Case Studies in Fungal Infections and Antifungal Therapy

Wayne L. Gold MD, FRCPCAnnual Meeting of the Canadian Society of Internal MedicineNovember 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 infections3. 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

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

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. FluconazoleC. VoriconazoleD. Lipid-formulation amphotericin B

How would you treat this patient?

A. An echinocandin Caspofungin, micafungin, anadulafungin

B. FluconazoleC. VoriconazoleD. 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 allbloodstream 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 patientsB. Follow-up blood cultures should be performed daily until

candidemia is clearedC. An echocardiogram is indicated for all patientsD. All venous catheters should be removed / changedE. 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 patientsB. Follow-up blood cultures should be performed daily until

candidemia is clearedC. An echocardiogram is indicated for all patientsD. All venous catheters should be removedE. 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

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. PosacazoleB. CaspofunginC. Amphtotericin BD. FluconazoleE. Voriconazole

Which agent is not active against Aspergillus species?

A. PosacazoleB. CaspofunginC. Amphtotericin BD. FluconazoleE. 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 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