Dijagnostikom vođena terapija invazivnih gljivičnih...

Dijagnostikom vođena terapija invazivnih gljivičnih infekcija kod hematoloških

bolesnika

Prof dr Ana Vidović

Klinika za hematologiju, KCS

30.maj 2018.

Sadržaj predavanja

Invazivne gljivične infekcije (IGI)-morbiditet i mortalitet

Faktori rizika za razvoj IGI

Vrste gljivičnih infekcija i dijagnostika IGI

Terapijski pristup (profilaksa, empirijska, preemptivna, ciljana-kauzalna terapija)

Izbor adekvatnog antimikotika

Ključne informacije

Invazivne gljivične infekcije

(IGI)-morbiditet i mortalitet

Faktori koji uslovljavaju povećanje stope gljivičnih infekcija u opštoj populaciji ljudi

• Povećanje broja imunokompromitovanih bolesnika

• Neutropenija ili poremećaj ćelijskog imuniteta

• Metaboličke bolesti (dijabetes, disfunkcija štitaste žlezde, bubrežna insuficijencija)

• Starenje populacije stanovništva

• Velika mobilnost stanovništva – putovanja I izlaganje lokalnim epidemiološkim endemičnim, gljivičnim patogenima

Warnock D. W. et al. J.Med.Mycol 2007;48:1-12.

Princip lečenja bolesnika sa hematološkim malignitetima (AML, ALL, agresivni NHL)

Dijagnoza

• Intenzivna hemioterapija

• Jatrogena aplazija koštane srži (ANC ≤ 0,5x109/l

Infekcije

• Febrilna neutropenija

• Primena širokospektralnih antibiotika (deeskalaciona terapija)

FN> 72-96h

• Antigljivična terapija:

• Empirijska (vođena febrilnošću); Preemptivna (serologija+ i/ili CT+); Kauzalna terapija (dokazana IGI)

Morrissey C.O. Et al.Leukemia &Lymphoma, 2011;52(2):179-93.

Incidenca IGI kod pacijenata sa hematološkim malignitetima

Pagano L, et al. Haematologica. 2006; 91(8):1068-75.

UKUPNA INCIDENCIJA

IGI JE BILA

4.6%

(br pacijenata 11.802)

6

Mortalitet kod gljivičnih infekcija

Aspergillus: 32-87%

Candida: 10- 49%

Fusarium: 70- 87%

Zygomycete: 44- 91%

Warnock D. W. et al. J.Med.Mycol 2007;48:1-12.

Faktori rizika za razvoj IGI

Faktori visokog rizika za razvoj invazivnih gljivičnihinfekcija

Primena visokodozne hemioterapije (AML, ALL, MDS)Imunosupresivna terapija

nakon alogene transplantacije k.srži i posebno razvoja GVHDprimena Anti-TNF-α agenasa (npr. infliximab)

Prethodna primena širokospektralnih antibiotika (posebno neadekvatna)Dugotrajna primena kortikosteroida (30mg/dnevo; 1mg/kg tt)Boravak u jedinicama intenzivne nege duže od 7 dana Neutropenija duže od 7 dana, sa nadirom broje neutrofila ≤100/µlPlasiran Centralni venski kateter- CVK (duže od 14 dana)Bubrežna insuficijencija, hemodijalizaKandidurija (više od 104cfu/ml) ili kolonizacija gljivama > 1 mestaNarušen integritet kože i sluznica (posebno GIT-a).Poremećaj fagocitne funkcije granulocitaPacijenti sa uznapredovalom HIV infekcijom.....

Segal B, Walsh T. Am Resp Crit Care Med 2006; 173: 707-17, Current Approaches to Diagnosis and Treatment of Invasive Aspergillosis.

