Antifungal Chemotherapy

Front 1

Main classes of anti-fungal chemotherapies:

Back 1

*polyenes
*anti-metabolites
*azoles --> imidazoles and triazoles
*echinocandins
*miscellaneous

Front 2

Main components of the fungal cell:

Back 2

-Chitin, bilayer, ergosterol

*w/i bi-layer, ergosterol is the tgt for the POLYENES
*Ergosterol synthesis pathway is the tgt for the AZOLES.
*ß-(1,3)-glucan is tgt of inhibitors
*tgts are in cell wall and cytoplasm, not cell membrane

Front 3

Summary of Anti-fungals and their tgts:

Back 3

Front 4

What are the polyenes?
-general uses, locations, smell

Back 4

*Amphotericin B and Nystatin ; these are ANTI-BIOTICS

*Polyene macrolides produced by different strains of the gram-positive bacteria Streptomyces (of the group Actinobacteria or Actinomycetes).

*Streptomycetes are found predominantly in soil and in decaying vegetation, and most produce spores

*Streptomycetes are noted for their distinct "earthy" odor

Front 5

As far as route of administration, how do the polyenes differ?

Back 5

Amphotericin B = Systemic

Nystatin = Topical

Front 6

4 formulations of Ampho B:

Back 6

*Amphotericin B deoxycholate – Conventional (Amphocin®, Fungizone®)

*Amphotericin B Colloidal Dispersion (ABCD; Amphocil™ or Amphotec™)

*Amphotericin B Lipid Complex (ABLC; Abelcet™)

*Liposomal Amphotericin B (L-AMB; Ambisome™)

Front 7

Unique chemical structure of polyenes that makes them work:

Back 7

*both hydrophilic and hydrophobic portions in both ampho B and nystatin.

Front 8

Why don't polyenes kill us humans?

Back 8

*preferentially bind to ergosterol, vice cholesterol
*500x binding to ergosterol

Front 9

Mechanism of Action of polyenes:

Back 9

*Binds to membrane sterols, preferentially to the primary fungal cell membrane sterol, ergosterol
*Disrupts osmotic integrity of the fungal membrane by forming pores in the cell membrane thus resulting in leakage of intracellular potassium, magnesium, sugars, and metabolites leading to cellular death
*The affinity for ergosterol (in fungal membranes) is 500 times greater than for cholesterol (in mammalian cell membranes)

Front 10

Antifungal spectrum of POLYENE effectiveness. 8

Back 10

Candida albicans
Candida non-albicans
Aspergillus spp.
Cryptococcus neoformans
Coccidioides immitis
Histoplasma capsulatum
Blastomyces dermatitidis
Sporothrix schenckii

Front 11

What fungi will NOT respond to amphotericin B?

Back 11

*C. lusitaniae.

*C. glabrata and C. krusei have intermediate susceptibility.

Front 12

Different dosing for different forms of ampho B?

Back 12

*Big, important differences.

Front 13

Pharmacokinetics of Ampho B:

Back 13

*Give slowly iv (2-4 hr); 0.5-1.5 mg/kg/day; with D5W
*Large volume of distro; Cmax 2 ug/mL; T1/2- 24 hr
*Complex excretion: 5% excreted in urine unchanged; metabolites found in urine for up to 3 months
*No change in dose with renal or hepatic dysfunction

Front 14

Toxicity of Ampho B:

Back 14

*Most toxic antimicrobial in clinical use today
*Fever, N/V, anorexia, hypotension, electrolyte disturbances
*Anaphylactoid reactions, phlebitis, bone marrow toxicity
*Nephrotoxicity is a big concern.

Front 15

What are the major side effects of Ampho B?
How can you mitigate them?

Back 15

*Infuse over 2 to 6 hours, avoid rapid administration (hypotension, hypokalemia, arrhythmias, and shock can occur)

*Most commonly observed:
-Nausea and vomiting, most common, usually occurring between 15 min to 3hrs following the dose
-Infusion-related side effects are fever, chills & myalgia.
Partially overcome by premedication with diphenhydramine and/or acetaminophen

*Nephrotoxicity is the major adverse effect limiting use
-The manifestations of nephrotoxicity are azotemia, decreased glomerular filtration, loss of urinary concentrating ability, renal loss of sodium and potassium, and renal tubular acidosis.

Front 16

Why are the newer formulations of Ampho B good?

