What are the antifungal properties and typical dosing of Fluconazole (Diflucan) for treating fungal infections?

Fluconazole Antifungal Properties and Dosing

Fluconazole is a bis-triazole antifungal agent with broad-spectrum activity against most Candida species and Cryptococcus, administered at doses ranging from 150 mg single-dose for vaginal candidiasis to 400-800 mg daily for serious systemic infections, with excellent oral bioavailability (>93%) and unique penetration into CSF and other body fluids. 1

Spectrum of Antifungal Activity

Fluconazole demonstrates potent activity against the following organisms:

• Candida albicans - Most susceptible species, with clinical cure rates of 84-90% for mucosal infections 2, 3
• Candida parapsilosis - Highly susceptible with 93% efficacy, making fluconazole or lipid formulation amphotericin B preferred initial therapy 4, 5
• Candida tropicalis - Good susceptibility with 82% efficacy 5
• Cryptococcus neoformans - Effective for both acute treatment and maintenance therapy of cryptococcal meningitis 4, 1

Critical Resistance Patterns

• Candida krusei - Intrinsically resistant; fluconazole has NO activity and should never be used 2, 5
• Candida glabrata - Variable activity with only 50% efficacy; echinocandins are preferred for documented infections 4, 2, 5
• Aspergillus species - Fluconazole lacks clinically meaningful activity against molds 6

Pharmacokinetic Properties

Fluconazole possesses unique pharmacokinetic advantages:

• Oral bioavailability exceeds 93%, making oral and IV dosing equivalent 1, 3
• Not affected by food, gastric pH, or hypochlorhydria - can be taken with or without food 1, 3
• Long half-life of 30-37 hours allows once-daily dosing 3, 7
• Excellent tissue penetration - achieves therapeutic concentrations in CSF (50-90% of plasma), vaginal secretions, saliva, sputum, and breast milk 3
• Low protein binding (11-23%) ensures high free drug availability 3
• Primarily renal elimination - 60% excreted unchanged in urine, requiring dose adjustment in renal impairment 1, 3

Dosing by Infection Type

Vaginal Candidiasis

• Single dose: 150 mg orally once - provides 84% long-term cure rate 1, 3
• For severe acute infections: 150 mg every 72 hours for 2-3 doses total 8
• For recurrent infections: Initial 10-14 day induction, then 150 mg weekly for 6 months 8

Oropharyngeal Candidiasis

• Mild disease: Topical agents preferred (clotrimazole troches 10 mg 5 times daily or nystatin suspension) 2, 8
• Moderate to severe disease: 200 mg loading dose on day 1, then 100-200 mg daily for 7-14 days 2, 8, 1
• Clinical resolution occurs within several days, but full 2-week course decreases relapse 1

Esophageal Candidiasis

• 200 mg loading dose on day 1, then 100 mg daily for minimum 3 weeks and at least 2 weeks after symptom resolution 2, 1
• Doses up to 400 mg daily may be used based on severity and response 1

Candidemia and Invasive Candidiasis

• 400 mg (6 mg/kg) daily for at least 2 weeks after blood culture clearance and symptom resolution 4, 2, 1
• For non-neutropenic patients who are less critically ill with no recent azole exposure, fluconazole with 800 mg loading dose is reasonable 4
• Echinocandins are preferred for critically ill patients, those with recent azole exposure, or suspected C. glabrata 4
• Central line removal is strongly recommended in non-neutropenic patients 4

Urinary Tract Candidiasis

• Symptomatic cystitis: 200 mg (3 mg/kg) daily for 2 weeks 2, 8
• Pyelonephritis: 200-400 mg (3-6 mg/kg) daily for 2 weeks 2, 8
• Daily doses of 50-200 mg have been used for uncomplicated UTI 1

Cryptococcal Meningitis

• Acute treatment: 400 mg loading dose on day 1, then 200-400 mg daily for 10-12 weeks after CSF culture negativity 1
• Liposomal amphotericin B 5 mg/kg daily with or without flucytosine is preferred for initial treatment, with fluconazole 400-800 mg daily as step-down therapy 4
• Maintenance/suppression in AIDS: 200 mg daily indefinitely to prevent relapse 1

