16.2 Fungal Classification, Opportunistic & Cutaneous/Subcutaneous Fungi

Fungal Classification, Opportunistic & Cutaneous/Subcutaneous Fungi

Quick Answer: Fungi are eukaryotes whose cell walls contain chitin and the membrane sterol ergosterol (animals use cholesterol). That biochemical difference is the foundation of selective antifungal therapy: azoles inhibit ergosterol synthesis, polyenes like amphotericin B bind ergosterol and pore-form, and allylamines block squalene epoxidase. PA-CAT items frequently test this drug-target link.

Fungal Structure and Growth Forms

Fungi grow as yeasts (single-celled, reproducing by budding), molds (multicellular tubes called hyphae that form a mycelium), or dimorphic fungi that switch between the two. Septate hyphae have cross-walls; coenocytic (aseptate) hyphae do not — the latter distinguish Mucorales (zygomycetes). Fungi reproduce by spores (sexual or asexual conidia). Most fungi are aerobic and saprophytic, decomposing organic matter in soil.

Opportunistic Fungi

Candida albicans is a yeast that forms pseudohyphae and true hyphae in tissue. It causes oral thrush and esophagitis in immunocompromised patients, vulvovaginal candidiasis after antibiotic use, and candidemia in patients with central venous catheters. Germ tube formation in serum is a classic rapid lab identification. Aspergillus fumigatus is a mold with septate hyphae that branch at acute (45°) angles; it causes allergic bronchopulmonary aspergillosis, aspergilloma (fungus ball in old TB cavities), and invasive aspergillosis in neutropenic patients. Cryptococcus neoformans is an encapsulated yeast with a polysaccharide capsule seen on India ink prep of CSF; it causes meningoencephalitis, classically in AIDS patients with CD4 < 100, and is associated with pigeon droppings. Capsular antigen is detected by cryptococcal antigen (CrAg) testing of serum or CSF.

Pneumocystis jirovecii was reclassified from a protozoan to a fungus on the basis of ribosomal RNA. It causes Pneumocystis pneumonia (PCP) in AIDS patients with CD4 < 200, presenting with dyspnea, dry cough, fever, and diffuse bilateral interstitial infiltrates with a low PaO₂. Diagnosis is by silver stain or immunofluorescence of induced sputum or bronchoalveolar lavage, showing cup-shaped cysts. Prophylaxis with trimethoprim-sulfamethoxazole is standard when CD4 < 200.

Cutaneous Fungi: Dermatophytes

Dermatophytes are keratinophilic fungi that digest keratin in skin, hair, and nails. The three genera are Trichophyton, Microsporum, and Epidermophyton. They cause tinea infections named by site: tinea corporis (ringworm of body), tinea pedis (athlete's foot), tinea cruris (jock itch), tinea capitis (scalp), and tinea unguium (onychomycosis). Diagnosis is by KOH prep of skin scrapings showing septate hyphae and arthroconidia. Wood's lamp fluoresces some Microsporum species. Topical azoles treat localized disease; oral terbinafine is used for nail and hair involvement.

Subcutaneous Fungi

Subcutaneous mycoses follow traumatic inoculation of soil or plant material into skin. Sporothrix schenckii is a dimorphic fungus causing sporotrichosis ("rose gardener's disease") after a thorn prick — a nodular, ulcerating lesion along lymphatic drainage. Chromoblastomycosis and mycetoma are other subcutaneous fungal diseases seen in tropical regions. Treatment is itraconazole or saturated potassium iodide for sporotrichosis.

Diagnostic Approach

A practical framework: an encapsulated yeast in CSF → Cryptococcus; septate acute-angle branching hyphae in lung → Aspergillus; pseudohyphae with budding yeast → Candida; cup-shaped cysts on silver stain in an AIDS patient → Pneumocystis; septate hyphae on KOH skin prep → dermatophyte. Pair the morphology with the host and the site.

Antifungal Therapy by Target

PA-CAT often pairs a drug with its mechanistic target, so review the full ladder:

• Amphotericin B — binds ergosterol, forms pores; nephrotoxicity (lipid formulations reduce this); used for severe systemic mycoses and Cryptococcus meningitis induction.
• Azoles (fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole) — inhibit lanosterol 14α-demethylase (CYP51), depleting ergosterol; check for CYP450 drug interactions and QT prolongation. Voriconazole is first-line for invasive aspergillosis; fluconazole for Candida and Coccidioides meningitis.
• Echinocandins (caspofungin, micafungin, anidulafungin) — inhibit β-1,3-glucan synthase, weakening the cell wall; used for candidemia and invasive candidiasis; low toxicity.
• Flucytosine — converted to 5-fluorouracil, inhibits DNA/RNA synthesis; used with amphotericin for Cryptococcus meningitis; bone-marrow toxicity limits monotherapy.
• Allylamines (terbinafine) — inhibit squalene epoxidase; topical/oral for dermatophytes, especially onychomycosis.

Host Factors

Risk stratification drives which fungus to suspect. Neutropenia points to invasive aspergillosis and candidemia. CD4 < 200 predicts Pneumocystis; CD4 < 100 predicts Cryptococcus and toxoplasmosis. Broad-spectrum antibiotics, central venous catheters, parenteral nutrition, and abdominal surgery predispose to Candida. Uncontrolled diabetes with ketoacidosis is the classic setting for rhinocerebral mucormycosis (Mucorales, non-septate hyphae invading the palate and sinuses). Recognizing the host risk factor first narrows the differential efficiently.

Candida Species Differentiation and Germ-Tube Workup

When a yeast is isolated from blood, urine, or a mucosal site, PA-CAT items often push you past "Candida" to the species level because antifungal susceptibility differs. The classic first step is the germ tube test: inoculate the yeast in serum at 37 °C for 2–3 hours; Candida albicans and C. dubliniensis produce germ tubes (short hyphal extensions without a constriction at the base), while C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis do not. A positive germ tube historically narrows the answer to C. albicans on exams. C. glabrata is intrinsically fluconazole-resistant and emerging in older and neutropenic patients; C. krusei is also fluconazole-resistant and seen in hematologic malignancy. C. parapsilosis dominates central-line and parenteral-nutrition candidemia and forms pseudohyphae on cornmeal agar without germ tubes. C. tropicalis tends toward disseminated disease in neutropenic hosts. CHROMagar Candida gives species-specific colony colors (albicans green, tropicalis blue-pink, krusei pink, glabrata cream) for rapid presumptive ID. Match the species to its susceptibility and host: fluconazole for C. albicans and C. parapsilosis; an echinocandin or amphotericin for C. glabrata and C. krusei until susceptibilities return. This species-level reasoning matters because empiric fluconazole may fail in resistant organisms, and the PA-CAT Bulletin expects you to connect a lab clue (germ tube, CHROMagar color, cornmeal morphology) with the right drug choice.