Flashcards in AntiFungal Basics, Amp B, Flucytosine and Azoles Deck (36):
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?
cell wall contains ergosterol (target for alot of anti fungals)
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?
1. Drugs that alter cell wall membrane permeability
--Polyenes: amp B and Nystatin
--Azoles: ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, clotrimazole and miconazole
2. Drugs that block nucleic acid synthesis (antimetabolites)
3. Drugs that disrupt microtubule function
4. Drugs that disrupt the fungal cell wall
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.
--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
--Candida albicans and Cryptococcus Neoformans
Organisms Causing Endemic Mycoses
--Histoplasma Capsulatum, Blastomyces Dermatitidis and Coccidioides Immitis
Aspergillus Fumigatus and Mucor
What are the PK for Amp B (polyene, cell wall membrane permeability alter)
---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 )
--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
--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
--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.
What is combo of flucytosine and amp B?
What is the spectrum and PK for flucytosine?
Fungistatic with narrow spectrum
--not used as a single agent b/c of its demonstrated synergy with other agents and to avoid resistance
--effective orally. distributed to most body tissues. reduce in renal failure patients
What are the uses and AE of flucytosine?
--tx of serious infections caused by susceptible strains of Candida and/or Cryptococcus
--used in combo with amp B for tx of systemic candidiasis and cryptococcosis so no resistance
--metabolism to the toxic anti-neoplastic compound 5-Fluorouracil
-bone marrow toxicity with anemia, leukopenia, thrombocytopenia
Next set of cards will be on the Azoles (Drugs that alter cell wall permeability). What are the drugs?
Systemic therapy of fungal disease
Imidazoles: Ketoconazole, Miconazole, Clotimazole
Triazoles: Itraconazole, Fluconazole, Voriconazole, Posaconazole
What is the MOA of Azoles?
Fungus specific (Not human) cytochrome P450 enzyme 14alpha sterol demethylase catalyzes the conversion of lanosterol to ergosterol
--azoles inhibit 14alpha sterol demethylase, thus reducing ergosterol synthesis. disrupting membrane function and increasing permeability
Imidazoles are less specific then triazoles therefore higher incidence of drug interactions and side effects.
What are AE of Azoles?
Most common AE: is minor GI upset
May cause abnormalities in liver enzymes
This next set of cards will go through each Azole and their features. First up is Ketoconazole (Imidazole). What are some features?
Seldom systemic agent
--other azoles have fewer AE and are preferred
Greater propensity to inhibit mammalian cytochrome P450 enzymes
Decrease plasma testosterone levels and cause gynecomastia, decreased libido and loss of potency in men and menstrual irregularities in women.
High doses may inhibit adrenal steroid synthesis and decrease plasma cortisol concentrations
Ketoconazole is a strong inhibitor of CYP3A4. As a consequence ketoconazole can potentiate what?
Toxicities of several drugs such as warfarin and cyclosporine
What drugs interfere with ketoconazole absorption?
Best absorbed at low gastric pH
---Antacids, H2 blockers or proton pump inhibitors interfere with absorption
What are the uses of ketoconazole?
Narrow Spectrum and AE systemic ketoconazole is rarely used for systemic mycoses
Used for chronic mucocutaneous candidasis and also effective against dermatophytes
The next azole is Fluconazole (Triazole). What are some features?
Oral bioavailability high
Oral and IV
Moderate inhibitor of CYP3A4
Strong inhibitor of CYP2C9 (increases plasma levels of phenytoin, zidovudine and warfarin)
Widest therapeutic index permitting aggressive dosing (due to few hepatic enzyme interactions)
Renal excretion accounts for over 90% elimination
What are the uses for Fluconazole (Triazole)?
--esophageal, oropharyngeal, vulvovaginal or urinary candidiasis
--consolidation and maintenance therapy of cryptococcal meningitis after induction therapy with amp B
--initial and secondary prophylaxis against cryptococcal meningitis
Alternative to amp B for patients with cryptococcal meningitis whose disease is not severe
Ineffective against Aspergillus and other Filamentous Fungi
Next azole to discuss is Itraconazole (Triazoles). What are some features?
Oral and IV
Metabolized in liver via CYP3A4. Metabolism may be affected by both inducers and by inhibitors of the enzyme
Strong Inhibitor of CYP3A4 -- may cause fetal arrhythmias when given with cisapride or quinidine
Potent anti-fungal with poor bioavailability
Poor CSF penetration
Absorption is increased by food and by low gastric pH. Absorption is reduced by drugs that decrease gastric acidity, such as antacids, H2 blockers, and proton pump inhibitors.
What are the uses of Itraconazole (Triazole)?
Preferred Azole for Mycoses due to the dimorphic fungi Blastomyces, Sporothrix and Histoplasma
Effective against Aspergillus (but has been replaced by voriconazole)
Used extensively for dermatophytoses and onychomycosis
Not active against Zygomycetes
The next azole to discuss is Voriconazole (Triazole). What are some features?
IV and oral (well absorbed)
Toxicities: rash, elevated liver enzymes, transient visual disturbances (occur in up to 30% of patients, include, blurring and changes in color vision or brightness)
Metabolized by and inhibits CYP2C10, CYP2C9, and CYP3A4.
More effective against Aspergillus and some species of Candida
Active against Fusarium
Not active against Zygomycetes
What are the uses for Voriconazole?
DOC: invasive aspergillosis
Tx: candidaemia, serous invasive candida infections, serious fungal infections caused by Scedosporium and Fusarium
The last azole to discuss is Posaconazole (triazole). What are some features?
Broadest spectrum member of the azole family
--has activity against Zygomycetes such as Mucor (amp B use to be the only agent for these infections)
Oral suspension and must be taken with high fat meals for adequate absorption
What are the uses for Posaconazole?
Prophylaxis of invasive Aspergillus and Candida Infections
Tx of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole
These last cards are review azole cards. First name the water solubility (WS) and absorption for azoles.
Ketoconazole: low (WS); Variable (Absorption)
Fluconazole: High (WS); High (Absorption)
Itraconazole: Low (WS); Variable (Absorption)
Voriconazole: High (WS); High (Absorption)
Posaconazole: Low (WS); High (Absorption)
Name the CSF:Serum Concentration ratio (CR) and Half Life (Hrs) for the azoles.
Ketoconazole: less than 0.1 (CR) ; 7-10 Hrs
Fluconazole: greater than 0.7 (CR); 22-31 Hrs
Itraconazole: less than 0.01 (CR); 24-42 Hrs
Voriconazole: 6 Hrs
Posaconazole: 25 Hrs