Management of systemic fungal infections Ajai Kumar Garg Department of Medicine School of Medical Sciences and Research Sharda Hospital, Greater Noida 4/15/2019

Introduction Fungi widely distributed in soil, plant debris, and organic substance Humid climate favorable for growth of fungi Opportunistic fungi- very low inherent virulence Uncommon in immunocompetent patients Usually affect immunocompromised host 4/15/2019

Human immunodeficiency virus infection High prevalence of diabetes mellitus Use of broad spectrum antibiotics / systemic steroids Patients receiving immunosuppressive and myelotoxic drugs for autoimmune diseases, malignancies, organ transplantation 4/15/2019

Candida and Aspergillus most common systemic fungal infection Severe disease in advanced HIV state Cryptococcosis and histoplasmosis: frequently occurring invasive fungal infection in patients with AIDS Mucormycosis common in diabetics 4/15/2019

Causative agents of Invasive Mycoses 4/15/2019

Risk factors Neutropenia: neutrophils <500/µl for more than 10 days 2. Prolonged use of corticosteroids (>3 weeks) 3. Persistent fever (>96 hours) refractory to appropriate broad spectrum antibiotics 4/15/2019

Risk factors… Prolonged neutropenia in the previous 60 days 4. Body temperature either >38°C or <36°C with any of the following predisposing conditions: Prolonged neutropenia in the previous 60 days Recent or current use of immunosuppressive agents in previous 30 days Previous episode of invasive fungal infection Coexistence of AIDS 5. Signs and symptoms indicating GVHD 4/15/2019

Risk factors… Prolonged hospitalization (>30 days) Stay in Intensive Care Unit Central venous access Total parenteral nutrition Invasive mechanical ventilation Major abdominal surgery, renal transplant 4/15/2019

Features suggesting invasive fungal infection Any new fever during prolonged severe neutropenia or immunosuppression Fever resistant to broad spectrum antibiotics in neutropenic patient Symptoms and signs of progressive upper respiratory tract infection Symptoms and signs of new, resistant or progressive lower respiratory infection Prolonged severe lymphocytopenia in chronic GVHD and immunosuppression 4/15/2019

Features suggesting invasive fungal infection… Periorbital or maxillary swelling and tenderness Palatal necrosis or perforation Features of focal neurological involvement or meningeal irritation with fever Unexplained mental changes with fever Papular or nodular skin lesions Intra-ocular signs of systemic fungal infection 4/15/2019

Invasive Candidiasis Candida infection blood born Usually endogenous from gut Wide spectrum of clinical manifestation Acute or chronic Superficial or deep seated May involve oral cavity, bronchi, lungs, GI tract, vagina C. albicans, C. tropicalis, C. glabrata 4/15/2019

Diagnosis of Candidiasis Microscopy of body fluids and biopsy material: hyphae or pseudohyphae can be seen in presence of inflammation Culture of blood and other body fluids / respiratory secretions / biopsy material Detection of β1,3 D-glucan : negative predictive value of ~90%, help exclude disseminated disease 4/15/2019

Candida species are commensal, their culture from sputum, the mouth, the vagina, urine, stool, or skin does not necessarily indicate an invasive, progressive infection. Positive cultures of specimens taken from normally sterile sites, such as blood, CSF, pericardium, pericardial fluid, or biopsied tissue, provide definitive evidence that systemic therapy is needed. 4/15/2019

Candidiasis 4/15/2019

Invasive Aspergillosis Exogenous infection Aspergillus fumigatus inhaled as aerosol Primarily affects lungs and sinuses Pulmonary aspergillosis can cause: Progressive destructive cavitary disease Pulmonary aspergilloma (occasionally complicated by life threatening infection) ABPA occurs almost exclusively in patients with asthma, cystic fibrosis 4/15/2019

Diagnosis of Aspergillosis Microscopy of sputum, BAL fluid, and stained biopsy material Culture of respiratory secretions and biopsy material Aspergillus antigen (galactomannan) in ‘high risk’ patients (positive results precedes clinical disease) Molecular testing (PCR) on whole blood Halo signs on HRCT chest: ground glass haziness surrounding a nodule Fungal ball in the cavity on CT chest 4/15/2019

Invasive pulmonary aspergillosis 4/15/2019

4/15/2019

Invasive pulmonary aspergillosis 4/15/2019

Cryptococcosis Systemic fungal infection with predilection for CNS C. neoformans ; C. gattii Isolated from droppings of pigeon and birds, rotting vegetables, fruits, diary products, wood, and soil Acquired usually in childhood by inhalation of aerosolized infectious particles Should be included in differential diagnosis in any patient with chronic meningitis 4/15/2019

Diagnosis of Cryptococcosis Demonstration of Cryptococcus by microscopy of CSF or other body fluids / secretions (India Ink preparation) Detection of Cryptococcal antigen in CSF and blood by latex agglutination Culture of CSF, blood, sputum, urine, and prostatic fluid 4/15/2019

