Cefiderocol is a novel siderophore cephalosporin antibiotic with excellent stability against nearly all β-lactamases, including metalloenzymes. It has demonstrated good clinical efficacy against infections caused by carbapenem-resistant Gram-negative bacteria (CRO), garnering significant attention from experts in the field of infectious diseases. At the 34th European Congress of Clinical Microbiology and Infectious Diseases (ESCMID Global 2024), a multicenter, open-label randomized study (abstract number: O0810) compared the efficacy of cefiderocol with standard therapy in treating healthcare-associated and hospital-acquired Gram-negative bloodstream infections (BSI). "Infectious Disease Frontier" invited Professor YongHong Xiao from The First Affiliated Hospital of Zhejiang University School of Medicine to provide professional commentary on this study, analyzing the potential and prospects of cefiderocol in treating Gram-negative BSI.Study Overview
Investigator-driven randomized controlled trial of cefiderocol versus standard therapy for healthcare-associated and hospital-acquired Gram-negative bloodstream infections (GAMECHANGER) (abstract number: O0810)
Background
Cefiderocol exhibits in vitro activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, having received approval from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). However, its efficacy in treating bloodstream infections (BSI) is still uncertain. Researchers conducted a multicenter, open-label randomized trial (NCT03869437) aimed at comparing cefiderocol with standard therapy (SOC) antibiotics in patients with hospital-acquired or healthcare-associated Gram-negative BSI.
Methods
The study recruited adult patients from 17 centers across 6 countries. Participants were randomly assigned in a 1:1 ratio to receive cefiderocol (2 g, administered over 3 hours, with dosing frequency adjusted according to renal function) or SOC determined by the treatment team within 48 hours of initial blood culture collection. The primary outcome was the all-cause mortality at 14 days. Secondary outcomes included 30-day and 90-day mortality, 14-day clinical and microbiological failure, 90-day microbiological failure, and colonization or infection with MDR bacteria or difficult-to-treat Clostridioides difficile infection. It was hypothesized that cefiderocol would be non-inferior to SOC, with a non-inferiority margin of 10% for the primary outcome.
Results
Among 9,144 screened patients, a total of 513 patients were included. The primary analysis population comprised 504 patients (cefiderocol group: 250 patients, SOC group: 254 patients).
BSI had diverse sources, including urinary tract infections (19%), intravascular catheter-related infections (18%), intra-abdominal infections (17%), and pneumonia (12%). Fifty-nine percent of patients were immunocompromised, with 21% having hematologic malignancies. Eleven percent of BSIs were polymicrobial. The most commonly isolated strains from blood cultures were Escherichia coli (33%), Klebsiella pneumoniae (30%), Pseudomonas spp. (11%), and Acinetobacter spp. (8%). One hundred twenty-one out of 504 patients (24%) were infected with at least one carbapenem-resistant strain identified by the microbiology laboratory of the participating institution.
In the cefiderocol group and SOC group, 20/250 (8.0%) and 17/254 (6.7%) patients, respectively, died within 14 days, meeting the primary outcome (risk difference 1.3%, 95% CI: -3.2 to 5.9; RR 1.20, 95% CI: 0.64 to 2.23), demonstrating non-inferiority.
Conclusion
Cefiderocol treatment for healthcare-associated or hospital-acquired Gram-negative BSI is non-inferior to SOC.
Expert Commentary
Cefiderocol, as a novel siderophore cephalosporin antibiotic, has shown good antibacterial activity against drug-resistant Gram-negative bacteria. It has been approved in the United States and the European Union for the treatment of complicated urinary tract infections, and its potential in treating BSI is also highly anticipated. Gram-negative BSI poses a serious threat to patient safety, highlighting the necessity for in-depth clinical research to explore safer and more effective treatment options.
This study employed an open-label rather than a blinded design, which may have introduced some bias to the study results. However, its multicenter, randomized controlled trial design still reflects a high level of scientific rigor. The study screened over 9,000 patients, with 504 patients ultimately included in the primary analysis. The study’s primary endpoint was the 14-day all-cause mortality, with secondary endpoints including 30-day and 90-day mortality rates and rates of clinical and microbiological failure at 14 and 90 days, as well as colonization or infection with MDR bacteria. The most common source of BSI was urinary tract infection, followed by intravascular catheter-related infections, intra-abdominal infections, and pulmonary infections. More than half of the patients were immunocompromised, with 21% being patients with hematologic malignancies. Regarding the distribution of BSI pathogens, Enterobacterales were the most common (Escherichia coli: 33%, Klebsiella pneumoniae: 30%), followed by Pseudomonas spp. (11%) and Acinetobacter spp. (8%).
It is noteworthy that only 24% of patients in the study were infected with bacteria resistant to carbapenems, and detailed data on this subgroup have not yet been disclosed, which somewhat limits our understanding of the effectiveness of cefiderocol in treating infections caused by specific resistant strains. Additionally, because SOC treatment regimens vary between countries and institutions, this could also impact the study results. Furthermore, more data on the treatment outcomes of infections caused by bacteria with different resistance mechanisms, such as strains producing KPC or metalloenzymes, have not been disclosed.
Cefiderocol is a cephalosporin antibiotic targeting drug-resistant bacteria, and this study focused on BSI caused by all Gram-negative bacteria, including many infections caused by susceptible strains or strains producing extended-spectrum β-lactamases (ESBL), for which cefiderocol may not be the first choice. Particularly in cases where Gram-negative bacterial infection is already confirmed within 48 hours of hospitalization, the use of cefiderocol seems to lack sufficient rationale.
We look forward to the researchers disclosing more relevant data, especially regarding subgroup analysis of carbapenem-resistant strains, which will help to more accurately assess the clinical value of cefiderocol. Moreover, since the study did not include data from medical institutions in mainland China, the applicability of its results is somewhat limited. We hope that future studies will cover a wider range of regions to provide more comprehensive and representative information.
Overall, this study provides valuable data on cefiderocol’s treatment of Gram-negative BSI, but its specific value and scope of application still require more support and validation from additional data. We anticipate the research team to further disclose detailed information for a more in-depth and comprehensive assessment of the study results.
Professor Xiao Yonghong, MD, PhD, is a professor, chief physician, and doctoral supervisor at the First Affiliated Hospital of Zhejiang University School of Medicine. He serves as the Deputy Director of the National Key Laboratory for Diagnosis and Treatment of Infectious Diseases, and as a WHO/WPRO consultant on antimicrobial resistance control. Additionally, he holds positions as a board member of the International Society of Chemotherapy, the Global Chinese Society of Microbiology and Infection, and the Western Pacific Association of Clinical Microbiology and Infection. He is also a member of various committees including the National Health Commission’s Expert Committee on Rational Drug Use and the Expert Committee on Pharmacy and Drug Therapy. Professor Xiao is extensively involved in academic and professional organizations, including being Vice Chairman of the Antibacterial Stewardship Committee of the Chinese Hospital Association, a standing committee member of the Chinese Medical Association’s Branch of Infectious Diseases, and a standing committee member of the Chinese Medical Association’s Branch of Bacterial and Fungal Infections. He has led numerous research projects funded by national and provincial grants, authored over 450 papers, including over 120 SCI-indexed articles, and edited or contributed to more than 30 books. For his contributions, he has received awards such as the First Prize of Provincial Natural Science Award and two Provincial Science and Technology Progress Awards. Professor Xiao is the founder of the National Bacterial Resistance Monitoring Network and a founding member of the BRICS Alliance. He is also the chief editor of the “National Antimicrobial Therapy Guidelines.”
