Drug Interactions Between Fluconazole and Azithromycin
There is no clinically significant pharmacokinetic interaction between fluconazole and azithromycin, and these medications can be safely co-administered without dose adjustment. 1
Evidence from FDA Drug Labels
The FDA label for fluconazole explicitly addresses this combination, stating that an open-label, randomized, three-way crossover study in 18 healthy subjects found no significant pharmacokinetic interaction between fluconazole and azithromycin when a single 800 mg oral dose of fluconazole was given with a single 1200 mg oral dose of azithromycin. 1
Similarly, the azithromycin FDA label confirms that when used in therapeutic doses, azithromycin had only a modest effect on fluconazole pharmacokinetics, and no dosage adjustment of either drug is recommended when co-administered. 2
Supporting Research Evidence
A dedicated pharmacokinetic study in healthy volunteers specifically evaluated this combination and confirmed that azithromycin does not alter the bioavailability of fluconazole, and fluconazole does not significantly alter azithromycin parameters. 3
Important QTc Prolongation Consideration
Both medications can independently prolong the QTc interval, which represents the primary clinical concern when using them together. 4
Risk Factors Requiring Monitoring:
- Pre-existing QTc prolongation or cardiac conduction abnormalities 4
- Concurrent use of other QT-prolonging medications 4
- Electrolyte abnormalities (hypokalemia, hypomagnesemia) 4
- High-dose fluconazole (≥400 mg daily) increases this risk 4, 5
Clinical Management Algorithm:
- Baseline ECG assessment may be considered in high-risk patients (those with cardiac history, electrolyte disturbances, or taking multiple QT-prolonging drugs) 4
- Monitor and correct electrolytes before initiating therapy, particularly potassium and magnesium 4
- Avoid adding a third QT-prolonging agent to this combination 4
- Use caution with azithromycin 1000 mg single doses, as higher doses are associated with more gastrointestinal side effects and potentially greater QTc effects 4
Guideline Context for Combined Use
The combination of antibiotics and antifungals is commonly employed in clinical practice for mixed or suspected polymicrobial infections without safety concerns beyond the QTc consideration. 6 Guidelines for travelers' diarrhea note that azithromycin has good tolerability overall, though sustained ventricular tachycardia has been observed in patients with prolonged QTc. 4
Common Pitfalls to Avoid
- Do not assume all azole-macrolide combinations are equivalent: Clarithromycin and erythromycin have significantly more CYP3A4 interactions than azithromycin, making azithromycin the preferred macrolide when combined with fluconazole. 4
- Do not overlook the patient's complete medication list: Fluconazole is a moderate CYP3A4 inhibitor and can increase levels of other drugs metabolized through this pathway (statins, calcium channel blockers, benzodiazepines). 1, 7
- Do not use fluconazole empirically in Southeast/South Asia for diarrheal illness if fluoroquinolone resistance is a concern, though this is unrelated to the azithromycin interaction. 4