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Table 3 Primary antifungal treatment options for the treatment of IA and special considerations in solid organ transplant recipients

From: Invasive aspergillosis in solid organ transplant patients: diagnosis, prophylaxis, treatment, and assessment of response

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

  1. IV Intravenous, PO Oral, ECG Electrocardiogram, TDM Therapeutic Drug Monitoring
  2. 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
  3. bHepatotoxicity was significantly less frequent in patients treated with isavuconazole as compared to voriconazole in a prospective randomized clinical trial [89]
  4. cIsavuconazole is associated with shortening of the QTc interval
  5. 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
  6. 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
  7. fIn cases of baseline QTc prolongation and/or co-administration with QTc prolonging agents, such as macrolides and fluroquinolones, regular QTc monitoring is recommended
  8. gAdditional, noteworthy toxicities include hypomagnesaemia, renal tubular acidosis, and elevated liver function tests