Mucormycosis Most acute and fulminant fungal infection Frequently fatal Caused by fungi belonging to class Zygomycetes Spores acquired via inhalation, percutaneous route, ingestion India contributes about 40% cases Associated with DM, immunocompromised state Typically involves rhino-facio-cranial area and lungs Invades vessels/arteries  embolization and necrosis of surrounding tissue 4/15/2019

Diagnosis of mucormycosis Microscopy of material from necrotic lesions, sputum, and BAL fluid Culture of nasal and palatal scrapings, biopsy material, and sputum PCR on whole blood (if available locally) 4/15/2019

Mucormycosis 4/15/2019

Mucormycosis 4/15/2019

Histoplasmosis Intracellular infection of reticuloendothelial system Acquired by inhalation 95% cases are subclinical or benign 5% develop chronic progressive lung disease All stages mimic tuberculosis CXR: pneumonia, hilar lymphadenopathy Fungal culture diagnostic gold standard (BAL,BMA, blood) 4/15/2019

Blastomycosis Endemic systemic pyogranulomatous mycosis Acquired by inhalation of conidia of Blastomyces Sporadically reported from India Primarily involves lung Infections may remain asymptomatic or may cause acute or chronic pneumonia 4/15/2019

Amphotericin B First systemic antifungal agent Fungicidal with broad spectrum activity Active against Aspergillus species Candida species Cryptococcus neoformans Mucormycosis 4/15/2019

Amphotericin B Only IV form available Infusion related reactions; if given rapidly (fever, chills, nausea, hypotension, hypoxia) Nephrotoxicity Lipid complex preparations: to avoid nephrotoxicity and infusion related side effects Dosage 0.5–1.0 mg/kg/day IV for 10–14 days Up to 1.5 mg/kg/day for disseminated infections 4/15/2019

Precautions: Amphotericin B Do not dilute with saline or mix with other drugs Monitor renal function and serum potassium closely Potassium supplements to compensate urinary losses Maintain high fluid and sodium intake Dosage reduced if renal function deteriorates (serum creatinine level rise by more than 50%) Infusion of mannitol may be useful Monitor blood count at weekly intervals 4/15/2019

Azoles Fungistatic drugs Inhibit ergosterol synthesis in cell wall Available in both oral and IV forms Hepatotoxicity main side effect No renal toxicity 4/15/2019

Fluconazole: spectrum of activity Candida species (reduced activity against C. glabrata, no activity against C. krusei) Cryptococcus neoformans Ineffective against Aspergillus and Zygomycetes Complete absorption after oral administration Absorption not affected by food 4/15/2019

Uses of fluconazole Oropharyngeal candidiasis Cryptococcal meningitis Deep forms of candidiasis in non-neutropenic patients With amphotericin B in treatment of cryptococcosis and deep forms of candidiasis (urinary tract and peritoneum) Prophylaxis against candidiasis Maintenance treatment to prevent relapse of cryptococcal meningitis in patients with AIDS 4/15/2019

Itraconazole: spectrum of activity Aspergillus species Candida species Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatitidis Ineffective against Zygomycetes Available in both Oral and IV forms 4/15/2019

Uses of Itraconazole Mucocutaneous candidiasis Alternative to amphotericin B for invasive aspergillosis Various superficial infections including dermatophytoses, pityriasis versicolor 4/15/2019

Voriconazole: spectrum of activity Candida species Aspergillus species Cryptococcus neoformans Ineffective against Zygomycetes Poor penetration into CSF Available in Oral and IV forms 4/15/2019

Voriconazole… Oral forms: dose adjustment not needed in renal insufficiency IV formulations: not given in moderated to severe renal insufficiency Dose adjustment needed in liver failure Visual disturbances, hepatitis, photosensitivity rash, hallucinations 4/15/2019

Uses of Voriconazole Fluconazole and itraconazole resistant Candida Itraconazole and amphotericin B resistant Aspergillus Not useful for Mucormycosis and Cryptococcal meningitis 4/15/2019

Posaconazole New drug with broad spectrum of activity Candida species Aspergillus Zygomycetes Not effective against cryptococcosis Available in oral forms only 4/15/2019

Uses of Posaconazole Fluconazole / itraconazole resistant oropharyngeal candidiasis Salvage therapy in immunocompromised patients with refractory aspergillosis May be used for mucormycosis (400mg q12h) 4/15/2019

Echinocandins New safe, parenteral antifungal drugs Fungicidal for all species of Candida Inhibit the enzyme β1,3 D-glucan synthase necessary for fungal cell wall synthesis Mainly used for invasive Candidiasis Salvage therapy for Aspergillosis No hepatic or renal toxicity 4/15/2019

Caspofungin Potent fungicidal activity against: • Candida albicans/ C. tropicalis/ C. glabrata Variable activity against: • Aspergillus No activity against: Cryptococcus neoformans / zygomycetes 4/15/2019

Uses of Caspofungin Invasive forms of Candidiasis; Comparable activity with amphotericin B Candidaemia Invasive aspergillosis; in patients who have failed to respond or who are intolerant to other antifungal agents 4/15/2019

