Originalvortrag von

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• Originalvortrag von
• Dr. Francesco Menichetti
• anläßlich des
• CANCIDAS Freestanding Symposiums
• 04.04.2003
• Hotel Bayerischer Hof, München
• Der Vortrag wurde uns mit freundlicher
  Genehmigung von Herrn Dr. Menichetti
• zur Weitergabe zur Verfügung gestellt.
• Bitte berücksichtigen Sie bei der Anwendung der
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Setting the Stage Addressing the Burden of
Fungal Infections

• Francesco Menichetti, M.D.
• Director, Infectious Diseases Unit
• Cisanello Hospital, PISA, Italy

3
IFI increasing incidence

• Hematologic malignancies (HSCT, GVHD)
• Solid organ transplant
• Surgery
• ICU

4
Mortality still unacceptably high

• 40 of all deaths from nosocomial infection are
  due to fungal infections
• Invasive candidiasis
• ICU patients gt30
• Invasive aspergillosis in neutropenic patients
• BMT gt90
• leukemia gt50

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Etiology of Fungal Infection in Cancer Patients
Candida spp(48)
Other (21)
Blastomyces Histoplasma Cryptococcus Fusarium Alte
rnaria Acremonium Mucor Trichosporon Penicillium S
accharomyces Chrysosporium Hansenula Malassezia Ph
ialophora Rhodotorula Scopulariopsis Geotrichum Cu
nninghamella Bipolaris
Aspergillus spp(31)
Data from Walsh et al. Rev Infect Dis. 1991
Bodey et al. Eur J Clin Microbiol Infect Dis.
1992 Meunier et al. Clin Infect Dis. 1992
Vazquez et al. J Infect Dis. 1993 Pannuti et
al. Cancer. 1992 Anaissie. Clin Infect Dis.
1992. Anaissie et al. Rev Infect Dis. 1989
Morrison et al. Am J Med. 1994.
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Innovations in transplant practice and the
impact on fungal infection

• Innovation Host Effect Fungal Sequelae
• Growth factors Shorter neutropenia Decrease
  infection rate
• PBSC Shorter neutropenia Decrease infection
  rate
• T cell depletion Slower CMI recovery Increase
  later infection rate
• Alternate donor Slower CMI recovery Increase
  later infection rate
• Fluconazole Decrease C. albicans
• Increase other Candida spp
• Emergence drug resistance
• Outpatient activity Increase exposure

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Increase in nosocomial primary bloodstream
infections caused by Candida spp.
Data from Lewis and Klepser. Am J Health Syst
Pharm 1999
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Bloodstream Infections Attributable to Candida
Species A Review

• Percent of Infections Reported (years studied)

Wingard, Rex et al, Nguyen et al, Present
Candida 1995 1995b 1996 StudySpecies (1952-199
2) (1989-1993) (1990-1994) (1992-1998)
Candida albicans 54 56 52 52 Candida
tropicalis 25 17 15 11 Candida glabrata 8 13 16 18
Candida parapsilosis 7 10 11 15 Candida
krusei 4 2 4 2 Candida spp 2 2 2 2
Reprinted with permission from Pfaller et al.
Diagn Microbiol Infect Dis. 1999.
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Candida non-albicans in certain malignancies

• Disease group Pathogen
• Solid tumors lymphoma C. glabrata
• C. parapsilosis
• Leukemia C. tropicalis
• Bone Marrow Transplant C. krusei
• Wingard, Clin Infect Dis 1995 20 115

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General patterns of susceptibility of Candida
species

• Candida species Fluconazole Itraconazole 5FC AmB
• C. albicans S S S S
• C. tropicalis S S S S
• C. parapsilosis S S S S
• C. glabrata S-DD/Ra S-DD/Rb S S/I
• C. krusei R S-DD/Rb I/R S/I
• C. lusitaniae S S S S/R
• a15 resistant b46 of glabrata and 31 krusei
  resistant

Rex. IDSA consensus panel. Clin Infect Dis
200030662
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Azole resistance of Candida bloodstream
infections
Pfaller. Antimicrob Agents Chemother 200044747
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Fungal outbreaks in BMT patients receiving
fluconazole

• CommonFungal species Author Resistant? source?
  
