What are the drug interactions of antifungal agents, including azoles, echinocandins, amphotericin B, and griseofulvin?

Drug Interactions with Antifungal Agents

Azole antifungals cause clinically significant drug interactions primarily through potent inhibition of CYP3A4, CYP2C9, and CYP2C19 enzymes, requiring dose reductions of 30-50% for concomitant immunosuppressants and intensive therapeutic drug monitoring to prevent life-threatening toxicities. 1

Azole Antifungals: Major CYP450-Mediated Interactions

Immunosuppressants (Critical Priority)

• Calcineurin inhibitors (tacrolimus, cyclosporine) and mTOR inhibitors (sirolimus) experience significant concentration increases when combined with azoles due to CYP3A4 inhibition 1, 2
• Reduce immunosuppressant doses by 30-50% immediately upon azole initiation to prevent nephrotoxicity, hepatotoxicity, and elevated serum creatinine 1, 2
• Monitor trough levels daily until steady state is achieved, then every 2-3 days until hospital discharge 2, 3
• Failure to reduce doses preemptively can lead to serious toxicity within days; conversely, excessive reduction risks graft rejection 1, 2
• Patients with CYP2C19 and CYP3A4 genetic polymorphisms may experience more pronounced interactions 1, 2

Cardiovascular Medications

• Calcium channel blockers (nifedipine, amlodipine, felodipine, verapamil) have increased plasma concentrations via CYP3A4 inhibition, requiring frequent monitoring for adverse events 4
• Warfarin and coumarin anticoagulants show increased prothrombin time with azoles (particularly fluconazole via CYP2C9 inhibition), necessitating careful PT/INR monitoring and dose adjustment 4, 5
• Digoxin levels increase due to P-glycoprotein inhibition by azoles, potentially causing digitalis toxicity that is exacerbated by azole-induced hypokalemia 4, 6
• QTc prolongation risk increases when azoles are combined with other QT-prolonging drugs (fluoroquinolones, macrolides, ondansetron, nilotinib, panobinostat) 1, 4

Antiretroviral Agents

• Variable bidirectional interactions occur with HIV medications, requiring azole level monitoring 1
• Combination use is frequent but complex due to multiple drug classes involved 1

Antimicrobials

• Rifampin/rifabutin dramatically decrease azole levels while their own levels increase; combined use with voriconazole, posaconazole, isavuconazole, or itraconazole is contraindicated or requires extreme caution 1
• Erythromycin with fluconazole should be avoided due to increased cardiotoxicity risk (QT prolongation, torsade de pointes, sudden cardiac death) 4

Central Nervous System Medications

• Benzodiazepines (midazolam, triazolam, alprazolam) have markedly increased concentrations via CYP3A4 inhibition, causing prolonged sedation 6, 7
• Carbamazepine metabolism is inhibited by fluconazole, with serum levels increasing 30%, risking carbamazepine toxicity; dose adjustment based on concentration monitoring is necessary 4
• Tricyclic antidepressants (amitriptyline, nortriptyline) have enhanced effects with fluconazole; measure levels at therapy initiation and after 1 week, adjusting doses accordingly 4
• Fentanyl elimination is significantly delayed by fluconazole, potentially causing fatal respiratory depression 4

Other Medications

• Statins (lovastatin, simvastatin) metabolized by CYP3A4 have increased concentrations, raising rhabdomyolysis risk 6, 7
• Celecoxib Cmax and AUC increase by 68% and 134% respectively with fluconazole 200 mg daily; consider halving celecoxib dose 4
• Cyclophosphamide with fluconazole increases serum bilirubin and creatinine; use with heightened monitoring 4
• Tyrosine kinase inhibitors require monitoring when combined with azoles due to CYP3A4 substrate effects 1

Corticosteroids

• Azoles increase corticosteroid levels, potentially exacerbating immunosuppression favorable for fungal growth and causing signs of excessive steroid exposure with prolonged coadministration 1

Therapeutic Drug Monitoring for Azoles

Agents Requiring TDM

• Itraconazole, voriconazole, and posaconazole suspension require TDM once steady state is reached to enhance efficacy, evaluate therapeutic failures from suboptimal exposures, and minimize toxicities 1
• Obtain serum trough levels for both the azole and potentially interacting drugs (cyclosporine, tacrolimus, sirolimus, tyrosine kinase inhibitors) 1

Agents Not Requiring Routine TDM

• Fluconazole has linear pharmacokinetics eliminating TDM need, though renal failure patients require dose modification 1
• Isavuconazole lacks defined therapeutic range data; TDM not routinely recommended 1
• Posaconazole delayed-release tablets and IV formulation have improved absorption and predictable bioavailability compared to suspension, potentially reducing TDM necessity 1

