cefiderocol (Rx)

>10%

HABP/VABP

• Elevated liver tests (16%)
• Hypokalemia (11%)

1-10%

cUTIs

• Diarrhea (4%)
• Infusion site reactions (4%)
• Constipation (3%)
• Rash (3%)
• Candidiasis (2%)
• Cough (2%)
• Elevated liver tests (2%)
• Headache (2%)
• Hypokalemia (2%)
• Nausea (2%)
• Vomiting (2%)

• <2%

  • Blood and lymphatic disorders: Thrombocytosis
  • Cardiac disorders: Congestive heart failure, bradycardia, atrial fibrillation
  • Gastrointestinal disorders: Abdominal pain, dry mouth, stomatitis
  • General system disorders: Pyrexia, peripheral edema
  • Hepatobiliary disorders: Cholelithiasis, cholecystitis, gallbladder pain
  • Immune system disorders: Drug hypersensitivity
  • Infections and infestations: Clostridioides difficile infection
  • Laboratory investigations: Prolonged prothrombin time and prothrombin time international normalized ratio, RBC urine positive, creatine phosphokinase increase
  • Metabolism and nutrition disorders: Decreased appetite, hypocalcemia, fluid overload
  • Nervous system disorders: Dysgeusia, seizure
  • Respiratory, thoracic, and mediastinal disorders: Dyspnea, pleural effusion
  • Skin and SC tissue disorders: Pruritus
  • Psychiatric disorders: Insomnia, restlessness

HABP/VABP

• Diarrhea (9%)
• Hypomagnesemia (5%)
• Atrial fibrillation (5%)

• <4%

  • Blood and lymphatic disorders: Thrombocytopenia, thrombocytosis
  • Cardiac disorders: Myocardial infarction, atrial flutter
  • Gastrointestinal disorders: Nausea, vomiting, abdominal pain
  • Hepatobiliary disorders: Cholecystitis, cholestasis
  • Infections and infestations: C. difficile infection, oral candidiasis
  • Laboratory investigations: Prolonged PT and PT-INR ratio, and activated partial thromboplastin time
  • Metabolism and nutrition disorders: Hypocalcemia, hyperkalemia
  • Nervous system disorders: Seizure
  • Renal and genitourinary disorders: Acute interstitial nephritis
  • Respiratory, thoracic, and mediastinal disorders: Cough
  • Skin and subcutaneous tissue disorders: Rash including rash erythematous

Contraindications

Severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of cefiderocol

Cautions

An increase in all-cause mortality was observed; reserve use for patients who have limited or no alternative treatment options for the treatment of cUTI

Closely monitor clinical response to therapy in patients with chronic urinary tract infection and hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP); increase in all-cause mortality in patients with carbapenem-resistant gram-negative bacterial infection reported; significance unknown

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions reported; reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens; discontinue therapy if an allergic reaction occurs

Cephalosporins may trigger seizures; nonconvulsive status epilepticus, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia reported with cephalosporins, particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment; if CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether to discontinue treatment

Dosage adjustment required in patients receiving continuous renal replacement therapy (CRRT) including CVVH, CVVHD, and CVVHDF; dosage should be based on effluent flow rate in patients receiving; while on CRRT, a patient’s residual renal function may change; improvements or reductions in residual renal function may warrant a change in dosage

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

C difficile-associated diarrhea

• C difficile-associated diarrhea (CDAD) reported
• CDAD may range in severity from mild diarrhea to fatal colitis
• Treatment with antibacterial agents alters normal flora of the colon and may permit overgrowth of C difficile
• If CDAD is suspected or confirmed, consider discontinuing antibacterial drugs not directed against C difficile; manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C difficile, and institute surgical evaluation as clinically indicated

Drug interaction overview

• Use may result in false-positive results in dipstick tests (urine protein, ketones, or occult blood); use alternate clinical laboratory methods of testing to confirm positive tests

Pregnancy

There are no available data on use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

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

Animal data

• Developmental toxicity studies with cefiderocol administered during organogenesis to rats and mice showed no evidence of embryofetal 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

Lactation

Unknown whether cefiderocol is excreted into human milk; however, cefiderocol-derived radioactivity was detected in the milk of lactating rats that received IV cefiderocol

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 on the breastfed infant or on milk production

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

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

Absorption

Peak plasma concentration

• cUTI: 115 mg/mL
• HABP/VAPT: 111 mg/mL
• Healthy volunteers: 91.4 mg/mL

AUC

• cUTI: 1944 mg⋅hr/mL
• HABP/VAPT: 1773 mg⋅hr/mL
• Healthy volunteers: 1175 mg⋅hr/mL

Distribution

Vd: 18 L

Plasma protein binding, primarily to albumin, of cefiderocol is 40-60%

Metabolism

Cefiderocol is minimally metabolized

Elimination

Half-life: 2-3 hr

Clearance: 5.18 L/hr

Primarily excreted by kidneys

Excretion: Urine (98.6% [90.6% unchanged]); feces (2.8%)

IV Incompatibilities

Compatibility with solutions containing other drugs or other diluents has not been established

IV Compatibilities

0.9% NaCl

Dextrose 5%

IV Preparation

Reconstitute vial with 10 mL of either 0.9% NaCl or D5W and gently shake to dissolve

Allow vial(s) to stand until foaming on the surface has disappeared (typically within 2 min); final volume of the reconstituted solution (1 gram/11.2 mL)

Reconstituted solution is for IV infusion only after dilution in an appropriate infusion solution

Withdraw appropriate volume of reconstituted solution from vial

Add to a 100-mL infusion bag containing 0.9% NaCl or D5W

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit

Infusions are clear, colorless solutions; discard any unused solution in the vial

Preparation of doses

• 2 grams: 22.4 mL of reconstituted cefiderocol
• 1.5 grams: 16.8 mL of reconstituted cefiderocol
• 1 gram: 11.2 mL of reconstituted cefiderocol
• 0.75 grams: 8.4 mL of reconstituted cefiderocol

IV Administration

• IV infusion only
• Infuse over 3 hr

Storage

Unused vials: Refrigerate at 2-8ºC (36-46ºF); protect from light; store in carton until time of use

Reconstituted vial: Store for up to 1 hr at room temperature; discard any unused reconstituted solution

Diluted infusion solution

• Store for up to 6 hr at room temperature OR
• Refrigerate at 2-8ºC (36-46ºF) for up to 24 hr
• Protect from light
• Complete infusion within 6 hours at room temperature