Voriconazole for Invasive Aspergillosis
Voriconazole is the first-line treatment for invasive aspergillosis, initiated with a loading dose of 6 mg/kg IV every 12 hours for 2 doses (day 1), followed by a maintenance dose of 4 mg/kg IV every 12 hours, with transition to oral therapy (200 mg every 12 hours) once the patient is clinically stable and can tolerate oral intake. 1, 2
Dosing Algorithm
Adults - Initial Therapy
- Loading dose: 6 mg/kg IV every 12 hours for the first 24 hours (2 doses total) 1, 3
- Maintenance dose: 4 mg/kg IV every 12 hours for minimum 7 days 1, 3
- Transition to oral: 200 mg PO every 12 hours once clinically improved and able to tolerate oral medications 1, 3
- Dose escalation if inadequate response: Increase oral dose to 300 mg every 12 hours (or IV to 4 mg/kg if already on lower dose) 1, 3
- Patients <40 kg: Use half the standard oral maintenance dose (100 mg every 12 hours, can increase to 150 mg if needed) 3
Pediatric Patients (≥2 years)
- Maintenance dose: 5-7 mg/kg IV every 12 hours (higher than adults due to accelerated metabolic clearance) 1, 4
- The European Medicines Agency specifically recommends 7 mg/kg twice daily to achieve plasma levels comparable to adults 1
- Loading regimens in pediatric populations remain inadequately studied 1
Neonates
- First-line: Liposomal amphotericin B (not voriconazole) 4
Critical Renal Impairment Considerations
In patients with creatinine clearance <50 mL/min, use ONLY oral voriconazole—never IV formulation. 5
- Oral dosing in renal impairment: Standard dosing applies (400 mg loading dose twice on day 1, then 200 mg twice daily)—no renal dose adjustment required 5
- Why avoid IV in renal impairment: The IV formulation contains sulfobutyl-ether cyclodextrin vehicle that accumulates when CrCl <50 mL/min, with uncertain toxicity consequences 1, 5
- Exception: Only use IV voriconazole in severe renal impairment if absolutely no alternative exists and benefits clearly outweigh risks 5
Hepatic Impairment Adjustment
- Mild to moderate hepatic impairment: Reduce maintenance dose by 50% 5
- Voriconazole is the only triazole requiring hepatic dose adjustment 5
Treatment Duration
- Minimum duration: 6-12 weeks 1, 2, 5
- Continue therapy: Throughout the period of immunosuppression and until lesions have resolved or stabilized on imaging 1, 4
- In the pivotal trial, median IV therapy was 10 days (range 2-85 days) and median oral therapy was 76 days (range 2-232 days) 1
Therapeutic Drug Monitoring (TDM)
TDM is strongly recommended due to high interpatient variability and narrow therapeutic window. 2, 4, 5
- Target trough levels: 0.72-2.13 μg/mL based on outcomes data 6
- When to monitor: Especially important with oral therapy, in cases of treatment failure, progressive infection, or to evaluate for potential toxicity 1, 2
- Why variability occurs: CYP2C19 polymorphisms cause wide variation in serum levels, with slow metabolizers more common in non-Indian Asian populations 1, 5
- Levels >2.13 μg/mL predict hepatotoxicity 6
Drug Interaction Management
Review ALL concurrent medications before initiating voriconazole. 1, 5
- Voriconazole is both a substrate and inhibitor of CYP2C19, CYP2C9, and CYP3A4 1, 5
- Dose increase needed with: Phenytoin or efavirenz co-administration 3
- CNS aspergillosis caveat: Significant drug interactions with anticonvulsant therapy require careful monitoring 1
Evidence Supporting Voriconazole as First-Line
The landmark randomized trial demonstrated voriconazole's superiority over amphotericin B deoxycholate: 7
- Successful response: 53% with voriconazole vs 32% with amphotericin B 7
- 12-week survival: 71% with voriconazole vs 58% with amphotericin B 7
- Fewer severe adverse events with voriconazole, though transient visual disturbances occurred in 45% of patients 7
A 2021 non-inferiority trial showed posaconazole was non-inferior to voriconazole (15% vs 21% mortality at day 42), with fewer treatment-related adverse events (30% vs 40%), supporting posaconazole as an alternative first-line option. 8
Alternative Primary Therapy
- Liposomal amphotericin B: 3-5 mg/kg/day IV for patients with voriconazole contraindications or intolerance 1, 2, 4
- Isavuconazole: 200 mg every 8 hours for 6 doses, then 200 mg daily (newer alternative with potentially better safety profile) 1, 9
Salvage Therapy Options
When primary therapy fails or is not tolerated: 1, 2
- Lipid formulations of amphotericin B (ABLC 5 mg/kg/day IV)
- Caspofungin (70 mg loading dose day 1, then 50 mg/day IV; pediatric dose 50 mg/m²/day)
- Micafungin (100-150 mg/day IV)
- Posaconazole (oral suspension 200 mg TID; tablet 300 mg BID day 1, then 300 mg daily; IV 300 mg BID day 1, then 300 mg daily)
- Itraconazole suspension (200 mg PO every 12 hours)
Combination Therapy
Primary combination therapy is NOT routinely recommended. 1, 2
- Consider adding another agent or switching drug classes only for salvage therapy in refractory cases 1, 2
- Combination of voriconazole with anidulafungin may serve as alternative for patients with limited drug tolerance 9
Common Pitfalls to Avoid
- Never use IV voriconazole in CrCl <50 mL/min unless no alternative exists 5
- Don't forget loading doses—critical for rapidly achieving therapeutic levels 5, 3
- Don't assume oral bioavailability is poor—voriconazole has excellent oral bioavailability in fed or fasted state 1
- Don't overlook drug interactions—review medication list before starting therapy 1, 5
- Don't skip TDM—especially with oral therapy or in treatment failure 2, 4, 5
- Aspergillus terreus is clinically resistant to amphotericin B—must use azole therapy 2
Special Clinical Scenarios
Invasive Sinus Aspergillosis
- Same medical therapy as invasive pulmonary aspergillosis 1
- Add surgical debridement as adjunct to medical therapy 1
CNS Aspergillosis
- Same dosing as invasive pulmonary aspergillosis 1
- Voriconazole achieves adequate CSF levels 1
- Highest mortality among all invasive aspergillosis patterns 1