514. The Impact of Xeruborbactam on <i>in vitro</i> Activity of Cefiderocol against a Panel of <i>Acinetobacter baumannii</i> Enriched in Isolates with Reduced Cefiderocol Susceptibility

Abstract Background Cefiderocol (CFDC) is a siderophore cephalosporin with potent activity against resistant gram-negative bacteria. Recent SIDERO-WT surveillance studies demonstrated potent activity of CFDC against 5,225 isolates of Acinetobacter baumannii complex (ACB) (MIC50/90=0.12/1 µg/mL; 96% susceptible using CLSI breakpoint) including 2,810 carbapenem-resistant isolates (MIC50/90=0.25/2 µg/mL; 94% susceptible). CFDC MIC values were higher (MIC50/90=4/8 µg/mL) against metallo-β-lactamase (MBL) producers (N=25 including 21 NDM producers; 0.48% of total ACB) and isolates that produced PER or VEB β-lactamase (N=103; 1.98% of total ACB; MIC50/90=128/256 µg/mL). Xeruborbactam (XER) is a novel beta-lactamase inhibitor that inhibits multiple serine-type β-lactamases (SBLs) and MBLs. In this study, we evaluated the combination of CFDC and XER against a challenge panel of ACB enriched with CFDC-resistant isolates. MIC50/90 of cefiderocol (CFDC) alone and in the presence of xeruborbactam (XER) against Acinetobacter baumannii Methods A challenge panel of 160 ACB isolates that included 59 PER- or VEB-producing and 22 NDM-producing isolates was used for this study. 144 (90%) and 136 (85%) isolates had CFDC MIC &amp;gt; 1 µg/mL (FDA non-susceptible breakpoint) and &amp;gt; 2 µg/mL (EUCAST non-susceptible PK/PD breakpoint), respectively. β-lactamases content was determined by PCR or whole genome sequencing. MICs were determined for CFDC alone and in combination with 1, 2 and 4 μg/mL of XER according to CLSI guidelines for CFDC using iron-depleted CAMHB. Results MIC50/MIC90 of CDFC alone and XER alone against 160 ACB were &amp;gt; 32/ &amp;gt; 32 and 16/ &amp;gt; 16 μg/mL, respectively. The addition of xeruborbactam at all concentrations resulted in a reduction of CFDC MICs. For the subset of 59 highly CFDC-resistant PER or VEB producers, XER at ≥ 2 µg/mL reduced CFDC MIC50/90 from &amp;gt; 32/ &amp;gt; 32 to 0.25/1 µg/mL, which is similar to MIC50/90 values observed for CFDC alone for all ACB from recent surveillance studies. XER at 4 μg/mL reduced MIC50/90 of NDM producers from 32/ &amp;gt; 32 μg/mL to 0.5/8 μg/mL. Conclusion Addition of XER significantly improved the activity of CFDC against isolates of ACB with elevated CFDC MICs. Disclosures Takafumi Hara, MSc, SHIONOGI &amp; CO., LTD.: Employee Naoki Ishibashi, MD, SHIONOGI &amp; CO., LTD.: Employee Dai Miyagawa, n/a, SHIONOGI &amp; CO., LTD.: Employee Motoyasu Onishi, PhD, Shionogi &amp; Co., Ltd.: Employee Olga Lomovskaya, PhD, Qpex Biopharma Inc.: Board Member|SHIONOGI &amp; CO., LTD.: Employee Yoshinori Yamano, PhD, Shionogi &amp; Co., Ltd.: Employee