P-1186. Pharmacodynamic Assessment of Combination of Cefiderocol with Xeruborbactam in Murine Thigh Infection Model

TL;DR

This study shows that combining cefiderocol with xeruborbactam improves bacterial killing in a mouse thigh infection model, especially against resistant strains.

Contribution

Demonstrates the enhanced efficacy of cefiderocol when combined with xeruborbactam in treating gram-negative bacterial infections.

Findings

Xeruborbactam restored cefiderocol activity against Enterobacterales and Acinetobacter baumannii with high MICs.

The combination achieved bacterial killing in all Pseudomonas aeruginosa isolates tested.

The combination was ineffective against one Acinetobacter isolate with a high MIC.

Abstract

Cefiderocol (FDC) is a siderophore-conjugated cephalosporin with potent activity against gram-negative bacteria including carbapenem-resistant strains. Higher minimum inhibitory concentrations (MICs) to FDC have been observed with isolates producing NDM- or PER/VEB-type β-lactamases together with other factors like iron transporters and PBP3 mutations. Xeruborbactam (XER) is a novel β-lactamase inhibitor that inhibits serine- and metallo-type β-lactamases. In this study, we evaluated the impact of XER on the efficacy of FDC in a murine thigh infection model.Table.Efficacy of FDC alone and in combination with XER against 19 strains in a murine thigh infection modelMICs of FDC were determined according to the 2024 CLSI guidance using iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) prepared from Chelex resin and BD-BBL Mueller-Hinton broth powder. MICs of FDC in combination with 4 µg/mL of XER were also determined using ID-CAMHB.

Efficacy of FDC alone and in combination with XER against 19 strains in a murine thigh infection model

MICs of FDC were determined according to the 2024 CLSI guidance using iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) prepared from Chelex resin and BD-BBL Mueller-Hinton broth powder. MICs of FDC in combination with 4 µg/mL of XER were also determined using ID-CAMHB.

A total of 19 isolates (6 Enterobacterales (ENT), 6 Pseudomonas aeruginosa (PA) and 7 Acinetobacter baumannii complex (ABC)) with FDC MIC values ranging from 0.5 to >32 µg/mL were used. The β-lactamase profile for each isolate was determined by PCR or whole genome sequencing. Mice were infected in the thigh and dosed subcutaneously with a humanized dosage regimen of FDC, 100 mg/kg q2h, with or without XER 20 mg/kg q2h, over 24 hours (both dosage regimens achieved 100% and 81.7% free time above MIC against 4 and 8 mg/L, respectively), starting 2 hours after inoculation. Change in viable bacterial cell counts in the thighs were determined from start to end of treatment.

In the 6 ENT strains, treatment with FDC resulted in no bacterial killing for 3 isolates with MIC values >4 µg/mL, the addition of XER resulted in bacterial killing in these isolates (Table). In the 7 ABC strains, treatment with FDC resulted in no bacterial killing for isolates with MICs >32 µg/mL, the addition of XER was able to restore the activity of FDC. FDC/XER was not effective against 1 ABC isolated with a FDC/XER MIC of 16 µg/mL. In the 6 PA isolates, treatment with FDC resulted in bacterial killing against 5 of the 6 isolates. The addition of XER resulted in bacterial killing against all 6 PA isolates.

The addition of XER significantly increased the efficacy of FDC in a murine thigh infection model against ENT and ACB.

Yoshinori Yamano, PhD, Shionogi HQ: Employee

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