Fungal infec,ons for the General Internist: Case reviews and update

Transcription

1 Fungal infec,ons for the General Internist: Case reviews and update Don Sheppard Director, Division of Infectious Diseases Professor in Medicine McGill University

2 Canadian Society of Internal Medicine Annual Meeting 2016 Conflict Disclosures Definition: A Conflict of Interest may occur in situations where the personal and professional interests of individuals may have actual, potential or apparent influence over their judgment and actions. I have received fees/honoraria and grant support from the following sources: Merck pharmaceuticals

3 Canadian Society of Internal Medicine Annual Meeting 2016 Some of the drugs, devices, or treatment modalities mentioned in this presentation are: itraconazole, fluconazole, amphotericin B, voriconazole, posaconazole, caspofungin, micafungin, anidulafungin I intend to make therapeutic recommendations for medications that have not received regulatory approval.

4 Learning objectives After completing this session the learner will be able to: Recognize common presentations of communityacquired invasive fungal infections, and confirm the diagnosis. Recognize patients at risk for, and with established hospital-acquired Candida infections, Choose the appropriate antifungal therapies for both of these groups of patients, and avoid common pitfalls of antifungal usage.

5 Case 1 47M with recurrent fever/night sweats PMH: Crohn s disease x1981 Viral pericarditis 1990 s Right pneumothorax 2005 Old TB? on CXR 2006, TST/IGRA negative Medications: 6MP and infliximab x 2006 Social: Frequent travel to Phoenix, Arizona Pet dogs and bird Smoking ~50 pack-years

6 Case 1 November-December Travel to Phoenix, Arizona and San Diego, California Jan Night sweats, chills, subjective fever (99F) RUL infiltrate on X-ray Rx 10 days Moxifloxacin February Intermittent dyspnea, SOBOE Left upper chest pleuritic pain Progression of bilateral upper lung zone consolidations

7 Case 1 September 2006 April 2013

8 CT Chest

9 What is your differential diagnosis?

10 Infectious causes Chronic pneumonia; immunocompromised host Bacterial Mycobacterial Chronic viral infection Malignancy Fungal n n n Aspergillus Dimorphic fungi Cryptococcal

11 Infectious causes Chronic pneumonia; immunocompromised host Bacterial Mycobacterial Chronic viral infection Malignancy Fungal n n n Aspergillus Dimorphic fungi Cryptococcus

12 Dimorphic fungi (Endemic Mycoses) Primary fungal pathogens Geographically restricted range Classically thermally dimorphic Yeast Form n Parasitic form n Tissue form n Cultured at 37 o C Mycelial Form n Saprophytic form n Cultured at 25 o C

13 Dimorpic Fungi (Endemic mycoses) Organism Range Environmental Associations Histoplasma capsulatum Blastomyces dermatiditis Cryptococcus gattii Coccidioides sp. Paracoccidioies brasiliensis Talaromyces marneffei

14 Dimorpic Fungi (Endemic mycoses) Organism Range Environmental Associations Histoplasma capsulatum Blastomyces dermatiditis North America River valleys Central and South America Bats (caves) Soil (construction projects) Cryptococcus gattii Coccidioides sp. Paracoccidioies brasiliensis Talaromyces marneffei

15 Dimorpic Fungi (Endemic mycoses) Organism Range Environmental Associations Histoplasma capsulatum Blastomyces dermatiditis Cryptococcus gattii North America River valleys Central and South America Manitoba to Maritimes Central and Eastern USA Bats (caves) Soil (construction projects) Beaver dams Forest exposure (?wood) Dogs highly susceptible Coccidioides sp. Paracoccidioies brasiliensis Talaromyces marneffei

16 Dimorpic Fungi (Endemic mycoses) Organism Range Environmental Associations Histoplasma capsulatum Blastomyces dermatiditis Cryptococcus gattii Coccidioides sp. North America River valleys Central and South America Manitoba to Maritimes Central and Eastern USA Pacific Northwest Tropics (particularly Australasia) Bats (caves) Soil (construction projects) Beaver dams Forest exposure (?wood) Dogs highly susceptible Pigeon droppings, Trees (native NW flora vs eucalyptus in tropics) Paracoccidioies brasiliensis Talaromyces marneffei

