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Addressing Challenges to Optimal Diagnosis and Treatment of Invasive Fungal Infections

Addressing Challenges to Optimal Diagnosis and Treatment of Invasive Fungal Infections. ?. Pretest Audience Response Question. Which of the following transplant procedures is associated with the highest risk of IFI? Liver Lung Small bowel. :01. ?. Pretest Audience Response Question.

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Addressing Challenges to Optimal Diagnosis and Treatment of Invasive Fungal Infections

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  1. Addressing Challenges to Optimal Diagnosis and Treatment of Invasive Fungal Infections

  2. ? Pretest Audience Response Question Which of the following transplant procedures is associated with the highest risk of IFI? Liver Lung Small bowel :01

  3. ? Pretest Audience Response Question • Which of the following pathogens is the most common cause of IFI among allogeneic hematopoietic stem cell transplant (HSCT) patients? • Candida • Aspergillus • Mucorales :01

  4. ? Pretest Audience Response Question According to the most recent surveillance data, what percentage of Candida blood isolates exhibit echinocandin resistance? 1% 3% 5% :01

  5. ? Pretest Audience Response Question Which of the following therapies is preferred for the treatment and prevention of invasive aspergillosis? Polyenes Triazoles Echinocandins :01

  6. Faculty Peter G. Pappas, MD, FACP William E. Dismukes Professor of Medicine PI, Mycoses Study Group University of Alabama at Birmingham Birmingham, Alabama

  7. Faculty Disclosures • Research: Amplyx Pharmaceuticals, Astellas Pharma US, Cidara Therapeutics, Gilead Sciences, Inc., IMMY, Merck, Scynexis, T2 Biosystems, Vical

  8. Identify challenges in the diagnosis of common invasive fungal infections (IFIs) and recognize clinical circumstances that require empirical treatment Review the emerging patterns and underlying mechanisms of fungal resistance Describe current guideline recommendations for the treatment of IFIs Learning Objectives

  9. Introduction

  10. Overview • IFIs are a significant cause of serious illness and mortality in immunocompromised patients • Estimated annual incidence in the US: • Transplant and ICU patients, and patients with cancer undergoing chemotherapy, are at extremely high risk for IFIs • Each day appropriate antifungal therapy is delayed is associated with a 50% increase in mortality and an additional $5000 in healthcare costs ICU, intensive care unit. Pfaller MA, et al. Future Microbiol. 2015;11(1),103-117; Pfaller MA, et al. Clin Infect Dis. 2006;43(suppl 1):S3-S14.

  11. Common IFIs • Candida • C. albicans • C. glabrata • C. tropicalis • C. parapsilosis • C. krusei • Aspergillus • A. fumigatus • Mucorales • Cryptococcus  • Histoplasma • Coccidioides • Blastomyces • Phaeohyphomycosis

  12. IFI Incidence Among Organ Transplant Patients Re: Small bowel transplants The number of intestinal transplants performed has increased sharply, from five in 1990 to 146 in 2016 in the United States alone, according to the Organ Procurement and Transplantation Network. https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/# Transplant-Associated Infection Surveillance Network (TRANSNET) Pancreas Heart Kidney Small Bowel Lung Liver Overall 14 12 10 8 6 4 2 0 Cumulative Incidence (%) 0 90 180 270 360 Days From Transplant Kontoyiannis DP, et al. Clin Infect Dis. 2010 Apr 15;50(8):1091-100; Pappas PG, et al. Clin Infect Dis. 2010;50(8):1101-1111.

  13. IFI Incidence Among Allogeneic Hematopoietic Stem Cell Transplant Patients TRANSNET: Cumulative Incidence of IFI Candidiasis NC/NA IFI Any IFI Aspergillosis 0.15 0.10 0.05 0.00 Probability of IFI 0 3 6 9 12 15 18 21 24 Months After Transplant Corzo-Leon et al. Mycoses. 2015;58(6):325-36.

  14. Impact of IFIs in the Hospital Setting Source: Healthcare Cost and Utilization Project 2004-2005. HSC/BMT, hematopoietic stem cell or bone marrow transplant; SE, standard error, SOT, solid organ transplant. Menzin et al. Am J Infect Control. 2011;39(4):e15-e20.

  15. Importance of Early Diagnosis and Treatment for Invasive Candidiasis Garey KW, et al. Clin Infect Dis. 2006;43(1):25-31.

  16. Diagnosis

  17. Diagnostic Challenges • Signs and symptoms are nonspecific • Invasive disease is difficult to distinguish from colonization • Available tests are limited by suboptimal sensitivity and/or specificity

  18. Culture and Direct Microscopy • Culture • Tissue • Acquisition is challenging • Blood • Suitable for fragile patients • ~50% sensitivity for candidemia • Lower for Aspergillus • Can be time-consuming • Often requires expertise • Direct Microscopy • Frequent false negatives and positives • Lower sensitivity relative to culture • Often requires expertise Guarner J, et al. ClinMicrobiol Rev. 2011;24(2):247-280.

