On the Front Lines in the Fight for Antimicrobial Stewardship: The Importance of AST

Strategic Alliance Partners | <b>Society of Infectious Diseases Pharmacists</b>

Antimicrobial stewardship and antimicrobial susceptibility testing (AST) remain critical in the race against antimicrobial resistance.

Antimicrobial susceptibility testing (AST) and reporting for antimicrobials informs and optimizes prescribing and detects resistance.1 It also serves as an important component of hospital antimicrobial stewardship (AMS) efforts to combat urgent multidrug-resistant (MDR) Gram-negative infections. When facing a critically ill patient with a suspected Gram-negative bacterial infection, delayed appropriate therapy can be lethal. This represents a particular challenge with the rapid pace at which resistant Gram-negative organisms emerge and render our existing antimicrobial arsenal less effective. In addition, lack of information about the nature of the infection is a weak link that contributes to antimicrobial resistance through improper prescribing. AMS remains critical in the race against antimicrobial resistance.

The value that AST provides to clinicians to inform antimicrobial selection in support of AMS efforts cannot be overstated. The Joint Commission recently issued Standard MM.09.01.01, effective January 1, 2017, requiring hospitals, critical access hospitals, and nursing care centers to implement and prioritize AMS programs.2 The standard outlines core components that should be present in all AMS programs; calls for education of clinicians, staff, and patients about antimicrobial resistance and the appropriate use of antimicrobials; and requires that hospitals and nursing care centers collect, analyze, and report data on their AMS programs and use these data to improve them. However, the standard does not address the role of AST in AMS or the challenges surrounding AST. Thus, it misses a key element in rapidly identifying infectious organisms and selecting the appropriate antimicrobial agents for treatment.

AST for Off-label Indications

Antimicrobials are widely used in critically ill adults, and in a significant number of cases, antimicrobials are used off label. Anywhere from 19% to 43% of critically ill patients with Gram-negative bacterial infections are treated with off-label antimicrobials.1 On the basis of in vitro and pharmacokinetic data, clinicians often prescribe antimicrobial agents for infections that are not listed specifically in the US Food and Drug Administration (FDA)-approved label, but represent logical uses. For example, a drug approved for complicated intra-abdominal infections might also show good concentrations in the lung; thus, a clinician might select that drug for a critically-ill patient with pneumonia when circumstances demand less conventional options. With highly-resistant pathogens, off-label antimicrobials may be the only active options. Off-label AST reporting and antimicrobial prescribing are vital in both AMS and patient care, particularly for Gram-negative organisms. In some cases, without off-label reporting, there would be no way to conduct AST for Gram-negative infections.

Delays Between Drug Approval and Updated AST Panels

The availability of AST results allows clinicians to make a more informed selection of antimicrobial agents, reducing the risk for inappropriate prescribing that could promote antimicrobial resistance. Unfortunately, the role of AST in AMS is undermined by delays, often by years, between approval of an antimicrobial agent by the FDA and FDA-approved inclusion of susceptibilities to that agent in commercial automated AST panels. The most recently cleared susceptibilities included in commercial AST are for ceftaroline, which was approved in 2010 and is primarily used to treat Gram-positive infections.

This delay is particularly challenging for newer agents, especially those used for multidrug-resistant organisms such as Pseudomonas aeruginosa and Klebsiella pneumoniae. Although the tests are under FDA review, there are currently no commercially available FDA-approved testing systems for antimicrobial agents that have been approved since 2012 such as ceftolozane-tazobactam (Zerbaxa) and ceftazidime-avibactam (Avycaz). Even as FDA-approved labels for these new drugs emphasize that they should be used only for patients with proven or strongly suspected infection by susceptible organisms, clinical laboratories are often not able to test and report susceptibilities for these pathogens.

The Regulatory Burden Surrounding AST

As described by Humphries and Hindler,3 a contributor to the delay is the regulatory environment itself. The FDA approves the inclusion of an organism’s antimicrobial susceptibility in a commercial automated AST panel only if that organism appears in the FDA-approved label for the antimicrobial and has shown both susceptibility in in vitro tests and efficacy in clinical trials. Because clinical trials are expensive, companies often choose to limit these studies to indications that are easier to study, even though in vitro data might hint at utility in other uses. The nature of clinical trials makes resistant pathogen studies particularly difficult to perform, leading to clinical data that is primarily generated in less-resistant strains of bacteria. The clinical effectiveness of an antimicrobial agent for other indications often becomes apparent years later.

