What is the pharmacokinetic/pharmacodynamic (PK/PD) dosing of ceftriaxone?

Ceftriaxone Pharmacokinetics and Pharmacodynamic Dosing

Ceftriaxone exhibits time-dependent bacterial killing with optimal efficacy when free drug concentrations remain above the MIC for 60-70% of the dosing interval, which is achieved through once or twice-daily dosing depending on infection severity and site. 1, 2

Key Pharmacokinetic Parameters

Absorption and Distribution

• Peak concentrations after IV infusion: 151 mcg/mL (1g dose) and 257 mcg/mL (2g dose) at 30 minutes post-infusion 3
• Bioavailability after IM injection is complete, with peak concentrations occurring at 2-3 hours: 81 mcg/mL (1g IM) and 46 mcg/mL (0.5g IM) 3, 4
• Volume of distribution: 5.78-13.5 L in healthy adults, indicating good tissue penetration 3
• Protein binding: 85-95% (concentration-dependent and saturable), with binding decreasing from 95% at concentrations <25 mcg/mL to 85% at 300 mcg/mL 3, 2

Elimination Characteristics

• Half-life in healthy adults: 5.8-8.7 hours 3
• Half-life in renal impairment: 11.9 hours (moderate, CrCl 31-60 mL/min) to 15.6 hours (severe, CrCl <15 mL/min) 5
• Excretion: 33-67% excreted unchanged in urine; remainder secreted in bile 3
• No dosage adjustment needed for renal or hepatic impairment up to 2g daily 3

Pharmacodynamic Principles

PK/PD Target Parameters

• Free AUIC (AUC/MIC) ≥125 is required for optimal efficacy, particularly in severe infections like meningitis 2
• Time above MIC (T>MIC): Ceftriaxone maintains concentrations above MIC for most susceptible organisms for 12-24 hours after a single 1g dose 4
• CSF penetration: Achieves 5.6 mcg/mL (50 mg/kg dose) to 6.4 mcg/mL (75 mg/kg dose) in inflamed meninges 3

MIC Considerations

• 1g daily dosing is adequate for organisms with MIC ≤2 mg/L 2
• Higher doses or twice-daily dosing required for organisms with MIC >2 mg/L or ceftriaxone-resistant strains 1, 2
• Treatment failures reported with 250-500mg doses, particularly for pharyngeal infections with elevated MICs 1

Clinical Dosing Algorithms

Adult Dosing by Infection Severity

Mild-to-Moderate Infections:

• 1g IV/IM once daily for most community-acquired infections (pneumonia, UTI, soft tissue) 1, 6
• Maintains therapeutic concentrations for 24 hours against susceptible pathogens 4

Severe Infections (Meningitis, Endocarditis):

• 2g IV every 12 hours (total 4g daily) for bacterial meningitis to ensure adequate CSF concentrations throughout dosing interval 1
• 2g IV once daily for endocarditis caused by highly susceptible organisms (MIC ≤0.12 μg/mL) 1
• 1-2g IV every 12 hours for gonococcal meningitis/endocarditis for 10-14 days (meningitis) or ≥4 weeks (endocarditis) 1

Disseminated Infections:

• 1g IM/IV every 24 hours for disseminated gonococcal infection, continuing 24-48 hours after clinical improvement, then switch to oral therapy 1

Pediatric Dosing

Neonates and Infants:

• 50 mg/kg once daily for UTI or bacteremia in infants 22-60 days old 7
• 25-50 mg/kg/day for neonatal gonococcal infections (7-14 days depending on site) 1
• 100 mg/kg/day divided every 12 hours OR 80 mg/kg/day once daily (maximum 4g) for endocarditis 7, 8

Meningitis (Special Consideration):

• 50-75 mg/kg IV achieves CSF concentrations of 5.6-6.4 mcg/mL with half-life of 4.3-4.6 hours 3
• Infants 22-28 days should receive ampicillin plus ceftazidime (NOT ceftriaxone) every 8 hours 7

Critical Dosing Pitfalls

When Standard Dosing Fails

• Elevated MICs (>2 mg/L): Increase to 2g twice daily or consider alternative agents 1, 2
• Penicillin-resistant pneumococci: Add vancomycin 15-20 mg/kg IV twice daily or rifampin 600mg twice daily to ceftriaxone regimen 1
• Patients ≥60 years with meningitis: Add amoxicillin 2g IV every 4 hours to cover Listeria monocytogenes 1

Protein Binding Considerations

• Only free (unbound) drug is microbiologically active 2
• At therapeutic concentrations, approximately 10-15% remains unbound and available for bacterial killing 2
• Free AUIC calculations are essential for predicting efficacy in severe infections 2

Accumulation with Multiple Dosing

• 15-36% accumulation occurs with repeated 12-24 hour dosing intervals 3
• This accumulation is beneficial and does not require dose adjustment in patients with normal renal function 3

Outpatient Parenteral Therapy Considerations

• Once-daily dosing (1-2g) is ideal for OPAT due to long half-life and convenience 7, 1
• Twice-daily dosing initially (2g every 12 hours), then transition to 4g once daily after 24 hours for stable, improving patients with reliable IV access 1
• Ceftriaxone stability and infrequent dosing reduce healthcare costs without compromising efficacy 7, 1