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Pharmacology of Antifungals — PG ENT Exam Notes

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PART 1: CLASSIFICATION OF ANTIFUNGALS

A. Polyenes

B. Azoles

• Ketoconazole (oral/topical)
• Clotrimazole (topical)
• Miconazole (topical)
• Econazole, Bifonazole (topical)

• Fluconazole — Candida, Cryptococcus
• Itraconazole — Candida, Aspergillus, dermatophytes, dimorphic fungi
• Voriconazole — Aspergillus (1st line), Candida, Fusarium
• Posaconazole — Aspergillus, Mucor, Fusarium
• Isavuconazole — Aspergillus, Mucor

C. Echinocandins

• Caspofungin, Micafungin, Anidulafungin
• Fungistatic against Candida; fungicidal against Aspergillus (in some contexts)

D. Allylamines

• Terbinafine — oral/topical; dermatophytes, tinea unguium

E. Antimetabolite

• Flucytosine (5-FC) — used only in combination (never monotherapy)

F. Topical Miscellaneous

• Tolnaftate, Naftifine, Ciclopirox, Haloprogin, Undecylenic acid, Griseofulvin (microtubule inhibitor)

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PART 2: PHARMACOLOGY (SHORT NOTES)

1. Polyenes — Amphotericin B

• Mechanism: Binds irreversibly to ergosterol in fungal cell membrane → forms pores → leakage of K⁺, Mg²⁺, protons → cell death. Fungicidal.
• Spectrum: Broadest of all antifungals — Candida, Aspergillus, Mucor/Rhizopus, Cryptococcus, Histoplasma, Blastomyces, Coccidioides. Exceptions: Pseudallescheria boydii, A. terreus (resistant)
• Formulations:
  • Conventional AmB (deoxycholate) — most nephrotoxic
  • Lipid formulations: AmBisome (liposomal), Abelcet (lipid complex), Amphotec (colloidal dispersion) — significantly reduced nephrotoxicity, used preferentially in ENT/rhinocerebral mucormycosis
• Side effects:
  • Infusion reactions: Fever, chills, dyspnea, hypotension — pre-medicate with hydrocortisone/acetaminophen; tolerance develops
  • Nephrotoxicity: Azotemia (universal), hypokalemia, renal tubular acidosis, anemia — monitor creatinine, K⁺. Damage correlates with cumulative dose
• ENT note: Drug of choice for mucormycosis; use liposomal formulation

2. Azoles — Mechanism

• Mechanism: Inhibit fungal cytochrome P450 enzyme 14α-demethylase → blocks conversion of lanosterol to ergosterol → depletion of ergosterol → disruption of membrane function. Fungistatic (except voriconazole for molds)
• Key drug interactions: Inhibit CYP3A4 — affect cyclosporine, warfarin, statins, phenytoin
• Fluconazole: Good CNS penetration; oral bioavailability ~90%; excreted renally
• Itraconazole: Poor CNS penetration; useful for ABPA, AFS
• Voriconazole: Best CNS penetration; visual disturbances (photopsia) characteristic side effect; 1st line for invasive aspergillosis
• Posaconazole: Active against Mucor — useful as step-down after AmB or salvage therapy in mucormycosis

3. Echinocandins

• Mechanism: Inhibit β-1,3-D-glucan synthase → blocks cell wall synthesis → fungal cell lysis (unique target — no human equivalent)
• Drugs: Caspofungin, micafungin, anidulafungin
• Spectrum: Candida (all species including azole-resistant), Aspergillus; NOT active against Mucor, Cryptococcus, Fusarium
• Route: IV only (poor oral bioavailability)
• Advantages: Minimal nephrotoxicity, minimal drug interactions
• ENT note: Useful for candidal pharyngitis/esophagitis in immunocompromised if azole-resistant

4. Flucytosine

• Mechanism: Transported into fungal cell → converted to 5-fluorouracil by fungal cytosine deaminase → inhibits thymidylate synthetase → blocks DNA synthesis. Mammalian cells lack cytosine deaminase → selective toxicity
• Use: Only in combination with AmB (synergistic) for cryptococcal meningitis
• Side effects: Bone marrow suppression, alopecia, hepatotoxicity (due to 5-FU formation by gut bacteria)
• Resistance: Develops rapidly if used alone

