Clinical Mycology U F Medical Students 12 05 07 Final2
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7. Top 10 fungi you need to worry about in clinical medicine Candida Candida Candida Candida Candida Candida Candida Aspergillus Aspergillus Everything else
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%
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.
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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
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
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
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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
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%
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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%
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 .
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
52. Early Diagnosis Can Be Helpful P <0.001 Greene RE, et al. Clin Infect Dis 2007;44:373-9
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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
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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
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