Mucormycosis¶
Chapter 224 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Fungal · Chapter 224
Key Clinical Points¶
- Caused by Mucorales fungi; highly invasive with high mortality (>90% in disseminated disease).
- Lipid amphotericin B (LAmB) is the first-line therapy except for mild localized disease.
- Surgical debridement is critical for improving outcomes.
- Key risk factors include hyperglycemia, acidosis, and iron overload (especially from deferoxamine).
- Histopathology shows characteristic broad, ribbon-like, nonseptate hyphae branching at right angles.
- Distinguished from aspergillosis by morphology; voriconazole may exacerbate mucormycosis.
- Rapid reversal of hyperglycemia and acidosis is critical for patient survival.
- Commonly involves rhino-orbital-cerebral, pulmonary, cutaneous, gastrointestinal, and disseminated sites.
DEFINITION & CLASSIFICATION¶
• Definition (Harrison's 22e): Mucormycosis is caused by fungi of the order Mucorales (subphylum Mucoromycotina). • Clinical Behavior: Highly invasive and relentlessly progressive; results in higher morbidity/mortality than many other infections. • Mortality Rates: - Disseminated disease: >90% mortality. - Comparison to Aspergillosis: Invasive aspergillosis has 30–70% mortality if treated vs. 100% if missed.
EPIDEMIOLOGY¶
• High-Risk Populations: - Patients with diabetes mellitus - Transplant recipients - Neutropenic patients - Patients on corticosteroids • Emerging Trends: Pandemic-associated cases linked to high-dose steroids in diabetic COVID-19 patients. • Geographic/Contextual Factors: - Higher incidence in India pre-pandemic. - Disseminated disease more common in itraconazole/voriconazole prophylaxis recipients. • Infection Routes: Cutaneous infections occur via trauma or medical devices.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Pathogens: Seven Mucorales families cause disease; Rhizopus species are most common in the Western Hemisphere. • Risk Factors: - Uncontrolled diabetes - Phagocytic defects - Iron overload (especially from deferoxamine use) • Mechanism of Virulence: - DKA enhances virulence via β-hydroxybutyrate and free iron. - Hyperglycemia promotes infection through multiple mechanisms, including GRP78 receptor upregulation.
Taxonomy of Fungi Causing Mucormycosis¶
• Primary Pathogens: - Mucoraceae: Rhizopus oryzae, R. delemar, R. microsporus, Rhizomucor pusillus, Mucor, Actinomucor - Lichtheimiaceae: Lichtheimia corymbifera (formerly Absidia) - Cunninghamellaceae: Cunninghamella - Others: Thamnidiaceae (Cokeromyces), Mortierellaceae (Mortierella), Saksenaceae (Saksena), Apophysomyces, Syncephalastraceae (Syncephalastrum). • Table 224-1: Lists the primary families and associated genera (e.g., Mucoraceae includes Rhizopus; Lichtheimiaceae includes Lichtheimia).
CLINICAL FEATURES¶
• Primary Syndromes: - Rhino-orbital-cerebral - Pulmonary - Cutaneous - Gastrointestinal - Disseminated
• Rhino-Orbital-Cerebral Disease: - Most common in diabetics. - Progression: Facial pain/numbness → conjunctival swelling → proptosis, chemosis, ophthalmoplegia → black necrotic eschar. - Critical Finding: Cavernous sinus thrombosis (ominous if bilateral).
• Pulmonary Disease: - Symptoms: Dyspnea, cough, hemoptysis. - Imaging: CT is superior to X-ray; shows lobar consolidation, nodules, and cavities.
• Cutaneous Disease: - Source: Trauma or medical devices. - Presentation: Necrotizing fasciitis. - Prognosis: ~80% mortality if untreated.
• Gastrointestinal Disease: - Population: Historically in neonates; now common in immunocompromised adults. - Symptoms: Abdominal pain, bleeding, perforation.
• Disseminated and Miscellaneous Forms: - Sites: Brain (most common), bones, trachea, kidneys, scalp (kerion), teeth. - Mortality: >90% in disseminated disease.
