Cefiderocol in Treating Critically Ill Patients with Carbapenem-Resistant Gram-negative Bacterial Infections

Thomas Lodise PharmD, PhD, a professor at the Albany College of Pharmacy and Health Sciences, actively researching the relationship between antibiotic exposure and patient response, shared insights into the study. He serves as a clinical pharmacy specialist at the Stratton VA Medical Center.

Analysis of the study revealed that patients administered cefiderocol achieved an overall clinical success rate of 84.3%, as defined by a composite of clinical cure and survival at Day 28. Additionally, the 28-day all-cause mortality rate stood at 21.5%.

Lodise emphasizes, “patients with infections every hour matters, when you delay therapy, you see a decrease in clinical response and an increase in mortality. But probably the thing that really struck me the most in this study is a high proportion of these individuals had resistance, and in fact a resistant gram-negative infection to other commonly used agents for carbapenem-resistant gram-negative infections.”

Respiratory tract infections were the most common (47.9%), primarily attributed to pathogens such as Pseudomonas aeruginosa (66.7%), Klebsiella pneumoniae (10.0%), and Stenotrophomonas maltophilia (7.7%), and 19.5% of patients presented with polymicrobial infections.

“In patients who receive cefiderocol within 3 days of infection, those who have less than 3 days of other antibiotics clinical success was 89.1% and mortality was 16.4%,” according to Lodise. “In contrast, those who receive other antibiotics for 7 days or more clinical success was 77% and mortality at 28 days was 28.7%.”

The study included 261 critically ill adult patients facing limited treatment options, with 64.8% exhibiting resistance to all tested antibiotics and 44.4% experiencing treatment failure with previous regimens.

According to Lodise, “nearly 2/3 of these people were admitted to the ICU (intensive care unit), nearly 1/2 were on mechanical ventilation, a 1/3 had septic shock, and interesting a 1/4 were on renal replacement therapy.”

Include, patients presented with various comorbidities, including immunosuppression (30.3%), solid or hematological tumors (23.8%), diabetes (22.2%), transplant (20.7%), chronic renal disease (13.0%), and chronic obstructive pulmonary disease (10.3%).

Cefiderocol, marketed as Fetcroja in Europe and Fetroja in the US and Japan, is indicated for treating infections caused by susceptible Gram-negative microorganisms in adults with limited treatment options. In the US, its indications include hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, and complicated urinary tract infections. Notably, in Japan, cefiderocol received approval for various diseases caused by strains resistant to carbapenem antibiotics among sensitive strains of specific bacteria.

“What distinguishes cefiderocol from other cephalosporin antibiotics is its unique molecular structure that takes advantage of bacteria's need for iron to survive,” according to Lodise. “You may or may not be aware that bacteria require iron for survival. And one of our host responses in patients with infections is our macrophages, you know, kind of release lactoferrin, which kind of binds up all available iron, creating an iron-deficient environment.”

While generally well-tolerated, cefiderocol comes with warnings, including an observed increase in all-cause mortality in patients with carbapenem-resistant Gram-negative bacterial infections compared to those treated with the best available therapy. Other cautions include hypersensitivity reactions, C diff-associated diarrhea, CNS adverse reactions, and the development of drug-resistant bacteria.

Overall, cefiderocol demonstrated favorable tolerability, with only 6 patients experiencing adverse drug reactions out of the 261 included in the study. However, clinicians are advised to consider the associated warnings and precautions when prescribing cefiderocol carefully.

References

Shionogi & Co, revealed groundbreaking findings from the largest European real-world evidence study, PERSEUS, at ESCMID running from April 27 to April 30, 2024. https://www.shionogi.com/us/en/news/2024/04/escmid-global-2024-shionogi-presents-real-world-data-demonstrating-efficacy-of-fetcroja-fetroja-cefiderocol-in-critically-ill-patients-with-certain-difficult-to-treat-bacterial-infections.html