Mycology from the perspective of the Clinician <ul><li>John R. Wingard, MD </li></ul><ul><li>University of Florida </li></...
<ul><li>Fungi are all around us </li></ul><ul><li>We touch them, we swallow them, we breathe them </li></ul><ul><li>There ...
Why so few invasive infections? <ul><li>Dumb luck </li></ul><ul><li>Most fungi are wimps </li></ul><ul><li>Some bugs are m...
 
 
What are the major fungi I need to worry about? <ul><li>Coccidiomycosis </li></ul><ul><li>Histoplasmosis </li></ul><ul><li...
Top 10 fungi you need to worry about in clinical medicine Candida Candida Candida Candida Candida Candida Candida Aspergil...
Nosocomial Bloodstream Infections in US Hospitals: 1995-2002 BSI=blood stream infection; CoNS=coagulase-negative staphyloc...
Mortality Due to Invasive Mycoses *Adults hospitalized in the US;  † Hospitalized patients with IA;  ‡ HSCT recipients. 1....
Increased Hospital Costs Associated  With Candidemia   Total cost of candidemia: $44,536* Adverse drug reactions $610 (1.4...
Estimated Annual Costs to US Economy <ul><li>Candida $3 billion </li></ul><ul><li>Aspergillus $1 billion </li></ul>
Candida <ul><li>Yeasts </li></ul><ul><li>Pseudohyphae </li></ul><ul><li>Part of the endogenous flora </li></ul><ul><ul><li...
 
Risk for Invasive Candidiasis  Is a Continuum <ul><li>High-risk patients </li></ul><ul><li>Surgery </li></ul><ul><li>Leuko...
Case 1 Patient with Acute Leukemia <ul><li>36 yo woman with AML in CR1 given HDAC to mobilize for stem cell collection & c...
 
What does this patient have? <ul><li>Bacterial abscesses </li></ul><ul><li>Spread of leukemia to liver </li></ul><ul><li>H...
Case 2 <ul><li>43 years old male, GSW to abdomen </li></ul><ul><ul><li>Arrives in shock </li></ul></ul><ul><ul><li>1.5 lit...
Course <ul><li>Venous and urinary catheters placed, intubated </li></ul><ul><li>Cefoxitin 1 gram IV en route to OR </li></...
Post-Operative Course <ul><li>Fever persists, now day 5 </li></ul><ul><li>Awake and lethargic </li></ul><ul><li>Abdominal ...
How Would You Evaluate? <ul><li>CT </li></ul><ul><li>Check catheter </li></ul><ul><li>Chest x Ray </li></ul><ul><li>Urine/...
Findings <ul><li>Aspirate grows  E. coli </li></ul><ul><li>Antibiotics modified </li></ul><ul><li>Fever persists </li></ul>
Evaluate for Fungus? <ul><li>He has the risk factors </li></ul><ul><li>He has other causes for fever </li></ul><ul><li>Tre...
Laboratory Results <ul><li>Negative blood cultures </li></ul><ul><li>Urine culture positive for Candida  </li></ul><ul><ul...
What Is the Diagnosis? <ul><li>Line-associated candidemia </li></ul>
Key clinical features in common <ul><li>Invasive Candida infections rarely are the first infection, more commonly “superin...
Candidiasis Spectrum of Infection Images courtesy of Kenneth V. Rolston, MD, and John R. Wingard, MD. Walsh et al.  Infect...
Who gets Candidemia? 2000 2001 2002 Nguyen, unpublished data from Shands at UF
Systemic Fungal Infections MANAGEMENT <ul><li>Remove focus of infection </li></ul><ul><li>Remove/decrease immunosuppressio...
Delaying Antifungal Therapy Until Blood Cultures are Positive: A Risk for Hospital Mortality <ul><li>157 patients with can...
Catheters & Candidemia <ul><li>Non-neutropenic </li></ul><ul><ul><li>#1 source!  </li></ul></ul><ul><li>Cancer patients </...
What are the targets for antifungal therapy? Cell membrane Fungi use principally ergosterol instead of cholesterol Cell Wa...