17 Dimorpic Fungi (Endemic mycoses) Organism Range Environmental Associations Histoplasma capsulatum Blastomyces dermatiditis Cryptococcus gattii North America River valleys Central and South America Manitoba to Maritimes Central and Eastern USA Pacific Northwest Tropics (particularly Australasia) Coccidioides sp. South West North America Desert dust Bats (caves) Soil (construction projects) Beaver dams Forest exposure (?wood) Dogs highly susceptible Pigeon droppings, Trees (native NW flora vs eucalyptus in tropics) Paracoccidioies brasiliensis Talaromyces marneffei

18 Dimorpic Fungi (Endemic mycoses) Organism Range Environmental Associations Histoplasma capsulatum Blastomyces dermatiditis Cryptococcus gattii North America River valleys Central and South America Manitoba to Maritimes Central and Eastern USA Pacific Northwest Tropics (particularly Australasia) Coccidioides sp. South West North America Desert dust Bats (caves) Soil (construction projects) Beaver dams Forest exposure (?wood) Dogs highly susceptible Pigeon droppings, Trees (native NW flora vs eucalyptus in tropics) Paracoccidioies brasiliensis Talaromyces marneffei South America Dust?

19 Dimorpic Fungi (Endemic mycoses) Organism Range Environmental Associations Histoplasma capsulatum Blastomyces dermatiditis Cryptococcus gattii North America River valleys Central and South America Manitoba to Maritimes Central and Eastern USA Pacific Northwest Tropics (particularly Australasia) Coccidioides sp. South West North America Desert dust Bats (caves) Soil (construction projects) Beaver dams Forest exposure (?wood) Dogs highly susceptible Pigeon droppings, Trees (native NW flora vs eucalyptus in tropics) Paracoccidioies brasiliensis Talaromyces marneffei South America Southeast Asia Dust? Bamboo rats

20 Infection Natural history mimics TB Infected by inhalation of airborne spores (not yeast cells) Outcome dependent on balance of host immunity and infecting inoculum Primary pulmonary infection Most asymptomatic residual granuloma or scarring Subset develop symptomatic pneumonia, most will resolve spontaneously

21 Extrapulmonary diseases Asymptomatic dissemination during primary infection detected later in life with calcified granulomas (particularly Histoplasma) Small percentage develop symptomatic disseminated disease during primary infection Can reactivate if decreased cellular immunity (pulmonary or non-pulmonary sites) Organ tropism by species n n n Coccidioidomyces and Cryptococcus CNS Blastomyces and Paracoccidioidomycosis skin, long bones and testes. Histoplasma and Talaromyces anywhere!

22 How would you work up the patient?

23 Diagnosis Clinical suspicion! Culture Respiratory samples Blood, bone marrow, CSF for disseminated disease Tissue biopsy best Serology Antibodies useful only for coccidiodomycosis, possilbly chronic histoplasmosis Antigen testing for all organisms now available

24 Fungal Antigen Testing Detects circulating fungal antigen Cross reactivity between fungi an issue Histoplasma/Blastomyces are proprietary and only performed by Mira Vista labs Sensitivity varies by disease and organism Most sensitive in disseminated disease Less sensitive in resolving disease Negative in latent disease, isolated pulmonary nodules

25 Urine Antigen Test Performance Organism Histoplasma capsulatum Blastomyces dermatiditis Sensitivity (Pneumonia) 83% acute 30% subacute 87% chronic Sensitivity (Disseminated) 92% urine 100% blood Comments 90% cross reaction with Blastomycosis 60% cross reaction with Coccidioidomycosis ~92% 88% >95% cross reaction with Histoplasmosis cases ~30% patients are urine positive, serum negative Cryptococcus sp % >95% Cross reacts with Trichosporon, higher sensitivity in HIV + patients Coccidioides sp. 50% (mild ds) 71% (mod to severe) 93% (CSF) Serum testing in mild disease was more sensitive (70%)

26 Antigen Detection in BAL Hage Resp Med 2006

27 Antigen for Follow-up Clinical relapse Ag (EIA Units) Ag (EIA Units) Time on therapy (months) Time on therapy (months) *Cryptococcal antigen kinetics are more variable

