Anti fungals

Introduction

• Mycology Review:

  1. Fungi:

     • Rounded, budding forms --yeast-like

       • Smooth in form

     • Hyphae -- molds

       • Fuzzy in form

• Fungi: Yeast

  1. Candida

     • Usually exhibit both budding and tubular elements (pseudohyphae)

  2. Cryptococcus

• Fungi: Molds

  1. Aspergillus

  2. Rhizopus

  3. dermatophytes (ringworm)

• Dimorphic fungi (rounded in tissues; mold-like when cultured) cause:

  1. Histoplasmosis

  2. Blastomycosis

  3. Sporotricosis

  4. Coccidiodomycosis

  5. Paracoccidioidomycosis

• Fungi cause human infection when:

  1. Spores reach lung or paranasal sinus

  2. Hyphae or spores inoculate skin or cornea

• Fungi have preferred route of infection. Examples:

  1. Epidural sites

     • Ringworm

     • Pityriasis versicolor (pityriasis: skin diseases --branny scales)

     • Piedra(fungal disease of the hair: shafts marked by hard, gritty nodules)

  2. Subcutaneous sites:

     • Sporotricosis (nodular lesions -- may form ulcers (lymph nodes, skin, subcutaneous tissue))

     • Mycetoma (granules)

Classes of Antifungal Drugs: Overview

• Topical Drugs

  • Imidazoles and triazoles: Mechanism of Action:--Inhibition of ergosterol synthesis in fungal cell walls; direct damage to fungal cytoplasmic membrane (topical)

• • • Topical agents effective in treating:

      1. Cutaneous candidiasis

      2. Pityriasis versicolor

      3. Mild-moderately severe ringworm of glabrous (smooth, bare) skin

    • Vaginal formulations: effective for

      1. Vulvovaginal candidiasis

  • Drugs for cutaneous application

    • Clotrimazole (Mycelex)

    • Econazole

    • Ketoconazole (Nizoral)

    • Sulconazole

    • Oxiconazole

    • Miconazole (Monistat)

  • Vaginal formulations

    • Imidazoles:

      1. Miconazole (Monistat)

      2. Clotrimazole (Mycelex)

      3. Tioconazole

      4. Butoconazole (Femstat)

    • Triazoles

      1. Terconazole (Terazol)

  • Polyene Macrolide Antibiotics

    • Broad-spectrum agents

      1. Mechanism of Action: combine with fungal cytoplasmic membrane sterol and increase membrane permeability

      2. Topical application:

         • Inactive against ringworm

         • Effective: candidiasis of skin and mucous membranes

         • Oral thrush -- nystatin suspension

         • Vaginal troches: effective vulvovaginal candidiasis

         • Nystatin (Mycostatin) and amphotericin B (Fungizone, Amphotec): topical l, useful in cutaneous candidiasis

  • Other Topicals

    • Same clinical spectrum as imidazoles for cutaneous mycoses:

      1. Ciclopirox olamine

      2. Haloprogin

      3. Terbinafine (Lamisil)

      4. Naftifine

    • Effective against ringworm, not candidiasis

      1. Undecylinic acid

      2. Tolnaftate

• Systemic Drugs

  • Griseofulvin

    1. Effective: ringworm (certain types)

    2. Ineffective: candidiasis

    3. Drug-drug interaction:

       • Phenobarbital

       • Coumarin-type anticoagulants

• Terbinafine (Lamisil)

  • As effective as itraconazole (Sporanox) (more effective than griseofulvin) in treating:

    1. Onychomycosis (disease of the nails of the fingers and toes caused by Epidermophyton floccosum, several species of Trichophyton, and Candida albicans.)

       • Nails become: white, thickened, brittle, opaque, friable {also called "ringworm of the nails"}

    2. Ringworm

• • 1. h

  • Drug-drug interaction:

    1. Terbinafine (Lamisil): decreases cyclosporine (Sandimmune, Neoral) concentrations.

    2. Terbinafine (Lamisil): increases cimetidine (Tagamet) concentration.

    3. Rifampin (Rimactane): decreases terbinafine (Lamisil) blood levels.

• Ketoconazole:

  • Variable absorption

  • Poor absorption in patients taking cimetidine (Tagamet) or other H₂ blockers or antacids

  • Primary Clinical Use: Ketoconazole (Nizoral)

    1. Blastomycosis

    2. Histoplasmosis

    3. Paracoccidioidomycosis

    4. Chronic mucocutaneous candidiasis

    5. Esophageal candidiasis

    6. Some forms: disseminated Coccidiodomycosis and pseudallescheriasis

    7. Partial improvement: cutaneous sporotricosis and chromoblastomycosi

• • 1. s.

