Approach to Fungal Infections

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1 Approach to Fungal Infections Michelle A. Barron, M.D. Professor of Medicine Division of Infectious Diseases University of Colorado Denver Disclosures Research Investigation with Astellas Pharma, US I have no other conflicts to disclose Objectives Determine who is at risk for invasive candidiasis and mold infections Identify diagnostic tools available for diagnosis of fungal infections Understand approach to treatment for fungal infections

2 Systemic Fungal Infections: Who Is at Risk? Hematopoietic Stem Cell Transplant (HSCT) Allogeneic Nonmyeloablative Autologous Malignancy Acute leukemia Other hematologic malignancy Solid neoplasms Solid Organ Transplant (SOT) Critical Care Concomitant Lung Disease/Critical Care General Surgery Moulds Yeast Clinical Presentation #1 46 yo male with HTN, DM admitted with critical aortic stenosis Underwent AV replacement with a St. Jude valve POD #4, noted to have fever and new infiltrate in RLL Tracheal aspirate obtained Gram stain shows yeast and GNR Started on empiric IV cefepime and vancomycin Was not tolerating tube feeds, so began TPN via CVC On POD #7, started having persistent daily fevers to C and cefepime changed to IV meropenem Can You Predict if the Patient Will Develop Invasive Candidiasis?

3 Common Risk Factors For Systemic Candida Infection Colonization by Candida spp. Central venous catheterization Total parenteral nutrition (TPN) Corticosteroid administration Neutropenia Immunosuppression Chemotherapy Cancer (especially hematologic malignancy) Prolonged use of broad spectrum antibiotics Three or more antibiotics ICU stay > 4 days Mechanical ventilation > 48 hours APACHE* II score > 10 Abdominal Surgery Diabetes mellitus *APACHE Acute Physiology and Chronic Health Evaluation Candida Score Candida Score (CS) 1 point for recent surgery, colonization with Candida at multiple sites, or on TPN Additional 2 points were given if severe sepsis was present Rule validated in a prospective multicenter cohort study in non-neutropenic, critically ill patients admitted for >7 days to the ICU Rate of IC was less than 5% in patients with CS < 3 who did not receive antifungal therapy Patients with a CS >3 had an RR of 5.98 for IC León et al. Crit Care Med. 2006;34: Leon et al. Crit Care Med. 2009; 37(5): Validated Prediction Rules for Invasive Candidiasis (IC) Bacteriology and Mycoses Study Group (BAMSG) Rule - Patients in ICU > 3 days AND 1 Major Risk factor: CVC, receiving antibiotics AND 2 Minor Risk factors: TPN, HD, surgery, pancreatitis, steroids, immunosuppressants Predictive value of the rule Incidence of IC of 10% (RR=4.4) Ostrosky-Zeichner et al. Eur J Clin Microbiol Infect Dis. 2007;26:

4 Blood cultures Traditional Diagnosis 57.8% positive with 2 or more organs involved at autopsy 8.3% positive in patients with hepatosplenic candidiasis Negative: 50% Biopsies and other cultures Not always feasible Contaminant vs real? Positive fundoscopic examination Candida endophthalmitis occurs in % of candidemia cases Odabasi et al. Clin Infect Dis. 2004;39: Ostrosky-Zeichner et al. Clin Infect Dis. 2005;41: Use of Beta-D-Glucan Assay to Diagnose Candidemia Author Population Sampling Sensitivity, % Specificity, % PPV,% NPV, % Obayashi 1 Febrile patients Single Odabasi 2 AML / MDS Multiple, Ostrosky- Zeichner 3 Mohr 4 Hospitalized patients ICU patients, surveillance Single Multiple, Obayashi et al. Lancet. 1995;345: Odabasi et al. Clin Infect Dis. 2004;39: Ostrosky-Zeichner et al. Clin Infect Dis. 2005;41: Mohr et al. J Clin Microbiol. 2011; 49(1): Clinical Presentation #1 Patient remains febrile and is becoming hypotensive IVF are administered and pressors are added What should be the immediate next step for management?