Cell Membrane Active Antifungals Cell membrane •  Polyene antibiotics -  Amphotericin B, lipid  formulations - Nystatin (t...
Antifungals acting on fungal DNA synthesis Cell membrane •  Polyene antibiotics •  Azole antifungals DNA/RNA synthesis •  ...
Cell Wall Active Antifungals Cell membrane •  Polyene antibiotics •  Azole antifungals DNA/RNA synthesis •  Pyrimidine ana...
Candidemia:  Current Treatment Guidelines <ul><li>Amphotericin 0.6-1.0 mg/kg/day IV </li></ul><ul><li>Fluconazole 400-800 ...
Typical Epidemiology of Candidemia & In Vitro Susceptibility of  Candida  spp.   <ul><li>NOTE:  Mixed species/others ~5% <...
Trends in US Mortality Due  to Mycotic Infections United States, 1980-1997 Aspergillus Rate per 100,000 Population Year 0....
Epidemiology of Candidemia: Impact of Prior Antifungal Therapy Uzun O et al.  Clin Infect Dis  2001;32:1713-17 Before we l...
Mechanisms of antifungal resistance <ul><li>Target enzyme modification </li></ul><ul><li>Ergosterol biosynthetic pathway <...
Aspergillus <ul><li>Moulds </li></ul><ul><li>True hyphae </li></ul><ul><li>Exogenous, airborne </li></ul><ul><ul><li>Soil ...
 
Invasive Aspergillosis Underlying Diseases Patterson/ASPERFILE Study Group, MEDICINE, 2000. 595 Patients Hematologic 29% B...
Acute Invasive Aspergillosis Sequential high-resolution CTs in 25 patients with neutropenia and IPA at diagnosis: median n...
Invasive Aspergillosis Other Clinical Presentations Images courtesy of Kenneth V. Rolston, MD . Stevens et al.  Clin Infec...
Case Continued
Case 3 Patient with acute leukemia <ul><li>51 yo man with AML </li></ul><ul><li>Cytogenetics:  intermediate risk category ...
Case 3 Radiography
Case 3 Bronchoscopy Culture:  Aspergillus fumigatus
Treatment principles <ul><li>Reduce immunosuppresion, restore immunity if possible </li></ul><ul><li>Start antifungal ther...
IDSA Aspergillus Treatment Guidelines for  Primary Therapy of Invasive Aspergillosis <ul><li>Preferred therapy: </li></ul>...
Early Diagnosis Can Be Helpful P <0.001 Greene RE, et al.  Clin Infect Dis  2007;44:373-9
Zygomycetes <ul><li>Resistant to voriconazole </li></ul><ul><li>Increased infections in setting of voriconazole prophylaxi...
Summary (1) <ul><li>Invasive fungal infections occur as a result of interplay between bug, host, and antimicrobial pressur...
Summary (2) <ul><li>Candida is the most common invasive fungal pathogen in hospitalized patients </li></ul><ul><ul><li>Par...
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Clinical Mycology U F Medical Students 12 05 07 Final2

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  • Abstract/p781 Table 7/p786
  • Need to verify units.
  • Faculty-was this percutaneous aspirate
  • Awaiting CT Scan
  • 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. Walsh TJ, Hiemenz JW, Anaissie E. Recent progress and current problems in treatment of invasive fungal infections in neutropenic patients. Infect Dis Clin North Am . 1996;10:365-400. Slide 39
  • 27 34
  • There are key differences between mammalian and fungal eukaryotic cells. This is the basis of drug selectivity.
  • 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.
  • 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.