28 Antigenemia clears first on therapy Wheat EOBT 2006

29 Diagnostic workup Induced sputum AFB negative x3 Culture 1+ Candida albicans Histoplasma urine & serum antigen negative Blastomyces urine antigen negative Coccidioides urine antigen & serum IgG negative Cryptococcal antigen negative Serum galactomannan negative Patient refused BAL and biopsy

30 What would you do next?

31 Treatment of dimorphic fungal disease Severe/disseminated disease Amphotericin B / Lipid associated Amphotericin B for all organisms Moderately severe or step-down therapy Fluconazole for the CNS fungi Crypto and Cocci Itraconazole for others Voriconazole and posaconazole are options Failures described with fluconazole for Histoplasma Echinocandins are largely inactive

32 Duration of therapy General principles Most patients deserve treatment unless disease has resolved 12 weeks for acute, uncomplicated disease 12 months for disseminated disease, severe illness or immunocompromised patients Transition from AmB to azole therapy is a clinical decision rather than a specific duration Prophylaxis is NOT recommended for patients with evidence for old disease that are starting immunosuppressive therapy Close monitoring All driven by expert opinion!

33 Case 1 Rx: Fluconazole 400 mg die for presumed coccidioidomycosis (6 months) Poorly compliant 3 months after stopping therapy Recurrence of night sweats and hemoptysis Now what!?

34 Case Sputum positive for Histoplasma capsulatum Urine antigen + Re-treated with itraconazole X 12 months TDM targeting trough >1 mg / ml Symptoms resolved Cavity collapsed and left with a residual to a scarred lesion

35 Histoplasmosis Distribution River valleys Ohio, Mississippi, St Lawrence

36 Acute Pulmonary Histoplasmosis: Massive exposure

37 Disseminated Histoplasmosis- Immunocompromised patient

38 Chronic Pulmonary Histoplasmosis: Immunocompetent patient

39 Rash decisions.

40 Case 71 year old man Past History Hypertension n Novasc CVA 2007 n Residual hemiparesis Pneumonia 6 months prior to presentation n n n Cough and fever for two weeks Treated with Azithro no response 4 weeks of amoxicillin clinical and radiologic resolution

41 Case HPI Nov n n n Burnt his wrist on the woodstove Developed red lesion treated with flamazine No response January n n May n n Similar lesion on his face and thigh Face lesion spontaneously resolved over 4 weeks New lesion on chin Wrist and thigh lesion enlarging

42 July

43 Diagnosis and Management What is your differential diagnosis How would you work this up?

44 Course CXR Completely normal Scraping of tissue sent for culture and sensitivity Microscopy negative Culture n Blastomyces dermatiditis

45 Sputum cytology specimen from pneumonia 3 months prior. Sputum C+S report: 4+ yeast

46 Blastomyces Geographically restricted Sylvan acquisition common 10 1) Bas-Saint-Laurent 2) Saguenay Lac-Saint-Jean 3) Capitale-Nationale 4) Mauricie 5) Estrie 6) Montréal 7) Outaouais 8) Abitibi-Témiscamingue 9) Côte-Nord 10) Nord-du-Québec 11) Gaspésie-Iles-de-la-Madeli ˆ 12) Chaudière-Appalaches 13) Laval 14) Lanaudière 15) Laurentides 16) Montérégie 17) Centre du Québec Number of cases per individuals: >

47 Cutaneous Blastomyces during Disseminated Disease

48 What treatment would you give?

49 Followup After 4 weeks itraconazole Facial lesion resolved Hand 90% improved Thigh 70% resolved BUT. New pedal edema! Why?

50 Itraconazole adverse events Hepatitis Best described should probably moniter LFT s monthly Negative inotrope Pedal edema and CHF reported Dose dependent and reversible Drug interactions Many CYP interactions IV > suspension > tablets for serum levels AND toxicity

51 Invasive Candidiasis Management Strategies.

52 Case 84 yo male presented with abdominal pain and fever. CT scan abdomen showed diverticulitis with possible small perforation. Treated with antibiotics on the ward, improved and discharged home on ciprofloxacin and flagyl. Returned 3 d later with acute abdomen and septic shock. Emergency laparotomy with subtotal colectomy and end ileostomy.

