Antifungicele sistemice

Clinica de Boli Infecioase Iai

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 Stafilococi coagulazo negativ Staphylococcus aureus Enterococci Candida spp Nr. izolate 3908 1928 1354 934 Inciden (%) 31.9 15.7 11.1 7.6

* 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 other Candida C. tropicalis 2% 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 53% albicans

11% 21% 42%

Candida glabrata Candida tropicalis Candida parapsilosis

26%

altele others

Adaptat dup Edmond et al. Clin Infect Dis 1999

Pacieni cu risc nalt

Factori de risc : Non neutropenici Neutropenici Neoplasm Transplant Antibioterapie cu spectru larg Tratament anterior cu Vancomicin

insuficien renal acut

nutriie parenteral ageni anti-anaerobi tratament anterior cu Vancomicin tratament chirurgical anterior cateterism intrvascular

Gazd imunocompromis
Intervenie chirurgical

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.

Cateterism intravascular

Candidemie Dobndit n Spital

Toate internrile

Candidiaz

Risc Crescut

Factor de Risc Antibiotice catetere IV Candida colonizare Hemodializ ATI ? 1.7 7.2 10.4 10.4
Deces prin candidemie

Leucemie ac. Transplanturi Arsuri Chirurgie GI Prematuritate Copii

Deces prin boal de fond

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

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

Inhibitori ai mitozei Poliene

Griseofulvin
Amfotericina B Amfo B liposomal Flucitozin Ketoconazol Fluconazol Itraconazol

Griseofulvin
Fungizone Abelcet Ancotil Nizoral Triflucan Sporanax Vfend Lamisil Cancidas

Cp
IV, Sol oral IV IV, Cp Cp IV, Ov. Ov. IV, Ov. Cp IV

1939
1951 1995 1957 1982 1990 1992 2002 1994 2001

Pyrimidine Azoli

Alilamine Candine

Voriconazol Terbinafina Caspofungin

Fungii
Membrana cell - ergosterol

Perete cell. - chitin - manoproteine - -glucan

Modul de Aciune al Antifungicelor

acetyl-Co-A
allylamines (e.g., terbinafina)

Sinteza de acizi nucleici

5-flucytosine

factorul de elongaie sodarine

squalene Azolii (e.g., fluconazole) sinteza de chitin nikkomycin Inihiia manoproteinelor K+ pradimicin Polyene (e.g., amphotericin B) ergosterol Sinteza de (1,3)-D-glucan Candine (e.g., caspofungin)

lanosterol

Antifungice mecanism de aciune

ECHINOCANDINE PNEUMOCANDINE

GLUCAN SINTAZA
PERETE

AMFOTERICIN, AZOLI, TERBINAFIN

MEMBRAN

SINTEZA ACIZILOR NUCLEICI INHIBIIE RIBOZOMAL DIVIZIUNE MITOTIC

5-FLUORO-CITOZIN

NUCLEU

SORDARIN GRISEOFULVIN

Diferitele Mecanisme de aciune al agenilor Antifungici: Implicaii asupra Eficacitii Locul de aciune Agentul

Activitate

Implicaii Clinice
Potent, spectru larg

Amphotericin-B Membran Cupleaz ergosterolul; produce moarte cell.Activitate fungicid

Azolii

Inhib CYP 450 Activitate Fungistatic responsibil de sintezaPoten variabil ergosterolului; i spectru de ac. la nivel afectare citoplasmatic a cell de mamifere membranar
Membran

Inhib. sintez. Perete Inhib sinteza glucan; Potent, spectru larg de 1,3 glucan rupe structurile peretelui, activitate antifungic; Caspofunginul 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):17751777; 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

Medicament Avantaje

Dezavantaje

Amfotericin B

Fungizon

Activ mpotrivaCandida, Aspergillus

Activ mpotriva Candida,

Nefrotoxicitate Potenial de toxicitate

Formula lipidic Aspergillus, Cryptococcus

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 Activ mpotriva Candida, Cryptococcus 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

Azoli

Fluconazol

Itraconazol

Activ mpotriva Candida, Aspergillus, Cryptococcus

Analog nucleozidic
Flucitosin Toxicitate selectiv

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]
Speciile de Candida Speciile de Aspergillus

[2,016,0 g/ ml]
Histoplasma capsulatum Coccidiodes imitis Blastomyces dermatitidis Sporothrix schenckii Speciile de Phiolophora

Intermediar

[16,0>64,0 g/ ml]
Cryptococcus neoformans Speciile de Fusarium Speciile de Rhizopus Speciile de Trichophyton Speciile de

Slab

Saccharomyces cerevisiae
Speciile de Alternaria Speciile de Curvularia Fonseca pedrosoi Scedosporium Pneumocystis carinii**

Speciile de Paracoccidiodes Speciile de Trichosporon

Speciile de Epidermophyton Pseudallescheria 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?

R E Z U L T A T

fluconazol

Empiric sau O O prim cultur pozitiv

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