MYCOSES ARE DIVISIBLE INTO TWO CATEGORIES

(4)

• SUPERFICIAL: MILD & FREQUENT (LATER)
•  DEEPER FUNGAL INFECTIONS
•  *SERIOUS, OFTEN SYSTEMIC, & INFREQUENT
•  *CAN EVEN BE LIFE-THREATENING ESP. FOR AIDS PATIENTS (*27% MORTALITY IN PATIENTS WITH FUNGAL SEPTICEMIA!!!

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PATTERN OF #1 DRUG USE FOR SYSTEMIC FUNGAL INFECTIONS

(9)

• *Ampho B alone for serious infections (9/3)
•  **Ampho B plus flucytosine for Cryptococcus
•  *A newer azole generally for milder infections
•  itraconazole (6/4),
•  fluconazole (5/2),
•  voriconazole (3/1)
•  posaconazole (0/3)
•  **Flucytosine alone #1 for Chromoblastomycosis or #2 for urinary candidiasis
•  **Septra alone only for Pneumocystis pneumonia
•  

Amphotericin B

General

(5)

• *Unsaturated chromophore  photooxidation
• *Large lipophillic region  ↓↓ water solubility
• **Mechanism: attaches to sterols & opens 4-5 A pores.
• **Fungistatic at low concs, fungicidal at high concs.
• **Specificity is due to difference in membrane sterols (i.e., cholesterol in man vs. ergosterol in fungi, algae, & protozoa).

Need pic

Amphotericin B

RX Uses

(9)

• **Mainstay reserved for only the most serious systemic fungal infections
•  **Also used x some parasitic infections:
•  1st  x  of primary amebic         meningoencephalitis
•  2nd  x  American cutaneous or mucocutaneous leishmoniasis
•  **2nd for chronic suppression of      Histoplasmosis or Cryptococcus in AIDS pts
•  ** Only used with flucytosine x Cryptococcus at 1/3-1/2 full dose because combo is less toxic
• *1 mg IV initial test dose is used to assess sensitivity to acute infusion reactions.
• *Hospital stay is 6-12 wk with daily infusions
• **However, it is only needed once weekly for chronic suppression of Histplasmosis of Cryptococcus (0.5-1 mg/kg IV)

ABDE of Fungizone: The Orginial Prototype

(5)

• **Fungizone is a colloidal suspension in 5% dextrose with sodium deoxycholate.
•  **Must be given IV or IT: other routes <5% absorption
•  **90-95% bound to cholesterol or lipoproteins which suggested new lipid-associated drug forms.
•  **Doesn’t cross BBB well
•  *Excreted slowly as inactive metabolites by kidneys so no change is needed for ↓ renal function **if given alone.

**Toxicities of Fungizone
Depend Greatly on the Route

 (5)

• Topical: irritation
•  Oral: n/v/d (*NB: one uses a related drug (Nystatin) if given orally)
•  IV: n/v/d + *chills & fever (50%), **nephrotoxicity (80%), headache, hypotension, & rapid breathing
•  IT: *UNIQUE CNS-RELATED TOXICITIES: headache, n/v, radiculitis, paresis, paresthesias, visual impairment
•  *Pregnancy Risk Classification =        B (all amphotericins)
•  

How to Assess Teratogenic Risk

FDA Ratings Picture

How to Assess Teratogenic Risk

Approximate % Decrease in Classes

(5)

A:  Multivitamins  (0.7%)

 B:  Acetaminophen, all Ampho-tericins  (19%)     

 C:  Beta Blockers, Atropine, Ketoconazole, Flucytosine (66%)

 D:  Phenytoin , Tretinoin (systemic), Ethanol (light drinker) (7%)

 X:  Thalidomide,  Alprazolam,  Isotretinoin, Conjugated Estrogens, Valproate, Atorvastatin (7%)

Toxicities of Fungizone

IV and IT

(1)

IV and IT are poorly tolerated by many even at low doses.  How poorly tolerated?

Toxicities of Fungizone

Nephrotoxicity

(5)

• **Nephrotoxicity is often the limiting factor in determining duration of Rx.
• *Na+ loading with normal saline lessens this effect if pts can tolerate the fluid load.
• *NT is due to increased plasma membrane permeability in kidney.
• *NT is reversible up to total dose of 4 gm.
• *A kidney workup is required prior to Rx.

