609. In vivo efficacy of human simulated exposures of cefiderocol (FDC) in combination with ceftazidime/avibactam (CZA) or meropenem (MEM) using in a 72 hour murine thigh infection model
Authors: Gill Christian M , Santini Debora , Takemura Miki , Longshaw Christopher M , Yamano Yoshinori , Echols Roger , Echols Roger , Echols Roger , Nicolau David P 
Published: December 2022

Abstract

Background
Acinetobacter baumannii continues to challenge clinicians as multi-drug resistance limits therapeutic options. CFDC possesses potent in vitro and in vivo activity however combination therapy has been recommended for A. baumannii due to its propensity for multiple resistance mechanisms. The present study utilized clinically relevant exposures of CFDC (2 g IV q8h 3 h infusion) in combination with CZA (2.5 g IV q8h 2 h infusion) or MEM (2 g IV q8h 3h infusion) to evaluate the bactericidal activity and resistance prevention.

Methods
15 clinical A. baumannii with the following FDC MICs were assessed: 2 mg/L, n = 3; 8 mg/L, n = 2; ≥ 32 mg/L, n = 10). CZA MICs ranged from 16 - &gt;64 mg/L while MEM MICs ranged from 4 - &gt;64 mg/L. Groups of 6 mice received sham control, CFDC HSR, CFDC + CZA HSR, or CFDC + MEM HSR for 72 h. 1 thigh per mouse was harvested to elucidated bacterial burden at 0 h (baseline) and at 72 h (or when the animal succumbed to infection). Efficacy of the combinations was assessed as change in log10 CFU/thigh relative to CFDC HSR. Development of resistance was defined as &gt; 4 fold increase in MIC relative to that from control animals.

Results
Untreated controls resulted in robust growth (3.48±0.67). Against isolates with CFDC MICs of 2 mg/L, 2/3 reached 1-log10 kill with CFDC HSR relative to baseline compared with 1/2 and 0/10 isolates with FDC MICs of 8 mg/L and ≥ 32 mg/L, respectively. Against all 15 isolates, CFDC + CZA HSR produced significant kill with a mean -4.77±1.93 reduction in log10 CFU/thigh relative to CFDC treated mice (15/15 ≥1-log10 kill relative to baseline). Similarly, CFDC + MEM HSR produced a mean reduction of -4.13±2.50 relative to CFDC treated mice (12/15 ≥1-log10 kill relative to baseline). Elevated MICs in CFDC treated animals occurred in 3/3 isolates with baseline MICs of 2 mg/L. Of these isolates, 1 developed elevated MICs with CFDC + CZA HSR compared with no isolates with CFDC + MEM HSR. Figure 1.
Change in log10 CFU/thigh relative to 0 h control after treatment with cefiderocol HSR, cefiderocol + ceftazidime/avibactam HSR, or cefiderocol + meropenem HSR in the 72 h murine thigh infection model. Cefiderocol MICs are displayed in parentheses.

Conclusion
The present study using clinical exposures of CFDC, CZA, and MEM suggest the enhanced microbiologic activity of these combinations relative to CFDC alone. Combinations also prevented the development of elevated MICs against 2/3 and 3/3 susceptible isolates with CFDC + CZA and CFDC + MEM, respectively. These data support the clinical evaluation of such combinations against A. baumannii with high CFDC MICs.

Disclosures
Christian M. Gill, PharmD, Shionogi: Grant/Research Support Miki Takemura, n/a, Shionogi: Employee Christopher M. Longshaw, PhD, Shionogi: Employee Yoshinori Yamano, PhD, Shionogi: Employee Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant David P. Nicolau, PharmD, Shionogi: Grant/Research Support.