????t??se?? ?a? ? ?e?ape?a t???

1
????t??se?? ?a? ? ?e?ape?a t???

• ???a S??ad?
• ?a???????

2
????t??se?? st? ??T

• O? s?st?µat???? µ???t?as???? ???µ??e?? st? ??T
  ap?te???? ??a p??ß??µa p?? s??e??? a????eta?.
• ? Candida e??a? t? s????te?? pa?????? a?t??.
• ?p?te?e? t? t?ta?t? ? p?µpt? s????te?a
  ap?µ????µe?? µ???????a??sµ? se ?a??????e?e?
  a?µat??.

Wagner, Antimicrob Agents Chemother
1995392520-2522 Trick, CID 200235627-30
3
Ep?pt?s? µ???t?as???? ???µ??e??
Candida, other fungi
Gram (-) bacilli 48
Vincent JL. JAMA 1995274639
4
The epidemiology of sepsis in the United States
from 1979 through 2000
Martin GS, et al. N Engl J Med,
2003348(16)1546-54
5
?p?d?µ??????a µ???t??se?? st? ??T

• ??µ?µ???te? ?a? ?f?µ???te?
• Candida sp gt 80 ???? t?? µ???t?? p?? p???a????
  ??s???µe?a??? ???µ??e??
• ?spergillus spp.
• A?ad??µe?a pa?????a (Fusarium,Rhizopus, ?a)

Trick WE et al. Clin Infect Dis
200235627 Beck-Sague CM et al. J Infect Dis
19931671247 CDC. Am J Infect Control 200331481
6
?a?????te? ???d???? ??a ???µ??? ap? Candida spp.

• ???t???ste??e?d?
• ?e?t????? ?a?et??e?
• ?p????sµ?? ap? Candida
• ??t?ß??t???
• ?e????????? ep?µßas?
• ??µ???a??a ?ast?e?te?????
• ?a?et??e? ??ste??
• ?ef???? a?ep???e?a

• ?????a
• ?a??t?? ??s??
• ?????e?a ??s??e?a?
• ???a????? ae??sµ??
• ????ap??? µeta???se??
• ?a?e?te???? d?at??f?
• ??ast??e?? ?2 ?p?d?????
• ??t?µ???t?as??? p??f??a??

Eggimann P. Lancet Infect Dis 20033685
7
?a?????te? ???d???? ??a d????t??? aspe??????s?
st? ??T

• ?etaµ?s?e?s? µ?e??? t?? ?st??
• ??µat???????? ?a????e?e?
• ???s??atasta?t??? ?e?ape?a
• ?etaµ?s?e?s? s?µpa??? ??????? (?pa?, ?ef???)
• S?st?µat??? ??s?µa
• ?????a ap?f?a?t??? p?e?µ???p??e?a
• ?????s? ?pat??
• Te?ape?a µe ste??e?d?
• ?a?atetaµ??? ??s??e?a st? ??T

Vandewoude KH et al. J Hosp Infection
200456269 Meersseman W et al. Am J Respir Crit
Care Med 2004170621-625
8
Autopsy study in university hospital 8000
autopsies (1978-1992), 74 autopsy rate
Groll AH, Trends in the postmortem epidemiology,
J Infect 96 3323
9
Te?ape?a µ???t?as???? ???µ??e?? st? ??T

1. ??te p??pe? ?a a???se? a???? µe a?t?µ???t?a??
   f??µa?a
2. ???? e??a? t? ?at?????? f??µa??

10
E?????? t?? a?t?µ???t?as????
Echinocandins, voric?nazole,
AmBisome
Amphocil
Abelcet
itraconazole
fluconazole
terbinafine
ketonazole
miconazole
5-flucytosine
Amphotericin B
Nystatin
Griseofulvin
1950
1960
1970
1990
2000
1980
11
??µ? t?? µ???t??
??tta???? t????µa
??tta???? µeµß????
?????a?
12
??????S??? ???S?S ???????????S??O? F?????O?

• S???es? DNA ?a? p??te????
• pe?taµ?d???
• ??faµ????e?

• ??tta???? t????µa
• S???es? ?????????
• ??????a?d??e?

