Cefiderocol for the Treatment of Multidrug-Resistant Gram-Negative Bacteria: A Systematic Review of Currently Available Evidence

Abstract

Cefiderocol is a novel synthetic siderophore-conjugated antibiotic that hijacks the bacterial iron transport systems facilitating drug entry into cells, achieving high periplasmic concentrations. This systematic review analyzed the currently available literature on cefiderocol. It summarized in vitro susceptibility data, in vivo antimicrobial activity, pharmacokinetics/pharmacodynamics (PK/PD), clinical efficacy, safety and resistance mechanisms of cefiderocol. Cefiderocol has potent in vitro and in vivo activity against multidrug-resistant (MDR) Gram-negative bacteria, including carbapenem-resistant isolates. But New Delhi Metallo-β-lactamase (NDM)- positive isolates showed significantly higher MICs than other carbapenemase-producing Enterobacterales, with a susceptible rate of 83.4% for cefiderocol. Cefiderocol is well-tolerated, and the PK/PD target values can be achieved using a standard dose regimen or adjusted doses according to renal function. Clinical trials demonstrated that cefiderocol was non-inferiority to the comparator drugs in treating complicated urinary tract infection and nosocomial pneumonia. Case reports and series showed that cefiderocol was a promising therapeutic agent in carbapenem-resistant infections. However, resistant isolates and reduced susceptibility during treatment to cefiderocol have already been reported. In conclusion, cefiderocol is a promising powerful weapon for treating MDR recalcitrant infections.

Epidemiology, Mechanisms of Resistance and Treatment Algorithm for Infections Due to Carbapenem-Resistant Gram-Negative Bacteria: An Expert Panel Opinion

“…Susceptibility rates over 90% are also reported for OXA-23- and OXA-24-like producers. However, in vitro studies showed the MICs for New Delhi metallo-β-lactamase (NDM) positive isolates to be significantly higher than those harboring other β-lactamase genes, with a susceptibility rate of 83.4% for cefiderocol [ 90 ]; the expression of NDM appears to facilitate the emergence of cefiderocol resistance by mutations in siderophore receptors [ 91 , 92 ].…”

Resistance to Cefiderocol Involved Expression of PER-1 β-Lactamase and Downregulation of Iron Transporter System in Carbapenem-Resistant Acinetobacter baumannii

“…2 Susceptibility surveillance has revealed the potent activity of CFDC against a wide range of carbapenem-resistant gram-negative bacteria (CR-GNB), including isolates of Acinetobacter baumannii, Enterobacterales, and Pseudomonas aeruginosa. 3 The CREDIBLE-CR trial showed that the clinical and microbiological efficacy of CFDC was comparable to that of the best available therapeutic agents for various CR-GNB infections. 4 However, resistance to CFDC has emerged among CR-GNB before its widespread use in clinical practice.…”

Prevalence and Phenotypic and Molecular Characterization of Carbapenemase-Producing Gram-Negative Bacteria in Gabon

“…The emergence and spread of carbapenemase-producing (CP) Gram-negative bacteria (GNB) represent a serious public health problem because effective therapeutic alternatives (e.g., colistin and cefiderocol) are not widely available in lowincome countries. [1][2][3] Therefore, carbapenems remain often the last available antibiotic class to treat infections caused by multidrug-resistant nonfermenter (Acinetobacter baumannii and Pseudomonas aeruginosa) and fermenter (Enterobacterales) GNB. 4,5 Acquired class A (KPC, IMI, GES), class B (IMP, VIM, NDM), and class D (OXA-48, OXA-181) carbapenemases are the most prevalent determinants of resistance to carbapenems.…”