Synergistic cefiderocol-containing antibiotic combinations active against highly drug-resistant Acinetobacter baumannii patient isolates with diverse resistance mechanisms

Abstract

Background: Acinetobacter baumannii is a nosocomial pathogen known for rapidly developing resistance to nearly all antibiotics, including last-line agents. Cefiderocol, a novel siderophore cephalosporin, has shown in vitro activity against A. baumannii and is now used clinically, but resistance is emerging. Data on cefiderocol-based antibiotic combinations are limited.

Objectives: To evaluate the in vitro activity of cefiderocol alone and in combination with other antibiotics against XDR and PDR A. baumannii clinical isolates, and to explore resistance mechanisms underlying cefiderocol synergy.

Methods: We tested 21 XDR/PDR clinical isolates and one NDM-1-producing strain using broth microdilution and checkerboard assays with cefiderocol and 17 antibiotics, including ceftazidime/avibactam, sulbactam/durlobactam, and amikacin. Synergy was determined through checkerboard assays and calculating fractional inhibitory concentration indices (FICI). WGS was used to identify resistance genes in selected strains.

Results: Cefiderocol alone was active against 66.7% of strains and demonstrated synergy with ceftazidime/avibactam and sulbactam/durlobactam in 100% and 95.2% of strains, respectively, and with amikacin, doxycycline and sulbactam in over half of strains. Cefiderocol-based combinations also reduced cefiderocol MICs against an NDM-1-producing strain. WGS revealed β-lactamases and resistance determinants among both susceptible and resistant isolates.

Conclusions: Several cefiderocol-containing combinations show strong in vitro synergy against XDR and PDR A. baumannii. These combinations, especially cefiderocol-ceftazidime/avibactam and cefiderocol-sulbactam/durlobactam, may enhance treatment of highly resistant A. baumannii strains and warrant further clinical investigation.

Figure 1.

Fractional inhibitory concentration index (FICI) values obtained from cefiderocol in combination with various antibiotics against A. baumannii strains M1–M22. FICI values in the synergistic range (≤0.5) are reported in blue; FICI values in the additive range (0.5–1.0) are reported in yellow; FICI values indicating no interaction (1.0–4.0) are reported in pink. FICI values indicating no interaction (1.0–4.0) are reported in pink.

Figure 2.

Representative checkerboard assay with cefiderocol and ceftazidime/avibactam against strain M1. Top: OD₆₀₀ measurements following 16 h of static growth at 37°C. The MIC value for ceftazidime/avibactam alone is highlighted. There is no highlighted MIC value for cefiderocol as the MIC exceeded the maximum starting concentration. No bacterial growth occurred in wells where OD₆₀₀ < 0.1, and above this cutoff, bacterial growth did occur. Bottom: FIC values were calculated for each drug (concentration/MIC) and added together for all wells where no growth was observed. Additive interactions (FICI between 0.5 and 1.0), and synergistic interactions (FICI ≤ 0.5) are indicated.

Figure 3.

Representative checkerboard assay with cefiderocol and sulbactam/durlobactam against strain M16. Top: OD₆₀₀ measurements following 16 h of static growth at 37°C. The MIC values for each drug alone are highlighted. No bacterial growth occurred in wells where OD₆₀₀ < 0.1, and above this cutoff, bacterial growth did occur. Bottom: FIC values were calculated for each drug (concentration/MIC) and added together for all wells where no growth was observed. Additive interactions (FICI between 0.5 and 1.0), and synergistic interactions (FICI ≤ 0.5) are indicated.

Figure 4.

Representative checkerboard assay with cefiderocol and amikacin against strain M6. Top: OD₆₀₀ measurements following 16 h of static growth at 37°C. The MIC values for each drug alone are highlighted. No bacterial growth occurred in wells here OD₆₀₀ < 0.1, and above this cutoff, bacterial growth did occur. Bottom: FIC values were calculated for each drug (concentration/MIC) and added together for all wells where no growth was observed. Additive interactions (FICI between 0.5 and 1.0), and synergistic interactions (FICI ≤ 0.5) are indicated.

Figure 5.

Representative checkerboard assay with cefiderocol and doxycycline against strain M11. Top: OD₆₀₀ measurements following 16 h of static growth at 37°C. The MIC values for each drug alone are highlighted. No bacterial growth occurred in wells where OD₆₀₀ < 0.1, and above this cutoff, bacterial growth did occur. Bottom: FIC values were calculated for each drug (concentration/MIC) and added together for all wells where no growth was observed. Additive interactions (FICI between 0.5 and 1.0), and synergistic interactions (FICI ≤ 0.5) are indicated.

Figure 6.

Representative checkerboard assay with cefiderocol and cefotaxime against strain BAA-3302. Top: OD₆₀₀ measurements following 16 h of static growth at 37°C. The MIC values for each drug alone are highlighted. No bacterial growth occurred in wells where OD₆₀₀ < 0.1, and above this cutoff, bacterial growth did occur. Bottom: FIC values were calculated for each drug (concentration/MIC) and added together for all wells where no growth was observed. Additive interactions (FICI between 0.5 and 1.0), and synergistic interactions (FICI ≤ 0.5) are indicated.