Target Concentrations

• Posaconazole prophylaxis: trough >0.7 mcg/mL (some sources accept >0.5 mcg/mL) 1
• Higher posaconazole levels (>1.5 mcg/mL) with delayed-release tablets have been anecdotally associated with increased toxicity 1

Amphotericin B Interactions

Nephrotoxic Synergy

• Aminoglycosides, cyclosporine, pentamidine enhance amphotericin B-induced renal toxicity; use concomitantly only with extreme caution and intensive renal function monitoring 8, 6

Electrolyte Disturbances

• Corticosteroids and ACTH potentiate amphotericin B-induced hypokalemia, predisposing to cardiac dysfunction; avoid unless necessary to control amphotericin B side effects, with close electrolyte and cardiac monitoring 8, 6
• Digitalis glycosides have enhanced toxicity due to amphotericin B-induced hypokalemia; monitor serum potassium and cardiac function closely, correcting deficits promptly 8
• Skeletal muscle relaxants (tubocurarine) have enhanced curariform effects from hypokalemia; monitor and correct potassium levels 8

Hematologic Interactions

• Antineoplastic agents enhance potential for renal toxicity, bronchospasm, and hypotension; give concomitantly only with great caution 8, 6
• Leukocyte transfusions cause acute pulmonary toxicity when given during or shortly after amphotericin B; separate infusions temporally and monitor pulmonary function 8

Antifungal Combinations

• Flucytosine with amphotericin B shows synergistic relationship but may increase flucytosine toxicity by enhancing cellular uptake and/or impairing renal excretion 8
• Azoles (ketoconazole, miconazole, clotrimazole, fluconazole) with amphotericin B may induce fungal resistance to amphotericin B based on in vitro and animal studies; use combination therapy with caution, especially in immunocompromised patients 8
• Preclinical studies show variable results: small additive effect against Candida albicans, no interaction against Cryptococcus neoformans, antagonism against Aspergillus fumigatus 1

Echinocandins (Caspofungin, Micafungin, Anidulafungin)

• Minimal drug interactions compared to azoles, with relatively low toxicity profiles 1, 9
• No marked P450 inhibition except minimal CYP3A4/5 effects in vitro 9
• Concomitant drug blood/plasma concentrations not significantly affected by echinocandins 9
• Itraconazole with micafungin showed possible antagonism in murine models, though clinical significance unclear 1
• Echinocandins are inhibitors of gastric P-glycoprotein (itraconazole, posaconazole specifically), potentially increasing systemic levels of affected drugs 1

Griseofulvin Interactions

• Warfarin-type anticoagulants have decreased activity due to griseofulvin-induced metabolism; patients require anticoagulant dosage adjustment during and after griseofulvin therapy 10
• Oral contraceptives have reduced effectiveness due to enhanced hepatic metabolism of estrogens, causing menstrual irregularities; alternate or second form of birth control indicated during concurrent use 10
• Cyclosporine levels decrease when coadministered with griseofulvin, reducing pharmacologic effects 10
• Salicylates have decreased serum concentrations with concurrent griseofulvin 10
• Barbiturates depress griseofulvin activity by decreasing plasma levels; dosage adjustment of antifungal may be required 10
• Alcohol causes nausea, vomiting, flushing, tachycardia, and severe hypotension when ingested during griseofulvin therapy 10

Terbinafine (Allylamine Class)

• Low potential for drug interactions overall 6
• Potent CYP2D6 inhibitor causing clinically significant interactions with substrates including nortriptyline, desipramine, perphenazine, metoprolol, encainide, and propafenone 7
• Interactions with substrates of other CYP isoforms are unlikely based on existing data 7

Critical Clinical Pitfalls to Avoid

• Inadequate monitoring frequency during the first week of azole-immunosuppressant coadministration can lead to serious toxicity or graft rejection 2, 3
• Failing to preemptively reduce tacrolimus/cyclosporine doses when initiating azoles results in rapid toxic accumulation 1, 2
• Overlooking cumulative effects when patients receive multiple CYP3A4 substrates simultaneously 2
• Ignoring the persistence of enzyme inhibition for 4-5 days after fluconazole discontinuation due to long half-life 4
• Underestimating QTc prolongation risk when combining azoles with other QT-prolonging medications, particularly in presence of hypokalemia 1, 4, 6
• Using posaconazole oral suspension with proton pump inhibitors, which increase gastric pH and reduce absorption, leading to subtherapeutic levels and breakthrough infections 1