Commercially Available Amphotericin Drugs

(4)

Lipid Ampho B Prep Summary

**Overall Comparison to Fungizone

(9)

• All still have to be administered IV
•  All are at least as effective as fungizone
•  All have the same spectrum as fungizone
•  Nephrotoxicity is generally less common & less severe
•  All are pregnancy safety rating B (but Ambisome is known    to cause a higher spontaneous abortion rate in rabbits)
•  All are much more costly (13-38X that of fungizone; $10/day) but you might avoid:
•  acute renal failure,
•  a prolonged hospital stay and great expense
•  possible death

Lipid Ampho B Prep Summary

**Ambisone

(4)

• **Ambisome (Liposomal amphotericin B) (prob. best)
•  Nephrotoxicity is lowest or near lowest (ca 50% less freq.)
•  Acute infusion-related reactions are least severe
•  Overall probably one of the best but it is the most expensive.

Flucytosine

Mechanism

(6)

• 5-Fluorocytosine is converted to 5-fluorouracil by cytosine deaminase
• **This enzyme is lacking in humans
• 5-fluorouracil is converted to 5-FUMP
• 5-FUMP is converted by thymidylate synthetase
• Flucytosine inhibits thymidylate synthetase causing the fungistatic result

Flucytosine

*Major Limitations

(4)

• Resistance can occur during Rx
• Must adjust for renal function as primarily excreted unchanged by glomerular filtration
• Normal,  t½ = 3-4 hr; with renal failure,  t½ = 200 hr
• If used with ampho B, remember amphoB is nephrotox

Flucytosine

*Major Toxicities

(5)

• Less common if <100 µg/ml
• Potentially lethal dose-related bone marrow depress.
• Enterocolitis with severe diarrhea (esp. freq. in combo with ampho B)
• Rare CNS effects: headache, vertigo, confusion, hallucinations
• Pregnancy risk rating = C

Flucytosine

** Clinical Uses

(3)

• Monotherapy x Chromoblastomycosis (1^st choice)
• Monotherapy x urinary candidiasis (alternate)
• Used with ampho B x Cryptococcus especially for meningitis in AIDs patients (it is super additive and faster)

Systemic Azoles

(5)

• ITRACONAZOLE
• FLUCONAZOLE
• VORICONAZOLE
• POSACONAZOLE
• KETOCONAZOLE (**Little used prototype)

Properties Common to all Azoles

(4)

• ** they inhibit 14-α lanosterol demethylase, a fungal microsomal CYP needed for ergosterol biosynthesis
• ** Low concentration = fungistatic
• ** High concentration = fungicidal
• **They have very broad antifungal spectra

Properties Common to all Azoles

** They Have Very Broad Antifungal Spectra

(8)

• ** Azoles encounter little fungal resistance
• Except for zygomycetes
• e.g, Mucor
• *Only Tx with Posaconazole

Properties Common to all Azoles

Resistance

(4)

• ** Azoles encounter little fungal resistance
• Except for zygomycetes
• e.g, Mucor
• *Only Tx with Posaconazole

Properties Common to all Azoles

Selectivity

(4)

• **Azoles aren’t completely selective for fungi over man
• ** The azoles cause mnay drug interactions
• ** All can inhibit one or more human liver CYPs which can increase the concentration of many other drugs
• **Conversely, use with some non-azole drugs can either increase or decrease the concentration of an azole

Properties Common to all Azoles

Drug Interactions

(13)

• *Major effects are underlined; in order of strength in table
• Itraconazole  
• Metabolized by & inhibits CYP3A4
• Fluconazole   
• Inhibits CYP2C9 + CYP2C19 + CYP3A4 + CYP1A2 (weak);
• most cleared in urine unmetab.
• Voriconazole 
• *Metabolized by and inhibits CYP2C19 (genetic polymorphism) + CYP2C9 + CYP3A4
• Posaconazole
• Inhibits CYP3A4 (not significantly metabolized)
• Ketoconazole
• Metabolized by CYP3A4;
• Inhibits CYP1A2 + 2C9 + 2A6 + 2C19 + [weak: 2B6 + 2C8] + [human sex, corticosteroid enzymes]

Properties Common to all Azoles

Drug Interactions

Itraconazole

(1)

Metabolized by & inhibits CYP3A4

Properties Common to all Azoles

Drug Interactions

Fluconazole

(6)

• Inhibits
• CYP2C9
• CYP2C19
• CYP3A4
• CYP1A2 (weak);
• Most cleared in urine unmetab. 

