Antifungal Drugs Flashcards
Drugs that alter cell membrane?
Drugs that alter cell membrane?
Polyenes
Azoles
Allylamines
Drugs that block nucleic acid synthesis
Flucytosine
Drugs that disrupt microtubule function
Griseofulvin
Drugs that disrupt the fungal cell wall
Echinocandins
SYSTEMIC DRUGS FOR SUBCUTANEOUS AND
SYSTEMIC MYCOSES
- Amphotericin B
- Flucytosine
- Azoles
- Echinocandins
Amphotericin B description and MOA? Antifungal activity?
• Polyene antibiotic.
MOA:
• Amphotericin B binds to ergosterol, forming
pores in the cell membrane.
• The pores allow leakage of intracellular ions and
macromolecules, leading to cell death.
Antifungal Activity:
• Antifungal agent with the broadest spectrum of
action.
• It has activity against the clinically significant
yeasts, the organisms causing endemic
mycoses, and the pathogenic molds.
AMPHOTERICIN B: PHARMACOKINETICS
• Amphotericin B is highly insoluble: formulated as
deoxycholate colloidal suspension.
• Poorly absorbed from the GI tract.
• Must be given IV.
• Penetration into the CSF is extremely low.
• Intrathecal therapy may be necessary for
meningeal disease.
Amphotericin B uses?
• Broad spectrum and fungicidal action: useful for
nearly all life-threatening fungal infections.
• Often used as initial induction regimen to
rapidly reduce fungal burden.
• Then patients continue therapy with an azole.
• Given by slow IV infusion.
• Amphotericin B is the preferred treatment for
deep fungal infections during pregnancy.
AMPHOTERICIN B: ADVERSE EFFECTS INFUSION-RELATED TOXICITY?
INFUSION-RELATED TOXICITY
• Nearly universal. Fever and chills, muscle
spasms, vomiting, headache and hypotension.
• Can be attenuated by slowing infusion rate or
decreasing daily dose.
• Pre-medication with antihistamines,
glucocorticoids, antipyretics or meperidine can
be helpful.
AMPHOTERICIN B: ADVERSE EFFECTS SLOWER TOXICITY Renal related?
• Amphotericin B also binds to cholesterol and forms
pores in mammalian cell membranes, leading to
renal toxicity.
• Renal impairment occurs in nearly all patients.
• Azotemia occurs in most patients.
• GFR may be decreased.
• Renal toxicity commonly presents with renal tubular
acidosis with severe magnesium and potassium
wasting.
• Renal damage can be attenuated with sodium
loading: it is common practice to administer saline
infusion with amphotericin B.
AMPHOTERICIN B: ADVERSE EFFECTS SLOWER TOXICITY other areas?
• Abnormalities of liver function tests occasionally
seen.
• Hypochromic normocytic anemia, due to reduced
erythropoietin production.
• Renal function should be monitored frequently
during amphotericin B therapy.
• It is also advisable to monitor liver function, serum electrolytes (particularly magnesium and
potassium), blood counts, and hemoglobin.
• Intrathecal administration can cause seizures and
serious neurological damage.
AMPHOTERICIN B: LIPID FORMULATIONS?
• The three FDA-approved lipid formulations of
amphotericin B are:
• Liposomal amphotericin B (L-AMB)
• Amphotericin B lipid complex (ABLC)
• Amphotericin B colloidal dispersion (ABCD)
• Nephrotoxicity is less common and less severe
with the lipid formulations.
FLUCYTOSINE description and 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-fluorodeoxyuridine
monophosphate (5-FdUMP) which inhibits
thymidylate synthetase, thus blocking synthesis of dTMP.
• Fluorouridine triphosphate (5-FUTP) is also
formed, which inhibits protein synthesis.
• Mammalian cells are unable to convert the
parent drug to its active metabolites.
• Combination of flucytosine and amphotericin
B is synergistic.
FLUCYTOSINE: SPECTRUM?
• Fungistatic
• Narrow spectrum.
• Not used as a single agent because of synergy
with other agents and to avoid development of
resistance.
FLUCYTOSINE: USES?
• Indicated only for serious infections caused by
susceptible strains of Candida and/or
Cryptococcus.
• Should be used in combination with
amphotericin B for the treatment of systemic
candidiasis and cryptococcosis in order to avoid resistance.
