Case Studies in Fungal Infections and Antifungal Therapy

Wayne L. Gold MD, FRCPC Annual Meeting of the Canadian Society of Internal Medicine November 4, 2017 Disclosures

. No financial disclosures or industry relations. Objectives

1. Review infections caused by two medically important classes of fungi that may be seen by specialists in Internal Medicine 2. Recognize risk factors for these infections 3. Understand diagnostic approaches to patients with these infections Objectives

4. Review available antifungal therapies . Classes of antifungal agents . Polyenes - Amphotericin B . Triazoles . Echinocandins . Spectrums of activity . Appropriate selection by clinical syndrome

Case 1 History

57-year-old woman . PMH . Type 2 diabetes mellitus . Dyslipidemia . Hypertension . Alcohol use disorder History of Present Illness

. Three-day history . Nausea, vomiting . Epigastric abdominal pain . Recent alcohol binge

. Dx: acute pancreatitis (imaging, biochemistry) History of Present Illness

. Course complicated by ARDS and sepsis . infected pancreatic necrosis requiring percutaneous drainage . ICU admission . Intubation, ventilation . Pressor support . IV piperacillin/tazobactam . Total parenteral nutrition - central venous catheter History of Present Illness

. Defervescence followed by recurrence of fever . Cultures: . Blood . Endotracheal secretions . Drainage fluid Blood culture …

Candida species Candida species

. Normal human commensal organisms . Skin . Gastrointestinal tract (mouth to anus) . Female genital tract . Expectorated sputum (oropharynx) . Most common species: . C. albicans, C. glabrata C. parapsilosis, C. tropicalis, C. krusei Mucocutaneous Candidiasis

. Oropharyngeal . Esophageal . AIDS . Malignancies and their treatments . Proton pump inhibitor therapy . Vaginal Invasive Candidiasis

. Normally non-pathogenic . Invasive candidiasis is the price paid for advances in modern medical therapies . Primarily a nosocomial infection or associated with ambulatory “medicalized” patients Host Defenses Against Invasive Candidiasis

. Intact skin . Intact mucous membranes . Normal sphincter function . Normal neutrophil number and function Risk Factors for Invasive Candidiasis

. Exposure to broad-spectrum antimicrobial therapy . Indwelling venous devices . Total parenteral nutrition (CVC, alimentation solution) . Gastrointestinal surgery . Neutropenia Cytotoxic chemotherapy . Intestinal mucositis . Solid organ transplantation . Intravenous drug use . Low-birth-weight . Adapted from Edwards JE Jr. Candida Species In Principles and Practice of Infectious Diseases 8th Edition Risk Factors for Invasive Candidiasis

. Bloodstream . Dissemination to: . Eyes (2-20%) . Bones/joints . Skin . Liver / spleen (immunocompromised hosts) . Heart Invasive Candidiasis - Diagnosis

. Culture-based techniques . Blood, tissue, fluids . Diagnostic imaging What antifungal agent would you select from empiric treatment of this patient with candidemia? How would you treat this patient?

A. An echinocandin . Caspofungin, micafungin, anadulafungin B. Fluconazole C. Voriconazole D. Lipid-formulation amphotericin B How would you treat this patient?

A. An echinocandin . Caspofungin, micafungin, anadulafungin B. Fluconazole C. Voriconazole D. Lipid-formulation amphotericin B

Empiric Treatment of Candidemia – Non-Neutropenic Patients . Fluconazole 800 mg iv/po in patients who are not critically ill and without prior azole exposure . An echinocandin is recommended as empiric therapy when fluconazole is patients not meeting these criteria . Voriconazole offers little advantage over fluconazole for most Candida species (enhanced mould activity) . Amphotericin B has a greater potential for toxicity than other classes Treatment of Candidemia – Non-Neutropenic Patients . Antifungal susceptibility testing is recommended for all bloodstream isolates . Candida glabrata is less susceptible to azole therapy . Candida krusei is intrinsically resistant to fluconazole . Candida parapsilosis is less susceptible to echinocandins . Transition from an echinocandin (if used as initial therapy) to fluconazole is recommended once patient has stabilized and if isolate is susceptible What other processes of care are indicated for this patient? Which of the following statements is false in patients with candidemia? A. A dilated ophthalmologic examination is indicated for all patients B. Follow-up blood cultures should be performed daily until candidemia is cleared C. An echocardiogram is indicated for all patients D. All venous catheters should be removed / changed E. Recommended duration of therapy is 2 weeks after documented clearance of candidemia in patients without metastatic complications Which of the following statements is false?

