Ceftriaxone

1. Drug Name

• Generic Name: Ceftriaxone

• Brand Names: Rocephin, Ceftriax, Ceftriox, and others.

2. Drug Classification

• Class: Antibiotic, Cephalosporin

• Subclass: Third-Generation Cephalosporin

3. Mechanism of Action

• Primary Action: Ceftriaxone is a broad-spectrum cephalosporin antibiotic that inhibits bacterial cell wall synthesis. It binds to and inactivates penicillin-binding proteins (PBPs), essential for bacterial cell wall formation. This leads to a weakened cell wall and eventual bacterial cell lysis, particularly in rapidly dividing bacteria.

• Spectrum of Activity: Ceftriaxone has a broad spectrum of activity against both gram-positive and gram-negative bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, Neisseria gonorrhoeae, Escherichia coli, and Klebsiella pneumoniae. It is resistant to many beta-lactamases, which makes it effective against organisms that produce these enzymes.

• Resistance: Some resistance occurs due to extended-spectrum beta-lactamases (ESBLs) or other resistance mechanisms in certain gram-negative pathogens, limiting its activity.

4. Pharmacokinetics

• Absorption: Ceftriaxone is not absorbed orally and must be administered parenterally (IV or IM). It has excellent bioavailability when given via these routes.

• Distribution: Ceftriaxone is widely distributed throughout the body, including the cerebrospinal fluid (CSF) when the meninges are inflamed, as well as the lungs, liver, kidneys, and bones. It has a large volume of distribution (Vd), indicating good tissue penetration.

• Metabolism: Ceftriaxone is not extensively metabolized in the liver but is instead excreted mostly unchanged in the urine. It is, however, partially metabolized to inactive metabolites.

• Excretion: The drug is predominantly excreted unchanged via the kidneys. Its half-life is approximately 6–9 hours, allowing for once-daily dosing in most cases.

• Special Considerations: Ceftriaxone does not require dose adjustments for mild-to-moderate liver impairment but does need adjustment for renal insufficiency, particularly in patients with a creatinine clearance (CrCl) less than 30 mL/min.

5. Indications

• Primary Indications:

  • Severe Infections: Ceftriaxone is indicated for a wide range of severe infections, including:

    • Pneumonia, including community-acquired pneumonia (CAP).

    • Bacterial meningitis (especially in pediatric patients).

    • Intra-abdominal infections (e.g., peritonitis).

    • Pyelonephritis and other complicated urinary tract infections (UTIs).

    • Septicemia and bacteremia.

    • Gonorrhea (uncomplicated).

    • Bone and joint infections (e.g., osteomyelitis).

    • Skin and soft tissue infections (e.g., cellulitis).

  • Surgical Prophylaxis: It is also used for prophylaxis in surgical procedures, particularly in high-risk surgeries like colorectal surgery.

• Off-label Uses:

  • Endocarditis (as part of combination therapy).

  • Lymes Disease (as part of combination therapy in children, particularly for central nervous system involvement).

  • Empiric Therapy for febrile neutropenia in combination with other antibiotics.

• Specific Populations: Ceftriaxone is used for serious infections in children, elderly, and immunocompromised patients, though it is contraindicated in neonates for specific conditions (see contraindications).

6. Dosage and Administration

• Adult Dosing:

  • Infections: The usual dose is 1–2 grams IV/IM once daily, with adjustments based on infection severity. For severe infections, doses can be increased up to 4 grams per day.

  • Meningitis: 2 grams IV once daily, typically for 7-14 days, depending on the causative organism.

  • Gonorrhea: Single 250 mg IM dose.

• Pediatric Dosing:

  • Infections: 50–75 mg/kg IV/IM once daily, typically up to 2 grams per day.

  • Meningitis: 100 mg/kg IV once daily, not exceeding 4 grams per day.

• Renal/Hepatic Adjustments: In patients with severe renal impairment (CrCl <30 mL/min), dose adjustments are necessary. Ceftriaxone can accumulate in patients with renal failure, and dosing frequency may need to be reduced. No adjustment is needed for mild liver impairment.

• Route of Administration: IV or IM (typically for hospital or outpatient use). The IM injection should be administered slowly into a large muscle mass to prevent tissue irritation.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity to ceftriaxone, cephalosporins, or any component of the formulation.

  • Neonates ≤28 days of age, especially those requiring calcium-containing intravenous solutions, as ceftriaxone can precipitate with calcium in the lungs and kidneys leading to fatal outcomes.

• Relative Contraindications:

  • Renal Impairment: Caution should be exercised in patients with severe renal impairment, as dose adjustments are necessary.

  • Gallbladder Disease: Ceftriaxone can cause biliary sludge or pseudocholelithiasis (gallbladder stones), particularly with prolonged therapy.

8. Warnings and Precautions

• Allergic Reactions: As with all beta-lactam antibiotics, serious hypersensitivity reactions, including anaphylaxis, may occur. Patients with a known history of penicillin allergy should use ceftriaxone with caution.

• Clostridium difficile-associated Diarrhea (CDAD): Ceftriaxone can alter gut flora, which may lead to CDAD, a potentially life-threatening condition.

