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).
Demonstrated in vitro activity in the presence of resistance mechanisms
|β-lactamase hydrolysis||Porin channel changes|
|Certain Enterobacteriaceae genetically confirmed to contain the following: ESBLs (TEM, SHV, CTX-M, oxacillinase [OXA]), AmpC, AmpC-type ESBL (CMY), serine-carbapenemases (such as KPC, OXA-48), and metallo-carbapenemases (such as NDM and VIM)||Certain P aeruginosa genetically confirmed to contain VIM, GES, and AmpC||Certain Acinetobacter baumannii containing OXA-23, OXA-24/40, OXA-51, and OXA-58||Some K pneumoniae isolates with OmpK35/36 porin deletion||Some isolates of P aeruginosa with OprD porin deletion|
IN VITRO DATA FOR LISTED ORGANISMS ARE AVAILABLE BUT THEIR CLINICAL SIGNIFICANCE IS UNKNOWN.
- 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 pump expression
- 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
For additional information see full Prescribing Information section 12.4.
Fetroja has been shown to be active against the following bacteria, both in vitro and in clinical infections
- Escherichia coli
- Enterobacter cloacae complex
- Klebsiella pneumoniae
- Proteus mirabilis
- Pseudomonas aeruginosa
Cefiderocol demonstrated in vitro activity against the following bacteria, but the clinical significance is unknown
- Acinetobacter baumannii
- Citrobacter freundii complex
- Citrobacter koseri
- Klebsiella aerogenes
- Klebsiella oxytoca
- Morganella morganii
- Proteus vulgaris
- Providencia rettgeri
- Serratia marcescens
- Stenotrophomonas maltophilia
Study design: cUTI, including pyelonephritis
TID=three times a day.
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 permitted.
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 population.
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.
The following table 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 the table below. 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 the second table below 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.
Composite, microbiological, and clinical response rates at the TOC visit—Micro-ITT population
|Treatment difference (95% CI)a|
|Composite response at TOC||183/252 (72.6%)||65/119 (54.6%)||18.6 (8.2, 28.9)|
|Microbiologic response TOC||184/252 (73.0%)||67/119 (56.3%)||17.3 (6.9, 27.6)|
|Clinical response TOC||226/252 (89.7%)||104/119 (87.4%)||2.4 (-4.7, 9.4)|
|CI=confidence interval; micro-ITT =microbiological intent-to-treat; TOC=Test of Cure.|
|a||The treatment difference and 95% CI were based on the Cochran-Mantel-Haenszel method.|
Composite endpoint of microbiological eradication and clinical response at the TOC visits in the micro-ITT by baseline pathogena subgroups
|Baseline pathogen subgroup||Fetroja
|Escherichia coli||113/152 (74.3)||45/79 (57.0)|
|Klebsiella pneumoniae||36/48 (75.0)||12/25 (48.0)|
|Proteus mirabilis||13/17 (76.5)||0/2 (0.0)|
|Pseudomonas aeruginosa||8/18 (44.4)||3/5 (60.0)|
|Enterobacter cloacae complex||8/13 (61.5)||3/3 (100.0)|
|a||Patients 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.
Please see Warnings and Precautions in the Important Safety Information below including:
- Increase in all-cause mortality in patients with carbapenem-resistant Gram-negative bacterial infections
- Hypersensitivity reactions
- Clostridioides difficile-associated diarrhea (CDAD)
- Seizures and other central nervous system adverse reactions
Serious adverse reactions and adverse reactions leading to discontinuation
In Trial 1, a total of 14/300 (4.7%) patients treated with Fetroja and 12/148 (8.1%) of patients treated with imipenem/cilastatin experienced serious adverse reactions. One death (0.3%) occurred in 300 patients treated with Fetroja as compared to none treated with imipenem/cilastatin. Discontinuation of treatment due to any adverse reaction occurred in 5/300 (1.7%) of patients treated with Fetroja and 3/148 (2.0%) of patients treated with imipenem/cilastatin. Specific adverse reactions leading to treatment discontinuation in patients who received Fetroja included diarrhea (0.3%), drug hypersensitivity (0.3%), and increased hepatic enzymes (0.3%).