A. A dilated ophthalmologic examination is indicated for all patients B. Follow-up blood cultures should be performed daily until candidemia is cleared C. An echocardiogram is indicated for all patients D. All venous catheters should be removed E. Recommended duration of therapy is 2 weeks after documented clearance in patients without metastatic complications Treatment of Candidemia – Neutropenic Patients . An echinocandin or lipid formulation of amphotericin B is recommended as initial therapy . During persistent neutropenia, transition to fluconazole can be done once patient has stabilized and if isolate is susceptible Blood culture …

Candida albicans Management and Outcome . Treatment initiated with caspofungin . Hemodynamically unstable . Lines changed . Dilated ophthalmologic examination - normal . Day 2 – afebrile . Day 3 – blood culture negative

Case 2 History

65-year-old man . PMH . Colorectal cancer - 2004 . Resection, adjuvant chemotherapy . Metastatic progression (lung, pelvis) - 2006 . Combination chemotherapy . capecitabine, irinotecan, bevacizumab . Treatment complicated by pulmonary embolism History of Present Illness

. Four weeks prior to presentation . Fever, dry cough treated with course of po antibiotics . Two-week history of purulent sputum, night sweats . Prescribed moxifloxacin Chest Radiograph History of Present Illness

. Fever resolved . Increasing dyspnea, streaky hemoptysis, anorexia, fatigue, night sweats . No cigarette smoking, IVDU . No recent travel . No history of TB exposure CT Thorax – Cavitary Lung Disease How would you investigate this patient? In consideration of a diagnosis of aspergillosis, which test is not recommended for diagnosis in this patient? A. Expectorated sputum for microbiologic and cytologic examination B. Fine needle aspiration of lesion with specimens sent for microbiologic and cytologic investigations C. Bronchoscopy with specimens sent for microbiologic and cytologic investigations D. Serum galactomannan In consideration of a diagnosis of aspergillosis, which test is not recommended for diagnosis in this patient? A. Expectorated sputum for microbiologic and cytologic examination B. Fine needle aspiration of lesion with specimens sent for microbiologic and cytologic investigations C. Bronchoscopy with specimens sent for microbiologic and cytologic investigations D. Serum galactomannan Invasive Aspergillosis - Diagnosis

. Diagnostic imaging . Culture-based techniques . Tissue, fluids Galactomannan in the Diagnosis of Aspergillosis

. A cell wall constituent that is released extracellularly . Recommended as a test for the diagnosis of invasive aspergillosis in high-risk populations . Hematologic malignancy, HSCT . Lacks sensitivity and specificity in other populations . Can be applied to bronchoscopy specimens . May be used for screening in high-risk populations – serial measurements Case – Sputum Examination

. Sputum culture . Negative for bacteria and fungi . AFB smear –negative Case – Fine Needle Aspiration

. Microbiology . Gram-stain - negative . No fungal elements seen . No bacterial or fungal pathogens isolated Cytology - Fine Needle Aspiration Cytology - Fine Needle Aspiration

. Fungal elements seen – septate hyphae, 45o angles . Foreign material seen

. Morphology compatible with Aspergillus species Aspergillus species

. Filamentous moulds . Environmental organisms – ubiquitous in soil, water Risk Factors for Invasive Aspergillosis

. Prolonged, profound neutropenia (>3 weeks) . Most common in hematological malignancies, HSCT . Solid organ transplantation . AIDS . Systemic corticosteroids . Primary immunodeficiency states (CGD) . Chronic lung disease . Anti TNFα agents . Marijuana use

Risk Factors for Invasive Aspergillosis

. Colonization . Pulmonary syndromes . Other organ disease Pulmonary Aspergillosis

. Mycetoma – “fungus ball” . Angioinvasive pulmonary aspergillosis . Chronic necrotizing pulmonary aspergillosis . Obstructing bronchial aspergillosis . HIV/AIDS . Bronchial aspergillosis – lung transplantation . Anastamotic dehiscence . Allergic bronchopulmonary aspergillosis

How would you treat this patient? Which agent is not indicated in the treatment of aspergillosis? A. Posacazole B. Caspofungin C. Amphtotericin B D. Fluconazole E. Voriconazole Which agent is not active against Aspergillus species?

A. Posacazole B. Caspofungin C. Amphtotericin B D. Fluconazole E. Voriconazole

Treatment of Aspergillosis . Voriconazole is recommended as first-line therapy for invasive aspergillosis . Early therapy is recommended in patients highly suspected for this condition while awaiting diagnostic testing results . Liposomal amphotercin B is recommended as alternative therapy . Posaconazole and isavuconazole may be used . Echinocandins are second-line therapie Management

. Voriconazole initiated . Clinical and radiographic improvement observed

Antifungal Therapy

. Amphotericin B . Broad purpose for yeasts and moulds . Nephrotoxicity . Electrolyte disturbance (K, Mg, Ca) . Infusion-related side effects (“shake and bake”) . Less adverse reactions with lipid formulations Antifungal Therapy . Triazoles . Yeast; Moulds with late generation agents (VOR, POS, ISUV) . Enhanced mould activity with posaconazole, isavuconazole . Inhibitors and substrates for CYP enzymes . drug-drug interactions

. May prolong QTc (isavuconazole may shorten QTc) . May cause hepatotoxicity . Voriconazole – photopsia . Therapeutic drug monitoring may be clinically helpful Antifungal Therapy

. EchinoCANDINS - . CANDida; second-line agent for Apergillus species . Generally well tolerated . Few drug interactions Conclusions

. Invasive fungal infections are the “collateral damage” of advances in medical therapy . Candida species and Aspergillus species are clinically important human pathogens – opportunistic pathogens . Increasing choices for antifungal therapy but … . Increasingly resistant fungi are being recognized as human pathogens