Cefiderocol

Urinary Tract Infection, Hospital-acquired Bacterial Pneumonia, Ventilator-associated Bacterial Pneumonia

Urinary Tract Infection Indicated for complicated urinary tract infections (cUTI), including pyelonephritis, caused by susceptible gram-negative microorganisms in adults who have limited or no alternative treatment options 2 gram IV q8hr for 7-14 days Duration of therapy should be dependent on infection severity and patient’s clinical status for up to 14 days Hospital-acquired and Ventilator-associated Bacterial Pneumonia Indicated for treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible Gram-negative microorganisms 2 grams IV q8hr for 7-14 days

Renal impairment CrCl >120 mL/min: 2 gram IV q6hr CrCl 60 to <120 mL/min: No dosage adjustment necessary CrCl 30 to <60 mL/min: 1.5 gram IV q8hr CrCl 15 to <30 mL/min: 1 gram IV q8hr End-stage renal disease (CrCl <15 mL/min) with or without intermittent hemodialysis (HD): 0.75 gram IV q12hr Patients requiring HD: Complete HD at the latest possible time before starting cefiderocol dosing; monitor renal function regularly and adjust dosage accordingly as renal function may change during therapy

Owing to elderly patients are more likely to have decreased renal function, care should be taken in dose selection and renal function should be monitored

Hepatic impairment Effects of hepatic impairment on the pharmacokinetics of cefiderocol have not been evaluated No dosage adjustment necessary in patients with impaired hepatic function

IV Administration IV infusion only Infuse over 3 hr IV Compatibilities 0.9% NaCl Dextrose 5% IV Preparation Reconstitute vial with 10 mL of either 0.9% NaCl or dextrose 5%; gently shake to dissolve Allow vial(s) to stand until foaming on the surface has disappeared (~2 minutes) Final volume of the reconstituted solution: 1 gram per 11.2 mL Withdraw appropriate volume of reconstituted solution from the vial Add withdrawn volume to 100 mL of 0.9% NaCl or dextrose 5% Visually inspect for particulate matter and discoloration before administration, whenever solution and container permit Infusions are clear, colorless solutions; discard any unused reconstituted 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

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

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 MONITORING PARAMETERS Monitor renal func

Not Classi 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

Cefiderocol 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

1-10% 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

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