For carbapenem-resistant Gram-negative infections, cefiderocol had similar clinical and microbiological efficacy compared to best available therapy, according to a study published in The Lancet Infectious Diseases.
In a randomized, open-label, pathogen-focused, descriptive phase-3 study, investigators enrolled adults 18 years or older who were admitted with nosocomial pneumonia, bloodstream infections/sepsis, or complicated urinary tract infections (UTI), and had evidence of a carbapenem-resistant Gram-negative pathogen (ClinicalTrials.gov, NCT02714595). Investigators randomized patients to receive either 2 g of intravenous cefiderocol over a 3-hour infusion every 8 hours or best available therapy, pre-specified by the investigator before randomization and comprised of a maximum of three drugs, for 7 to 14 days.
Of 150 patients, 101 received cefiderocol and 49 received best available therapy. Demographic and baseline clinical characteristics were generally similar between groups. Among the intention to treat (ITT) population, 45% (n=67) had nosocomial pneumonia, 31% (n=47) had bloodstream infections or sepsis, and 25% (n=36) had complicated UTIs. Numerically in the cefiderocol group, more patients were aged 65 and older, had moderate or severe renal impairment, or was in an intensive care unit (ICU) at randomization.
Within the ITT population, 118 patients comprised the carbapenem-resistant microbiological ITT population, indicating they had at least one carbapenem-resistant pathogen at baseline. The most frequent resistant pathogens included Acinetobacter baumannii (n=54), Klebsiella pneumoniae (n=39), and Pseudomonas aeruginosa (n=22).
Rates of clinical cure in the cefiderocol group for:
- Nosocomial pneumonia: 50% (20/40; 95% CI, 33.8-66.2)
- Bloodstream infection or sepsis: 43% (10/23; 95% CI, 23.2-65.5)
- Complicated UTI: 53% (9/17; 95% CI, 27.8-77.0)
Rates of clinical cure in the best available therapy group for:
- Nosocomial pneumonia: 53% (10/19; 95% CI, 28.9-75.6)
- Bloodstream infection or sepsis: 43% (6/14; 95% CI, 17.7-71.1)
- Complicated UTI: 20% (1/5; 95% CI, 0.5-71.6)
In subgroup analyses of clinical and microbiological outcomes at test of cure, investigators observed numerical differences by age, pathogen group, region, race, and Acute Physiology and Chronic Health Evaluation II score. The composite endpoint of survival without changing antibiotic due to toxicity or absence of efficacy occurred in 63% (50/80) in the cefiderocol group and 61% (23/38) in the best available therapy group (treatment difference, 1.1%; 95% CI, -17.7 to 20.0).
Treatment-emergent adverse events were observed in 91% of patients (92/101) in the cefiderocol group and 96% of patients (47/49) in the best available therapy group. By the end of the study, 34% (34/101) of cefiderocol patients and 18% (9/49) of best available therapy patients had died.
Limitations to the study include the use of descriptive statistics only without inferential hypothesis testing, the small sample size and heterogenous population, the use of Acute Physiology and Chronic Health Evaluation II scores only as a stratification factor to balance severity of illness and several further limitations to the composite endpoint.
“[T]he patient population in this study represents a real clinical scenario with a high unmet need, and the study findings provide evidence of the efficacy and safety of cefiderocol for physicians treating such patients,” the investigators concluded.
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Bassetti M, Echols R, Matsunaga Y, et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. Published online October 12, 2020. doi: 10.1016/S1473-3099(20)30796-9.