FLUCYTOSINE: ADVERSE EFFECTS?
• Result from metabolism (possibly by intestinal
flora) to 5-fluorouracil.
• Bone marrow toxicity is the most common.
Description of Azole?
List 3 imidazoles?
- Relatively nontoxic oral drugs.
- Important role in systemic therapy.
- Classified as imidazoles or triazoles.
Imidazoles
• Ketoconazole
• Miconazole
• Clotrimazole
List 4 Triazoles?
- Itraconazole
- Fluconazole
- Voriconazole
- Posaconazole
Azoles MOA?
• The fungal cytochrome P450 enzyme 14-α-sterol demethylase catalyzes the conversion of lanosterol to ergosterol.
• Azoles inhibit the enzyme, thus reducing ergosterol synthesis.
• This disrupts membrane function and increases
permeability.
• Specificity of azole drugs results from their
greater affinity for fungal than for human P450
enzymes.
• Triazoles are more specific than imidazoles.
Azoles AE?
- Relatively nontoxic.
* Most common adverse reaction: minor GI upset.
Ketoconazole description and moa?
• Inhibits mammalian cytochrome P450 enzymes.
• Can 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 PK?
• Strong inhibitor of CYP3A4. It can potentiate the
toxicities of several drugs such as warfarin and
cyclosporine.
• Best absorbed at low gastric pH: antacids, H2
blockers or proton pump inhibitors interfere with
absorption of ketoconazole.
• Poor penetration in the CSF.
Ketoconazole uses?
• Due to its narrow spectrum and adverse effects
ketoconazole is rarely used for systemic
mycoses.
• Still used for superficial mycoses
Fluconazole PK?
- Good CSF penetration.
- High oral bioavailability.
- Available in oral and IV formulations.
- Moderate inhibitor of CYP3A4.
- Strong inhibitor of CYP2C9: can increase plasma levels of phenytoin, zidovudine and warfarin.
Fluconazole uses?
• DOC in esophageal, oropharyngeal,
vulvovaginal or urinary candidiasis.
• DOC for candidemia.
• DOC for coccidioidomycosis.
• DOC for consolidation and maintenance therapy of cryptococcal meningitis after
induction with amphotericin B.
• Alternative to amphotericin B for non-severe
criptococcal meningitis.
• DOC for initial and secondary prophylaxis
against cryptoccocal meningitis.
• Ineffective against Aspergillus or other
filamentous fungi.
Itraconazole PK?
• Metabolized primarily by CYP3A4.
• Strong inhibitor of CYP3A4. May cause potentially fatal arrhythmias when given
concurrently with cisapride or quinidine.
• Poor bioavailability.
• Penetrates poorly in CSF.
• Absorption reduced by antacids, H2 blockers
and proton pump inhibitors.
Itraconazole uses?
• Preferred azole for mycoses due to the
dimorphic fungi Blastomyces, Sporothrix and
Histoplasma.
• Effective against Aspergillus, but has been
replaced by voriconazole for this indication.
• Used for dermatophytoses and onychomycosis.
Voriconazole spectrum, DOC, pk, drug interaction and AE?
• Spectrum similar to itraconazole.
• DOC for invasive aspergillosis.
• Transient visual disturbances occur in up to 30% of patients.
• Voriconazole is metabolized by and inhibits
CYP2C19, CYP2C9 and CYP3A4.
• The significant number of drug interactions due
to its metabolism through the various hepatic
enzymes may limit its use.
Posaconazole pk and spectrum?
• Spectrum similar to itraconazole, but it has
activity against Zygomycetes such as Mucor.
• Inhibits CYP3A4.
ECHINOCANDINS: CASPOFUNGIN description, spectrum, pk, moa?
• Large cyclic peptides linked to a long-chain
fatty acid.
• Active against candida and aspergillus but
not Cryptococcus neoformans.
• Only available IV.
• Inhibit synthesis of beta(1-3)-D-glucans in the
fungal cell wall.
• This results in disruption of the fungal cell wall
and cell death.
DRUGS FOR SUPERFICIAL MYCOSES
- SYSTEMIC DRUGS
* TOPICAL DRUGS
SYSTEMIC DRUGS FOR SUPERFICIAL MYCOSES?