Candida Endophthalmitis

• For susceptible isolates: 800 mg loading dose, then 400-800 mg (6-12 mg/kg) daily for at least 4-6 weeks 4
• With macular involvement, add intravitreal amphotericin B or voriconazole injection 4
• Ophthalmology consultation mandatory for all candidemia patients within first week 4

Osteoarticular Candidiasis

• 400 mg (6 mg/kg) daily for 6 weeks OR echinocandin for 2 weeks followed by fluconazole for at least 4 weeks 4
• Surgical drainage mandatory for septic arthritis 4
• Prosthetic device removal strongly recommended; if impossible, chronic suppression with fluconazole 400 mg daily 4

Prophylaxis in High-Risk Patients

• Bone marrow transplant: 400 mg daily starting several days before anticipated neutropenia, continuing for 7 days after neutrophil count >1000 cells/mm³ 1
• Solid organ transplant (liver, pancreas, small bowel): 200-400 mg (3-6 mg/kg) daily for 7-14 days postoperatively 4
• Chemotherapy-induced neutropenia: 400 mg (6 mg/kg) daily during neutropenia 4

Pediatric Dosing

The following equivalencies provide comparable exposure to adults 1:

• 3 mg/kg pediatric = 100 mg adult dose
• 6 mg/kg pediatric = 200 mg adult dose
• 12 mg/kg pediatric = 400 mg adult dose (maximum 600 mg/day)

Specific Pediatric Indications

• Oropharyngeal candidiasis: 6 mg/kg loading dose, then 3 mg/kg daily for ≥2 weeks 1
• Esophageal candidiasis: 6 mg/kg loading dose, then 3 mg/kg daily (up to 12 mg/kg for severe disease) for ≥3 weeks 1
• Cryptococcal meningitis: 12 mg/kg loading dose, then 6-12 mg/kg daily for 10-12 weeks after CSF clearance 1
• Neonates (gestational age 26-29 weeks): Same mg/kg dose as older children but administered every 72 hours for first 2 weeks of life, then daily 1

Renal Dose Adjustment

• Loading dose: Give full initial dose (50-400 mg) regardless of renal function 1
• CrCl >50 mL/min: 100% of standard dose 1
• CrCl ≤50 mL/min (no dialysis): 50% of standard dose 1
• Hemodialysis: 100% of dose after each dialysis session; on non-dialysis days, give reduced dose per CrCl 1

Loading Dose Strategy

• A loading dose of twice the daily maintenance dose is recommended on day 1 to achieve steady-state concentrations by day 2 1
• This applies to all multiple-dose regimens except single-dose vaginal therapy 1

Common Pitfalls and Caveats

• Never use fluconazole for C. krusei infections - intrinsic resistance makes treatment failure certain 2, 5
• Candida isolated from respiratory secretions usually represents colonization, not infection, and rarely requires treatment 2
• Denture-related candidiasis requires denture disinfection in addition to antifungal therapy to prevent treatment failure 8
• Relapse is common in immunocompromised patients (40% in AIDS patients with oropharyngeal candidiasis) - consider maintenance therapy 3
• Drug interactions: Monitor patients on warfarin (increased anticoagulation) and oral hypoglycemics (inhibits tolbutamide metabolism) 7
• Maximum recommended daily dose is 1600 mg to avoid neurological toxicity 3
• All candidemia patients require dilated retinal examination within first week (delay until neutrophil recovery in neutropenic patients) to detect endophthalmitis 4

Treatment Duration Principles

• Continue therapy until clinical parameters and laboratory tests indicate active infection has subsided - inadequate treatment duration leads to recurrence 1
• AIDS patients with cryptococcal meningitis or recurrent oropharyngeal candidiasis require lifelong maintenance therapy to prevent relapse 1
• Candidemia: Minimum 2 weeks after blood culture clearance and symptom resolution 4, 2