Table 3.

Primary antifungal treatment options for the treatment of IA and special considerations in solid organ transplant recipients

Agent	Dose	Recommendation	Potential Adverse Events	Potential Drug Interactions	Additional Considerations	Monitoring
Voriconazole	Induction: 6 mg/kg IVa every 12 h the first day Maintenance: 4 mg/kg IVa, 200-300 mg PO twice daily	1st line [14]	-Hepatotoxicityb -Visual changes -Neurologic toxicity -Rash and photosensitivity -Periostitis -QTc prolongationc	-Sirolimusd -Tacrolimusd -Cyclosporined	-Non-linear pharmacokinetics -Strong inhibitor of CYP3A4 -Moderate inhibitor of CYP2C19 and 2C9 -Metabolized via CYP2C19, 2C9 and 3A4 - < 2% of voriconazole is excreted in the urine	-Liver function tests −12-lead ECGf -Voriconazole TDMd -Sirolimus, tacrolimus, and cyclosporine TDMd
Isavuconazole	Induction: 200 mg three times daily the first 2 days Maintenance: 200 mg daily	1st line [15] Primary alternative [14]	-Hepatotoxicityb	-Sirolimuse -Tacrolimuse -Cyclosporinee	-Linear pharmacokinetics -Moderate inhibitor of CYP3A4 -Metabolized via CYP3A4 -Isavuconazole may cause QTc shortening	-Liver function tests -Sirolimus, tacrolimus, and cyclosporine TDMe
Liposomal Amphotericin B	3–5 mg/kg daily IV	Primary alternative [14, 15]	- Nephrotoxicityg			-Renal function and electrolytes

IV Intravenous, PO Oral, ECG Electrocardiogram, TDM Therapeutic Drug Monitoring

^aIV voriconazole is not recommended in patients with renal dysfunction (glomerular filtration rate < 50 mL/min) due to the potential of nephrotoxicity associated with the IV formulation vehicle of cyclodextrin

^bHepatotoxicity was significantly less frequent in patients treated with isavuconazole as compared to voriconazole in a prospective randomized clinical trial [89]

^cIsavuconazole is associated with shortening of the QTc interval

^dVoriconazole may significantly increase sirolimus levels, therefore close monitoring of sirolimus TDM is recommended in case of co-administration. Significant dose reductions of sirolimus, tacrolimus and cyclosporine are commonly required when any of these agents is co-administered with voriconazole

^eEarly data suggest that isavuconazole administration does not significantly affect blood concentrations of sirolimus and tacrolimus [90]. Until more data become available, it is advised to closely monitor immunosuppression TDM while co-administered with isavuconazole

^fIn cases of baseline QTc prolongation and/or co-administration with QTc prolonging agents, such as macrolides and fluroquinolones, regular QTc monitoring is recommended

^gAdditional, noteworthy toxicities include hypomagnesaemia, renal tubular acidosis, and elevated liver function tests