Medical Pharmacology 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 and 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 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

    • 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 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 chromoblastomycosis.

  •  Common toxicities: Ketoconazole (Nizoral)

    • Nausea, anorexia, vomiting (occasional)

  •  Uncommon toxicities:

    • Hepatotoxicity (idiosyncratic) which 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 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

  •   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

      • 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

  • Cryptococcal Meningitis

    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

  • 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 River 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).

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.