  • Invasive mycotic infections are a growing problem, especially in the settings of critical care and compromised immune function. Epidemiology provides valuable information about trends in mortality, changing rates of infection, and directions for future studies to develop more effective and specific therapies. McNeil and colleagues analyzed National Center for Health Statistics multiple-cause-of-death record tapes, which include information from all death certificates filed in the United States, for deaths due to the major systemic mycotic diseases in the years 1980 through 1997. The mortality rate for candidiasis (not associated with HIV infection) rose steadily to a peak in 1989. Since then, the rate has fallen by 50%, although it remains high. In contrast, mortality rates for aspergillosis (not associated with HIV infection) have risen steeply, peaking in 1995 with a rate of 0.42 deaths per 100,000 population. This represents a 357% increase in mortality since 1980. The investigators pointed to 3 main factors for the emergence of fungal diseases: the HIV epidemic, the many advances made in modern medicine that have created opportunities for infection (for example, solid organ transplantation and BMT), and the aging of the population. McNeil MM, Nash SL, Hajjeh RA, et al. Trends in mortality due to invasive mycotic diseases in the United States, 1980-1997. Clin Infect Dis . 2001;33:641-647. Slide 37
  • Molecular mechanisms of azole resistance. In a susceptible cell, azole drugs enter the cell through an unknown mechanism, perhaps by passive diffusion. The azoles then inhibit lanosterol 14-  demethylase ( ERG11 ) (pink circle), blocking the formation of ergosterol. Two types of efflux pumps are expressed at low levels. The CDR proteins are ABC transporters (ABCT) with both a membrane pore (green tubes) and two ABC domains (green circles). The MDR protein is an Major Facilitator transport protein (MF) with a membrane pore (red tubes). ABC transporters use ATP as their energy source, whereas MF transporters use the proton motive force. In a “model” resistant cell, the azoles also enter the cell through an unknown mechanism. In a resistant cell, the azoles are blocked from interacting normally with the target enzyme because the enzyme can be modified. Lanosterol 14-  demethylase is encoded by the gene ERG11. Several genetic alterations have been identified that are associated with the ERG11 gene of C. albicans , including point mutations in the coding region, overexpression of the gene, gene amplification (which leads to overexpression) and gene conversion or mitotic recombination. Several different specific point mutations (dark slices in pink circles) have been identified by comparing azole-resistant clinical isolate with a sensitive isolate from a single strain of C. albicans. The first point mutation to be identified within ERG11 of a clinical isolate of C. albicans which altered the fluconazole sensitivity of the enzyme was discovered in 1997 by White et al. This mutation results in the replacement of arginine with lysine at amino acid 467 of the ERG11 gene (abbreviated R467K). Overexpression of ERG11 has been described in several different clinical isolates. In each case, the level of overexpression is not substantial (less than a factor of 5). It is difficult to assess the contribution of ERG11 overexpression to a resistant phenotype, since these limited cases of overexpression have always accompanied other alterations associated with resistance, including the R467K mutation, and overexpression of genes regulating efflux pumps. In addition to alterations in the lanosterol demethylase, a common mechanism of resistance is an alteration in other enzymes in the same biosynthetic pathway (dark slices in blue spheres). The sterol components of the plasma membrane are modified (darker orange of membrane). Finally, the azoles are removed from the cell by overexpression of the CDR genes (ABCT) and MDR (MF). The CDR pumps are effective against many azole drugs, while MDR appears to be specific for fluconazole. Overexpression of the transporters may be a result of gene amplification or increased gene transcription. The more efficient removal of the azoles means that the drugs never reach their therapeutic concentrations within the cell. For more detail read: White T.C., Marr K.A., Bowden R.A. Clinical Microbiology Reviews 1998 11 ; 382-402. Available on internet at aac.asm.org/.