Back 16

*Amphotericin B traditional mainstay of antifungal therapy…but has changed..
*Its lipid formulations are promising due to their ability to reduce the toxicity of amphotericin B
*Lipid formulations are currently licensed for use when amphotericin B therapy fails or is unacceptably toxic. The use of lipid formulations in specific clinical settings is under continuing investigation
*All less nephrotoxic, more expensive, generally as effective as amphotericin B
*Systemic toxicity is less with Abelcet & Liposomal amphotericin B
*Primary indications - intolerance to amphotericin B and disseminated aspergillosis

Front 17

Back 17

Liposomal Amphotericin B (AmBisome®)

Front 18

LAMB Characteristics:
*how is it different than regular ampho B?

Back 18

*Incorporating AMB into a liposome alters the drug’s pharmacokinetic profile, but maintains its antifungal activity

*Lower volume of distribution and a reduced clearance than the conventional formulation
-Dramatic increase in Cmax and AUC (Cmax of 83 vs. 1.1)

*The liposomal formulation has a much larger therapeutic index, which allows for a higher dosage of AMB to be given

*The effect of the dramatic increase in Cmax and AUC in the clinical setting is still debated

Front 19

Describe resistance issues in Ampho B:

Back 19

*Resistance is rare either before or after treatment
*Usually due to decreased ergosterol levels in cell wall of fungi
*May occur in strains of Candida spp. and Aspergillus spp.
*Poor correlation between in vitro and in vivo results...means we don't always know what's going on.

Front 20

Discuss flucytosine (5-FC).
When/how is it used?
dosing?

Back 20

*oral antifungal agent
*resistance develops rapidly
*used mainly in combination with amphotericin B in the treatment of cryptococcal meningitis (25 mg/kg/day divided over four times daily)

Front 21

Discuss the MOA of flucytosine (5-FC):

Back 21

*Conversion to 5-FU (5-fluorouracil)
*In this form it inhibits DNA synthesis and PRO synthesis

*Side effects are NVD b/c it kills good bacteria in the gut.

Front 22

5-fluoro-cytosine--PK:

Back 22

*Available orally, 100% absorbed, inexpensive
*renally excreted, excellent CSF penetration (75% of blood levels
*short T ½ - 3-4 hr, Cmax-25-50ug/ml (monitor blood levels)
*Reduce dose with renal dysfunction

Front 23

5-fluoro-cytosine--toxicity:

Back 23

*GI side effects, hepatotoxicity
*Major toxicity-Bone marrow suppression-especially when given with amphotericin B and other nephrotoxic drugs
*Major limitation-rapid development of resistance in Candida, Cryptococcal infections [NEVER USE IN MONOTHERAPY]

Front 24

List the azoles:

Back 24

Ketoconazole
Clotrimazole (Lotrimin®)
Itraconazole (Sporanox®)
Fluconazole (Diflucan®)
Voriconazole (Vfend®)
Posaconazole (Noxafil®)

Front 25

List the imidazoles.
List the triazoles.
What's the structural ∆ b/t the two?

Back 25

*2 N atoms vs. 3
*Fluconazole frequently Rxd b/c it works against Candida

Front 26

What kinds of things do azoles work vs?

What is resistant to them?

Back 26

*Resistance to fluconazole in krusei
*glabrate is dose-dependent

Front 27

What is structurally significant about Itraconazole and Ketoconazole that affects their function?

Back 27

-They are bases and must be in the presence of an acid iot be ionized to be active.
-A ppi will cause big problems with its effectiveness.
-Take with apple sauce or Coke.

Front 28

MOA of the Azoles:

Back 28

Front 29

What's the relative occurrence of different Candida species in pts?

Back 29

*About half albicans, half non-albicans
*Important to know, b/c some drugs don't work on krusei, etc.
*Mostly see non-albicans in immunocompromised pts.

Front 30

Describe the effects of the azoles on the fungal cell membrane:

Back 30

Front 31

PK of the azoles:

Back 31

*Available orally, limited V/D
*hepatically metabolized; low CSF levels; (except fluconazole)
*long T ½ - 12-24 hr, requires gastric acidity for absorption
*Reduce dose with hepatic dys. - or renal dysfunction (for fluconazole)

Front 32

Toxicity of the azoles:
-major drug interactions?