• C. krusei Wingard Yes Yes
• C. glabrata Wingard Yes ?
• C. parapsilosis Bowden No Yes

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Risk factors for fluconazole-resistant
Candidiasis in HIV-infected patients

• Factor Cases Controls P value
• Days of therapy 272 14 lt0.001
• No. treatments 3.1 1.8 0.004
• CD4 count 11 71 0.004
• Maenza, J Infect Dis 173 219, 1996

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Predictive value of Candida surveillance cultures

• Species Positive Negative
• C. albicans
• Sandford, 1980 2 100
• Pfaller, 1987 15 91
• Martino, 1989 12 99
• C. tropicalis
• Sandford, 1980 60 98
• Pfaller, 1987 58 94

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Management of patients with candidemia

• Debated issues
• What antifungal agent
• CVC removal

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Should indwelling intravenous catheters be
changed in candidemic patients?

• 15 of 20 investigators would change all
  nonsurgically implanted lines
• 5 of 21 investigators would change surgically
  implanted lines (i.e. Hickman , Broviac), and 16
  would attempt to sterilize the blood

Consensus on the management of severe candidal
infectionsEdwards JE et a. Clin Infect Dis 1997
2543-59
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Candida mannoproteinemia (MP) to differentiate
CVC-related candidemia from invasive disease
(ID) Girmenia et al. J Clin Microbiol
199735903-6



1/31(3.2) MP positive /all serum samples
8/16 (50) MP positive/ all serum samples
15/36 (42) MP positive/ all serum samples
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Types of non-Candida fungal infections

• Aspergillus spp. 70
• Fusarium 8
• Alternarium 5
• Others 17
• Morrison, Am J
  Med 1994 96 497

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Invasive Aspergillosis Mortality Review of
Literature after 1995
Review of 1941 Patients from 50 Studies
Lin S-J et al, Clin Infect Dis 2001 32358-66
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Invasive aspergillosis responses to
antifungal therapy by host group
Patterson TF, et al. Medicine, 200079250-60
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Incidence Risk factors after allogeneic
peripheral blood transplants

• No. 395
• 162 myeloablative
• 162 myeloablative, CD34 selected
• 71 reduced intensity conditioning regimen
• 50 cases in 46 pts (14) 32 cases of
  aspergillus
• Risk factors for non-Candida fungal infections
• Moderate or severe GVHD OR 4.6, p 0.0001
• Steroid prophylaxis OR 2.1, p 0.04
• Risk by no. of factors
• None 4
• One 11
• Two 33
• Martino, Blood 98 (11) 208a, Abstract 8662001

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Epidemiology of Aspergillus Infections in Marrow
Transplantation

• 158 pts with invasive aspergillosis
• Increase in incidence from 5.7-11.2
• Bimodal onset 16 and 96 days after transplant
• Within 40 days underlying disease, donor type,
  season and no laminar flow increased risk
• After 40 days age, underlying disease, donor
  type , GVHD, neutropenia, and steroid use,
  increased risk
• Only 31 of patients neutropenic

Wald et al, JID 19971751459
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Aspergillosis in Transplant
Prevalence Outcome

• Type Invasive Colonized MR
  Attributable MR
• Liver 1.7 0.5 87 16.9
• Lung 8.4 10.4 55 9.3
• Heart 6.2 no data 78 15.4
• Renal 0.7 1.7 75 no data
• Pancreas 1.0 no data 100 no
  data
• BMT 6.4 2.2 92 92

Singh, Focus 1998
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Liver transplant trends in IFIs

• Reassessment of need/type of IFI prophylaxis in
  liver transplants?