  • 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. Caillot D, Couaillier J-F, Bernard A, et al. Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol . 2001;19:253-259. Stevens DA, Kan VL, Judson MA, et al. Practice guidelines for diseases caused by Aspergillus . Clin Infect Dis . 2000;30:696-709. Walsh TJ, Hiemenz JW, Anaissie E. Recent progress and current problems in treatment of invasive fungal infections in neutropenic patients. Infect Dis Clin North Am . 1996;10:365-400. Slide 55
  • 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. Stevens DA, Kan VL, Judson MA, et al. Practice guidelines for diseases caused by Aspergillus . Clin Infect Dis . 2000;30:696-709. Walsh TJ, Hiemenz JW, Anaissie E. Recent progress and current problems in treatment of invasive fungal infections in neutropenic patients. Infect Dis Clin North Am . 1996;10:365-400. Slide 56
  • Pharmacology_R1 03/25/10 05:30
  • 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 NEEDED
  • Clinical Mycology U F Medical Students 12 05 07 Final2

    1. 1. Mycology from the perspective of the Clinician <ul><li>John R. Wingard, MD </li></ul><ul><li>University of Florida </li></ul><ul><li>Gainesville, FL </li></ul>
    2. 2. <ul><li>Fungi are all around us </li></ul><ul><li>We touch them, we swallow them, we breathe them </li></ul><ul><li>There are more than 100.000 fungi in nature </li></ul><ul><li>Yet only about 100 cause human disease </li></ul><ul><li>Most cause superficial infections, some cause allergic reactions </li></ul><ul><li>Few cause invasive infections </li></ul>Fungal Fast Facts
    3. 3. Why so few invasive infections? <ul><li>Dumb luck </li></ul><ul><li>Most fungi are wimps </li></ul><ul><li>Some bugs are meaner than others </li></ul><ul><li>Some people are meaner than others </li></ul><ul><li>A little of all of these </li></ul>
    4. 6. What are the major fungi I need to worry about? <ul><li>Coccidiomycosis </li></ul><ul><li>Histoplasmosis </li></ul><ul><li>Candida </li></ul><ul><li>Aspergillus </li></ul><ul><li>Zygomycetes </li></ul>
    5. 7. Top 10 fungi you need to worry about in clinical medicine Candida Candida Candida Candida Candida Candida Candida Aspergillus Aspergillus Everything else
    6. 8. Nosocomial Bloodstream Infections in US Hospitals: 1995-2002 BSI=blood stream infection; CoNS=coagulase-negative staphylococci. Surveillance and Control of Pathogens of Epidemiologic Importance (SCOPE) study. Wisplinghoff H, et al. Clin Infect Dis. 2004;39:309-317. % BSI % Crude Mortality Rank Pathogen BSI per 10,000 admissions Total (n=20,978) ICU (n=10,515) Non-ICU (n=10,515) Total ICU Non-ICU 1. CoNS 15.8 31.3 35.9 26.6 20.7 25.7 13.8 2. S aureus 10.3 20.2 16.8 23.7 25.4 34.4 18.9 3. Enterococcus spp 4.8 9.4 9.8 9.0 33.9 43.0 24.0 4. Candida spp 4.6 9.0 10.1 7.9 39.2 47.1 29.0 5. E coli 2.8 5.6 3.7 7.6 22.4 33.9 16.9 6. Klebsiella spp 2.4 4.8 4.0 5.5 27.6 37.4 20.3 7. P aeruginosa 2.1 4.3 4.7 3.8 38.7 47.9 27.6 8. Enterobacter spp 1.9 3.9 4.7 3.1 26.7 32.5 18.0 9. Serratia spp 0.9 1.7 2.1 1.3 27.4 33.9 17.1 10. A baumannii 0.6 1.3 1.6 0.9 34.0 43.4 16.3
    7. 9. Mortality Due to Invasive Mycoses *Adults hospitalized in the US; † Hospitalized patients with IA; ‡ HSCT recipients. 1. Pappas PG, et al. Clin Infect Dis . 2003;37:634-643; 2. Wisplinghoff H, et al. Clin Infect Dis. 2004;39:309-317; 3. Perfect J, et al. Clin Infect Dis . 2001;33:1824-1833; 4. Marr KA, et al. Clin Infect Dis . 2002;34:909-917. Pathogen Overall Mortality Candida spp 40% Aspergillus spp 62% Other Invasive moulds ( Fusarium spp., Zygomycetes) ~80% Scedosporium spp. 100%
    8. 10. Increased Hospital Costs Associated With Candidemia Total cost of candidemia: $44,536* Adverse drug reactions $610 (1.4%) Diagnostic procedures $1513 (3.4%) Hospital stay $37,681 (84.6%) Antifungal therapy $4710 (10.5%) *1997 dollars. Rentz AM, et al. Clin Infect Dis. 1998;27:781-788.