- Griseofulvin
- Terbinafine
- Ketoconazole
- Fluconazole
- Itraconazole
Griseofulvin overview, moa
• Only use: treatment of dermatophytosis.
• Absorption improved when given with fatty
foods.
MECHANISM OF ACTION
• Disrupts mitotic spindle and inhibits mitosis.
GRISEOFULVIN: USES
• Severe dermatophytoses of the skin, hair, and
nails.
• Largely replaced by newer antifungal drugs like
itraconazole and terbinafine.
• Induces P450 enzymes: increases metabolism
of a number of drugs, including warfarin.
TERBINAFINE description, moa, uses?
• Allylamine. • Available in oral formulation. • Inhibition of squalene epoxidase prevents synthesis of ergosterol. • It also causes accumulation of toxic levels of squalene in the fungal cell. • Effective in onychomycosis.
TERBINAFINE: ADVERSE EFFECTS?
- GI upsets, rash, headache, taste disturbances.
- Elevations in serum liver transaminases.
- Inhibits CYP2D6.
Which azoles are used for treatment of dermatophytosis?
• Ketoconazole, fluconazole and itraconazole are commonly used orally in
the treatment of dermatophytoses.
TOPICAL DRUGS FOR SUPERFICIAL MYCOSES?
- Nystatin
- Amphotericin B
- Clotrimazole
- Miconazole
- Ketoconazole
- Terbinafine
Nystatin overview and moa
- Polyene macrolide.
- Structurally similar to amphotericin B.
- Same mechanism of action.(binding to ergosterol)
Nystatin pk and AE?
- Too toxic for IV administration.
- Used only for candidiasis.
- Supplied in preparations for cutaneous, vaginal, or oral administration.
- Not absorbed from the GI tract, skin, or vagina.
- As a result it has little significant toxicity.
Topical amphotericin B used for?
cutaneous candidiasis.
Which two topical azoles used for superficial mycoses?
• The two azoles most commonly used
topically are clotrimazole and miconazole.
• Both available over-the-counter
Terbinafine uses?
- Available as topical creams.
* Effective for tinea cruris and tinea corporis.
Primary therapy for each Infection?
Esophageal candidiasis
Urinary candidiasis
Oropharyngeal
candidiasis
Vulvovaginal candidiasis
Recurrent vulvovaginal
candidiasis
Candidemia
Cutaneous candidiasis
Infection Primary Therapy
Esophageal candidiasis- IV or Oral Fluconazole
Urinary candidiasis IV or Oral Fluconazole
Oropharyngeal
candidiasis
Mild: Topical Clotrimazole or Nystatin.
Moderate to severe: Oral Fluconazole
AIDS patient: Oral Fluconazole
Vulvovaginal candidiasis Topical Azoles or Oral Fluconazole
Recurrent vulvovaginal
candidiasis
Oral Fluconazole
Candidemia IV Fluconazole or an IV Echinocandin
Cutaneous candidiasis Topical Amphotericin B or Topical
Azole or Topical Nystatin
Description of pneumocystis jirovecii pneumonia?
• Pneumocystis jirovecii is the cause of Pneumocystis pneumonia (PCP).
• The organism is a fungus but it does not
respond to antifungals.
• P carinii is now recognized to be the cause of
animal infections.
PCP clinically presents as?
• PCP is a common cause of pneumonia in
immunosuppressed patients.
• It is the most common opportunistic infection in
HIV-infected patients.
• Symptoms include fever, dyspnea, and cough.
Therapy for PCP? Alternative therapies?
THERAPY • DOC: co-trimoxazole. • Co-trimoxazole is also DOC for prevention of P jiroveci infection in immunocompromised individuals.
• Alternative therapies are: • Clindamycin + primaquine • Dapsone + trimethoprim • Atovaquone • Pentamidine • Patients with moderate-to-severe disease should also be given prednisone.
Treatment for infection
Cryptococcosis
Invasive aspergillosis
Mucormycosis
Fusariosis
Onychomycosis
Cryptococcosis Amphotericin B + Oral FlucytosineThen Oral Fluconazole
Invasive aspergillosis IV and then Oral Voriconazole
Mucormycosis Amphotericin B
Fusariosis Amphotericin B
Onychomycosis Oral Terbinafine or Oral Itraconazole
or Oral Fluconazole
