Third-Generation Cephalosporin-Resistant Enterobacterales Are Critical Priority Pathogens, Too!

LETTER

The review by Butler et al. (1) is a comprehensive look at pipeline antibacterial agents for WHO priority pathogens. It is reassuring that many innovative companies are endeavoring to ensure that clinicians will have options to treat carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa (CRPA), and Acinetobacter baumannii (CRAB). But, what about the other critical priority pathogens, the third-generation cephalosporin (3GC)-resistant Enterobacterales (2)? This group of resistant pathogens often seems to go overlooked, and in this review, was not included in Tables 3 or 4 or acknowledged in the Conclusion. Yet, they are leading causes of antimicrobial resistance (AMR)-attributed deaths globally (3).

Resistance to 3GC in Enterobacterales is predominantly due to the production of extended-spectrum β-lactamases (ESBL). According to the CDC, 197,400 cases and 9,100 deaths from infections due to ESBL-producing Enterobacterales occurred in hospitalized patients in 2017 in the United States (4). These numbers are 9 and 5 times greater than the combined cases and deaths arising from CRE (13,100 cases/1,100 deaths) and CRAB (8,500 cases/700 deaths), respectively (4). This comparison is not meant to diminish the toll and specter of CRE and CRAB, only to remind the readership that ESBL should not be overlooked as a priority for development of new agents. Of the 4 agents with ESBL activity included in the review, 3 are carbapenems/penems (benapenem, tebipenem, and sulopenem), and one is carbapenem-sparing, the β-lactam/β-lactamase inhibitor combination of cefepime/enmetazobactam.

The concept of carbapenem-sparing therapies for ESBL is a tenet of antimicrobial stewardship. Carbapenems are considered “last-resort” agents (5). However, in the face of limited treatment options for ESBL-producing pathogens (which often exhibit resistance to other classes of agents), increasing ESBL rates, and generic (cheap) carbapenems, the deck appears to be stacked in favor of increased carbapenem usage and, consequently, exacerbation of carbapenem resistance.

All movements start with raising awareness, which in this case, means appreciating that 3GC-resistant Enterobacterales are on the WHO critical priority list and a central player in carbapenem resistance. According to the SENTRY surveillance program, CRE rates remain below 5% (mean of all participating countries) (6). Developing carbapenem-sparing therapies for 3GC-resistant Enterobacterales would extend the directive of the WHO by not only providing a cure for a critical priority pathogen but also by aiming to curtail resistance to the carbapenems, the most potent class of β-lactams. In the current battle against AMR, a concerted strategy that supports the concurrent development of therapies for the most resistant pathogens and strategies to slow the course of carbapenem resistance development is worth investing in.