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D- mycology Fungi introduction. Fungi are all around us We touch them, we swallow them, we breathe them There are more than 1.5 million fungal species.

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Presentation on theme: "D- mycology Fungi introduction. Fungi are all around us We touch them, we swallow them, we breathe them There are more than 1.5 million fungal species."— Presentation transcript:

1 D- mycology Fungi introduction

2 Fungi are all around us We touch them, we swallow them, we breathe them There are more than 1.5 million fungal species in nature Yet only about 100 cause human disease Most cause superficial infections, some cause allergic reactions Few cause invasive infections Fungal Fast Facts

3 Why so few invasive infections? A.Dumb luck B.Most fungi are wimps C.Some bugs are meaner than others D.Some people are meaner than others E.A little of all of these

4 Host/Pathogen Balance: Normal Circumstances Host Factors Anatomical barriers Adaptive immunity Innate defenses Virulence Fungal Burden Fungal Factors Protection Infection Why so few Invasive Infections?

5 Fungi as Primary Pathogens in Healthy Individuals

6 Conditions that disrupt immune defenses Neutropenia Immunosuppression Fungi as Opportunists

7 What are the major fungi I need to worry about? A.Coccidiomycosis B.Histoplasmosis C.Candida D.Aspergillus E.Cryptococcus F.Zygomycetes

8 Mortality Due to Invasive Mycoses Pathogen Overall Mortality Candida spp40% Aspergillus spp62% Other Invasive moulds (Fusarium spp., Zygomycetes) ~80% Scedosporium spp.100% *Adults hospitalized in the US; † Hospitalized patients with IA; ‡ HSCT recipients. 1. Pappas PG, et al. Clin Infect Dis. 2003;37: ; 2. Wisplinghoff H, et al. Clin Infect Dis. 2004;39: ; 3. Perfect J, et al. Clin Infect Dis. 2001;33: ; 4. Marr KA, et al. Clin Infect Dis. 2002;34:

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10 Risk for Invasive Candidiasis Is a Continuum High-risk patients Surgery Leukopenia Burns Premature infants Exposures ICU >7 days CVCs Antibiotics TPN Colonization If candidemia develops… ~40% die ~60% survive CVCs=central venous catheters; TPN=total parenteral nutrition. Rex JH, et al. Adv Intern Med. 1998;43: ; Pappas PG, et al. Clin Infect Dis. 2003;37:

11 Case 1 Patient with Acute Leukemia 36 yo woman with AML in CR1 given HDAC to mobilize for stem cell collection & consolidation Discharged on ciprofloxacin, no fluconazole Day 15 admitted for sepsis; blood cultures grew ESBL E. coli (sensitive only to imipenem, meropenem, gentamycin) She received imipenem + vancomycin Fever persists CT scan done 7 days later

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13 What does this patient have? Bacterial abscesses Spread of leukemia to liver Hemangiomas Hepatic candidiasis

14 Case 2 43 years old male, GSW to abdomen –Arrives in shock –1.5 liter combined blood loss from trauma and surgery –Sigmoid colon injury with fecal contamination –Renal laceration –Hypothermia and acidosis

15 Course Venous and urinary catheters placed, intubated Cefoxitin 1 gram IV en route to OR Exploratory laparotomy Left nephrectomy Sigmoid colectomy and colostomy

16 Post-Operative Course Fever persists, now day 5 Awake and lethargic Abdominal exam: typical post-op

17 What tests would you order? CT Check catheter Chest x Ray Urine/blood culture Percutaneous aspirate

18 Findings Aspirate grows E. coli Antibiotics modified Fever persists

19 Evaluate for Fungus? He has the risk factors He has other causes for fever Treat “presumptively” for fungus? (or) Wait for positive fungus culture? Which drug if you treat?

