The Antibiotic Resistance Laboratory Network (AR Lab Network) – Bridging the Gap by Offering Expanded Antimicrobial Susceptibility Testing

Written By: Paula Snippes Vagnone, AR Lab Network Central Region Lab Coordinator, Minnesota Department of Health, Public Health Laboratory, St. Paul, MN

Infections caused by isolates of carbapenemase-producing Enterobacteriaceae that are resistant to nearly all available antimicrobial agents are difficult to treat and a significant cause of morbidity and mortality. In contrast to serine carbapenemase (eg, KPC)- producers, isolates of Enterobacteriaceae that produce metallo-β-lactamases (MBL) are the most challenging, as these are resistant to meropenem-vaborbactam and ceftazidime-avibactam, the newest beta-lactam combination agents. However, isolates of Enterobacteriaceae with MBLs (eg, NDM, VIM, and IMP) have been shown to be susceptible to a combination of ceftazidime + avibactam + aztreonam. This combination is listed in the Sanford Guide as the primary option for treatment of serious infections caused by MBL-producing Enterobacteriaceae.¹ Providing antimicrobial susceptibility testing of an isolate to aztreonam, ceftazidime-avibactam,² and aztreonam-avibactam³ can provide useful information to guide patient treatment. Of note, the betalactam combination of aztreonam-avibactam is in Phase III clinical trials.

Most clinical laboratories find it difficult to test some of the newer antimicrobial agents that might warrant consideration for treatment of highly resistant organisms. It can take years before these drugs are available on commercial antimicrobial susceptibility testing systems used in clinical laboratories. The AR Lab Network⁴ has introduced a new testing approach to bridge the gap. A pilot program was initiated in 2019 at four of the seven AR Lab Network regional laboratories (Minnesota, New York Wadsworth, Tennessee, and Wisconsin) to provide expanded antimicrobial susceptibility testing (ExAST). This program will be extended in 2020 to the remaining AR Lab Network regional laboratories. However, ExAST is now available to all health care facilities in the United States and it is suggested that you contact your state or local public health laboratory (PHL) to determine which AR Lab Network regional laboratory is currently serving your facility for ExAST. Testing is available free-ofcharge for highly resistant isolates that meet specific criteria. An HP D300e Digital Dispenser is used for on-demand production of minimal inhibitory concentration (MIC) panels⁵ that are used for CLSI reference broth microdilution (BMD) testing of the newest antimicrobial agents. This testing is CLIA compliant and enables AR Lab Network regional laboratories to perform ExAST with a quick turn-around time.

Based on the current national need, ExAST at the AR Lab Network regional laboratories will offer testing (and reporting as indicated) of MBL-producing isolates of Enterobacteriaceae with the following antimicrobials and antimicrobial combinations:

• Aztreonam – MIC and interpretation will be reported.
• Ceftazidime-avibactam – MIC and interpretation will be reported.
• Aztreonam-avibactam – MIC will be reported with no interpretation (agent not FDA-approved and no CLSI or FDA breakpoints are available).

The report sent back to your laboratory will include a comment similar to the following to help explain the results: “For aztreonam-avibactam, a minimum inhibitory concentration (MIC) is reported without an interpretation because clinical breakpoints for this drug combination have not been established. This drug demonstrates in vitro activity against metallo-β-lactamase (MBL) producing Enterobacteriaceae. Its clinical efficacy is under evaluation in clinical trials. Surveillance data indicate that MICs of MBL-producing isolates of Enterobacteriaceae (n = 580) ranged from ≤ 0.015/4 to 8/4 μg/mL.”

Since this MIC testing has been validated in each of the AR Lab Network regional laboratories performing ExAST, the MIC result with the comment can be reported by the submitting laboratory. 

What is the purpose of ExAST?

• To provide clinicians, hospital laboratories, and public health laboratories with a resource for testing highly resistant organisms with newer agents not widely available on current antimicrobial susceptibility testing systems.

