What is the recommended antifungal therapy for patients at risk for fungal infections?

Recommended Antifungal Therapy for Patients at Risk for Fungal Infections

The choice of antifungal prophylaxis or treatment depends critically on the specific fungal pathogen suspected, the site of infection, and the patient's immune status—with voriconazole for invasive aspergillosis, fluconazole for most Candida infections, and amphotericin B for mucormycosis being the primary targeted therapies. 1

Risk Stratification and Prophylaxis

High-Risk Patients Requiring Prophylaxis

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT), those receiving induction chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), and those with graft-versus-host disease requiring immunosuppressive therapy should receive posaconazole prophylaxis. 2

• Posaconazole is the only azole with activity against zygomycete fungi (mucormycosis), making it uniquely valuable for prophylaxis in high-risk hematologic malignancy patients 3
• For patients with severe renal impairment receiving posaconazole delayed-release tablets, close monitoring for breakthrough fungal infections is mandatory due to variable drug exposure 4

Patients at Risk for Invasive Candidiasis

• High-risk surgical patients, neonates, and neutropenic patients with asymptomatic candiduria should be treated as disseminated candidiasis 1
• Fluconazole prophylaxis should be restricted to high-risk ICU patients only 2
• Risk factors include central venous catheters, broad-spectrum antibacterial use, prolonged ICU stay, total parenteral nutrition, mucosal Candida colonization, and renal failure 2

Empirical and Pre-emptive Therapy

For Persistently Febrile Neutropenic Patients

Caspofungin is the first-line choice for empirical treatment of persistent fever in neutropenic patients, with liposomal amphotericin B (L-AmB) as the second-line option. 2

• Amphotericin B deoxycholate (AmB-d) 0.7–1.0 mg/kg/day, voriconazole, itraconazole, echinocandins, or L-AmB 3 mg/kg/day are all acceptable options 1
• Use radiologic studies and laboratory markers (such as galactomannan antigen) rather than fever alone to stratify the likelihood of invasive fungal infection 1

Pre-emptive Therapy Guidance

• Favor amphotericin B deoxycholate for patients at risk of invasive zygomycosis (mucormycosis) 1
• Favor voriconazole when radiological presentations are consistent with invasive aspergillosis along with positive galactomannan antigen 1

Targeted Therapy by Pathogen

Invasive Candidiasis

Non-Neutropenic Patients Without Severe Sepsis

• Fluconazole is the drug of choice for non-neutropenic patients with no severe sepsis, no septic shock, and no recent azole exposure 5
• For candidemia without persistent fungemia or metastatic complications, treat for 3 weeks 1

Patients with Severe Sepsis or Septic Shock

• Caspofungin is the first-line choice for patients with severe sepsis and septic shock 5
• An echinocandin should be considered first-line in non-neutropenic patients, with the option to switch to fluconazole for susceptible Candida species 2

Neutropenic Patients

• Caspofungin or micafungin are preferred over anidulafungin as first-line treatment 2
• Amphotericin B deoxycholate is considered first choice for empirical therapy in neutropenic patients 5

Species-Specific Therapy

• For C. albicans, C. tropicalis, or C. parapsilosis: fluconazole is the drug of choice 5
• For C. glabrata or C. krusei: caspofungin or amphotericin B deoxycholate are first-line therapies 5

Site-Specific Candida Infections

CNS Candidiasis

• AmB-d with or without flucytosine (5-FC); fluconazole 400–800 mg (6–12 mg/kg) daily for patients unable to tolerate AmB-d 1
• Remove intraventricular devices 1
• Treat until all signs, symptoms, CSF abnormalities, and radiologic abnormalities resolve 1

Candida Endophthalmitis

• AmB-d 0.7–1 mg/kg with 5-FC, fluconazole, L-AmB, voriconazole, or echinocandin 1
• Duration of therapy is at least 4–6 weeks, determined by repeated examinations 1

Urinary Tract Infections

• Asymptomatic cystitis: therapy not usually needed unless high-risk surgical patients, neonates, or neutropenic patients 1, 6
• Symptomatic cystitis: fluconazole 200 mg (3 mg/kg) daily for 14 days 1, 7, 6
• Pyelonephritis: fluconazole 200–400 mg (3–6 mg/kg) daily for 14 days 1

