Invasive Fungal Diseases 2018: Updates for Internists

Transcription

1 Invasive Fungal Diseases 2018: Updates for Internists Methee Chayakulkeeree, MD, PhD Associate Professor, Division of Infectious Diseases and Tropical Medicine Department of Medicine, Faculty of Medicine Siriraj Hospital Mahidol University, Bangkok, Thailand

2 Topics: Updates on Yeasts Candida spp. Cryptococcus spp. Molds Hyaline molds Aspergillus spp. Fusarium spp.

3 Invasive Candidiasis

4 Pathogenesis of Invasive Candidiasis Invasive candidiasis Candidemia Deep seated candidiasis: Intra abdominal candidiasis* Kullberg, BJ, Arendrup, MC. N Engl J Med 2015; 373:

5 Disseminated Candidiasis Chorioretinitis Hepatosplenic abscess Skin lesions

6 Candidemia >250,000 people/year with > 50,000 deaths Incidence: 2 and 14 cases per 100,000 persons 6.87 cases per 1000 ICU patients Mostly in ICUs and neutropenic patients 4th most common bloodstream infection Mortality 25 60% 1. Arendrup MC. Curr Opin Crit Care 2010; 16: Cleveland AA, et al. PLoS One 2015; 10: e Wisplinghoff H, et al. Clin Infect Dis 2004; 39:

7 Risk Factors for Invasive Candidiasis Broad spectrum antibiotics Neutropenia Multifiocal Candida colonization Central venous catheter Major abdominal surgery Immunosuppressive agents Medical co morbidities or interventions: diabetes, burns, hemodialysis, parenteral nutrition 1. Kullberg, BJ., and Arendrup, MC. N Engl J Med 2015;373: Chakrabarti, A. Intensive Care Med. 2015, 41,

8 Immunoparalysis in Sepsis Immunoparalysis in sepsis

9 Antifungal Susceptibility Species Fluconazole Itraconazole Voriconazole Posaconazole Amphotericin B Echinocandins C. albicans S S S S S S C. tropicalis S to R S S S S S C. parapsilosis S S S S S S to R C. glabrata S DD to R S DD to R S DD to R S DD to R S to I S C. krusei R S DD to R S S S to I S S DD, Susceptible dose dependent; I, Intermediate; S, Susceptible Prior azole exposure is important! Modified from CID 2009: 48:503 35

10 Antifungal Susceptibility Species Fluconazole Itraconazole Voriconazole Posaconazole Amphotericin B Echinocandins C. albicans S S S S S S C. tropicalis S to R S S S S S C. parapsilosis S S S S S S to R C. glabrata S DD to R S DD to R S DD to R S DD to R S to I S C. krusei R S DD to R S S S to I S C. lusitaniae S S S S S to R S C. guilliermondii S to R S to R S to r S to r S S to R C. auris R R R R R S to r S DD, Susceptible dose dependent; I, Intermediate; S, Susceptible Prior azole exposure is important! Modified from CID 2009: 48:503 35

11 Candida auris in the NEWS 4 th November 2016

12 Candida auris Often multidrug resistant to most antifungal drugs Difficult to identify with standard laboratory methods Can be misidentified in labs without specific technology Infection control issues: outbreaks in healthcare settings Can survive on surface for 4 weeks auris qanda.html

13 Candida auris: Susceptibility No established MIC breakpoints 93% resistant to fluconazole > 50% of C. auris isolates were resistant to voriconazole 35% resistant to amphotericin B 7% resistant to echinocandins 41% resistant to 2 classes 4% resistant to 3 classes auris alert.html Lockhart SR, et al. Clin Infect Dis 2017; 64;

14 Species Distribution of Candida in Asia Tan BH., et al. Clin Microbiol Infect 2015; 21:

15 Species Distribution of Candida in Asia Tan BH., et al. Clin Microbiol Infect 2015; 21:

16 Species Distribution of Candida in Asia All Brunei Korea Philippines Singapore Taiwan Thailand Vietnam C. albicans C. tropicalis C. parapsilosis C. grabrata C. krusei Tan TY., et al. Med Mycol 2016; 54: 417 7

