Cefiderocol is an
injectable siderophore cephalosporin discovered and being developed by Shionogi & Co., Ltd., Japan. As with other β-
lactam antibiotics, the principal antibacterial/bactericidal activity of
cefiderocol occurs by inhibition of Gram-negative bacterial cell wall synthesis by binding to
penicillin binding proteins; however, it is unique in that it enters the bacterial periplasmic space as a result of its
siderophore-like property and has enhanced stability to β-lactamases. The chemical structure of
cefiderocol is similar to both
ceftazidime and
cefepime, which are third- and fourth-generation
cephalosporins, respectively, but with high stability to a variety of β-lactamases, including AmpC and extended-spectrum β-lactamases (ESBLs).
Cefiderocol has a pyrrolidinium group in the side chain at position 3 like
cefepime and a carboxypropanoxyimino group in the side chain at position 7 of the cephem nucleus like
ceftazidime. The major difference in the chemical structures of
cefiderocol,
ceftazidime and
cefepime is the presence of a
catechol group on the side chain at position 3. Together with the high stability to β-lactamases, including ESBLs, AmpC and carbapenemases, the microbiological activity of
cefiderocol against aerobic Gram-negative bacilli is equal to or superior to that of
ceftazidime-avibactam and
meropenem, and it is active against a variety of Ambler class A, B, C and D β-lactamases.
Cefiderocol is also more potent than both
ceftazidime-avibactam and
meropenem versus Acinetobacter baumannii, including
meropenem non-susceptible and multidrug-resistant (MDR) isolates.
Cefiderocol's activity against
meropenem-non-susceptible and Klebsiella pneumoniae
carbapenemase (KPC)-producing Enterobacteriales is comparable or superior to
ceftazidime-avibactam.
Cefiderocol is also more potent than both
ceftazidime-avibactam and
meropenem against all resistance phenotypes of Pseudomonas aeruginosa and against Stenotrophomonas maltophilia. The current dosing regimen being used in phase III studies is 2 g administered intravenously every 8 h (q8 h) using a 3-h infusion. The pharmacokinetics of
cefiderocol are best described by a three-compartment linear model. The mean plasma half-life (t½) was ~ 2.3 h, protein binding is 58%, and total drug clearance ranged from 4.6-6.0 L/h for both single- and multi-dose infusions and was primarily renally excreted unchanged (61-71%).
Cefiderocol is primarily renally excreted unchanged and clearance correlates with
creatinine clearance. Dosage adjustment is thus required for both augmented renal clearance and in patients with moderate to severe renal impairment. In vitro and in vivo pharmacodynamic studies have reported that as with other
cephalosporins the pharmacodynamic index that best predicts clinical outcome is the percentage of time that free
drug concentrations exceed the minimum inhibitory concentration (%fT > MIC). In vivo efficacy of
cefiderocol has been studied in a variety of humanized
drug exposure murine and rat models of
infection utilizing a variety of MDR and extremely
drug resistant strains.
Cefiderocol has performed similarly to or has been superior to comparator agents, including
ceftazidime and
cefepime. A phase II prospective, multicenter, double-blind, randomized clinical trial assessed the safety and efficacy of
cefiderocol 2000 mg q8 h versus
imipenem/cilastatin 1000 mg q8 h, both administered intravenously for 7-14 days over 1 h, in the treatment of complicated
urinary tract infection (cUTI, including
pyelonephritis) or acute uncomplicated
pyelonephritis in hospitalized adults. A total of 452 patients were initially enrolled in the study, with 303 in the
cefiderocol arm and 149 in the
imipenem/cilastatin arm. The primary outcome measure was a composite of clinical cure and microbiological eradication at the test-of-cure (TOC) visit, that is, 7 days after the end of treatment in the microbiological intent-to-treat (MITT) population. Secondary outcome measures included microbiological response per pathogen and per patient at early assessment (EA), end of treatment (EOT), TOC, and follow-up (FUP); clinical response per pathogen and per patient at EA, EOT, TOC, and FUP; plasma, urine and concentrations of
cefiderocol; and the number of participants with adverse events. The composite of clinical and microbiological response rates was 72.6% (183/252) for
cefiderocol and 54.6% (65/119) for
imipenem/cilastatin in the MITT population. Clinical response rates per patient at the TOC visit were 89.7% (226/252) for
cefiderocol and 87.4% (104/119) for
imipenem/cilastatin in the MITT population. Microbiological eradication rates were 73.0% (184/252) for
cefiderocol and 56.3% (67/119) for
imipenem/cilastatin in the MITT population. Additionally, two phase III clinical trials are currently being conducted by Shionogi & Co., Ltd., Japan. The two trials are evaluating the efficacy of
cefiderocol in the treatment of serious
infections in adult patients caused by
carbapenem-resistant Gram-negative pathogens and evaluating the efficacy of
cefiderocol in the treatment of adults with hospital-acquired
bacterial pneumonia,
ventilator-associated pneumonia or
healthcare-associated pneumonia caused by Gram-negative pathogens.
Cefiderocol appears to be well tolerated (minor reported adverse effects were gastrointestinal and
phlebitis related), with a side effect profile that is comparable to other
cephalosporin antimicrobials.
Cefiderocol appears to be well positioned to help address the increasing number of
infections caused by
carbapenem-resistant and MDR Gram-negative bacilli, including ESBL- and
carbapenemase-producing strains (including metallo-β-lactamase producers). A distinguishing feature of
cefiderocol is its activity against resistant P. aeruginosa, A. baumannii, S. maltophilia and Burkholderia cepacia.