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Mechanistic Deep Dive
Aspergillus Pathogenesis
- Inhaled conidia â germinate in tissue
- Hyphal invasion of vessels
- Tissue infarction
- Hemorrhage
- Neutrophil-mediated immunity critical (neutropenia â invasion)
Mucormycosis Vascular Invasion
- Hyphae directly invade blood vessels
- Thrombosis, infarction
- Rapid spread
- Iron + glucose enhance growth
Resistance Patterns
- Azole-resistant Aspergillus (TR34/L98H, TR46/Y121F/T289A): environmental + clinical; threat
- Echinocandin-resistant Candida glabrata: emerging
- Multidrug-resistant Candida auris: global threat
Recent Trials & Updates
SECURE (2016) â Isavuconazole vs Voriconazole for IPA
- Non-inferior
- Less toxicity
- IDSA 2016 endorsement
CAM (COVID-Associated Mucormycosis) â India Outbreak 2021
- Massive epidemic in India during COVID wave
- DM + steroids + COVID + oxygen
- High mortality
- Aggressive amphotericin + surgery
Rezafungin (2023 FDA Approved)
- Long-acting echinocandin (weekly)
- Candida infections
- ReSTORE trial
Ibrexafungerp (2021)
- Oral glucan synthase inhibitor
- Echinocandin-resistant Candida
- Approved for vulvovaginal candidiasis; expanding
Olorofim
- Orotomide class
- For azole-resistant Aspergillus, Scedosporium, Lomentospora
- Phase 2-3
- Promising
Fosmanogepix
- Inhibits GPI synthesis
- Broad spectrum including Candida + Aspergillus + endemic + Mucorales
- Phase 2-3
MSG-15 (Voriconazole + Anidulafungin in IPA)
- Combination therapy for severe IPA
- Marginal benefit, increased toxicity
- Now selected use
CAPA Specific Trials + Guidelines (2020-2024)
- ECMM/ISHAM definitions
- Standard antifungal approach
- Watch for early detection
High-Yield Specialist Points
Voriconazole Pharmacology
- CYP2C19 polymorphism affects metabolism
- Therapeutic drug monitoring (target 1-5.5 mg/L)
- Drug interactions extensive (CYP3A4 inhibitor)
- Visual disturbances, hepatotoxicity, photosensitivity, fluoride excess (long-term)
- Skin cancer risk with prolonged use
Posaconazole
- Newer extended-spectrum azole
- Anti-mucormycosis activity (unlike voriconazole)
- For prophylaxis in high-risk neutropenic
- IV + oral formulations
Echinocandins
- Caspofungin, micafungin, anidulafungin, rezafungin (long-acting)
- Anti-Candida
- Anti-Aspergillus (combination therapy)
- Not for Cryptococcus or endemic mycoses
Flucytosine
- Used with amphotericin for Cryptococcus
- Monitor for bone marrow suppression
- Renal dose adjustment
Bronchoscopy + Galactomannan
- BAL galactomannan more sensitive than serum
- Combine for diagnosis
- Specifically helpful in immunocompromised
PCP + HIV Special Considerations
- AIDS-defining illness
- ART start within 2 weeks
- Watch IRIS
- Prophylaxis after treatment continues until CD4 > 200 Ã 3 mo
Aspergillus + Cystic Fibrosis
- ABPA common (treatment Ch305)
- IPA possible during severe exacerbation
- Aspergilloma in cavities
Phaeohyphomycosis
- Dematiaceous (pigmented) fungi
- Less common
- Voriconazole, posaconazole
Endemic Mycoses in Travelers
- Returning traveler with respiratory symptoms
- Geographic + occupational history
- Multiple specific tests required
Talaromyces marneffei Recognition
- Common in Taiwan returning from SE Asia + HIV
- Umbilicated skin papules (mimics molluscum)
- Pancytopenia
- Specific antifungal regimen
Pearls
- PCP: HIV CD4 < 200; TMP-SMX + adjunctive steroids if PaO2 †70
- IPA: neutropenia; halo + air crescent; isavuconazole / voriconazole first-line (SECURE)
- Mucormycosis: DKA, iron overload, COVID-19; amphotericin + surgery
- Cryptococcus + HIV: amphotericin + flucytosine â fluconazole
- Endemic mycoses: geographic exposure history critical
- Talaromyces marneffei: SE Asia + HIV + skin papules
- β-D-glucan: pan-fungal except cryptococcus + mucor
- PCP prophylaxis: TMP-SMX for HIV CD4 < 200