Cefiderocol

Cefiderocol is a siderophore cephalosporin that uses bacterial iron transport to enter the periplasm. It is a reserve drug for carbapenem-resistant Gram-negative infection, including Acinetobacter baumannii, Stenotrophomonas maltophilia, metallo-beta-lactamase producers and multidrug-resistant Pseudomonas aeruginosa.

Classification. Beta-lactam, siderophore cephalosporin.

Mechanism. Chelates ferric iron and enters through iron transport channels, then blocks penicillin-binding proteins; stable against most serine and metallo-beta-lactamases.

Spectrum. Enterobacterales (including carbapenemase producers), Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, Burkholderia. Not active against Gram-positive cocci or anaerobes.

Pharmacokinetics. IV only. Half-life 2 to 3 hours. Protein binding about 58%. About 90% excreted unchanged in urine.

Reserve agent; specialist use only. Maximum 8 g daily in augmented renal clearance.

Adults, creatinine clearance 60 to 119 mL/min. 2 g IV over 3 hours every 8 hours. - Complicated urinary tract infection: 7 to 14 days. - Hospital-acquired and ventilator-associated pneumonia: 7 to 14 days. - Carbapenem-resistant infection with limited options (bacteraemia, other sites): 2 g every 8 hours, often combined with a second active agent in Acinetobacter infection.

Children. Not established; use specialist advice.

Alternatives. Ceftazidime avibactam with aztreonam (metallo-beta-lactamase producers), sulbactam-based combinations, colistin-based regimens.

Contraindications. Hypersensitivity to cefiderocol or any cephalosporin.

Mortality signal. In an early comparative study of carbapenem-resistant infection, all-cause mortality was higher than with best available therapy, mostly in Acinetobacter infection. The reason is unclear, and combination therapy is often used for Acinetobacter.

Adverse effects. Diarrhoea, infusion-site reactions, rash, hypokalaemia, raised liver enzymes. Serious: anaphylaxis, Clostridioides difficile infection, seizures, interstitial nephritis, positive direct Coombs test.

Laboratory interference. False-positive dipstick results for urine protein, ketones and occult blood.

Interactions. No clinically important cytochrome P450 interactions.

Common prescribing errors. Giving the infusion over 30 minutes instead of 3 hours, not adjusting for renal function (including high clearance), using it empirically, and not combining it for Acinetobacter infection.

Special groups.

• Pregnancy and breastfeeding: limited data; use only if the benefit outweighs unknown risk.
• Older adults: adjust by kidney function.
• Kidney impairment: creatinine clearance 120 mL/min or more 2 g every 6 hours; 60 to 119 mL/min 2 g every 8 hours; 30 to 59 mL/min 1.5 g every 8 hours; 15 to 29 mL/min 1 g every 8 hours; under 15 mL/min or intermittent haemodialysis 0.75 g every 12 hours, given after the session on dialysis days.
• Liver impairment: no adjustment.
• Region: availability in East Africa is very limited.

Preparation. Reconstitute each 1 g vial with 10 mL of 0.9% sodium chloride, then dilute to 100 mL in 0.9% sodium chloride or 5% glucose and infuse over 3 hours.

Baseline and monitoring. - Baseline: allergy history, cultures with susceptibility testing, creatinine clearance, potassium. - During treatment: creatinine clearance twice weekly (dose changes as function changes); potassium and liver tests weekly. - No therapeutic drug monitoring.

Stop rules. Stop for anaphylaxis, seizures, severe skin reaction or severe diarrhoea.

Referral and escalation. Infectious diseases consultation is needed for every use.