Mucocutaneous Candidiasis

• Oropharyngeal: nystatin suspension 200,000–400,000 U po qid, fluconazole 100–200 mg/day, or itraconazole 200 mg/day for 7–14 days 1
• Esophageal: fluconazole 200–400 mg/day or itraconazole 200 mg/day po for 14–21 days 1

Invasive Aspergillosis

Primary Therapy

Voriconazole is recommended for primary (upfront) therapy of invasive aspergillosis. 8, 2, 5

• Voriconazole, L-AmB, echinocandins, or itraconazole are options for pulmonary and extrapulmonary aspergillosis 1
• Voriconazole was associated with satisfactory global responses in 43.7% of aspergillosis cases in salvage therapy 8
• Treatment should continue until resolution or stabilization of all clinical and radiographic manifestations 1

Salvage Therapy

• Caspofungin, voriconazole (if not used for primary therapy), or liposomal amphotericin B are recommended for refractory disease 5

Combination Therapy

• Combination therapy with caspofungin plus voriconazole or liposomal amphotericin B should be considered in critically ill patients 5

CNS Aspergillosis

• Voriconazole, AmB-d, echinocandins, L-AmB, or itraconazole 1
• Surgical resection of infected tissue if possible 1
• Beware of drug interactions between anticonvulsant therapy and voriconazole 1

Invasive Zygomycosis (Mucormycosis)

Liposomal amphotericin B is the drug of choice, with surgical resection of infected tissue being mandatory. 1

• High-dose amphotericin B can be considered when surgical intervention is not feasible 1
• Aggressive surgical debridement is mandatory for optimal outcomes 1

Cryptococcosis

CNS or Disseminated Disease

• AmB-d plus flucytosine (5-FC) for 2 weeks for mild-to-moderate disease, followed by fluconazole for 10–12 weeks 1
• L-AmB for 6–10 weeks is an alternative 1
• Management of elevated intracranial pressure is critical: keep initial CSF opening pressure <200 mmH₂O 1
• Serial lumbar drainage if CSF opening pressure ≥250 mmH₂O to achieve closing pressure <200 mmH₂O or 50% of initial opening pressure 1

Special Populations and Considerations

Pediatric Patients

• Voriconazole loading dose of 6 mg/kg every 12 hours IV on Day 1, followed by 4 mg/kg every 12 hours IV thereafter 9
• When feasible, switch from IV to oral (100 mg or 200 mg twice daily for patients weighing <40 kg or ≥40 kg, respectively) 9
• Success rates were highest in pediatric patients with chronic granulomatous disease (62%) 9

Renal Impairment

• Dose adjustment of fluconazole may be necessary for patients with renal impairment 7
• Patients with severe renal impairment receiving posaconazole should be monitored closely for breakthrough fungal infections 4

Drug Interactions

• Posaconazole should not be administered with drugs that prolong QTc interval and are metabolized through CYP3A4 4
• Concomitant administration of posaconazole with midazolam increases midazolam plasma concentrations by approximately 5-fold; patients must be monitored closely 4
• Reserve azole antifungals for patients receiving vincristine only when no alternative antifungal treatment options exist, due to risk of neurotoxicity 4
• In patients with CLL/SLL, posaconazole is contraindicated during venetoclax initiation and ramp-up phase due to risk of tumor lysis syndrome 4

Hepatic Monitoring

• Liver tests should be evaluated at the start of and during posaconazole therapy 4
• Discontinuation must be considered if clinical signs and symptoms consistent with liver disease develop 4

Common Pitfalls and Caveats

• Patients with severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving posaconazole delayed-release tablets 4
• Failure to remove or replace indwelling catheters may lead to persistent Candida infection 6
• Treating asymptomatic candiduria in non-high-risk patients is not recommended 6
• Candida isolated from lower respiratory tract does not require therapy; lower respiratory tract Candida infection is rare and requires histopathologic evidence to confirm diagnosis 1
• Elimination of predisposing factors (including temporary discontinuation of medications like SGLT2 inhibitors for severe infections) is essential for treatment success 7
• Reversal of immunosuppression, if feasible, is important for favorable outcomes in invasive aspergillosis 1
• Always consider species identification and susceptibility testing when selecting therapy, as resistance patterns vary significantly among Candida species 6