53 Evolution of CT Abdomen Original presentation Return to ER

54 What would you do at this point? 1. Continue same antibiotics pending culture results 2. Change to broad spectrum therapy with piperacillin-tazobactam 3. Add an antifungal 4. Begin both piperacillin-tazobactam and an antifungal

55 Invasive Candidiasis Two types of diseases Bloodstream infection (sepsis) catheter or translocation Intra-abdominal candiasis (BC %) Gain entry from breaches in mucosal surfaces n Intestinal surgery or perforation n Chemotherapy (mucositis) n Intravenous catheters Two major patient populations at risk n ICU and surgical patients n Hematology-oncology patients

56 Prophylactic Antifungal Therapy in Repeat GI Surgery 60% 50% 40% 30% 20% Fluconazole Placebo 10% 0% Candida peritonitis Colonization Mortality 43 pa,ents with 2 nd surgery for perfora,on or anastamo,c leak Fluconazole 400mg qd vs placebo Eggimann et al. Cri,cal Care Medicine. 1999; 27(6): ,.

57 Case Continued. Started on piperacillin-tazobactam 48 hours later remains febrile What would you do at this point? 1. Continue broad spectrum anti-bacterial coverage and wait for culture results. 2. Add vancomycin to cover for resistant gram positives 3. Add empiric fluconazole coverage just in case. 4. Add an echinocandin because the likelihood of fungal infection is high.

58 Candidemia is common Country Sites Period # patients Incidence per 1000 admissions % Bloodstream Infections Canada % USA % India % Kothari et al. Indian J Med Microbiol 2009 Karlowsky et al. Diagn Microbiol Infect Dis 1997 Taylor et al. Mycoses 1994 Edmond et al CID 1999 Xess et al. Infection 2007 Microbiology Newsletter, Sir Gangaram Hospital, July 2007

59 Quebec ICU Surveillance Nosocomial bloodstream infections ( ) 13% CNS S. aureus Candida sp Enterococcus sp. Klebsiella sp. Enterobacter sp. Other gram - Other gram + P. aeruginosa E. coli Catheter associated bloodstream infections n=502

60 Quebec ICU Surveillance Nosocomial bloodstream infection mortality 41% Candida sp. S. aureus CNS Gram negatives Enterococcus Polymicrobial Total reported deaths = 46,

61 Data E. coli 2% Klebsiella sp. 4% Autres entérobactéries 9% Pseudomonas sp. 2% Bacillus sp. 2% Autres 6% SCN 38% Klebsiella sp. 4% Autres entérobactéries 4% S. aureus 8% Autres 4% SCN 34% Candida sp. 12% Enterococcus sp. 19% S. aureus 13% All Infections Enterococcus sp. 13% Candida sp. 27% Fatal Infections Only 12% of S. aureus were MRSA (~1% all organisms)

62 Early Appropriate Therapy is Crucial Garey K W et al. Clin Infect Dis. 2006;43:25-31 Morrell, M. et al Antimicrob. Agents Chemother. 49(9):

63 Early Source Control in Candida Sepsis is also Crucial Adequate source control Removal of any pre-existing central vein catheters Surgical or radiologic procedures to drain abscesses or other fluid collections thought to be the source of Candida infection

64 Directed therapy - Synthesis Standard approach is suboptimal Mortality remains high Strong evidence that early appropriate therapy modifies this risk Waiting for definitive microbiologic diagnosis leads to unacceptable delays New approaches Empiric therapy of high risk patients Use clinical algorithms and biomarker (diagnostic driven) approaches

65 Empiric therapy Questions: 1. Which patients should we treat? 2. How do we choose the most effective agents for empiric therapy?