    9. 11. Estimated Annual Costs to US Economy <ul><li>Candida $3 billion </li></ul><ul><li>Aspergillus $1 billion </li></ul>
    10. 12. Candida <ul><li>Yeasts </li></ul><ul><li>Pseudohyphae </li></ul><ul><li>Part of the endogenous flora </li></ul><ul><ul><li>Skin </li></ul></ul><ul><ul><li>Gut </li></ul></ul><ul><ul><li>Mucosal surfaces </li></ul></ul><ul><li>Portal of entry: breach in skin or mucosa </li></ul><ul><li>Most infections are due to person’s own flora </li></ul>
    11. 14. Risk for Invasive Candidiasis Is a Continuum <ul><li>High-risk patients </li></ul><ul><li>Surgery </li></ul><ul><li>Leukopenia </li></ul><ul><li>Burns </li></ul><ul><li>Premature infants </li></ul><ul><li>Exposures </li></ul><ul><li>ICU > 7 days </li></ul><ul><li>CVCs </li></ul><ul><li>Antibiotics </li></ul><ul><li>TPN </li></ul><ul><li>Colonization </li></ul><ul><li>If candidemia develops … </li></ul><ul><li>~40% die </li></ul><ul><li>~60% survive </li></ul>CVCs=central venous catheters; TPN=total parenteral nutrition. Rex JH, et al. Adv Intern Med . 1998;43:321-369; Pappas PG, et al. Clin Infect Dis . 2003;37:634-643.
    12. 15. Case 1 Patient with Acute Leukemia <ul><li>36 yo woman with AML in CR1 given HDAC to mobilize for stem cell collection & consolidation </li></ul><ul><li>Discharged on ciprofloxacin, no fluconazole </li></ul><ul><li>Day 15 admitted for sepsis; blood cultures grew ESBL E. coli (sensitive only to imipenem, meropenem, gentamycin) </li></ul><ul><li>She received imipenem + vancomycin </li></ul><ul><li>Fever persists </li></ul><ul><li>CT scan done 7 days later </li></ul>
    13. 17. What does this patient have? <ul><li>Bacterial abscesses </li></ul><ul><li>Spread of leukemia to liver </li></ul><ul><li>Hemangiomas </li></ul><ul><li>Hepatic candidiasis </li></ul>
    14. 18. Case 2 <ul><li>43 years old male, GSW to abdomen </li></ul><ul><ul><li>Arrives in shock </li></ul></ul><ul><ul><li>1.5 liter combined blood loss from trauma and surgery </li></ul></ul><ul><ul><li>Sigmoid colon injury with fecal contamination </li></ul></ul><ul><ul><li>Renal laceration </li></ul></ul><ul><ul><li>Hypothermia and acidosis </li></ul></ul>
    15. 19. Course <ul><li>Venous and urinary catheters placed, intubated </li></ul><ul><li>Cefoxitin 1 gram IV en route to OR </li></ul><ul><li>Exploratory laparotomy </li></ul><ul><li>Left nephrectomy </li></ul><ul><li>Sigmoid colectomy and colostomy </li></ul><ul><li>6u PRBC, 4u FFP, 10u PLTS intraoperatively </li></ul>
    16. 20. Post-Operative Course <ul><li>Fever persists, now day 5 </li></ul><ul><li>Awake and lethargic </li></ul><ul><li>Abdominal exam: typical post-op </li></ul>
    17. 21. How Would You Evaluate? <ul><li>CT </li></ul><ul><li>Check catheter </li></ul><ul><li>Chest x Ray </li></ul><ul><li>Urine/blood culture </li></ul><ul><li>Percutaneous aspirate </li></ul>
    18. 22. Findings <ul><li>Aspirate grows E. coli </li></ul><ul><li>Antibiotics modified </li></ul><ul><li>Fever persists </li></ul>
    19. 23. Evaluate for Fungus? <ul><li>He has the risk factors </li></ul><ul><li>He has other causes for fever </li></ul><ul><li>Treat “presumptively” for fungus? Wait for positive fungus culture? </li></ul><ul><li>Which drug if you treat? </li></ul>