DIFFERENTIAL DIAGNOSIS¶
• Fungal Pathogens: - Aspergillosis - Fusariosis - Scedosporiosis - Dematiaceous fungi - Entomophthoromycoses (Basidiobolus/Conidiobolus) — distinguished by culture. • Bacterial/Other: - Bacterial orbital cellulitis - Klebsiella rhinoscleroma - Tolosa-Hunt syndrome.
DIAGNOSTIC APPROACH¶
- Initial Identification:
- Definitive diagnosis: Culture from sterile site OR histopathology showing aseptate hyphae.
- Probable diagnosis: Nonsterile cultures + clinical/radiographic evidence.
- Histopathology (Preferred):
- Biopsy with PAS or hematoxylin-eosin staining; most effective for identifying broad, ribbon-like, nonseptate hyphae (Figure 224-1).
- Molecular Testing:
- PCR: Not FDA-approved but may aid in diagnosis.
MANAGEMENT & TREATMENT¶
• Core Management Pillars: 1. Early therapy 2. Surgical debridement (improves outcomes significantly) 3. Reverse risk factors (e.g., hyperglycemia, acidosis) 4. Treat underlying malignancy.
• Antifungal Therapy Strategy: - First-line: Lipid amphotericin B (LAmB) for most cases; AmB deoxycholate only for mild localized disease. - CNS Disease: Dose escalation required (LAmB 7.5–10 mg/kg). - Monitoring: Avoid iron administration and limit RBC transfusions.
• Specific Antifungal Options (Table 224-2): - AmB deoxycholate: 1.0–1.5 mg/kg once daily (standard); 5–10 mg/kg (less nephrotoxic, better CNS penetration). - ABLC: 5 mg/kg once daily (less nephrotoxic than AmB deoxycholate; consider with echinocandins). - Isavuconazole: 200 mg q8h imes 6 then daily (FDA approved, useful if septate mold vs. mucormycosis is unclear). - Posaconazole: 200 mg four times per day (lower blood levels than isavuconazole; salvage therapy only). - Combination Therapy: - Echinocandins: Synergistic in murine models; better outcomes in rhino-orbital-cerebral cases. - Lipid polyene + azole (posaconazole or isavuconazole): Standard doses, but no evidence of superiority over monotherapy.
PROGNOSIS & COMPLICATIONS¶
• Mortality: - >90% in disseminated disease. - Poor outcomes associated with: Brain involvement, endophthalmitis, or endocarditis. • Critical Intervention: Rapid reversal of hyperglycemia and acidosis is essential for survival.
SPECIAL POPULATIONS¶
• Drug Interactions/Selection: - Voriconazole: May exacerbate mucormycosis; avoid if mucormycosis is suspected. - Isavuconazole: Consider in cases where septate mold vs. mucormycosis is not yet established. • Complex Cases: - Dual infection with septate molds possible in immunocompromised patients. - Multidisciplinary care required for complex presentations.
KEY PEARLS & HIGH-YIELD POINTS¶
• Morphology is Key: Histopathology showing broad, ribbon-like, nonseptate hyphae with wide-angle branching distinguishes Mucorales from Aspergillus. • Don't Delay: Do not delay chemotherapy for mucormycosis; antifungals only temporize the condition. • Rapid Action: Mortality is extremely high in disseminated disease; rapid reversal of metabolic derangements (hyperglycemia/acidosis) is a priority. • Avoid Iron: Avoid iron administration and limit RBC transfusions to prevent fungal growth.
