Mechanism Of Action
FETROJA is an antibacterial drug [see Microbiology].
The percent time of dosing interval that unbound plasma concentrations of cefiderocol exceed the minimum
inhibitory concentration (MIC) against the infecting organism best correlates with antibacterial activity in
neutropenic murine thigh and lung infection models with Enterobacteriaceae, P. aeruginosa, A. baumannii, and
S. maltophilia. Compared to a 1-hour infusion, a 3-hour infusion increased the percent time of dosing interval
that unbound plasma concentrations of cefiderocol exceed the MIC. The in vivo animal pneumonia studies
showed that the antibacterial activity of cefiderocol was greater at the human equivalent dosing regimen of 3-
hour infusion compared to that of 1-hour infusion.
At doses 1 and 2 times the maximum recommended dosage, FETROJA does not prolong the QT interval to any
clinically relevant extent.
In cUTI patients with CLcr 60 mL/min or greater, the mean cefiderocol Cmax was 138 mg/L and AUC was 394.7
mg·hr/L (as 1184 mg·hr/L of daily AUC) after multiple (every 8 hours) FETROJA 2-gram doses infused over 1
hour (1/3 of the recommended infusion duration).
In healthy volunteers, the mean cefiderocol Cmax and AUC was 89.7 mg/L and 386 mg·hr/L, respectively, after
a single FETROJA 2-gram dose was infused over 3 hours. Cefiderocol Cmax and AUC increased proportionally
The geometric mean (±SD) cefiderocol volume of distribution was 18.0 (±3.36) L. Plasma protein binding,
primarily to albumin, of cefiderocol is 40% to 60%.
Cefiderocol terminal elimination half-life is 2 to 3 hours. The geometric mean (±SD) cefiderocol clearance is
estimated to be 5.18 (±0.89) L/hr.
Cefiderocol is minimally metabolized [less than 10% of a single radiolabeled cefiderocol dose of 1 gram (0.5
times the approved recommended dosage) infused over 1 hour].
Cefiderocol is primarily excreted by the kidneys. After a single radiolabeled cefiderocol 1-gram (0.5 times the
approved recommended dosage) dose infused over 1 hour, 98.6% of the total radioactivity was excreted in urine
(90.6% unchanged) and 2.8% in feces.
No clinically significant differences in the pharmacokinetics of cefiderocol were observed based on age (18 to
93 years of age), sex, or race. The effect of hepatic impairment on the pharmacokinetics of cefiderocol was not
Patients With Renal Impairment
Approximately 60% of cefiderocol was removed by a 3- to 4-hour hemodialysis session.
Cefiderocol AUC fold changes in subjects with renal impairment compared to subjects with CLcr 90 to 119
mL/min are summarized in Table 4.
Table 4 Effect of Renal Impairment on the AUC of Cefiderocola
Geometric Mean Ratios (90% CI)b
|60 to 89 (N=6)
||1.37 (1.15, 1.62)
|30 to 59 (N=7)
||2.35 (2.00, 2.77)
|15 to 29 (N=4)
||3.21 (2.64, 3.91)
||4.69 (3.95, 5.56)
|aAfter a single FETROJA 1-gram dose (0.5 times the approved recommended dosage)
bCompared to AUC in subjects with CLcr 90 to 119 mL/min (N=12)
Patients With CLcr 120 mL/min Or Greater
Increased cefiderocol clearance has been observed in patients with CLcr 120 mL/min or greater. A FETROJA
2-gram dose every 6 hours infused over 3 hours is predicted to provide cefiderocol exposures comparable to
those in patients with CLcr 90 to 119 mL/min [see DOSAGE AND ADMINISTRATION].
Drug Interaction Studies
No clinically significant differences in the pharmacokinetics of furosemide (an organic anion transporter
[OAT]1 and OAT3 substrate), metformin (an organic cation transporter [OCT]1, OCT2, and multi-drug and
toxin extrusion [MATE]2-K substrate), and rosuvastatin (an organic anion transporting polypeptide [OATP]1B3
substrate) were observed when co-administered with cefiderocol.
In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically
Cytochrome P450 (CYP) Enzymes
Cefiderocol is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9,
CYP2C19, CYP2D6, CYP2E1, or CYP3A4. Cefiderocol is not an inducer of CYP1A2, CYP2B6, or CYP3A4.