  19. Culture-independent Diagnostic Tests: Sensitivity and Specificity *Meta-analysis BAL, bronchoalveolar fluid. Pfaller MA. Invasive fungal infections and approaches to their diagnosis. In: Andrew S, Tang Y-W, eds. Methods in Microbiology. Philadelphia, PA: Elsevier;2015.

  20. Relative Advantages and Disadvantages of Diagnostic Tests Pemán J, et al. Mycoses. 2009;53(5):424-433.

  21. Pharmacologic Treatment Options

  22. Timeline of Antifungal Development Adapted from: Chapman SW, et al. Trans Am ClinClimatol Assoc. 2008;119:197-215.

  23. Antifungal Indications by Class Nett JE, et al. Infect Dis Clin North Am. 2016;30(1);51-83.

  24. Sites of Therapeutic Action Membrane function Polyenes Ergosterol synthesis Azoles Cell wall synthesis Echinocandins Nucleic acid synthesis 5-Fluorocytosine Adapted from: Moriyama B, et al. Mycoses. 2014;57(12):718-733.

  25. Isavuconazole vs Voriconazole for Invasive Aspergillosis 100 90 80 70 60 50 40 30 20 10 0 Isavuconazole Voriconazole Survival (%) Treatment difference (95% CI) -1.1 (-8.9 to 6.7) P=.744 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Study Day Maertens JA, et al. Lancet. 2016;387(10020):760-769.

  26. Isavuconazole vs Amphotericin B for Invasive Mucormycosis Isavuconazole (n=21) Amphotericin B (n=33) 100 90 80 70 60 50 40 30 20 10 0 Survival Probability (%) HR 0.831(95% CI 0.367-1.882); P=.653 0 7 14 21 28 35 42 49 56 63 70 77 84 Treatment Day Marty FM, et al. Lancet Infect Dis. 2016;16(7):828-837.

  27. Combined Azole and Echinocandin Therapy vs Azole Monotherapy in Invasive Aspergillosis 1.00 0.75 0.50 0.25 0.00 Voriconazole and anidulafungin (n=135) Voriconazole and placebo (n=142) Censored data Survival Distribution Function 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Time to Death (week) Marr KA, et al. Ann Intern Med. 2015;162(2):81-89.

  28. Important Antifungal Drug-Drug Interactions *Oral capsule; **oral solution. CYP450, cytochrome P450; OATP1B1, organic anion transporting polypeptide 1B1.

  29. Treatment Recommendations for Invasive Candidiasis • Initial therapy • An echinocandin • Fluconazole in select patients (not critically ill and unlikely to be infected with a fluconazole-resistant strain) • Susceptibility testing • Azole in clinically relevant Candida isolates • Echinocandin with prior echinocandin treatment, or C. glabrataor C. parapsilosis Pappas PG, et al. 2016 IDSA Guidelines. Clin Infect Dis. 2016;62(4):409-417.

  30. Treatment Recommendations for Invasive Candidiasis (cont’d) • L-AmB for neutropenic patients (although toxicity is a concern) • Empiric therapy: • Fluconazole for high-risk patients in adult ICUs with >5% rate of invasive candidiasis • High-risk patients: • Intra-abdominal infection • Recent abdominal surgery • Anastomotic leaks • Necrotizing pancreatitis L-AmB, liposomal amphotericin B. Pappas PG, et al. 2016 IDSA Guidelines. Clin Infect Dis. 2016;62(4):409-417.

  31. Treatment Recommendations for Invasive Aspergillosis • For suspected infection, initiate therapy during diagnostic evaluation • Triazoles preferred for invasive aspergillosis treatment and prevention • Voriconazole as initial therapy for invasive pulmonary infection • Consider combination with an echinocandin for high-risk patients • Routine susceptibility testing not recommended except for suspected azole-resistance or lack of therapeutic response • Continue therapy for at least 6 to 12 weeks Patterson TF, et al. 2016 IDSA Guidelines. Clin Infect Dis. 2016;63(4):e1-e60.

  32. Treatment Recommendations for Invasive Aspergillosis (cont’d) • AmB-d or L-AmB for initial and salvage therapy if voriconazole cannot be administered • Echinocandins as salvage therapy (alone or combination; not for routine initial monotherapy) • Prophylaxis • Initiate posaconazole, voriconazole, and/or micafungin for prolonged neutropenia • Consider aerosolized AmB with prolonged neutropenia and lung transplant Patterson TF, et al. 2016 IDSA Guidelines. Clin Infect Dis. 2016;63(4):e1-e60.

