Antifungals

Front 1

Amphotericin B

Back 1

- IV/intrathecal/topical polyene macrolide antibiotic
- Treat systemic mycosis (esp. immunocompromised pts.), fungal meningitis, and mucocutaneous/cutaneous candidiais
- Binds ergosterol to form membrane pores → fungicidal
- Rare resistance; decreased ergosterol in PM or decreased drug affinity
- Excreted unchanged in bile and urine (half-life = 15 days)
- Acute fever/hypotension/tachypnea → give with antipyretics/hydrocortisone
- Dose-dependent nephrotoxicity (exacerbated by aminoglycosides, nitrogen mustard, and cyclosporine)
- Reversible anemia after two weeks
- Increases digitalis toxicity
- Increases NM blockade of nicotinic anticholinergics

Front 2

Chlotrimazole

Back 2

- Topical imidazole
- OTC to treat tinea infections, pityriasis versicolor, and cutaneous/vaginal/oropharyngeal candidiasis
- Not absorbed systemically

Front 3

Ketoconazole

Back 3

- Oral imidazole
- Broad spectrum antifungal, but not used in gravely ill or immunocompromised individuals
- Inhibits 14-alpha-demethylase → prevents conversion of lanosterol to ergosterol; excess 14-alpha-demethysterols disrupt PM
- Resistance occurs via mutation of 14-alpha-demethylase or increased drug efflux
- Absorption from GI tract requires pH < 3 (H2 blockers/antacids decrease availability); poor CNS penetration
- Frequent GI side effects
- Disrupts cytochrome P450 enzyme systems → inhibits steroid biosynthesis (testosterone/cortisol) leading to dysmenorrhea, gynecomastia, impotence
- Increases cyclosporine/phenytoin toxicity and oral anticoagulant efficacy
- Rifampin/phenytoin induce CYP450 enzymes → acclerated clarance
- CI with concomitant terfenadine/erythromycin due torsades de pointes from QT interval elongation when given with terfenadine or erythromycin

Front 4

Itraconazole

Back 4

- Oral triazole (but very similar to ketoconazole)
- Similar use as ketoconazole (broad spectrum systemic infections), + efficacy against lymphocutaneous sporotrichosis and aspergillosis
- Same mechanism and resistance as ketoconazole
- Should be taken with meals (2/3 less absorption on empty stomach)
- Good tissue penetration, but none found in CSF/urine (metabolites are excreted in urine after CYP450 metabolism)
- Fewer side effects than ketoconazole, but causes QT prolongation at high concentrations
- Increases level of many drugs (warfarin, digoxin, cyclosporine, phenytoin, etc.)
- H2 antagonists (cimetidine), isoniazid, phenytoin, and rifampin decrease levels
- Clarithromycin, indinavir, and ritonavir increase levels

Front 5

Fluconazole

Back 5

- Oral/IV triazole
- DOC for oropharyngeal/esophageal candidiasis and cryptococcal meningitis (esp. in AIDS); no aspergillosis activity
- Same mechanism and resistance as ketoconazole
- Excreted in urine unchanged
- GI side effects are common; can cause allergic rash, Stevens-Johnson syndrome and acute hepatic necrosis
- Increases phenytoin/cyclosporine toxicity and oral anticoagulant efficacy
- Less likely to cause QT interval elongation with concomitant terfenadine than ketoconazole or itraconazole

Front 6

Voriconazole

Back 6

- Oral/IV triazole (similar to flucazone)
- Therapeutic niche is invasive aspergillosis
- Same mechanism and resistance as ketoconazole
- Extensively metabolized by CYTP450 isotypes (2C9, 2C19, 3A4); drugs that induce isotypes increase voriconazole metabolism and inhibitors decrease metabolism

Front 7

Flucytosine

Back 7

- Oral 5-fluoro cytosine analog
- Treat chromoblasomycosis (alone) and cryptococcosis/systemic candidiasis (+ amphotericin B); limited therapeutic use due to resistance and serious side effects
- Deaminated to 5-fluoruracil → incorporated into RNA or converted to 5-fluorodeoxyUMP → inhibit thimidylate synthase
- Resistance via decreased uptake or decreased pro-drug conversion
- Excreted unchanged with 3-5 hour half-life
- Dose-dependent bone marrow suppression (potentially fatal)
- Dose dependent leucopenia/thrombocytopenia/enterocolitis in setting of AIDS, azotemia, or concomitant amphotericin B

Front 8

Caspofungin

Back 8

- IV echinocandin
- Treat aspergillosis, esophageal candidiasis (not DOC), and candidiasis prophylaxis in immunocompromised individuals
- Inhibit synthesis of cell wall polysaccharide, beta-D-glucan
- Resistance via mutation of target enzyme and drug efflux
- More drug interactions (decreases tacrolimus levels) and more expensive than micafungin
- CI with cyclosporine

Front 9

Micafungin

Back 9

- IV echinocandin
- Treat esophageal candidiasis (not DOC) and candidiasis prophylaxis in immunocompromised individuals
- Inhibit synthesis of cell wall polysaccharide, beta-D-glucan
- Resistance via mutation of target enzyme and drug efflux
- Fewer drug interactions (decreases tacrolimus levels) and less expensive than caspofungin
- CI with cyclosporine

Front 10

Griseofulvin

Back 10

- Oral penicillium griseofulvum derived antibiotic
- Treat superficial mycoses (tinea diseases)
- Disrupts mitotic spindle/mitosis by binding polymerized microtubeles
- Uptake into fungal cells is energy dependent
- Poor solubility, so delivered as microsized powder; accumulates in keratinocytes
- Minor side effects, but hepatotoxicity with acute intermittent porphyria may occur
- Barbiturates decrease absorption
- Decreases activity of oral contraceptives and anticoagulants