Ceftriaxone
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Ceftriaxone
Class: Third-generation cephalosporin (β-lactam antibiotic)
Route: IV or IM only (not orally bioavailable)
Mechanism of Action
Ceftriaxone inhibits bacterial cell wall synthesis by binding penicillin-binding proteins (PBPs), blocking the final cross-linking step of peptidoglycan. This leads to a defective cell wall and bactericidal activity. Like all β-lactams, its core β-lactam ring is essential for this activity.
Antimicrobial Spectrum
Compared to 1st and 2nd-generation cephalosporins, ceftriaxone has expanded gram-negative coverage:
| Category | Coverage |
|---|---|
| Gram-positive | Streptococcus pneumoniae, Streptococcus spp., Staphylococcus aureus (MSSA only) |
| Gram-negative | Neisseria meningitidis, N. gonorrhoeae, Haemophilus influenzae (including β-lactamase producers), E. coli, Klebsiella, Proteus, Citrobacter, Serratia, Providencia |
| CSF penetration | Yes — adequate levels for meningitis |
| NOT active against | MRSA, Pseudomonas aeruginosa, Enterococcus, Listeria, AmpC/ESBL-producing organisms, anaerobes (limited), Enterobacter (risk of AmpC induction) |
Third-generation cephalosporins should be avoided for Enterobacter infections even if the isolate appears susceptible in vitro — AmpC derepression can produce resistance during therapy. — Katzung's Basic and Clinical Pharmacology, 16th Ed.
Pharmacokinetics
| Parameter | Value |
|---|---|
| Half-life | 7–8 hours (uniquely long — allows once-daily dosing) |
| Protein binding | High (~95%) |
| CNS penetration | Yes (adequate for bacterial meningitis) |
| Elimination | Biliary (35–45%) + renal; unlike all other 3rd-gen cephalosporins, no renal dose adjustment needed |
| IV peak | 60–140 mcg/mL after 1 g IV |
The biliary excretion is a key distinguishing feature — ceftriaxone is the only cephalosporin that does not require dose adjustment in renal failure. — Katzung's, p. 1251
Clinical Indications & Dosing
Adults
| Indication | Dose |
|---|---|
| Most serious infections | 1–2 g IV/IM q24h |
| Meningitis | 2 g IV q12h |
| Endocarditis / Osteomyelitis | 2 g IV q24h |
| Uncomplicated gonorrhea (<150 kg) | 500 mg IM × 1 dose |
| Uncomplicated gonorrhea (≥150 kg) | 1 g IM × 1 dose |
| PID (severe) | 1 g IV q24h + doxycycline + metronidazole × 14 days |
| Endocarditis prophylaxis (dental) | 1 g IV/IM 30–60 min before procedure |
Pediatric (Harriet Lane Handbook)
| Indication | Dose |
|---|---|
| Mild/moderate infections | 50–75 mg/kg/day ÷ q12–24h IV/IM (max 2 g/day) |
| Meningitis / severe | 100 mg/kg/day ÷ q12h IV/IM (max 2 g/dose, 4 g/day) |
| Lyme disease | 50–75 mg/kg/dose IV once daily (max 2 g/dose) |
| Acute otitis media | 50 mg/kg IM/IV × 1–3 doses (max 1 g/dose) |
| Gonococcal prophylaxis (neonate) | 25–50 mg/kg × 1 dose IM/IV (max 250 mg) |
Key Clinical Uses
- Bacterial meningitis — drug of choice (with vancomycin for empiric coverage pending susceptibilities; for penicillin MIC ≥2.0 µg/mL pneumococci, add vancomycin)
- Community-acquired pneumonia (moderate-severe, hospitalized)
- Gonorrhea and PID
- Lyme disease (neurologic or severe)
- Sepsis / bacteremia
- Intra-abdominal infections (often paired with metronidazole for anaerobic coverage)
- UTI (complicated)
- Surgical prophylaxis (some protocols)
- Endocarditis prophylaxis (penicillin-allergic patients)
Adverse Effects
- Hypersensitivity — rash, urticaria, anaphylaxis (cross-reactivity with penicillins is low but possible)
- GI — diarrhea, C. difficile colitis, transient elevated LFTs
- Biliary — reversible cholelithiasis/biliary sludging ("pseudolithiasis"), jaundice — due to high biliary concentration; use with caution in patients with gallbladder disease
- Hematologic — positive Coombs test, thrombocytopenia, leukopenia (rare)
- Neurologic — encephalopathy, seizures, myoclonus (post-marketing, rare)
- Lab interference — false-positive urinary glucose (Clinitest/Benedict's), interference with serum creatinine (Jaffe method)
Critical Safety Points
⚠ Neonates: Ceftriaxone is contraindicated in hyperbilirubinemic neonates (displaces bilirubin from albumin → kernicterus risk). Do not mix with IV calcium-containing solutions in any patient <28 days old — fatal ceftriaxone-calcium precipitates in lungs and kidneys have been reported. In neonates, an alternative 3rd-gen cephalosporin (e.g., cefotaxime) is preferred. — Harriet Lane Handbook, 23rd Ed.
No renal dose adjustment required — biliary excretion compensates.
Resistance Mechanisms
- ESBL-producing organisms — not susceptible (ESBLs hydrolyze extended-spectrum cephalosporins)
- AmpC β-lactamase — inducible in Enterobacter, Serratia, Citrobacter, Pseudomonas; avoid even if in vitro susceptible
- Ceftriaxone is not resistant to these enzymes; combination with β-lactamase inhibitors (as in ceftazidime-avibactam) addresses ESBL/AmpC resistance for other agents
Sources: Katzung's Basic and Clinical Pharmacology, 16th Ed. | Harriet Lane Handbook, 23rd Ed. | Goldman-Cecil Medicine | Lippincott Illustrated Reviews: Pharmacology
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