Chapter 37:  Antifungal Drugs

Introduction

• Mycology Review:

• Fungi:

  • rounded, budding forms --yeast-like

    • smooth in form

  • Hyphae -- molds

    • fuzzy in form

• Fungi:Yeast

  • Candida

    • usually exhibit both budding and tubular elements (pseudohyphae)

  • Cryptococcus

• Fungi: Molds

  • Aspergillus

  • Rhizopus

  • 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:

      • cutaneous candidiasis

      • pityriasis versicolor

      • mild-- moderately severe ringworm of glabrous (smooth, bare) skin

    • Vaginal formulations: effective for

      • vulvovaginal candidiasis

  • Drugs for cutaneous application:

    1. clotrimazole (Mycelex)

    2. econazole

    3. ketoconazole (Nizoral)

    4. sulconazole

    5. oxiconazole

    6. 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:

      • Mechanism of Action: combine with fungal cytoplasmic membrane sterol -- increase membrane permeability

      • 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 -- 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:

    • Effective: ringworm (certain types)

    • Ineffective: candidiasis

    • Drug-drug interaction:

      1. phenobarbital

      2. 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

  • Most common side effect: gastrointestinal distress

  • Uncommon, but serious side effects: pancytopenia, hepatitis, rash

  • 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 in AIDS patients)

  • poor absorption -- 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 chromoblastomycosis.

  •  Common toxicities: Ketoconazole (Nizoral)

    • nausea, anorexia, vomiting (occasional)

  •  Uncommon toxicities:

    •  hepatotoxicity (idiosyncratic) -- may be serious/fatal

    • endocrine effects: gynecomastia, decrease serum testosterone, decreased libido, decreased adrenal cortical reserve, decreased potency in males, menstrual irregularities

  •  Drug-drug interactions: Ketoconazole (Nizoral)

    • rifampin (Rimactane) (in some patients taking isoniazid also): decreased ketoconazole levels (plasma)

    • ketoconazole: increases cyclosporine and cisapride levels

    • 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 seven 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

  •  Contraindicated in pregnancy

• 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)

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 (see for T cell accounts less than 100 per microliter):

    • Candida infections: esophagus, lungs, bronchi, trachea -- -- 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

• Leading cause of meningitis in HIV patients.

• Cryptococcus neoformans, a fungus: -- life threatening infection in 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 patients:amphotericin B in combination with flucytosine.

  • 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

• Most commonly seen:in regions where Histoplasma capsulatum is endemic. (Mississippi and Ohio River Valley).

• For these geographic reasons, there are about 0. 5% of histoplasmosis-AIDS cases in the United States overall.

• Generally a late manifestation of HIV (median CD4 T cell count for patients with histoplasmosis -- 33 per microliter); 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: maintenance -- amphotericin or oral itraconazole (Sporanox).

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