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Antifungicele sistemice

Prof. dr. Vasile Luca


Clinica de Boli Infecioase Iai

Tipul de factori (boal)


Factori asociai gazdei

Criterii
Neutropenie < 500 PN/mmc timp de > 10 zile
Febr persistent >96 ore refractar la terapie antibiotic
adecvat
Temperatur > 38C sau < 36C sau una din urmtoarele
condiii n utlimele 60 zile:
Neutropenie (> 10 zile)
Utilizare recent sau curent de imunosupresoare cu 30
zile nainte
Existena unui episod dovedit sau probabil de infecie
fungic invaziv ntr-un episod anterior de neutropenie (>
10 zile)
Coexistena SIDA
Semne i simptome sugestive pentru sindromul gref contra
gazd
Utilizare prelungit de corticoizi (> 30 zile) cu 60 zile
anterior internrii

(CID sept 2005, 41 (sup6)

Criterii microbiologice

Detecia de fungi (Aspergilus, Fusarium, Zigomicete,


Scedosporium) sau Criptococus n culturi de sput sau LBA
Detecia de fungi prin microscopie direct sau culturi din
aspiratele sinusale
Detecie de Criptococcus spp din sput sau LBA
Detecia de Aspergilus n LBA, LCR sau > 2 hemoculturi
Detecie de Criptococcus n snge
Detecia de elemente fungice la examenul microbiologic
direct n umori considerate sterile
Detecia de Candida n urin n absena cateterului urinar
Detecia Candida n hemoculturi

Infecii ale SNC


majore

minore

Imagini radiologice ce sugereaz o infecie a SNC


(mastoidit, focare pneumice, empiem extradural)
LCR negativ pentru ali patogeni sau boli maligne
(prin cultur sau ex. microscopic)
Semne neurologice de focalizare (convulsii
localizate, hemiparez, paralizii de nervi cranieni
Alterare a strii mentale
Semne de infecie meningean
Modificri citologice i biochimice ale LCR

Infecii fungice diseminate


majore

Candidoz diseminat
majore

Leziuni cutanate papuloase sau nodulare (fr alt


etiologie)
Semne sugestive intraoculare de diseminare
hematogen (corioretinit, endoftalmit)
abcese mici n organe int (glob ocular, ficat, splin)
evideniate prin CT, RMN sau ultrasonografie

Infecii fungice emergente


LEVURI
Candida sp
C albicans
C tropicalis
C parapsilosis
C guillermondii
C krusei
C lusiatniae
C dublininsis
Criptococcus
Trichosporon
Rodotorula

Forme filamentoase
- Aspergilus
- Fusarium
- Scedosporium
- Mucor...
Forme dimorfe
- Histoplasma
- Coccidioides
- Blastomyces

Ameninare :creterea infeciei cu fungi


Cretere a numrului cazurilor de infecie sever
Infecia sistemic cu Candida
A patra cauz de infecie nosocomial n SUA
Agent patogen

Nr. izolate

Inciden (%)

3908
1928
1354
934

31.9
15.7
11.1
7.6

Stafilococi coagulazo negativ


Staphylococcus aureus
Enterococci
Candida spp

* In a 3-year (1995-1998) surveillance study of 49 hospitals in the United States.


Adapted from Edmond MB et al Clin Infect Dis 1999;29:239-244.
Andriole VT J Antimicrob Chemother 1999;44:151-162; Uzun O, Anaissie EJ Ann Oncol 2000;11:1517-1521.

Incidena i Distribuia Infeciilor Nosocomiale


Hematogene
n = 10617
Stafilococi Coag-neg
Staphylococcus aureus
Enterococi
Candida species
Escherichia coli
Klebsiella spp
Enterobacter spp
Pseudomonas spp
Serratia spp
Streptococi Viridans
Edmond et al. Clin Infect Dis 1999

Inciden
%
32
16
11
8
6
5
5
4
1
1

Neutropenie
9%

4%

Mortalitate
%
21
25
32
40
24
27
28
33
26
23

ntr-un studiu internaional de supraveghere a infeciilor sistemice:

Cele mai frecvente specii de Candida izolate


C. krusei
C. tropicalis 2% other Candida
spp 5%
8%
C. parapsilosis
15%

C. albicans
54%

C. glabrata
16%
Adapted from Pfaller MA et al and The SENTRY Participant Group Antimicrob Agents Chemother 2000;44:747-751.

Ratele de mortalitate n cazul infeciilor cu


Candida i Aspergillus

Infeciile micotice = a 4-a cauz de


mortalitate prin infec. nosocomiale
Mortalitate

Candida 40% la bb.


cu cancere

Aspergillus pn la
90%* la transplantai

*La cei crora li s-a efectuat transplant


Edmond MB Clin Infect Dis 1999;29:239244; Paterson DL Medicine 1999;78(2):123138.

