642. In Vitro Activity of Cefiderocol and Comparator Agents Against Molecularly Characterized Enterobacterales Clinical Isolates Causing Infection in United States Hospitals (2020-2021)
Authors: Mendes Rodrigo E , Kimbrough John H , Kantro Valerie , Shortridge Dee , Sader Helio S , Streit Jennifer M , Castanheira Mariana 
Published: December 2022

Abstract

Background
Cefiderocol (CFDC) is a siderophore cephalosporin that hijacks the Gram-negative bacteria iron transport system 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 SENTRY Antimicrobial Surveillance Program in the USA.

Methods
8,328 ENT were collected from 32 sites in 2020-2021. Susceptibility testing was performed by broth microdilution. CFDC testing used iron-depleted media. CLSI breakpoints were used. E. coli, K. pneumoniae, and P. mirabilis with ceftriaxone, ceftazidime, or aztreonam MIC ≥2 μg/mL, and any ENT displaying MIC ≥2 μg/mL for imipenem (excluded for P. mirabilis, P. penneri, and indole-positive Proteeae) or meropenem (MER), were subjected to genome sequencing and screening of β-lactamase genes.

Results
In general, CFDC (≥ 99.9% susceptible [S]), imipenem-relebactam (IMR; 99.4-100%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; 98.4%S) and CZA (MIC50/90, 1/8 μg/mL; 91.2%S) were the most active agents against carbapenem-nonS isolates, whereas IMR (MIC50/90, 0.25/4 μg/mL; 81.6%S) and MEV (MIC50/90, 0.12/8 μg/mL; 86.4%S) had suboptimal activity. CFDC (MIC50/90, 0.5/2 μg/mL), IMR (MIC50/90, 0.12/0.5 μg/mL), MEV (MIC50/90, 0.03/0.5 μg/mL), and CZA (MIC50/90, 1/2 μg/mL) were active (100%S) against the KPC subset. CFDC (MIC, 0.5-4 μg/mL; 100%S) was also active against ENT carrying MBL genes, whereas CFDC (MIC, 0.5-2 μg/mL; 100%S) and CZA (1-4 μg/mL; 100%S) were active against isolates carrying blaOXA-48-like.

Conclusion
CFDC activity was consistent, regardless of 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 reinforce 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|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Office for Assistant Secretary of Defense for Health Affairs: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support|Spero Therapeutics: Grant/Research Support John H. Kimbrough, PhD, AbbVie: Grant/Research Support|GSK: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: Grant/Research Support Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support Helio S. Sader, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Pfizer: Grant/Research Support Jennifer M. Streit, BS, MT(ASCP), Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.