Mycology from the perspective of the Clinician

1. Mycology from the perspective of the Clinician John R. Wingard, MD University of Florida Gainesville, FL

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

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

5. Fungi as Primary Pathogens in Healthy Individuals

7. What are the major fungi I need to worry about? Coccidiomycosis Histoplasmosis Candida Aspergillus Cryptococcus Zygomycetes

8. Mortality Due to Invasive Mycoses

10. Risk for Invasive Candidiasis Is a Continuum High-risk patients Surgery Leukopenia Burns Premature infants Exposures ICU >7 days CVCs Antibiotics TPN Colonization

11. Case 1Patient 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

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 Need to verify units.Need to verify units.

17. What tests would you order? CT Check catheter Chest x Ray Urine/blood culture Percutaneous aspirate Faculty-was this percutaneous aspirateFaculty-was this 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 Awaiting CT ScanAwaiting CT Scan

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. CandidiasisSpectrum of Infection Candidiasis is a spectrum of infections which may be cutaneous, mucosal, or deeply invasive. Deeply invasive infections include candidemia, disseminated candidiasis, or single-organ candidiasis. Candida species are the most frequent cause of invasive fungal infections in neutropenic patients. Although C albicans is the most common cause of candidemia, there has been a shift to non-albicans species in recent years. This slide illustrates some of the clinical manifestations of candidiasis. Panel A shows the hand of a 47-year-old woman with refractory acute AML who developed Candida krusei fungemia and had multiple showers of cutaneous lesions such as the ones depicted. Panel B shows a patient with AML and oral candidiasis. Panel C is a computed tomography (CT) scan of a patient with AML who developed chronic systemic candidiasis. The lesions depicted here developed after recovery from neutropenia. Panel D depicts Candida chorioretinitis, a finding in nonneutropenic patients with dissemination. Candidiasis is a spectrum of infections which may be cutaneous, mucosal, or deeply invasive. Deeply invasive infections include candidemia, disseminated candidiasis, or single-organ candidiasis. Candida species are the most frequent cause of invasive fungal infections in neutropenic patients. Although C albicans is the most common cause of candidemia, there has been a shift to non-albicans species in recent years. This slide illustrates some of the clinical manifestations of candidiasis. Panel A shows the hand of a 47-year-old woman with refractory acute AML who developed Candida krusei fungemia and had multiple showers of cutaneous lesions such as the ones depicted. Panel B shows a patient with AML and oral candidiasis. Panel C is a computed tomography (CT) scan of a patient with AML who developed chronic systemic candidiasis. The lesions depicted here developed after recovery from neutropenia. Panel D depicts Candida chorioretinitis, a finding in nonneutropenic patients with dissemination.

24. Who gets Candidemia?

25. Systemic Fungal InfectionsMANAGEMENT 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 157 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)

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.

28. What are the targets for antifungal therapy? There are key differences between mammalian and fungal eukaryotic cells. This is the basis of drug selectivity. There are key differences between mammalian and fungal eukaryotic cells. This is the basis of drug selectivity.

29. Cell Membrane Active Antifungals Above are antifungals which target the cell membrane. First of all we will look at the azole family. These drugs are far less toxic than amphotericin B.Above are antifungals which target the cell membrane. First of all we will look at the azole family. These drugs are far less toxic than amphotericin B.

30. Antifungals acting on fungal DNA synthesis Flucytosine is an anti-metabolite type of antifungal drug. It is a synthetic fluorinated pyrimidine which is available for intravenous infusion or oral administration. It is marketed as Ancotil.Flucytosine is an anti-metabolite type of antifungal drug. It is a synthetic fluorinated pyrimidine which is available for intravenous infusion or oral administration. It is marketed as Ancotil.

31. Cell Wall Active Antifungals

32. Treatment Guidelines for Candidemia:Infectious Disease Society of America 20041,2 This slide presents the current guidelines of the Infectious Disease Society of America (IDSA) for the treatment of candidiasis.1,2 References: 1. Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treatment of candidiasis. Clin Infect Dis. 2004;38:161�189. 2. Perfect JR. Antifungal resistance: the clinical front. Oncology. 2004;18(suppl):15�22. This slide presents the current guidelines of the Infectious Disease Society of America (IDSA) for the treatment of candidiasis.1,2 References: 1. Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treatment of candidiasis. Clin Infect Dis. 2004;38:161�189. 2. Perfect JR. Antifungal resistance: the clinical front. Oncology. 2004;18(suppl):15�22.