Vrste gljivičnih infekcija i dijagnostika IGI

KVASNICE PLESNI

CANDIDA ASPERGILLUS

Porast incidencije!!!357% (1980-2008)

Invazivne plesni

33 vrste patogene za ljude

A. fumigatus > A. flavus > A. terreus >A. niger

A. terreus i A. nidulans (rezistentni na AmB)

IPA

Aspergillus180 vrsta

Klinički oblici Zygomycosa

Rhinocerebralna→Kod bolesnika sa D. Mellitusom tip 2

Pulmonalna→Najčešće kod imunokompromitovanih bolesnika (akutne leukemije, nakon intenzivne hemioterapije; GVHD nakon BMT; prethodna terapija Voriconasolom; malnutricija)

Diseminovana→kao komplikacije prethodna dva klinička oblika

C.albicans > 50%• C.glabrata

(R) na AmB i triazole

• C.tropicalistežak klinički tok

• C.krusei(R) na Flukonazol

• C.lusitaniae iC.guillermondii(R) na AmB

Canida četvrti uzročnik sepse u ICU(kateteri)

Hepatosplenična kandidijaza

„Dijagnostika IGI je još uvek nezadovoljavajuća“J. Maertens

191 bolesnik sa hematološkim malignitetom

Dokazana IA→7 bolesnika

Verovatna IA →30 bolesnika

Verovatna IGI →2 bolesika

Moguća IGI →97 bolesnika

Primena biomarkera u dijagnozi IGI ključna

Raspoloživi biomarkeri u dijagnozi IGI

Galactomannan (GM) za IA → A II

Beta – Glukan za IC i IA → B II

Kriptokokus Antigen za Kriptokokozu → A II

Mannan (Mn) / anti – Mannan (A- Mn) za IC →

Za IC (B III); za hepatospleničnu kandidijazu ikandidemiju C II

PCR za IA- za sada NEMA preporukaNivo pouzdanosti potvrđen od strane EORTC/ MSG (European

Organisation for research and Treatment of Cancer / Mycosis Study Group)

Posteraro B et al. Critical Care 2011;15:1-10

Galactomannan (GM)

GM je komponenta ćelijskog zida Aspergillus spp

Cirkulišući GM se može detektovati u : serumu, plazmi, BAL-u , SCF i drugim telesnim tečnostima

Cut-off index za pozitivnost → 0,5

Vrednosti GM zavise od:

Primene beta-laktamskih antibiotika (ukrštena reaktivnost, posebno Piperacili- Tazobactam)

Primene antigljivičnih lekova (posebno Voriconasol i Posaconasol-profilaksa)

Nivoa neutropenije i imunosupresije

Renalnog klirensa, hepatičnog metabolizma

Nivoa oksemije, Ph krvi

Posteraro B et al. Critical Care 2011;15:1-10

Dijagnostički značaj određivanja galaktomanana (GM) kod visokorizičnih pacijenata sa IGI

GM može biti pozitivan pre kliničkih simptoma infekcije

Rutinski GM skrining vodi ka ranoj primeni antifungalne terapije kod 7.3% pacijenata koji nisu imali kliničke simptome IGI

GM- koristan u praćenju terapijskog odgovora

Ruhnke M et al. Ann Oncol. 2011 Sept [Epub ahead of print]

Marchetti O, et al. Bone Marrow Transplant. 2011 sept 19. doi: 10.1038/bmt.2011.178. 22

Serijski CTVR kod 25 bolesnika (neutropenija <0.5x109/L):

medijana plućnih lezija 2; bilateralnost 48%

D0: halo D4: promer ↑, halo ↓ D7: vazdušni srp

Caillot D. Et al. J Clin Oncol. 2001.

Tranzitorni halo: <5d; rast infiltrata tokom 7 d → stabilizacija → vazdušni srp

nespecifično Prekasno!!!specifično

IA pluća

25

Metode laboratorijske dijagnoze IGI

MIKOLOŠKE

(KONVENCIONALNE METODE)

1. MIKROSKOPSKI PREGLEDBOLESNICKOG MATERIJALA

direkni mikroskopski preparat(DMP)

patohistologija (PH)

2. IZOLACIJA GLJIVA IZ BOLESNICKOG MATERIJALA

mikološka kultura (MK)-"zlatnistandard"

IMUNOLOŠKE

DOKAZIVANJE ANTITELA (At)

DOKAZIVANJE ANTIGENA (Ag)

DOKAZIVANJE BIOMARKERA MOLEKULARNE

DOKAZIVANJE DNK (PCR)

DOKAZANA VEROVATNA GI

26Ruhnke M et al. Ann Oncol. 2011 Sept, Marchetti O, et al. Bone Marrow Transplant. 2011 sept 19. doi: 10.1038/bmt.2011.178.

