🧫 Fungal cell biology & antifungals
🔬 Structure
- Cell wall: chitin, β-glucan, mannoproteins
- Membrane: ergosterol (analogous to cholesterol)
- Ribosomes: 80S (eukaryotic)
💊 Drug targets
- Azoles – inhibit ergosterol synthesis (lanosterol 14α-demethylase)
- Polyenes (amphotericin B) – bind ergosterol, form pores
- Echinocandins – inhibit β-glucan synthase
- Flucytosine – inhibits DNA/RNA synthesis
Clinical pearl: Amphotericin B has higher affinity for ergosterol than cholesterol, but nephrotoxicity limits use. Lipid formulations reduce toxicity.
🔬 Fungal morphology & dimorphism
HyphaeYeastsPseudohyphaeDimorphic
- Hyphae: filamentous units; septate (cross-walls) vs coenocytic (nonseptate, broad, irregular branching).
- Yeasts: unicellular, round/oval; reproduce by budding (blastoconidia).
- Pseudohyphae: elongated yeast cells with constrictions at septa (e.g., Candida).
- Dimorphic fungi: switch between mold (environment, 25°C) and yeast (tissue, 37°C). Key genera: Histoplasma, Blastomyces, Coccidioides, Sporothrix, Paracoccidioides.
High‑yield: Thermal dimorphism is a virulence trait; tissue forms are typically yeast or spherules (Coccidioides).
Spore types
- Conidia – asexual, airborne
- Blastoconidia – buds
- Arthroconidia – fragmentation of hyphae
- Spherules/endospores – unique to Coccidioides (in tissue)
🧪 Diagnostic methods
🔬 Microscopy
- KOH wet mount – clears keratin, reveals hyphae/yeasts
- Calcofluor white – binds chitin, fluorescent (fast)
- Silver stain (GMS) – black/gray; excellent for Pneumocystis
- PAS – hot pink fungal elements
- India ink – capsule halo (Cryptococcus); low sensitivity
🧪 Culture & serology
- Sabouraud agar (with antibiotics) – inhibits bacteria
- Serology: antibody (complement fixation), antigen detection (e.g., cryptococcal capsular Ag, galactomannan)
- Molecular: PCR, nucleic acid probes
- Skin test – epidemiological, not diagnostic (indicates exposure)
Remember: Histoplasma can be detected in peripheral blood (RES), Cryptococcus antigen in CSF is highly sensitive.
🦠 Superficial & cutaneous mycoses
Malassezia furfur
- Lipophilic yeast, normal skin flora.
- Pityriasis versicolor: hypopigmented macules on trunk; KOH shows “spaghetti & meatballs” (yeast + hyphae); Wood lamp → coppery-orange fluorescence.
- Treatment: topical selenium sulfide or azoles.
- Risk: premature infants on IV lipids → fungemia.
Dermatophytes (Trichophyton, Microsporum, Epidermophyton)
- Infect keratinized tissues (skin, hair, nails). No systemic invasion.
- Tinea corporis, cruris, pedis, capitis, unguium. Itching prominent.
- Diagnosis: KOH (arthroconidia), Wood lamp (Microsporum → yellow-green).
- Treatment: topical azoles/tolnaftate; oral griseofulvin/azoles for hair/nail.
- ID reaction (dermatophytid): allergic response to circulating antigens.
Clinical pearl: Zoophilic strains cause more inflammation than anthropophilic.
🌿 Subcutaneous mycoses
Sporothrix schenckii
- Dimorphic (mold in environment, cigar-shaped yeast in tissue).
- Traumatic inoculation (roses, thorns, moss).
- Sporotrichosis: lymphocutaneous nodules; pulmonary in alcoholics.
- Treatment: itraconazole (mild), amphotericin B (severe).
“Rose gardener’s disease” – classic lymphocutaneous spread.
🌎 Systemic (endemic) mycoses
Histoplasma Coccidioides Blastomyces Paracoccidioides
All cause acute pulmonary (often self-limiting) or chronic/disseminated disease.
Histoplasma capsulatum
- Ohio/Mississippi river valleys; bird/bat droppings.
- Intracellular yeast in RES cells (narrow-neck budding).
- “Fungus flu”: hepatosplenomegaly, calcified lesions.
- Dissemination in AIDS; treat with itraconazole or amphotericin B.
Coccidioides immitis
- Southwestern US (San Joaquin Valley).
- Arthroconidia → spherules with endospores in tissue.
- Valley fever: erythema nodosum (good prognosis).
- Risk: pregnancy (3rd trimester), immunocompromised.
Blastomyces dermatitidis
- Upper Great Lakes, southeastern US; rotting wood.