35. Invasive AspergillosisUnderlying Diseases

36. Acute Invasive Aspergillosis Invasive aspergillosis may target the lungs, the sinuses, the skin, or the central nervous system (CNS). Invasive pulmonary aspergillosis (IPA) is the most common respiratory fungal infection in neutropenic patients and can be fatal. Computed tomography scans show dense, well- circumscribed pulmonary infiltrate. This may be accompanied by the �halo sign� (an area of low attenuation around a nodular lesion) followed by the �crescent sign� (an air crescent caused by contracting infarcted tissue). Chest pain, cough, and hemoptysis are other possible signs of invasive aspergillosis. These sequential thoracic CT scans show the presentation and evolution over 7 days of Aspergillus pneumonia. Caillot and colleagues analyzed 25 patients with proven IPA to establish the typical timing of CT results. In 24 of 25 patients, a CT scan was performed early after the occurrence of IPA (baseline or day 0) and a typical halo sign was observed in all scans. Subsequent sequential CT scans were obtained at approximately days 3, 7, and 14. At baseline, 100% of scans showed the halo sign. By day 7, only 22% still showed this sign. The investigators concluded that the CT halo sign is a highly effective modality for diagnosing IPA. The brief duration of the halo sign demonstrated the value of early CT. The CT crescent sign began to appear at day 3, but by day 7 it was still found on only 28% of scans. By day 14, it could be detected on 63% of scans, but the authors concluded that this sign, in contrast to the halo sign, was not useful for prompt diagnosis. Invasive aspergillosis may target the lungs, the sinuses, the skin, or the central nervous system (CNS). Invasive pulmonary aspergillosis (IPA) is the most common respiratory fungal infection in neutropenic patients and can be fatal. Computed tomography scans show dense, well- circumscribed pulmonary infiltrate. This may be accompanied by the �halo sign� (an area of low attenuation around a nodular lesion) followed by the �crescent sign� (an air crescent caused by contracting infarcted tissue). Chest pain, cough, and hemoptysis are other possible signs of invasive aspergillosis. These sequential thoracic CT scans show the presentation and evolution over 7 days of Aspergillus pneumonia. Caillot and colleagues analyzed 25 patients with proven IPA to establish the typical timing of CT results. In 24 of 25 patients, a CT scan was performed early after the occurrence of IPA (baseline or day 0) and a typical halo sign was observed in all scans. Subsequent sequential CT scans were obtained at approximately days 3, 7, and 14. At baseline, 100% of scans showed the halo sign. By day 7, only 22% still showed this sign. The investigators concluded that the CT halo sign is a highly effective modality for diagnosing IPA. The brief duration of the halo sign demonstrated the value of early CT. The CT crescent sign began to appear at day 3, but by day 7 it was still found on only 28% of scans. By day 14, it could be detected on 63% of scans, but the authors concluded that this sign, in contrast to the halo sign, was not useful for prompt diagnosis.

37. Invasive Aspergillosis Sinonasal aspergillosis has a high mortality rate in immunocompromised patients; mortality can approach 100% in some subgroups. Computed tomography findings with sinusitis include mucosal thickening and bone erosion. Full sinus eschar may be observed on the nasal turbinate(s) during physical exam. Aspergillosis of the CNS can manifest as a cerebral abscess, an epidural abscess, meningitis, or a subarachnoid hemorrhage. Mortality rates exceed 90%. Figures A and B depict a man with refractory AML who was neutropenic for more than 45 days and developed disseminated aspergillosis, including sino-orbital disease and cerebritis. Cutaneous infections are usually secondary to hematogenous dissemination from a lung infection in highly immunocompromised patients. Lesions begin as erythematous papules, become pustular, and eventually develop a central escalation covered with a black eschar surrounded by an elevated border. Cutaneous lesions can also develop as a manifestation of primary cutaneous infection where organisms enter at sites where the skin is broken. Figure C depicts a patient with multiple myeloma who developed pain and black eschar at the site of intravascular catheter insertion as a manifestation of primary cutaneous infection. Biopsy of the site revealed the presence of primary aspergillosis. Sinonasal aspergillosis has a high mortality rate in immunocompromised patients; mortality can approach 100% in some subgroups. Computed tomography findings with sinusitis include mucosal thickening and bone erosion. Full sinus eschar may be observed on the nasal turbinate(s) during physical exam. Aspergillosis of the CNS can manifest as a cerebral abscess, an epidural abscess, meningitis, or a subarachnoid hemorrhage. Mortality rates exceed 90%. Figures A and B depict a man with refractory AML who was neutropenic for more than 45 days and developed disseminated aspergillosis, including sino-orbital disease and cerebritis. Cutaneous infections are usually secondary to hematogenous dissemination from a lung infection in highly immunocompromised patients. Lesions begin as erythematous papules, become pustular, and eventually develop a central escalation covered with a black eschar surrounded by an elevated border. Cutaneous lesions can also develop as a manifestation of primary cutaneous infection where organisms enter at sites where the skin is broken. Figure C depicts a patient with multiple myeloma who developed pain and black eschar at the site of intravascular catheter insertion as a manifestation of primary cutaneous infection. Biopsy of the site revealed the presence of primary aspergillosis.

38. Case 3Patient with acute leukemia 51 yo man with AML Cytogenetics: intermediate risk category Induced with 3 + 7 (Idarubicin + cytarabine) Pneumonia at time of count recovery Bone marrow shows pt to be in CR1

39. Case 3Radiography

40. Case 3Bronchoscopy

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

43. Early Diagnosis Can Be Helpful

44. Zygomycetes Resistant to voriconazole Increased infections in setting of voriconazole prophylaxis1,2 Frequent cause of breakthrough infection in patients receiving voriconazole1,2 Increased incidence of Zygo infections at MDACC3 Case-control study of Zygo (n=27) vs IA (n=54) patients Risks among leukemia patients are diabetes, malnutrition, and voriconazole prophylaxis Fact Check: Figures from Kontoyiannis reference 3, fig 1 from article Bullet 2: abstract in Imhof article; table 1 of marty Bullet 3: see bullet 2 Bullet 4: Kontoyiannis in abstract� NOTE: For sub-bullet it says risk for leukemia patients? not sure of accuracy of this statement, as the article itself states that zygomycosis infection occurred in leukemia pts OR BMT patients (not sure if BMT population includes those with other hematologic malignancies)? PERMISSION NEEDEDFact Check: Figures from Kontoyiannis reference 3, fig 1 from article Bullet 2: abstract in Imhof article; table 1 of marty Bullet 3: see bullet 2 Bullet 4: Kontoyiannis in abstract� NOTE: For sub-bullet it says risk for leukemia patients? not sure of accuracy of this statement, as the article itself states that zygomycosis infection occurred in leukemia pts OR BMT patients (not sure if BMT population includes those with other hematologic malignancies)? PERMISSION NEEDED

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