Antifungal Agents



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Antifungal Agents

Classification of Antifungal Drugs


Classification

Drugs

Antibiotics



Amphotericin B

Griseofulvin

Nystatin


Antimetabolite

Flucytosine

Azoles


Imidazoles

-KMC & E


Triazoles

-Itraconazole

-Fluconazole


Topical


(Superficial Infections)

Clotrimazole

Econazole

Nystatin

Miconazole

Tolnaftate

Amphotericin B



Systemic


Ketoconazole

Miconazole

Itraconazole

Fluconazole

Flucytosine


Allylamine

Terbinafine

Oral


Griseofulvin

Ketoconazole





Drug


PK

MOA

Resistance

Uses

Adverse Effects

Amphotericin B



(polyene compound)

-poorly absorbed from GI tract


-poor penetration into CNS
-IV
-intrathecal infusions can be done for CNS infections

-Unchanged excretion


-polyene antibiotic binds to sterol component of fungal cell membrane

disruption of permeability of cell membrane by creating punch holes, allowing electrolytes to leak out of cell  cell death

-due to decreased levels of ergosterol and alteration in fungal cell membrane


1. Histoplasma capsulatum


2. Cryptococcus neoformans
3. Blastomyces dermatitides
4. Aspergillus

5. Candida albicans


6. Topical Amph B for mucocutaneous candidiasis (lotion, cream, ointment)

1. Electrolyte imbalance ass. w/fall in BP; pts manifest as hypokalemia

2. IV admin may be ass. w/fever, chills, pain, n/v (tx w/hydrocortisone)

3. Reversible nephrotoxicity

-azotemia

- plasma creatinine

-renal tubular acidosis

4. Neurological defects

5. Anemia due to suppression of erythrocyte production esp in HIV pts taking AZT

6. Thrombophlebitis at IV site

-ABCD, ABLC, AmBisome


Drug


PK

MOA

Resistance

Uses

Adverse Effects

Flucytosine


-well absorbed from GI


-reaches CSF
-p.o. antimycotic

-Susceptible organisms deaminate flucytosine to 5-fluorouracil and is then incorporated into RNA causing functional disability and structural changes


-(mammalian cells do not convert flucytosine into 5-fluorouracil; they do not have permeases to take up and have low levels of deaminase)

-Occurs due to loss of permeases which transports drug into fungal cell


-can also occur due to decreased activity of uridine monophosphate deaminases which convert flucytosine into 5-fluorouracil

1. Cryptococcus

2. Candida (esp UTI’s)

3. Torulopsis glabrata that causes chromomycosis
Predominantly used w/amphotericin B

(Ampho B punches holes allowing Flucytosine to enter)

**This combo is DOC in Meningitis caused by crypto or Candida**

1. Bone marrow depression causing leukopenia and thromobytopenia


2. N/V, diarrhea, severe enterocolitis
(damage of DNA during rapid division of cells such as bone marrow and GI epithelium could be a possible reason )

Ketoconazole


-p.o.

-acidic environment required for dissolution of detoconazole

-simultaneous admin of H2 blockers/antacids can impair absorption

-compete w/cyclosproine for hepatic metabolism  increased levels  nephrotoxicity

-Warfarin effect enhanced

-Rifampin enhances ketoconazole met



-Impairs biosynthesis of ergosterol for cytoplasmic membrane (inhibits sterol 14  demethylase: microsomal cyto P450 dependent enzyme)





1. Non-meningeal blastomycosis


2. Coccidioides immitis
3. Paracoccidioidomycosis
4. Candida albicans
5. pts who are not gravely ill and immunologically competent

1. N/V, anorexia, dizziness, rash

2. Inhibits steroid synthesis by inhibiting p450 decreasing androgen synthesis, gynecomastia, decreased libido and azoospermia (high doses ass.w/transient fall in testosterone and ACTH)

3. Liver dysfunction ass. w/ an increase in transaminases

4. Teratogenic effect in experimental animals; syndactyly in rats

5. Cardiotoxicity if admin w.terfenadine or astemizole

Fluconazole


-well absorbed from GI


-enters CSF




1. Esophageal candidiasis in pts w/AIDS

2. Single dose in vaginal candidiasis

3. Prevent relapses of cryptococcal meningitis in AIDS pts after initial tx w/Amphotericin


1. Rash, eosinophilia, SJS

2. Thrombocytopenia in AIDS pts

3. Concurrent admin of fluconazole can increase plasma conc of phenytoin, solfonylureas, warfari and cyclosporine

Econazole











-available as cream

1. Candida and other dermatophytes



1. local erythema

2. burning

3. itching




Drug


PK

MOA

Resistance

Uses

Adverse Effects

Clotrimazole











-Topical application/local use

-Tinea, otomycosis

-versicolor infections

-Cutaneous and vulvovaginal candida





Miconazole











-dermatological cream, spray, powder, lotion, vaginal cream

-Tinea pedis

-Cruris

-Versicolor



-Vulvovaginal candidiases, ---Trichophyton



Nystatin

-too toxic for IV use


-more toxic on systemic admin
-not absorbed from GI, skin, vagina

-structurally similar to Amphotericin B;

