AntiFungal Basics, Amp B, Flucytosine and Azoles Flashcards
Infections caused by fungi are called mycoses. Fungal infections can be classified according to the initial site of infection. What are the categories?
Superficial mycoses: affect the outermost layers of the skin, mucous membranes, hair and nails. Principal infections in this group are the dermatophytoses and superficial forms of candidiasis
Subcutaneous Mycoses: affect the dermis, subcutaneous tissues and adjacent bone
Systemic Mycoses: affect internal organs. Systemic mycoses are the most difficult to treat and they are often life threatening.
–candidiasis, cryptococcosis, and Aspergillosis are the three most common systemic infections in humans.
What are some differences in fungal vs mammals?
Fungal: cell wall contains ergosterol (target for alot of anti fungals) Eukaryotic Mammalian: cell wall contains cholesterol
There has been a rise in the incidence of fungal infections. With Candidemia now the fourth most common cause of septicemia. What is the reason for this increased incidence of fungal infections?
Greater numbers of individuals who are immunosuppressed: undergoing cancer chemotherapy, following organ transplant or infected with HIV
The antifungal drugs are classified based on MOA. What are the various categories?
- Drugs that alter cell wall membrane permeability
- -Polyenes: amp B and Nystatin
- -Azoles: ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, clotrimazole and miconazole
- -Allylamines: Terbinafine - Drugs that block nucleic acid synthesis (antimetabolites)
- -Flucytosine - Drugs that disrupt microtubule function
- -Griseofulvin - Drugs that disrupt the fungal cell wall
- -Echinocandins: caspofungin
Antifungal drugs are then classified based on clinical use. First lets discuss the drugs used for SQ and systemic mycoses. First up is Amphotericin B( polyene). What is the MOA?
Polyene macrolide antibiotic produced by Streptomyces Nodsus.
MOA:
–exploits the difference in lipid composition of fungal and mammalian cell membranes. Ergosterol, a cell membrane sterol, is found in the cell membrane of fungi and cholesterol is predominant in bacteria and humans.
—AMP B binds to ergosterol, forming pores in the cell membrane. Pores allow leakage of intracellular ions and macromolecules, leading to cell death
What is the antifungal activity of Amp B (polyene, cell wall membrane permeability alter)
Broadest spectrum of action
Yeast including:
–Candida albicans and Cryptococcus Neoformans
Organisms Causing Endemic Mycoses
–Histoplasma Capsulatum, Blastomyces Dermatitidis and Coccidioides Immitis
Pathogenic Molds:
Aspergillus Fumigatus and Mucor
What are the PK for Amp B (polyene, cell wall membrane permeability alter)
Highly insoluble
—formulated as a deoxycholate colloidal suspension which is poorly absorbed from the GI tract and must be given IV
Low penetration into the CSF, vitreous humor and amniotic fluid but does cross the placenta
What are the uses for Amp B?
Broad Spectrum of Activity
–useful for all life threatening mycotic infections (although newer, less toxic agents have largely replaced it )
DOC:
–mucormycosis, cryptococcal meningitis, histoplasmosis, blastomycosis, coccidiomycosis, extracutaneous sporotrichosis, fusariosis and other severe systemic fungal infections.
Often given to patients with neutropenia who have fever and do not respond to broad spectrum antibacterial agents over 5-7 days.
Amphotericin B is often used as the initial induction regimen in order to ?
Reduce fungal burden and is then replaced by one of the newer azole drugs for chronic therapy.
–such induction is especially important for immunocompromised patients and those with sever fungal pneumonia, severe cryptococcal meningitis or disseminated infections with one of the endemic mycoses.
For treatment of systemic fungal disease, Amp B is given how?
Slow IV infusion
Amphotericin B is the preferred treatment for what kind of infections during pregnancy?
Deep fungal infections
What are some AE of Amphotericin B?
Infusion Related Toxicity:
–nearly universal; fever, chills, muscle spasms, vomiting, headache, and hypotension. Try slowing infusion rate or decreasing daily dose. Pre Medicate with anti-histamines, glucocorticoids, antipyretics or meperidine.
AE of Amphotericin B continued
Slower Toxicity:
- -Binds to cholesterol and forms pores in mammalian cell membranes, leading to leakage of cytoplasmic contents and cell death, which results in renal toxicity
- -renal impairment occurs in nearly all patients and azotemia in most patients
- -renal toxicity presents with renal tubular acidosis with severe magnesium and potassium wasting. Renal damage can be attenuated with sodium loading and commonly patients get a saline infusion with the amp B.
- -other abnormalities: liver, hypochromic normocytic anemia and intrathecal admin cause seizures and neuro damage.
AE of Amphotericin B continued
Lipid formulations(IV) of Amp B:
–come about due to attempt to reduce nephrotoxicity
Package of Amp B in lipid carriers in order to prevent high drug exposure to the proximal tubule of the nephron.
Liposomal Amphotericin B (L-AMB), Amphotericin B lipid complex (ABLC), and Amphotericin B colloidal Disperson (ABCD).
The next anti-fungal drug is one that blocks Nucleic Acid Synthesis, Flucytosine. What is the MOA?
Synthetic pyrimidine antimetabolite
MOA:
–taken by fungal cells via the enzyme cytosine permease
–converted intracellularly first to 5-Fluorouracil (5-FU) and then to 5-Flurodeoxyuridine Monophosphate (5-Fdump) which inhibits Thymidylate Synthetase, thus blocking synthesis of dTMP and forming Flurouridine Triphosphte (5-FUTP) which inhibits protein synthesis.
