What are the possible drug interactions with intravenous ceftriaxone?

Drug Interactions with Intravenous Ceftriaxone

Critical Calcium-Containing Solutions Interaction

The most clinically significant drug interaction with IV ceftriaxone is with calcium-containing solutions, which can form fatal precipitates and is absolutely contraindicated in neonates ≤28 days old. 1

Calcium Interaction Details:

• Do not use diluents containing calcium (Ringer's solution, Hartmann's solution) to reconstitute or dilute ceftriaxone 1
• Never administer simultaneously with calcium-containing IV solutions via Y-site, including parenteral nutrition 1
• Neonates (≤28 days): Absolute contraindication for any calcium-containing IV solutions due to risk of ceftriaxone-calcium precipitation and death 1, 2
• Patients >28 days: May receive ceftriaxone and calcium-containing solutions sequentially only if infusion lines are thoroughly flushed between administrations with compatible fluid 1, 3
• Cardiopulmonary adverse events including seven infant deaths have been reported with concomitant ceftriaxone-calcium infusion 2

Common Pitfall:

The physical binding of ceftriaxone to calcium salts when both are given intravenously can cause precipitation leading to end-organ damage 4. This interaction does not occur with oral calcium products or intramuscular ceftriaxone 1.

Incompatible Antimicrobials in Admixtures

Ceftriaxone is physically incompatible with several antimicrobials and must not be mixed in the same solution or administered simultaneously through the same IV line. 1

Incompatible Drugs Requiring Sequential Administration:

• Vancomycin: Incompatible in admixtures; must be given sequentially with thorough line flushing between administrations 5, 1
• Aminoglycosides: Incompatible in admixtures; administer sequentially with line flushing 1
• Amsacrine: Incompatible in admixtures 1
• Fluconazole: Incompatible in admixtures 1

Administration Protocol for Incompatible Drugs:

When these drugs must be given with ceftriaxone, administer by intermittent IV infusion sequentially, with thorough flushing of IV lines with compatible fluids between administrations 1. Simultaneous administration may lead to precipitation, reduced efficacy, and potential catheter occlusion 5.

Compatible Drug Combination

Metronidazole (Flagyl IV) is compatible with ceftriaxone at specific concentrations:

• Concentration must not exceed 5-7.5 mg/mL metronidazole with ceftriaxone 10 mg/mL 1
• Admixture stable for 24 hours at room temperature only in 0.9% sodium chloride or 5% dextrose 1
• Do not refrigerate the admixture as precipitation will occur 1
• Metronidazole concentrations >8 mg/mL will precipitate 1

Drug-Food Interactions

Tetracyclines and divalent/trivalent cations: Physical binding occurs between tetracyclines and calcium from milk, antacids, or enteral formulas, limiting gastrointestinal absorption 4. This is relevant when ceftriaxone is used in combination regimens.

Risk Factors for Adverse Events

Beyond direct drug interactions, certain factors increase risk of ceftriaxone-related adverse events:

• Previous allergic reactions to cephalosporins, penicillins, or beta-lactam antibiotics (9.6% of adverse events occurred in patients with positive allergy history) 6
• Rapid IV injection: Identified as a risk factor for serious adverse events; neonates should receive infusions over 60 minutes to reduce bilirubin encephalopathy risk 1, 6
• Unlabeled use: Associated with 2.9% of adverse events 6

Hypersensitivity Cross-Reactivity

Patients with documented allergies to penicillins or other beta-lactam antibiotics should receive alternative antibiotics when possible, as cross-reactivity occurs 6. Hypersensitivity reactions occurred in 2.99% of patients overall and 3.3% of pediatric patients 7.