New Drug: Fetroja (Cefiderocol)

What It Is

Cefiderocol is a new siderophore cephalosporin with activity against gram-negative aerobic bacteria.^1,2 It doesn’t currently have an assigned “generation” but is structurally similar to cefepime and ceftazidime, and has an additional side chain.²

Cefiderocol has a unique mechanism of action.² It is bactericidal (inhibits cell wall synthesis), like other cephalosporins. However, it enters bacteria via active iron transport (not through porin channels like other cephalosporins).^1,4

Cefiderocol does NOT provide adequate activity against infections caused by gram-positive or anaerobic bacteria.^1,5

Indication

Cefiderocol is approved for the treatment of complicated UTIs in adults, including pyelonephritis, in patients with limited or no alternative options.^1,2

Susceptible organisms causing complicated urinary tract infections (based on in vitro AND clinical activity) may include Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas.¹

Cefiderocol displays in vitro activity against many CRE types (e.g., Klebsiella pneumoniae carbapenemase [KPC],
OXA-48) and resistant Pseudomonas, Acinetobacter, and Stenotrophomonas. Data are needed to confirm in vitro activity and demonstrate safety and efficacy for cefiderocol in patients with CRE-related infections.^1,2,5,6

Dosing and Administration

The usual dose of cefiderocol is 2 grams IV every eight hours for seven to 14 days (specific duration of therapy should be based on the severity of infection and the patient’s clinical status).¹ Administer by IV infusion over three hours.¹

Dosage adjustments are NOT necessary in patients with hepatic impairment, but ARE needed with renal impairement:¹

Renal function (CrCl [mL/min])¹

Dose (grams)¹

Dosing Frequency¹

≥120

2

every SIX hours

60 to 119

2

every EIGHT hours

30 to 59

1.5

every EIGHT hours

15 to 29

1

every EIGHT hours

<15 with or without dialysis

0.75

every TWELEVE hours

Safety and Monitoring

Cefiderocol’s most common adverse reactions (≥2%) are diarrhea, constipation, nausea, vomiting, rash, candidiasis, cough, increased liver enzymes, headache, hypokalemia, and infusion-site reactions (e.g., redness, inflammation, pain, itching).¹

Monitor patients receiving cefiderocol that have impaired renal function (i.e. CrCl <60 mL/min) and adjust doses as necessary.¹

There is some concern for increased mortality with use for infections other than complicated UTIs. (For more information, see the “Place in Therapy” row.)

Cefiderocol can cause hypersensitivity reactions.¹ It is too soon to know about cross-reactivity with other beta-lactams.

Pregnancy and Lactation

There are no human data available about cefiderocol during pregnancy or lactation.¹

Animal data does not suggest risk associated with cefiderocol use during pregnancy.¹

Animal data indicates cefiderocol excretion into the milk of lactating rats.¹ However, most cephalosporins are considered safe during lactation.⁷

Drug-Drug and Laboratory Interactions

Cefiderocol has no known significant drug-drug interactions.¹

Cefiderocol may lead to false-positive results in dipstick tests (e.g., urine protein, ketones, occult blood). Use alternate testing to confirm positive results in patients receiving cefiderocol.¹

Dosage Forms/Cost

IV cefiderocol 1 gm vials are supplied as powder for reconstitution.¹

Each 1 gm vial of cefiderocol costs ~$185, meaning the typical dose (2 gm IV every eight hours) will cost ~$1,100/day.^a

Preparation, Stability, and Administration

Store cefiderocol vials in the refrigerator at 36° to 46°F (2° to 8°C) and in the original carton (to protect from light).¹

Reconstitute each cefiderocol 1 gm vial with 10 mL of either 0.9% sodium chloride or 5% dextrose injection.¹ Final volume will be about 11.2 mL.¹

Store reconstituted cefiderocol at room temperature (for up to one hour).¹

Further dilute cefiderocol prior to administration in 100 mL of 0.9% saline or D5W as follows:.¹

• 2 grams: use two 1 gm vials to draw up a total of 22.4 mL
• 1.5 grams: use two 1 gm vials to draw up a total volume of 16.8 mL
• 1 gram: use one 1 gm vial to draw up 11.2 mL
• 0.75 gram: use one 1 gm vial to draw up 8.4 mL

Cefiderocol infusion bags are stable at room temperature for up to four hours.¹

Place in Therapy

Cefiderocol (2 gm IV every eight hours) appears to work just as well as imipenem-cilastatin (1 gm IV every eight hours) for complicated UTIs (treated for seven to 14 days) caused by multidrug-resistant, gram-negative organisms
[Evidence Level A-1].³

More data are needed to demonstrate the safety and efficacy of cefiderocol in other types of infections.

• There are several case reports documenting successful use of cefiderocol in other infections.² For example, a case report showed compassionate use of cefiderocol successfully treated an intra-abdominal infection caused by multi-drug resistant Pseudomonas aeruginosa, when other options could not be used.⁵
• There is some evidence of increased mortality in critically ill patients being treated for carbapenem-resistant nosocomial pneumonia or bloodstream infections compared primarily to colistin-based combination therapies.² However, not all studies have seen an increase in mortality. For example, preliminary data suggest there was no difference in mortality when cefiderocol was compared to meropenem in the treatment of hospital-acquired, ventilator-associated, or healthcare-associated bacterial pneumonia (note these pathogens were carbapenem-susceptible).⁶

Save cefiderocol for salvage therapy when other treatments (e.g., new beta-lactam/beta-lactamase combos, polymyxins) are not viable options (e.g., due to allergies, adverse effects, susceptibility testing).^2,4