Skip to Content

Cefiderocol

Class: Siderophore Cephalosporins
Chemical Name: (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetyl]amino]-3-[[1-[2-[(2-chloro-3,4-dihydroxybenzoyl)amino]ethyl]pyrrolidin-1-ium-1-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
Molecular Formula: C30H34ClN7O10S2
CAS Number: 1225208-94-5
Brands: Fetroja

Medically reviewed by Drugs.com. Last updated on Feb 24, 2020.

Introduction

Cefiderocol sulfate tosylate is a siderophore cephalosporin.1

Uses for Cefiderocol

Cefiderocol sulfate tosylate has the following uses:

Cefiderocol sulfate tosylate is a cephalosporin antibacterial indicated for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by susceptible gram-negative bacteria in patients 18 years of age or older who have limited or no alternative treatment options.1

Approval of this indication is based on limited clinical safety and efficacy data for cefiderocol sulfate tosylate.1

To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefiderocol sulfate tosylate and other antibacterial drugs, cefiderocol sulfate tosylate should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.1

Cefiderocol Dosage and Administration

General

Cefiderocol sulfate tosylate is available in the following dosage form(s) and strength(s):

For injection: 1 gram of cefiderocol as a lyophilized powder for reconstitution in single-dose vials.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration
  • Patients with creatinine clearance (Clcr) of 60–119 mL/min: Administer 2 grams of cefiderocol every 8 hours by intravenous (IV) infusion over 3 hours.1

  • Patients with Clcr less than 60 mL/min or Clcr of 120 mL/min or greater: Dosage adjustments are required.1

  • See full prescribing information for instructions on preparation of cefiderocol sulfate tosylate doses.1

  • See full prescribing information for drug compatibilities.1

Cautions for Cefiderocol

Contraindications

Cefiderocol sulfate tosylate is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol and other β-lactam antibacterial drugs or other components of cefiderocol sulfate tosylate.1

Warnings/Precautions

Increase in All-cause Mortality in Patients with Carbapenem-resistant Gram-negative Bacterial Infections

An increase in all-cause mortality was observed in patients treated with cefiderocol sulfate tosylate as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically-ill patients with carbapenem-resistant gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against gram-negative bacteria. Most of the BAT regimens contained colistin.1

The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-day all-cause mortality was higher in patients treated with cefiderocol sulfate tosylate than in patients treated with BAT [25/101 (24.8%) vs. 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with cefiderocol sulfate tosylate than in patients treated with BAT through day 49 [34/101 (33.7%) vs. 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by gram-negative organisms, including non-fermenters such as Acinetobacter baumannii, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection or underlying comorbidities. The cause of the increase in mortality has not been established. The safety and efficacy of cefiderocol sulfate tosylate has not been established for the treatment of nosocomial pneumonia, bloodstream infections, or sepsis.1

Reserve cefiderocol sulfate tosylate for use in patients who have limited or no alternative treatment options for the treatment of cUTI. Closely monitor the clinical response to therapy in patients with cUTI.1

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving β-lactam antibacterial drugs. Hypersensitivity was observed in cefiderocol sulfate tosylate clinical trials. These reactions are more likely to occur in individuals with a history of β-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.

Before therapy with cefiderocol sulfate tosylate is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other β-lactam antibacterial drugs. Discontinue cefiderocol sulfate tosylate if an allergic reaction occurs.1

Clostridioides Difficile-associated Diarrhea

Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including cefiderocol sulfate tosylate. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.1

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.1

If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.1

Seizures and Other Central Nervous System Adverse Reactions

Cephalosporins, including cefiderocol sulfate tosylate, have been implicated in triggering seizures. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins, particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust cefiderocol sulfate tosylate dosage based on creatinine clearance. Anticonvulsant therapy should be continued in patients with known seizure disorders.

