Therapeutics ID Bergman Flashcard

Risk Factors for Fungal Diseases

  • Chronic Sinusitis (antibiotic use)
  • Trauma/burn victims(damaged tissue)
  • GI surgery (damaged tissue)
  • Leukemia (neutropenia, tissue damage, antibiotics)
  • Prosthetic devices (foreign material)
  • Transplant patients (immunosuppression)
  • HIV/AIDS (lymphopenia, neutropenia)
  • Diabetes Mellitus (hyperglycemia, immunosuppression)
  • TPN (prosthetic material, hyperglycemia)
  • Cushing’s Syndrome (excessive corticosteroid production)
  • Corticosteroid use (immunosuppression)

For empirical treatment, Candida albicans is sensitive to:

  • Fluconazole
  • Amphotericin B
  • Echinocandins

For empirical treatment, Candida glabrata is sensitive to:

  • Fluconazole (resistance developing)
  • Amphotericin B (resistance developing)
  • Echinocandins

For empirical treatment, Candida parapsilosis is sensitive to:

  • Fluconazole
  • Amphotericin B
  • Echinocandins (sensitive-intermediate)

For empirical treatment, Candida tropicalis is sensitive to:

  • Fluconazole
  • Amphotericin B
  • Echinocandins

For empirical treatment, Candida krusei is sensitive to:

  • Echinocandins
  • Amphotericin B (resistance developing)

Fluconazole: Administration, ADME

  • PO and IV
  • Good F: IV = PO
  • Broad distribution in tissues (CSF penetration)
  • Some drug interactions (CYP 2C9)
  • The only azole that is eliminated renally –> dosing adjustments in kidney failure
  • Good against Candida and Cryptococcus

 

 

Itraconazole: Administration, ADME, Spectrum

  • Water insoluble
  • Highly variable bioavailability (food and acidic pH help with absorption)
  • Long time to Css (7-15 days PO)
  • Non-Linear Kinetics
  • Activity against Candida and molds
  • Good against endemic dimorphic fungi (histoplasmosis)
  • Many drug interactions

Problems/Advantages of using Cyclodextrin for the formulation of Itraconazole

  • Problem: Accumulates in renal failure patients and may cause CNS side effects
  • Advantage: Makes Itraconazole more water soluble in the suspension formulation

Hydroxy-Beta-Cyclodextrin Formulations: Oral Sol’n of Itraconazole

  • F increases by 50-68% over capsules (DO NOT INTERCHANGE)
  • Better absorption on empty stomach

Hydroxy-Beta-Cyclodextrin Formulations: IV formulation of Voriconazole

  • Used as part of a quick loading scheme
  • Reach Css in 3-7 days
  • No data beyond 14 days of therapy

Voriconazole: Spectrum, Administration

  • Enhanced activity against:

Aspergillus sp.

Candida sp. (C. krusei and C. glabrata)

Molds resistant to other oral agents

  • PO and IV
  • Not affected by acid suppression
  • Michaelis-Mentin Kinetics

Voriconazole: Side Effects

  • Elevated Liver Enzymes (happens with ALL azoles) – reversible
  • Visual Disturbances – reversible
  • Skin rash/photosensitivity
  • Drug Interactions (CYP 2C9, 3A4)

Posaconazole: Administration, Absorption, Spectrum

  • Oral suspension (IV being studied)
  • Absorption an issue (best with high fat meal, needs to be divided out for best result)
  • Prophylaxis of Candida and Aspergillus

Flucytosine: MOA, Administration, ADRs

  • PO
  • MOA: Pyrimidine analog (disrupts fungal DNA synthesis by inhibiting thymidine synthetase)
  • Resistance develops rapidly
  • ONLY used in COMBINATION (synergy with AmphoB)
  • ADRs: Marrow toxicity, hepatic, and GI

Amphotericin B: MOA, Spectrum

  • Conventional micelle form: deoxycholate
  • MOA: Binds ergosterol in fungal cell membranes
  • Fungicidal (concentration dependent killing)
  • Broad Spectrum

