ID: Echinocandins, griseofulvin, Polyenes, Pyrimidine, Antifungals, Lamisil

fungal cell walls

Humans don’t have a cell wall, can target the fungi while minimizing likelihood of toxicities to patient being treated

• Parenteral!!
• Caspofungin (Cancidas)
• Anindulafungin
• (Eraxis)
• Micafungin (Mycamine)

• Fungal cells have both an outer cell wall and a cell membrane.
• Cell wall is thought to provide structural rigidity.
• Chitin & beta-1,3-glucan are responsible for the cell wall’s rigidity.
• Beta-1,3-glucan is synthesized via beta-1,3-glucan synthase
• Echincandins inhibit beta-1,3-glucan synthase so the cell wall is not as strong.
• This leads to cell lysis.

• Severe invasive fungal infections: 
• Candida (fungicidal)·        
• Aspergillus (fungistatic)

• common: diarrhea, N/V, fever, hypokalemia, HA, thrombocytopenia
• serious: anaphylaxis, hemolytic anemia, hepatotoxicity, renal impairment, sepsis

an antifungal used for dermatophytes

Griseofulvin

• Tinea: dermatophyte infections (Trichophyton, Microsporum & Epidermophyton) of the skin & hair
• when to use? When topicals don’t work

• Griseofulvin is deposited into keratin precursor cells (increases keratin resistance to fungal infection)
• Disrupts mitotic spindle
• Then it is taken up by fungal cells & binds to fungal proteins, including tubulin
• Tubulin is needed to separate dividing   chromosomes
• Thus, griseofulvin inhibits cell division in fungi

• Griseofulvin is a hepatic enzyme inducer; thus it reduces the half-life of other drugs metabolized by CYP3A4.
• Lots of interactions!!!
• Half-life is 24 hours

• Photosensitivity
• GI upset
• Headache
• Dizziness
• Rash
• Urticaria
• Confusion

• Porphyria
• Pregnancy
• Hepatic failure
• Caution if hypersensitive to penicillin

• Amphotericin B
• Nystatin

• Cholesterol, found in human cell membranes and ergosterol, found in fungal cell membranes, are examples of sterols.
• Polyenes bind sterols.  They bind ergosterol with higher affinity than cholesterol.
• Polyenes bind to ergosterol and create channels in the fungal membrane.
• Ions leak out of the channels, killing the cell
• Binding of polyenes  to cholesterol is responsible for the toxicities.
• The polyenes become integrated into the fungal membrane and pores are formed

less affinity

Serious invasive or systemic fungal infections

• Amphotericin B is frequently the only effective treatment available for potentially life-threatening fungal disease.
• In each case, its possible life-saving benefit must be balanced against its dangerous side effects.

• formulations are not bioequivalent!
• Amphotericin B salts
• Liposomal amphotericin:  this formulation incorporates the drug into small lipid vesicles
• Amphotericin B lipid complex (ABLC) : a non-liposomal formulation that complexes with two phospholipids

• Amphotericin has a long half-life  (15 days)
• It accumulates in and is slowly released from tissues

• Nephrotoxicity
• Infusion reactions*
• Electrolyte abnormalities

• Noninvasive candidal infections, including·         oropharyngeal thrush·  
• vaginal candidiasis·        
• intertriginous candidal infections

The yeast Candida Albicans can cause thrush

• Curd-like patches inside the mouth·        
• Oral thrush is common in babies, young kids, immunocompromised and the elderly

• Too toxic for parenteral administration
• Poor oral absorption
• Used topically and as an oral rinse (swish and swallow)

Flucytosine (Ancoban)

• Flucytosine interferes with DNA & RNA replication
• Flucytosine is transported in  to susceptible fungi by an enzyme called, cytosine permease, only present in fungi.
• Flucytosine is converted to 5-fluorouracil  (5-FU) which is then converted to  (5-FDUMP).
• 5-FDUMP is an irreversible inhibitor of thymidine synthetase needed for DNA replication.
• How does it block protein synthesis? Acts like an analog§  Blocks RNA and DNA synthesis

• Severe fungal infections ·        
• Nausea or vomiting may be reduced or avoided if the capsules are given a few at a time over a fifteen minute period.
• Flucytosine should be used in combination with amphotericin B due to the emergence of resistance to flucytosine

• Given orally; well absorbed
• Renal elimination; thus dosage adjustments required in renal impairment

renal impairment

• Cardiac arrest
• Respiratory arrest
• GI bleed
• Renal failure
• Bone marrow suppression
• Toxic epidermal necrolysis
• hepatotoxocity
• Common; chest pain, dyspnea, rash, N&V, abdominal pain, diarrhea

• Terbinafine (Lamisil)      
• Topical formulation (Lamisil AT)

• Remember, ergosterol is a component of the fungal cell membrane
• Terbinafene blocks the production of lanosterol via inhibition of sqaulene epoxidase.
• Results in a decrease in ergosterol production

• Fungal infection of the nails
• Tinea capitus
• Tinea pedis, tinea corporis & tinea cruris·         (usually topical)

• Metabolized by the liver
• Lipid soluble; distributes into nails, skin & fat
• Long half-life
• Avoid use is CrCl <50
• Avoid use in hepatic impairment

• Liver failure
• Stevens Johnson syndrome
• SLE exacerbation
• Psoriasis exacerbation
• Anaphylaxis
• Neutropenia
• Also; headache, fever, upper respiratory infection, cough, rash, dyspepsia

• Fingernails: 6 weeks
• Toenails: 12 weeks