Third Generation Cephalosporins

Third generation cephalosporins (ceftriaxone, cefotaxime, ceftazidime, and the oral agents cefixime, cefpodoxime, cefdinir and ceftibuten) have broad Gram-negative activity, strong activity against streptococci and meningococci, and good CSF penetration for the parenteral agents. Ceftazidime separates from the rest by its antipseudomonal activity and weak Gram-positive cover. They are the most used parenteral antibacterials worldwide.

Mechanism. PBP binding with time-dependent killing; stable to many narrow-spectrum beta-lactamases but hydrolysed by ESBLs, AmpC enzymes (including inducible chromosomal AmpC) and carbapenemases.

Pharmacokinetics. Ceftriaxone is highly protein-bound with a half-life of 6 to 9 hours, balanced elimination between kidney and bile, and non-linear binding at high doses. Cefotaxime has a short half-life (1 hour) with an active metabolite. Ceftazidime is renally cleared (half-life 1.5 to 2 hours). Oral agents are modestly absorbed; cefixime has a half-life of 3 to 4 hours.

Gaps. Enterococci, Listeria, MRSA, atypicals; ceftriaxone has poor Pseudomonas activity; ceftazidime is unreliable against MSSA and streptococci; no agent is reliable for ESBL or AmpC-derepressed organisms.

• Ceftriaxone: once-daily, first line for meningitis, severe community infection, gonorrhoea, enteric fever, Lyme neuroborreliosis, spontaneous bacterial peritonitis and viridans streptococcal endocarditis.
• Cefotaxime: equivalent spectrum, used in neonates and where ceftriaxone interactions with calcium or bilirubin matter; needs frequent dosing.
• Ceftazidime: antipseudomonal use (melioidosis, febrile neutropenia, cystic fibrosis exacerbation), with a partner for Gram-positive cover.
• Cefixime, cefpodoxime, cefdinir: oral step-down; cefixime for gonorrhoea alternatives and enteric fever in children.

Adult regimens (normal renal function).

• Ceftriaxone 1 to 2 g IV or IM every 24 hours (maximum 4 g daily). Bacterial meningitis: 2 g every 12 hours. Gonorrhoea: 1 g IM once (500 mg in some regimens). Enteric fever: 2 g daily for 7 to 14 days. Viridans streptococcal endocarditis: 2 g daily for 4 weeks. Lyme neuroborreliosis: 2 g daily for 14 to 28 days. Spontaneous bacterial peritonitis: 2 g daily for 5 days; prophylaxis in variceal bleeding 1 g daily for up to 7 days.
• Cefotaxime 1 to 2 g IV every 8 hours; meningitis 2 g every 4 to 6 hours (maximum 12 g daily).
• Ceftazidime 2 g IV every 8 hours (maximum 6 g daily). Melioidosis: 2 g every 6 to 8 hours (or meropenem) for at least 10 to 14 days, followed by eradication therapy for 12 weeks.
• Cefixime 400 mg orally once daily or 200 mg every 12 hours; cefpodoxime 100 to 400 mg every 12 hours.
• Children: ceftriaxone 50 to 100 mg/kg daily (maximum 4 g); meningitis 100 mg/kg daily in one or two doses; cefotaxime 150 to 200 mg/kg daily in three or four divided doses; ceftazidime 150 mg/kg daily in three divided doses.

Selection. Empirical therapy for meningitis, sepsis of community origin, pyelonephritis, biliary sepsis (with metronidazole where anaerobes are likely), and enteric fever. Where AmpC producers (Enterobacter, Citrobacter freundii, Serratia) or ESBL producers are likely, cefepime or a carbapenem is preferred. Local resistance rates in enteric fever, E. coli and Klebsiella determine empirical value.

Contraindications. Severe hypersensitivity to cephalosporins. Ceftriaxone is contraindicated in neonates with hyperbilirubinaemia (displaces bilirubin), in premature neonates, and in neonates receiving or expected to receive calcium-containing intravenous fluids within 48 hours (fatal lung and kidney precipitates). In adults, calcium-containing fluids may be given sequentially with line flushing.

Serious effects. Anaphylaxis; C. difficile infection; biliary sludge and pseudolithiasis; immune haemolytic anaemia; encephalopathy and seizures in renal failure (ceftazidime); selection of ESBL carriage; neutropenia in prolonged courses.

Interactions. Warfarin, aminoglycosides, probenecid; calcium infusions with ceftriaxone in neonates.

Monitoring. Renal function; liver tests and full blood count weekly in prolonged courses; INR with warfarin; neurological state in renal impairment.

Special groups.

• Pregnancy and breastfeeding: acceptable.
• Renal impairment: ceftriaxone needs no adjustment unless combined with severe hepatic impairment (maximum 2 g daily). Cefotaxime: halve the dose when creatinine clearance is under 20 mL/min. Ceftazidime: 1 g every 12 hours at 31 to 50 mL/min; 1 g every 24 hours at 16 to 30 mL/min; 500 mg every 24 hours at 6 to 15 mL/min; 500 mg every 48 hours under 5 mL/min.
• Older adults: monitor for C. difficile and neurotoxicity.
• Region: ESBL carriage and resistant Salmonella Typhi are widespread in East Africa; ceftriaxone use is common and should be confined to clear indications.