ANTIFUNGALS Flashcards
TYPES OF FUNGAL INFECTIONS
• Fungal infections can be classified according to the initial site of infection.
• Superficial mycoses: affect skin, mucous membranes, hair, and nails. The main infections in this group are the dermatophytoses and superficial forms of candidiasis.
• Subcutaneous mycoses: affect the dermis, subcutaneous tissues and adjacent bone.
• Systemic mycoses: affect internal organs.
–> are the most difficult to treat, they are often life-threatening
–> 3 most common systemic fungal infections are:
- CANDIDIASIS
- CRYPTOCOCCIS
- ASPERGILLOSIS
ANTIFUNGAL DRUGS
Fungi are eukaryotic. Because of their phylogenetic similarity, fungi and humans have homologous metabolic pathways for energy production, protein synthesis, and cell division. Consequently, there is greater difficulty in developing selective antifungal agents than in developing selective antibacterial agents.
The fungal cell membrane contains ERGOSTEROL rather than the cholesterol found in mammalian membranes. This chemical characteristic has been exploited in the development of antifungal agents.
The last two decades have seen a rise in the incidence of fungal infections. Candidemia is now the fourth most common cause of septicemia.
The increased incidence of fungal infections is associated with greater numbers of individuals who are immunosuppressed:
- undergoing cancer chemotherapy,
- following organ transplant, or
- infected with HIV.
DRUGS THAT ALTER CELL MEMBRANE PERMEABILITY
1) Polyenes
Amphotericin B
Nystatin
2) Azoles
Ketoconazole
Fluconazole
Itraconazole
V oriconazole
Posaconazole
Clotrimazole
Miconazole
3) • Allylamines
Terbinafine
AMPHOTERACIN B
MOA
SYSTEMIC DRUG FOR SUBCUTANEOUS + SYSTEMIC MYCOSES
MECHANISM OF ACTION
-Amphotericin B is selective in its fungicidal effect because it exploits the difference in lipid composition of fungal and mammalian cell membranes. Ergosterol, a cell membrane sterol, is found in the cell membrane of fungi, whereas the predominant sterol of bacteria and human cells is cholesterol.
Amphotericin B binds to ergosterol, forming pores in the cell membrane. The pores allow leakage of intracellular ions and macromolecules, leading to cell death.
Some binding to human membrane sterols does occur, probably accounting for the drug’s prominent toxicity.
AMPHOTERICIN B: ANTIFUNGAL ACTIVITY
+ PK
Antifungal agent with the BROADEST SPECTRUM of action.
It has activity against the clinically significant yeasts, including Candida albicans and Cryptococcus neoformans; the organisms causing endemic mycoses, including Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis; and the pathogenic molds, such as Aspergillus fumigatus and mucor.
PK:
Amphotericin B is highly insoluble: formulated as deoxycholate colloidal suspension.
Poorly absorbed from the GItract.
Must be given IV.
PenetrationintotheCSFisextremelylow.
Intrathecaltherapymaybenecessaryfor meningeal disease.
AMPHOTERICIN B USES:
• Due to its broad spectrum of activity and fungicidal action, amphotericin B remains a useful agent for nearly all life-threatening mycotic infections, although newer, less toxic agents have largely replaced it for most conditions.
Amphotericin B is the drug of choice for mucormycosis, cryptococcal meningitis, histoplasmosis, blastomycosis, coccidioidomycosis, extracutaneous sporotrichosis, fusariosis, and other severe systemic fungal infections.
Amphotericin B is often given to selected patients with profound neutropenia who have fever that does not respond to broad-spectrum antibacterial agents over 5-7 days.
Amphotericin B is ***_often used as the initial induction regimen in order to rapidly reduce fungal burden****_ and is then replaced by one of the newer azole drugs for chronic therapy or prevention of relapse.
Such induction therapy is especially important for immunosuppressed patients and those with severe fungal pneumonia, severe cryptococcal meningitis, or disseminated infections with one of the endemic mycoses.
Once a clinical response has been elicited, these patients then often continue maintenance therapy with an azole; therapy may be lifelong in patients at high risk for disease relapse.
For treatment of systemic fungal disease, amphotericin B is given by slow IV infusion.
Amphotericin B is the preferred treatment for deep fungal infections during pregnancy.
AMPHOTERACIN B ADVERSE EFFECTS
INFUSION-RELATED TOXICITY
• Nearly universal . Fever and chills, muscle spasms, vomiting, headache and hypotension.
Can be attenuated by slowing infusion rate or decreasing daily dose.
Pre-medication with antihistamines, glucocorticoids, antipyretics or meperidine can be helpful.
AMPHOTERACIN B
SLOWER TOXICITY
Amphotericin B also binds to cholesterol and forms pores in mammalian cell membranes, leading to leakage of cytoplasmic contents and cell death, which results in renal toxicity.
Renal impairment occurs in nearly all patients.
Azotemia occurs in most patients. Patients may exhibit a decrease in glomerular filtration rate and renal tubular function.
Renal toxicity commonly presents with renal tubular acidosis with severe magnesium and potassium wasting.
Renal damage can be attenuated with sodium loading: it is common practice to administer saline infusion with the daily doses of amphotericin B.
Abnormalities of liver function tests occasionally seen.
Hypochromic normocytic anemia, due to reduced erythropoietin production by damaged tubular cells.
Intrathecal administration can cause seizures and serious neurological damage.
Renal function should be monitored frequently during amphotericin B therapy. It is also advisable to monitor on a regular basis liver function, serum electrolytes (particularly magnesium and potassium), blood counts, and hemoglobin concentrations.
