cefiderocol and Bacterial-Infections

The aim of this study was to investigate the clinical efficacy and safety of cefiderocol in the treatment of acute bacterial infections.. The PubMed, Embase and Cochrane Library databases as well as the clinical trials registries of ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched up to 8 November 2020. Only randomised controlled trials (RCTs) that compared the treatment efficacy of cefiderocol with that of other antibiotics for adult patients with acute bacterial infections were included in this meta-analysis. The primary outcome was clinical response at test of cure (TOC).. Three RCTs, including one phase 2 and two phase 3 trials, were included. No significant difference in clinical response rate was observed between cefiderocol and comparators [odds ratio (OR)=1.04]. In a subgroup analysis, no significant difference was observed in the clinical response at TOC between cefiderocol and comparators in patients with nosocomial pneumonia (OR=0.92) or complicated urinary tract infection (OR=1.28). In addition, all-cause mortality at Days 14 and 28 did not differ between the cefiderocol and control groups (14-day mortality, OR=1.25; 28-day mortality, OR=1.12). Furthermore, cefiderocol was associated with similar microbiological response to comparators at the TOC assessment (OR=1.44). Finally, cefiderocol was associated with a similar risk of adverse events as comparators.. Cefiderocol can achieve similar clinical and microbiological responses as comparators for patients with serious bacterial infections. In addition, cefiderocol shares a safety profile similar to that of comparators.

Topics: Adult; Anti-Bacterial Agents; Bacterial Infections; Cefiderocol; Cephalosporins; Humans; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Abscess; Anti-Bacterial Agents; Bacteremia; Bacterial Infections; Cefiderocol; Cephalosporins; Compassionate Use Trials; Drug Resistance, Multiple, Bacterial; Humans; Klebsiella pneumoniae; Male; Middle Aged; Pancreatitis; Pseudomonas aeruginosa; Staphylococcus aureus; Treatment Outcome

Topics: Bacterial Infections; Cefiderocol; Cephalosporins; Humans; Treatment Outcome

Iron is an essential nutrient for bacterial growth, replication, and metabolism. Humans store iron bound to various proteins such as hemoglobin, haptoglobin, transferrin, ferritin, and lactoferrin, limiting the availability of free iron for pathogenic bacteria. However, bacteria have developed various mechanisms to sequester or scavenge iron from the host environment. Iron can be taken up by means of active transport systems that consist of bacterial small molecule siderophores, outer membrane siderophore receptors, the TonB-ExbBD energy-transducing proteins coupling the outer and the inner membranes, and inner membrane transporters. Some bacteria also express outer membrane receptors for iron-binding proteins of the host and extract iron directly from these for uptake. Ultimately, iron is acquired and transported into the bacterial cytoplasm. The siderophores are small molecules produced and released by nearly all bacterial species and are classified according to the chemical nature of their iron-chelating group (ie, catechol, hydroxamate, α-hydroxyl-carboxylate, or mixed types). Siderophore-conjugated antibiotics that exploit such iron-transport systems are under development for the treatment of infections caused by gram-negative bacteria. Despite demonstrating high in vitro potency against pathogenic multidrug-resistant bacteria, further development of several candidates had stopped due to apparent adaptive resistance during exposure, lack of consistent in vivo efficacy, or emergence of side effects in the host. However, cefiderocol, with an optimized structure, has advanced and has been investigated in phase 1 to 3 clinical trials. This article discusses the mechanisms implicated in iron uptake and the challenges associated with the design and utilization of siderophore-mimicking antibiotics.

Topics: Bacterial Infections; beta-Lactams; Cefiderocol; Cephalosporins; Drug Design; Drug Development; Drug Resistance, Bacterial; Gram-Negative Bacteria; Humans; Iron; Models, Molecular; Siderophores