2172. Activity of Cefiderocol and Comparator Agents Against Molecularly Characterized Multidrug-resistant Enterobacterales Clinical Isolates from United States Hospitals (2020–2022)
Authors: Mendes Rodrigo E , Kimbrough John H , Kantro Valerie , Shortridge Dee , Sader Helio S , Castanheira Mariana 
Published: November 2023

Abstract

Background
Cefiderocol (CFDC) is a siderophore cephalosporin that hijacks the iron transport system of Gram-negative bacteria to facilitate cell entry and reach its target. CFDC remains stable to hydrolysis in the presence of serine β-lactamases (ESBLs, KPC, and OXA-type carbapenemases) and metallo-β-lactamases (MBL). CFDC and comparator activities were analyzed against Enterobacterales (ENT), including molecularly characterized isolates, as part of the US SENTRY Antimicrobial Surveillance Program.

Methods
11,884 ENT were collected from 33 sites in the USA in 2020–2022. Susceptibility (S) testing was performed by broth microdilution. CFDC testing utilized iron-depleted media. CLSI breakpoints were used. E. coli, K. pneumoniae, and P. mirabilis with ceftriaxone, ceftazidime, or aztreonam MIC ≥ 2 μg/mL plus any ENT displaying an MIC ≥ 2 μg/mL for imipenem (excluding P. mirabilis, P. penneri, and indole-positive Proteeae) or meropenem (MER) were subjected to genome sequencing and screening of β-lactamase genes.

Results
CFDC (99.8%S), imipenem-relebactam (IMR; 98.0%S), meropenem-vaborbactam (MEV; 100%S), and ceftazidime-avibactam (CZA; 100%S) were active against carbapenem-susceptible ENT that carried ESBL and/or AmpC genes (Table). CFDC (MIC50/90, 0.5/4 μg/mL; 97.6%S) and CZA (MIC50/90, 1/8 μg/mL; 91.5%S) were the most active agents against carbapenem-nonS isolates, whereas IMR (MIC50/90, 0.25/4 μg/mL; 81.2%S) and MEV (MIC50/90, 0.12/8 μg/mL; 87.9%S) had suboptimal activity. CFDC (MIC50/90, 0.5/4 μg/mL), IMR (MIC50/90, 0.12/0.5 μg/mL), MEV (MIC50/90, 0.03/1 μg/mL), and CZA (MIC50/90, 1/2 μg/mL) were active (98.7–100%S) against the KPC subset. CFDC (MIC, 2/4 μg/mL; 90.9%S) was also active against ENT carrying MBL genes, whereas CFDC (MIC, 0.5-2 μg/mL; 100%S) and CZA (0.5-4 μg/mL; 100%S) were active against isolates carrying blaOXA-48–like.

Conclusion
CFDC activity against ENT was consistent, regardless of isolate phenotypes or genotypes, including against isolates carrying carbapenemase genes other than blaKPC, where approved β-lactam/β-lactamase inhibitor combinations showed limited activity. These data emphasize CFDC as an important option for the treatment of infections caused by ENT and resistant subsets.

Disclosures
Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support John H. Kimbrough, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Dee Shortridge, PhD, Melinta: Grant/Research Support|Shionogi: Grant/Research Support Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support