Cefiderocol is not an inhibitor of OATP1B1, MATE1, P-glycoprotein (P-gp), breast
cancer resistance protein (BCRP), or bile salt export pump transporters. Cefiderocol is not a substrate of OAT1,
OAT3, OCT2, MATE1, MATE2-K, P-gp, or BCRP.
Mechanism Of Action
FETROJA is a cephalosporin antibacterial with activity against Gram-negative aerobic bacteria. Cefiderocol
functions as a siderophore and binds to extracellular free ferric iron. In addition to passive diffusion via porin
channels, cefiderocol is actively transported across the outer cell membrane of bacteria into the periplasmic
space using a siderophore iron uptake mechanism. Cefiderocol exerts bactericidal action by inhibiting cell wall
biosynthesis through binding to penicillin-binding proteins (PBPs).
Cefiderocol has no clinically relevant in vitro activity against most Gram-positive bacteria and anaerobic
bacteria. Cefiderocol has shown in vitro activity against some isolates of S. maltophilia, and meropenemresistant
Enterobacteriaceae, P. aeruginosa, and A. baumannii. Cefiderocol is active against some P. aeruginosa and A. baumannii isolates resistant to meropenem, ciprofloxacin, and amikacin. Cefiderocol is active against
some E. coli isolates containing mcr-1.
Cefiderocol demonstrated in vitro activity against certain Enterobacteriaceae genetically confirmed to contain
the following: ESBLs (TEM, SHV, CTX-M, oxacillinase [OXA]), AmpC, AmpC-type ESBL (CMY), serinecarbapenemases
(such as KPC, OXA-48), and metallo-carbapenemases (such as NDM and VIM). Cefiderocol
demonstrated in vitro activity against certain P. aeruginosa genetically confirmed to contain VIM, GES, AmpC
and certain A. baumannii containing OXA-23, OXA-24/40, OXA-51, OXA-58. Cefiderocol has demonstrated
in vitro activity against some K. pneumoniae isolates with OmpK35/36 porin deletion and some isolates of P.
aeruginosa with OprD porin deletion.
Cross-resistance with other classes of antibacterial drugs has not been identified; therefore, isolates resistant to
other antibacterial drugs may be susceptible to cefiderocol.
Cefiderocol does not cause induction of AmpC beta-lactamase in P. aeruginosa and E. cloacae. The frequency
of resistance development in Gram-negative bacteria including carbapenemase producers exposed to
cefiderocol at 10x minimum inhibitory concentration (MIC) ranged from 10-6 to 10-8.
In vitro, MIC increases that may result in resistance to cefiderocol in Gram-negative bacteria, have been
associated with the presence of beta-lactamases including AmpC beta-lactamase overproduction, modifications
of penicillin binding proteins, and mutations of transcriptional regulators that impact siderophore or efflux
In vitro, the addition of the beta-lactamase inhibitors (such as avibactam, clavulanic acid, and dipicolinic acid)
results in the lowering of MICs of some isolates with relatively high MICs (range 2 to 256) to cefiderocol.
Interaction With Other Antimicrobials
In vitro studies showed no antagonism between cefiderocol and amikacin, ceftazidime/avibactam,
ceftolozane/tazobactam, ciprofloxacin, clindamycin, colistin, daptomycin, linezolid, meropenem, metronidazole,
tigecycline, or vancomycin against strains of Enterobacteriaceae, P. aeruginosa, and A. baumannii.
Activity Against Bacteria In Animal Infection Models
In a neutropenic murine thigh infection model using a humanized dose (2 grams every 8 hours), cefiderocol
demonstrated 1log10 reduction in bacterial burden against most Enterobacteriaceae A. baumannii, and P.
aeruginosa including some carbapenemase-producing isolates with MICs of ≤ 4 mcg/mL.
In an immunocompetent rat pneumonia model, reduction in bacterial counts in the lungs of animals infected
with K. pneumoniae with MICs ≤8 mcg/mL and P. aeruginosa with MICs ≤ 1mcg/mL was observed using
humanized cefiderocol dose.
In an immunocompetent murine urinary tract infection model, cefiderocol reduced bacterial counts in the
kidneys of mice infected with Enterobacteriaceae, and P. aeruginosa isolates with MICs ≤ 1 mcg/mL. In an
immunocompromised murine systemic infection model, cefiderocol increased survival in mice infected with E.
cloacae, S. maltophilia, and Burkholderia cepacia isolates with MICs ≤0.5 mcg/mL compared to untreated
mice. In an immunocompetent murine systemic infection model, cefiderocol increased survival in mice
infected with S. marcescens and P. aeruginosa isolates with MICs ≤1 mcg/mL compared to untreated mice. The
clinical significance of the above findings is not known.