17 Invasive Candidiasis Positive blood culture 75% Positive blood culture 38% Candidemia Missing 50% for Deep seated blood culture candidiasis Positive tissue culture ~ 40% Clancy and Nguyen CID 2013;56:

18 Diagnostic Tests Tests Sensitivity Specificity Turn around time Blood culture NA hours Βeta D glucan hours Candida mannan antigen and hours anti mannan antibody PCR In house hours SeptiFast hours T2 Candida panel hours Kullberg BJ and Arendrup MC.N Engl J Med 2015;373:

19 The EMPIRICUS Study Empirical Micafungin Treatment and Survival Without Invasive Fungal Infection in Adults With ICU Acquired Sepsis, Candida Colonization, and Multiple Organ Failure Timsit JF, et al. JAMA. 2016;316(15):

20 INTENSE Study Adults who presented with a generalized or localized intraabdominal infection (community acquired or nosocomially acquired) requiring surgery and an ICU stay Empirical antifungal treatment did NOT show benefit in candidemia and intra abdominal candidiasis Knitsch W, Vincent JL, Utzolino S, et al. Clin Infect Dis 2015;61:1671 8

21 Candidiasis Guidelines Non-neutropenia IDSA guidelines 2016 ESCMID guidelines 2012 Recommendation Evidence SoR QoE Echinocandins (caspofungin, micafungin, anidulafungin) Liposomal amphotericin B 3-5 mg/kg/day Strong Moderate A I Strong Low B I Fluconazole mg/day Strong Moderate C I Voriconazole 6/3 mg/kg/day - - B I Amphotericin B lipid complex 5 mg/kg/day Amphotericin B deoxycholate mg/kg/day Strong Low C II - - D I Pappas PG, et al. CID 2016;62:e1 50 Cornely OA, et al. Clin Microbiol Infect 2012; 18 (Suppl. 7): 19 37

22 Candidiasis Guidelines Neutropenia IDSA guidelines ESCMID guidelines Recommendation Evidence SoR QoE Echinocandins (caspofungin, micafungin, anidulafungin) Liposomal amphotericin B 3 5 mg/kg/day Strong Moderate A (Cas, Mic) B (Anid) Strong Moderate B II II Fluconazole mg/day Weak Low C II Voriconazole 6/3 mg/kg/day Weak Low C II Amphotericin B lipid complex 5 mg/kg/day Amphotericin B deoxycholate mg/kg/day Strong Low C II D II Pappas PG, et al. CID 2016;62:e1 50 Cornely OA, et al. Clin Microbiol Infect 2012; 18 (Suppl. 7): 19 37

23 บ ญช ยาหล กแห งชาต บ ญช จ.2 Micafungin ในกรณ ด อยา fluconazole ด อยา fluconazole หมายถ ง หร อ ม ผลทดสอบความไวของเช อ candida ย นย นว าด อต อย า fluconazole ม ความเส ยงส งท เช อจะด อยา fluconazole ได แก เป น non albicans Candida ร วมก บม > ประว ต ใช ยา กล ม triazoles มาก อนมากกว า 7 ว นภายใน 3 เด อน หร อ > ให ก ารร กษาด วยยา fluconazole ไปแล วนาน 5 ว น และย งม ผลเพาะเช อใน เล อดข นเช อ candida อย ด งน น ต องเพาะเช อข น

24 บ ญช ยาหล กแห งชาต บ ญช จ.2 Micafungin ในกรณ ไม สามารถใช Amphotericin B ไม สามารถใช ยา amphotericin B ได เน องจากเก ดหร อเคยเก ด อาการไม พ งประสงค จากการใช ยา amphotericin B ม ความร นแรงระด บ 3 ข นไป2 และไม สามารถควบค มด วยว ธ การอ น ๆ ได เช น egfr< 60 ml/min (ท งน ต องไม ใช ผ ป วยท ม ภาวะไตวายเร อร งท ได ร บ การท า long term renal replacement therapy อย เด ม) ผ นแพ ยา