  • Common toxicities: Ketoconazole (Nizoral)

    1. Nausea, anorexia, vomiting (occasional)

  • Uncommon toxicities:

    1. Hepatotoxicity (idiosyncratic) which may be serious/fatal

    2. Endocrine effects: gynecomastia, decrease serum testosterone, decreased libido, decreased adrenal cortical reserve, decreased potency in males, menstrual irregularities

  • Drug-drug interactions: Ketoconazole (Nizoral)

    1. Rifampin (Rimactane) (in some patients taking isoniazid also): decreased ketoconazole levels (plasma)

    2. Ketoconazole: increases cyclosporine and cisapride levels

    3. Ketoconazole: increased possibility of terfenadine (Seldane) or astemizole (Hismanal) cardiotoxicity

  • Contraindicated in pregnancy (present in breast milk)

• Itraconazole: (Sporanox)

  • Superior to ketoconazole in safety and efficacy

  • Less hepatotoxicity and hormonal suppression

  • Clinical Use: Itraconazole (Sporanox)(first 7 same as ketoconazole)

    1. Blastomycosis

    2. Histoplasmosis

    3. Paracoccidioidomycosis

    4. Chronic mucocutaneous candidiasis

    5. Esophageal candidiasis

    6. Some forms: disseminated Coccidiodomycosis and pseudallescheriasis

    7. Partial improvement: cutaneous sporotricosis and chromoblastomycosis.

    8. Some cases of:

       • Onychomycosis

       • Sporotricosis

       • Cryptococcosis

       • Aspergillosis

• Drug-drug interactions: Itraconazole

  • Following drugs decrease itraconazole blood levels:

    • Rifampin

    • Carbamazepine

    • H₂ receptor blockers

    • Phenytoin

  • Itraconazole may induce cardiotoxicity when coadministered with:

    • Digoxin

    • Terfenadine

    • Astemizole

  • Itraconazole may induce nephrotoxicity when coadministered with cyclosporine

  • Itraconazole inhibits metabolism of:

    • Midazolam

    • Triazolam

    • Tacrolimus

    • Cisapride

    • Oral hypoglycemic drugs

• • Fluconazole: (Diflucan)

  • Excellent oral bioavailability

  • Clinical use: Fluconazole (Diflucan)

    • Oropharyngeal and esophageal candidiasis

    • Catheter-acquired candidemia (immunocompetent patient-- along with removal of catheter)

    • Initial and maintenance treatment for AIDS-associated cryptococcal meningitis (probably following an initial 2 week course of IV amphotericin B)

    • Maintenance treatment: coccidioidal meningitis (alternative to intrathecal amphotericin B maintenance tthe therapy)

    • Reduces incidence of deep candidiasis and among patients receiving allogenic bone marrow transplants.

    • Reduction of the frequency of cryptococcosis and mucosal candidiasis in AIDS patients with CD4 T cell count < 200 per microliter (particularly effective in AIDS-patient subgroups with CD4 T cell count < 50 per microliter)

    • Less effective than itraconazole:

      • Blastomycosis

      • Histoplasmosis

      • Sporotricosis

    • Ineffective: Aspergillosis, mucormycosis

• • • 
      

  • Adverse effects: Fluconazole

    • Common: nausea, abdominal distress (may be dose-limiting

    • Allergic rash -- common in HIV patients

    • Fatal cases of Stevens-Johnson syndrome: in HIV-infected patient groups

    • Alopecia (prolonged administration at higher doses, reversible upon discontinuation of treatment)

    • Rare: anaphylaxis, hepatic necrosis, neutropenia

  • Pharmacokinetics: fluconazole (Diflucan)

    • 80%: excreted unchanged by the kidney

    • Dosage adjustment required for patients with diminished creatinine clearance.

  • Drug-drug interactions: fluconazole (Diflucan)

    • Fluconazole administration increases plasma levels of:

      • Phenytoin (Dilantin), cyclosporine (Sandimmune, Neoral), warfarin (Coumadin), rifabutin (Mycobutin)

Sheppard,D. and Lampiris, H.W., Antifungal Agents, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 780-786. Bennett, J.E. Fungal Infections (Section 15: Infectious Diseases), In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., andBraunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp. 1148-1163

Fungal Infections in HIV

• Candidiasis

  • Candida infections: the most common fungal infections in HIV patients.

    • Often occur early in HIV disease.

  • May signify onset of clinical manifestation of immunodeficiency.