Candida

Aspergillus

Dimorphics

Amphotericin: Side Effects

  • Acute (infusion) Toxicities:

Fever, Chills, Rigors

Hypotension

Arrhythmias

Thrombophlebitis

 

  • Chronic Toxicities:

Nephrotoxicity

Hypokalemia

Hypomagnesemia

Sodium wasting

Anemia

Amphotericin B Administration

  • IV only
  • Mix ONLY in D5W, NOT in NS
  • Prehydrate with NS (250-1000 ml)
  • Premedicate with acetaminophen and diphenhydramine (to prevent shaking, chills)

Advantages of Lipid Amphotericin B

 

  • The lipid-based Amphotericin B forms appear to be less nephrotoxic than Amphotericin B Deoxycholate
  • They have not been proven superior over AmB-D, nor do they have a survival benefit over AmB-D
  • L-AmB seems to be associated with milder infusion effects than all other forms
  • Despite all the advantages, very cost prohibitive

 

Amphotericin B Colloid Dispersion: Side Effects
High-rate of infusion-related adverse effects –> rarely used
Caspofungin: Indications

  • Candidemia
  • Invasive Infections
  • Aspergillus

 

Micafungin: Indications

  • Candidemia
  • Prophylaxis after BMT

Anidulafungin: Indications

  • Candidemia
  • Invasive Infections

Echinocandins: Spectrum, MOA, ADRs, ADME

  • Fungicidal against Candida
  • Fungistatic against Aspergillus
  • Lack activity against Cryptococcus and dimorphics
  • MOA: inhibit Beta-D-Glucan synthase
  • Minimal ADRs and drug interactions
  • Minimal renal clearance
  • Minimal CSF Penetration
  • IV only

Treatment of Candidemia

  • Amphotericin B or Echinocandins DOC for unstable patients
  • Fluconazole is alt. in stable patients and is preferred once sp. is known
  • Candida species should influence selection
  • IV lines should be changed if possible

 

Treatment for Oral Candidiasis (thrush)

  • Nystatin
  • Clotrimazole troche
  • Fluconazole

Treatment for Esophageal Candidiasis

  • Fluconazole
  • Echinocandins

Treatment for Vaginal Candidiasis (thrush)

  • Topicals agents (Miconazole, Clotrimazole)
  • Fluconazole

Treatment for Candiduria
Fluconazole
Treatment of Invasive Aspergillosis

  • Voriconazole
  • Lipid Based Amphotericin B
  • Caspofungin (other Echinocandins as well)

 

Treatment for Cryptococal Meningitis

  • Amphotericin B + Flucytosine x 6-10 weeks

OR

  • Amphotericin B + Flucytosine x 2 weeks followed by fluconazole x 10 weeks
  • Fluconazole + flucytosine (2nd line)
  • Fluconazole + Amphotericin B (alt)
  • Lipid Based Amphotericin B (alt)

 

Treatment for Histoplasmosis

  • Itraconazole

OR

  • Posaconazole

OR

  • Amphotericin B (IV if really serious)

 

Treatment for Endemic Fungi: Blastomycosis

  • Itraconazole

OR

  • Amphotericin B

Treatment for Endemic Fungi: Coccidiodomycosis

  • Itraconazole

OR

  • Amphotericin B

Treatment for Superficial Fungal Infections: Tinea pedis, Tinea cruris, etc. EXCEPT Tinea unguium

  • Topical azoles

OR

  • Topical Allylamines (terbinafine, butenafine)

Treatment for Superficial Fungal Infections: Onychomycosis (Tinea unguium)

  • PO terbinafine x 6 weeks for fingernals, 12 weeks for toenails (monitor LFTs)

OR

  • PO itraconazole (pulse or daily) x 2-4 months

OR

  • Ciclopirox qHS x 48 weeks

Types of Yeasts

  • Candida species
  • Cryptococcus neoformans

Types of Molds

  • Aspergillus sp.
  • Zygomycetes (Mucor, Rhizopus)

Types of Dimorphic fungi

  • Histoplasma capsulatum
  • Blastomyces dermatitidis
  • Coccidioides immitis

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