Case Studies in Fungal Infections and Antifungal Therapy

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 8 th Edition

Invasive / Disseminated 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

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

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, 45 o 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

Aspergillosis Clinical Syndromes 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

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 QT c (isavuconazole may shorten QT c ) 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