AMPHOTERACIN B: LIPID FORMULATIONS
Attempts to reduce nephrotoxicity have led to the development of lipid formulations of amphotericin B for IV infusion.
The strategy is to package amphotericin B in lipid carriers in order to prevent high drug exposure to the proximal tubule of the nephron.
1) Liposomal amphotericin B (L-AMB),
2) Amphotericin B lipid complex (ABLC), and
3) Amphotericin B colloidal dispersion (ABCD)
–> are the three FDA-approved lipid formulations of amphotericin B.
NEPHROTOXICITY IS LESS COMMON + LESS SEVERE with these lipid formulations
FLUCYTOSINE
MOA
SYNTHETIC PYRIMIDINE ANTIMETABOLITE
MECHANISM OF ACTION
Taken by fungal cells via the enzyme ***_cytosine permease.****_
Converted intracellularly first to 5-fluorouracil (5-FU) and then to 5-fluorodeoxyuridine monophosphate (5-FdUMP) which inhibits thymidylate synthetase, thus blocking synthesis of dTMP.
–> the DUMP inhibits the thmidylate synthetase
Fluorouridine triphosphate (5-FUTP) is also formed, which inhibits protein synthesis.
–> FU Protein, says the FU(t)P
Mammalian cells are unable to convert the parent drug to its active metabolites.
Combination of flucytosine and amphotericin B is synergistic.
FLUCYTOSINE
SPECTRUM
NEVER PLAY THE FLUTE ALONE!!!
- FungiSTATIC
- Narrow spectrum.
Not used as a single agent because of its demonstrated synergy with other agents and to avoid the development of secondary resistance.
FLUCYTOSINE
USES
fluCytosine –> Candida, Cryptococcus
Indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus.
Should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis in order to avoid the emergence of resistance.
FLUCYTOSINE
AE
- Result from metabolism (possibly by intestinal flora) to the toxic antineoplastic compound 5-fluorouracil.
- Bone marrow toxicity with anemia, leukopenia, thrombocytopenia are the most common adverse effects.
- Derangement of liver enzymes is less frequent.
- Toxic enterocolitis can occur.
AZOLES
KINDS?
The relatively nontoxic oral azole drugs were introduced in the 1980s and since then have played an increasingly important role in the systemic therapy of fungal disease.
Synthetic compounds, that are fungiSTATIC
Classified as imidazoles or triazoles.
IMIDAZOLES = MCK
1) KETOCONAZOLE
2) MICONAZOLE
3) CLOTRIMAZOLE
TRIAZOLES
1) ITRACONAZOLE
2) FLUCONAZOLE
3) VORICONAZOLE
4) POSACONAZOLE
AZOLES
MOA
Inhibit fungal sterol (ergosterol) synthesis by inhibiting the cytochrome P-450 enzyme that converts lanosterol to ergosterol. = 14α-sterol demethylase!!!!
The fungus-specific cytochrome P450 enzyme 14α-sterol demethylase catalyzes the conversion of lanosterol to ergosterol.
–> Azole antifungal drugs inhibit 14α-sterol demethylase, thus reducing ergosterol synthesis. This disrupts membrane function and increases permeability.
Specificity of azole drugs results from their greater affinity for fungal than for human P450 enzymes. Imidazoles are less specific than triazoles, accounting for their higher incidence of drug interactions and side effects.
AZOLES:
AE
Relatively nontoxic.
Most common adverse reaction: minor gastrointestinal upset.
May cause abnormalities in liver enzymes.
Very rarely: clinical hepatitis.
KETOCONAZOLE
is an IMIDAZOLE
KETO anyone’s heart = TITTIES –> causes gynecomastia –> not used anymore because it inhibits liver enzymes (cytochrome p450)
–> best absorbed at LOW PH (keto my heart is to get on your knees)
First oral azole introduced into clinical use. Now seldom used as systemic agent. The other azoles have fewer adverse effects and are generally preferred.
Inhibits mammalian cytochrome P450 enzymes.
Can decrease plasma testosterone levels and cause gynecomastia, decreased libido and loss of potency in men and menstrual irregularities in women.
High doses may inhibit adrenal steroid synthesis and decrease plasma cortisol concentrations.
Strong inhibitor of CYP3A4. It can potentiate the toxicities of several drugs such as warfarin and cyclosporine.
Best absorbed at low gastric pH: antacids, H2 blockers or proton pump inhibitors interfere with absorption of ketoconazole.
Poor penetration in the CSF.
KETOCONAZOLE
USES
-d/t its narrow spectrum and AE, is rarely used for systemic mycoses, but is STILL USED FOR SUPERFICIAL MYCOSES
FLUCONAZOLE
FLUCONAZOLE –> is a FLU –> it enters the CNS really well –> is used for CRYPTOCOCCAL MENINGITIS
–> DOC for CANDIDA + MOST COCCIDIOIDES
–> has the WIDEST THERAPEUTIC INDEX out of all azoles
Good CSF penetration.
Unlike ketoconazole and itraconazole, its oral bioavailability is high.
Available in oral and IV formulations.
Moderate inhibitor of CYP3A4.
Strong inhibitor of CYP2C9: can increase plasma levels of phenytoin, zidovudine and warfarin.
Because of fewer hepatic enzyme interactions and better gastrointestinal tolerance, fluconazole has the widest therapeutic index of the azoles, permitting more aggressive dosing in a variety of fungal infections.
Renal excretion accounts for over 90% of elimination.
WHICH AZOLE REACHES THE HIGHEST CONCENTRATION IN THE CSF?
FLUCONAZOLE
