146. Heteroresistance to cefiderocol among <i>Pseudomonas aeruginosa</i> clinical isolates harboring changes in TonB-dependent receptor pathways and AmpC

Abstract Background Cefiderocol (FDC) is an iron siderophore cephalosporin with activity against multi-drug resistant (MDR) Gram-negative bacteria. Despite high rates of in vitro susceptibility, treatment failure the emergence resistance still a concern. Heteroresistance, or presence sub-population strain that tests susceptible by standard methods, has been suggested as potential mechanism for this observation. Previously, we showed MDR Pseudomonas aeruginosa (PA) changes transporters (TBDR) responsible FDC uptake had decreased zone diameters on Kirby-Bauer (KB) testing compared to MDR-PA wild-type TBDRs. Here, investigated prevalence heteroresistance (HR) among TBDR mutants using population analysis profile-area under curve assay (PAP). Table 1.Pseudomonas characteristicsFigure 1.PAP-AUC results v. non-mutant controls Methods Previously sequenced isolates were selected mutations genes within primary import pathways (pirA, pirRS, piuA, piuD). Isolates harboring pre-existing (n=12) P. PA01 and 5 MDR-clinical MICs performed broth microdilution (BMD) depleted media (IDM). For PAP, grown overnight IDM before serial dilution plating agar increasing concentrations FDC. Agreement between BMD, KB, PAP-AUC HR detection was assessed. Results On 10 12 tested (MIC range ≤0.5-2 µg/mL), all control MIC ≤0.5 µg/mL (Table 1). None strains per PAP (Fig However, group, 50% either (n=2) (n=4) phenotype. Resistance occurred setting both exogenous β-lactamase (OXA-15 variant) AmpC variant (PDC-205). Of isolates, one change Ω-loop (E221K), while other three only PirR frameshift mutation. BMD not able identify any isolates. Conclusion A greater number than Mutations TBDRs could be marker non-susceptibility therapeutic failure. Disclosures Cesar A. Arias, MD, PhD, Entasis Phramceuticals: Grant/Research Support|MeMed Diagnostics: Support|Merck: Support William R. Miller, Therapeutics: Support|UpToDate: Royalties - Topic Contributor.