Nursing Pharmacology:  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 include:

  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 which involves nodular lesions that may form ulcers. Typical involvement includes lymph nodes, skin, and subcutaneous tissue.

     • Mycetoma {granules}

Classes of Antifungal Drugs: Overview

• Topical Drugs

  • Imidazoles and triazoles:

    • Mechanism of Action involves inhibition: of ergosterol synthesis in fungal cell walls  with subsequent direct damage to fungal cytoplasmic membrane .

    • 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)

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 (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.