• ??tta??p?asµat??? µeµß????
• S???es? e???ste?????
• ????e?
• ???????a ?µf?te?????? ?/ ??stat???

• ???f???? ????? st???? d??s??
• S??µat?sµ?? µ????s????a????, p???ap?as?asµ??
  ??tt???? ?.a.
• G????e?f???ß???

• ??d??µes?? µetaß???sµ??
• S???es? ?????e?????? ?????, aµ??????? ?a?
  p???aµ????
• ???µe??p??µ?
• S???faµe???a????
• 5-f???????t?s???

13
?µf?te?????? ?

• ?p?µ??????e ??a p??t? f??? t? 1953
• ??ast??? ??a?t? t?? pe??ss?t???? µ???t??
• Candida, Cryptococcus
• Aspergillus, Mucor, Rhizopus
• Histoplasma capsulatum, ?a.
• ?p?????? ste???? µ???t?? µe a?t??? st?? ???
• C.lusitaniae, Aspergillus terreus
• Y???? p??te???s??des? (95)
• ?ata??µeta? se ????? t??? ?st???

14
???????a (?µf?te?????? ?,??stat???)
AmB
15
??p?? d??s?? t?? ?µf?te???????
16
???s? st?? µeµß???? t?? ??tt???? t?? ???ast????
Amphotericin B
Cell Membrane
Cholesterol
17
??????t?ta de?????????? ???

• ?µese? a?ep. e????e?e?, p?? eµfa?????ta? ?at? ?
  ???? µet? t?? ????s?
• p??et??, ????, a???e??a, ?a?t?a, ?µet??,
  ?efa?a???a
• spa???te?a ?p?tas?, e????µa, a????sa?e?
  d?ata?a???, a????µ?a ?.a.

18
??????t?ta de?????????? ???
? ??e?a ?ef???? a?ep???e?a p?? p???a?e? ? ???
ap?te?e? t? ?????te?? p??ß??µa st??? as?e?e?? t??
??T

• ??ep. e????e?e? p?? eµfa?????ta? µet? t?? ????s?
• ??p??? s?µpt?µata, ???µß?f?eß?t?? (s????)
• ?ef??t?????t?ta (s????)
• ?ef???? a?ep???e?a
• ?ef??s????a??a?? ????s?
• ???ß? ?ef????? s?µp????s??
• ?p??a??a?µ?a ?a? ap??e?a ?a???? ap? t??? ?ef????
• ???e? ??e?t????t???? d?ata?a???
• ??µat????????
• ??a?µ?a (s????)
• T??µß?pe??a, ??s???f???a, a????????tta?a?µ?a
  (sp???a)

19
??p?d?a??? µ??f?? ?µf?te??????? ?
20
??p?d?a??? µ??f?? ?µf?te??????? ?
21
??p?d?a??? µ??f?? ?µf?te??????? ?

• ??e??e?t?µata se s??s? µe t?? ????? ???
• ?e??µ??? ?ef??t?????t?ta
• ?e??µ??e? a?t?d??se?? s?et???µe?e? µe t?? ????s?
  (p??et?? ?a? ?????)
• S?????t??? µe ??? se d??f??e? µe??te? de?
  fa??eta? ?a ????? µe?a??te?? ap?te?esµat???t?ta.
• ?e?????t?µa ????? ??st??

22
Key Biopharmaceutical Differences of the
Amphotericin B Formulations
AmB-d Fungizone L-AmB AmBisome ABLC Abelcet ABCD Amphotec
Mol AmB 34 10 35 50
Lipid Config. Micelles SUVs Ribbon-like Disk like
Diameter (µm) lt 0.4 0.08 1.6-11.0 0.12-0.14
Dosage 0.5-1 mg/kg 3-5 mg/kg 5 mg/kg 3-4 mg/kg
Cmax (vs. AmB-d) - Increased Decreased Decreased
AUC (vs. AmB-d) - Increased Decreased Decreased
Vd (vs. AmB-d) - Decreased Similar Increased
Cl (vs. AmB-d) - Decreased Increased Similar
Nephrotox.
Infusion Tox. High Mild Moderate Moderate
Groll, Piscetelli and Walsh Adv. Pharmacol
199844343-500.
23
????e?

