Antifungal Medications for Systemic Fungal Infections

Invasive Candidiasis and Candidemia

For invasive candidiasis and candidemia, initiate an echinocandin immediately as first-line therapy: caspofungin (70 mg loading dose, then 50 mg daily), micafungin (100 mg daily), or anidulafungin (200 mg loading dose, then 100 mg daily). 1

First-Line Therapy Selection

Echinocandins are strongly preferred over azoles for critically ill patients, those with recent azole exposure, or suspected azole-resistant species due to superior efficacy and safety profiles 2, 1
Liposomal amphotericin B (3-5 mg/kg daily) is an acceptable alternative if echinocandins cannot be tolerated 2, 1
Amphotericin B deoxycholate should not be used when more effective and less toxic agents are available 2

Step-Down Therapy

After clinical improvement and when the isolate is fluconazole-susceptible, transition to fluconazole 400 mg daily (6 mg/kg) 2, 1, 3
For Candida krusei infections, switch to oral voriconazole 200 mg twice daily as an alternative 2

Duration and Monitoring

Continue therapy for at least 14 days after the first negative blood culture and complete resolution of attributable signs and symptoms 2, 1
Remove central venous catheters whenever feasible, as catheter removal is independently associated with lower mortality 2, 1
For persistent positive blood cultures, obtain imaging (CT or ultrasound of genitourinary tract, liver, spleen) to identify deep-seated infection 1

Species-Specific Considerations

For C. parapsilosis, fluconazole is more appropriate than echinocandins, though continuing echinocandins may be considered if clinical and microbiological response is adequate 2
For chronic disseminated (hepatosplenic) candidiasis in neutropenic patients, use liposomal amphotericin B (3-5 mg/kg daily) or an echinocandin initially, then step down to fluconazole 400 mg daily once stable 1

Invasive Aspergillosis

Voriconazole is the drug of choice for all forms of invasive aspergillosis, including pulmonary, CNS, sinus, endocarditis, osteomyelitis, and skin/soft tissue infections. 4

Dosing and Administration

Loading dose: 400 mg (6 mg/kg) IV every 12 hours for two doses on Day 1 2, 4
Maintenance: 200 mg (3-4 mg/kg) IV or PO every 12 hours 2, 4
Alternative maintenance: 4 mg/kg IV every 12 hours for severe infections 4

Duration and Surgical Considerations

Treat until resolution or stabilization of all clinical and radiographic manifestations (median: 10 days IV followed by 76 days oral) 4
Surgical resection is recommended when feasible for pulmonary lesions near great vessels, chest wall invasion, CNS infections, sinus infections, and skull base osteomyelitis 4
For skull base osteomyelitis, prolonged therapy (3-6 months or longer) is required until complete resolution 4

Alternative Agents

Liposomal amphotericin B (3-5 mg/kg daily) is an alternative for patients who cannot tolerate voriconazole 2
Itraconazole is preferred for chronic cavitary pulmonary aspergillosis, with voriconazole as an acceptable alternative 4

Mucormycosis (Zygomycosis)

Liposomal amphotericin B at high doses (10 mg/kg daily) is the treatment of choice for mucormycosis, combined with aggressive surgical debridement. 2

Critical Management Points

Voriconazole is contraindicated for mucormycosis and should never be used 4, 1
Amphotericin B deoxycholate (3-10 mg/kg daily) is an alternative if liposomal formulation is unavailable 2
Surgical resection of infected tissue is mandatory and should be pursued aggressively 2
High-dose liposomal amphotericin B (10 mg/kg daily) combined with surgery achieved 62% survival at 12 weeks, though renal impairment occurred in 40% of patients (mostly transient) 2

Cryptococcal Meningitis

For CNS or disseminated cryptococcosis, initiate amphotericin B deoxycholate (0.7-1.0 mg/kg daily) plus flucytosine (25 mg/kg four times daily) for 2 weeks. 2

Induction and Consolidation

Alternative induction: liposomal amphotericin B (4-6 mg/kg daily) for 6-10 weeks 2
After induction, transition to fluconazole 400 mg daily for a minimum of 8 weeks 2
Total treatment duration: 10-12 weeks for CNS disease, then maintenance therapy 2