Moguća infekcija “possible”- specifičan CT nalaz - Da, ali galactomannan test- negativan

Verovatna infekcija “probable”- jasna radiografska potvrdainfekcije +2 ili više poz. uzoraka na Galactomannan

Dokazana- “documented” infekcija - poz. histopatološki pregled tkiva na Aspergilus ili poz. kultura dobijena invazivnom procedurom (otvorena biopsija pluća, traheobronhijalna ili perkutana iglena biopsija)- retko izvodljivo kod hematoloških bolesnika zbog trombocitopenije

U rutinskoj٭ dijagnostici IGI preporučene dijagnostičke procedure: visoko rezolutivni CT toraksa, Galactomannan test (ELISA)

Dijagnostikovanje IGI

27Ruhnke M et al. Ann Oncol. 2011 Sept, Marchetti O, et al. Bone Marrow Transplant. 2011 sept 19. doi: 10.1038/bmt.2011.178.

Terapijski pristup (profilaksa, empirijska, preemptivna, ciljana-

kauzalna terapija)

Kontiniuum antigljivične strategije

Ciljanaprofilaksa

Empirijska

terapija

Pre-emptivna terapija

Direktna-ciljana

terapija

Maschmeyer G. et al. Eur J Clin Microbiol Infect Dis 2013;32:679-689.

Kada primeniti profilaksu IGI?

• Kada je incidenca za IGI visoka

• Kada je mogući ishod bolesti loš

• Kada je teško dijagnostiikovati ili isključiti IGI

• Kada troškovi lečenja IGI prevazilaze cenu primenjene profilkse/ empirijske terapije

• Kada su dostupni jeftini, dobro tolerabilni i efiksani agensi za profilksu /empirijsku terapiju

• Kada je nizak rizik od indukcije resistencije

Profilaksa nije obavezna kod svih bolesnika sa neutropenijom

ECIL-6 guidelines, Haematologica 2017;102(3):433-444.

Visoko rizični bolesnici, febrilni ali bez dokaza za IGI

Febrilnošću dirigovana- Empirijska terapija:definicija

– Primenjuje se kod prolongirane, izraženeneutropenije (ANC<500)

– Kod persistirajuće febrilnosti (4-7 dana) nepoznatogporekla, refraktarne na lečenje širokospektralnimantibioticima

– Ipak, invasivna gljivična infekcija ne može biti pravilo

Cardonnier C et al. Clin Infect Dis 2009;48:1042-51.

Dijagnostikom-dirigovana terapija Pre-emptivna terapija

Započinje se kada je invazivna gljivična infekcija vrlo izvesna

•Klinički dokaziIli halo znak

ili• mikološki dokazi

Ili Aspergillus galactomannan pozitivan

Visok-rizični bolesnici + klinički ilimikrobiološki dokaz za IFI

Cardonnier C et al. Clin Infect Dis 2009;48:1042-51.

SVI PACIJENTIDavanje antigljivičnog

leka tokom perioda postojanja rizika

infekcije

SPECIFIČNA TERAPIJA

FEBRILNI

PACIJENTI

4 dana bez

odgovora na

Ab terapiju

POZITIVNI DG.

TESTOVIDOKAZANO

NIJEPRISUTNA

NIJEISKLJUČENA

SUSPEKTNA PRISUTNA

GM esej ili CT;bez simptoma

IFI/EORTC/MSG

PROFILAKSA EMPIRIJSKA TERAPIJA PREEMPTIVNA Th

Terapijske strategije u IGI

IZGLEDI DA OBOLJENJE POSTOJI

33ECIL-6 guidelines, Haematologica 2017;102(3):433-444.

proven

probable

possible

proven

probable

possible

Budućnost lab. dg. IGI kod nas

34ECIL-6 guidelines, Haematologica 2017;102(3):433-444.

Izbor adekvatnog antimikotika

Idealni antigljivični lek bi trebalo da ima...

