Fourth Generation Cephalosporins

Fourth generation cephalosporins are represented by cefepime, which combines the Gram-negative breadth and antipseudomonal activity of ceftazidime with better Gram-positive cover (MSSA and streptococci) and greater stability to AmpC beta-lactamases. Cefpirome and cefozopran are used only in a few regions.

Mechanism. PBP binding with time-dependent killing. Cefepime is a zwitterion that crosses the outer membrane quickly, binds PBP3 and PBP2 of Gram-negatives and is a poor substrate for chromosomal AmpC. It is hydrolysed by ESBLs and carbapenemases.

Pharmacokinetics. Not absorbed orally. Half-life about 2 hours, 85 percent excreted unchanged by the kidney, so accumulation in renal impairment is the main route to toxicity. Good penetration into lung, bile, peritoneal fluid and inflamed meninges.

Spectrum. Streptococci, MSSA, Enterobacterales including AmpC producers, Pseudomonas aeruginosa, H. influenzae. Not active against MRSA, enterococci, anaerobes, Stenotrophomonas or carbapenemase producers. Activity against ESBL producers is unreliable even when reported susceptible and a carbapenem is preferred for serious infection.

Cefepime is the principal agent. Compared with ceftazidime it is more active against Gram-positives and AmpC producers; compared with piperacillin-tazobactam it lacks anaerobic activity and has a higher neurotoxicity risk in renal impairment.

Adult regimens (normal renal function).

• Febrile neutropenia, hospital-acquired pneumonia, Pseudomonas infection, severe sepsis: 2 g IV every 8 hours (maximum 6 g daily). Extended infusion over 3 to 4 hours improves target attainment in critical illness after a first dose over 30 minutes.
• Complicated urinary infection, mild to moderate pneumonia, skin infection: 1 to 2 g IV every 12 hours.
• Nosocomial meningitis (Pseudomonas, resistant Gram-negatives): 2 g IV every 8 hours.
• Intra-abdominal infection: 2 g every 8 to 12 hours plus metronidazole 500 mg IV every 8 hours.
• Children: 50 mg/kg IV every 8 to 12 hours (maximum 2 g each dose); febrile neutropenia 50 mg/kg every 8 hours.

Selection. Preferred empirical antipseudomonal cephalosporin when AmpC-producing organisms (Enterobacter cloacae, Klebsiella aerogenes, Citrobacter freundii) are likely. Avoid as sole therapy for ESBL infection. Use with metronidazole when anaerobes are likely, since it has no anaerobic activity.

Contraindications. Severe hypersensitivity to cephalosporins; caution in renal impairment, epilepsy and older adults.

Serious effects.

• Neurotoxicity: confusion, myoclonus, hallucinations, non-convulsive status epilepticus, coma, usually within 2 to 7 days of starting and in renal impairment or with doses not adjusted. It reverses over days after stopping; haemodialysis removes cefepime.
• C. difficile infection; anaphylaxis; positive Coombs test; transient transaminase rise; thrombocytopenia.

Interactions. Aminoglycosides (additive nephrotoxicity), probenecid, loop diuretics (nephrotoxicity); caution with other seizure-threshold lowering drugs (carbapenems, fluoroquinolones).

Monitoring. Renal function at baseline and every 2 to 3 days, with a dose recalculated at each change; mental state daily in renal impairment or critical illness; full blood count weekly.

Special groups.

• Pregnancy and breastfeeding: acceptable when needed.
• Renal impairment (for a usual regimen of 2 g every 8 hours): 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. In haemodialysis, 1 g on day 1 and then 500 mg to 1 g daily with the dose given after dialysis.
• Older adults: high risk of neurotoxicity; calculate clearance rather than relying on serum creatinine.
• Critical illness with augmented clearance: avoid under-dosing; use extended infusion.