20 Laboratory Results Negative blood cultures Urine culture positive for Candida –C. albicans identified by PNA-FISH You examine his eyes

21 What Is the Diagnosis?

22 Key clinical features of Candida infections Invasive Candida infections rarely are the first infection, more commonly “superinfections” They are opportunists –Breach in host barriers by catheters, trauma, surgery –Impaired immune defenses –Antimicrobial agents Bacterial flora suppressed by antibiotics Certain fungi are suppressed by specific antifungal agents Risk for infection determined by interplay of bug, host, and environmental pressures –Microbe’s virulence factors –Impairment of host defenses –Selection of resistant bugs by antimicrobial agents used Fever often the only clinical manifestation

23 Candidiasis Spectrum of Infection Images courtesy of Kenneth V. Rolston, MD, and John R. Wingard, MD. Walsh et al. Infect Dis Clin North Am. 1996;10: Cutaneous fungemia Chorioretinitis Disseminated Mucosal

24 Who gets Candidemia? Nguyen, unpublished data from Shands at UF

25 Systemic Fungal Infections MANAGEMENT  Remove focus of infection  Remove/decrease immunosuppression  Restore Immune Function  Begin antifungal therapy - EARLY!

26 Delaying Antifungal Therapy Until Blood Cultures are Positive: A Risk for Hospital Mortality Morrell M, et al. Antimicrob Agents Chemother 2005;49: patients with candidemia Initiation of antifungal therapy after blood culture  <12 hours: 9 (5.7%)  12 to 24 hours: 10 (6.4%)  24 to 48 hours: 86 (54.8%)  > 48 hours: 52 (33.1%) Independent determinants of hospital mortality  APACHE II score (one-point increments) (p <0.001)  Prior antibiotics (p = 0.028)  Administration of antifungal therapy 12 hours after the first positive blood culture (p = 0.018) (n=9) (n=10) (n=86) (n=52)

27 Catheters & Candidemia Non-neutropenic –#1 source! Cancer patients –Tunneled lines are less often sources –The gut is probably a frequent source in neutropenic patients with mucositis  Consider changing lines. May help some pts. Start Rx

28 What are the targets for antifungal therapy? Cell membrane Fungi use principally ergosterol instead of cholesterol Cell Wall Unlike mammalian cells, fungi have a cell wall DNA Synthesis Some compounds may be selectively activated by fungi, arresting DNA synthesis. Atlas of fungal Infections, Richard Diamond Ed Introduction to Medical Mycology. Merck and Co. 2001

29 Cell Membrane Active Antifungals Cell membrane Polyene antibiotics - Amphotericin B, lipid formulations - Nystatin (topical) Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole - Posaconazole - Miconazole, clotrimazole (and other topicals)

30 Antifungals acting on fungal DNA synthesis Cell membrane Polyene antibiotics Azole antifungals DNA/RNA synthesis Pyrimidine analogues - Flucytosine Cell wall Echinocandins

31 Cell Wall Active Antifungals Cell membrane Polyene antibiotics Azole antifungals DNA/RNA synthesis Pyrimidine analogues - Flucytosine Cell wall Echinocandins -Caspofungin -Micafungin -Anidulafungin Atlas of fungal Infections, Richard Diamond Ed Introduction to Medical Mycology. Merck and Co. 2001

32 Treatment Guidelines for Candidemia: Infectious Disease Society of America ,2 Condition Primary therapy Alternative therapy Amphotericin B + fluconazole 4–7 days then fluconazole Fluconazole or caspofungin Fluconazole Non- neutropenic adults Chronic disseminated candidiasis Neutropenic adults Amphotericin B or fluconazole or caspofungin Amphotericin B (conventional or liposomal) Amphotericin B (conventional or liposomal) or caspofungin 1. Pappas PG et al. Clin Infect Dis. 2004;38:161– Perfect JR. Oncology. 2004;18(suppl):15–22.