Properties Common to all Azoles

Drug Interactions

Voriconazole

(4)

• *Metabolized by and inhibits
• CYP2C19 (genetic polymorphism) CYP2C9
• CYP3A4

Properties Common to all Azoles

Drug Interactions

Posaconazole

(1)

Inhibits CYP3A4 (not significantly metabolized)

Properties Common to all Azoles

Drug Interactions

Ketoconazole

(8)

• Metabolized by CYP3A4
• Inhibits
• CYP1A2
• CYP2C9
• CYP2A6
• CYP2C19
• weak: CYP2B6 + CYP2C8
• human sex, corticosteroid enzymes

Properties Common to all Azoles

Drug Interactions

Take Home Lesson

When using an azole, carefully look for possible drug interactions with other medications!!

Properties Common to all Azoles

Topical and Oral

(4)

• **When given topically or orally, all azoles have some capacity to be teratogenic and/or embryotoxic. 
•  *Oral voriconazole is pregnancy risk class D so there is clear evidence for human damage.
•  *All other azoles are pregnancy risk class C.
•  **Ampho B is preferred in pregnant women.
•  

Properties Common to all Azoles

**Major Therapeutic Advantages of the Newer Azoles Over Ampho B +/- Flucytosine

(3)

• better tolerated than amphoB or flucytosine
• can be given orally rather than IV
• hospitalization isn’t required
•  

Itraconazole (Sporanox)

(6)

• **1st choice for treatment and/or chronic suppression of histoplasmosis in AIDS patients
•  **Used for oral Rx of onychomycoses (a dermatophyte)
•  *Powder in capsules is dependent on gastric acidity for absorption (like ketoconazole); in contrast, the drug solution is more bioavailable on an empty stomach.
•  *Little itraconazole gets into:
•  the CSF (so don’t use it for meningitis)
•  the urine (so don’t use it for fungal UTIs) 

Itraconazole (Sporanox)

Toxicities

(4)

• Generally well tolerated but
• n/v & abdominal discomfort (10-15%),
• headache (4%),
• *rash (11% poss. including Stevens-Johnson Syndrome)
• *IV itraconazole has *cyclodextrin which accumulates in patients with reduced renal function.

Itraconazole (Sporanox)

Contraindicated

(6)

• *Contraindicated in pts with
• ventricular dysfunction; 
• can cause hypocalcemia,
• edema,
• hypertension,
• reduced myocardial function

Fluconazole (Diflucan)

Rx Uses

(6)

• **Agent of choice for chronic suppression of:
•  Cryptococcal infections in immunocompromised pts
•  Systemic or vaginal candidiasis
•  Recurrent candidiasis in HIV patients
•  **Used for both Cryptococcal & Coccidiodial meningitis because it gets into CSF so well
•  **Used in a single dose for vaginal yeast infections (perhaps the most common use for Diflucan)

Fluconazole (Diflucan)

ABDE

(7)

• **Its PK properties are equivalent after oral or IV administration so gastric acidity is not important for fluconazole.
•  **Given only once per day because t½ = 30 hr.
•  **80% appears in urine unchanged; little metabolism by CYPs; flu- just inhibits them.
•  **Widely distributed throughout body with      Vd equal to total body water.   *Drug concentrations relative to plasma:
•  saliva = 1,
•  *CSF = 0.5-0.9,
•  *urine & skin = 10

Fluconazole (Diflucan)

Toxicities

(7)

• Fluconazole is generally well tolerated.
• Most Common Adverse Effects:
• Headache,
• GI problems (2-4%; dry mouth, N/V/D),
• *skin rash (2%) with possible Stevens-Johnson Syndrome.
•  **Rarely causes prolongation of QT intervals
• Rarely causes abnormal liver function.