• Širokospektralnu aktivnost (prema kvasnicama i plesnima)

– Brzu i visoko fungicidnu aktivnost, da je stabilan prema rezistenciji

– Potencijalnu in vivo aktivnost (posebno kod neutropeničnih

bolesnika)

• Dobru farmakokinetiku (AUC)

– Obe formulacije, oralnu i parenteralnu

– Dobru penetrantnost u sve tkivne prostore

– Nisku toksičnost, minimalnu sklonost za interakciju sa drugim

lekovima

• Prihvatljivu cenu

1950~ 1970~80 1997~ 2002~ 2004

Early AzolesClotrimazoleMiconazole

Ketoconazole

AmbisomeAbelcet

Amphocil

2nd Tri-azole: VoriconazoleEchinocandins: Caspofungin

PolyenesNystatin

Amphotericin B

1st Tri-azolesFluconazoleitraconazole

Micafungin

Posaconazole

1990~

Antigljivični lekovi

NCCN Guidelines Version 1.2017

Prevention and Treatment of Cancer-Related Infections

NCCN Guidelines IndexTable of Contents

Discussion

KEY: ALL = acute lymphoblastic leukemia, AML = acute myeloid leukemia, MDS = myelodysplastic syndromes, GVHD = graft-versus-host disease, HCT = hematopoietic cell transplant, HSV = herpes simplex virus

OVERALL INFECTION

RISK IN PATIENTS WITH

CANCERa

DISEASE/THERAPY EXAMPLES ANTIFUNGAL PROPHYLAXISf,l DURATION

ALL Consider:

•Fluconazolem or Micafunginn

•Amphotericin B productso (category 2B)

Until

resolution of

neutropeniaINTERMEDIATE TO

HIGH

MDS (neutropenic)

AML (neutropenic)

Consider:

•Posaconazolem (category 1)

•Voriconazolem, Fluconazolem, Micafunginn, or

Amphotericin B productso (all category 2B)

Autologous HCT with mucositisj Consider:

•Fluconazolem or Micafunginn (both category 1)

Autologous HCT without mucositis Consider no prophylaxis (category 2B) N/A

Allogeneic HCT (neutropenic)

See Antipneumocystis Prophylaxis (INF-6)

Consider:

•Fluconazolem or Micafunginn (both category 1)

•Voriconazolem, Posaconazolem, or Amphotericin B productso

(all category 2B)

Continue

during

neutropeniap

Significant GVHDk

See Antipneumocystis Prophylaxis (INF-6)

Consider:

•Posaconazolem (category 1)

•Voriconazolem, Echinocandin, Amphotericin B productso (all

category 2B)

Until

resolution of

significant

GVHD

www.nccn.org (accessed on May 2018)

NCCN Guidelines Version 1.2017

Prevention and Treatment of Cancer-Related Infections

NCCN Guidelines IndexTable of Contents

Discussion

ANTIFUNGAL AGENTS: AZOLES

AZOLESa DOSE SPECTRUM COMMENTS/CAUTIONS

Fluconazole In adults with normal renal

function: 400 mg IV/PO

daily

• Active against Candida

• Active against coccidioidomycosis

and C. neoformans

• Candida glabrata is associated with variable resistance

in vitro and Candida krusei is always resistant

• Inactive against molds (eg, Aspergillus sp.,

Zygomycetes)

Isavuconazonium

sulfateLoading dose 372 mg IV/

PO every 8 h x 6 doses

then maintenance dose

372 mg IV/PO daily

• Active against invasive

aspergillosis and mucormycosis in

patients with cancer and in HCT

recipients1,2,3

• Can be considered in patients intolerant or refractory

to first-line anti-mold therapy

• Potential drug interactions are important to consider

Itraconazoleb 400 mg PO daily; Loading

dose 200 mg PO TID x 3

days, then

maintenance dose 200 mg

PO BID

• Active against Candida, Aspergillus

sp., and some of the rarer molds

• Active against dimorphic fungi and

C. neoformans

• Itraconazole has negative inotropic properties and is

contraindicated in patients with significant cardiac

systolic dysfunction

• Use with caution in the capsule formul ation with H2

blockers and PPIs

www.nccn.org (accessed on May 2018)