In addition, both the FDA and Clinical and Laboratory Standards Institute (CLSI) establish clinical breakpoints for susceptibility to an antimicrobial, and CLSI updates its breakpoints more often in response to new information, such as emerging resistance mechanisms. By law, however, commercial AST systems must use only clinical breakpoints cleared by the FDA. When the FDA does update its breakpoints, it cannot force AST system developers to update their devices. FDA guidance suggests that developers revise the breakpoints on their devices within 90 days of publication of the updated FDA breakpoints. However, developers rarely do. In this environment, clinical microbiology laboratories are limited in the susceptibilities they can report.

Recently, the FDA has proposed even more stringent criteria for commercial automated AST, restricting reportable antimicrobial susceptibilities only to indications studied in clinical trials and listed in the drug label. Increased restriction could interfere severely with off-label AST reporting and antimicrobial prescribing and compromise AMS efforts. The workload for clinical microbiology laboratories would increase. A deficit of reported information would lead to more tests initiated at a clinician’s request, and because the susceptibility of a particular drug-bug combination might not be included in an automated AST panel, the laboratories would have to perform these tests manually, which some may not be either equipped or staffed to do. As AST for some “drug-bug” combinations become more burdensome, clinical microbiology laboratories would be less likely to do it. Without such testing, clinicians’ choices of empiric antimicrobial agents would be less informed, and they would be more likely to prescribe suboptimal but broader-spectrum antimicrobials that might “cover their bases.” Thus, the restrictions would increase the inappropriate prescribing AMS programs aim to reduce.

In the longer term, increased restrictions on commercial automated AST would also harm patient care. Because of high expenses and low profit margins, few companies already undertake antimicrobial development. If it becomes a requirement that companies assess their antimicrobials for multiple indications in clinical trials to have those susceptibilities included in commercial AST panels, more companies might determine that antimicrobial development is too expensive, leaving fewer companies in the field and fewer new antimicrobials in the market. Increased restriction could also slow technological development, with fewer companies and fewer resources devoted to the development of new rapid diagnostic and AST devices.

Rapid organism identification has improved patient care and decreased the time to targeted therapy during treatment scenarios that are measured in minutes and hours. Thus, technology enabling rapid organism identification has resulted in reduced mortality and morbidities, such as length of hospital stay and cost. However, the restrictions described above may slow development of urgently-needed antimicrobial agents and may negatively affect patient care.

Addressing These Challenges

Ideally, pharmaceutical companies, diagnostic device companies, and the FDA Centers that regulate them would align their priorities and marry FDA-approved inclusion of antimicrobial susceptibilities in commercial AST systems with approval of the antimicrobials themselves. However, this is unlikely. Panels for automated systems to determine susceptibility of some Gram-negative strains to drugs such as ceftolozane-tazobactam and ceftazidime-avibactam are being developed, with some likely to be commercially available within the next year.

In the meantime, clinicians can increase awareness of existing challenges to AST, particularly among their colleagues outside of the infectious disease field. Clinicians also can work with their microbiology laboratories toward manual testing of resistant isolates to determine whether new antimicrobial agents are appropriate. Such testing will take time and effort, but are necessary when it is best for patient care.

Hospitals are on the front lines of the urgent public health threat of antimicrobial resistance. While taking steps to prioritize AMS programs is a good first step, clinicians can deepen their commitment to addressing these concerns by better understanding the factors in play surrounding AST. By working collaboratively with their hospital’s clinical microbiology laboratory, clinicians can move the needle in terms of employing accurate, rapid diagnostics, leading to better patient outcomes.

Dr. Gallagher is a clinical professor at Temple University School of Pharmacy and clinical pharmacy specialist in infectious diseases at Temple University Hospital, both in Philadelphia. He also is the director of the PGY2 Residency in Infectious Diseases Pharmacy at Temple. He is an active member of SIDP.

References

  1. Stover, KR, Bland CM, Gallagher JC. The point of antimicrobial susceptibility testing is to inform antimicrobial prescribing. Clin Infect Dis. 2017;64(1):103-104. doi: 10.1093/cid/ciw686.
  2. The Joint Commission. Approved: new antimicrobial stewardship standard. Joint Commission Perspectives. 2016;36(7). https://www.jointcommission.org/assets/1/6/New_Antimicrobial_Stewardship_Standard.pdf. Accessed April 19, 2017.
  3. Humphries, RM, Hindler JA. Emerging resistance, new antimicrobial agents … but no tests! The challenge of antimicrobial susceptibility testing in the current U.S. regulatory landscape. Clin Infect Dis. 2016;63(1):83-88. doi: 10.1093/cid/ciw201.