Reference Tables¶
TABLE 223-3 Treatment of Aspergillosis a INDICATION Invasive disease b¶
Harrison's 22e, p.1717
| INDICATION | PRIMARY TREATMENT | PRECAUTIONS | SECONDARY TREATMENT | COMMENTS |
|---|---|---|---|---|
| Invasive diseaseb | Voriconazole, isavuconazole, posaconazole |
Drug interactions (especially with voriconazole)c |
AmB, caspofungin, micafungin |
As primary therapy, azoles have a 20% higher response rate than AmB. Therapeutic drug monitoring is recommended for voriconazole and isavuconazole in ICU patients. |
| Posaconazole tablet, itraconazole solution SUBA-itraconazole |
Vincristine, cyclophosphamide interaction |
Micafungin, aerosolized AmB |
||
| Single aspergilloma | Surgical resection | Multicavity disease: poor outcome of surgery, medical therapy preferable |
Itraconazole, voriconazole, intracavity AmB |
Single large cavities with an aspergilloma are best resected. Relapse reduced by pre- and perioperative antifungal therapy. |
| Voriconazole, itraconazole |
Poor absorption of itraconazole capsules with proton pump inhibitors or H blockers 2 |
Posaconazole, IV AmB, IV micafungin |
||
| ABPA/SAFS (“fungal asthma”) |
Itraconazole | Some glucocorticoid interactions, including with inhaled formulations |
Voriconazole, posaconazole, inhaled AmB |
Long-term therapy is helpful in most cases. No evidence indicates whether therapy modifies progression to bronchiectasis/fibrosis. |
| 224 | Mucormycosis Brad Spellberg, Ashraf S. Ibrahim |
TABLE 224-1 Taxonomy of Fungi Causing Mucormycosis (Subphylum Mucoromycotina, Order Mucorales) FAMILY Mucoraceae¶
Harrison's 22e, p.1718
| FAMILY | GENUS (SPECIES LISTED FOR SOME) |
|---|---|
| Mucoraceae | Rhizopus oryzae Rhizopus delemar Rhizopus microsporus Rhizomucor Mucor Actinomucor |
| Cunninghamellaceae | Cunninghamella |
| Mortierellaceae | Mortierella |
| Syncephalastraceae | Syncephalastrum |
TABLE 224-2 Antifungal Options for the Treatment of Mucormycosis a DRUG First-Line Antifungal Therapy AmB deoxycholate¶
Harrison's 22e, p.1721
| DRUG | RECOMMENDED DOSAGE | ADVANTAGES AND SUPPORTING STUDIES | DISADVANTAGES |
|---|---|---|---|
| First-Line Antifungal Therapy | |||
| AmB deoxycholate | 1.0–1.5 mg/kg once per day | • >5 decades of clinical experience • Inexpensive • FDA approved for treatment of mucormycosis |
• Highly toxic • Poor CNS penetration |
| 5–10 mg/kg once per day | • Less nephrotoxic than AmB deoxycholate • Better CNS penetration than AmB deoxycholate or ABLC • Better outcomes than with AmB deoxycholate in murine models and a retrospective clinical review |
||
| ABLC | 5 mg/kg once per day | • Less nephrotoxic than AmB deoxycholate • Murine and retrospective clinical data suggest benefit of combination therapy with echinocandins |
• Expensive • Possibly less efficacious than LAmB for CNS infection |
| Second-Line/Salvage Option | |||
| 200 mg of isavuconazole (372 mg of isavuconazonium sulfate), load q8h × 6 followed by once-daily dosing |
• Efficacy similar to that of LAmB in mouse models • FDA approved for treatment of mucormycosis • May be a rational empirical option when septate mold vs mucormycosis is not yet established |
||
| Posaconazole | 200 mg four times per day | • In vitro activity against the Mucorales, with lower MICs than isavuconazole • Retrospective data for salvage therapy in mucormycosis |
• Substantially lower blood levels than isavuconazole • No data on initial therapy for mucormycosis, and no evidence for posaconazole in combination with other therapy • Experience limited, potential use for salvage therapy |
| Combination Therapyb | |||
| Standard echinocandin doses | • Favorable toxicity profile • Synergistic in murine disseminated mucormycosis • Retrospective clinical data suggest superior outcomes for rhino-orbital-cerebral mucormycosis. |
||
| Lipid polyene plus azole (posaconazole or isavuconazole) |
Standard doses | • Favorable toxicity profile | • Limited efficacy data, with no available evidence of superiority vs monotherapy |
| Standard doses | • Maximal aggressiveness |