Distribuia Infeciilor cu Candida n


seciile cu pacieni critici
n = 934
47%
non-albicans

11%

Candida glabrata
42%

21%

Candida tropicalis
Candida parapsilosis

26%

altele
others

Adaptat dup Edmond et al. Clin Infect Dis 1999

53%
albicans

Pacieni cu risc nalt


Factori de risc :
Non neutropenici

Neutropenici

insuficien renal acut

Neoplasm

nutriie parenteral

Transplant

ageni anti-anaerobi

Antibioterapie cu spectru larg

tratament anterior cu Vancomicin

Tratament anterior cu Vancomicin

tratament chirurgical anterior


cateterism intrvascular

Gazd imunocompromis
Intervenie chirurgical
Cateterism intravascular

Blumberg HM, Jarvis WR, Soucie JM et al and the NEMIS Study Group Clin Infect Dis 2001;33:177-186;
Garber G Drugs 2001;61(suppl 1):1-12.
National Epidemiology of Mycosis Survey (NEMIS) was a prospective, multicenter study conducted at 6 US sites from 1993-1995 to examine rates of risk factors for
the development of candidal bloodstream infections (CBSIs) among patients in surgical and neonatal ICUs >48h. Among 4276 patients, 42 CBSIs occurred.

Candidemie Dobndit n Spital


Toate internrile

Leucemie ac.
Transplanturi
Arsuri
Chirurgie GI
Prematuritate
Copii

Factor de Risc
Antibiotice
catetere IV
Candida
colonizare
Hemodializ
ATI

Adapted from Wenzel Clin Infect Dis 1995;20:1531-4

1.7
7.2
10.4
10.4
?

Su
pr
av
ie
u
ir e

Risc Crescut

Candidiaz

Deces prin
candidemie

Deces prin
boal de
fond

EORTC
IFICG

Noi venii pe Harta Fungilor

Incidena

tropicalis
lusitaniae

glabrata
parapsilosis

krusei
guillermondii

Candida
albicans
ormans
Cryptococcus neof

Aspergillus species

Alternaria

Pseudallescheria boydii
Coccidioidomycosis
Mucor/Rhizopus
Rhodotorula
Penicillium marneffei
Fusarium
Trichosporon beigelii
Malassezia furfur
Blastomycosis

Timp

EORTC
IFICG

Creterea Aspergillus-ului

1-2 mm / or

G.P. Bodey*
15-30% din pacientii cu Candida
Invasiva autopsiai
Nu au primit
niciodat terapie
sistemic

????

antifungic

* Personal communication from Dr. G. P. Bodey, an infectious


disease specialist at the MD Anderson Cancer Center

!!!!

Antifungice sistemice disponibile


Familia

DCI

Produs

Prezentare

An

Cp

1939

IV, Sol oral

1951

Inhibitori ai
mitozei

Griseofulvin

Griseofulvin

Poliene

Amfotericina B

Fungizone

Amfo B
liposomal

Abelcet

IV

1995

Pyrimidine

Flucitozin

Ancotil

IV, Cp

1957

Azoli

Ketoconazol

Nizoral

Cp

1982

Fluconazol

Triflucan

IV, Ov.

1990

Itraconazol

Sporanax

Ov.

1992

Voriconazol

Vfend

IV, Ov.

2002

Alilamine

Terbinafina

Lamisil

Cp

1994

Candine

Caspofungin

Cancidas

IV

2001

Fungii
Membrana cell
- ergosterol

Perete cell.
- chitin
- manoproteine
- -glucan

Modul de Aciune al Antifungicelor


acetyl-Co-A

Sinteza de acizi
nucleici

allylamines
(e.g., terbinafina)

5-flucytosine

sodarine

squalene

sinteza de chitin

Azolii (e.g.,
fluconazole)
lanosterol

factorul de elongaie

nikkomycin
K

Inihiia manoproteinelor
pradimicin

Polyene (e.g.,
amphotericin B)
ergosterol

Sinteza de
(1,3)-D-glucan
Candine (e.g.,
caspofungin)

Antifungice mecanism de aciune


ECHINOCANDINE
PNEUMOCANDINE
GLUCAN SINTAZA
PERETE

AMFOTERICIN, AZOLI, TERBINAFIN

SINTEZA ACIZILOR NUCLEICI


INHIBIIE RIBOZOMAL
DIVIZIUNE MITOTIC

MEMBRAN

5-FLUORO-CITOZIN

NUCLEU

SORDARIN
GRISEOFULVIN

Diferitele Mecanisme de aciune al agenilor Antifungici: Implicaii


asupra Eficacitii

Agentul

Locul de aciune

Activitate

Implicaii Clinice

Amphotericin-B Membran

Cupleaz ergosterolul;
produce moarte cell.