• Biliary Sludging: Ceftriaxone has been associated with the formation of biliary precipitates, particularly in children. This may result in asymptomatic hyperbilirubinemia or gallbladder sludge, though this is not typically clinically significant unless accompanied by symptoms.

• Renal Impairment: Use caution in patients with renal failure. Renal function should be monitored during therapy, especially in those on prolonged treatment.

9. Adverse Effects

• Common Adverse Effects (≥10%):

  • Diarrhea

  • Rash

  • Nausea

  • Vomiting

  • Pain or swelling at the injection site (for IM/IV administration)

• Less Common but Clinically Significant:

  • Hypersensitivity reactions: urticaria, angioedema, anaphylaxis

  • Biliary sludge (particularly in children) and pseudomembranous colitis

  • Elevated liver enzymes (transaminases), especially with prolonged therapy

  • Seizures (rare)

• Serious Adverse Reactions:

  • Hematologic: eosinophilia, thrombocytopenia, leukopenia, agranulocytosis

  • Hepatic: cholestatic jaundice, liver toxicity

  • Renal: interstitial nephritis, acute renal failure

  • Serious allergic reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis

10. Drug Interactions

• Major Drug Interactions:

  • Calcium-containing Solutions (e.g., Ringer’s lactate): In neonates, ceftriaxone can bind with calcium, leading to fatal precipitates in the lungs and kidneys. Therefore, ceftriaxone should not be used in combination with calcium-containing intravenous solutions in neonates.

  • Warfarin: Ceftriaxone can enhance the anticoagulant effect of warfarin by altering the gut flora and reducing vitamin K production, increasing the risk of bleeding.

  • Probenecid: Probenecid inhibits the renal excretion of ceftriaxone, increasing its serum concentration.

• Food-Drug Interactions: There are no significant food-drug interactions with ceftriaxone, though it should be administered parenterally for optimal bioavailability.

• Lab Test Interference: Ceftriaxone may interfere with certain laboratory tests, including the Coombs test and some blood glucose tests.

11. Clinical Pharmacology

• Pharmacodynamics: Ceftriaxone is bactericidal, with a prolonged half-life that allows for once-daily dosing. It is effective against a broad range of pathogens, particularly gram-negative organisms and some resistant gram-positive bacteria.

• Additional Effects: Ceftriaxone is especially useful for treating infections caused by Neisseria gonorrhoeae and other sensitive organisms in the outpatient setting. Its excellent penetration into the CSF makes it a key agent for bacterial meningitis.

12. Special Populations

• Pregnancy: Category B – No known risk to the fetus in humans. Ceftriaxone is considered safe for use during pregnancy, especially in treating serious infections.

• Lactation: Ceftriaxone is excreted into breast milk in small amounts, but it is generally considered safe for breastfeeding mothers.

• Pediatrics: Ceftriaxone is commonly used in pediatric patients, especially for infections like meningitis and pneumonia. However, it should be avoided in neonates due to the risk of precipitating calcium-binding.

• Geriatrics: No specific dosage adjustments are necessary for elderly patients unless renal dysfunction is present.

• Renal/Hepatic Dysfunction: Dose adjustments are required for patients with renal failure (CrCl <30 mL/min). Liver adjustments are generally not required unless there is hepatic dysfunction.

13. Therapeutic Uses

• First-line Indications:

  • Meningitis, pneumonia, and gonorrhea.

  • Empiric therapy for febrile neutropenia and intra-abdominal infections.

  • Surgical prophylaxis in high-risk surgeries.

• Combination Therapy: Ceftriaxone may be used in combination with other antibiotics like metronidazole or aminoglycosides for synergistic effects in polymicrobial infections.

14. Monitoring and Follow-Up

• Lab Tests: Monitoring of renal function (serum creatinine) is important, especially in patients with preexisting renal conditions or those on long-term therapy.

• Symptom Monitoring: Watch for any signs of hypersensitivity reactions, gastrointestinal symptoms, or changes in liver function.

• Toxicity Monitoring: Although rare, monitor for any signs of hematological abnormalities or renal dysfunction.

15. Overdose Management

• Symptoms of Overdose: Symptoms may include gastrointestinal distress, nausea, vomiting, diarrhea, and, rarely, seizures.

• Treatment Protocols: In the case of overdose, gastric lavage and activated charcoal may be employed within a few hours of ingestion. There is no specific antidote for ceftriaxone overdose, and management is symptomatic.

• Supportive Measures: In cases of severe overdose, monitoring of renal and hepatic function is recommended, and symptomatic management should be employed.

16. Patient Counseling Information

• Key Points to Discuss with Patients:

  • Complete the entire course of therapy as prescribed, even if symptoms resolve before finishing the medication.

  • Notify healthcare providers of any history of allergies, especially to cephalosporins or penicillin.

  • Inform the healthcare provider if you experience symptoms of an allergic reaction, such as rash, swelling, or difficulty breathing.

• Signs/Symptoms to Watch For:

  • Seek medical help if you experience signs of a severe allergic reaction or gastrointestinal symptoms like blood in stools.

  • Notify your provider if you have a history of gastrointestinal conditions or experience persistent diarrhea during therapy.