  • Generally easy to control

  • Range of infections:

    • Oral cavity (thrush): white, exudate on posterior oropharynx.

    • In late stages of HIV infection

      • Candida infections: esophagus, lungs, bronchi, trachea which may be indicative of severe immunodeficiency.

      • Esophagitis, not responsive to therapy directed at Candida, may be due to an other causes, such as, cytomegalovirus infection, HSV, Kaposi sarcoma, lymphoma

• • Treatment

    • Oral or vaginal Candida: topical nystatin (Mycostatin) or clotrimazole (Mycelex) troches.

    • In severe cases: systemic therapy-- ketoconazole (Nizoral) or fluconazole (Diflucan)

      • Fluconazole (Diflucan) may be preferable (ketoconazole may be less well absorbed in patients with high gastric pH)

    • Another option for management of severe cases: IV amphotericin B, then oral fluconazole.

• Cryptococcosis

  • 
    

• 
  Attribution:

  • Meintjes G Update on cryptococcal disease in patients with HIV infection https://www.youtube.com/watch?v=si_IJiJ65Co (6/2014)

  • HIV/AIDS (CDC) YouTube Channel: https://www.cdc.gov/hiv/basics/whatishiv.html

• • Leading cause of meningitis in HIV patients.

  • Cryptococcus neoformans, a fungus which can be a life threatening infection in about 6% to 12% of AIDS patients.

  • Generally occurs with advanced disease (CD4⁺ T cell counts < 100 per microliter)

  • Cryptococcus neoformans enters the body through the respiratory tract, but the infection sites are generally the brain and meninges.[CNS infection -- 67% to 85%]

    • Patients present with subacute meningioencephalitis

    • Patients, in addition to meningitis, may present with cryptococcoma.

    • Common symptoms:

      • Fever (frequency: 100%)

      • Altered mental status

      • Headache

      • Meningeal signs

    • Pulmonary manifestation: 40% of patients with CNS infection

      • Common symptoms:

        • Fever

        • Cough

        • Dyspnea

    • Definitive diagnosis: organism culture from spinal fluid, blood, bone marrow, sputum, or tissue

• • Cryptococcal Infections: Treatment

    • Therapy: initiated immediately when antigen or culture tests our positive for cryptococcal infection

    • Standard therapy in HIV with cryptococcal meningitis patients: amphotericin B in combination with flucytosine followed by fluconazole.

      • Due to neutropenia, more than half of patients will not be able to receive the full course of flucytosine treatment.

    • Since over 50 percent of HIV patients will suffer a relapse, following amphotericin B treatment, patients should be maintained on fluconazole indefinitely.

    • Fluconazole is sometimes used as prophylaxis against candidal and cryptococcal infections when CD4 T cell count < 100 per microliter.

• Histoplasmosis

• Attribution:

  • Cochrane P Histoplasma capsulatum and Histoplasmosis https://www.youtube.com/watch?v=z3PJzOwcGeE (7/2011)

  • Paul Cochrane YouTube Channel: https://www.youtube.com/channel/UCmAoWKrvG4oIe7j_taqb_7A

• • 
    Most commonly seen in regions where Histoplasma capsulatum is endemic. (Mississippi and Ohio Riv

• • er Valley).

  • Generally a late manifestation of HIV (occasionally, histoplasmosis is the first presenting clinical indication.)

  • Histoplasma capsulatum: may present initially as a pulmonary infection, disseminated disease is the most common presentation in HIV

• • Clinical presentations:

    • Fever

    • Weight loss

    • Lymphadenopathy

    • Hepatosplenomegaly

    • Bone marrow involvement (33%):

      • Thrombocytopenia

      • Neutropenia

      • Anemia

    • Abnormal chest x-ray (50% of patients: diffuse interstitial infiltrate or diffuse small nodules)

  • Diagnosis: organism culture from blood, bone marrow, or tissue.

  • Treatment: initially amphotericin B the for maintenance, amphotericin or oral itraconazole (Sporanox).

Amphotericin B (Fungizone, Amphotec)

Fluconazole (Diflucan)

Itraconazole (Sporanox)

Naftifine

Clotrimazole (Mycelex)

Flucytosine (Ancobon)

Ketoconazole (Nizoral)

Nystatin (Mycostatin)

Econazole

Griseofulvin

Miconazole (Monistat)

Oxiconazole

Sulconazole

Terbinafine (Lamisil)

Sheppard,D. and Lampiris, H.W., Antifungal Agents, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p 786.

Fauci, A.S. and Lane, H.C., Human Immunodeficiency Virus (HIV) Disease: AIDS and Related Disorders:. In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., andBraunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1833-1835.