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26 Life Cycle of Cryptococcus

27 Pathogenic cryptococci Cryptococcus neoformans Reservoir: bird excreta Infect mainly immunocompromised hosts Cryptococcus gattii Reservoir: eucalyptus tree Infect mainly in immunocompetent hosts

28 Cryptococcus gattii The Giant Capsule C. neoformans vs. C. gattii

29 L-canavanine glycine bromothymol blue (CGB) agar: C. gattii C. gattii C. neoformans

30 Current species Proposed species Cryptococcus neoformans (serotypes A and D) Cryptococcus neoformans Cryptococcus deneoformans Cryptococcus gattii (serotypes B and C) Cryptococcus gattii Cryptococcus deuterogattii Cryptococcus tetragattii (Cryptococcus decagattii) Cryptococcus bacillisporus

31 Cryptococcosis Clinical presentations Meningoencephalitis* Pulmonary cryptococcosis Cutaneous cryptococcosis Disseminated cryptococcosis Other forms Risk Factors HIV/AIDS (CD4 < 100 cells/mm 3 ) Corticosteroid/Immunosuppressive treatment Organ transplantation Normal host (?) anti GM CSF autoantibodies

32 Clinical Characteristics C. neoformans C. gattii Host (mainly in) Immunocompromised Immunocompetent Organ involvement CNS > Lungs Lungs > CNS Complications Cryptococcoma Hydrocephalus Large lesion Less More Antifungal susceptibility More susceptible to fluconazole Less susceptible to fluconazole Treatment response Good Required more surgical intervention and prolonged antifungal treatment Clin Microbiol Rev 2014;27(4): , IDSA guideline 2010 for cryptococcosis Clin Infect Dis 1995;21(1):28 34, Braz J Mcrobiol 2015;46(4):

33 Pulmonary Cryptococcosis in NON- HIV C. gattii

34 Pulmonary Cryptococcosis in a 70-yearold Non-HIV Woman CXR CT Chest Serum cryptococcalantigenpositive 1:32

35 A 57-year-old man post KT 8 year Mucormycosis Cryptococcosis

36 CNS Cryptococcosis in a 66-yearold non-hiv Man CT abdomen C. gattii molecular VGI CT brain

37 A Woman post Tsunami Hit A 48 year old woman hit by tsunami while walking on the beach on Lanta island A very small puncture wound was found over the left shin in which got worse after 2 weeks of antibacterial treatment Culture was sent and grew C. gattii, molecular type VGII (Picture from other source) Post treatment Cutaneous cryptococcosis Leechawengwongs M, et al. Medical Mycology Case Reports 2014;6:31 33

38 Diagnosis India ink preparation Staining: Gram, Wright Culture Cryptococcal antigen Serum and CSF Sensitivity % and specificity 93 98%

39 Antifungal Treatment of Cryptococcosis 1. Cryptococcal Meningoencephalitis in HIV** 2. Cryptococcal Meningoencephalitis in Transplant Recipients 3. Cryptococcal Meningoencephalitis in non HIV and non transplant Patients 4. Nonmeningeal Cryptococcosis

40 Treatment of Cryptococcal Meningoencephalitis in HIV Patients Antifungal treatment Duration Evidence Induction therapy - Amphotericin B ( mg/kg/d) + 2 weeks A I flucytosine or 5 FC (100 mg/kg/d)* - L AMP (3 4 mg/kg/d) + 2 weeks B II flucytosine or 5 FC (100 mg/kg/d) - Amphotericin B ( mg/kg/d) or L AMP (3 4 mg/kg/d) monotherapy 4 6 weeks B II Alternatives for induction therapy - Amphotericin B (0.7 mg/kg/d) + fluconazole (800 mg/d) 2 weeks B I Consolidation therapy: fluconazole (400 mg/d) 8 weeks A I Maintenance therapy: fluconazole (200 mg/d) > 1year A I *Discontinue of secondary prophylaxis when CD 4 > 100 cells/mm 3 and virological suppressed for 3 months CID 2010;50:

41 Combination Therapy in Cryptococcal Meningitis 5 FC ถ กบรรจ ในบ ญช ยาหล ก แห งชาต บ ญช ง. Day JN, et al. N Engl J Med 368;14:

42 Management of Increased ICP As important as antifungal treatment CSF pressure 25 cm with symptoms LP to reduce OP 50% or to normal (20 cmh 2 O) Persistent pressure 25 cm with symptoms Repeat LP daily until stabilized for > 2 days Consider temporary percutaneous lumbar drains or ventriculostomy Permanent ventriculoperitoneal (VP) shunts when Fail conservative measures Perfect et al. CID 2010;50

43 Cryptococcal Diseases and HIV Isolated cryptococcal antigenemia in HIV Positive serum cryptococcal antigen without disease Treated with oral fluconazole 400 mg for weeks Antiretroviral therapy should be initiated 4 6 weeks after treatment of cryptococcal meningoencephalitis

44 Cryptococcal Diseases in Non- HIV Meningoencephalitis in non HIV Lack of evidence based study Preferred a longer induction therapy (4 6 weeks) Tend to have neurological deficit and cryptococcomas Extra CNS disease Non severe: oral fluconazole 400 mg/day 6 12 months Severe or cryptococcemia: treat as CNS disease Perfect et al. CID 2010;50

45 Hyalohyphomycosi s

46 Invasive Aspergillosis 70% of invasive mold infections Commonly caused by Aspergillus fumigatus Most common pulmonary aspergillosis Risk Factors Neutropenia** Chemotherapy Corticosteroid use Transplants (stem cell and solid organ)

47 Halo sign, Air crescent sign, Cavities ULTRAVIST 370 LOC: THK: 7 FFS IV contrast Late Arterial Phase R L ma: 123 KVp: 120 Acq: 4 C: -585 W: W 1800

48 Diagnosis of Invasive Aspergillosis Definite case Histopathology: septate hyphae with acute angle branching Differential diagnosis: Fusarium and Scedosporium Culture

49 Diagnosis of Aspergillosis Using Galactomannan Galactomannan Serum and BAL galactomannan is recommended in hematologic malignancies and HSCT BAL but NOT serum galactomannan can be used for routine blood screening in patients receiving mold active antifungal agents Can be used for treatment monitoring บ ญช ยาหล กแห งชาต บ ญช จ.2 สามารถใช BAL galactomannan เป นเกณฑ ในการร บยา Voriconazole ได Patterson TF., et al. Clin Infect Dis 2016;63(4):e1 60

50 2016 IDSA Guidelines for Management of Invasive Aspergillosis Primary treatment Voriconazole (strong recommendation; high quality evidence) Duration: at least 6 12 weks Alternative therapies Liposomal AmB (strong recommendation; moderate quality evidence) Isavuconazole (strong recommendation; moderate quality evidence) Has activity against mucormycosis Less adverse effect than voriconazole Tablet: Good absorption (better than posaconazole suspension) IV form: No cyclodextrin Combination antifungal therapy with voriconazole and an echinocandin Considered in select patients with documented IPA (weak recommendation; moderate quality evidence) Patterson TF., et al. Clin Infect Dis 2016;63(4):e1 60

51 A 30 year old male with leukemia and prolonged chemotherapy induced neutropenia

52 Blood Culture: Fusarium solani Skin lesions found in 60 80% Multiple papules or deep set, painful nodules, ulcerated, pus draining, echthyma gangrenosum

53 Diagnosis Beta D glucan and galactomannan Skin biopsy: Septate hyphae Resemble Aspergillus Culture: Skin biopsy culture Positive blood culture about 50 % Branching septate hyphae and microconidia Macroconidia

54 Treatment of Fusariosis No standard treatment established Survival is always associated with the recovery from neutropenia Antifungal therapy Voriconazole** Amphotericin B high dose ( mg/kg/day) * บ ญช ยาหล กแห งชาต บ ญช จ.2 Voriconazole สามารถใช ในการร กษา fusariosis และ scedosporiasis

55 Thank you Aspergillus fumigatus

56 SiID 2018