    20. 24. Laboratory Results <ul><li>Negative blood cultures </li></ul><ul><li>Urine culture positive for Candida </li></ul><ul><ul><li>C. albicans identified by PNA-FISH </li></ul></ul><ul><li>You examine his eyes </li></ul>
    21. 25. What Is the Diagnosis? <ul><li>Line-associated candidemia </li></ul>
    22. 26. Key clinical features in common <ul><li>Invasive Candida infections rarely are the first infection, more commonly “superinfections” </li></ul><ul><li>They are opportunists </li></ul><ul><ul><li>Breach in host barriers by catheters, trauma, surgery </li></ul></ul><ul><ul><li>Impaired immune defenses </li></ul></ul><ul><ul><li>Antimicrobial agents </li></ul></ul><ul><ul><ul><li>Bacterial flora suppressed by antibiotics </li></ul></ul></ul><ul><ul><ul><li>Certain fungi are suppressed by specific antifungal agents </li></ul></ul></ul><ul><li>Risk for infection determined by interplay of bug, host, and environmental pressures </li></ul><ul><ul><li>Microbe’s virulence factors </li></ul></ul><ul><ul><li>Impairment of host defenses </li></ul></ul><ul><ul><li>Selection of resistant bugs by antimicrobial agents used </li></ul></ul><ul><li>Fever often the only clinical manifestation </li></ul>
    23. 27. 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;10:365-400. Cutaneous fungemia Chorioretinitis Disseminated Mucosal
    24. 28. Who gets Candidemia? 2000 2001 2002 Nguyen, unpublished data from Shands at UF
    25. 29. Systemic Fungal Infections MANAGEMENT <ul><li>Remove focus of infection </li></ul><ul><li>Remove/decrease immunosuppression </li></ul><ul><li>Restore Immune Function </li></ul><ul><li>Begin antifungal therapy - EARLY ! </li></ul>
    26. 30. Delaying Antifungal Therapy Until Blood Cultures are Positive: A Risk for Hospital Mortality <ul><li>157 patients with candidemia </li></ul><ul><li>Initiation of antifungal therapy after blood culture </li></ul><ul><li><12 hours: 9 (5.7%) </li></ul><ul><li>12 to 24 hours: 10 (6.4%) </li></ul><ul><li>24 to 48 hours: 86 (54.8%) </li></ul><ul><li>> 48 hours: 52 (33.1%) </li></ul><ul><li>Independent determinants of hospital mortality </li></ul><ul><li>APACHE II score (one-point increments) (p <0.001) </li></ul><ul><li>Prior antibiotics (p = 0.028) </li></ul><ul><li>Administration of antifungal therapy 12 hours after the first positive blood culture (p = 0.018) </li></ul>Morrell M, et al. Antimicrob Agents Chemother 2005;49:3640-5 (n=9) (n=10) (n=86) (n=52)
    27. 31. Catheters & Candidemia <ul><li>Non-neutropenic </li></ul><ul><ul><li>#1 source! </li></ul></ul><ul><li>Cancer patients </li></ul><ul><ul><li>Tunneled lines are less often sources </li></ul></ul><ul><ul><li>The gut is probably a frequent source in neutropenic patients with mucositis </li></ul></ul><ul><ul><li>Consider changing lines. May help some pts. </li></ul></ul>Start Rx
    28. 32. 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. 1999 Introduction to Medical Mycology. Merck and Co. 2001
