• 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)

• Fluconazole
• Amphotericin B
• Echinocandins

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

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

• Fluconazole
• Amphotericin B
• Echinocandins

• Echinocandins
• Amphotericin B (resistance developing)

• 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

• 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

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

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

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

• 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

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

• 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

• 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

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

Candida

Aspergillus

Dimorphics

• Acute (infusion) Toxicities:

Fever, Chills, Rigors

Hypotension

Arrhythmias

Thrombophlebitis

• Chronic Toxicities:

Nephrotoxicity

Hypokalemia

Hypomagnesemia

Sodium wasting

Anemia

• 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

• Candidemia
• Invasive Infections
• Aspergillus

• Candidemia
• Prophylaxis after BMT

• Candidemia
• Invasive Infections

• 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

• 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

• Nystatin
• Clotrimazole troche
• Fluconazole

• Fluconazole
• Echinocandins

• Topicals agents (Miconazole, Clotrimazole)
• Fluconazole

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

• 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)

• Itraconazole

OR

• Posaconazole

OR

• Amphotericin B (IV if really serious)

• Itraconazole

OR

• Amphotericin B

• Itraconazole

OR

• Amphotericin B

• Topical azoles

OR

• Topical Allylamines (terbinafine, butenafine)

• 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

• Candida species
• Cryptococcus neoformans

• Aspergillus sp.
• Zygomycetes (Mucor, Rhizopus)

• Histoplasma capsulatum
• Blastomyces dermatitidis
• Coccidioides immitis