Micafungin approved for Treatment of oesophageal candidiasis Prophylaxis in patients receiving stem cell transplant Anidulafungin approved for Candidaemia in non-neutropenic patients Candida oesophagitis, peritonitis, intra-abdominal infections 4/15/2019

Flucytosine Fungicidal effect on Candida and Cryptococcus Act by interfering DNA synthesis Given orally, good penetration into CSF Not used as a single agent because of development of resistance Recommended with amphotericin B for Cryptococcal meningitis and Candida meningitis Bone marrow depression 4/15/2019

Oesophageal candidiasis Fluconazole 200 mg/day orally;14-21 days Fluconazole-refractory disease Itraconazole (oral solution) ≥ 200 mg/day Amphotericin B: 0.3–0.7 mg/kg/day IV Caspofungin: 70 mg on first day50 mg/day IV, 7-21 days 4/15/2019

Candidaemia Non-neutropenic patients: Catheter removal Fluconazole 800 mg loading dose, followed by 400 mg/day, 2 weeks Amphotericin B 0.5-1 mg/kg/day, 2 weeks Persistent neutropenia: Catheter removal Amphotericin B: 1 mg/kg/day Liposomal amphotericin B: 1-3 mg/kg/day Caspofungin: 70mg first day, then 50 mg/day (infuse over 1 h) 4/15/2019

Removal of ventricular prosthetic devices Candida meningitis: Amphotericin B 0.7-1.0 mg/kg/day plus flucytosine 25 mg/kg qid Removal of ventricular prosthetic devices Candida endocarditis: Valve resection Amphotericin B: 0.7 mg/kg/day plus flucytosine 25 mg/kg qid Candida endophthalmitis: Amphotericin B plus flucytosine, followed by fluconazole 400–800 mg, 6-12 weeks 4/15/2019

Acute invasive aspergillosis Voriconazole: IV 6 mg/kg, q12hx2 doses then 4 mg/kg q12h, followed by 200 mg PO q12 h (when tolerated orally) Amphotericin B: 1.0–1.5 mg/kg/day or Liposomal amphotericin B: 3–5 mg/kg/day Itraconazole: PO 400–600 mg/day x 4 days then 200 mg q12h OR IV 200 mg q12h 4 doses then 200 mg/day for 2 weeks (infuse over 1 h) Poor response, if neutrophil count does not recover 4/15/2019

Acute invasive aspergillosis… Caspofungin: Used in patients who have failed to tolerate other antifungal drugs Dose: 70 mg IV first day50 mg/day subsequent days (infuse over 1 h) Variable duration of treatment 4/15/2019

Cryptococcosis Meningitis in normal hosts Amphotericin B: 0.7–1.0 mg/kg/day, plus flucytosine 37.5 mg/kg q6h for 6-10 weeks Amphotericin B: 0.7–1.0 mg/kg/day, plus flucytosine 100 mg/kg/day for 2 weeks, followed by fluconazole 400 mg per day for 10 weeks, then 200 mg/day for 6–12 months as maintenance therapy 4/15/2019

Cryptococcosis Meningitis in AIDS Amphotericin B 0.7–1.0 mg/kg/day plus flucytosine 100 mg/kg/day for 2 weeks, followed by fluconazole 400 mg/day for 10 weeks, then 200 mg/day lifelong If CD4 count increases above 100–200/cmm following HAART, maintenance treatment can be discontinued 4/15/2019

Rhinocerebral mucormycosis Control of diabetic acidosis Aggressive surgical debridement of all necrotic tissue Amphotericin B: 1.0–1.5 mg/kg/day Liposomal amphotericin B: 5-10 mg/kg/d Should be continued till resolution of clinical and radiological signs and recovery from underlying immunosuppression 4/15/2019

Therapeutic choice for fungal infections Indication Primary therapy Secondary therapy Disseminated candidiasis Fluconazole Caspofungin, Amphotericin B Invasive aspergillosis Voriconazole Itraconazole, Amphotericin B, Posaconazole, Caspofungin Cryptococcal meningitis Liposomal amphotericin B plus flucytosine Mucormycosis Amphotericin B Posaconazole Persistent neutropenic fever not responding to antibiotics 4/15/2019

Summary Systemic fungal infections are common in immunocompromised patients with persistent neutropenia, DM, HIV infection, and immunosuppressive therapy. Candida, Aspergillus, Cryptococcus, and Zygomycetes are common systemic fungal infections. Diagnosis is difficult due to lack of optimum laboratory facilities. Clinician should have a high index of suspicion for fungal infection in immunocompromised patient with febrile illness not responding to broad spectrum antibiotics. 4/15/2019

Thank you 4/15/2019

Acute GVHD Erythematous maculopapular rash Persistent anorexia or diarrhoea Deranged LFT Diagnosis by skin or liver biopsy 4/15/2019

Chronic GVHD Malar rash Sicca syndrome Arthritis Obliterative bronchiolitis Bile duct degeneration Cholestasis Develops in 20-50% patients surviving for more than three months 4/15/2019