Voriconazole (VFEND)

(4)

• **Modified fluconazole with a spectrum similar to that of itraconazole.
•  **Its most important Rx use is against potentially lethal invasive aspergillosis; even better than ampho B for this app.
•  **Very active against Fusarium spp (best azole).
•  **Important as “salvage therapy” x Scedosporium or Fusarium

Voriconazole (VFEND)

ADME

(4)

• *Like fluconazole:
• **Unique among azoles in that it:
• Dosage adjustment is:
• *Like itraconazole

Voriconazole (VFEND)

ADME

*Like fluconazole:

(3)

• PK properties are identical after oral or IV admin.
• Gastric acidity isn’t needed for absorption.
• Excellent tissue distribution (Vd = 4.6 L/kg)

Voriconazole (VFEND)

ADME

**Unique among azoles in that it:

(5)

• Is primarily metabolized by CYP2C19.
• Exhibits genetic polymorphisms.  
• 15-20% of asians and 
• 3-5% of caucasians or blacks are slow metabolizers; 
• therefore, they can have 4x higher systemic concentrations of vori-.

Voriconazole (VFEND)

ADME

Dosage adjustment is:

(2)

• *Needed in pts with mild/moderate cirrhosis (because slow metabolizers)
•  *Not needed in pts with poor renal function as <2% is excreted in urine.

Voriconazole (VFEND)

ADME

*Like Itraconazole

(1)

IV Vfend contains cyclodextrin which builds up in pts with reduced renal 

Voriconazole (VFEND)

Toxicity

(8)

• **Unique Visual Changes are frequent (30%) but transient.
•  Blurred vision,
•  Photophobia,
•  Altered color or image perception. 
•  If the patient perceives vision change:
•  Shouldn’t drive at night
•  Shouldn’t engage in any hazardous task
•  *Photosensitivity, rash (6%)

Voriconazole (VFEND)

Toxicity

**Rare

(3)

• Stevens-Johnson Syndrome (like fluconazole)
• Hallucinations,
• confusion (like flucytosine)

Voriconazole (VFEND)

Toxicity

Pregnancy

(1)

**Pregnancy Risk Factor = D

Posaconazole

General

(5)

• Newest
• **Similar in structure and antifungal spectrum to itraconazole but more potent.
•  *Similar in adverse effects to fluconazole.
•  **Unique among azoles in that it must be taken with    high-fat meals for adequate absorption (like griseofulvin)
•  *Primarily eliminated in feces & urine (less) with little metabolism so only inhibits CYPs.

Posaconazole

Rx Uses

(6)

• **Only azole that is active against Zygomycetes (e.g., Mucor). 
• Ampho B is the best alternate.
• **Approved for antifungal prophylaxis:
• Of invasive Aspergillus and Candida
• In pts with leukemia to prevent mycoses
• **Has been used successfully to treat refractory mycoses

A New Antifungal Drug Class

(7)

• The Echinocandins
• Drugs
• Caspofungin (Cancidas)
• The prototype
• Micafungin (Mycamine)
• Anidulafungin (Eraxis)
• The newest
•  

Overview of Echinocandins

All are Very Similar in that:

(8)

• **All block synthesis of B(1,3)-D-glucan  (a fungal cell wall component) which explains their selectivity.
•  **Once-daily IV preps with very similar efficacies & toxicities.
•  *Their clearance is by hydrolysis and N-acetylation followed by excretion in urine & feces; t1/2 is ca 10 hr. 
•  Mild/moderate hepatic insufficiency increases the AUC by 55-76%.
•  *All are generally well tolerated but adverse effects incl. phlebitis at injection sites, anaphylaxis, hemolysis, (N/V/D, rash,…).
•  **All are embryotoxic/teratogenic in animals; preg. risk factor  = C)
•  **They are first-place drugs for Tx of oral/esophageal or systemic candidiasis; often useful even if fungi are resistant to azoles.
•  **Useful as alternates for Tx of invasive Aspergillosis.

Overview of Echinocandins

One Unique Function

(2)

• **One unique function of micafungin (Mycamine): 
• FDA-approved as an alternative for prophylaxis of invasive Candida infections in patients undergoing hematopoietic stem cell transplantation (HSCT).
•  

Ketoconazole

General 

(2)

• **This prototypic azole is a cheap alternative but has now been almost  replaced by itra-, flu-, posa- or voriconazole.
• *Only occasionally used as an alternate for candidiasis & for Paracoccidioides

Ketoconazole 

Toxicities

(8)

• **Unique in that it causes a dose-dependent decrease in [testosterone] and [estrogen] resulting in:
• oligospermia,
• gynecomastia,
• loss of libido,
• loss of potency, and, in women,
• menstrual irregularities.
• **Unique in that high doses cause a dose-dependent decrease in [corticosteroid]
• *Commonly causes anorexia, N/V; less likely if taken with food or at bedtime.