Generic Name

Ceftriaxone

Mechanism

• Inhibition of cell‑wall synthesis: Binds to penicillin‑binding proteins (PBPs) 2, 3, 4, and 5, preventing cross‑linking of the peptidoglycan layer.
• Result: Leads to osmotic lysis and bacterial death, primarily bactericidal.
• Note: Activity is preserved against β‑lactamases (except extended‑spectrum β‑lactamases) and is not substantially affected by oxidoreductase or efflux mechanisms.

Pharmacokinetics

• Absorption: Not absorbed orally; given IV or IM.
• Distribution: Highly protein‑bound (~8595 % to albumin). Extensively distributes into tissues (CSF, meninges, lungs, joints) and achieves therapeutic concentrations in CSF even with a normal BBB.
• Metabolism: Minimal hepatic metabolism; largely excreted unchanged.
• Elimination: Renally cleared.
• Half‑life: ~8 h in healthy adults; prolongs to ~12 h in elderly/renal impairment.
• Steady‑state: Achieved after 2‑3 days with continuous infusion.

Indications

• Severe meningoencephalitis (e.g., *Neisseria meningitidis*, *Streptococcus pneumoniae*).
• Hospital‑acquired pneumonia (including ventilator‑associated).
• Bacterial sepsis (Gram‑negative sepsis).
• Complicated intra‑abdominal infections (with *Enterobacteriaceae*, *Escherichia coli*).
• Severe skin/soft‑tissue infections (SAB, *Streptococcus pyogenes*).
• Pelvic inflammatory disease, *Chlamydia trachomatis* in concomitant therapy.
• Empiric therapy for community‑acquired pneumonia with potential Listeria contamination (if combined with ampicillin).

Contraindications

• Anaphylaxis or severe hypersensitivity to cephalosporins (cross‑reactivity with penicillins).
• History of severe granulocytopenia from previous ceftriaxone.
• Severe hepatic impairment: increased serum levels; use cautiously.
• Biliary disease: risk of bilirubin gallstones and sludge; avoid in patients with biliary obstruction.
• Pregnancy: Category C; use only if benefits outweigh risks.
• Pediatric use: Age < 2 yrs and renal impairment: dose adjustment needed.

Warnings:
• Potential for superinfection (e.g., C. difficile); monitor diarrhea.
• Neutropenia, thrombocytopenia, and serum electrolyte disturbances (hypophosphatemia, hypomagnesemia).
• Allergic reactions may be severe; monitor for anaphylaxis.
• Drug interactions: May potentiate the anticoagulant effect of heparin; monitor aPTT.

Dosing

• Administration tip: Dilute in 250 mL normal saline; infuse over 60–120 min to minimize infusion‑related reactions.
• Loading dose: Often 2 g IV for severe infections; subsequent maintenance as per above.

Adverse Effects

Common (≤ 10 %)
• GI: Nausea, vomiting, mild diarrhea.
• Hepatic: Transient transaminase elevation (often  10 %)**
• Allergic reactions: Anaphylaxis, urticaria, angioedema.
• Hematologic: Neutropenia, thrombocytopenia, anemia.
• Nephrotoxicity: Acute tubular necrosis in high doses or renal impairment.
• Metabolic: Hypophosphatemia, hypomagnesemia (especially with repeated high doses).
• Superinfection: C. difficile colitis, yeast overgrowth.

Rare (≤ 1 %)
• Seizures (high CNS concentrations).
• Liver failure/acute hepatic injury.
• Bile duct stone formation in pediatric patients.

Monitoring

• Renal function: Serum creatinine, BUN, CrCl before dosing and every 3–5 days (or sooner if clinical decline).
• Liver profile: ALT, AST, bilirubin baseline and every 5–7 days.
• Complete blood count (CBC): Baseline, every 4–7 days during therapy.
• Electrolytes (phosphate, magnesium): Baseline, then every 5–7 days if high dose > 2 g daily.
• Signs of superinfection: Monitor stool for blood/mucus; consider DIC scoring if severe GI symptoms.
• Infusion reactions: Observe for 30 min post‑infusion for hypersensitivity.

Clinical Pearls

• Dual therapy synergy: Combine with vancomycin for MRSA coverage in CAP or SSTI when local resistance is a concern; avoid overlap with piperacillin‑tazobactam to reduce resistance pressure.
• CSF penetration: Despite reduced CSF penetration after 1 g IV daily, continuous infusion (e.g., 2 g/24 h) maintains therapeutic CSF trough levels in meningitis.
• Immunocompromised patients: Use 2 g IV every 12 h for *Neisseria meningitidis* in neutropenic hosts; consider IVIg if severe sepsis.
• Reversal of drug‑induced leucopenia: G‑CSF can be considered in patients developing neutropenia after 7+ days of ceftriaxone.
• Differential diagnosis in rash: Separate ceftriaxone‑induced exanthema from polymorphic drug reactions; SJS/TEN are rare but necessitate discontinuation.
• Drug interactions: Avoid concurrent use of ceftriaxone and tetracyclines due to mutual antagonism in treating *H. influenzae*.
• Pediatric dosing intricacies: In children under 2 years, consider ampicillin‑ceftriaxone for meningitis to cover Listeria, but monitor for *C. difficile* due to broad spectrum.
• Renal dosing nuances: Despite 85 % protein binding, volume of distribution does not adequately mask cumulative toxicity in renal failure; thus, hold dosing interval in CrCl < 30 mL/min.

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• References for quick access
• Lexicomp® (Ceftriaxone).
• Sanford Guide to Antimicrobial Therapy, 2024 edition.
• FDA Drug Label, Ceftriaxone (3‑M, 2002).
• UpToDate: Ceftriaxone dosing & Toxicity.