Cephalosporins

Cephalosporins are beta-lactam antibiotics built on the 7-aminocephalosporanic acid nucleus. They are classified into generations by spectrum, with the first generation favouring Gram-positive cocci and later generations adding Gram-negative breadth, antipseudomonal activity or MRSA activity. They are among the most used antibacterials in hospital and community practice.

Mechanism. PBP binding with time-dependent bactericidal action. Cephalosporins are more resistant to staphylococcal penicillinase than penicillin but are hydrolysed by ESBLs, AmpC enzymes and carbapenemases.

Pharmacokinetics. Mostly renally cleared as unchanged drug. Exceptions: ceftriaxone (about 40 percent biliary, half-life 8 hours, once daily dosing), cefotaxime (hepatic deacetylation). Cefuroxime, ceftriaxone, cefotaxime, ceftazidime and cefepime enter CSF when meninges are inflamed. Cefazolin does not.

Intrinsic gaps. No generation reliably covers enterococci, Listeria, atypical bacteria or (except ceftaroline and ceftobiprole) MRSA.

Representative adult doses (normal renal function).

• Cefazolin 1 to 2 g IV every 8 hours; prophylaxis 2 g (3 g at 120 kg or more) within 60 minutes before incision, repeated after 4 hours.
• Cefalexin 500 mg to 1 g orally every 6 to 8 hours.
• Cefuroxime 750 mg to 1.5 g IV every 8 hours; 250 to 500 mg orally every 12 hours.
• Ceftriaxone 1 to 2 g IV or IM every 24 hours; 2 g every 12 hours for meningitis. Gonorrhoea: 1 g IM once (500 mg in some regimens).
• Cefotaxime 1 to 2 g IV every 6 to 8 hours; 2 g every 4 to 6 hours for meningitis.
• Ceftazidime 2 g IV every 8 hours.
• Cefepime 2 g IV every 8 hours for febrile neutropenia and Pseudomonas; 1 to 2 g every 12 hours for less severe infection.
• Cefixime 400 mg orally daily (or 200 mg every 12 hours); enteric fever 20 mg/kg daily in children.

Selection. Use the narrowest generation that covers the likely organism. First generation for MSSA and skin infection; third generation for meningitis, severe community infection and enteric fever; cefepime or ceftazidime for Pseudomonas; ceftriaxone is first line empirical therapy in meningitis. Avoid third generation agents when AmpC-producing organisms are likely to be the cause of serious infection.

Contraindications. Prior severe hypersensitivity to a cephalosporin. Ceftriaxone is contraindicated in neonates with hyperbilirubinaemia, and in neonates needing calcium-containing intravenous solutions (fatal precipitates).

Serious effects.

• Anaphylaxis (rare); delayed rash; cross-reactivity with penicillins about 2 percent, higher with shared side chains.
• C. difficile infection and selection of ESBL carriage.
• Cefepime neurotoxicity (encephalopathy, myoclonus, non-convulsive status) in renal impairment or overdose.
• Ceftriaxone: biliary sludge and pseudolithiasis, immune haemolytic anaemia.
• Hypoprothrombinaemia and disulfiram-like reaction with side chain methylthiotetrazole agents (cefotetan, cefoperazone).

Interactions. Warfarin (potentiated), probenecid (raised levels), aminoglycosides (additive nephrotoxicity), live typhoid vaccine.

Monitoring. Renal function; INR with warfarin; full blood count in prolonged courses; mental state with cefepime.

Special groups.

• Pregnancy and breastfeeding: acceptable.
• Renal impairment: reduce cefazolin, cefuroxime, ceftazidime, cefepime and cefotaxime; ceftriaxone needs adjustment only in combined severe renal and hepatic failure (limit to 2 g daily).
• Children: weight-based doses (ceftriaxone 50 to 100 mg/kg daily, maximum 4 g).
• Region: ceftriaxone is widely used in East Africa and ESBL carriage is common, so overuse should be limited to clear indications.