What are the recommended newer antifungals (e.g. voriconazole, posaconazole, isavuconazonium sulfate) for treating severe or invasive fungal infections in high-risk patients with impaired health status?

Newer Antifungals: Evidence-Based Recommendations

For high-risk patients with severe or invasive fungal infections, voriconazole remains the gold standard for invasive aspergillosis, posaconazole provides superior prophylaxis in neutropenic patients with reduced mortality, and isavuconazole offers a well-tolerated alternative when standard agents are contraindicated due to drug interactions or QTc prolongation concerns.

Voriconazole: Established Second-Generation Triazole

Invasive Aspergillosis Treatment

• Voriconazole is the drug of choice for pulmonary and CNS invasive aspergillosis, with dosing of 6 mg/kg IV twice daily for 2 doses (loading), then 3-4 mg/kg twice daily maintenance 1.
• For CNS aspergillosis specifically, voriconazole is preferred over other agents due to excellent CNS penetration, though clinicians must monitor for drug interactions with anticonvulsants 1.
• Voriconazole is recommended as first-line for empirical and pre-emptive therapy when radiological presentations suggest invasive aspergillosis, particularly with positive galactomannan antigen 1.

Invasive Candidiasis

• For candidemia, voriconazole (loading 6 mg/kg IV twice daily for 2 doses, then 3 mg/kg twice daily) is an alternative to echinocandins and fluconazole 1.
• Voriconazole can be used as step-down therapy for chronic disseminated candidiasis and CNS candidiasis in stable patients 1.
• For Candida endophthalmitis, voriconazole is listed as an alternative option with treatment duration of at least 4-6 weeks 1.

Toxicity Profile and Monitoring

• Significant toxicities include neurologic and ophthalmic adverse events, with long-term use associated with severe photosensitivity, cutaneous malignancies, elevated serum fluoride levels, and periosteitis 1.
• The IV formulation contains cyclodextrin vehicle that may accumulate in renal dysfunction, requiring caution 1.
• Voriconazole has complicated drug-drug interactions requiring careful management 1.

Posaconazole: Superior Prophylaxis with Mortality Benefit

Prophylaxis in High-Risk Populations

• Posaconazole prophylaxis (200 mg three times daily with oral suspension; 300 mg once daily after loading with delayed-release tablets) significantly reduces invasive fungal infections and provides a survival benefit in neutropenic patients with acute myeloid leukemia or myelodysplastic syndromes receiving induction/reinduction chemotherapy 1, 2.
• In the pivotal trial, posaconazole reduced invasive fungal infections during treatment (2% vs 8%; P<0.001) and at 100 days (5% vs 11%; P=0.003) compared to fluconazole/itraconazole, with reduced invasive aspergillosis (1% vs 7%; P<0.001) and significant survival benefit (P=0.04) 1.
• For allogeneic HSCT recipients with severe GVHD, posaconazole is as effective as fluconazole with reduced incidence of invasive aspergillosis and overall invasive fungal infections 1.
• Posaconazole prophylaxis is recommended during induction chemotherapy for the duration of neutropenia in patients with chemotherapy-induced neutropenia 1.

Treatment of Invasive Aspergillosis

• In a 2021 phase III randomized controlled trial, posaconazole was noninferior to voriconazole as primary therapy for invasive aspergillosis, with participants experiencing fewer treatment-related adverse events in the posaconazole group 1.

Formulation Considerations

• Posaconazole delayed-release tablets are NOT substitutable with oral suspension due to differences in dosing and bioavailability 2.
• Delayed-release tablets: loading dose 300 mg twice daily on day 1, then 300 mg once daily; can be administered with or without food 2.
• For patients unable to eat a full meal, delayed-release tablets should be used instead of oral suspension for prophylaxis 2.

Safety Profile

• A 2020 meta-analysis showed posaconazole significantly reduced invasive fungal infections (RR 0.57; 95% CI 0.42-0.79) and invasive aspergillosis (RR 0.36; 95% CI 0.15-0.85) compared to placebo 1.
• However, patients taking posaconazole had higher incidence of withdrawal due to adverse effects 1.
• Generally well tolerated with rare serious adverse events, primarily liver toxicity 1.

Isavuconazole: Newest Alternative with Favorable Safety Profile

FDA-Approved Indications

• Isavuconazole (isavuconazonium sulfate) was approved in March 2015 for treatment of invasive aspergillosis and invasive mucormycosis in adult patients 1, 3.

Invasive Aspergillosis

• Isavuconazole demonstrated non-inferiority to voriconazole for primary treatment of invasive mould disease in the SECURE trial, with all-cause mortality at day 42 of 19% vs 20% (adjusted difference -1.0%; 95% CI -7.8 to 5.7) 4.
• Isavuconazole-treated patients had significantly lower frequency of hepatobiliary disorders (9% vs 16%; p=0.016), eye disorders (15% vs 27%; p=0.002), and skin/subcutaneous tissue disorders (33% vs 42%; p=0.037) compared to voriconazole 4.
• Drug-related adverse events were reported in 42% of isavuconazole patients vs 60% of voriconazole patients (p<0.001) 4.

Clinical Advantages

• Isavuconazole may be considered for antifungal prophylaxis when standard therapy is contraindicated due to drug interactions or risk of QTc prolongation 1.
• Linear pharmacokinetics with little evidence for drug-drug interactions, potentially eliminating need for therapeutic drug monitoring 3, 5.
• Available in both oral and intravenous formulations with favorable safety profile, notably absence of QTc prolongation 3.
• Reduced drug-drug interactions relative to voriconazole 3.

Real-World Experience

• A single-center study found breakthrough invasive fungal disease rate of 8.5% for patients receiving isavuconazole prophylaxis, with improved tolerability compared to historical data for posaconazole and voriconazole 6.
• Primary reasons for choosing isavuconazole included QTc shortening effects, decreased risk of acute kidney injury, broader spectrum of activity, and concern for breakthrough on other prophylactic agents 6.

Current Limitations

• Evidence for invasive candidiasis is not as robust as for aspergillosis; isavuconazole use may be reserved as step-down oral option when other azoles cannot be used due to tolerability or spectrum limitations 3.
• Post-marketing surveillance needed to better understand safety, efficacy, and need for serum concentration monitoring 3.

Critical Clinical Pitfalls to Avoid

Azole Selection Errors

• Do not use azoles for empirical therapy in patients who have received an azole for prophylaxis due to risk of resistance 1.
• Azoles should not be used in patients at risk of invasive zygomycosis; favor amphotericin B for these patients 1.

Formulation Substitution

• Never substitute posaconazole oral suspension with delayed-release tablets or vice versa without dose adjustment 2.

Monitoring Requirements

• Voriconazole requires therapeutic drug monitoring due to pharmacokinetic variability and drug-drug interactions 1.
• Beware of drug interactions between voriconazole and anticonvulsant therapy in CNS infections 1.

Surgical Considerations

• Surgical intervention is mandatory for invasive zygomycosis and recommended for pulmonary aspergillosis lesions in proximity to great vessels, pericardium, chest wall invasion, or persistent hemoptysis 1.
• Intravascular catheter removal is strongly recommended for candidemia 1.