5 Next Steps for Management A. Change antibiotic therapy B. Add IV fluconazole C. Add an IV echinocandin (e.g. micafungin, anidulafungin, or caspofungin) D. Send a beta-d-glucan assay E. Do nothing and monitor Time-Dependent Mortality: The Justification for Empiric Therapy Delay in treatment is an independent determinant of hospital mortality All patients (N=157) Delay, 33.1% No delay, 11.1% Hospital Mortality, % < >48 Delay in Start of Antifungal Treatment, h Morrell et al. Antimicrob Agents Chemother. 2005;49: Empiric Therapy: A Failed Attempt 270 ICU patients FLU 800 mg vs placebo Composite end point for success No fever No IFI No d/c due to toxicity No need for other antifungals Patients, % FLUC Success PLACEBO Failure Schuster et al. Ann Intern Med. 2008;149:83-90.

6 Clinical Presentation #1 Labs: WBC 15.0, Hb 13.0; Cr 1.1 Blood cultures: 3 bottles drawn on separate days all positive for yeast Susceptibilities of Candida spp. Species Flu Itra Vori Posa Isav Mica Caspo Anid L- AmB C. albicans S S S S S S S S S C. tropicalis S S S S S S S S S C. parapsilosis S S S S S S* S* S* S C. glabrata S-DD to R S-DD to R C. krusei R S-DD to R S S S S S S S to I S S S S S S S to I C. lusitaniae S S S S S S S S S to R C. auris R N/T S to R N/T N/T S S S S to R Flu= fluconazole; Itra=itraconazole; Vori=voriconazole; Posa=posaconazole; Isav=isavuconazole; Mica=micafungin; Caspo=caspofungin;Anid=anidulafungin; L-AmB= liposomal amphotericin B; S= sensitive; S-DD= sensitive to dose dependent; R= resistant; I= intermediate; N/T not tested; *Higher MICs have been reported with clinical failures Candida auris New species of Candida identified in Isolated from the external ear canal of a patient hospitalized at a Tokyo hospital Considered an emerging infection World-wide reports of infections including blood-stream infections Accounted for 5.3% of Candidemia in India CDC issued alert describing 7 US cases (5 blood stream, 1 UTI, and 1 ear infection) from May 2013-August Satoh K, et al. Microbiol Immunol 2009; 53: Vallabhaneni S, et al. MMWR, (44):

7 Epidemiology Lamoth F and Kontoyiannis DP. JID : Microbiology/Sensitivities Commonly mis-identified as C. haemulonii, C. famata, Rhodotorula glutinis, S. cerevisiae, or Candida sp. Variable resistance Most are resistant to fluconazole Variable in vitro resistance to voriconazole (range, 3-73%, of isolates) Resistance to ampho B reported in 13-35% Most are susceptible to echinocandins (5-10% resistance) Lamoth F and Kontoyiannis DP. JID : Risk Factors Case-control study compared patients with candidemia secondary to C. auris vs other Candida species in Indian ICUs 1400 pts with candidemia 74 (5.3%) were secondary to C. auris Risk factors: Longer stay in ICU Underlying respiratory illness Vascular surgery Antifungal exposure Rudramurthy SM, et al. J. Antimicrob Chemother 2017; 72:

8 Infection Control Issues Risk to public health Has potential to spread by horizontal transmission and cause outbreaks Has ability to cause severe, event fatal disease Has a multi-drug resistant profile There is a paucity of new antifungals with unique mechanisms of action Lamoth F and Kontoyiannis DP. JID : Clinical Presentation #2 Pt is a 70 yo WM s/p heart transplant 2 months PTA who presented with a complaint of loss of appetite Approximately 1.5 weeks PTA, pt developed N/V, anorexia, and cough with low-grade fever He was diagnosed at a community hospital with pneumonia and was started on antibiotics Fevers resolved, but he continued to experience cough with sputum production, malaise, and fatigue Clinical Presentation #2 CXR - left lower lobe pneumonia CT scan of the chest - left lung pleural effusion and progressive LLL consolidation What is the likely infectious cause?

9 Likely Cause of Infection A. Candida infection B. Staphylococcus aureus C. Resistant Gram negative bacteria D. Aspergillus or some other type of mold Incidence of Invasive Aspergillus Infections by Type of SOT Mean Incidence of IA (%) Liver Lung Heart Kidney Pancreas Small bowel Adapted from Singh, N. Clin Infect Dis :

10 Spectrum of Disease Invasive Aspergillosis (IA) Lungs are the most common site of disease Sinus disease also prominent in some centers CNS is the most common secondary site of invasive disease Organism grows fast and invades blood vessels Can present as cerebral hemorrhage Cutaneous disease Manifestation of hematogenous seeding from a primary focus of infection Can occur at old IV sites or open wound sites Cutaneous Aspergillus Infections Eschar Eschar at previous catheter insertion site Mays, SR, et al. Amer J Clin Derm (1): Diagnosis Definitive diagnosis requires both histopathology and cx of Aspergillus spp. Gomori methamine silver (GMS) stain and Periodic acid-schiff (PAS) stains valuable tissue stains Acute-angle branching, septated nonpigmented hyphae Histopathology cannot distinguish between Aspergillus from Fusarium and other molds Very important to always obtain cultures too