5. Terbinafine (Allylamine)

• Mechanism: Inhibits squalene epoxidase → squalene accumulation + ergosterol depletion → fungicidal for dermatophytes
• Use: Tinea unguium (onychomycosis), tinea capitis — oral; pulse dosing regimens available
• Side effects: GI disturbance, ageusia (loss of taste — important exam point), headache

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PART 3: ROLE OF ANTIFUNGALS IN ENT — DETAILED

I. OTOMYCOSIS (Fungal Otitis Externa)

• Warm, humid ear canal (swimmers, tropical climates)
• Chronic moisture (hearing aid users)
• Modified radical mastoid cavities
• EAC trauma, prior antibiotic use
• Immunocompromise

1. Aural toilet — meticulous cleaning/suction, repeated; dry ear precautions
2. Acidifying/drying agents: Gentian violet, boric acid in alcohol — creates hostile pH
3. Topical antifungals (1st line pharmacological):
   • Clotrimazole 1% solution/cream — most widely used
   • Ketoconazole ointment
   • Cresylate otic solution
   • CSF powder (Chloromycetin + Amphotericin B [Fungizone] + Sulfanilamide) — for mastoid cavity otomycosis
4. Systemic antifungals: Reserved for refractory disease or suspected invasive fungal OE in immunocompromised patients
   • Oral itraconazole or fluconazole
   • IV AmB / voriconazole for invasive disease

Exam tip: Pruritus > pain = fungal OE; Aspergillus most common organism; topical clotrimazole = 1st line drug

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II. FUNGAL RHINOSINUSITIS

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A. Mycetoma (Fungal Ball)

• Single sinus (usually maxillary), dense fungal mass, no mucosal invasion
• Organism: Aspergillus fumigatus/niger
• Treatment: Surgical — FESS (wide antrostomy, irrigation and removal of fungal debris); no antifungal therapy required post-operatively
• Monitor for sclerotic/osteolytic changes in sinus walls

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B. Allergic Fungal Sinusitis (AFS) / Allergic Fungal Rhinosinusitis (AFRS)

1. Type I hypersensitivity (atopy — skin test or RAST positive)
2. Nasal polyposis
3. Characteristic CT findings (heterogeneous opacification with central hyperdensity)
4. Eosinophilic mucin without tissue invasion
5. Positive fungal stain/culture from mucin

1. Surgery (FESS) — remove mucin, polyps, open all involved sinuses
2. Systemic + topical corticosteroids — cornerstone of medical management; reduces mucosal inflammation and recurrence
   • Oral prednisolone post-op (tapered over weeks)
   • Topical nasal steroids long-term
3. Antifungal therapy (adjunct, controversial):
   • Itraconazole (200 mg BD) — reduces steroid requirement, decreases recurrence
   • Voriconazole — for refractory cases
   • Not primary treatment — surgery + steroids are primary
4. Immunotherapy (subcutaneous/SLIT) — reduces Th2 response, decreases recurrence

Exam tip: AFRS is NOT an infection — it is a hypersensitivity reaction. Antifungals are adjunct, not primary. Steroids + surgery = primary treatment.

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C. Acute Invasive Fungal Rhinosinusitis (AIFRS)

• Aspergillus species (A. fumigatus > A. flavus): Septate hyphae, branch at 45° acute angles
• Mucor/Rhizopus (Mucormycosis — Class Zygomycetes): Non-septate, ribbon-like hyphae, branch irregularly at 90°; Rhizopus oryzae = most virulent

• Fevers, facial swelling, nasal congestion
• Black eschar/necrosis of nasal mucosa or palate — pathognomonic
• Orbital involvement: Ophthalmoplegia, proptosis, vision loss
• Intracranial extension: Cavernous sinus thrombosis, CNS invasion
• Loss of nasal sensation — early warning sign

• Aspergillus: Septate hyphae, 45° branching
• Mucor: Non-septate hyphae, 90° branching, angioinvasion
• Stains: Calcofluor-white, GMS (Grocott methenamine silver)

• CT: Non-specific mucosal thickening early; bony erosion = late/advanced finding
• MRI: Better for assessing extent of angioinvasion (loss of contrast enhancement in devitalized tissue)

