Details of Amphotericin B

MOA?

Resistance?

SOA?

PK?

Adverse Reactions?

Lipid Formulations?

*An Amphoteric Polyene macrolide

- Binds to membrane sterols (ergosterol in fungals); Lanosterol is converted to ergosterol in fungals, cholesterol in humans.  Forms amphotericin pores in the cell wall to increase permeability

- Resistance is by replacement of ergosterol with another sterol derivative

- SOA is systemic infectinos of Candida or aspergillis for Skin, GI, or respiratory infections

- Given IV suspension with slow infusion, poorly penetrates CNS, but can penetrate CNS if given intrathecally; excreted slowly by kidneys

- Adverse reactions include headache, nausea, vomiting, weight loss, phlebitis.  Flu-like symptoms (must discontinue use).  Impaired renal function by decreasing GFR with vasoconstriction of aff. arteriole.  Increases compounds with Nitrogen in the blood.  Anemia

- Fungiosome Deoxylate ($24/day) - all comparisons made to this.

- Ambisome; increase [blood], decrease nephrotox, decrease infusion tox, $1300/day

- Aspergillis, candida, and Cryptococcus Amphotec - decrease [blood], decrease nephrotox, increase infusion tox, $660/day

- Abelcet; No change in [blood], decrease nephrotox, increase infusion tox, $570/day

*Block fungal lipid biosynthesis by interfering with fungal P450 that catalyzes production of ergosterol (ERG-11 gene).  Mutation of in these leads to resistance.

Fluconazole, Itraconazole, Ketoconazole, Clotrimazole

Details of Fluconazole:

Administration?
PK?

SOA?

Adverse effects?

- Can be administered orally or IV, oral administration not affected by food.

- Widely distributed, including the CNS

- Excreted by kidneys

- Treatment for cryptococcal meningitis and candida

- Teratogen

- Causes nausea and vomiting

- Inhibits activity of human CYP450

Details of Itraconazole:

Administration?

PK?

Adverse effects?

- Can be administered orally or IV (should avoid antacids, PPI's, and H2 antags)

- 99% bound to plasma protein

- No CNS penetration

- Treatment for candida, histoplasma, and aspergillis

- IV can lead to phlebitis

- oral can lead to nausea/vomiting

- Inhibits activity of CYP450

- Rifampin, carbamezapine, and phenytoin increase metabolism of itraconazole

Details of Ketoconazole:

Administration?

PK?

Side effects?

- Can be administered orally (Avoid anti-acid meds)

- Extensively metabolized by liver

- Affects human steroid molecules (testosterone), can lead to gynecomastia in males and menstrual irregularities in women.

- Rifampin and Phenytoin increase metabolism of this drug

- Inhibits metabolism of cyclosporine, indinavir, and midazolam

- Known teratogen

- Secreted in breast milk

- Administered orally to treat pharyngeal candida

- Administered topically to treat vginal candidiasis

Details of Flucytosine:

MOA?

Resistance?

PK?

Adverse reactions?

* Selective for permease in fungal cells (to penetrate) and cytosine deaminase

- Prevents thymidylate synthase from converting dUMP to dTMP

- Resistance is decrease in permease, or UMP phosphorylase.

- Orally effective, widely distributed, excreted by kidneys, synergistic with azoles

- Adverse reactions include elimination of GI tract bacteria, BONE marrow toxicity (anemia, leucopenia, thrombocytopenia)

Details of Griseofulvin:

MOA?

PK?

SOA?

Adverse effects?

- Inhibits fungal cell mitosis (Static effect) by binding microtubules

- Orally effective, absorbed better with McDonald's

- Excreted as metabolite by kidney

- Treatment for hair, skin, and nail infections (Long term 6-12 months)

- Induces CYP450

- Nausea, vomiting, headache, leucopenia

Details of Caspofungin:

MOA?

PK?

SOA?

Adverse effects?

- Blocks B1 and 3D glucan to weaken cell wall

- Only given IV

- Highly metabolized by hydrolysis and acetylation

- Excreted in bile and kidneys

- Treatment for aspergillis in those that don't respond or can't amphotericin B

- Fever, phlebiitis, nausea, vomiting, headache

Details of Terbinafine:

MOA?

PK?

SOA?

Adverse effects?

- Inhibits squalene epoxidase to prevent cells from making ergosterol

- Orally effective but high first pass effect

- Accumulates in fat cells

- Not for use in people with kidney or liver disease

- GI irritation, headache, rash

- Treatment for skin or nail infections

- Rifampin increases metabolism of terbinafine

- Cimetidine inhibits metabolism of terbinafine