NCCN Guidelines Version 1.2017

Prevention and Treatment of Cancer-Related Infections

NCCN Guidelines IndexTable of Contents

Discussion

ANTIFUNGAL AGENTS: AZOLES (continued)

AZOLESa DOSE SPECTRUM COMMENTS/CAUTIONS

Posaconazoleb • Prophylaxis:

Loading dose 300 mg PO

tablet BID on day 1 and then

maintenance dose 300 mg PO

daily

Loading dose 300 mg IV every

12 h on day 1 and then

maintenance dose 300 mg IV

daily

• Effective as prophylaxis in

neutropenic patients with

myelodysplastic syndrome and

acute myeloid leukemia7, and in

HCT recipients with significant

GVHD8

• Active against Candida,

Aspergillus sp., some

Zygomycetes sp., and some of the

rarer molds

• Active against dimorphic fungi and

C. neoformans

• Evaluated as treatment of refractory infection (but not

FDA-approved) in several invasive fungal diseases

• Data on posaconazole as primary therapy for invasive

fungal infections are limited

• Liquid formulation should be administered with a full

meal or liquid nutritional supplement or an acidic

carbonated beverage. Tablet is better absorbed,

though it should be taken with food.

• Alternative antifungal therapy should be considered for

patients who cannot eat a full meal or tolerate an oral

nutritional supplement

• Proton pump inhibitors decrease posaconazole plasma

concentration with oral solution

• Potential drug interactions are important to considerVoriconazoleb • Loading dose 200 mg PO BID for

patients >40 kg or 100 mg PO BID

for patients <40 kg IV 6 mg/kg

every 12 h x 2 doses, then

maintenance dose 4 mg/ kg IV

every 12 h (for invasive

aspergillosis);4

• Loading dose 6 mg/kg IV every 12

h x 2 doses, then maintenance

dose 3–4 mg/kg IV every 12 h 200

mg PO BID for patients >40 kg or

100 mg PO BID for patients <40

kg for non-neutropenic patients

with candidemia5

• Active against Candida, Aspergillus

sp., and some of the rarer molds

• Active against dimorphic fungi and

C. neoformans

• Standard of care as primary therapy for

invasive aspergillosis (category

1)4,6

• Effective in candidemia in non-

neutropenic patients5

• Poor activity against Zygomycetes

• Long-term complications resulting from metabolic

irregularities may include increased risk for squamous

cell carcinoma and hyperphosphatemia

• Fluorosis may occur with prolonged use and is

associated with bone/muscle pain

• Evidence for combination therapy remains limited9

• IV formulation should be used with caution in patients

with significant renal dysfunction

• Potential drug interactions are important to consider

www.nccn.org (accessed on May 2018)

NCCN Guidelines Version 1.2017

Prevention and Treatment of Cancer-Related Infections

NCCN Guidelines IndexTable of Contents

Discussion

ANTIFUNGAL AGENTS: EMPIRIC AMPHOTERICIN B FORMULATIONSc

AMPHOTERICIN B

FORMULATIONSdDOSE SPECTRUM COMMENTS/CAUTIONSf

Amphotericin B

deoxycholate (AmB-D)

Varies by indication,

generally 0.5–1.5 mg/kg IV

daily

Broad spectrum of

antifungal activity including

Candida Aspergillus sp.,

(excluding Aspergillus

terreus) Zygomycetes, rarer

molds,

C. neoformans, and

dimorphic fungi

• Substantial infusional and renal toxicity including

electrolyte wasting

• Saline loading may reduce nephrotoxicity

• Infusional toxicity may be managed with anti-pyretics,

an anti-histamine, and meperidine (for rigors)

Amphotericin B lipid

complex (ABLC)

5 mg/kg/IV daily for

invasive mold infections

Reduced infusional and renal toxicity compared to

AmB-D

Liposomal amphotericin B

(L-AMB)

3–5 mg/kg IV daily10,e Reduced infusional and renal toxicity compared to

AmB-D

www.nccn.org (accessed on May 2018)

NCCN Guidelines Version 1.2017

Prevention and Treatment of Cancer-Related Infections

NCCN Guidelines IndexTable of Contents

Discussion

ANTIFUNGAL AGENTS: ECHINOCANDINS

ECHINOCANDINS9,g DOSE SPECTRUM COMMENTS/CAUTIONS

Anidulafungin 200 mg IV x 1 dose, then 100 mg/IV

daily

Active against Candida

and Aspergillus sp. Not

reliable or effective

against other fungal

pathogens.

