Cefiderocol, a New Siderophore Cephalosporin for the Treatment of Complicated Urinary Tract Infections Caused by Multidrug-Resistant Pathogens: Preclinical and Clinical Pharmacokinetics, Pharmacodynamics, Efficacy and Safety

Abstract

Cefiderocol (Fetroja ®) is a siderophore cephalosporin and has demonstrated potent activity against extended-spectrum betalactamases producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and nonfermenting Gram-negative bacilli, including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter baumannii, Burkholderia cepacia, and Klebsiella pneumoniae. However, cefiderocol has limited activity against Gram-positive bacteria and anaerobes like Bacterodies fragilis. In the APEKS-cUTI study, 183 (73%) of 252 patients in the cefiderocol group versus 65 (55%) of 119 patients in the imipenem-cilastatin group achieved the composite outcome of clinical and microbiological eradication of Gram-negative bacteria (treatment difference of 18.58%; 95% CI 8.23-28.92, p = 0.0004) in complicated urinary tract infections (cUTIs). Cefiderocol was non-inferior to imipenem-cilastatin in cUTIs caused by Gram-negative bacteria such as E. coli, K. pneumoniae, P. aeruginosa, Proteus mirabilis, Enterobacter cloacae, Morganella morganii, and Citrobacter freundii. Cefiderocol required dose adjustment in patients with renal impairment and percentage of time that free drug concentrations above the minimum inhibitory concentration (%fT > MIC) best correlated with clinical outcomes. The most common adverse events with cefiderocol were gastrointestinal symptoms such as diarrhea, constipation, nausea, vomiting, or upper abdominal pain. Two phase III clinical trials, the CREDIBLE-CR study and the APEKS-NP study, investigated the efficacy and safety of cefiderocol for the treatment of pneumonia or cUTI, and both studies showed higher all-cause mortality associated with cefiderocol. Therefore, the use of cefiderocol should be limited only to the treatment of cUTIs from Gramnegative bacteria, especially in patients who have limited or no alternative treatment options.

Present and Future Perspectives on Therapeutic Options for Carbapenemase-Producing Enterobacterales Infections

“…Another recently approved antibiotic in the fight against CRE is cefiderocol, also known as S-649266 [ 143 ]. According to the latest data, cefiderocol has been noted as one of the most potent antimicrobial compounds in the fight against fermenting and non-fermenting Gram-negative pathogens, including CRE [ 144 ]. Cefiderocol differs from all the agents mentioned above in that it provides activity against all four classes of β-lactamases [ 265 ].…”

“…Cefiderocol is a parenteral cephalosporin siderophore that shares some structural similarities with cefepime and ceftazidime. However, according to the latest data, cefiderocol has been noted as one of the most potent antimicrobial compounds in the fight against fermenting and non-fermenting Gram-negative pathogens, including CRE [ 144 ]. Cefiderocol was approved in September 2019 by the FDA to treat complicated UTIs and is currently under investigation in phase III trials regarding its effectiveness against pneumonia and other infections caused by CRE [ 143 ].…”

Synthetic Approaches toward Certain Structurally Related Antimicrobial Thiazole Derivatives (2010-2020)

“…One of Cefiderocol characters is 2-aminothiazole ring connected to C3 of cephem ring (Figure 3). 14 A monobactam antibiotic, Aztreonam contains aminothiazole ring in its side chain, like cephalosporins, so it is active against Gram-negative bacteria. 15 β-Lactamase inhibitors include thiazolidine ring fused with -lactam ring like Sulbactam and Tazobactam which is used in combination with ceftolozane (Zerbaxa ® ) to treat severe abdominal and urinary tract infections (Figure 4).…”

Comment on ‘Cefiderocol, a New Siderophore Cephalosporin for the Treatment of Complicated Urinary Tract Infections Caused by Multidrug-resistant Pathogens: Preclinical and Clinical Pharmacokinetics, Pharmacodynamics, Efficacy and Safety’

“…We read with interest the paper by Lee et al, which reviewed the in vitro, in vivo, and clinical data on cefiderocol [ 1 ]. However, we would like to address and highlight for your readers, the inaccurate characterization of all-cause mortality (ACM) in the APEKS-NP (NCT03032380, EudraCT 2016-003020-23) clinical trial and the subsequent conclusion drawn from this mischaracterization.…”

“…From these results, Lee et al draw the conclusion that cefiderocol should be limited only to the treatment of cUTIs from Gram-negative bacteria [ 1 ]. Our organization, as well as the FDA and European Medicines Agency, examined these results and concluded that cefiderocol can be used in patients with cUTI and HAP/VAP as evidenced by cefiderocol’s current FDA-approved indication as well as the pathogen-focused indication in the European Union [ 4 , 5 ].…”