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.