Note: CDC through the AR Lab Network plans to expand testing as new or novel antimicrobial treatment options become available for serious infections caused by multi-drug resistant organisms.

What are the required criteria* for submitting an isolate for ExAST?

• Any species of Enterobacteriaceae from any specimen source that tests not susceptible to all beta-lactams, including either ceftazidime-avibactam or meropenem-vaborbactam (these isolates may be MBL-producing isolates with few effective treatment options) is acceptable for submission.

-OR-

• Enterobacteriaceae possessing NDM, VIM, or IMP genes confirmed by a molecular test and which are not susceptible to all or the majority of antimicrobial agents already tested.

In addition, please note:

• Unless the isolate is a molecularly-confirmed MBL, testing for ceftazidime-avibactam and meropenem-vaborbactam should be performed before consideration is given to accepting the isolate for ExAST.
• Results for aztreonam from the submitting laboratory will be considered on a case by case basis and in context with all other results available on the isolate.
• The submitting laboratory must include the clinical team in conversations with AR Lab Network regarding ExAST.

*Although these are the basic criteria, exceptions may be made. Suitability for testing will be explored when you contact your AR Lab Network laboratory about a specific isolate/patient.

What is the current ExAST process at the AR Lab Network regional laboratory?

• Once received, the isolate is confirmed as an MBL producer by performance of the following tests (even if such testing was performed at the submitting laboratory): BMD, modified carbapenem inactivation method (mCIM), and molecular testing for KPC, NDM, VIM, IMP, OXA.
• An isolate that is confirmed as an MBL producer will be tested for susceptibility to aztreonam, ceftazidime + avibactam, and avibactam + aztreonam. The special MIC testing may be performed on a highly resistant isolate even if it is not confirmed as an MBL (NDM, VIM, IMP) producer if there is suspicion it may produce a novel carbapenemase.
• ExAST turn-around time is three business days from the time the isolate is received.

How do I request ExAST?

• Contact the AR Lab Network regional laboratory serving your facility. Staff at the regional laboratory will discuss the requirements for submission (eg, isolate’s resistance characteristics) and will provide instructions to you for submitting your isolate.
• You can access the AR Lab Network site for more information about your facility’s AR Lab Network regional laboratory and ExAST by clicking here.

 

References:

¹ Gilbert DN, Chambers HF, Eliopoulos GM, Saag MS, Pavia AT, et al. The Sanford Guide to Antimicrobial Therapy. 2019. Antimicrobial Therapy, Inc. Sperryville, VA.

² Marshall S, Hujer AM, Rojas LJ, et al. Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae? Antimicrob Agents Chemother. 2017;61(4):e02243-16.

³ Biedenback DJ, Kazmierczak K, Bouchillon SK, et al. In vitro activity of aztreonam-avibactam against a global collection of gram-negative pathogens from 2012 and 2013. Antimicrob Agents Chemother. 2015. 59(7): 4239-4248.

⁴ Centers for Disease Control and Prevention. Antibiotic/Antimicrobial resistance (AR/AMR), Laboratory Testing and Resources. https://www.cdc.gov/drugresistance/laboratories.html. Accessed May 21, 2019.

⁵ Smith KP, Kirby JE. Verification of an automated, digital dispensing platform for at-will broth microdilution-based antimicrobial susceptibility testing. J Clin Microbiol. 2016;54(9):2288-2293.

---

This article came from AST News Update, Volume . 4, Issue 2 – June 2019  which is produced by the CLSI Outreach Working Group (ORWG). The ORWG is part of the CLSI Subcommittee on Antimicrobial Susceptibility Testing (AST) and was established in 2015. The formation of the working group originated in a desire to efficiently convey information regarding contemporary AST practices, recommendations, and resources to the clinical microbiology community. They welcome suggestions from you about any aspect of CLSI documents, educational materials, or their Newsletters.