33 Aspergillus Moulds True hyphae Exogenous, airborne Soil Water / storage tanks in hospitals etc Food Compost and decaying vegetation Fire proofing materials Bedding, pillows Ventilation and air conditioning systems Computer fans Portal of entry: nasal passages, respiratory tract Potential for hospital outbreaks

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35 Patterson/ASPERFILE Study Group, MEDICINE, Patients Hematologic 29% BMT/Allo 25% Solid Transplant 9% AIDS 8% Other Immune 6% Pulm 9% Other 5% None 2% BMT/Auto 7% Invasive Aspergillosis Underlying Diseases

36 Acute Invasive Aspergillosis Sequential high-resolution CTs in 25 patients with neutropenia and IPA at diagnosis: median number of lesions=2, bilateral in 48% Baseline: halo Day 4: ↑size, ↓halo Day 7: air crescent Halo transitory: <5 days; increased volume for 1 week → stabilization → air crescent IPA=invasive pulmonary aspergillosis. Slide courtesy of Kieren A. Marr, MD.. Caillot et al. J Clin Oncol. 2001:19:

37 Invasive Aspergillosis Other Clinical Presentations. Images courtesy of Kenneth V. Rolston, MD. Stevens et al. Clin Infect Dis. 2000;36: ;. Walsh et al. Infect Dis Clin North Am. 1996;10: B. Cerebritis A. Sino-orbital disease C. Cutaneous infection

38 Case 3 Patient with acute leukemia 51 yo man with AML Cytogenetics: intermediate risk category Induced with (Idarubicin + cytarabine) Pneumonia at time of count recovery Bone marrow shows pt to be in CR1

39 Case 3 Radiography

40 Case 3 Bronchoscopy Culture: Aspergillus fumigatus

41 Treatment principles Reduce immunosuppresion, restore immunity if possible Start antifungal therapy promptly –Polyenes –Mould-active azoles –Echinocandins Consider surgical resection of infarcted tissue in certain situations

42 IDSA Aspergillus Treatment Guidelines for Primary Therapy of Invasive Aspergillosis Preferred therapy: Voriconazole is recommended for the primary treatment of invasive aspergillosis in most patients Alternative Agents: Liposomal therapy could be considered as alternative primary therapy in some patients (AI).

43 Early Diagnosis Can Be Helpful P<0.001 Greene RE, et al. Clin Infect Dis 2007;44:373-9

44 Zygomycetes Resistant to voriconazole Increased infections in setting of voriconazole prophylaxis 1,2 Frequent cause of breakthrough infection in patients receiving voriconazole 1,2 Increased incidence of Zygo infections at MDACC 3 –Case-control study of Zygo (n=27) vs IA (n=54) patients Risks among leukemia patients are diabetes, malnutrition, and voriconazole prophylaxis 1. Marty PM et al. N Eng J Med. 2004;350: Imhof A et al. Clin Infect Dis. 2004;39: Kontoyiannis et al. J Infect Dis. 2005;191: Incidence of IA per 1,000 Patient-Days Incidence of Zygomycosis per 1,000 Patient-Days Year Aspergillus Zygomycetes Amphotericin B Voriconazole Total Grams Dispensed to Hematological Malignancy and BMT Services Sep-02 Oct-02 Nov-02 Dec-02 Jan-03 Feb-03 Mar-03 Apr-03 May-03 Jun-03 Jul-03 Aug-03 Sep-03 Oct-03 Nov-03 Dec-03 Jan-04 Feb-04 Mar-04 Apr-04

45 Summary (1) Invasive fungal infections occur as a result of interplay between bug, host, and antimicrobial pressures –Organism’s inherent virulence –Impaired host defenses tips balance in organism’s favor –Ecological advantage offered by suppression of other microbes in the host environment Invasive fungal infections are mostly opportunistic –Take advantage of breach in host defense

46 Summary (2) Candida is the most common invasive fungal pathogen in hospitalized patients –Part of endogenous flora –Portal of entry: skin, mucosa –Fever is often the only manifestation –Usually disseminates via bloodstream –Early recognition and treatment is key to successful treatment Aspergillus is much less common but even more deadly –Airborne –Portal of entry: nasal passages, respiratory tract –Pneumonia, sinusitis usual presentation


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