Chapter 37  ·  Module 2
Azole Antifungals — Fluconazole and Itraconazole
Mechanism, pharmacokinetics, spectrum, resistance, and drug interactions
CYP51 = cytochrome P450 51 (lanosterol 14-alpha-demethylase)  ·  CYP3A4/2C9/2C19 = human cytochrome P450 isoforms  ·  TDM = therapeutic drug monitoring  ·  CNS = central nervous system  ·  INR = international normalized ratio
Mechanism of Action
Target
CYP51 Inhibition
  • Triazole N coordinates heme iron of fungal CYP51 (ERG11)
  • Blocks lanosterol → ergosterol conversion
  • Ergosterol depletion + toxic sterol accumulation
  • Effect: fungistatic against most yeasts and molds
Human CYP Inhibition
Basis of Drug Interactions
  • Same triazole N also inhibits human CYP enzymes
  • Fluconazole: potent CYP2C9; moderate CYP3A4, CYP2C19
  • Itraconazole: potent CYP3A4 + P-glycoprotein
  • Never generalize interactions across azole class
Pharmacokinetics Comparison
Property Fluconazole Itraconazole
Oral bioavailability ~90% — food and pH independent Capsule: ~55% (requires food + acid); Solution: ~60% (fasting, less pH-dependent)
CNS penetration Excellent — CSF 60–80% of plasma Poor — high lipophilicity and protein binding
Elimination Renal (80% unchanged) — adjust dose if creatinine clearance below 50 mL/min Hepatic CYP3A4 — no renal adjustment needed
TDM Not routinely required Required — target trough above 1.0 mcg/mL for treatment
Cardiac caution QT prolongation at high doses Contraindicated in heart failure (negative inotrope)
Spectrum and Species Rules
Fluconazole Covers
Candida (susceptible), Cryptococcus, Endemic fungi
  • C. albicans, C. tropicalis, C. parapsilosis — susceptible
  • C. glabrata — reduced susceptibility; test before use
  • C. krusei — intrinsic resistance; never use fluconazole
  • Cryptococcus neoformans — consolidation and maintenance
  • Coccidioides, Histoplasma — yes; Aspergillus — no
Itraconazole Adds
Aspergillus + dimorphic fungi
  • Aspergillus species (not first-line; step-down or mild disease)
  • Histoplasma — drug of choice for mild to moderate disease
  • Blastomyces — non-CNS disease
  • Sporothrix — lymphocutaneous form
  • Onychomycosis (dermatophytes) — alternative to terbinafine
Resistance Mechanisms
Mechanism 1
ERG11 Mutation
  • Point mutations in CYP51 target enzyme
  • Reduces azole binding affinity
  • Primarily fluconazole resistance
Mechanism 2
Efflux Pumps
  • CDR1/CDR2: cross-resistance to all azoles
  • MDR1: fluconazole-specific efflux
  • Most common in C. glabrata
Mechanism 3
ERG3 Mutation
  • Alters sterol product — removes toxic intermediate
  • Bypasses azole effect
  • Also reduces polyene susceptibility
Key Drug Interactions
Drug Pair Azole Action Required
Tacrolimus / cyclosporine Both Reduce calcineurin inhibitor dose 50–75% before first azole dose; monitor trough daily
Warfarin Fluconazole (primary) Check INR within 3–5 days; expect 2–3x increase; reduce warfarin dose proactively
Simvastatin / lovastatin Itraconazole Contraindicated — rhabdomyolysis risk; switch to pravastatin or rosuvastatin
Rifampin Itraconazole Essentially contraindicated — reduces itraconazole to subtherapeutic levels
Clinical Rule — Step-Down to Fluconazole

Fluconazole is appropriate as oral step-down after echinocandin induction for candidemia only when all of the following are met: patient is clinically stable, blood cultures are negative, species is confirmed fluconazole-susceptible, and neutropenia has resolved. C. glabrata and C. krusei are not candidates for fluconazole step-down.