Updates in Antimicrobial Stewardship: What Do Health System Pharmacists Need to Consider?

Among the most important initiatives affecting health systems in the United States in 2017 was The Joint Commission (TJC) mandate requiring antimicrobial stewardship (AMS) programs at all acute-care and critical-access hospitals in the country,¹ along with similar requirements proposed by CMS.² Those requirements have thrust antibiotic susceptibility testing (AST) methods into the spotlight as part of the AMS solution, while also elevating the role of infectious disease pharmacists and microbiologists within health systems in the establishment and implementation of AMS programs. What recent developments in AST should health system pharmacists be aware of to confidently embrace their roles as AMS stakeholders?

Here are 3:

1. Molecular rapid diagnostic tests (mRDTs) are changing clinical practice.The advent of mRDTs, such as FilmArray blood culture identification, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and Verigene BC-GP and BC-GN (gram-positive and gram-negative blood culture), has revolutionized microbiology laboratories. When combined with AMS interventions, mRDTs enhance the efficiency of stewardship programs and improve health economic outcomes and patient care.^3-11 A recent systematic review and meta-analysis of studies involving 5920 patients with bloodstream infections found that combining AMS with mRDT decreased mortality by 36% compared with conventional microbiology methods, while also reducing time to effective therapy by 5.03 hours and hospital length of stay by 2.48 days.¹²

In addition to reducing or eliminating the lag time between susceptibility testing and the receipt of results, the elucidation of the relationship between the genotype and phenotype of a bacterium is key to the value of mRDTs. Whereas identification specialists have previously relied primarily on phenotypic susceptibility testing based on an antibiotic agent’s breakpoint, mRDTs reveal the underlying genetic mechanism that causes that phenotypic resistance or susceptibility. This is exciting because access to both genotypic and phenotypic information has tremendous implications for patient care and the selection of therapy. For example, a normal, phenotypic-only commercial AST system would identify a Pseudomonas aeruginosastrain as carbapenem-resistant, for which a physician might empirically start ceftolozane/tazobactam. On the other hand, an mRDT such as the Verigene BC-GN system might identify theIMP metallo-β-lactamase gene, which would inactivate ceftolozane/tazobactam and force the clinician to use an alternative regimen.Rapid identification of resistance mechanisms is important because multidrug-resistant pathogens such as Klebsiella pneumoniae and P aeruginosaare evolving and developing resistance in ways that specialists are just beginning to understand. The more effectively we can target not just the resistant strain but also the mechanisms of resistance, the more precisely we can target antimicrobial therapy and, ideally, optimize treatment outcomes.

2. New breakpoints are on the horizon. Antibiotic breakpoints established by the FDA have often differed from those set by the Clinical and Laboratory Standards Institute (CLSI),¹³based on the latter’s greater reliance on microbiological data, pharmacokinetic/pharmacodynamic data, and published clinical outcomes. A new set of breakpoints is forthcoming from the National Antimicrobial Susceptibility Testing Committee for the United States (USCAST),¹⁴ which essentially aims to emulate the European Committee on Antimicrobial Susceptibility Testing,¹⁵whose breakpoints are generally lower and more conservative than those historically used by the CLSI. However, the USCAST breakpoint recommendations may cause confusion in microbiology labs, and many labs are limited in terms of which breakpoints they can adopt because of the inflexibility of most commercial AST systems. It therefore remains to be seen how many AMS teams and individual labs will adopt the USCAST breakpoints in lieu of the CLSI breakpoints or use some combination of both. Regardless, this is an issue that health system pharmacists will need to monitor.

3. Direct-from-specimen (DFS) tests will drive further change.Another potentially revolutionary development in AST is the emergence of newer technologies that enable DFS testing without incubation or organism growth.T2 Biosystems’ T2Candida assay, the only FDA-approved direct-from-whole-blood mRDT, can detect as few as 1 CFU/mL of 5 Candida species (C albicans, C glabrata, C krusei, C parapsilosis, and C tropicalis) in 3 to 5 hours, and the fully automated, self-contained instrument requires less than 5 minutes of hands-on time.¹⁶The Accelerate PhenoTest BC Kit, from Accelerate Diagnostics, is approved only for blood isolates from culture growth, though it may be developed and approved in the future for DFS use from many different sources, including ascites, cerebrospinal fluid, fluid aspirates, respiratory, tissue specimens, and urine, as well as catheter tips, drains, swabs, and wound dressings. In addition to identifying bacteria and yeast, the Accelerate BC Kit/AST technology can detect at least 90% of gram-positive and -negative organisms and resistant phenotypes, can differentiate nonsusceptible and susceptible isolates of Staphylococcus aureus, and provide susceptibility/resistance reports in about 4 to 5 hours.¹⁷ It can also identify carbapenemase production in K pneumoniae¹⁸ and identify and quantitate the burden of P aeruginosa and S aureus from respiratory tract specimens.¹⁹

Facilitating Implementation of New AST Technologies

As health systems look to new AST technologies to decrease costs, enhance the efficiency and reach of their AMS programs, and improve patient outcomes, pharmacists will need to consider how best to implement and optimize their use, particularly in terms of identifying specific types of patients for whom these tests are appropriate. Whereas the significant up-front capital and overall costs of many mRDTs may make them cost-effective for only larger academic medical centers, health system pharmacists may be able to use the CMS and TJC mandates to justify their adoption and implementation. Development of a solid business plan, including consideration of the cost centers and types of costs involved in AST implementation and use, will therefore be crucial to securing administrative buy-in. Health systems should also establish multidisciplinary laboratory test utilization committees to thoroughly evaluate each AST, similar to the rigorous process employed by pharmacy and therapeutics committees to evaluate medications.