• Voriconazole IV — 1st line (superior to AmB in clinical trials)
  • Loading: 6 mg/kg IV q12h × 2 doses; Maintenance: 4 mg/kg IV q12h
  • Switch to oral once stable (90% bioavailability)
• Liposomal AmB — alternative / combination
• Caspofungin — salvage or combination with voriconazole

• Liposomal Amphotericin B (AmBisome) — drug of choice (5–10 mg/kg/day)
  • Conventional AmB also used but more nephrotoxic
• Posaconazole — step-down oral therapy after AmB stabilization, OR salvage
  • Isavuconazole — newer option, IV and oral
• Echinocandins + Mucor: NOT effective — Mucor is intrinsically resistant
• Voriconazole + Mucor: NOT effective — voriconazole has no activity against Zygomycetes (critical exam point)

CRITICAL EXAM POINTS:

• Mucormycosis = Liposomal AmB (NOT voriconazole)
• Aspergillosis = Voriconazole (NOT AmB as first-line)
• Echinocandins = NO activity vs Mucor or Cryptococcus
• Posaconazole = the only azole active against Mucor

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D. Chronic Invasive Fungal Rhinosinusitis

• Indolent course (months to years); most common in Sudan/India/immunocompetent
• Aspergillus flavus most common
• Treatment: FESS debridement + systemic antifungals (itraconazole or voriconazole long-term)

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III. LARYNGOPHARYNGEAL / ORAL CANDIDIASIS

• Organisms: Candida albicans (commonest), C. tropicalis, C. glabrata
• Predisposing: HIV/AIDS, steroids (inhaled or systemic), diabetes, broad-spectrum antibiotics, dentures
• Presents with white plaques on oral mucosa/tongue (easily wiped off leaving erythematous base), dysphagia

1. Nystatin oral suspension (swish and swallow) — 1st line in mild, immunocompetent
2. Clotrimazole troches (lozenges) — 10 mg 5 times/day; oral + esophageal thrush
3. Fluconazole oral 150 mg single dose or 100–200 mg/day × 7–14 days — for moderate/severe or immunocompromised; preferred for esophageal candidiasis
4. Itraconazole solution — fluconazole-refractory cases
5. Voriconazole / Echinocandins (IV) — fluconazole-resistant Candida (C. krusei intrinsically resistant to fluconazole; C. glabrata often dose-dependent susceptible)

Note: C. krusei = always fluconazole-resistant; use voriconazole or caspofungin Note: Echinocandins are preferred for esophageal candidiasis in critically ill patients

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IV. DEEP NECK SPACE FUNGAL INFECTIONS

• Rare; usually in immunocompromised (post-transplant, neutropenia)
• Aspergillus or Mucor can invade deep neck spaces
• Treatment: Voriconazole (Aspergillus) or Liposomal AmB (Mucor) + surgical drainage

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V. LARYNGEAL CANDIDIASIS

• Hoarseness, odynophagia in immunocompromised
• Laryngoscopy: White plaques on vocal cords
• Treatment: Fluconazole oral; systemic azoles

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QUICK DRUG SUMMARY TABLE FOR ENT

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HIGH-YIELD EXAM POINTS FOR PG ENT

1. Otomycosis: Aspergillus niger > Candida; pruritus > pain; topical clotrimazole = drug of choice
2. AFRS: NOT an infection; IgE-mediated + Th2; surgery + steroids primary; antifungals adjunct
3. Mucormycosis: Non-septate hyphae at 90°; associated with DKA; Liposomal AmB = drug of choice; voriconazole and echinocandins have NO activity
4. Aspergillus AIFRS: Septate hyphae at 45°; Voriconazole = 1st line
5. Fungal ball: Surgery (FESS) alone; no antifungals needed
6. Oral candidiasis: Mild = nystatin/clotrimazole; moderate–severe/immunocompromised = fluconazole
7. C. krusei = intrinsically fluconazole-resistant; use voriconazole
8. Amphotericin B broad spectrum but fungus resistant: P. boydii, A. terreus
9. Posaconazole = only azole with anti-Mucor activity
10. Echinocandins active ONLY against Candida and Aspergillus — not Mucor, not Crypto
11. Serial nasal debridement every 2–3 days is mandatory in AIFRS
12. Reversal of underlying immunocompromise is the most critical factor in AIFRS survival

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