313. Genomic Features Associated with Non-susceptibility to Cefiderocol in Pseudomonas aeruginosa and Cross-resistance to Novel β-lactam/β-lactamase Inhibitors in the Prospective Observational Pseudomonas (POP) study
Authors: Egge Stephanie L , Thornton Phillip C , Flores Erika , de Paula Baptista Rodrigo , Clarke Karim , Arias Cesar A , Tam Vincent , Satlin Michael J , Miller William R 
Published: January 2025

Abstract

Background
Cefiderocol (FDC) is a last-line agent used to treat carbapenem-resistant P. aeruginosa (CR-PA). We evaluated the prevalence of FDC heteroresistance (hR) and non-susceptibility (NS) in the POP cohort and associations with genes previously related to FDC resistance.Figure 1.Proportion of isolates harboring genomic feature by geographic region (US vs non-US).

Methods
972 genomes from the multicenter, global POP study were screened for mutations in genes implicated in decreased FDC susceptibility: ampC, pirR, pirS, pirA, piuA/D, ftsI, cpxS and exogenous β-lactamases. A representative population was selected to encompass all variants as well as controls obtained by phylogenetically mapping each mutant isolate with a closest non-mutant isolate (n=187). All strains were assessed by broth microdilution (BMD) and population analysis profile (PAP). FDC NS was defined as minimum inhibitory concentration (MIC) ≥ 8 μg/m. hR was determined by PAP area under the curve &gt; 80, per the 99% confidence interval for PAO1. Chi-squared test was used to assess correlation of ceftolozane-tazobactam (C/T), ceftazidime-avibactam (CZA), and imipenem-relebactam (IMR) categorization and FDC hR/NS as well as gene correlations with FDC hR/NS and geographic region of the isolate.

Association between FDC phenotype and MIC category of novel β-lactam/β-lactamase inhibitor combinations.

Results
Over 20% of isolates displayed a NS or hR FDC phenotype (n=39: 28 hR, 11 MIC ≥ 8 μg/mL), equally distributed among US and non-US isolates (Fig 1, P =0.36). Isolates with increased C/T, CZA, and IMR MICs were more likely to be FDC NS or hR (Tbl 1). IMR susceptibility was low across FDC NS, hR and susceptible cohorts. The combination of mutations in both ampC and the PirRS system demonstrated higher risk for FDC NS or hR (Tbl 2, P = 0.0003), but isolated mutations in either ampC or PirRS did not increase risk for FDC NS or hR. VEB and NDM β-lactamases were present in non-US isolates and their presence correlated with FDC NS or hR (Tbl 2, P = 0.0003, 0.0017). Mutations in the PirRS system showed a geographic predisposition in US isolates (Fig 1, P= 0.0047), while exogenous β-lactamases were associated with international isolates (P &lt; 0.0001).

Genotypic determinants associated with FDC susceptibility phenotype.

Conclusion
NS and hR to FDC is prevalent globally among CR-PA and is associated with reduced C/T, CZA, and IMR susceptibility. NS and hR isolates were associated with mutations in ampC, pirRS, and the exogenous β-lactamases VEB, NDM. Further studies are needed to define clinical significance of FDC hR.

Disclosures
Cesar A. Arias, MD, MSc, PhD, UpToDate, Inc.: Royalties Vincent Tam, Pharm. D., AbbVie Inc: Advisor/Consultant Michael J. Satlin, MD, AbbVie: DSMB participant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Selux Diagnostics: Grant/Research Support|SNIPRBiome: Grant/Research Support William R. Miller, M.D., Merck: Grant/Research Support|UptoDate: Royalties