• Empiric therapy for candidemia and invasive

candidiasis (category 1), pending susceptibility data

• Efficacy established compared to fluconazole as

primary therapy for candidemia and invasive

candidiasis15

• Excellent safety profileCaspofungin • 70 mg IV x 1 dose, then 50 mg IV

daily; (35 mg IV daily for patients

with moderate liver disease)

• Some investigators use 70 mg IV

daily as therapy for aspergillosis

in second-line therapy

• Primary therapy for candidemia and invasive

candidiasis (category 1)11

• Treatment for invasive, refractory aspergillosis. Similar

efficacy compared to AmB-D as primary therapy for

candidemia and invasive candidiasis but significantly

less toxic11

• 45% success rate as therapy for invasive, refractory

aspergillosis12

• Similar efficacy, but less toxic compared with L-AMB

as empiric therapy for persistent neutropenic fever11

• Excellent safety profile

Micafungin • 100 mg IV daily for candidemia

and 50–100 mg/d IV as

prophylaxis

• 150 mg IV daily used at some

centers for Aspergillus sp.

infection in second-line therapy

• Primary therapy for candidemia and invasive

candidiasis (category 1)

• Similar efficacy compared to caspofungin13 and

compared to L-AMB14 as primary therapy for

candidemia and invasive candidiasis

• Excellent safety profile

www.nccn.org (accessed on May 2018)

Evolution over time of the grading system used for treatment of invasive Candida and

Aspergillus infections

ECIL-6 guidelines, Haematologica 2017;102(3):433-444.

ECIL-6 recommendations for initial first-line treatment of candidemia

ECIL-6 guidelines, Haematologica 2017;102(3):433-444.

ECIL-6 recommendations for first-line treatment of candidemia after species identification

ECIL-6 guidelines, Haematologica 2017;102(3):433-444.

ECIL-6 recommendations for first-line treatment of invasive aspergillosis

ECIL-6 guidelines, Haematologica 2017;102(3):433-444.

Ključne porukeVisokorizični bolesnici za razvoj IGI-IA:

AML, ALL, NHL na visokodoznoj hemioterapiji Primena T deplecirajućih lekova (Fludarabin,

anti CD52) Boravak u jedinicama IN Dugotrajna neutropenija (>7d) sa br.

lkc<0,1x109/l Odustvo laminarnog toka vazduha u sobama

Obavezna brza dijagnostika u pravcu IGI →

GM, Mn, CT toraksa

Ključne porukeProfilaksa visokorizičnih bolesnika→ DA, OBAVEZNOEmpirijska terapija →ZAPOČETI NAJKASNIJE 72 h OD ODRŽAVANJA FEBRILNOSTI (PORED PRIMENE ŠIROKOSPEKTRALNIH ANTIBIOTIKA)DIJAGNOSTIČKI VOĐENA TERAPIJA (PREEMPTIVNA) →cilj kome težimo →lek izboraza Invazivnu aspergilozu → VORIKONAZOL; lekovi izbora za Invazivnu Candidijazu → Ehinokandini (Caspofungin, Mycafungin)

Kontinuirana edukacija medicinskog osoblja

Koji su bolesnici pod visokim rizikom za razvojinvazivnih gljivičnih infekcija?

1. Bolesnici sa akutnom mijeloblastnomleukemijom nakon primene indukcione terapije

2. Bolesnici nakon alogene transplantacijematičnim ćelijama hematopoeze

3. Bolesnici sa limfomima lečeni visokodoznomhemioterapijom

Lek izbora u lečenju Invazivne Aspergiloze plućaje?

1. Voriconasol

2. Cansidas

3. Itraconasol

4. Fluconasol

Terapija izbora u lečenju Invazivne Zygomycosepluća je?

1. Fluconasol

2. Mycamin

3. Liposomalni Amphotericin B

4. Voriconasol

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