Cefiderocol (Monograph)

Brand name: Fetroja
Drug 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: C₃₀H₃₄ClN₇O₁₀S₂3C₃₀H₃₄ClN₇O₁₀S₂ • 4C₇H₈O₃S • H₂SO₄ • xH₂O
CAS number: 2009350-94-9

Medically reviewed by Drugs.com on Nov 6, 2023. Written by ASHP.

Introduction

Antibacterial; β-lactam antibiotic; siderophore cephalosporin.

Uses for Cefiderocol

Respiratory Tract Infections

Treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens.

Urinary Tract Infections

Treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, caused by susceptible Enterobacter cloacae complex, E. coli, K. pneumoniae, Proteus mirabilis, and Ps. aeruginosa.

One of several preferred options for treatment of cUTIs caused by carbapenem-resistant Enterobacterales (CRE) and cUTIs caused by Ps. aeruginosa with difficult-to-treat (DTR) resistance.

Cefiderocol Dosage and Administration

Administration

Administer by IV infusion.

IV Administration

Available as lyophilized powder that must be reconstituted and diluted prior to IV infusion.

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution and Dilution

Reconstitute appropriate number of single-use vials containing 1 g of cefiderocol by adding 10 mL of 0.9% sodium chloride injection or 5% dextrose injection to each vial. Gently shake vial(s) to dissolve the powder; allow to stand until foaming disappears (typically takes ≤2 minutes). Final volume in each reconstituted vial is approximately 11.2 mL. Preferably should be diluted immediately following reconstitution, but may be stored in the vial for up to 1 hour at room temperature.

To prepare diluted solution, transfer appropriate volume of reconstituted cefiderocol solution from the vial(s) into a 100-mL IV infusion bag containing 0.9% sodium chloride injection or 5% dextrose injection. (See Table 1.)

The reconstituted and diluted solution for IV infusion should appear clear and colorless; do not use if solution is discolored or contains particulates. Discard any unused solution remaining in vial(s).

The diluted solution is stable in the IV infusion bag for up to 6 hours at room temperature. Although diluted solution may be stored for up to 24 hours in a refrigerator (2–8°C) protected from light, complete the IV infusion within 6 hours after removal from refrigeration.

Rate of Administration

Administer by IV infusion over 3 hours.

Dosage

Available as cefiderocol sulfate tosylate; dosage expressed in terms of cefiderocol.

Adults

Hospital-acquired and Ventilator-associated Bacterial Pneumonia (HABP/VABP)

IV

Cl_cr 60–119 mL/minute: 2 g every 8 hours.

Cl_cr ≥120 mL/minute (e.g., seriously ill patients receiving IV fluid resuscitation): 2 g every 6 hours.

Recommended treatment duration is 7–14 days; base duration on clinical status of patient.

Complicated Urinary Tract Infections (cUTIs)

IV

Cl_cr 60–119 mL/minute: 2 g every 8 hours.

Cl_cr ≥120 mL/minute (e.g., seriously ill patients receiving IV fluid resuscitation): 2 g every 6 hours.

Recommended treatment duration is 7–14 days; base duration on clinical status of patient.

Special Populations

Hepatic Impairment

Dosage adjustment not needed.

Renal Impairment

Adults with Cl_cr <60 mL/minute, including those receiving hemodialysis: Reduce dosage. (See Table 2.)

Adults with Cl_cr <60 mL/minute receiving continuous renal replacement therapy (CRRT), including continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration (CVVHDF): Base dosage on CRRT effluent flow rate. Dosage recommendations are intended for initial cefiderocol dosing; may need to adjust dosage based on residual renal function and clinical status of the patient. (See Table 3.)

In those with fluctuating renal function, regularly monitor Cl_cr and adjust dosage as needed.

Cl_cr estimated by Cockcroft-Gault equation.

Cefiderocol is removed by hemodialysis (60% of a dose removed by 3- to 4-hour hemodialysis session); administer initial dose immediately after a hemodialysis session.

