Ceftriaxone

Ceftriaxone is a once-daily parenteral third-generation cephalosporin and the most widely used injectable antibiotic for meningitis, community-acquired sepsis, severe pneumonia, enteric fever, gonorrhoea and Lyme neuroborreliosis.

Classification. Beta-lactam, third-generation cephalosporin.

Mechanism. Blocks penicillin-binding proteins; stable to many beta-lactamases but hydrolysed by ESBL and AmpC enzymes.

Spectrum. Streptococci, pneumococci (including intermediate penicillin resistance), meningococci, Haemophilus influenzae, Neisseria gonorrhoeae, Salmonella, Borrelia, MSSA (moderate), and non-ESBL Enterobacterales. Not active against Pseudomonas, Enterococcus, Listeria, MRSA or most anaerobes.

Pharmacokinetics. IV or IM. Half-life 6 to 9 hours. Protein binding 85 to 95%, concentration-dependent. Elimination is about 50% renal and 50% biliary, so adjustment is needed only in combined severe kidney and liver failure. Good CSF penetration with inflamed meninges.

No loading dose. Maximum 4 g daily.

Adults.

• Pneumonia, urinary, skin, intra-abdominal and pelvic infection: 1 to 2 g IV or IM once daily.
• Sepsis and bacteraemia: 2 g IV once daily.
• Bacterial meningitis: 2 g IV every 12 hours (4 g daily) for 7 to 14 days depending on organism.
• Streptococcal endocarditis (susceptible): 2 g once daily for 4 weeks, or with gentamicin for 2 weeks in selected cases.
• Enterococcal endocarditis: 2 g every 12 hours with ampicillin 2 g every 4 hours for 6 weeks.
• Enteric fever, severe: 2 to 4 g IV once daily for 10 to 14 days (by susceptibility).
• Uncomplicated gonorrhoea: 1 g IM as a single dose.
• Lyme neuroborreliosis: 2 g once daily for 14 to 28 days.
• Spontaneous bacterial peritonitis: 2 g once daily for 5 days.
• Variceal haemorrhage prophylaxis in cirrhosis: 1 g once daily for up to 7 days.
• Surgical prophylaxis: 1 to 2 g IV before incision.
• Epidemic meningococcal disease with limited resources: a single dose of 100 mg/kg (adults 4 g) is used in some settings.

Children. 50 to 80 mg/kg once daily (maximum 4 g); meningitis 100 mg/kg/day as one dose or split every 12 hours (maximum 4 g daily).

Neonates. 20 to 50 mg/kg once daily; avoid in premature neonates, jaundice and any neonate who needs calcium-containing IV fluids.

Alternatives. Cefotaxime, cefepime, meropenem for ESBL or AmpC.

Contraindications. Cephalosporin hypersensitivity. In neonates under 28 days: hyperbilirubinaemia, prematurity and concurrent calcium-containing IV solutions.

Calcium precipitation. Fatal pulmonary and renal precipitates have occurred in neonates given ceftriaxone and calcium. In patients over 28 days the two may be given sequentially through compatible lines after a thorough flush, but never mixed or given together at a Y-site.

Adverse effects. Diarrhoea, rash, injection-site pain, eosinophilia. Serious: anaphylaxis, biliary sludge and pseudolithiasis (especially with high doses, children and fasting), immune haemolytic anaemia, Clostridioides difficile infection, severe cutaneous reactions, encephalopathy in renal failure, kernicterus in neonates.

Interactions. Calcium-containing infusions; warfarin INR rise; probenecid does not change clearance meaningfully; aminoglycosides (physical incompatibility); oral typhoid vaccine.

Common prescribing errors. Mixing with calcium, once-daily dosing for meningitis, using it for Listeria or ESBL infection, and giving to a jaundiced neonate.

Special groups. - Pregnancy and breastfeeding: acceptable. - Older adults: no routine adjustment. - Kidney impairment: no change unless liver failure coexists; with combined impairment limit to 2 g daily. - Liver impairment: no change unless kidney failure coexists. - Region: widely used in East Africa; MDR typhoid and ESBL Enterobacterales reduce effectiveness in some settings, and local susceptibility guides empirical choice.

Preparation. IV: reconstitute with water for injection and give by injection over 2 to 4 minutes (1 g in 10 mL) or infuse over 30 minutes (60 minutes in neonates). IM: dissolve 1 g in 3.5 mL of 1% lidocaine without adrenaline; maximum 1 g at one site. Never use lidocaine solutions for IV injection.

Baseline and monitoring. - Baseline: allergy history, cultures before first dose, bilirubin in neonates, full blood count, creatinine. - During treatment: full blood count and liver tests weekly in prolonged courses; abdominal ultrasound if biliary pain. - No therapeutic drug monitoring.

Stop rules. Stop for anaphylaxis, severe skin reaction, haemolysis or symptomatic biliary sludge.

Referral and escalation. Infectious diseases for endocarditis, neurological infection and treatment failure at 48 to 72 hours; neonatal or paediatric teams for any neonatal use.