What is the recommended dosing of posoconazole (Noxafil) for the treatment of mucormycosis?

Posaconazole Dosing in Mucormycosis

Posaconazole should be dosed at 400 mg twice daily (800 mg/day total) for salvage therapy of mucormycosis, not as first-line treatment. 1, 2

Role and Clinical Positioning

• Posaconazole is recommended exclusively for salvage therapy (BII evidence), not primary treatment (CIII evidence). 1, 2
• Liposomal amphotericin B at ≥5 mg/kg/day remains the first-line agent for all mucormycosis cases. 1, 3, 4
• Salvage indications include: refractory disease despite amphotericin B, intolerance to amphotericin B formulations, or need for prolonged maintenance therapy. 1

Specific Dosing Regimen

Standard Adult Dosing

• 400 mg twice daily (BID) using delayed-release tablets is the recommended dose. 1, 2
• Alternative regimen: 200 mg four times daily (QID) using oral suspension, though BID dosing is preferred for adherence. 1
• Target trough serum concentration: 0.7-1.0 μg/mL. 1, 2
• Therapeutic drug monitoring is strongly recommended where available. 1, 2

Pediatric Dosing (≥2 years)

• Posaconazole is recommended for salvage therapy in children ≥2 years and adolescents based on adult efficacy data. 1, 2
• Dosing should achieve similar target trough concentrations (0.7-1.0 μg/mL). 1
• Not recommended with strong evidence for first-line pediatric therapy due to lack of clinical efficacy data in this population. 1, 2

Clinical Efficacy Data

• Complete or partial response rates: 60-80% in salvage therapy. 1, 2
• Survival rate: 72% in the ECMM registry of mucormycosis patients receiving posaconazole. 1, 2
• In a retrospective analysis of 96 published case reports, complete response was achieved in 64.6% with overall mortality of 24%. 5
• Multivariate analysis showed posaconazole-based therapy was an independent predictor of favorable outcome (P=0.01). 1

Treatment Duration

• Continue posaconazole until complete clinical and radiological resolution of infection AND permanent reversal of predisposing factors. 2, 3
• Median treatment duration in compassionate use trials: 182 days (range 8-1004 days). 1
• No specific duration is defined; treatment is individualized based on clinical response and imaging. 2

Combination Therapy Considerations

• Lipid amphotericin B (3-5 mg/kg/day) plus posaconazole (800 mg/day) is recommended with CIII evidence (weak recommendation). 1, 2
• Combination with caspofungin plus lipid amphotericin B is an alternative (BII evidence). 1, 3
• Animal models showed no benefit of combining liposomal amphotericin B with posaconazole, but human data from 32 patients showed potential benefit. 1

Critical Adjunctive Measures (Non-Negotiable)

Surgical Intervention

• Surgery combined with antifungal therapy is strongly recommended (AII evidence) whenever feasible. 1, 2, 3, 4
• Mandatory for: rhino-orbito-cerebral disease, soft tissue infections, and localized pulmonary lesions. 1, 3, 4
• Survival was directly associated with surgical resection in posaconazole salvage studies. 1

Reversal of Predisposing Conditions

• Control of underlying conditions is critical (AII evidence). 1, 3, 4
• Discontinue or taper corticosteroids when feasible. 3, 4
• Correct diabetic ketoacidosis rapidly. 3, 4
• Reduce other immunosuppressive therapy. 3, 4
• Administer G-CSF if neutropenic. 4

Common Pitfalls and Caveats

Timing Issues

• Delaying treatment initiation increases 12-week mortality two-fold when deferred ≥6 days from symptom onset. 1, 4
• Posaconazole should NOT be used as monotherapy for primary treatment due to insufficient clinical data. 1, 6

Pharmacokinetic Considerations

• Posaconazole oral suspension must be administered with fatty food to optimize absorption. 7
• The delayed-release tablet formulation provides more consistent absorption than suspension. 2, 8
• Monitor serum levels where possible, as MICs of Mucorales (1-4 mg/mL) are higher than Aspergillus species. 1

Species-Specific Activity

• In vitro activity varies by species: 80% of Rhizopus spp. have MIC ≤0.5 mg/mL, but Mucor circinelloides shows 0% susceptibility at this breakpoint. 1
• Posaconazole shows modest efficacy in animal models compared to amphotericin B. 1

When NOT to Use Posaconazole

• Do NOT use as first-line monotherapy—this is a CIII recommendation (weak, based on opinion). 1
• Do NOT combine with deferasirox (AI evidence—strong recommendation against). 1, 3
• Avoid in children <2 years due to lack of safety and efficacy data. 1

Practical Algorithm for Posaconazole Use

1. First-line failure or intolerance? → Start posaconazole 400 mg BID 1, 2
2. Surgery feasible? → Perform urgently before or concurrent with posaconazole 1, 2, 3
3. Underlying condition reversible? → Address immediately (steroids, diabetes, neutropenia) 3, 4
4. Therapeutic drug monitoring available? → Target trough 0.7-1.0 μg/mL 1, 2
5. Clinical/radiological improvement? → Continue until complete resolution 2, 3
6. Consider maintenance therapy → Posaconazole long-term (BIII evidence) 1, 3