PHARMACOTHERAPY III PHCY 510 University of Nizwa College of Pharmacy and Nursing School of Pharmacy PHARMACOTHERAPY III PHCY 510 Lecture 10 Infectious Diseases “Fungal Infections” Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy, CPN University of Nizwa

Course Outcome Upon completion of this lecture the students will be able to Describe etiology, clinical presentations and treatment options of superficial and invasive fungal infections, Individualize the antifungal treatments.

Types Yeast: unicellular, oval cells: Cryptococcus neoformans meningitis Yeast-like: like yeast but produce pseudohyphae e.g. Candida albicans, C. flavus or C. niger. superficial or deep seated candidal infections. Molds: produce hyphae as in rotten food, Aspergillus fumigatus. pulmonary infections Dimorphic fungi: exists either as yeast at body temp, or as mold at room temp. e.g: Penicillium spp. Fungi may cause superficial or deep human infections

Superficial Fungal Infections Thrush: Candida ‐ oral and vaginal infection Dermatophytosis (Tinea ringworm) Pityriasis versicolour (Tinea versicolour) Invasive Fungal Infections (Systemic Mycoses) In both healthy and immunocompromised histoplasmosis, coccidioidomycosis, cryptococcosis, blastomycosis, paracoccidioidomycosis, and sporotrichosis. In immunocompromised Candida albicans, Aspergillus spp., Trichosporon, Torulopsis (Candida) glabrata, Fusarium, Alternaria, Cryptococcus neoformans and Mucor

Candida albicans: Common yeast‐like fungi Part of the GIT normal flora The infection is usually endogenous Other species include: C. glabrata, C. krusi and C. tropicalis Superficial infection is common as oral and vaginal thrush and occasionally nail infection Predisposing factors include: Presence of dentures Use on steroid inhalers Use of anti‐bacterials Diabetes, pregnancy, and oral contraceptives Immunosuppressed patients

Clinical Presentation Thrush – oral and vaginal: – Sore mouth with white patches of fungus on the mucosa and tongue. – Vaginal discharge which is thick and creamy and accompanied by itching Esophageal candidiasis: in immunocompromised patients. Nails: infection of subcutaneous tissue around and under the nail. Inflamed pustules, itching and fissuring of the skin Oral Candidiasis

Treatment Polyenes: insoluble, not absorbed from GIT e.g. nystatin, amphotericine B Imidazoles: topical: econazole, clotrimazole Triazoles: systemic: fluconazole and itraconazole For treatment of oral or vaginal candidiasis (thrush), these agents are applied: Topically (nystatin, econazole, clotrimazole) Orally (nystatin, fluconazole )

Hematogenous Candidiasis Candida is generally acquired via GI tract seeding to deep organs such as the eye, brain, heart, and kidney occurs. Acute onset of fever, tachycardia, tachypnea, and occasionally chills or hypotension. Amphotericin B may be switched to fluconazole (IV or oral) for completion of therapy. Fluconazole and caspofungin is as efficacious as amphotericin B in the treatment of invasive candidiasis.

Dermatophytosis (Tinea ringworm) Caused by molds: trichophyton and epidermophyton • Usually infect skin, nails and hair • Acquired from soil, animals or humans • Clinical feature: Skin: Ringworm - a circular inflamed lesion Nail: thick discolored nail Scalp: scaling, itching, inflammation, and hair loss • Treatment: topically for small areas: imidazoles, terbinafine • Systemic for large areas, nails and hair: Griseofulvin:

Pityriasis versicolour (Tinea versicolour) Caused by Malassezia furfur: requires fatty acids present in sebum (oily or fatty secretion of sebaceous glands). Clinical Features: scaly, pigmented patches scattered over the trunk, neck and shoulders + dandruff Diagnosis: microscopy of scraping from the patches Treatment: Topical: 2% selenium sulfide, terbinafine or imidazole topically. Oral: Itraconazole for 7 days in severe cases

Histoplasmosis is an endemic mycosis caused by the pathogenic fungus, H. capsulatum. Influenza like illness, arthritis, severe arthralgia, Chronic pulmonary symptoms and apical lung lesions that progress with inflammation, cavitation, and fibrosis are characteristic of this form of illness. Mild, self-limited disease without immunosuppression- oral ketoconazole or IV amphotericin B. In AIDS patients, intensive 12-week primary treatment is followed by lifelong suppressive (maintenance) therapy with itraconazole. Itraconazole 200 mg twice daily may be used to complete a 12-week course.