• ?µ?da???e?
• ???t??µa????
• ?????a????
• ?et????a????
• ???a???e?
• F??????a????
• ?t?a???a????
• ???????a????
• ??sa???a????

24
???a??sµ?? d??s?? t?? a?????
?a??ste????
????ste????
C14-?-deµe????s?
25
?? ????e? pa?eµßa????? st? ß??s???es? t??
????ste?????
Azole target is a P450 enzyme Azoles also
effect mammalian P450 enzymes
Cell Wall
Cell Membrane
Ergosterol
26
T??a???e?

• ????t?stat????
• ??ast???? ??a?t? Candida sp. ?a? Cryptococcus sp.
• ?? ?e?te?e? t??a???e? (ß??????a????,
  p?sa???a????) e??a? µ???t??t??e? ??a?t? e?d??
  Aspergillus ?a? Fusarium.
• ?????ep?d???? µe ?1-a?t??staµ?????,
  a?t??e?p?asµat???, ste??e?d?, a?t?µ????ß?a??,
  ?p??e?d?, f??µa?a t?? ?a?d?a??e?a???, ????f??µa?a.

27
T??a???e???ep???µ?te? ?????e?e?

• S?µpt?µata apt? ?ast?e?te???? (?a?t?a, ?????a??
  ?????, ?µet??, d??????a).
• ??????µa
• ?efa?a???a
• ????s? ?pat???? e???µ?? se 1 ?? 7 t??
  pe??pt?se??
• Se ??????s? ?????? d?se?? ?t?a???a????? ??e?
  a?afe??e? ?p??tas?, ?p??a??a?µ?a ?a? pe??fe????
  ??d?µa.

Luna et al. Otolaryngol Clin North Am
200033(2)277-99
28
F??????a????

• ?????e?ta? ?a? ap? t? st?µa ?a? e?d?f??ß?a
• ?? ??a t??t? pe??p?? t?? C.non-albicans e??a?
  a??e?t??? st? f??????a????
• ? C.krusei pa???s???e? p??ta a?t???
• ? C.glabrata s?????? d?s?e?a?t?µe??
• ?e? d?a ??a?t? ?f?µ???t??

29
?t?a???a????

• ??e??e?te? t?? f??????a????? st? f?sµa t??, af??
  pe???aµß??e? ?a? t??? asp?????????
• ?e???e?te? fa?µa??????t???
• ???a? p??t?µ?te?? t? per os d????µa t??
  ?t?a???a????? se ?????de?t????, p?? a????e? t?
  ß??d?a?es?µ?t?t? t?? ?at? 30

30
???????a????

• ?a?????? t?? f??????a?????
• POS ?a? IV
• ??s?????a se s?st?µat??? µ???t?as?
• 6 mg/kg o? d?? p??te? d?se??
• 3-4 mg/kg ???e d?de?a ??e?
• Se pe??pt?s? ?p?a? ?pat???? a?ep???e?a?, ? d?s?
  ?a p??pe? ?a µe???eta? st? µ?s?, µet? ap? µ?a
  a????? d?s? f??t?s??
• Se as?e?e?? µe ???a?s? ??eat?????? lt50ml/min,
  p??t?µ?te?? ? ap? t?? st?µat?? ??????s?.

31
???????a????

• In vitro d?ast???t?ta ?a? ?at? t?? a??e?t???? st?
  f??????a???? Candida sp, pe???aµß????ta? ?a? t??
  C.krusei, ?a??? ?a? ?at? Aspergillus sp,
  Fusarium sp ?a? Penicillium marneffei
• ?e? e??a? d?ast??? ??a?t? ????µ???t??
• ??de??e?? ??????s??
• Se s?st?µat??? aspe??????s?
• Se d????t???? ???µ??e?? ap? e?d? Candida
  a??e?t??? st? f??????a????
• Se s?ßa??? ???µ??e?? ap? Scedosporium spp ?a?
  Fusarium spp.

32
???????a????

• ??ep???µ?te? e????e?e?
• ??ast????µe? d?ata?a??? ???se??
• ??ata?a?? ?pat???? e???µ??

33
??sa???a????