Back 32

*GI side effects (10%), hepatotoxicity (<1%), skin eruption (5%)
*Major drug interactions – hepatic Cytochrome p450 metabolized drugs (keto>itra>vori>fluconazole)
*Inhibition of androgens, sterols
*Voriconazole-reversible visual changes (30%); acute delirium (1%)

Front 33

Drug of choice for aspergillosis?

Back 33

Voriconazole

Front 34

Azole interactions in the GI tract:

Back 34

*esp. CYP3A4

Front 35

Azole inhibitors of CYP P450:
What general effect do they have?

Back 35

*Turns off metabolism; causes drug to build up.
*More toxicity; more drug-drug interactions.
*Hard to predict the exact result in individual pts.

Front 36

Azole inducers of CYP P450:
What general effect do they have?

Back 36

*Most important one is Rifampin (in TB pts, staph infections).
*Turns on metabolism; causes drug to be broken down more quickly; means you must dose higher.
*VERY significant reductions in levels of azoles.

Front 37

List a shite-ton of drugs that may be affected by CYP 450 metabolism:

Back 37

Front 38

How do fungi become resistant to azoles?

Back 38

*efflux pumps -- MIC (minimum inhibitory concentration) increases slightly (slight resistance)

Front 39

What sites on the fungal cell membrane are sites for resistance to azoles?

Back 39

Front 40

What all is Fluconazole effective against? What is it NOT effective vs?

Back 40

Front 41

What is Vorizonazole good vs?

What is its MOA?

Back 41

*works vs C. lusitaniae when AMB doesn't*

Front 42

What are the Echinocandins? What do they inhibit?

Back 42

Caspofungin (Cancidas®)
Mycofungin (Mycamine®)
Anidulafungin (Eraxis®)

*Beta-glucan inhibitors

Front 43

Where in the fungal cell membrane do echinocandins work?

Back 43

Front 44

What is Caspofungin effective vs?
Dosing?
Effect on P450?

Back 44

*Activity against most species of Aspergillus and Candida
*Use: Aspergillosis in amphotericin intolerant patients (and itraconazole failures) well tolerated in early clinical trials – Dose 70mg loading: 50mg IV/day, disseminated candidiasis (as effective as Amphotericin B – less toxic).
*Minimal renal excretion; modest hepatic metabolism and excretion (decrease dose with moderate-severe liver disease).
*No effect on cytochrome P 450 system.

Front 45

PK summary of Echinocandins:

Back 45

*IV only
*Anidulafungin in pts with bad livers.
*Urinary excretion can be a concern in UTI pts.

Front 46

What all do Caspofungins work vs?

Back 46

*Shows fluconazole doesn't work vs glabrata and krusei; but Caspofungins do.

Front 47

Indications for caspofungin Rx:

Back 47

*Micafungin and Anidulafungin now available-for candidiasis
*Caspofungin: Candidiasis and invasive aspergillosis

*PK/PD: iv only, hepatic excretion, no effect on cytochrome P450 enzymes, dose at 70 mg loading and 50 mg iv daily

Front 48

Adverse reactions and drug reactions for caspofungins:

Back 48

*Decrease dose for severe liver disease (35mg/day)
*Side effects allergy (rare), drug interactions with cyclosporin A
*Rifampin increases hepatic excretion- increase dose to 70 mg/day; consider increasing dose for other enzyme inducers-efavirenz, nevirapine, phenytoin, dexamethasone

Front 49

How does the SE profile of the caspofungins compare to that of AMB?

Back 49

*caspofungin is similar to all the other Echinocandins in its SEs.

Front 50

Summary of all the echinocandins' effectiveness against species of both aspergillus and candida:

Back 50

Front 51

Discuss Terbinafine:
-how does it work
-metabolism
-indication?

Back 51

*Lamisil
*Allylamine- inhibits egrosterol synthesis at squalene epioxidase
*hepatically metabolized by not CYP450 dependent; Long T ½ -24-36 hr, orally adminisitered at 250 mg/day
*Primary indication: onychomycosis-12 wk- toes-6 wk fingers

Front 52

Discuss Iodines in antifungal therapy:
indications
SE profile

Back 52

*SSKI-still used for lymphocutaneous forms of sporotrichosis
*Side effects-bronchorrhea, drooling, acne, thyroid disturbances
*Start with 1 cc in Juice TID-increase to 4 cc TID as tolerated
*Itraconazole has largely replaced SSKI-remains inexpensive alternative

Front 53

Breakdown of Preferred treatments for Systemic Mycosis by fungus type in Standard and Compromised Pts:

Back 53