Azolii

Inhib CYP 450


Activitate Fungistatic
responsibil de sinteza Poten variabil
ergosterolului;
i spectru de ac. la nivel
afectare
citoplasmatic a cell de mamifere
membranar

Membran

Inhib. sintez. Perete


1,3 glucan
Caspofunginul

Potent, spectru larg


Activitate fungicid

Inhib sinteza glucan; Potent, spectru larg de


rupe structurile peretelui, activitate antifungic;
i ca atare produce
potenial efecte aditive
liza celular
n combinaie terapeutic*

*As shown in vitro


Adaptar dup Andriole VT J Antimicrob Chemother 1999;44:151-162; Graybill JR et al Antimicrob Agents Chemother
1997;41(8):1775-1777; Groll AH et al Adv Pharmacol 1998;44:343-500; Franzot S, Casadevall A Antimicrob Agents Chemother
1997;41(2):331-336.

Opiunile actuale n tratamentul antifungic


Amfotericin B

Medicament

Fungizon

Avantaje
Activ mpotrivaCandida,
Aspergillus

Dezavantaje

Nefrotoxicitate
Potenial de toxicitate

Activ mpotriva Candida,

Nefrotoxicitate
Potenial de toxicitate
Nefrotoxicitatea este mai mic Ratele de reacie acut determinate de
dect n cazul amfotericinei B infuzie nu difer substanial de cele
convenionale
observate n cazul amfotericinei B
convenionale

Formula lipidic Aspergillus, Cryptococcus

Azoli

Fluconazol

Itraconazol

Activ mpotriva Candida,


Cryptococcus

Activ mpotriva Candida,


Aspergillus, Cryptococcus

Analog nucleozidic
Flucitosin

Toxicitate selectiv

Ineficace mpotriva Aspergillus


Potenial dezvoltare de rezisten
Puternic inhibitor al sistemului citocromului
P450 3A4 poate provoca evenimente
cardiovasculare severe n asociere cu
anumite medicamente, contraindicat n
disfuncii renale severe. Hipersensibilitate n
caz de hepatit i hepatotoxicitate, rezisten
constatat
Activitate slab mpotriva Candida,
Cryptococcus
Dezvoltare rapid de rezisten

Andriole VT J Antimicrob Chemother 1999;44:151162; Groll AH Adv Pharmacol 1998;44:343-500; Onishi J Antimicrob Agents Chemother 2000;44:368377; Stone
EA Clin Ther 2002;24(3):351-377; Sporanox (Itraconazole) Injection Prescribing Information; Fluconazole Prescribing Information

Noile antifungice
Triazoli
Voriconazol (Vfend)
Posaconazol
Ravuconazol
Echinocandine
Caspofungin (Cancidas)
Mycafungin
Anidulafungin
Nystatin liposomal (Nyotran)
Sordarin
Nyckomycine

Inhibitorii sintezei de glucan


3 Familii:
Echicandinele/pneumocandinele:
Caspofungin
Anidulafungin
Micafungin
Papulacandinele
Terpenoizii acidici

Spectrul de activitate in vitro al Caspofungin


Concentraiile minime inhibitorii * (g/ml)
Puternic
[0,032,0 g/ ml]

Intermediar

Slab

[2,016,0 g/ ml]

[16,0>64,0 g/ ml]

Speciile de Candida

Histoplasma capsulatum

Cryptococcus neoformans

Speciile de Aspergillus

Coccidiodes imitis

Speciile de Fusarium

Saccharomyces cerevisiae

Speciile de Paracoccidiodes Speciile de Trichosporon

Speciile de Alternaria

Blastomyces dermatitidis

Speciile de Rhizopus

Speciile de Curvularia

Sporothrix schenckii

Speciile de Trichophyton

Fonseca pedrosoi
Scedosporium

Speciile de Phiolophora

Speciile de

Pneumocystis carinii**

Speciile de EpidermophytonPseudallescheria boydii

*Date provenind de la MRL, Laboratorul naional de testare pentru fungi i Laboratorul naional de referine micologice
**Pe baza datelor in vivo
Bartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001.

Caspofungin : indicaii
Candidoza sistemic la pacieni neutropenici i nonneutropenici

In plus:
Aspergiloz sistemic la pacieni non-responderi sau
cu toleran sczut la terapia standard
Candidoza esofagian
Candidoza orofaringian
Data on file, MSD.

Strategia Viitoare mpotriva Candidiazei


posibil diseminate?

Empiric
sau
O
O prim
cultur
pozitiv

R
E
Z
U
LT
A
T

ep
c
s
su

tib

il

fluconazol

inhibitor
Voriconazol
sintez
risc de aspergiloz Amphotericin B i.v.
glucan
Caspofungin
Caspofungin C
U
i.v.
re
L
zi
st
T
en
Caspofungin
t
U
sau
R
noi azoli orali
I