• ?a?????? t?? ?t?a???a?????, e????sta
  ?dat?d?a??t?
• ??a??s?µ? µ??? se ap? t?? st?µat?? µ??f?
• ???? e??? f?sµa d?ast???t?t?? p?? ?a??pte?
  p???????? ??µ?µ???te? ?a? ?f?µ???te?, ?p??
  Candida spp, Aspergillus spp, Fusarium spp,
• Scedosporium spp, Bipolaris, ?a? Zygomycetes
• ????te?e? a????ep?d??se?? µe ???a f??µa?a se
  s??s? µe t?? ???e? a???e?

34
??????a?d??e?

• ??p?pept?d?a
• ? s???et?s? t?? ?????????, ß??s?eta? st??
  p?asµat???tta???? µeµß???? ?a? pa???e?
  ß-(1,3)-D-????????
• ? ß-(1,3)- D-???????? e??a? e?d??? st??? µ???te?
  Candida spp ?a? Aspergillus spp
• ? Cryptococcus neofomans ??e? ?????? a-(1,3) ?
  a-(1,6) ???????? ?a? ??? a?t? de? e??a?
  e?a?s??t??

35
??????a?d??e? ??p?? d??s??
b-(1,6)-glucan
Fungal cell wall
Phospholipid bilayer of the fungal cell membrane
b-(1,3)-glucan
Ergosterol
b-(1,3)-glucan synthase
36
?etaß??? t?? s???es?? t?? ??tta????? t????µat??
37
?etaß??? t?? s???es?? t?? ??tta????? t????µat??
38
E?????a?d??e?-F?sµa ??a?t? ??µ?µ???t??

• ????t??t??e? ??a?t? Candida spp. ?e???aµßa??µ????
  p????? e?d?? a??e?t???? st? f??????a????
• C. albicans C. tropicalis C. glabrata C.
  krusei lt C. parapsilosis C. lusitaniae
• ?aµµ?a d?ast???t?ta ??a?t? C.neoformans

Kuhn et al. Antimicrob Agent Chemother
2002461773-80.
39
??????a?d??e?
F?sµa

• Candida albicans
• C. glabrata
• C. guillermondii
• C. krusei
• C. parapsilosis
• C. pseudotropicalis
• C. tropicalis
• C. lusitaniae

• Aspergillus spp
• Histoplasma capsulatum
• Paracoccidiodes sp
• Coccidiodes immitis
• Pneumocystis carinii

40
??????a?d??e?

• ?asp?f??????? 2001
• ???af??????? 2005
• ??s?fa???? ?a?t??t?as?
• ???f??a?? se µetaµ?s?e?s? µ?e???
• ????t???af??????? 2006
• ??s?fa???? ?a?t??t?as?
• ?a?t??ta?µ?a
• ?e??t???t?da
• ??d??????a?? ap?st?µata ap? Candida spp.

41
?asp?f???????

• Ydat?d?a??t?, µ??? ?F.
• ?????? ?µ?se?a? ???? 9-10 ??e?
• ?etaß????eta? ?????? st? ?pa?
• S???e?t???eta? st? ?pa?, t??? p?e?µ??e?, t???
  ?ef???? ?a? t? sp???a
• ?????ep?d?? µe ?????sp?????, ta?????µ???.

42
?asp?f???????

• ??de??e?? ??????s??
• ?a?t??ta?µ?a
• ?e??t???t?da ? ?????a?? ap?st?µa ap? Candida sp.
• Aspe??????s? p?? de? a?tap?????eta? st? ?e?ape?a
  µe ???a a?t?µ???t?as???
• ?µpe????? ?e?ape?a p??et?? a???st?? a?t??????a?
  se ??dete??pe?????? as?e?e??.

43
Te?ape?a µ???t?as???? ???µ??e?? st? ??T

1. ??te p??pe? ?a a???se? a???? µe a?t?µ???t?a??
   f??µa?a
2. ???? e??a? t? ?at?????? f??µa??

