Antifungals Flashcards
Amphotericin B
systemic antifungal, an amphoteric polyene macrolide
associates with ergoterol in fungal membrane and forms a pore which ions leak out of, also generates oxidative free radicals
lipid vehicles serve as an ampotericin reservoir that helps increase affinity to ergosterol
IV; intrathecal, bladder installation; intraocular; topical, distributes to organs but not to CNS - not hepatically metabolized and excreted in the urine
Biphasic: Initial 15-48 hours; Terminal ~15 days
Spectrum of Amphotericin B
Opportunistic fungi • Candida • Aspergillus spp. • Cryptococcus neoformans • Zygomycetes − Z. absidia, Z. mucor, and Z. rhizopus
Endemic fungal pathogens • Histoplasma capsulatum • Blastomyces dermatididis • Coccidioides immitis • Paracoccidioides brasiliensis
endemic can also be opportunistic
Treats severe fungal pneumonia, fungal peritonitis, severe cryptococcal meningitis, candidal cystitis and other bladder fungal infections, bone marrow transplantation prophylaxis
Toxicities of Amphotericin B
Nephrotoxicity
- Azotemia occurs in >80% of patients - elevated BUN
- decreased renal prefusion, renal tubular injury and acidosis
anemia - from decreased erythopoietin (from kidney damage)
infusions related - Fever, chills, rigor, vomiting, headache, malaise, hypotension, tachypnea and Thrombophlebitis
Intrathecal – Headache, fever common; arachnoiditis, delirium, seizures
Flucytosine
fluorinated pyrimidine analog related to 5-fluorouracil
oral prodrug, rapid, good penetration of CSF, renal excretion - extreme caution in patients with renal impairment
gets in by cytosine permeases then deaminated to 5-FU -> decrease DNA and protein synthesis
Used for therapy in combination with -
amphotericin B for cryptococcal meningitis
itraconazole for chromoblastomycosis
active against candida
Flucytosine Resistance and Toxicities
Resistance is through loss of cytosine permease transporter and decreased cytosine deaminase activity
Resistance emerges rapidly when used alone
Toxicities Bone marrow suppression Hepatotoxicity: reversible GI: nausea, vomiting, diarrhea; severe enterocolitis Rash
narrow therapeutic window
what patients should flucytosine be cautioned in?
- Renal dysfunction
- Bone marrow depression
- Hepatic impairment
Azole Antifungals - the drugs
systemic - Ketoconazole, Itraconazole, Fluconazole, Voriconazole, Posiconazole*
Topical use -ketoconazole, clotrimazole, miconazole, econazole and terconazole
Azole antifungal MOA and resistance
inhibition of ergosterol biosynthesis > 14-α sterol demethylase which stops conversion of lanosterol to ergosterol
causes accumulation of 14-α methyl sterols impairs function of membrane enzyme systems
resistance through modification of target enzymes (ERG11 gene), efflux pumps and increased production of 14-α sterol demethylase: C. albicans, C. glabrata
Ketoconazole
azole antifungal
Oral, variable bioavailability, CYP3A4, half life 7-10 h
Largely replaced by itraconazole and fluconazole - because of adverse effects and lower spectrum
Adverse effects
drug specific- ↓ Steroidogenesis: gynecomastia, decreased libido, oligospermia, and menstrual irregularities
adrenal suppression with high doses
class effects - minor GI, increased hepatic enzymes, rare clinical hepatitis, prolongation of QT interval, v. arrhythmias
Itraconazole
azole antifungal
oral, CYP3A4, half life 24-42 h, variable bioavailability
Used for Onychomycosis and indolent nonmeningeal infections - drug of choice: • Blastomycosis • Sporotrichosis • Paracoccidioidomycosis • Histoplasmosis
Adverse Effects
Edema, hypertension, hypokalemia, and negative inotropic effect
Hearing loss
class effects - minor GI, increased hepatic enzymes, rare clinical hepatitis, prolongation of QT interval, v. arrhythmias
Fluconazole
Azole antifungal
Oral, IV with high bioavailabiltity, renal elimination, distributes to the CNS, half life 22-31 h
Uses
DOC: cryptococcal meningitis
Candidemia; mucocutaneous candidiasis
Propholaxis for allogeneic bone marrow transplantation
Adverse Effects
Rash (Stevens-Johnson syndrome)
alopecia
nausea, vomiting, taste perversion
class effects - minor GI, increased hepatic enzymes, rare clinical hepatitis, prolongation of QT interval, v. arrhythmias
Voriconazole
Azole, antifungal,
Oral, IV. high bioavailability, distributes to CNS, hepatic -CYP2C9/19, half life 6h
Uses
DOC: invasive aspergillosis
Candidemia - fluconazole-resistant
Adverse Effects
Blurred vision; color vision changes; photophobia
Severe photosensitivity and dermatological reactions
class effects - minor GI, increased hepatic enzymes, rare clinical hepatitis, prolongation of QT interval, v. arrhythmias
Posaconazole
Azole antifungal, broadest spectrum
Oral, IV, variable bioavailability, Hepatic non-CYP metabolism, half life 25 h
used for:
•Aspergillosis prophylaxis (immunocompromised pts)
•Candida oropharyngeal infections
•Salvage therapy for invasive fungal infections
Only clinical activity against mucomyocosis
Adverse Effects
Headaches and GI disturbances
Class effects - minor GI, increased hepatic enzymes, rare clinical hepatitis, prolongation of QT interval, v. arrhythmias
Azole class adverse effects
minor GI, increased hepatic enzymes, rare clinical hepatitis, prolongation of QT interval, v. arrhythmias
Azole Drug Interactions
High potential of DIs
interacts with drugs that prolong QT interval - can cause V. Arrhythmias
(antiarrhythmics, TCA, antipsychotics)
cyclosporine and tacrolimus - nephrotoxicity
Erythromycin, Clarithromycin, Telithromycin - inhibit metabolism
Lovastatin, Simvastatin, Atorvastatin ⇒ rhabdomyolysis
chemotherapy