Management of Elevated Intracranial Pressure

Measure CSF opening pressure at diagnosis; keep initial pressure <200 mmH₂O 2
If opening pressure ≥250 mmH₂O, perform serial lumbar drainage to achieve closing pressure <200 mmH₂O or 50% of initial opening pressure 2
Repeat lumbar puncture at week 2 or earlier if clinically indicated to monitor for persistent elevated pressure 2

Maintenance Therapy

For AIDS patients: fluconazole 200 mg daily until CD4 >100/μL and undetectable HIV RNA viral load sustained for 3 months 2
For solid organ transplant recipients: reduce immunosuppressive therapy (consider lowering corticosteroids first) 2

Alternative Regimens

Fluconazole 400-800 mg daily (6-12 mg/kg) if amphotericin B is intolerable 1
Voriconazole may be used as step-down therapy in clinically stable patients 2, 1

Mucocutaneous Candidiasis

Oropharyngeal Candidiasis (Thrush)

Uncomplicated disease: fluconazole 100-200 mg daily for 7-14 days 1, 5
Alternatives: itraconazole 200 mg daily or clotrimazole troches 10 mg five times daily for 7-14 days 1, 5
Refractory or severe disease: amphotericin B deoxycholate 0.3 mg/kg/day IV, an echinocandin, or voriconazole 1, 5
For recurrent disease: fluconazole 100 mg three times weekly for chronic suppression 5

Esophageal Candidiasis

First-line: fluconazole 200-400 mg daily for 14-21 days until clinical improvement 1, 5
When fluconazole cannot be used: itraconazole 200 mg daily PO, amphotericin B deoxycholate 0.3-0.7 mg/kg/day IV, an echinocandin, or voriconazole 1, 5

CNS Candidiasis

Preferred initial regimen is amphotericin B deoxycholate 0.7-1 mg/kg daily with or without flucytosine. 1

If amphotericin B is intolerable, fluconazole 400-800 mg daily (6-12 mg/kg) is acceptable 1
Voriconazole may be used as step-down therapy in clinically stable patients 1
Remove intraventricular devices whenever possible 1
Continue treatment until all clinical signs, CSF abnormalities, and radiologic findings have resolved 1

Candida Endophthalmitis

Treatment options include amphotericin B deoxycholate 0.7-1 mg/kg with flucytosine, fluconazole, liposomal amphotericin B, voriconazole, or an echinocandin. 1

Minimum treatment duration: 4-6 weeks, guided by serial ophthalmologic examinations 1
Severe endophthalmitis or vitreitis warrants surgical intervention 1
Diagnostic vitreal aspiration is recommended when the causative organism is unknown 1

Empiric Therapy in Critically Ill Patients

Initiate empiric antifungal therapy immediately in critically ill immunosuppressed patients with risk factors for invasive candidiasis, no alternative fever source, and signs of septic shock. 1

Preferred Empiric Regimens

For non-neutropenic ICU patients: an echinocandin (caspofungin, anidulafungin, or micafungin) 1
Fluconazole 800 mg loading then 400 mg daily is acceptable only when there is no recent azole exposure and the patient is not colonized with azole-resistant Candida 1

Duration

Continue empiric therapy for 2 weeks in patients who improve 1
If no clinical response after 4-5 days and no invasive candidiasis is confirmed, antifungal therapy may be discontinued 1

Key Safety Considerations and Pitfalls

Echinocandin Safety Profile

Caspofungin demonstrated significantly lower infusion-related adverse reactions (20-35%) compared to amphotericin B (49-52%) 6
Nephrotoxicity with caspofungin (3%) was significantly lower than amphotericin B (12%) in patients with baseline creatinine clearance >30 mL/min 6
Caspofungin has the best safety profile and tolerability with very low potential for drug interactions among systemic antifungals 7

Critical Contraindications

Never use voriconazole for mucormycosis—amphotericin B formulations are mandatory 4, 1
Never use fluconazole as initial therapy in critically ill patients, those with recent azole exposure, or those at risk for azole-resistant species 1
Amphotericin B deoxycholate should be avoided when more effective and less toxic agents are available due to limited efficacy and poor safety profile 2

Monitoring and Duration Pitfalls

Premature discontinuation leads to relapse—duration must be based on documented clearance and symptom resolution, not arbitrary time frames 1
Regular monitoring of clinical response and radiographic findings is essential throughout treatment 4

What antifungal medications are recommended for systemic fungal infections such as candidemia, invasive candidiasis, aspergillosis, mucormycosis, and cryptococcal meningitis?

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