44
St?at?????? ??????s?? a?t?µ???t?a???

1. ???f??a?t??? ??????s? se as?e?e?? ?????? ???d????
   p?? de? pa???s?????? s?µpt?µata ???µ????
2. ?µpe????? a???? se s?µpt?µat????? as?e?e?? ??
   ?p???? ????? pa?????te? ???d???? ??a s?st?µat???
   µ???t?as?
3. ??asta?t??? a???? (pre-emptive) se s?µpt?µat?????
   as?e?e?? ?????? ???d???? p?? ????? ??p??a
   e???µata, ???????, a?t????????? ? e??ast???a??
   p?? ??t??? t?? ?p???a µ???t?as???? ???µ????
4. Te?ape?a ap?dede??µ???? µ???t?as???? ???µ????.

45
DIAGNOSTIC TESTS FOR INVASIVE CANDIDIASIS
culture histology
antigen antibody mannan
PCR 1-3-ß-D-glucan
C-Reactive Protein (CRP), procalcitonin
(PCT), interleukin-6 (IL-6)
46
TIMING OF THE INTERVENTION
Peter Donnelly Ben dePauw
prophylaxis
empirical
pre-emptive
47
Te?ape?a µ???t?as???? ???µ??e?? st? ??T

1. ??te p??pe? ?a a???se? a???? µe a?t?µ???t?a??
   f??µa?a
2. ???? e??a? t? ?at?????? f??µa??

48
???F?????

• F??????a????
• ?p?te?esµat??? se ?s??? ????? ?p?ß???e? se
  µetaµ?s?e?s? µ?e??? t?? ?st?? ? ?pat??
• ?eta-a????s? ???f??a?? µe f??????a???? se
  ?e??????????? as?e?e?? ??T µe??s?
  µ???t?as???? ???µ??e??, a??? ep?ß??s? ?d?a.
• ? p??f??a?? se ????? t??? ?e??????????? as?e?e??
  st? ??T de? s???st?ta?

Goodman et al, NEJM1992326845-851 Winston et
al, Ann Intern Med 131729-737 Shorr et al, Crit
Care Med 20051928-1935
49
??????S??S-???F?????-???T????? ??S?S
??ata?a?? f?a?µ??
?????t??? ??s??
??????? ap????sµ??
???f??a??
50
????????? / ???S???????

• S???st?ta? se as?e?e?? p?? ?????
• ?p????sµ? µe Candida sp. se p????? est?e?
• ?????? pa?????te? ???d????, ?p?? pa?atetaµ???
  ???s? a?t?ß??t????, ?e?t????? ??aµµ??,
  pa?e?te???? d?at??f?, ?e??????e?? (?d?a?te?a st?
  ?ast?e?te????) ?a? pa?atetaµ??? pa?aµ??? st? ??T
• ???et?? p?? de? µp??e? ?a ap?d??e? se ???? a?t?a

Pappas et al, Clin Infect Dis 200438161-189
51
????????? / ???S???????

• ???s?µ?p????µe?a f??µa?a
• F??????a????
• ?µf?te?????? ?
• ?asp?f???????
• ???????a????
• ?? a???se? a???? µe e????? f?sµat?? ?a? µet?
  ap?µ????e? µ???ta? µe e?a?s??s?a st?
  f??????a????, s???st?ta? ap????µ???s?.

52
S?????t??? F?sµa ??ast???t?ta? ??t?µ???t?a???
Fa?µ????

• ????te? AMB FCZ
  ITZ VZ PCZ RCZ CF MF AF
• Candida albicans
• Candida tropicalis
• Candida parapsilosis
• Candida krusei
• Candida glabrata
• Cryptococcus neoformans
• Histoplasma capsulatum
• Blastomyces dermatitidis
• Coccidiodes immitis
• Paracocci brasiliensis
• Pneumocystis carinii
• Aspergillus fumigatus
• Mucor spp
• Rhizopus spp
• Fusarium spp

????te? ??? FCZ ITZ
VZ PCZ RCZ CF MF AF
Adapted from JP Donnelly
53
Susceptibilities of Aspergillus spp. and
Non-Aspergillus moulds
susceptible
Diekema DJ, et al. J Clin Microbiol 2003413623
54
????S???F?S
55
G?? ?? ???F???T??? ????? ??????????

• ???????s?
• ????µ? d?????s?
• G??s? t?? s?µpe??f???? t?? e?????
• ???a??? a?t?µet?p?s?

56
PREVENTION