FETROJA has been shown to be active against the following bacteria, both in vitro and in clinical infections
Enterobacter cloacae complex
Cefiderocol demonstrated in vitro activity against the following bacteria, but the clinical significance is
unknown. At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC)
less than or equal to the susceptible breakpoint for cefiderocol. However, the efficacy of cefiderocol in treating
clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.
Citrobacter freundii complex
For specific information regarding susceptibility test interpretive criteria and associated test methods and
quality control standards recognized by FDA for this drug, please see https://www.fda.gov/STIC.
Complicated Urinary Tract Infections, Including Pyelonephritis
A total of 448 adults hospitalized with cUTI (including pyelonephritis) were randomized in a 2:1 ratio and
received study medications in a multinational, double-blind trial (Trial 1) (NCT02321800) comparing
FETROJA 2 grams intravenously (IV) every 8 hours (infused over 1 hour) to imipenem/cilastatin 1g/1g IV
every 8 hours (infused over 1 hour) for 7 to 14 days. No switch from IV to oral antibacterial therapy was
Efficacy was assessed as a composite of microbiological eradication and clinical cure in the microbiological
intent-to-treat (Micro-ITT) population, which included all patients who received at least a single-dose of study
medication and had at least one baseline Gram-negative uropathogen. Other efficacy endpoints included the
microbiological eradication rate and the clinical response rate at the Test of Cure (TOC) visit in the Micro-ITT
The Micro-ITT population consisted of 371 patients of whom 25% had cUTI with pyelonephritis, 48% had
cUTI without pyelonephritis, and 27% had acute uncomplicated pyelonephritis. Complicating conditions
included obstructive uropathy, catheterization, and renal stones. The median age was 66 years, with 24% of
patients over the age of 75 years, and 55% of the population was female. The median duration of therapy in
both treatment groups was 9 days (range: 1-14 days). Of the 371 patients, 32% had CLcr >50-80 mL/min, 17%
had CLcr 30-50 mL/min, and 3% had CLcr <30 mL/min at baseline. Concomitant Gram-negative bacteremia
was identified in 7% of patients. In the Micro-ITT population, the most common baseline pathogens were E.
coli and K. pneumoniae.
Table 5 provides the results of a composite of microbiological eradication (all Gram-negative uropathogens
found at baseline at ≥ 105 CFU/mL reduced to < 104 CFU/mL) and clinical response (resolution or improvement
of cUTI symptoms and no new symptoms assessed by the investigator) at the TOC visit 7 +/- 2 days after the
last dose of study drug. The response rates for the composite endpoint of microbiological eradication and
clinical response at the TOC visit were higher in the FETROJA arm compared with imipenem/cilastatin as
shown in Table 5. Clinical response rates at the TOC visit were similar between FETROJA and
imipenem/cilastatin. Most patients with microbiological failure at the TOC visit in either treatment arm did not
require further antibacterial drug treatment. Subgroup analyses examining composite outcomes by baseline
pathogen are shown in Table 6 and demonstrated responses consistent with the overall population. Subgroup
analyses examining outcomes by age, gender, and/or outcomes in patients with renal impairment, concomitant
bacteremia, complicated UTI with or without pyelonephritis, or acute uncomplicated pyelonephritis
demonstrated responses were consistent with the overall population.
Table 5 Composite, Microbiological, and Clinical Response Rates at the TOC Visit – Micro ITT
|Composite response at TOC
||18.6 (8.2, 28.9)
|Microbiologic response TOC
||17.3 (6.9, 27.6)
|Clinical response TOC
||2.4 (-4.7, 9.4)
|CI = confidence interval; Micro-ITT = microbiological intent-to-treat; TOC = Test of Cure
|aThe treatment difference and 95% CI were based on the Cochran-Mantel-Haenszel method.
Table 6 Composite Endpoint of Microbiological Eradication and Clinical Response at the TOC
Visits in the Micro-ITT by Baseline Pathogena Subgroups
|Baseline Pathogen Subgroup
|Enterobacter cloacae complex
|aPatients may have been infected with more than one pathogen in the baseline urine culture.
In the FETROJA treatment group, 61 (24.2%) bacterial isolates were ESBL producers compared with 32
(26.9%) in the imipenem/cilastatin group. The composite response rate of patients with these ESBL isolates at
the TOC visit was consistent with the overall results.