RCT Cefiderocol vs BAT for Treatment of Gram Negative BSI

Infections with antibiotic resistant bacteria cause a significant burden of disease worldwide. Bloodstream infections may arise from a variety of sources, are commonly encountered in clinical practice, and are associated with significant morbidity and mortality. Antibiotics that have activity against a broad spectrum of pathogens are commonly suggested in treatment guidelines to adequately cover bloodstream infections. Increasing rates of resistance to antibiotics commonly used for bloodstream infection are problematic and may lead to initial empiric therapy not having activity against the pathogen isolated. In patients with bloodstream infections and sepsis, delay until the receipt of effective therapy is associated with an increase in mortality. Increasing rates of antibiotic resistance in Gram-negative organisms due to the presence of extended spectrum beta lactamases (ESBL), hyperproduction of AmpC enzymes, carbapenemases and other mechanisms of resistance are identified in common hospital and healthcare associated pathogens including Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. Uncommonly, Gram-negative organisms such as Klebsiella pneumoniae and, in tropical areas such as south-east Asia and northern Australia, Burkholderia pseudomallei can cause severe community-acquired pneumonia resulting in bloodstream infection. Cefiderocol (previously S-649266) is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. The catechol side chain enables ferric iron ion binding, and the resulting complex of cefiderocol and iron ions is actively transported into bacteria via ferric iron transporter systems with subsequent destruction of cell wall synthesis. Cefiderocol has been shown to be potent in vitro against a broad range of Gram-negative organisms, including carbapenem-resistant Enterobacteriaceae (CRE) and multi-drug resistant (MDR) P. aeruginosa and A. baumannii . This activity is considered to be due to not only efficient uptake via the active siderophore systems but also the high stability of cefiderocol against carbapenemase hydrolysis. Limited in vitro data suggests cefiderocol may have activity against B. pseudomallei. Recent clinical data has shown cefiderocol to be effective in the setting of complicated urinary tract infections , including patients with concomitant bacteremia. A study examining the use of cefiderocol in the setting of infections caused by carbapenem-resistant organisms is currently underway, as is a study of cefiderocol for hospital acquired pneumonia (ClinicalTrials.gov NCT02714595 \& NCT03032380). Given the broad spectrum of activity against Gram-negative organisms, including those with resistant phenotypes, cefiderocol may be an ideal agent for empiric use in the setting of bloodstream infections acquired in the hospital or healthcare setting but as yet no clinical trial has examined this.