Common adverse reactions
Selected adverse reactions occurring in ≥2% of patients receiving Fetroja in the cUTI trial
|Adverse reaction||Fetrojaa (N=300)||Imipenem/
|Infusion site reactionsc||4%||5%|
|Elevations in liver testsf||2%||<1%|
|cUTI=complicated urinary tract infection.|
|a||2 grams IV over 1 hour every 8 hours (with dosing adjustment based on renal function).|
|b||1 gram IV over 1 hour every 8 hours (with dosing adjustment based on renal function and body weight).|
|c||Infusion site reactions include infusion site erythema, inflammation, pain, pruritis, injection site pain, and phlebitis.|
|d||Rash includes rash macular, rash maculopapular, erythema, skin irritation.|
|e||Candidiasis includes oral or vulvovaginal candidiasis, candiduria.|
|f||Elevations in liver tests include alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, blood alkaline phosphatase, hepatic enzyme increased.|
|g||Hypokalemia includes blood potassium decreased.|
For more on Adverse Reactions, see full Prescribing Information.
The recommended duration of treatment with Fetroja is 7 to 14 days. The duration of therapy should be guided by the severity of infection and the patient’s clinical status for up to 14 days.
Recommended dosage and dosage adjustments of Fetroja for adult patients
|Estimated creatinine clearance (CLcr)a||
|60 to 119 mL/min (Recommended dosage)||2 grams||Every 8 hours||3 hours|
|30 to 59 mL/min||1.5 grams||Every 8 hours||3 hours|
|15 to 29 mL/min||1 gram||Every 8 hours||3 hours|
(ESRD patients with or without intermittent HDb)
|0.75 gram||Every 12 hours||3 hours|
|≥120 mL/min||2 grams||Every 6 hours||3 hours|
|a||CLcr=creatinine clearance estimated by Cockcroft-Gault equation.|
|b||Cefiderocol is removed by HD; thus, complete HD at the latest possible time before the start of cefiderocol dosing.|
|ESRD=end-stage renal disease; HD=hemodialysis.|
- For patients with fluctuating renal function, monitor CLcr and adjust dosage accordingly
No dosage adjustment of Fetroja is recommended in patients with CLcr 60 to 89 mL/min.
Dose adjustment is required in patients with CLcr 15 to 59 mL/min, and in patients with end-stage renal disease or who are receiving hemodialysis (HD). In patients requiring HD, complete HD at the latest possible time before the start of cefiderocol dosing. Monitor renal function regularly and adjust the dosage of Fetroja accordingly as renal function may change during the course of therapy.
CLcr 120 mL/min or greater may be seen in seriously ill patients, who are receiving intravenous fluid resuscitation. Dosage adjustment of Fetroja is required in patients with CLcr 120 mL/min or greater. Monitor renal function regularly and adjust the dosage of Fetroja accordingly as renal function may change during the course of therapy.
Fetroja vials should be stored refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light. Store in the carton until time of use. Reconstituted and diluted solutions of Fetroja can be stored at room temperature (see Dosage and Administration).
Preparation and Administration
Preparation of Fetroja solution for administration
Fetroja is supplied as a sterile, lyophilized powder that must be reconstituted and subsequently diluted using aseptic technique prior to intravenous infusion.
Fetroja solution for administration is compatible with: 0.9% sodium chloride injection, USP and 5% dextrose injection, USP. The compatibility of Fetroja solution for administration with solutions containing other drugs or other diluents has not been established.
Preparation of Fetroja doses
|Number of 1-gram Fetroja vials
to be reconstituted
|Volume to withdraw from
|Total volume of Fetroja reconstituted solution for
further dilution into at least 100 mL
|2 grams||2 vials||11.2 mL (entire contents) of each vial||22.4 mL|
|1.5 grams||2 vials||11.2 mL (entire contents) of first vial AND
5.6 mL from second vial
|1 gram||1 vial||11.2 mL (entire contents)||11.2 mL|
|0.75 gram||1 vial||8.4 mL||8.4 mL|
Storage of reconstituted solutions
Upon reconstitution with the appropriate diluent, the reconstituted Fetroja solution in the vial should be immediately transferred and diluted into the infusion bag. Reconstituted Fetroja can be stored for up to 1 hour at room temperature. Discard any unused reconstituted solution.
Diluted Fetroja infusion solution
The diluted Fetroja infusion solution in the infusion bags is stable for up to 4 hours at room temperature.