    29. 33. 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. 34. Antifungals acting on fungal DNA synthesis Cell membrane • Polyene antibiotics • Azole antifungals DNA/RNA synthesis • Pyrimidine analogues - Flucytosine Cell wall • Echinocandins
    31. 35. 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. 1999 Introduction to Medical Mycology. Merck and Co. 2001
    32. 36. Candidemia: Current Treatment Guidelines <ul><li>Amphotericin 0.6-1.0 mg/kg/day IV </li></ul><ul><li>Fluconazole 400-800 mg/kg/day IV or PO </li></ul><ul><li>Caspofungin 70 mg LD, then 50 mg/day IV </li></ul><ul><li>Treat for 14 days after last positive culture and resolution of signs and symptoms </li></ul><ul><li>Remove all intravascular catheters, if possible </li></ul>Pappas, Clin Infect Dis 2004; 38: 161
    33. 37. Typical Epidemiology of Candidemia & In Vitro Susceptibility of Candida spp. <ul><li>NOTE: Mixed species/others ~5% </li></ul><ul><li>S=Susceptible S-DD=Susceptible-Dose Dependent I=Intermediate R=Resistant </li></ul>Pappas PG et al, Clin Infect Dis 2004;38:161-89; Bartizal K et al, Antimicrob Agents Chemother 1997;41:2326-32; Patterson TF. J Chemother 1999;11:504-12; Pfaller MA et al, Antimicrob Agents Chemother 2002;46:1723-7; Pfaller MA et al, J Clin Microbiol 2002;40:852-6 Species Frequency % Flu Itra AmB Vori Posa Candins C. albicans 46 S S S S S S C. glabrata 20 S-DD / R S-DD / R S / I S / I S / I S C. parapsilosis 14 S S S S S S / I C. tropicalis 12 S S S S S S C. krusei 2 R S-DD / R S S S S C. dubliniensis <1 S / S-DD S S / I S / I S / I S C. lusitaniae <1 S S S / R S S S
    34. 38. Trends in US Mortality Due to Mycotic Infections United States, 1980-1997 Aspergillus Rate per 100,000 Population Year 0.6 0.4 0.2 0.0 1981 1986 1991 1996 McNeil et al. Clin Infect Dis . 2001;33:641-647. Candida
    35. 39. Epidemiology of Candidemia: Impact of Prior Antifungal Therapy Uzun O et al. Clin Infect Dis 2001;32:1713-17 Before we leave Candida: Clouds on the Horizon Breakthrough (n=49) Non-Breakthrough (n=430) Mortality: 50% vs 76%
    36. 40. Mechanisms of antifungal resistance <ul><li>Target enzyme modification </li></ul><ul><li>Ergosterol biosynthetic pathway </li></ul><ul><li>Efflux pumps </li></ul><ul><li>Drug import </li></ul>White TC, Marr KA, Bowden RA. Clin Microbiol Review 1998;11:382-402
    37. 41. Aspergillus <ul><li>Moulds </li></ul><ul><li>True hyphae </li></ul><ul><li>Exogenous, airborne </li></ul><ul><ul><li>Soil </li></ul></ul><ul><ul><li>Water / storage tanks in hospitals etc </li></ul></ul><ul><ul><li>Food </li></ul></ul><ul><ul><li>Compost and decaying vegetation </li></ul></ul><ul><ul><li>Fire proofing materials </li></ul></ul><ul><ul><li>Bedding, pillows </li></ul></ul><ul><ul><li>Ventilation and air conditioning systems </li></ul></ul><ul><ul><li>Computer fans </li></ul></ul><ul><li>Portal of entry: nasal passages, respiratory tract </li></ul><ul><li>Potential for hospital outbreaks </li></ul>
    38. 43. Invasive Aspergillosis Underlying Diseases Patterson/ASPERFILE Study Group, MEDICINE, 2000. 595 Patients Hematologic 29% BMT/Allo 25% Solid Transplant 9% AIDS 8% Other Immune 6% Pulm 9% Other 5% None 2% BMT/Auto 7%
    39. 44. 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 . 2001:19:253-259 .
