What are the latest treatment options and dosing recommendations for newer antifungals (such as isavuconazonium, posaconazole, and voriconazole) in patients with fungal infections?

Newer Antifungals: Evidence Update

For invasive aspergillosis, both isavuconazole and posaconazole are non-inferior to voriconazole for primary treatment, with isavuconazole offering superior tolerability and fewer drug interactions, making it the preferred newer agent when voriconazole is not suitable. 1, 2

Isavuconazole: The Newest Triazole

FDA-Approved Indications and Key Advantages

• Isavuconazole is FDA-approved for invasive aspergillosis and mucormycosis, representing the most recent addition to the advanced triazole class 3
• Critical advantages over voriconazole include: no QTc prolongation, more predictable pharmacokinetics, simplified drug interaction profile, and superior tolerability 3, 2
• Isavuconazole demonstrated non-inferiority to voriconazole for invasive mould disease with 19% vs 20% all-cause mortality at day 42 (treatment difference -1.0%, 95% CI -7.8 to 5.7) 2

Tolerability Profile

• Drug-related adverse events occurred in 42% of isavuconazole patients versus 60% with voriconazole (p<0.001) 2
• Significantly lower rates of hepatobiliary disorders (9% vs 16%, p=0.016), eye disorders (15% vs 27%, p=0.002), and skin disorders (33% vs 42%, p=0.037) compared to voriconazole 2
• Real-world data shows breakthrough invasive fungal disease rate of 8.5%, comparable to historical posaconazole and voriconazole data 4

Clinical Positioning

• Primary indications include patients requiring QTc shortening, those at risk for acute kidney injury, and cases of breakthrough fungal disease on other prophylactic agents 4
• Not FDA-approved for invasive candidiasis after failing to achieve non-inferiority to caspofungin 3

Posaconazole: Expanded Role with New Formulations

Efficacy Data and Formulation Advantages

• Posaconazole demonstrated non-inferiority to voriconazole for invasive aspergillosis with 15% vs 21% mortality at day 42 (treatment difference -5.3%, 95% CI -11.6 to 1.0, p<0.0001) 1
• Intravenous and delayed-release tablet formulations provide improved systemic absorption compared to the original oral suspension 1
• Posaconazole is the only azole with activity against zygomycete fungi, a unique advantage over all other triazoles 5

Dosing Recommendations

• Loading dose: 300 mg twice daily on day 1, followed by 300 mg once daily for days 2-84 for both IV and oral formulations 1
• Treatment duration typically 12 weeks or less for invasive aspergillosis 1
• No dose adjustment required for renal impairment with delayed-release tablets 6

Safety Profile

• Treatment-related adverse events occurred in 30% of posaconazole patients versus 40% with voriconazole (treatment difference -10.2%, 95% CI -17.9 to -2.4) 1
• Most common adverse events (>3% incidence): increased AST/ALT, nausea, hypokalaemia, and vomiting 1
• Important contraindications include concomitant use with sirolimus, certain CYP3A4 substrates causing QT prolongation, HMG-CoA reductase inhibitors metabolized by CYP3A4, ergot alkaloids, and venetoclax 6

Voriconazole: Established Standard with Known Limitations

Current Role and Dosing

• Voriconazole remains first-line for invasive aspergillosis per established guidelines, particularly for CNS involvement 7
• Standard dosing: 6 mg/kg IV twice daily on day 1, then 4 mg/kg IV twice daily or 200 mg PO twice daily 1, 2
• Preferred agent when radiological presentations are consistent with invasive aspergillosis along with positive galactomannan antigen 7

Key Limitations

• Visual disturbances, hallucinations, and blurred vision are common adverse effects 1
• Significant drug interactions with anticonvulsants require careful monitoring, particularly in CNS aspergillosis where both agents may be needed 7
• Higher rates of hepatotoxicity (increased ALT, AST, alkaline phosphatase, γ-glutamyltransferase) compared to newer agents 1

Clinical Decision Algorithm

When to Choose Isavuconazole

• Patients with baseline QTc prolongation or at risk for arrhythmias 3, 4
• Patients with renal impairment or at high risk for acute kidney injury 4
• Complex drug regimens where simplified interaction profile is advantageous 3
• Patients who experienced intolerance to voriconazole 2, 4

When to Choose Posaconazole

• Suspected or confirmed mucormycosis (zygomycosis), as it is the only azole with activity against these organisms 5
• Prophylaxis in high-risk hematologic malignancy patients (particularly AML and allogeneic HSCT) 4
• Breakthrough fungal infections on other prophylactic agents 4
• Patients requiring once-daily dosing for adherence 1

When to Continue Voriconazole

• CNS aspergillosis where extensive clinical experience exists 7
• Patients already stable on voriconazole without adverse effects 1
• Resource-limited settings where newer agents are unavailable 2

Critical Drug Interactions and Monitoring

Calcineurin Inhibitor Interactions

• All three agents inhibit CYP3A4 and increase levels of cyclosporine and tacrolimus, requiring dose reductions and therapeutic drug monitoring 8, 6
• Isavuconazole has the least complicated interaction profile among the three 3

Contraindicated Combinations

• Posaconazole is contraindicated with sirolimus, venetoclax, ergot alkaloids, and certain statins (simvastatin, lovastatin) 6
• All azoles require caution with midazolam, vinca alkaloids, and antiretroviral drugs 8, 6

Common Pitfalls to Avoid

• Do not substitute posaconazole oral suspension for delayed-release tablets or IV formulation due to different pharmacokinetics and bioavailability 6
• Monitor for hepatotoxicity with all azoles, though rates are lower with isavuconazole and posaconazole versus voriconazole 1, 2
• Assess renal function before initiating therapy, particularly for voriconazole IV formulation which contains cyclodextrin vehicle 3
• Check baseline and periodic ECGs when using voriconazole or posaconazole in patients with risk factors for QT prolongation 6, 3
• Verify electrolytes (potassium, magnesium) before and during therapy as hypokalemia increases risk of arrhythmias 6