Dosage recommendations for CRRT patients are intended to provide initial cefiderocol dosage; may need to adjust dosage based on residual renal function and clinical status of patient.

Ultrafiltrate flow rate for CVVH, dialysis flow rate for CVVHD, or ultrafiltrate flow rate plus dialysis flow rate for CVVHDF.

Geriatric Patients

Select dosage with caution. Dosage adjustments not required based on age; adjust dosage based on renal function.

Cautions for Cefiderocol

Contraindications

• Known history of severe hypersensitivity to cefiderocol or other β-lactam antibacterials or other components of the preparation.

Warnings/Precautions

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

Increased all-cause mortality observed in patients treated with cefiderocol compared with best available therapy (BAT) in a multinational, randomized, open-label trial in critically-ill patients with carbapenem-resistant gram-negative bacterial infections. BAT regimens varied according to local practices and consisted of 1–3 antibacterials with activity against gram-negative bacteria. Most BAT regimens contained colistin (commercially available in US as colistimethate sodium).

The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections^{† [off-label]}, or sepsis^{† [off-label]}. The 28-day all-cause mortality was higher in patients treated with cefiderocol (24.8%) than in those treated with BAT (18.4%); all-cause mortality through day 49 remained higher in those treated with cefiderocol. Generally, deaths were in patients with infections caused by gram-negative bacteria, including non-fermenters such as A. baumannii complex, Stenotrophomonas maltophilia, and Ps. aeruginosa, and were the result of worsening or complications of infection or underlying comorbidities. Cause of the increase in mortality not established.

Closely monitor clinical response in patients receiving cefiderocol for treatment of HABP/VABP or cUTIs.

Hypersensitivity Reactions

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

Prior to initiation of cefiderocol therapy, query patients about previous hypersensitivity reactions to cephalosporins, penicillins, or other β-lactam antibacterials.

Discontinue cefiderocol if an allergic reaction occurs.

Superinfection/Clostridioides difficile-associated Diarrhea

Possible emergence and overgrowth of nonsusceptible organisms (e.g., Candida).

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly Clostridium difficile).

C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including cefiderocol, and may range in severity from mild diarrhea to fatal colitis. C. difficile produces toxins A and B which contribute to development of CDAD; hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.

Consider CDAD if diarrhea develops during or after therapy and manage accordingly. Obtain careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.

If CDAD is suspected or confirmed, discontinue antibacterial therapy not directed against C. difficile whenever possible. Initiate appropriate anti-infective therapy directed against C. difficile (e.g., fidaxomicin, vancomycin, metronidazole), supportive therapy (e.g., fluid and electrolyte management, protein supplementation), and surgical evaluation as clinically indicated.

Seizures and Other CNS Adverse Reactions

Cephalosporins, including cefiderocol, have been implicated in triggering seizures. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia reported with cephalosporins, particularly in patients with a history of epilepsy and/or when recommended cephalosporin dosages were exceeded in patients with renal impairment.

Base cefiderocol dosage on Cl_cr (see Dosage under Dosage and Administration). In patients with known seizure disorder, continue anticonvulsant therapy during cefiderocol therapy.

If CNS adverse reactions (including seizures) occur, neurological evaluation indicated to determine whether cefiderocol should be discontinued.

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of cefiderocol and other antibacterials, use only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.

Information on test methods and quality control standards for in vitro susceptibility testing of antibacterials and specific interpretive criteria for such testing recognized by FDA is available at [Web]. For most antibacterials, including cefiderocol, FDA recognizes the standards published by the Clinical and Laboratory Standards Institute (CLSI).

Laboratory Test Interference

May cause false-positive results in urine dipstick tests (e.g., urine protein, ketones, or occult blood). If positive results reported for such dipstick tests, use alternative clinical laboratory methods to confirm results.

Specific Populations

Pregnancy

No data available on use of cefiderocol during pregnant to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Although available studies cannot definitively establish an absence of risk, published data from prospective cohort studies, case series, and case reports over several decades regarding use of cephalosporins in pregnant women have not identified an association between cephalosporin use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

In rats and mice, no evidence of embryofetal toxicity, including drug-induced fetal malformations or reductions in fetal viability, and no evidence of developmental toxicity.