66 Universal antifungal treatment Empiric fluconazole vs placebo in febrile ICU patients 40 Percent of Subjects Placebo Fluconazole 0 Composite success All Candida Invasive Candida Candidemia No significant difference in outcome Very low rates of candidemia

67 Risk factor based approaches Candida Score Sepsis (severe) Colonization (multifocal) TPN Surgery (particularly GI) CS>3 is positive Sensitivity 61%, Specificity 86% Leon et al. Crit Care Med 2006;34(3):

68 Biomarker approachs β-d-glucan Cell wall constituent of Candida and most fungi Complicated and costly assay Many false positives from sample collection and other fungi Cutoff for positivity is 80 pg/ml Sensitivity reported as 81.3% in candidiasis, specificity 83.8% for all fungal diseases

69 Prospective Multicenter Evaluation 1107 non-neutropenic ICU patients (5% IC rate) 16 % Patients developing Candidasis CS<3 CS>3 BDG<75 BDG>75 Test Sensitivity (%) Specificity (%) Candida score β-d Glucan Leon et al. Crit Care Med 2009;37(5):

70 Prospective Single Center Evaluation 95 Septic ICU patients (17% IC rate) % Patienst developing Candidiasis CS<3 CS>3 BDG<75 BDG>75 Test Sensitivity (%) Specificity (%) Candida score β-d Glucan Posteraro et al. Crit Care 2011; 15(5):R249

71 Back to our patient! Blood cultures grew yeast. What would you do now? 1. Ignore it, it s a contaminant 2. Start fluconazole 3. Start an echinocandin 4. Start Amphotericin

72 Which antifungal agent? 1. Resistance considerations 2. Efficacy 3. Cost 4. Toxicity The initial clinical decision usually occurs without final microbiology

73 Classic Resistance Profiles C. albicans Fluconazole S; Echinocandin S C. glabrata Fluconazole R/S-DD; Echinocandin S C. parapsilosis Fluconazole S; Echinocandin S/I C. tropicalis Fluconazole S; Echinocandin S C. krusei Fluconazole R; Echinocandin S

74 International Surveillance Studies on Invasive Candidiasis 80% % of Isolates 60% 40% USA Canada India 20% 0% C. albicans C. glabrata C. parapsilosis C. tropicalis C. krusei C. guillermondii Other St-Germain et al. 2006; ISHAM Chakrabarti A. J Postgrad Med 2005;51:S16-S20

75 In addition to resistance, what about Intrinsic Efficacy?

76 Is Fluconazole Non-inferior to AmB? % Successful Outcome % 70% A 58% 50% A 69% *P= % B Amphotericin B Fluconazole A = 400 mg/day B = 800 mg/day Amphotericin B + Fluconazole 0 Candidemia I Rex et al. NEJM, 1994 Canadian Candidemia Study, Phillips et al. EJCMID, 1997 Candidemia II Rex et al. CID 2003

77 Echinocandins IV only Non-toxic, no significant drug interactions Wealth of new data Broad spectrum of action against all candida sp How do they compare to fluconazole and AmB?

78 Efficacy of Echinocandins * Response (%) Caspofungin AmB 0 Micafungin L-AmB 0 Anidulafungin Fluco Reboli AC. et al. NEJM 2007;356: Kuse E-R, et al. Lancet 2007;369: Mora-Duarte J et al. NEJM 2002;347:

79 Andes et al. Clin Infect Dis 2012;54(8):

80 European Guidelines Drug Strength of Rec. Quality of Evidence Comments Echinocandins A 1 Consider local epidemiology (C. parapsilosis Fluconazole C 1 Limited spectrum, inferiority to anidulafungin, may be better than echinocandins against C. parapsilosis Liposomal AmB B 1 Similar efficacy as micafungin, higher renal toxicity than micafungin Voriconazole B 1 Limited spectrum compared to echinocandins, drug drug interactions, limitation of IV formulation in renal impairment, consider therapeutic drug monitoring

81 Back to our patient! Fluconazole started. 3 days later speciation reveals C. glabrata. Blood cultures still positive Caspofungin started. Clinical improvement ensued over 2 weeks and patient discharged to the ward.

82 So how do we put it all together Increased use of early effective therapy is necessary to improved outcomes in invasive Candidiasis Early therapy is initiated in the absence of microbiology and should be based on local epidemiology PLUS use of highly effective agents Use of Candida score or BDG is helpful to target early therapy Microbiological support is useful in guiding stepdown therapy, and managing failures or difficult cases.

83 Thank you!