ID: Antimicrobials #4 - Antifungals Year 2 Flashcards
interacts selectively with ergosterol containing
membranes
Amphotericin B
fungi produce less ergosterol or have thicker
membranes, so that pores don’t form as easily.
Resistance to Amphotericin B
Pharmacokinetics of Amphotericin B
Not well absorbed Oral Extensive distribution (very hydrophobic) Excretion Biliary, and renally with long half life (>15 days)
Amphotericin B
Adverse reactions.
Nephrotoxicity with systemic administration
Anemia (75% incidence)
Resistance via efflux pumps (mdr); target mutation
Azoles: Imidazole and triazoles
Azoles: Imidazole and triazoles MOA
Inhibit ergosterol biosynthesis (lanosterol 14-α demethylase; Erg11) by OXIDATION of a methyl group
Fungistatic/cidal depending on the concentration and bug
Moderately broad spectrum; some activity vs Aspergillus
Ketoconazole and Itraconazole kinetics
Absorption. Good orally; antacids hinder absp
Distributed to keratinocytes and vaginal secretions
Hepatic metabolism/ excretion.
A broader spectrum triazole
with fewer adverse effects
Itraconazole
Ketoconazole S/E
- Inhibits P450
- reversible endocrine abnormalities
- gynecomastia
- GI disturbances
- teratogenic
- rare – hepatitis
Completely orally available and distributed well, even to CSF
Fluconazole
4th most common nosocomial infection
Candidiasis (yeast)
Disseminated infection, especially meningoencephalitis.
Meningitis may lead to permanent neurologic damage.
Cryptococcosis (yeast)
“San Joachin Valley fever”
Meningitis - permanent neurologic damage.
Mortality is high in AIDS and lung disease patients
Coccidiomycosis
~40 million people have been infected.
Of newly infected people ~10% will have symptoms
Histoplasmosis
Permanent lung damage with chronic disease.
Mortality rate is about 5%.
Blastomycosis
Drug of choice for Cryptococcal meningitis (AIDS)
Drug of choice for Coccidioidal meningitis
Fluconazole
Fluconazole S/E
-GI upset- worsens at high dose
-Rarely hepatic failure
- teratogenic
-inhibits metabolism of rifampin, theophylline,
warfarin, etc.
Chitin
Give fungal wall structure
Glycosylated proteins on fungal surface
Mannoproteins
High toxicity
Nephrotoxicity
Amphotericin B
Nystatin (topical)
Drug interactions, rash, fever,
GI- NV
Caspofungin
Micfungin
Anidulafungin
GI upset (n/v/d) rashes, enterocolitis Rev hepatic disfunction. *Bone marrow depression
Flucytosine
RNA and DNA synthesis
fungicidal
Headache (10%)
GI upset, rashes
Candida superinfection
Griseofulvin
Microtubules-inhibition of
mitosis fungicidal/static
Minor GI upset rash, headache.
Taste disturbances.
Drug interactions.
Contraindicated in pregnancy
Terbinafine
Inhibits squalene oxidase in
ergosterol biosynthesis.
RNA and DNA synthesis
fungicidal
Flucytosine
Microtubules-inhibition of
mitosis fungicidal/static
Griseofulvin
Inhibits squalene oxidase in
ergosterol biosynthesis.
Terbinafine
Ergosterol synthesis
inhibition-P450
fungicidal
Azoles Ketoconazole Itraconazole Fluconazole Voriconazole Posaconazole
Fungal membrane
disruption
fungicidal
Amphotericin B
Nystatin (topical)
Invasive aspergillosis – salvage
therapy
Candidiasis
Empirical therapy
Caspofungin
Micfungin
Anidulafungin
*teacher seems to care what works on aspergillus
severe fungal infections
blastomycosis, histoplasmosis,
aspergillosis, coccidioidomycosis
in immunocompromised host
Amphotericin B
Nystatin (topical)
Dermatophytes: hair skin nails
Systemic/topica
Griseofulvin
Terbinafine
Amphotericin B
Nystatin (topical)
SE
High toxicity
Nephrotoxicity
Azoles Ketoconazole Itraconazole Fluconazole Voriconazole Posaconazole
SE
GI upset (n/v/diarrhea) itching K: Gynecomastia inhib of steroid biosynth. P450 interactions. Hepatitis-rare Avoid in pregnancy P450 drug interactions
Caspofungin
Micfungin
Anidulafungin
SE
Drug interactions, rash, fever,
GI- NV
Flucytosine
SE
GI upset (n/v/d) rashes, enterocolitis Rev hepatic dysfunction. Bone marrow depression
Griseofulvin
SE
Headache (10%)
GI upset
rashes
Candida superinfection
Terbinafine
SE
Minor GI upset rash HA Taste disturbances. Drug interactions. Contraindicated in pregnancy
Fluconazole
Voriconazole
Posaconazole
Special Bugs
F: Crypt. and Coccid meningitis
V: Invasive aspergillosis
P: Asp. and Cand. prophylaxis
Azoles Bugs
Dermaphytes, yeasts, dimorphic fungi-coccidioides, blastomyces, histoplasm
The side effects of azole anti fungals comes from
CYP 450
Used in combination for severe infections with amphotericin B
Orally available and distributes well (to CSF)
Flucytosine
Only drug you can use in prego
Ampho B
SCARY!
