Cefepime

Cefepime is a parenteral fourth-generation cephalosporin with broad Gram-negative cover, including Pseudomonas and AmpC producers, and good Gram-positive cover. It is a first-line drug for febrile neutropenia and hospital-acquired sepsis.

Classification. Beta-lactam, fourth-generation cephalosporin.

Mechanism. Blocks penicillin-binding proteins; stable against AmpC beta-lactamases and many others, but hydrolysed by ESBLs.

Spectrum. MSSA, streptococci, pneumococci, Haemophilus, Neisseria, Enterobacterales (including Enterobacter and Citrobacter with AmpC), Pseudomonas aeruginosa. Poor against anaerobes, enterococci and MRSA; not reliable against ESBL or carbapenemase producers.

Pharmacokinetics. IV or IM. Half-life about 2 hours. Protein binding 20%. About 85% excreted unchanged in urine. CSF penetration is adequate in meningitis.

No loading dose except continuous or extended infusion. Maximum 6 g daily.

Adults. - Uncomplicated urinary and mild to moderate infection: 1 g IV every 12 hours. - Pneumonia (moderate): 1 to 2 g IV every 12 hours. - Severe infection, Pseudomonas, nosocomial pneumonia, febrile neutropenia: 2 g IV every 8 hours. - Intra-abdominal infection: 2 g every 8 to 12 hours with metronidazole 500 mg every 8 hours. - Extended infusion: 2 g over 3 to 4 hours every 8 hours after a 2 g loading dose over 30 minutes. - Pseudomonas meningitis: 2 g every 8 hours for 21 days.

Children 2 months to 16 years. 50 mg/kg every 8 to 12 hours (maximum 2 g a dose); neutropenia and severe infection 50 mg/kg every 8 hours. Neonates: 30 to 50 mg/kg every 12 hours.

Alternatives. Piperacillin tazobactam, ceftazidime, meropenem, ciprofloxacin.

Contraindications. Cephalosporin hypersensitivity.

Adverse effects. Diarrhoea, rash, phlebitis, raised liver enzymes, positive direct Coombs test. Serious: anaphylaxis, severe skin reactions, haemolytic anaemia, neutropenia, Clostridioides difficile infection.

Neurotoxicity. Encephalopathy, myoclonus and non-convulsive status epilepticus can occur, usually 1 to 10 days into treatment, most often with unadjusted doses in kidney impairment and in older adults. Stop the drug; haemodialysis removes it.

Interactions. Aminoglycosides and loop diuretics (nephrotoxicity), probenecid, warfarin INR rise, oral typhoid vaccine.

Common prescribing errors. Not reducing the dose in renal impairment, adding no anaerobic cover in abdominal sepsis, and assuming activity against ESBL organisms or enterococci.

Special groups. - Pregnancy and breastfeeding: acceptable. - Older adults: neurotoxicity risk; adjust by kidney function. - Kidney impairment, for the 2 g every 8 hours regimen: creatinine clearance 30 to 60 mL/min 2 g every 12 hours; 11 to 29 mL/min 2 g every 24 hours; under 11 mL/min 1 g every 24 hours.

For the 1 g every 12 hours regimen: 30 to 60 mL/min 1 g every 24 hours; 11 to 29 mL/min 500 mg every 24 hours; under 11 mL/min 250 mg every 24 hours. Haemodialysis: 1 g on day one, then 500 mg every 24 hours (1 g every 24 hours in febrile neutropenia), given after dialysis. - Liver impairment: no adjustment. - Obesity: use full doses.

Preparation. IV: reconstitute in water for injection, dilute in 50 to 100 mL of 0.9% sodium chloride or 5% glucose and infuse over 30 minutes (3 to 4 hours in extended infusion). IM: reconstitute with 1% lidocaine for mild infection only.

Baseline and monitoring. - Baseline: allergy history, cultures, creatinine, full blood count. - During treatment: daily creatinine and mental status in acute illness; full blood count twice weekly; liver tests in prolonged courses. - No routine therapeutic drug monitoring.

Stop rules. Stop for new confusion, myoclonus or seizures not otherwise explained, anaphylaxis, severe skin reaction or cytopenia.

Referral and escalation. Infectious diseases for Pseudomonas bacteraemia, febrile neutropenia that persists beyond 72 hours, and when ESBL infection is suspected.