- Broad-based budding yeast, double-contoured wall.
- Less likely to self-resolve; treat even acute infection.
Paracoccidioides brasiliensis
- South/Central America (Brazil).
- Multiple buds (pilot wheel) in tissue.
- Juvenile: lymphadenopathy, hepatosplenomegaly; adult: pulmonary fibrosis, oral lesions.
Treatment summary: Itraconazole for mild/moderate, amphotericin B for severe/disseminated.
⚠️ Opportunistic fungi
Aspergillus fumigatus
- Septate, dichotomous branching at 45°.
- Allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, invasive disease (neutropenia, CGD).
- Treatment: voriconazole (invasive), itraconazole (ABPA).
Candida albicans
- Germ tube positive; pseudohyphae and true hyphae in tissue.
- Thrush, esophagitis, vaginitis, perleche, septicemia with endophthalmitis.
- Risk: antibiotics, immunosuppression, diabetes, IVDU.
- Treatment: topical azoles, nystatin, fluconazole/amphotericin B for disseminated.
Cryptococcus neoformans
- Encapsulated yeast, pigeon droppings.
- Meningitis (HIV, Hodgkin), pulmonary infection.
- CSF: antigen detection (LPA), India ink (halo), culture (urease+).
- Treatment: amphotericin B + flucytosine, then fluconazole.
Mucorales (Rhizopus, Mucor, Absidia)
- Nonseptate, broad ribbon-like hyphae, right-angle branching.
- Rhinocerebral mucormycosis: diabetic ketoacidosis, neutropenia.
- Rapid invasion; treat with debridement + amphotericin B.
Pneumocystis jirovecii
- Fungus (silver stain cysts); extracellular.
- Pneumonia in AIDS (CD4 < 200), malnourished infants.
- X-ray: ground-glass, bilateral infiltrates.
- Treatment: TMP-SMX (mild), dapsone (moderate).
📊 Comparison tables
Dimorphic fungi · tissue forms
| Fungus | Environmental form | Tissue form | Endemic region |
|---|---|---|---|
| Histoplasma | Hyphae + macroconidia | Intracellular yeast (narrow bud) | Ohio/Mississippi valleys |
| Coccidioides | Arthroconidia | Spherules + endospores | Southwestern US |
| Blastomyces | Hyphae with conidia | Broad-based budding yeast | Great Lakes, SE US |
| Paracoccidioides | Septate hyphae | Multiple buds (pilot wheel) | Central/South America |
| Sporothrix | Hyphae + rosette conidia | Cigar-shaped yeast | Worldwide |
Opportunistic fungi · key features
| Fungus | Morphology | Predisposition | Classic disease |
|---|---|---|---|
| Aspergillus | Septate, 45° branching | Neutropenia, CF, asthma | ABPA, aspergilloma, invasive |
| Candida | Pseudohyphae, germ tubes | Antibiotics, DM, HIV | Thrush, esophagitis, septicemia |
| Cryptococcus | Encapsulated yeast | HIV, Hodgkin | Meningitis |
| Mucorales | Nonseptate, broad | DKA, neutropenia | Rhinocerebral mucormycosis |
| Pneumocystis | Cysts (silver stain) | CD4 < 200 | Pneumonia (PCP) |
Antifungal drug targets
| Class | Mechanism | Examples | Notable side effects |
|---|---|---|---|
| Azoles | Inhibit ergosterol synthesis | Fluconazole, itraconazole, voriconazole | Hepatotoxicity, CYP interactions |
| Polyenes | Bind ergosterol, pore formation | Amphotericin B | Nephrotoxicity, infusion reactions |
| Echinocandins | Inhibit β-glucan synthase | Caspofungin, micafungin | Well tolerated, limited oral |
| Flucytosine | Inhibits DNA/RNA synthesis | 5-FC | Myelosuppression, GI |
💡 High‑yield pearls & exam points
- Dimorphic fungi – endemic in specific geographic areas; tissue forms are diagnostic.
- Cryptococcus – India ink (insensitive), antigen detection is the gold standard.
- Pneumocystis – does not stain with H&E; silver stain shows cysts.
- Mucor – rapid, angioinvasive; debridement is essential.
- Candida – germ tube test (serum at 37°C) positive for C. albicans.
- Histoplasma – intracellular in macrophages; “tiny yeast” with narrow bud.
- Aspergillus – galactomannan antigen; voriconazole is first-line.
- Antifungal resistance – azole resistance emerging in Aspergillus, Candida.
Board style: “A patient from Ohio with flu-like symptoms, hepatosplenomegaly, and calcified lung nodules” → Histoplasma.