Drug Interaction Warning: Erythromycin IV and Fluconazole PO
This combination should be avoided or used with extreme caution due to significant risk of QT prolongation and potentially fatal cardiac arrhythmias (torsades de pointes).
Mechanism of Interaction
- Both erythromycin and fluconazole independently prolong the QT interval through different mechanisms, creating additive cardiotoxic effects 1
- Fluconazole inhibits cytochrome P-450 enzymes, which can increase serum concentrations of erythromycin and amplify its cardiotoxic effects 2, 1
- This interaction has been documented with other macrolide-azole combinations, where accumulation of the macrolide antibiotic led to altered cardiac repolarization 1
Clinical Recommendations
If Combination is Absolutely Necessary:
- Obtain baseline ECG before initiating therapy and monitor QTc interval closely throughout treatment
- Avoid in patients with: pre-existing QT prolongation, electrolyte abnormalities (hypokalemia, hypomagnesemia), bradycardia, or concurrent use of other QT-prolonging medications
- Correct electrolyte abnormalities (potassium >4.0 mEq/L, magnesium >2.0 mg/dL) before starting therapy
- Monitor ECG at 24-48 hours after initiation and with any dose changes
- Discontinue immediately if QTc exceeds 500 msec or increases >60 msec from baseline
Safer Alternative Strategies:
For the bacterial infection (replacing erythromycin IV):
- Consider azithromycin (lower QT risk than erythromycin) or non-macrolide alternatives based on the specific infection and susceptibility patterns
- If macrolide is essential, consider switching to oral erythromycin once patient can tolerate PO, as IV formulation carries higher risk
For the fungal infection (fluconazole considerations):
- Fluconazole oral bioavailability is excellent (>90%) even in critically ill patients with compromised GI function, achieving equivalent serum concentrations to IV administration 3
- For invasive candidiasis, fluconazole 400-800 mg daily (6-12 mg/kg) is recommended as step-down therapy after initial stabilization 4
- For less severe fungal infections, consider topical therapy or lower fluconazole doses (100-200 mg daily) to minimize drug interaction risk 5
Common Pitfalls to Avoid
- Do not assume that oral fluconazole has lower interaction risk than IV—the interaction is pharmacodynamic (QT prolongation) and pharmacokinetic (enzyme inhibition), not route-dependent 2, 1
- Do not overlook that critically ill patients often have multiple risk factors for QT prolongation (sepsis, electrolyte disturbances, renal dysfunction) that compound this interaction risk
- Do not forget to review the complete medication list for other QT-prolonging agents that may be contributing to risk