-polyene antibiotic binds to sterol component of fungal cell membrane

disruption of permeability of cell membrane by creating punch holes, allowing electrolytes to leak out of cell  cell death




1. Candidiasis of skin, vagina and GI not dermatophytes






Griseofulvin

-absorption increased w/fatty meal


-barbituates decrease absorption of drug from GI tract
-drug distributed to keratin and stratum corneum

Disrupting mitotic spindles by interacting w/polymerized tubules




1. Fungistatic effect against

-microsporum,

-epidermophyton,

-trichophyton


1. h/a disappears when therapy discontinues

2. peripheral neuritis

3. lethargy

4. mental confusion

5. fatigue, syncope

6. blurred vision, vertigo

7. augmentation of OH effects

8. GI:


-n/v, diarrhea, flatulence

-heartburn,

-dry mouth, angular stomatitis

9. induce hepatic microsomal enzymes; increase rate of met of warfarin and reduce efficacy of BC pills

10. Teratogenic, carcinogenic

Tolnaftate


Haloprogin

Undecylenic Acid










1. Candida albicans

2. Dermatophytes









Fungus

Condition Caused

1st line treatment

other treatment options



Candida

Cutaneous and Vaginal thrush

Topical Nystatin

Imidazole derivative



Ketoconazole

Fluconazole



Oral thrush

Clotrimazole

Nystatin


Ketoconazole

Deep-seated infection

Amphotericin B + Flucytosine





Coccidioides immitis

Disseminated non-meningeal infection

Amphotericin B

Ketoconazole

Itraconazole



Meningeal infections

Intrathecal Amphotericin B

Intrathecal Miconazole


Histoplasma capsulatum

Chronic pulmonary disease

Ketoconazole

Itraconazole



Amphotericin B

Disseminated infection

Amphotericin B

Ketoconazole


Blastomycosis dermititdes

Superficial

Deep-seated infections includuing cutaneous, mucous, resp and CNS infection



Ketoconazole

Itraconazole



Amphotericin B

Paracoccidioides brasiliensis

Superficial and deep-seated infections

Ketoconazole

Itraconazole



Amphotericin B followed by sulfonamide

Mucormycosis

Superficial and deep-seated infections

Amphotericin B




Sprorthrix schenckii

Cutaneous manifestations

Itraconazole




Extracutaneous manifestations

Amphotericin B




Aspergillus

Invasive type in IC pts

Amphotericin B

Itraconazole

Cryptococcus neoformans

Pulmonary lesions

Amphotericin B




Meningitis

Amphotericin B + Flucytosine



Questions:


Matching I (MOA)

  1. Griseofulvin

  2. Flucytosine

  3. Fluconazole

  4. Amph B / Nystatin

    1. MOA involves disruption of microtubular association……………………………………………………………….griseofulvin

    2. Drug converted to 5FU and inhibits thymidylate synthase; uses permeases and deaminases………………………...flucytosine

    3. Inhibits cyt P450 mediated demethylation of lanosterol, leading to inhibition of sterol synthesis……………………fluconazole

    4. Polyene binds to fungal steroid component and causes damage to integrity of cell membrane………………………Amph B/ Nystatin

Mathing II (AE)

  1. Ketoconazole

  2. Flucytosine

  3. Amph B

  4. Griseofulvin

    1. Produces antiandrogenic effect and gynecomastea……………………………………………………………ketoconazole

    2. Neutropenia, thrombocytopenia, depression of bone marrow could occur……………………………………Flucytosine

    3. Electrolyte imbalance, n/v. fever with chills, nephrotoxicity………………………………………………….Amph B

    4. Increase in rate of metabolism of warfarin and oral contraceptives……………………………………….. …Griseofulvin




  1. Which of the following is the DOC in systemic infection of Cryptococcus neoformans?

    1. Griseofulvin

    2. Nystatin

    3. Clotrimazole

    4. Miconazole

    5. Amphotericin B

    6. Econazole


Amphotericin B


  1. All of the following are true about Fluconazole except:

    1. It has good distribution and enters the CSF

    2. It’s used in AIDS to prevent relapse of Cryptococcus meningitis

    3. Associated with Steven Johnson Syndrome

    4. Concurrent administration of phenytoin, sulfonylureas, warfarin, cyclosporine is associated w/and increase in plasma concentration

    5. Associated with high incidence of gynecomastea and loss of libido


Answer: E; it is NOT ass. w/gynecomastea or loss of libido




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