What is the recommended treatment regimen for Isavuconazole (Isavuconazonium sulfate) in invasive fungal infections?

Isavuconazole Treatment Regimen for Invasive Fungal Infections

Isavuconazole should be administered as 200 mg (372 mg of isavuconazonium sulfate) three times daily for the first two days (6 loading doses given every 8 hours), followed by 200 mg once daily starting on day 3, available in both intravenous and oral formulations. 1

Loading and Maintenance Dosing

• Loading phase: Administer 200 mg IV or PO every 8 hours for 6 doses over the first 48 hours 1
• Maintenance phase: Continue with 200 mg IV or PO once daily beginning on day 3 1
• Both IV and oral formulations are bioequivalent and can be used interchangeably without dose adjustment 1
• IV formulation should be given in 200 mL of 5% dextrose infused over 2-3 hours 1

Approved Indications and Clinical Context

Invasive Aspergillosis:

• Isavuconazole demonstrated non-inferiority to voriconazole in Phase 3 trials with 62% favorable response rate versus 60% for voriconazole 1
• Can be used as primary therapy or salvage therapy after failure of other antifungals 2
• Real-world data shows 40% favorable response at 6 weeks and 60% at 12 weeks in high-risk hematologic malignancy patients 2

Invasive Mucormycosis:

• Approved as an alternative to liposomal amphotericin B for primary therapy 1
• Day-42 mortality with isavuconazole (33%) was similar to amphotericin B (41%) in matched case-control analysis 3
• Should be considered when amphotericin B is contraindicated, not tolerated, or in patients with renal impairment 4

Treatment Duration by Indication

COVID-19 Associated Mucormycosis (CAM):

• Primary therapy: 4-6 weeks of induction and consolidation treatment 1
• Maintenance therapy: 3-6 months until resolution of clinical signs and symptoms 1
• Duration should be tailored based on underlying immune status 1

Invasive Aspergillosis:

• Minimum treatment duration of 6-12 weeks 1
• Continue until resolution based on site of disease, evidence of improvement, and degree/duration of immunosuppression 1

Key Pharmacokinetic Advantages

• No QTc prolongation: Unlike posaconazole, isavuconazole causes dose-dependent QTc shortening, making it preferred for patients at risk of arrhythmias 4
• Renal safety: Preferred over amphotericin B formulations in patients with renal impairment 4
• Fewer drug interactions: Reduced CYP3A4 interactions compared to voriconazole, though still requires monitoring with calcineurin inhibitors and other CYP3A4 substrates 4, 5
• No therapeutic drug monitoring required: Unlike voriconazole and posaconazole suspension, routine TDM is not necessary with standard dosing 4

Critical Pitfalls to Avoid

Inadequate dosing in ECMO patients:

• Standard dosing may not achieve therapeutic concentrations in patients on extracorporeal membrane oxygenation 6
• Consider measuring trough concentrations (target >1-2 μg/mL) and increasing dose to 744 mg daily if needed 6
• High protein binding (>99%) and lipophilicity lead to drug sequestration in ECMO circuits 6

Drug-drug interactions:

• Reduce calcineurin inhibitor and mTOR inhibitor doses by 30-50% when initiating isavuconazole 5
• Avoid combination with rifampin/rifabutin as they dramatically decrease isavuconazole levels 5
• Monitor levels of immunosuppressants (cyclosporine, tacrolimus, sirolimus) closely 5
• Avoid concurrent use with vinca alkaloids due to severe neurotoxicity risk 5

Delayed treatment initiation:

• Prompt initiation after diagnosis is critical; delays >6 days result in 2-fold increase in mortality at 12 weeks 1
• For mucormycosis, surgical debridement should not be delayed and must accompany antifungal therapy 1

Combination Therapy Considerations

• Monotherapy is generally preferred; combination therapy with amphotericin B did not show improved outcomes in real-world data 2
• Combination may be considered in selected patients with CNS aspergillosis or refractory disease 1
• Echinocandins should not be used as primary monotherapy but can be effective in salvage combinations 1

Monitoring and Safety

• Adverse events occur in approximately 4% of patients, most commonly hepatotoxicity 2
• Monitor liver function tests regularly 4
• No routine therapeutic drug monitoring required unless patient on ECMO or suspected treatment failure 6
• Favorable safety profile with lower discontinuation rates compared to other azoles 4, 2