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:
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
3) • Allylamines
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
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.
Amphotericin B is highly insoluble: formulated as deoxycholate colloidal suspension.
Poorly absorbed from the GItract.
Must be given IV.
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
• 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.
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
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.
NEVER PLAY THE FLUTE ALONE!!!
Not used as a single agent because of its demonstrated synergy with other agents and to avoid the development of secondary resistance.
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.
-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.
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
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.
Most common adverse reaction: minor gastrointestinal upset.
May cause abnormalities in liver enzymes.
Very rarely: clinical hepatitis.
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.
-d/t its narrow spectrum and AE, is rarely used for systemic mycoses, but is STILL USED FOR SUPERFICIAL MYCOSES
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.
KNOW THESE ALL
Drug of choice in esophageal, oropharyngeal, vulvovaginal or urinary candidiasis.
Drug of choice for candidemia.
Drug of choice for coccidioidomycosis.
Drug of choice for consolidation and maintenance therapy of cryptococcal meningitis after induction therapy with amphotericin B.
Alternative to amphotericin B for patients with criptococcal meningitis whose disease is not severe.
Drug of choice for initial and secondary prophylaxis against cryptoccocal meningitis.
IN-effective against Aspergillus or other filamentous fungi.
ITRA --> I TRied to put it in her ass, but she was a STRONG INHIBITOR of CYP3A4. It does somewhat work for ASSpergillis --> also works on DIMORPHIC FUNGI (as in bisexual b/c putting in butt?)
--> put it in there, will cause a FATAL ARRYTHMIA when you give with cisapride or quinidine
Metabolized primarily by CYP3A4.
Strong inhibitor of CYP3A4. May cause potentially fatal arrhythmias when given concurrently with cisapride (prokinetic agent used in GI) or quinidine (malaria).
Penetrates poorly in CSF.
Absorption reduced by antacids, H2 blockers and proton pump inhibitors.
Preferred azole for mycoses due to the dimorphic fungi (I TRied to go bisexual)
2) Sporothrix and
Effective against Aspergillus, but has been replaced by voriconazole for this indication.
Used extensively for dermatophytoses and onychomycosis.
Not active against Zygomycetes.
VORE that invasive animal just INVADES ASSES
-spectrum similar to itraconazole --> gets an eye infection when it invades --> gets VISUAL DISTURBANCES!!!
DOC FOR INVASIVE ASPERGILLOSIS****
V for Visual DISTURBANCES***
Transient visual disturbances occur in up to 30% of patients.
Voriconazole is metabolized by and inhibits CYP2C19, CYP2C9 and CYP3A4.
The significant number of drug interactions due to its metabolism through the various hepatic enzymes may limit its use.
POSA --> is a POSER --> is similar to ITRA
--> makes a Z with his fingers for Zygomycetes, and spits on the ground for MUCOR
• Spectrum similar to itraconazole, but it ***has activity against Zygomycetes such as Mucor.****
WHICH AZOLE REACHES THE HIGHEST CONCENTRATION IN THE CSF?
CApsofungin only works against CAndida and ASPERGILLUS --> does so by inhibiting B-1-3-D-GLUCANS (inhibit the BIG DICK 13 GLUCANS)
Newest class of antifungal drugs.
Large cyclic peptides linked to a long-chain fatty acid.
Active against CAndida and Aspergillus but NOT Cryptococcus neoformans.
Only available IV .
****Inhibit synthesis of β(1-3)-D-glucans**** in the fungal cell wall. This results in disruption of the fungal cell wall and cell death.
DRUGS FOR SUPERFICIAL MYCOSES
FIT KG (kevin garnett)
• Fluconazole (not Flucytosine)
Superficial (cutaneous) mycoses are caused by dermatophytes or Candida. The dermatophytes are a group of filamentous fungi. Most cutaneous infections are dermatophytic.
Skin, hair, or nails may be affected. Infections are classified by the area of the body involved.
GRISEOFULVIN --> GREASES UP the MICROTUBULES of the fungus thus disrupting the mitotic spindle and inhibits mitosis --> how can you tell someone's greasy? you look at their hair, nails, and skin
Only use: treatment of dermatophytosis.
Absorption improved when given with fatty foods.
MECHANISM OF ACTION
Interacts with microtubules of the fungus to disrupt mitotic spindle and inhibit mitosis.
Indicated for severe dermatophytoses of the skin, hair, and nails.
Largely replaced by newer antifungal drugs like itraconazole and terbinafine.
Griseofulvin induces liver P450 enzymes, thus increasing the metabolism of a number of drugs, including warfarin.
People with turban's always SQUATTING waiting for bomb to go off. --> TERBINAFINE --> inhibits the SQUALENE EPOXIDASE (squating epoxidase) --> prevent formatoin of lanosterol (precursor to ergosterol)
Available in oral formulation.
MECHANISM OF ACTION
In the ergosterol synthesis pathway, squalene is converted to lanosterol by the action of the fungal enzyme squalene epoxidase. Terbinafine inhibits ***squalene epoxidase***, thus preventing formation of lanosterol, which is a precursor of ergosterol. It also causes accumulation of toxic levels of squalene in the fungal cell, making it fungicidal under most circumstances.
Drug of choice for treating dermatophytoses and, especially, ONYCHOMYCOSES. **** --> infection of the FINGER or TOE NAIL (people with turbans always have the messiest nails!!!)
--> can also get WEIRD TASTE IN MOUTH (maybe feeling a little guilty about the bomb?)
--> It is better tolerated, requires shorter duration of therapy, and is more effective than either azoles or griseofulvin.
GI upsets, rash, headache, taste disturbances.
***Terbinafine does not affect the P450 system and has no significant drug interactions.**