What are the contraindications for using Ceftriaxone (a cephalosporin antibiotic) in patients, particularly those with a history of severe hypersensitivity reactions, hyperbilirubinemia, or impaired renal function?

Ceftriaxone Contraindications

Absolute Contraindications

Ceftriaxone is absolutely contraindicated in patients with known hypersensitivity to ceftriaxone or any cephalosporin, in premature neonates up to 41 weeks postmenstrual age, in hyperbilirubinemic neonates, and in neonates ≤28 days requiring calcium-containing IV solutions. 1

Hypersensitivity Reactions

• Documented ceftriaxone allergy: Patients with prior confirmed hypersensitivity to ceftriaxone must avoid the drug entirely 1
• Other cephalosporin allergies with similar side chains: Cross-reactivity occurs primarily through R1 side chain similarity, not the beta-lactam ring 2
  • Ceftriaxone shares R1 side chains with amoxicillin, ampicillin, and cefotaxime 2
  • Patients with immediate-type allergies to these agents should avoid ceftriaxone 2
• Severe delayed-type reactions: Patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome to any beta-lactam should avoid all beta-lactams including ceftriaxone 2, 3

Penicillin Allergy Considerations

• Cross-reactivity between penicillins and cephalosporins is only 2-4.8%, far lower than the historically cited 10% 2
• The key determinant is R1 side chain similarity, not the shared beta-lactam ring 2
• Patients with penicillin allergies can receive ceftriaxone if they tolerated penicillins with dissimilar side chains (e.g., piperacillin) 2
• Patients with confirmed immediate-type reactions to amoxicillin or ampicillin should avoid ceftriaxone due to identical R1 side chains 2, 3

Neonatal Contraindications

Age-Based Restrictions

• Premature neonates: Absolutely contraindicated up to 41 weeks postmenstrual age (gestational age + chronological age) 1
• Term neonates ≤28 days: Contraindicated if requiring calcium-containing IV solutions 1

Hyperbilirubinemia

• All hyperbilirubinemic neonates must not receive ceftriaxone 1
• Ceftriaxone displaces bilirubin from serum albumin binding sites, creating risk of bilirubin encephalopathy 1
• This contraindication applies regardless of the degree of hyperbilirubinemia 1

Calcium-Containing Solutions

• Fatal ceftriaxone-calcium precipitation has occurred in neonatal lungs and kidneys 1
• Never administer ceftriaxone to neonates ≤28 days who require or are expected to require calcium-containing IV solutions, including parenteral nutrition 1
• Crystalline material observed at autopsy in fatal cases, sometimes with visible precipitate in IV lines 1
• This contraindication is specific to neonates; older patients require 48-hour separation between ceftriaxone and calcium-containing solutions 4

Nuanced Neonatal Considerations

• The evidence against ceftriaxone in neonates remains limited, particularly given the cefotaxime shortage 5
• In low-risk term neonates without hyperbilirubinemia and no calcium exposure, ceftriaxone could be considered on a case-by-case basis 5
• This represents expert opinion balancing theoretical risk against lack of therapeutic alternatives 5

Relative Contraindications and Precautions

Renal Impairment

• Dosage adjustment is NOT necessary for renal impairment when daily dose is ≤2g 6
• Ceftriaxone has dual hepatic and renal elimination, providing a safety margin 6
• Elimination half-life increases only twofold (from ~6.5 to 11.7-17.3 hours) even in severe renal impairment 6, 7
• Plasma clearance decreases less than 50% in renal failure 6
• Monitor plasma concentrations in dialysis patients, as a small percentage show substantially prolonged half-life 6
• Hemodialysis does not significantly remove ceftriaxone 6

Combined Hepatic and Renal Dysfunction

• Dosage modification is necessary only when both hepatic AND renal dysfunction coexist 7
• This reflects ceftriaxone's dual elimination pathway 7

Lidocaine Considerations

• IV administration of ceftriaxone solutions containing lidocaine is absolutely contraindicated 1
• When using lidocaine as a solvent for IM injection, verify all lidocaine contraindications first 1

Common Pitfalls to Avoid

• Do not assume cephalosporin cross-reactivity based on class alone—side chain structure determines risk 2, 8
• Tolerance to one cephalosporin (e.g., cefazolin) does not predict tolerance to ceftriaxone if side chains differ 8
• A documented case showed anaphylaxis to ceftriaxone despite tolerating 4 days of cefazolin, mediated by ceftriaxone's unique R2 side chain 8
• Do not use the 48-hour calcium separation rule in neonates ≤28 days—they require absolute avoidance 1
• Do not reflexively avoid ceftriaxone in all penicillin-allergic patients—only those with reactions to amoxicillin/ampicillin require avoidance 2