Blastomycosis is an endemic fungal infection caused by B. dermatitidis. Brief flulike illness, resembling bacterial pneumonia, sudden infection with acute respiratory distress syndrome (ARDS). Ketoconazole therapy for the treatment of self limited pulmonary disease. Itraconazole, 200 to 400 mg/day, is effective as a first-line agent in the treatment of non–life-threatening, non-CNS blastomycosis. CNS disease should be treated with amphotericin B for a total cumulative dose greater than 1 g.

Coccidioidomycosis is caused by C Coccidioidomycosis is caused by C. immitis, a thermal dimorphic fungus like H. capsulatum and B. dermatitidis. Acute respiratory illness is misdiagnosed as viral bronchitis; symptoms are accompanied by myalgia, malaise, and fatigue that persist for several weeks. “Valley fever” is a syndrome characterized by erythema nodosum and erythema multiforme. Symmetrical arthritis of ankle or other joints (‘‘desert rheumatism’’). Amphotericin B IV (0.5 to 1.5 mg/kg/day), Ketoconazole (400 mg orally daily), IV or oral fluconazole (usually 400 to 800 mg daily, max-1,200 mg/day without complications), and Itraconazole (200 to 300 mg orally twice daily as either capsules or solution).

Cryptococcosis is a noncontagious, systemic mycotic infection caused by soil yeast Cryptococcus neoformans. Disease localize in lungs or spread to other tissues like CNS, and skin. Headache, fever, nausea, vomiting, mental status changes, and neck stiffness are generally observed. With symptomatic infection, fluconazole or amphotericin B is warranted. The combination of amphotericin B with flucytosine for 6 weeks is used for treatment of cryptococcal meningitis. An alternative is amphotericin B for 2 weeks followed by fluconazole for an additional 8 to 10 weeks. Suppressive therapy with fluconazole 200 mg/day for 6 to 12 months is optional.

Aspergillus Infections are cause by three most commonly pathogenic forms are A. fumigatus, A. flavus, and A. niger. Acquired by inhalation of airborne conidia that are small enough (2.5 to 3 mm) to reach alveoli or paranasal sinuses. Superficial or locally invasive infections of ear, skin, or appendages can be managed with topical antifungal therapy. Allergic manifestations of Aspergillus range in severity from mild asthma to allergic bronchopulmonary aspergillosis characterized by severe asthma with wheezing, fever, malaise, weight loss, chest pain, and a cough productive of blood-streaked sputum. Voriconazole is the drug of choice for primary therapy aspergillosis because of improved survival and fewer side effects. In patients who cannot tolerate voriconazole, amphotericin B can be used.

Conventional Amphotericin B (Fungizone): Usual dose = 1mg/kg iv infusion in dextrose 5% (1‐6 wks) Can be given as a bladder wash‐out as 50mg/L Contraindicated in renal impairment Causes hypokalaemia. Amphotericin B lipid formulations: I. Encapsulated in liposomes (Ambisome): Dose: 3‐7 mg/kg iv infusion in dextrose 5% Can be used for patient with impaired renal function Causes hypokalaemia II. As a complex with lipid molecules (Abelcet): Dose: 5 mg/kg iv infusion in dextrose 5% Causes hypokalaemia and infusion reaction

Key Points Nephrotoxicity (but less with lipid formulated) and Infusion related toxicity are associated with amphotericine B. Hepatotoxicity is associated with azoles (ketoconazole) and flucytosine Bone marrow suppression: flucytosine Drug interactions: azoles (voriconazole) To avoid precipitation of amphotericin B in IV infusion it should only be diluted in dextrose 5% Itraconazole absorption is impaired when given with antacids or omeprazole.