Study on the Combination of Cefiderocol and Tetracycline Analogues for Treating Carbapenem-Resistant Acinetobacter baumannii

Academic Background

Carbapenem-resistant Acinetobacter baumannii (CR-AB) is one of the major pathogens responsible for hospital-acquired infections, often leading to severe conditions such as ventilator-associated pneumonia, meningitis, peritonitis, and bacteremia. Due to its multidrug resistance (MDR), particularly to carbapenem antibiotics, treatment options for CR-AB infections are extremely limited, and the associated mortality rates are high. In recent years, the emergence of novel antibiotics such as cefiderocol (a siderophore cephalosporin) and new tetracycline analogues (e.g., eravacycline and omadacycline) has provided new hope for treating CR-AB infections. However, the synergistic effects of combining cefiderocol with tetracycline analogues have not been thoroughly investigated. Therefore, this study aimed to evaluate the in vitro and in vivo synergistic antibacterial activity of cefiderocol in combination with tetracycline analogues against CR-AB.

Source of the Paper

This paper was co-authored by Yuhan Yin, Na Xu, and Xinjie Wang from the Department of Respiratory Medicine at Anqiu People’s Hospital and Handan Hospital of Traditional Chinese Medicine in China. The paper was submitted on July 22, 2024, revised, and accepted on December 14, 2024. It was published in The Journal of Antibiotics with the DOI 10.1038/s41429-024-00801-8.

Research Process and Results

1. Bacterial Strains and Carbapenemase Gene Detection

The study first collected 48 clinical isolates of CR-AB from non-duplicate patients with ventilator-associated pneumonia between 2018 and 2022. All strains were screened for eight common carbapenemase genes (e.g., OXA-23, OXA-48, OXA-51) using PCR. The results showed that all 48 isolates carried the blaOXA-51 gene, with 43 also harboring the blaOXA-23 gene. No other carbapenemase genes were detected.

2. Antimicrobial Susceptibility Testing and Checkerboard Synergy Analysis

The study used iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) for cefiderocol susceptibility testing, while the minimum inhibitory concentration (MIC) for other antibiotics was determined using CAMHB. The checkerboard method was employed to evaluate the synergistic effects of cefiderocol combined with tetracycline analogues (minocycline, tigecycline, eravacycline, and omadacycline). The results showed that the combination of cefiderocol and eravacycline exhibited the most significant synergy, with 50% of the isolates showing synergistic effects (FICI ≤ 0.5). The synergistic rates for cefiderocol combined with minocycline, tigecycline, and omadacycline were 35.4%, 33.3%, and 37.5%, respectively. None of the combinations exhibited antagonistic effects.

3. Time-Kill Assays

The study further assessed the bactericidal effects of cefiderocol combined with tetracycline analogues using time-kill assays. The results demonstrated that the combination of cefiderocol and eravacycline exhibited bactericidal activity (≥3 log10 CFU/mL reduction) in 8 isolates, while the combination of cefiderocol and tigecycline showed bactericidal activity in 5 isolates. No bactericidal activity was observed for the combinations of cefiderocol with minocycline or omadacycline.

4. Neutropenic Murine Thigh Infection Model

To validate the in vitro results, the study evaluated the in vivo efficacy of cefiderocol combined with tetracycline analogues using a neutropenic murine thigh infection model. The results showed that for the AB-2 isolate, which was susceptible to minocycline, combination therapy reduced bacterial counts by nearly 2 log10 CFU/thigh. For the AB-26 isolate, which was resistant to minocycline, the combination of cefiderocol and eravacycline still reduced bacterial counts by nearly 2 log10 CFU/thigh, while other combination therapies resulted in less than 1 log10 CFU/thigh reduction.

Conclusions and Significance

This study demonstrated that the combination of cefiderocol and tetracycline analogues exhibits synergistic antibacterial activity both in vitro and in vivo, with the combination of cefiderocol and eravacycline showing particularly significant synergy. These findings provide a new therapeutic strategy for treating CR-AB infections, especially in cases involving multidrug-resistant strains, where combination therapy may be more effective than monotherapy. Additionally, the study highlighted the potential of eravacycline in treating CR-AB infections, as its MIC values were generally lower than those of other tetracycline analogues.

Research Highlights

1. Discovery of Synergy: The combination of cefiderocol and eravacycline showed synergistic effects in 50% of CR-AB isolates, offering a new option for clinical treatment.
2. In Vivo Validation: The results of in vitro experiments were validated using a murine model, further supporting the feasibility of combination therapy.
3. Potential of Eravacycline: Eravacycline demonstrated lower MIC values in treating CR-AB infections, indicating its potential as a key drug for such infections.

Additional Valuable Information

The study also noted that although cefiderocol monotherapy exhibited strong antibacterial activity in vitro, bacterial regrowth was observed in time-kill assays, suggesting that monotherapy may not completely eradicate the bacteria. Therefore, combination therapy may be a more effective strategy. Furthermore, the study emphasized the need for further research into the combination of cefiderocol with other antibiotics to address the challenges posed by CR-AB infections.

---

Through this study, we have gained a deeper understanding of the combination of cefiderocol and tetracycline analogues for treating CR-AB infections, providing new insights for clinical practice. Future clinical studies and in vitro/in vivo experiments will further validate the clinical application value of these findings.