11 Which One is Aspergillus? GMS stain of Aspergillus fumigatus GMS stain of Chaetomium perlucidum Photo on left: Photo on right: Courtesy of Nancy Madinger, MD Radiographic Appearance of Invasive Aspergillosis Halo Sign Crescent Sign Galactomannan (GM) antigen tests GM is found in the cell wall of Aspergillus species It is released by the fungus into serum during its growth in tissues ELISA for GM has been validated as a surrogate marker for detection of IA with some false positive tests IDSA guidelines for the treatment of IA Resolution of GM antigenemia should not be used as a sole criterion for discontinuation of antifungal therapy Serial monitoring of GM with high-resolution thoracic CT scanning in high-risk neutropenic patients led to improved preemptive and empirical antifungal therapy Kedzierska A, et al. Eur J Clin Microbiol Infect Dis. 2007;26: Walsh TJ, et al. Clin Infect Di.s 2008;46: Maertens J, et al. Clin Infect Dis. 2005;41:

12 Utility of Galactomannan Detection in BAL Samples in Pulmonary IA # of pts Type of specimen Sens (%) Spec (%) PPV (%) NPV (%) 80* Serum BAL # Serum BAL GM detection in BAL fluid more sensitive than serum for diagnosing pulmonary IA early in untreated patients *Becker, MJ, et al. Br J Haematol : # Clancy, CJ, et al. J Clin Micro (6): IDSA Guidelines for the Tx of Aspergillosis Primary therapy: Triazoles (voriconazole, posaconazole, or isavuconazole) Therapeutic drug monitoring is recommended for voriconazole and posaconazole Alternative therapy: Amphotericin B and lipid derivatives (use when azoles cannot be used) Echinocandins effective in salvage therapy (either alone or in combination) Patterson TF, et al. CID. 2016;63(4):e1-60. Prevention in the Hospital Positive pressure rooms for immunocompromised hosts HEPA filtration in BMT wards 99.97% efficiency for removing particles >0.3 µm at >12 air changes per hour Environmental sampling Air sampling Water sampling Chang, CC, et al. Internal Medicine Journal :

13 Clinical Presentation #3 28 WM with IVDU developed redness and irritation at injection site Treated for cellulitis Area worsened and bx performed Lalayanni, C, et al. J of Hospital Infection : What is the Etiology of the Infection? A. Aspergillus B. Mucormycoses C. Candida infection D. Staphylococcus aureus Risk Factors for Mucormycosis Immunosuppression Neutropenia Corticosteroid therapy Organ transplantation HIV infection Metabolic Diabetic ketoacidosis Uncontrolled DM Deferoxamine therapy Chronic metabolic acidosis Skin or soft tissue breakdown Burn wounds Traumatic inoculation Surgical wounds Miscellaneous IVDU Neonatal prematurity Malnourishment

14 Cutaneous and Soft Tissue Disease Commonly occurs at pre-existing lesion Causes acute inflammation, tissue swelling, & pus formation with progression to necrosis Necrotizing fasciitis may occur Lesions from hematogenous seeding tend to be nodular with minimal destruction of the epidermis but with ecchymotic center Must biopsy lesions and send for histopathology & culture to diagnose Spectrum of Disease Rhinocerebral and sinus disease Most common form of Mucormycosis 2/3 occur in the setting of diabetic ketoacidosis Pulmonary disease Mostly seen in profoundly neutropenic patients or pts on prolonged corticosteroid therapy Disseminated disease Occurs in severely immunocompromised pts or in pts undergoing deferoxamine therapy Lung is the most common site Rhinocerebral Mucormycosis Rhinocerebral zygomycosis caused by Rhizopus oryzae extensive involvement of the orbit and associated MRI image

15 Treatment Reversal of underlying predisposing condition Aggressive surgical debridement of all devitalized tissue Amphotericin B deoxycholate or lipid amphotericin products should be first line Posaconazole and Isavuconazole has good activity but is active only against certain species No efficacy with fluconazole, voriconazole or Echinocandin class Questions?

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