosA).  Although the clinical relevance of this is unknown, it is clear that disk diffusion greatly overcalls resistance compared to agar dilution for non-E. coli Enterobacteriales and the decision was made to strengthen the language around not testing non-E. coli Enterobacteriales, due to inaccuracy of the test.  

Establishment of Cefidericol Breakpoints

Breakpoints were set for a cefidericol and Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Acinetobacter baumannii, and Enterobacteriaceae. This is ahead of the completion of the FDA trial but it was felt there were enough microbiologic, PK/PD and clinical data to set breakpoints to avoid delay in publishing if the drug gets FDA approval.