Singh N et al. Transplant 2002736367
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Diagnosis aspergillosis

• Positive sputum culture or bronchial washings
  strong presumptive evidence of invasive infection
  in susceptible patients
• Histopathology with silver or PAS staining for
  blood vessel invasion
• CT scan may detect halo sign or air-crescent sign
• Sandwich ELISA for galactomannan may have high
  sensitivity (85)
• PCR tests useful but lack specificity

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Evolution of CT scan images in IPA
Air-space consolidation
halo sign
air-crescent sign
D 0 - 5
D 5 - 10
D 10 - 20
Neutropenia
Caillot et al. 2001
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Aspergillus galactomannan detection
Verweij PE. ICAAC, 2001(Abstract 1276)
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IDSA Practice Guidelines for Aspergillus

• Early management
• Prompt, aggressive diagnosis (BIII)
• Therapy initiated on suspicion of diagnosis
  (BIII)
• Antifungal therapy
• Intravenous therapy initiated (BIII)
• AmB deoxycholate at max. doses (1-1.5 mg/kg/d)
  (BIII)
• Lipid AmB impaired renal function or intolerance
  (AII)
• Itraconazole oral therapy, sequential use (CIII)
• Adjunctive therapy Surgery, combinations,
  immunotherapy (CIII)
• New therapies and diagnostic tools needed to
  improve prognosis

Stevens DA et al, Clin Infect Dis 200030696-709
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Antifungals mechanisms of action

• Amphotericin B ergosterol synthesis (fungal
  plasma membrane)
• Azoles lanosterol ? ergosterol (14
  ?-demethylase)
• Flucytosine fungal protein synthesis
• Echinocandins fungal cell wall (glucan
  synthesis)

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Rationale for antifungal combinations

• Different mechanism of action
• Possible synergism
• Increasing fungistatic/cidal activity may be
  useful in the compromised host
• Combination therapy might reduce the emergence of
  resistance (?)
• Combination therapy might reduce the required
  dose for any single drug (less toxicity and cost)

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Caspofungin plus Amphotericin B in vitro

• In vitro synergy study of caspofungin (Cas)
  cAmB against 14 Aspergillus 6 Fusarium
  clinical isolates
• Checkerboard antifungal susceptibility tests
• Cas cAmB synergistic or additive no
  antagonism
• Arikan S. et al. AAC 2002 46 245-247

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Kontoyannis D.P. et al. ICAAC 2002, Abstract
M-1820
Caspofungin plus Ambisome for IA in vivo

• Caspofungin plus Ambisome for IA in pts with HM
• 50 pts 28 with documented IA, 22 with possible
  IA
• 45 received combo as primary therapy 55 as
  salvage t.
• Overall response 46
• Response in documented IA 21 in probable IA
  77
• Response in documented IA as primary therapy
  41 as salvage therapy in refractory IA 6
  only!!!

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Caspofungin plus Voriconazole in vitro

• In vitro study against 48 clinical isolates of
  Aspergillus spp.
• MICs determined by the NCCLS broth microdilution
  method
• Synergy, defined as an FIC index lt 1, was
  detected in 87.5 of the interactions
• Partial synergism (FIC index of 1.0 to 2.0) was
  found in 8.3
• No antagonism was observed
• Animal models required to validate the in vitro
  data

Perea S. et al. AAC 2002, 46 3039-41
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Caspofungin plus Voriconazole animal model

• Immunosuppressed transiently neutropenic guinea
  pig model of IA
• Mortality occurred in 12 of 12 untreated controls
• Mortality in 4/12 treated with 1 mg/Kg/day and
  6/12 with 2.5 mg/Kg/day of caspofungin
• No mortality occurred with CAS plus VRC (or VRC
  alone)
• Combination therapies with Cas and VRC reduced
  colony counts in tissues 1.000-fold over those
  for the controls
• CAS plus VRC was the only regimen that
  significantly reduced the number of positive
  cultures

Kirkpatrick WR et al. AAC 2002, 46 2564-68
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CAVEAT

• Combination antifungal therapy is routinely
  used in many hematological units !!
• We need more data
• In vitro experiments and animal models may
  suggest what should be tested in humans (?)
• Narrative-based medicine (well described case
  report, combining lab and clinical informations)
  may be useful to plan RCTs
• New antifungal drugs (Ambisome, Caspofungin,
  Voriconazole) very expensive (also for NHS in
  developed countries) combinations may be budget
  destroyers !!!!

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Summary

• Increasing incidence of invasive fungal
  infections
• Changing epidemiology and more species
• Need for faster and more specific diagnosis
• New antifungal drugs
• Need for new therapeutic strategies