    40. 45. Invasive Aspergillosis Other Clinical Presentations Images courtesy of Kenneth V. Rolston, MD . Stevens et al. Clin Infect Dis . 2000;36:696-709; Walsh et al. Infect Dis Clin North Am . 1996;10:365-400 . B. Cerebritis A. Sino-orbital disease C. Cutaneous infection
    41. 46. Case Continued
    42. 47. Case 3 Patient with acute leukemia <ul><li>51 yo man with AML </li></ul><ul><li>Cytogenetics: intermediate risk category </li></ul><ul><li>Induced with 3 + 7 (Idarubicin + cytarabine) </li></ul><ul><li>Pneumonia at time of count recovery </li></ul><ul><li>Bone marrow shows pt to be in CR1 </li></ul>
    43. 48. Case 3 Radiography
    44. 49. Case 3 Bronchoscopy Culture: Aspergillus fumigatus
    45. 50. Treatment principles <ul><li>Reduce immunosuppresion, restore immunity if possible </li></ul><ul><li>Start antifungal therapy promptly </li></ul><ul><ul><li>Polyenes </li></ul></ul><ul><ul><li>Mould-active azoles </li></ul></ul><ul><ul><li>Echinocandins </li></ul></ul><ul><li>Consider surgical resection of infarcted tissue in certain situations </li></ul>
    46. 51. IDSA Aspergillus Treatment Guidelines for Primary Therapy of Invasive Aspergillosis <ul><li>Preferred therapy: </li></ul><ul><ul><li>Voriconazole is recommended for the primary treatment of invasive aspergillosis in most patients </li></ul></ul><ul><li>Alternative Agents: </li></ul><ul><ul><li>Liposomal therapy could be considered as alternative primary therapy in some patients (AI). </li></ul></ul>
    47. 52. Early Diagnosis Can Be Helpful P <0.001 Greene RE, et al. Clin Infect Dis 2007;44:373-9
    48. 53. Zygomycetes <ul><li>Resistant to voriconazole </li></ul><ul><li>Increased infections in setting of voriconazole prophylaxis 1,2 </li></ul><ul><li>Frequent cause of breakthrough infection in patients receiving voriconazole 1,2 </li></ul><ul><li>Increased incidence of Zygo infections at MDACC 3 </li></ul><ul><ul><li>Case-control study of Zygo (n=27) vs IA (n=54) patients </li></ul></ul><ul><ul><ul><li>Risks among leukemia patients are diabetes, malnutrition, and voriconazole prophylaxis </li></ul></ul></ul>1. Marty PM et al. N Eng J Med . 2004;350:950. 2. Imhof A et al. Clin Infect Dis . 2004;39:743. 3. Kontoyiannis et al. J Infect Dis . 2005;191:1350. 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Incidence of IA per 1,000 Patient-Days 2000 2001 2002 2003 0.00 0.21 0.18 0.15 0.12 0.09 0.06 0.03 Incidence of Zygomycosis per 1,000 Patient-Days Year Aspergillus Zygomycetes Amphotericin B Voriconazole 0 1000 800 600 400 200 1800 1600 1400 1200 2000 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
    49. 54. Summary (1) <ul><li>Invasive fungal infections occur as a result of interplay between bug, host, and antimicrobial pressures </li></ul><ul><ul><li>Organism’s inherent virulence </li></ul></ul><ul><ul><li>Impaired host defenses tips balance in organism’s favor </li></ul></ul><ul><ul><li>Ecological advantage offered by suppression of other microbes in the host environment </li></ul></ul><ul><li>Invasive fungal infections are mostly opportunistic </li></ul><ul><ul><li>Take advantage of breach in host defense </li></ul></ul>
    50. 55. Summary (2) <ul><li>Candida is the most common invasive fungal pathogen in hospitalized patients </li></ul><ul><ul><li>Part of endogenous flora </li></ul></ul><ul><ul><li>Portal of entry: skin, mucosa </li></ul></ul><ul><ul><li>Fever is often the only manifestation </li></ul></ul><ul><ul><li>Usually disseminates via bloodstream </li></ul></ul><ul><ul><li>Early recognition and treatment is key to successful treatment </li></ul></ul><ul><li>Aspergillus is much less common but even more deadly </li></ul><ul><ul><li>Airborne </li></ul></ul><ul><ul><li>Portal of entry: nasal passages, respiratory tract </li></ul></ul><ul><ul><li>Pneumonia, sinusitis usual presentation </li></ul></ul>

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