Antifungal Prophylaxis in Bilateral Lung Transplant Recipients on ECMO
Direct Recommendation
For a bilateral lung transplant recipient on potent immunosuppressants supported by ECMO, use systemic voriconazole or itraconazole as first-line prophylaxis rather than amphotericin B, with inhaled amphotericin B reserved as an adjunct or alternative if azole toxicity or drug interactions become prohibitive. 1
Guideline-Based Rationale
Primary Prophylaxis Strategy
The Infectious Diseases Society of America strongly recommends systemic triazoles (voriconazole or itraconazole) or inhaled amphotericin B for 3-4 months after lung transplantation (strong recommendation; moderate-quality evidence). 1
Systemic azoles are preferred over inhaled amphotericin B for lung transplant recipients with:
- Mold colonization pre- or post-transplant
- Mold infections in explanted lungs
- Single-lung transplant recipients (weak recommendation; low-quality evidence) 1
In your ECMO-supported patient with augmented immunosuppression, antifungal prophylaxis must be reinitiated or continued when receiving thymoglobulin, alemtuzumab, or high-dose corticosteroids (strong recommendation; moderate-quality evidence). 1
Comparative Efficacy in Lung Transplant Recipients
Universal prophylaxis is more effective than targeted prophylaxis in preventing invasive fungal infections after lung transplantation. 2
Universal prophylaxis with itraconazole ± inhaled amphotericin B resulted in 10% invasive fungal infection rate versus 30% with targeted prophylaxis (HR = 4.32, P = 0.0064). 2
Posaconazole demonstrates superior efficacy compared to itraconazole in critically ill lung transplant recipients, with 10% versus 33% requiring transition from prophylaxis to therapy (P = 0.029). 3
Recent evidence suggests universal prophylaxis with inhaled amphotericin B plus systemic voriconazole for 3-6 months may be optimal, with slight preference for amphotericin B due to better safety profile. 4
Practical Considerations for ECMO Patients
Drug Administration Challenges
Absorption of oral azoles is highly problematic in critically ill patients:
68% of posaconazole suspension concentrations were subtherapeutic in critically ill lung transplant recipients, compared to only 10% with tablets. 3
55-60% of itraconazole and posaconazole concentrations fail to reach therapeutic targets (≥500 µg/L for itraconazole, ≥700 µg/L for posaconazole) in this population. 3
Therapeutic drug monitoring is mandatory for all systemic azoles in ECMO-supported patients due to unpredictable absorption and drug-drug interactions. 5
Safety Profile Comparison
Amphotericin B nephrotoxicity is particularly concerning in ECMO patients:
Lipid formulations of amphotericin B reduce nephrotoxicity but do not eliminate mortality risk in high-risk transplant recipients. 1
Systemic amphotericin B deoxycholate receives a D recommendation due to inferior safety profile compared to azoles. 1
Azole-related complications:
Voriconazole causes hepatotoxicity in up to 60% of lung transplant patients, with 14% discontinuing due to adverse effects. 1
Tacrolimus-azole interactions require aggressive monitoring: 11.7% of patients experience supratherapeutic tacrolimus levels with posaconazole, associated with mean 21.6 µmol/L creatinine rise. 5
Spectrum of Coverage
Both agents provide adequate mold coverage, but with different considerations:
Amphotericin B provides broader coverage including Fusarium species, which have intrinsic echinocandin resistance and occur in up to 32% of lung transplant patients with 67% mortality. 6
Posaconazole offers mucormycosis coverage that standard amphotericin B formulations also provide, but with potentially better tolerability. 7
Voriconazole demonstrated 1.5% invasive aspergillosis rate in universal prophylaxis versus 23.5% in guided prophylaxis. 1
Algorithmic Approach for Your Patient
Step 1: Initial Agent Selection
Start with IV voriconazole (loading: 6 mg/kg IV q12h × 2 doses; maintenance: 4 mg/kg IV q12h):
- Provides immediate systemic levels independent of GI absorption 8
- Covers both Aspergillus and Candida species 8
- Strong guideline support for lung transplant recipients 1
Step 2: Add Inhaled Amphotericin B
Combine with inhaled liposomal amphotericin B 25 mg daily:
- Achieves 92% efficacy without systemic absorption 1
- Avoids systemic amphotericin toxicity 1
- Provides local airway protection where risk is highest 1
Step 3: Monitoring Protocol
Mandatory monitoring includes:
- Voriconazole trough levels (target 1-5.5 mcg/mL) within 3-5 days 8
- Tacrolimus levels every 2-3 days initially, expect 50-80% dose reduction 5
- Liver function tests weekly for first month 7
- Serum creatinine twice weekly 5
Step 4: Transition Strategy
If voriconazole toxicity or drug interactions become unmanageable:
- Switch to liposomal amphotericin B 3-5 mg/kg IV daily as second-line option (strong recommendation; high-quality evidence) 1, 8
- Continue inhaled amphotericin B regardless of systemic agent 4
- Consider isavuconazole 200 mg IV q8h × 6 doses, then 200 mg daily if available, for better tolerability 8
Step 5: Duration
Continue prophylaxis for minimum 3-4 months post-transplant or throughout duration of augmented immunosuppression, whichever is longer (strong recommendation; moderate-quality evidence). 1
Critical Pitfalls to Avoid
Do not use systemic amphotericin B as first-line prophylaxis when effective azole alternatives exist, given nephrotoxicity risk in ECMO patients with already compromised renal perfusion. 1
Do not rely on oral azole formulations in ECMO-supported patients without therapeutic drug monitoring—absorption is too unpredictable. 3
Do not use echinocandins for primary prophylaxis—they lack mold activity and Fusarium species have intrinsic resistance. 6
Do not discontinue tacrolimus monitoring when initiating azoles—the interaction is profound and can cause acute kidney injury. 5