It is important to remember that no available AST covers the entire microbiological spectrum. Nevertheless, the future of AMS and AST is bright, as new mRDT technologies are already helping accelerate the optimization of antimicrobial therapy by providing more timely susceptibility reporting, a trend that holds great promise for improving treatment outcomes for patients facing some of the world’s toughest infections.

Eric Wenzler, PharmD, BCPS, AAHIVP, is an assistant professor of pharmacy practice at the University of Illinois College of Pharmacy in Chicago.

References

1. The Joint Commission. Approved: new antimicrobial stewardship standard. jointcommission.org/assets/1/6/New_Antimicrobial_Stewardship_Standard.pdf. Published July 2016. Accessed April 10, 2018.

2. Department of Health and Human Services, CMS. Medicare and Medicaid programs; hospital and critical access hospital (CAH) changes to promote innovation, flexibility, and improvement in patient care; proposed rule. Fed Regist. 2016;81(116). gpo.gov/fdsys/pkg/FR-2016-06-16/pdf/2016-13925.pdf. Accessed April 10, 2018.

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4. Pardo J, Klinker KP, Borgert SJ, Butler BM, Giglio PG, Rand KH. Clinical and economic impact of antimicrobial stewardship interventions with the FilmArray blood culture identification panel. Diagn Micribiol Infect Dis. 2016;84(2):159-164. doi: 10.1016/j.diagmicrobio.2015.10.023.

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6. Lockwood AM, Perez KK, Musick WL, et al. Integrating rapid diagnostics and antimicrobial stewardship in two community hospitals improved process measures and antibiotic adjustment time. Infect Control Hosp Epidemiol. 2016;37(4):425-432.doi: 10.1017/ice.2015.313.

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8. Wenzler E, Goff DA, Mangino JE, Reed EE, Wehr A, Bauer KA. Impact of rapid identification of Acinetobacter baumannii via matrix-assisted laser desorption ionization time-of-flight mass spectrometry combined with antimicrobial stewardship in patients with pneumonia and/or bacteremia. Diagn Microbiol Infect Dis. 2016;84(1):63-68. doi: 10.1016/j.diagmicrobio.2015.09.018.

9. Carreno JJ, Lomaestro BM, Jacobs AL, Meyer RE, Evans A, Montero CL. Assessment of time to clinical response in patients with sepsis treated before and after implementation of a matrix-assisted laser desorption ionization time-of-flight blood culture identification algorithm. Infect Control Hosp Epidemiol. 2016;37(8):916-923. doi: 10.1017/ice.2016.105.

10. MacVane SH, Nolte FS. Benefits of adding a rapid PCR-based blood culture identification panel to an established antimicrobial stewardship program. J Clin Microbiol.2016;54(10):2455-2463. doi: 10.1128/JCM.00996-16.

11. MacVane SH, Hurst JM, Boger MS, Gnann JW Jr. Impact of a rapid multiplex polymerase chain reaction blood culture identification technology on outcomes in patients with vancomycin-resistant enterococcal bacteremia. Infect Dis (Lond). 2016;48(10):732-737. doi: 10.1080/23744235.2016.1185533.

12. Timbrook TT, Morton JB, McConeghy KW, Caffrey AR, Mylonakis E, LaPlante KL. The effect of molecular rapid diagnostic testing on clinical outcomes in bloodstream infections: a systematic review and meta-analysis. Clin Infect Dis.2017;64(1):15-23. doi: 10.1093/cid/ciw649.

13. Clinical and Laboratory Standards Institute. clsi.org. Accessed April 10, 2018.

14. USCAST: The National Antimicrobial Susceptibility Testing Committee for the United States. uscast.org. Accessed April 10, 2018.

15. European Committee on Antimicrobial Susceptibility Testing. eucast.org. Accessed April 10, 2018.

16. Pfaller MA, Wolk DM, Lowery TJ. T2MR and T2Candida: novel technology for the rapid diagnosis of candidemia and invasive candidiasis. Future Microbiol.2016;11(1):103-117.doi: 10.2217/fmb.15.111.

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19. Metzger S, Frobel RA, Dunne WM Jr. Rapid simultaneous identification and quantitation of Staphylococcus aureus and Pseudomonas aeruginosa directly from bronchoalveolar lavage specimens using automated microscopy. Diagn Microbiol Infect Dis. 2014;79(2):160-165.doi: 10.1016/j.diagmicrobio.2013.11.029.