Crosses the placenta in rats (<0.5% of a dose detected in fetuses).

Lactation

Not known whether cefiderocol distributes into human milk, affects breast-fed infants, or affects milk production.

Distributed into milk in rats (peak milk concentrations approximately 6% of peak plasma concentrations).

Consider developmental and health benefits of breast-feeding and the importance of cefiderocol to the woman along with potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.

Pediatric Use

Safety and efficacy not established in patients <18 years of age.

Geriatric Use

Patients with HABP/VABP: In a clinical trial, 56.1% were ≥65 years of age and 27% were ≥75 years of age. Incidence of adverse reactions in those ≥65 years of age was similar to that reported in younger adults; incidence did not differ between those ≥65 years of age and those ≥75 years of age.

Patients with cUTIs: In a clinical trial, 52.7% were ≥65 years of age and 22.3% were ≥75 years of age. No overall differences in safety or efficacy between geriatric patients and younger adults.

Cefiderocol is substantially excreted by the kidneys; risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients more likely to have decreased renal function, select dosage with caution and consider monitoring renal function. Dosage adjustments not needed based on age; base dosage in geriatric patients on renal function. (See Renal Impairment under Dosage and Administration.)

Hepatic Impairment

Effects of hepatic impairment on pharmacokinetics of cefiderocol not evaluated; not expected to alter elimination of the drug since hepatic metabolism/excretion represents a minor pathway.

Renal Impairment

Dosage adjustment required in patients with Cl_cr <60 mL/minute, including those receiving hemodialysis.

Dosage adjustment required in patients receiving CRRT, including CVVH, CVVHD, and CVVHDF; base dosage in such patients on effluent flow rate. (See Renal Impairment under Dosage.) Consider that residual renal function may change in patients receiving CRRT and improvements or reductions in residual renal function may warrant dosage adjustment.

Monitor renal function regularly and adjust cefiderocol dosage as needed.

Common Adverse Effects

Patients with HABP/VABP: Elevated liver enzymes, hypokalemia, diarrhea, hypomagnesemia, atrial fibrillation.

Patients with cUTIs: Diarrhea, infusion site reactions, constipation, rash, candidiasis (oral or vulvovaginal candidiasis, candiduria), cough, elevated liver enzymes, headache, hypokalemia, nausea, vomiting.

Drug Interactions

Does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro. Does not induce CYP1A2, 2B6, or 3A4 in vitro.

Does not inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump transporters, organic anion transporting polypeptide (OATP) 1B1, or multidrug and toxin extrusion (MATE) 1; not a substrate of P-gp, BCRP, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, MATE1, or MATE2-K.

Specific Drugs

Cefiderocol Pharmacokinetics

Absorption

Following IV infusion, peak plasma concentrations and AUC increase proportionally with dose.

Plasma Concentrations

In patients with HABP/VABP infections or cUTIs receiving 2 g of cefiderocol every 8 hours given by IV infusion over 3 hours (dosage adjusted based on renal function), mean peak plasma concentrations were 111 or 115 mg/L, respectively.

Distribution

Extent

In patients with pneumonia requiring mechanical ventilation who received a 2-g dose by IV infusion over 3 hours (dose adjusted based on renal function) at steady state, cefiderocol concentrations measured in epithelial lining fluid at end of the IV infusion and at 2 hours after completion of the infusion ranged from 3.1–20.7 mg/L and 7.2–15.9 mg/L , respectively.

Plasma Protein Binding

40–60%, primarily albumin.

Elimination

Metabolism

Minimally metabolized (<10% of a dose).

Elimination Route

Primarily excreted by the kidneys. After a single 1-gram dose given by IV infusion over 1 hour, 98.6% of the dose excreted in urine (90.6% as unchanged drug) and 2.8% excreted in feces.

Removed by hemodialysis (60% of a dose removed by 3- to 4-hour hemodialysis session).

Half-life

Terminal elimination half-life is 2–3 hours.

