Lecture 5

Diseases caused by fungal infection. Range from superficial dermatophytoses to life-threatening invasive infections. Approximately one billion people affected annually worldwide; ~7 million life-threatening infections; ~2 million deaths per year — comparable to tuberculosis.

The dominant sterol in fungal cell membranes; the fungal counterpart to cholesterol in human cells. Essential for membrane integrity, fluidity, and function. Target (directly or indirectly) of three antifungal drug classes: allylamines, azoles, and polyenes.

The principle that an antimicrobial drug should harm the pathogen more than the host. Harder to achieve with fungi than with bacteria because fungi are eukaryotes. The three exploitable differences are ergosterol vs. cholesterol in the membrane, the chitinlucan cell wall (absent in humans), and fungal cytosine deaminase (absent in humans).

The two main structural polysaccharides of the fungal cell wall. Humans have no cell wall and no equivalent enzymes. β-1,3-glucan synthase is the molecular target of the echinocandins, providing the cleanest selective toxicity in the antifungal pharmacopoeia.

A fungal enzyme that converts the prodrug flucytosine into 5-fluorouracil inside the fungal cell. Human cells lack this enzyme, providing the basis for flucytosine's selectivity. Gut bacteria do express it, which explains the bone-marrow toxicity seen with prolonged flucytosine use.

The first committed enzyme of the ergosterol biosynthesis pathway. Converts squalene to squalene epoxide. Molecular target of the allylamines (terbinafine). Inhibition causes both squalene accumulation (toxic) and ergosterol depletion (defective membrane)

The fungal CYP450 enzyme that converts lanosterol to ergosterol. Molecular target of all azole antifungals. The same enzyme is also targeted by agricultural triazole fungicides — the basis for environmentally driven azole resistance in Aspergillus

Antifungal class that inhibits squalene epoxidase. Terbinafine is the clinically important member. Fungicidal against dermatophytes. Topical (OTC) for tinea pedis/corporis/cruris; oral for tinea unguium and tinea capitis. Highly keratinophilic. Oral courses require liver function monitoring.

The largest antifungal drug class. Inhibit fungal lanosterol 14-α-demethylase (CYP51), depleting ergosterol and producing a defective membrane. Fungistatic. Two subclasses: imidazoles (mostly topical) and triazoles (systemic). Major clinical issue is human CYP450 inhibition causing dozens of drug interactions.

The older azole subclass, mostly topical. Mnemonic COMET-K: Clotrimazole, Oxiconazole, Miconazole, Econazole, Tioconazole, Ketoconazole. These are the OTC creams, shampoos, and vaginal antifungals.

The systemic azole subclass — the drugs you actually prescribe in inpatient and outpatient practice. Mnemonic FIT VIP: Fluconazole, Itraconazole, Terconazole, Voriconazole, Isavuconazole, Posaconazole

Oral and IV triazole antifungal. Moderate inhibitor of CYP2C9, 2C19, and 3A4. Key interactions: warfarin (raises INR), phenytoin, cyclosporine, sulfonylureas. First-line for many Candida infections and for cryptococcal meningitis maintenance therapy

Triazole antifungal and strong CYP3A4 inhibitor. Dangerous interactions with tacrolimus and cyclosporine (transplant toxicity), statins (rhabdomyolysis), benzodiazepines, and dihydropyridine calcium channel blockers

Strong CYP2C19, 2C9, and 3A4 inhibitor. First-line for invasive aspergillosis. Voriconazole + sirolimus is contraindicated. Therapeutic drug monitoring (TDM) is required because of variable metabolism.

Triazole antifungal, strong CYP3A4 inhibitor with a profile similar to itraconazole. Important counseling point: take with a fatty meal — absorption falls off sharply without dietary fat

The dominant pharmacy issue with azole antifungals. Because azoles inhibit human CYP enzymes (the same chemical feature that lets them inhibit fungal CYP51), they raise serum concentrations of dozens of substrate drugs. Highest-risk combinations include voriconazole + sirolimus (contraindicated), itraconazole + statins (rhabdomyolysis), and fluconazole + warfarin (bleeding).

Antifungal class that binds ergosterol directly in the fungal membrane and forms transmembrane pores, causing osmotic lysis. Fungicidal. Mnemonic NAN: Natamycin, Amphotericin B, Nystatin

IV polyene with the broadest spectrum of any antifungal. Reserved for severe, life-threatening systemic mycoses — cryptococcal meningitis (with flucytosine), severe invasive candidiasis, mucormycosis. Nicknamed 'amphoterrible' for dose-limiting nephrotoxicity, infusion reactions, and electrolyte wasting.