If CNS adverse reactions, including seizures, occur, patients should undergo a neurological evaluation to determine whether cefiderocol sulfate tosylate should be discontinued.1

Development of Drug-resistant Bacteria

Prescribing cefiderocol sulfate tosylate in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and may increase the risk for development of drug-resistant bacteria.1

Specific Populations

Pregnancy

Risk Summary: There are no available data on cefiderocol sulfate tosylate use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1

Available data from published prospective cohort studies, case series, and case reports over several decades with cephalosporin use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1

Developmental toxicity studies with cefiderocol administered during organogenesis to rats and mice showed no evidence of embryo-fetal toxicity, including drug-induced fetal malformations, at doses providing exposure levels 1.4 times (rats) or 2 times (mice) higher than the average observed in cUTI patients receiving the maximum recommended daily dose.1

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.1

Human Data: While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association with cephalosporin use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups.1

Animal Data: Developmental toxicity was not observed in rats at intravenous doses of up to 1000 mg/kg/day or in mice at subcutaneous doses of up to 2000 mg/kg/day given during the period of organogenesis (gestation days 6-17 in rats and 6-15 in mice). No treatment-related malformations or reductions in fetal viability were observed. Mean plasma exposure (AUC) at these doses was approximately 1.4 times (rats) and 2 times (mice) the daily mean plasma exposure in cUTI patients that received 2 grams of cefiderocol infused intravenously every 8 hours.1

In a pre- and postnatal development study, cefiderocol was administered intravenously at doses up to 1000 mg/kg/day to rats from day 6 of pregnancy until weaning. No adverse effects on parturition, maternal function, or pre- and postnatal development and viability of the pups were observed.1

In pregnant rats, cefiderocol-derived radioactivity was shown to cross the placenta, but the amount detected in fetuses was a small percentage (<0.5%) of the dose.1

Lactation

Risk Summary: It is not known whether cefiderocol is excreted into human milk; however, cefiderocol-derived radioactivity was detected in the milk of lactating rats that received the drug intravenously. When a drug is present in animal milk, it is likely that the drug will be present in human milk. No information is available on the effects of cefiderocol sulfate tosylate on the breast-fed infant or on milk production.1

The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for cefiderocol sulfate tosylate and any potential adverse effects on the breast-fed child from cefiderocol sulfate tosylate or from the underlying maternal condition.1

Data: Cefiderocol-derived radioactivity was detected in milk following intravenous administration to lactating rats. The peak level in rat milk was approximately 6% of the peak plasma level.1

Pediatric Use

Safety and efficacy of cefiderocol sulfate tosylate in pediatric patients younger than 18 years of age have not been established.1

Geriatric Use

Of the 300 subjects treated with cefiderocol sulfate tosylate in the cUTI trial, 158 (52.7%) were 65 years of age and older, and 67 (22.3%) were 75 years of age and older. No overall differences in safety or efficacy were observed between these subjects and younger subjects.1

Cefiderocol sulfate tosylate is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. No dosage adjustment is required based on age. Dosage adjustment for elderly patients should be based on renal function.1

Renal Impairment

No dosage adjustment of cefiderocol sulfate tosylate is recommended in patients with Clcr of 60–89 mL/min.1

Dose adjustment is required in patients with Clcr of 15–59 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 cefiderocol sulfate tosylate accordingly as renal function may change during the course of therapy.1

Clcr of 120 mL/min or greater may be seen in seriously ill patients who are receiving intravenous fluid resuscitation. Dosage adjustment of cefiderocol sulfate tosylate is required in patients with Clcr of 120 mL/min or greater. Monitor renal function regularly and adjust the dosage of cefiderocol sulfate tosylate accordingly as renal function may change during the course of therapy.1

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of cefiderocol have not been evaluated. Hepatic impairment is not expected to alter the elimination of cefiderocol as hepatic metabolism/excretion represents a minor pathway of elimination for cefiderocol. Dosage adjustments are not necessary in patients with impaired hepatic function.1

Common Adverse Effects

The most frequently occurring adverse reactions in greater than or equal to 2% of patients treated with cefiderocol sulfate tosylate were diarrhea, infusion site reactions, constipation, rash, candidiasis, cough, elevations in liver tests, headache, hypokalemia, nausea, and vomiting.1