  33. Therapeutic Drug Monitoring Additional studies needed to assess role of TDM for isavuconazole and posaconazole extended-release tablet and intravenous formulations. CNS, central nervous system; GI, gastrointestinal; TDM, therapeutic drug monitoring. Patterson TF, et al. 2016 IDSA Guidelines. Clin Infect Dis. 2016;63(4):e1–e60.

  34. Prevention of IFIs

  35. Strategies for IFI Prevention • Environmental exposure reduction (frequently not feasible) • Pharmacologic prophylaxis during a period of risk

  36. Prophylactic Treatment: Low Infection Risk Discussion of the central issue surrounding when to initiate treatment Infection Prevention Safety

  37. Prophylactic Treatment: High Infection Risk Discussion of the central issue surrounding when to initiate treatment Safety Infection Prevention

  38. General Risk Factors for IFI Host predisposition Neutropenia ≥3 weeks Environmental factors Kriengkauykiat J, et al. ClinEpidemiol. 2011;3:175-191.

  39. Specific Risk Factors for Invasive Candidiasis • Colonization • Central venous catheter • Hemodialysis • Clinically unstable presentation (acute renal failure, shock, disseminated intravascular coagulation) • Surgery (complicated or repeated abdominal) • Anti-anaerobic antibiotic agents • Total parenteral nutrition or intralipid agents • Prolonged ICU stay Kriengkauykiat J, et al. ClinEpidemiol. 2011;3:175-191.

  40. Specific Risk Factors for Invasive Aspergillosis • Graft vs host disease (acute grades 2-4 or chronic) • Hematocrit type (mismatched-related donor at greatest risk) • Underlying hematologic disease (myelodysplastic syndrome or acute myeloid leukemia) • Corticosteroid (dose and duration) • T-cell-depleting therapy • Cytomegalovirus infection • Ganciclovir use • Polymorphisms (TLR4, TNF, or IL-10) • Hematopoietic cell transplantation in nonlaminar air flow room IL, interleukin; TLR4, toll-like receptor 4; TNF, tumor necrosis factor. Kriengkauykiat J, et al. ClinEpidemiol. 2011;3:175-191.

  41. Antifungal Resistance

  42. Candida Resistance Patterns in the United States Percentageof Candida blood isolates tested showing fluconazole, echinocandin, or multi-drug resistance by surveillance year Centers for Disease Control and Prevention. Fungal diseases. Invasive candidiasis statistics.https://www.cdc.gov/fungal/diseases/candidiasis/invasive/statistics.html. Accessed October 12, 2017.

  43. Azole-resistant Aspergillus fumigatus in the United States 2011-2013 • Most A isolates were itraconazole-susceptible • ~5% required an MIC > established epidemiologic cutoff value = 1 μg/mL Pham CD, et al. Emerg Infect Dis. 2014;20(9):1498–1503. 

  44. Mechanisms of Resistance • Biofilms • Drug target modification • Decreased intracellular drug levels • Regulation of drug transporters • Chromosomal anomalies

  45. Antimicrobial Stewardship: Elements of a Successful Program Create a collaborative group Identify need via audit Provide educational programs Implement local guidelines Perform Daily audits Implement rapid diagnostics Provide bedside interventions Andruszko B, et al. CurrClinMicrobiol Rep. 2016;3(3):111-119.

  46. The Multidisciplinary Team ID Specialist Pediatric ID Specialist Medical Microbiologist Hematologist Hospital Pharmacist Administrative Support Staff ID, infectious disease. Adapted from: Agrawal S, et al. J AntimicrobChemother. 2016;71(suppl 2):ii37-ii42.

  47. The Multidisciplinary Team (cont’d) ID Specialist Pediatric ID Specialist Medical Microbiologist • Patient risk factors • Conventional tests • Biomarkers • Molecular diagnostics • Imaging Hematologist Hospital Pharmacist Administrative Support Staff Adapted from: Agrawal S, et al. J AntimicrobChemother. 2016;71(suppl 2):ii37-ii42.

  48. The Multidisciplinary Team (cont’d) ID Specialist Optimal Antifungal Therapy Pediatric ID Specialist Medical Microbiologist • Patient risk factors • Conventional tests • Biomarkers • Molecular diagnostics • Imaging Hematologist Hospital Pharmacist Administrative Support Staff Adapted from: Agrawal S, et al. J AntimicrobChemother. 2016;71(suppl 2):ii37-ii42.

  49. Case Evaluations

  50. Case Evaluation #1: Patient Description John is an 18-year-old who underwent a splenectomy following a car accident. He has a central line in place and has been receiving broad-spectrum antibiotics since surgery. He develops a fever of 102° F and has negative blood cultures as part of the workup. 1

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