Topical polyene formulated as a 5 percent ophthalmic suspension. The only FDA-approved antifungal eye drop in the United States. First-line treatment for fungal keratitis caused by Fusarium, Aspergillus, and Candida species. Typical clinical context: corneal trauma involving plant matter (agricultural injury, tree branch) or contact lens wearers using contaminated solutions. Same mechanism as other polyenes — binds ergosterol, forms membrane pores, fungicidal — but too toxic
for systemic use, so the indication is restricted to the eye.

Topical polyene; too toxic for systemic use. Oral suspension (swish and swallow) for oropharyngeal candidiasis (thrush). Topical cream for cutaneous candidiasis

Lipid-formulated amphotericin B. Substantially less nephrotoxic than conventional amphotericin B deoxycholate. Preferred form in current US practice whenever available

Fever, rigors, chills, and nausea during amphotericin B infusion. Standard premedication is acetaminophen plus diphenhydramine; meperidine is added if rigors are severe.

Antifungal class that noncompetitively inhibits β- 1,3-glucan synthase (encoded by FKS1/FKS2), disrupting the fungal cell wall. Fungicidal against Candida; fungistatic against Aspergillus. IV only — large peptides, not orally absorbed. Mnemonic MAC: Micafungin, Anidulafungin, Caspofungin. First-line for invasive candidiasis and Candida auris. Safest IV antifungal class

Fungal enzyme that synthesizes β-glucan, the main structural polysaccharide of the fungal cell wall. Encoded by FKS1 and FKS2 genes — the site of resistance mutations. Absent in human cells, providing exceptional selective toxicity

CDC URGENT THREAT fungus (callback to Lectures 3–4). Multidrug-resistant; often resistant to fluconazole and sometimes to amphotericin B. Echinocandins are first-line. Persists on hospital surfaces and causes outbreaks in long-term care facilities and ICUs.

Prodrug pyrimidine analog. Enters fungal cells via cytosine permease and is converted to 5-fluorouracil by fungal cytosine deaminase. 5-FU inhibits thymidylate synthase (blocks DNA) and is incorporated into RNA (blocks protein synthesis). Almost always combined with amphotericin B for cryptococcal meningitis induction. Never used as monotherapy — resistance develops rapidly. Toxicity: pancytopenia and hepatotoxicity (gut bacteria convert some 5-FC to 5-FU)

The classic indication for the flucytosine + amphotericin B combination. Standard induction regimen worldwide; fluconazole is used for consolidation and maintenance. Most common in advanced HIV/AIDS.

Oldest oral antifungal still in clinical use. Binds fungal tubulin and inhibits mitotic spindle assembly. Fungistatic. Spectrum: dermatophytes only — no activity against Candida, Aspergillus,Cryptococcus, or any systemic fungus. Oral only; must be taken with a fatty meal. Historically first- line for tinea capitis in children, now being replaced by oral terbinafine.

Unlike azole antifungals (CYP inhibitors), griseofulvin INDUCES CYP enzymes. This speeds up the metabolism of warfarin and oral contraceptives, reducing their effectiveness. Female patients require backup contraception during therapy

Fungi that infect keratinized tissue — skin, hair, nails. Cause the tinea infections (tinea pedis, corporis, cruris, capitis, unguium). Treated with topical terbinafine or imidazoles (OTC) for most sites; oral therapy required for tinea capitis and tinea unguium because the drug must reach hair follicles or nail beds

Dermatophyte infection of the scalp. Requires oral therapy because topical agents cannot reach the hair follicle. Historically treated with griseofulvin; oral terbinafine is now widely used because of shorter courses and comparable efficacy.

Dermatophyte infection of the nail. Requires oral terbinafine because topical agents cannot penetrate the nail plate. Treatment courses are long: ~6 weeks for fingernails, ~12 weeks for toenails. Counsel patients that the nail will not look normal until the new healthy nail grows out.

Fungistatic drugs (azoles, flucytosine, griseofulvin) inhibit fungal growth but rely on the host immune system to clear the infection. Fungicidal drugs (allylamines, polyenes, echinocandins against Candida) actively kill fungi. The distinction is clinically important in immunocompromised patients, who may not be able to clear an infection without a fungicidal agent.

The application of stewardship principles — right drug, right dose, right duration, narrowest effective spectrum — to antifungal use. Especially important because the antifungal pipeline is much smaller than the antibiotic pipeline; every drug lost to resistance is harder to replace

Resistance to medical azoles in Aspergillus fumigatus driven by environmental exposure to triazole fungicides used in agriculture (propiconazole, tebuconazole, difenoconazole). These fungicides share the lanosterol 14-α- demethylase mechanism with medical azoles. Patients can be infected with resistant strains without ever taking an antifungal — an ecological resistance problem analogous to agricultural antibiotic use covered in Lectures 3–4.

On the CDC watch list for emerging fungal resistance threats. When voriconazole (first-line) fails, second-line options include echinocandins or amphotericin B — all more toxic, more expensive, and not always as effective