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

Abstract

Acinetobacter baumannii is a nosocomial pathogen notorious for rapidly acquiring resistance to nearly all antibiotics, including last-line agents. Cefiderocol (FDC) is a novel siderophore cephalosporin antibiotic with in vitro activity against A. baumannii that is now used clinically, but resistance is emerging. There is limited data regarding FDC-containing antibiotic combinations with synergistic activity against A. baumannii, which may increase the potency of the drug and reduce resistance development. In this study, we evaluated the activity of FDC alone and in combination with other antibiotics against 21 extensively drug-resistant (XDR) and pandrug-resistant (PDR) A. baumannii clinical isolates. FDC possesses strong in vitro activity and was highly effective in combination with ceftazidime-avibactam (CAZ-AVI) and sulbactam-durlobactam (SUL-DUR), as well as amikacin, doxycycline, and sulbactam. We also identified several FDC-containing combinations effective against a metallo-{beta}-lactamase (MBL)-producing strain. Previously, we performed whole genome sequencing on selected strains in our collection, allowing for the identification of resistance genes and mechanisms associated with susceptibility patterns and synergy outcomes. These findings highlight promising FDC-based combinations for treating highly drug-resistant A. baumannii infections and provide insight into the genetic basis of FDC resistance and response. Author SummaryAcinetobacter baumannii is a frequent cause of hospital-acquired pneumonia, and bloodstream and wound infections in vulnerable populations, such as those who are critically ill or immunocompromised. Infections caused by A. baumannii are a growing problem in hospitals around the world, especially because of increasing resistance to almost all available antibiotics. Physicians have few treatment options available, which leads to high mortality rates. One newer antibiotic, cefiderocol, has shown promise against these infections, but resistance to this drug is already emerging. In our study, we looked for combinations of cefiderocol with other traditional and newly available antibiotics that work better together than alone. We tested these combinations against over 20 highly drug-resistant strains isolated from patients, including one strain that produces a strong resistance enzyme called NDM-1. We found that pairing cefiderocol with certain drugs, especially ceftazidime-avibactam, sulbactam-durlobactam, amikacin, and doxycycline, often worked significantly better than using cefiderocol alone. These combinations were able to prevent the growth of even the most resistant strains in our collection. Our work highlights new potential treatment options that physicians may use in the future to help patients with these dangerous, life-threatening infections, especially when standard antibiotics are no longer effective.