Special Populations

Renal impairment: AUC increases with decreasing renal function.

Patients receiving CRRT: In vitro data indicate effluent flow rate of CRRT is the major determinant of cefiderocol clearance. Dosage recommendations based on effluent flow rate (see Renal Impairment under Dosage and Administration) are predicted to provide cefiderocol exposures similar to those observed when a dosage of 2 g every 8 hours is used in patients not receiving CRRT.

Patients with Cl_cr ≥120 mL/minute (e.g., seriously ill receiving IV fluids): Increased cefiderocol clearance. Increasing dosage to 2 g every 6 hours in such patients provides exposures comparable to patients with Cl_cr of 90–119 mL/minute receiving 2 g every 8 hours.

Hepatic impairment: Effect on pharmacokinetics not evaluated.

Age (18–19 years of age), sex, and race do not have clinically important effects on pharmacokinetics of the drug.

Stability

Storage

Parenteral

Powder for Injection

2–8°C. Protect from light; store in original carton.

May store reconstituted solution in the vial for up to 1 hour at room temperature.

Following reconstitution and dilution, stable in the IV infusion bag for up to 6 hours at room temperature. May store in a refrigerator (2–8°C) for up to 24 hours protected from light; after removal from refrigeration, must complete IV infusion within 6 hours.

Compatibility

Parenteral

Solution Compatibility1

Actions and Spectrum

• Siderophore cephalosporin antibacterial. Cefiderocol is a conjugate that contains a cephalosporin core with side chains similar to those in some other cephalosporins (cefepime, ceftazidime) and a catechol group that functions as an iron-chelating siderophore.

• Cefiderocol is actively transported across the outer bacterial cell membrane into the periplasmic space by a siderophore iron uptake mechanism; in addition, passive diffusion of the drug into bacterial cells occurs via porin channels. After entry into the periplasmic space, cefiderocol dissociates from the iron and binds to penicillin-binding proteins (PBPs), primarily PBP3, and inhibits peptidoglycan synthesis.

• The structure and unique mechanism of action of cefiderocol results in enhanced stability against hydrolysis by many β-lactamases, including extended-spectrum β-lactamases (ESBLs) (e.g., TEM, SHV, CTX-M) and carbapenemases (e.g., KPC, NDM, VIM, IMP, OXA-23, OXA-48-like, OXA-51-like, OXA-58).

• Usually bactericidal in vitro.

• Spectrum of activity includes various gram-negative aerobic bacteria, including some multidrug-resistant gram-negative aerobic bacteria.

• Active in vitro and in clinical infections against A. baumannii complex, E. coli, E. cloacae complex, K. pneumoniae, P. mirabilis, Ps. aeruginosa, and S. marcescens.

• Although active in vitro against some other gram-negative aerobes, including Achromobacter, Burkholderia cepacia complex, Citrobacter freundii complex, C. koseri, K. aerogenes, K. oxytoca, Morganella morganii, P. vulgaris, Providencia rettgeri, and Stenotrophomonas maltophilia, efficacy for treatment of infections caused by these bacteria not established.

• In vitro studies indicate that a combination of β-lactamases (including AmpC β-lactamase overproduction), modifications of PBPs, and mutations of transcriptional regulators that impact siderophore or efflux pump expression can result in increased cefiderocol MICs and may result in resistance to the drug in gram-negative bacteria.

• E. cloacae complex with AmpC-mediated resistance to ceftazidime/avibactam that also was resistant to cefepime and had reduced susceptibility to cefiderocol in vitro reported. Cross-resistance between cefiderocol and other antibacterial classes not reported to date.

Advice to Patients

• Advise patients that antibacterials, including cefiderocol, should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).

• Importance of completing full course of therapy, even if feeling better after a few days.

• Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with cefiderocol or other antibacterials in the future.

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

• Advise patients that diarrhea is a common problem caused by antibacterials, including cefiderocol. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. Importance of contacting a clinician if severe watery and bloody diarrhea occurs.

• Inform patients that cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when dosage was not reduced and in patients with a history of epilepsy.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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.

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