Fluconazole vs. Itraconazole for Fungal Infections
Fluconazole is recommended for Candida infections, particularly C. albicans, C. parapsilosis, and C. tropicalis, while itraconazole is preferred for broader spectrum coverage including molds and dermatophytes, though it has more drug interactions and variable bioavailability. 1
Spectrum of Activity
- Fluconazole has good activity against most Candida species (except C. krusei which is intrinsically resistant) and Cryptococcus neoformans, but limited activity against molds and some dermatophytes 1, 2
- Itraconazole has broader spectrum activity against yeasts, dermatophytes, and molds including Aspergillus species, making it more versatile for various fungal infections 3, 4
Pharmacokinetic Differences
- Fluconazole has excellent bioavailability (>90%), good penetration into cerebrospinal fluid, and is primarily excreted unchanged in urine with a long half-life (22-32 hours) allowing for once-daily dosing 2, 5
- Itraconazole has variable bioavailability (especially capsules), poor penetration into cerebrospinal fluid, and undergoes extensive hepatic metabolism with numerous drug interactions 3, 6
- Fluconazole remains detectable in toenails for up to 6 months after therapy discontinuation, allowing for once-weekly dosing in onychomycosis 1, 7
Clinical Applications
Candidiasis
- For candidemia due to C. albicans and C. parapsilosis, fluconazole is recommended as first-line therapy or step-down therapy after initial echinocandin or amphotericin B treatment 1
- For oropharyngeal candidiasis, both agents are effective, but fluconazole is generally preferred due to better tolerability and simpler dosing 1, 6
- For esophageal candidiasis, clinical response rates are similar between fluconazole and itraconazole (approximately 86%) 6
Onychomycosis
- Terbinafine is superior to both agents for dermatophyte onychomycosis and should be considered first-line 1, 8
- Itraconazole is considered second-line therapy for onychomycosis 1
- Fluconazole (450 mg weekly for at least 6 months for toenails) may be used as an alternative when first and second-line agents cannot be tolerated 1, 7
- Mycological cure rates with fluconazole range from 47-62% for toenail infections, which is lower than rates with itraconazole or terbinafine 1, 7
Invasive Fungal Infections
- For empirical therapy in neutropenic patients, itraconazole has broader coverage against molds compared to fluconazole 1
- Itraconazole is more effective than fluconazole for prophylaxis of invasive fungal infections in high-risk patients but has more side effects, particularly gastrointestinal 1
Safety and Tolerability
- Fluconazole is generally better tolerated with fewer drug interactions as it is a weaker inhibitor of cytochrome P450 enzymes 1, 2
- Common adverse effects of fluconazole include headache, skin rash, gastrointestinal complaints, and insomnia 1, 5
- Itraconazole has more significant drug interactions and gastrointestinal side effects, which often limit its use 1, 3
- Adverse effects leading to treatment discontinuation occur in 20% of patients receiving fluconazole 150 mg weekly, increasing to 58% with higher doses (300-450 mg) 1, 7
Formulations and Administration
- Fluconazole is available in oral and intravenous formulations with consistent bioavailability regardless of formulation 2, 5
- Itraconazole is available as capsules, oral solution, and intravenous solution, with the oral solution having better bioavailability than capsules 6, 3
- Itraconazole capsules should not be used for prophylaxis of invasive fungal infections due to variable and deficient bioavailability 1
- Itraconazole oral solution should be taken on an empty stomach to achieve adequate absorption 1
Clinical Decision Algorithm
For Candida infections (particularly C. albicans, C. parapsilosis, C. tropicalis):
- Choose fluconazole as first-line therapy 1
For mold infections (including Aspergillus) or broader spectrum coverage:
For onychomycosis:
For patients with significant drug interactions or hepatic impairment:
Common Pitfalls and Caveats
- Itraconazole oral solution has significantly better bioavailability than capsules but must be taken on an empty stomach 1
- Fluconazole requires dose adjustment in renal impairment as it is primarily excreted unchanged in urine 2, 5
- Fluconazole is ineffective against C. krusei (intrinsic resistance) and has limited activity against molds 1, 9
- Therapeutic drug monitoring should be considered for itraconazole due to variable absorption and bioavailability 3
- Neither agent should be used as empirical therapy if they have been used for prior prophylaxis due to risk of resistance 1