Ceftriaxone - Drug Monograph

Introduction

Ceftriaxone is a broad-spectrum third-generation cephalosporin antibiotic widely used in clinical practice. It was first approved by the FDA in 1984 and remains a cornerstone of therapy for numerous bacterial infections due to its extended spectrum of activity against Gram-positive and Gram-negative organisms, convenient once-daily dosing, and excellent tissue penetration.

Mechanism of Action

Ceftriaxone exerts its bactericidal effect by inhibiting bacterial cell wall synthesis. It binds to penicillin-binding proteins (PBPs) located on the inner membrane of the bacterial cell wall. This binding disrupts the final transpeptidation step of peptidoglycan synthesis, resulting in the formation of defective cell walls and subsequent osmotic instability and cell lysis. As a beta-lactam antibiotic, its activity is enhanced against Gram-negative bacteria due to improved stability against beta-lactamases compared to earlier cephalosporins.

Indications

FDA-approved indications include:

• Lower respiratory tract infections
• Skin and skin structure infections
• Urinary tract infections
• Uncomplicated gonorrhea
• Pelvic inflammatory disease
• Bacterial septicemia
• Bone and joint infections
• Intra-abdominal infections
• Meningitis
• Surgical prophylaxis

Off-label uses include:

• Lyme disease (neurologic manifestations)
• Endocarditis prophylaxis in high-risk patients
• Typhoid fever
• Spontaneous bacterial peritonitis

Dosage and Administration

• Adults: 1-2 g IV/IM every 24 hours
• Severe infections: Up to 2 g every 12 hours
• Meningitis: 2 g IV every 12 hours
• Gonorrhea: 250 mg IM single dose

• Renal impairment: No dosage adjustment required
• Hepatic impairment: Maximum 2 g/day in combined hepatic/renal impairment
• Elderly: No dosage adjustment required
• Pediatrics: 50-75 mg/kg/day (not to exceed 2 g/day)
• Neonates: Dose varies by age and weight

• IV: Dilute in appropriate IV fluid, infuse over 30 minutes
• IM: Reconstitute with 1% lidocaine HCl to reduce pain

Pharmacokinetics

• Absorption: Well absorbed after IM administration; complete bioavailability with IV administration
• Distribution: Extensive tissue penetration, including CSF (especially with inflamed meninges), volume of distribution ~5.8-13.5 L
• Protein binding: Concentration-dependent, 85-95% bound to plasma proteins
• Metabolism: Not significantly metabolized
• Elimination: Dual elimination pathway (renal and biliary), half-life 6-9 hours
• Excretion: 33-67% excreted unchanged in urine, remainder in feces

Contraindications

• Known hypersensitivity to ceftriaxone or other cephalosporins
• History of severe hypersensitivity reactions to penicillins or other beta-lactams
• Hyperbilirubinemic neonates, particularly those premature
• Use of calcium-containing IV solutions in neonates

Warnings and Precautions

• Hypersensitivity reactions: Cross-reactivity may occur in penicillin-allergic patients (approximately 1-10%)
• Clostridium difficile-associated diarrhea: May range from mild to life-threatening
• Hemolytic anemia: Has been reported with cephalosporins
• Seizure risk: May occur in patients with renal impairment when doses are not appropriately adjusted
• Biliary sludge: Reversible pseudolithiasis may occur
• Vitamin K deficiency: May occur with prolonged use due to suppression of gut flora
• Superinfection: Possible emergence of resistant organisms

Drug Interactions

• Warfarin: May potentiate anticoagulant effect (monitor INR)
• Calcium-containing products: Risk of precipitation in neonates and infants
• Aminoglycosides: Potential additive nephrotoxicity
• Probenecid: May decrease renal excretion and increase ceftriaxone levels
• Chloramphenicol: Antagonistic effect possible
• Oral contraceptives: Possible decreased efficacy

Adverse Effects

• Diarrhea (2-7%)
• Injection site reactions (1-2%)
• Rash (1-2%)
• Elevated liver enzymes (1-3%)

• Anaphylaxis
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Hemolytic anemia
• Neutropenia/thrombocytopenia
• Pseudomembranous colitis
• Interstitial nephritis
• Seizures
• Biliary pseudolithiasis

Monitoring Parameters

• Clinical response to therapy
• Signs of hypersensitivity reactions
• Complete blood count with differential
• Liver function tests
• Renal function tests
• Coagulation parameters with prolonged therapy
• Stool frequency and consistency (for C. difficile)
• Therapeutic drug monitoring in special populations

Patient Education

• Complete the full course of therapy even if feeling better
• Report any signs of allergic reaction (rash, itching, swelling)
• Report severe diarrhea, especially if bloody or containing mucus
• Avoid alcohol during and for 72 hours after therapy completion
• Inform healthcare providers of all medications being taken
• Use alternative contraception if taking oral contraceptives
• Report unusual bleeding or bruising
• Notify provider if pregnant or planning pregnancy

References

1. Ceftriaxone [package insert]. Lake Forest, IL: Hospira Inc.; 2021. 2. Bradley JS, Wassel RT, Lee L, et al. Intravenous ceftriaxone administration. Clin Infect Dis. 2020;71(2):489-496. 3. Owens RC Jr, Ambrose PG. Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis. 2005;41 Suppl 2:S144-S157. 4. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(2):147-159. 5. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52(3):e18-e55. 6. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267-1284. 7. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing. 32nd ed. CLSI supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2022.