Drug Interactions

Specific Drugs and Laboratory Tests

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Use alternate testing methods to confirm positive results of dipstick tests (urine protein, ketones, or occult blood).1

Actions and Spectrum

Mechanism of Action

Cefiderocol sulfate tosylate is a cephalosporin antibacterial.1

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.1

Cefiderocol exerts bactericidal action by inhibiting cell wall biosynthesis through binding to penicillin-binding proteins (PBPs).1

Spectrum

Cefiderocol sulfate tosylate is active against gram-negative aerobic bacteria. The drug has no clinically relevant in vitro activity against most gram-positive bacteria or anaerobic bacteria.1

Cefiderocol has shown in vitro activity against some isolates of Stenotrophomonas maltophilia and meropenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Cefiderocol is active against some P. aeruginosa and A. baumannii isolates resistant to meropenem, ciprofloxacin, and amikacin. Cefiderocol is active against some Escherichia coli isolates containing mcr-1.1

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), serine-carbapenemases (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, or AmpC and certain A. baumannii containing OXA-23, OXA-24/40, OXA-51, or OXA-58. Cefiderocol has demonstrated in vitro activity against some Klebsiella pneumoniae isolates with OmpK35/36 porin deletion and some isolates of P. aeruginosa with OprD porin deletion.1

Cefiderocol sulfate tosylate has been shown to be active against the following bacteria, both in vitro and in clinical infections: 1

Gram-negative Bacteria: Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa.1

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.1

Gram-negative Bacteria: Acinetobacter baumannii, Citrobacter freundii complex, Citrobacter koseri, Klebsiella aerogenes, Klebsiella oxytoca, Morganella morganii, Proteus vulgaris, Providencia rettgeri, Serratia marcescens, Stenotrophomonas maltophilia.1

Resistance

Cross-resistance with other classes of antibacterial drugs has not been identified; therefore, isolates resistant to other antibacterial drugs may be susceptible to cefiderocol.1

Cefiderocol does not cause induction of AmpC β-lactamase in P. aeruginosa and E. cloacae. The frequency of resistance development in gram-negative bacteria, including carbapenemase producers, exposed to cefiderocol at 10× minimum inhibitory concentration (MIC) ranged from 10-6 to 10-8.1

In vitro, MIC increases that may result in resistance to cefiderocol in gram-negative bacteria have been associated with the presence of β-lactamases (including AmpC β-lactamase overproduction), modifications of penicillin binding proteins, and mutations of transcriptional regulators that impact siderophore or efflux pump expression.1

In vitro, the addition of β-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.1

Advice to Patients

Serious Allergic Reactions

Advise patients and their families that allergic reactions, including serious allergic reactions, could occur with cefiderocol sulfate tosylate and that serious reactions require immediate treatment. Ask patients about any previous hypersensitivity reactions to cefiderocol sulfate tosylate, other β-lactams (including cephalosporins), or other allergens.1

Potentially Serious Diarrhea

Advise patients and their families that diarrhea is a common problem caused by antibacterial drugs, including cefiderocol sulfate tosylate. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, tell patient to contact his or her healthcare provider.1

Seizures

Counsel patients on the implication of cephalosporins in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced and in patients with a history of epilepsy.1

Antibacterial Resistance

Patients should be counseled that antibacterial drugs, including cefiderocol sulfate tosylate, should only be used to treat bacterial infections. They do not treat viral infections (e.g., influenza, common cold). When cefiderocol sulfate tosylate is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may decrease the effectiveness of the immediate treatment and increase the likelihood that bacteria will develop resistance and will not be treatable by cefiderocol sulfate tosylate or other antibacterial drugs in the future.1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Cefiderocol Sulfate Tosylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, Powder, for Solution

1 g (of cefiderocol)

Fetroja

Shionogi Inc.

AHFS Drug Information. © Copyright 2021, Selected Revisions February 24, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Shionogi Inc. Fetroja (Cefiderocol sulfate tosylate) INTRAVENOUS prescribing information. 2019 Nov. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=75c0c785-38e0-4049-a6fb-b77581f5b35c