Comparing the activity of novel antibiotic agents against carbapenem-resistant Enterobacterales clinical isolates

Abstract

Objective: We compared the activity of 8 novel β-lactam and tetracycline-derivative antibiotics against a cohort of clinical carbapenem-resistant Enterobacterales (CRE) isolates and investigated the incremental susceptibility benefit of the addition of an aminoglycoside, fluoroquinolone, or polymyxin to the β-lactam agents to assist with empiric antibiotic decision making. Methods: A collection of consecutive CRE clinical isolates from unique patients at 3 US hospitals (2016–2021) was assembled. Broth microdilution was performed to obtain antimicrobial susceptibility testing results. Mechanisms of carbapenem resistance were investigated through short-read and long-read whole-genome sequencing. Results: Of the 603 CRE isolates, 276 (46%) were carbapenemase producing and 327 (54%) were non–carbapenemase producing, respectively. The organisms most frequently identified were Klebsiella pneumoniae (38%), Enterobacter cloacae complex (26%), and Escherichia coli (16%). We obtained the following percent susceptibility to novel β-lactam agents: ceftazidime-avibactam (95%), meropenem-vaborbactam (92%), imipenem-relebactam (84%), and cefiderocol (92%). Aminoglycosides and the polymyxins provided greater incremental coverage as second agents, compared to fluoroquinolones. Amikacin and plazomicin exhibited the greatest additive value. Ceftazidime-avibactam, meropenem-vaborbactam, and cefiderocol were active against 94% of the 220 KPC-producing isolates. Cefiderocol was active against 83% of the 29 NDM-producing isolates. Ceftazidime-avibactam had 100% activity against the 9 OXA-48-like–producing isolates. Tigecycline had the highest activity compared to other tetracyclines against KPC, NDM, or OXA-48-like–producing isolates. Conclusion: Selection among novel agents requires a nuanced understanding of the molecular epidemiology of CRE. This work provides insights into the comparative activity of novel agents and the additive value of a second antibiotic for empiric antibiotic decision making.

Meropenem-Vaborbactam Activity against U.S. Multidrug-Resistant Enterobacterales Strains, Including Carbapenem-Resistant Isolates

“…The nonCP CRE frequency in our study was 13.1% of the CRE cohort, similar to the results of a recent study by Castanheira et al on isolates from 71 U.S. hospitals, which identified a nonCP CRE frequency of 14.8% ( 10 ), but in contrast to the results of Tamma et al on isolates from three U.S. hospitals, which identified a nonCP CRE frequency of 54% ( 26 ). It is possible that the high nonCP CRE rate reported by Tamma et al ( 26 ) represents a local clonal spread. The nonCP CRE rate for European CRE strains was 17.7% in the study by Sader et al ( 23 ), with Poland having a greater number than other European countries in additional recent studies ( 24 , 27 ).…”

Novel Antimicrobial Agents for Gram-Negative Pathogens

“…Unfortunately, many beta-lactamase-producing microorganisms can produce up to four beta-lactamases and carry determinants for many antimicrobial classes beyond beta-lactams [ 92 , 174 ]. Nonetheless, the aminoglycosides, polymyxins, and high-dose tigecycline could increase coverage if combined with the beta-lactams [ 175 , 176 ].…”

Cefiderocol, a Siderophore Cephalosporin, as a Treatment Option for Infections Caused by Carbapenem-Resistant Enterobacterales

“…The safety profile of the newer agents is a key benefit for the treatment of patients with CRE infections. Beta-lactams are preferred over polymyxins or aminoglycosides, which may be nephrotoxic [159].…”