USMLE STEP 1 • PHARMACOLOGY

Antifungals, mapped

Tap the fungal cell, then connect target → prototype → organism → toxicity.

Where each class hits

Cell wall: echinocandins inhibit β-1,3-D-glucan synthase → unstable wall. Fungicidal vs Candida; fungistatic vs Aspergillus.

Human cellsNo ergosterol or cell wall

Exam anchorTarget selectivity first

AmB

Polyenes

Amphotericin B: binds ergosterol → pores. Broad, severe systemic mycoses; cryptococcal induction with flucytosine; mucormycosis. Infusion fever/chills, nephrotoxicity, ↓K⁺, ↓Mg²⁺, anemia. Liposomal form lowers renal toxicity.

Nystatin: topical/oral nonabsorbed Candida—thrush, diaper rash.

-azole

Azoles

Inhibit fungal CYP450 14α-demethylase (CYP51) → ↓ergosterol. Most inhibit human CYPs and prolong QT.

Fluconazole: Candida, Cryptococcus step-down; excellent CSF/urine. Itraconazole: dimorphic fungi; CHF warning. Voriconazole: invasive Aspergillus; visual symptoms, photosensitivity, skin cancer risk. Posaconazole: prophylaxis in high-risk neutropenia; Mucor activity. Isavuconazole: Aspergillus/Mucor; uniquely shortens QT. Ketoconazole: ↓steroids → gynecomastia, ↓libido, adrenal suppression.

-fgn

Echinocandins

Caspofungin, micafungin, anidulafungin. Block β-1,3-D-glucan cell-wall synthesis. Invasive Candida; salvage/combination Aspergillus. IV only; generally well tolerated, possible hepatotoxicity/histamine flushing.

5-FC

Flucytosine

Fungal cytosine deaminase converts it to 5-FU → blocks DNA/RNA synthesis. Good CSF penetration. Used with amphotericin B for cryptococcal meningitis. Bone-marrow suppression and hepatotoxicity; rapid resistance alone.

TERB

Terbinafine

Inhibits squalene epoxidase → toxic squalene accumulation. First-line oral onychomycosis; dermatophytes. Hepatotoxicity, taste/smell disturbance.

GRIS

Griseofulvin

Disrupts microtubules; deposits in keratin precursor cells. Dermatophytes, especially tinea capitis. CYP inducer, hepatotoxic, teratogenic; disulfiram-like effect.

Organism → best-known Step 1 choice

→

Candida, mucosal

Nystatin or azole; esophageal disease often fluconazole.

→

Invasive candidiasis

Echinocandin initially; fluconazole in selected stable/susceptible cases.

→

Cryptococcal meningitis

Induction: amphotericin B + flucytosine. Consolidation/maintenance: fluconazole.

→

Invasive Aspergillus

Voriconazole classic first-line association; isavuconazole alternative. Echinocandin is not primary monotherapy.

→

Mucormycosis

Urgent surgical debridement + liposomal amphotericin B; isavuconazole/posaconazole alternatives.

→

Histoplasma / Blastomyces

Itraconazole if mild–moderate; amphotericin B if severe.

→

Sporothrix schenckii

Itraconazole. Remember rose gardener + nodular lymphangitis.

→

Dermatophytes

Terbinafine for nails; griseofulvin classically for tinea capitis.

→

Pneumocystis jirovecii

Not treated with standard antifungals: TMP-SMX is first-line.

One-liners that steal points

Ampho-terrible = nephrotoxicity + electrolyte wasting + infusion reactions.

Vori = vision and photosensitivity; it is the Aspergillus prototype.

Flucytosine needs a friend: monotherapy rapidly selects resistance.

Itra hurts contraction: negative inotrope—avoid in heart failure.

Isavuconazole is inverse: short QT, unlike most azoles.

Echinocandins hit the wall: Candida/Aspergillus, but poor for Cryptococcus and Mucor.

Mechanism traps

Azoles inhibit 14α-demethylase; terbinafine inhibits squalene epoxidase. Both reduce ergosterol by different steps.

Amphotericin B binds existing ergosterol; it does not block synthesis.

Flucytosine is selectively activated inside fungi by cytosine deaminase.

Griseofulvin protects newly formed keratin; treatment continues until infected keratin is replaced.

Rapid checkpoint

1. Neutropenic patient with invasive Aspergillus: prototype drug?

Voriconazole is the classic Step 1 association; watch for visual symptoms and photosensitivity.

2. Which antifungal uniquely shortens QT?

Isavuconazole is the azole exception: it shortens rather than prolongs QT.

3. Amphotericin B plus which drug for cryptococcal induction?

Flucytosine adds fungal-selective DNA/RNA inhibition and penetrates CSF.

4. Drug for onychomycosis that inhibits squalene epoxidase?

Terbinafine causes toxic squalene accumulation; remember liver and taste toxicity.

Antifungals: Step 1 Map