Invazivne gljivične infekcije kod hematooških

bolesnika

Prof dr Ana Vidović

Hotel Inn, 20. jun 2018.

O čemu će biti reči

Incidenca IGI kod hematoonkoloških

bolesnika

Najčešći uzročnici IGI kod hematoloških

bolesnika

Nivoi dijagnostike IGI

Nivoi terapije IGI

Vodiči/strategija lečenja hematoonkoloških

bolesnika sa IGI u 2017.godini (NCCN i ECIL 6)

Raspoloživost antmikotika u Srbiji, šta kaže

praksa, šta RFZO?

Incidenca IGI kod hematoonkoloških bolesnika

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); Preemtivna (serologija+ i /ili CT+); Kauzalna terapija (dokazana IGI)

Visoka incidenca IGI kod hematoloških bolesnika

Pagano L et al. Haematologica 2006; 91: 1068-1075

Malignitet Incidenca IFI Incidence Molds Incidence Yeasts

AML 12 % 7.9 % 4.4 %

ALL 6.5 % 4.3 % 2.2 %

CML 2.5 % 2.3 % 0.2 %

CLL 0.5 % 0.4 % 0.1 %

NHL 1.6 % 0.9 % 0.7 %

HD 0.7 % 0.35 % 0.35 %

MM 0.5 % 0.3 % 0.2 %

≤1%

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.

Mortalitet kod gljivičnih infekcija

Aspergillus: 32-87%

Candida: 10- 49%

Fusarium: 70- 87%

Zygomycete: 44- 91%

Najčešći uzročnici IGI kod hematoloških

bolesnika

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

Aspergillus

180 vrsta

IGI/ Aspergiloza

• A. flavus i A. fumigatus najvažniji patogeni roda Asp.

Dijagnoza IA

Klinička slika

+.......

• CT pluća visoke rezolucije

• Sendvič-ELISA galaktomanan test

(senz i spec > 90%)

• Endoskoposke metode + biopsije

• Direktna mikroskopija (sputum, BAL, uzorak tkiva)

• kulture

• Glukan test

• PCR

Akutna invazivna aspergiloza (IA): oblici

• AKUTNA INVAZIVNA PLUĆNA ASPERGILOZA

- progresivna pneumonija

- simptomi poput drugih pneumonija

- nereagovanje na antibiotik

• AKUTNI INVAZIVNI SINUSITIS

-lokalno širenje u orbite i lobanjsku šupljinu

• DISEMINOVANA ASPERGILOZA

- sek. hematogeno širenje - bilo koji organ (bubreg, jetra, mozak, srce)

-SIRS

- visoka smrtnost

CT pregled u Dg IA

• uraditi ga 48-72h

• preseci na 1 cm a kroz leziju na 1 mm

• Karakteristični nalaz:

– halo (pojas niske atenuacije) oko područja konsolidacije

– vazdusni polumesec unutar konsolidacije

– Kavitacija unutar nodulusa

– nazubljena ivica konsolidacije

– kavitacija ili nodulus uz krvni sud

– Konsolidacija trouglasta sa bazom ka periferiji

Invazivna Aspergiloza pluća

CT

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

Ređi oblici IA (NEJM)

Dijagnoza sistemske kandidoze

• teška

• Dokazati prisustvo u tkivu ili kulturi (npr. krv)

• Serologija: mala poz. prediktivna vrednost

• Obećavaju:

lateks aglut. test na manan (deo glj. zida)

određivanje DNK kandide

Klinički oblici sistemske kandidoze kod

hematoloških bolesnika

• kandidemija

• akutna diseminovana kandidoza

• hronična diseminovana kandidoza

• endokarditis

• kandidoza CNS-a

(mesto ulaska: GIT ili i.v. kateteri)

C.albicans > 50%

Non albicans sojevi:

• C.glabrata

(R) na AmB i triazole

• C.tropicalis

težak klinički tok

• C.krusei

(R) na Flukonazol

• C.lusitaniae i

C.guillermondii

(R) na AmB

Canida četvrti uzročnik sepse u ICU

(kateteri)

Dani

Pro

ca

na

t

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25

C. albicans

C. glabrata

C. tropicalis

C. krusei

C. parapsilosis

others

Viscoli et al. Clin Infect Dis 1999

Preživljavanje u zavisnosti od

soja kandide

Invazivna kandidoza

• teška infekcija

• ugrožava život bolesnika

• zahvata više organa (hematogeno širenje).

• kandidemija + klinički simptomi i znaci teške infekcije

(sepse).

• Prognoza – kao u septičnom šoku.

Diseminovana kandidoza

Akutna

• brzoprogresivni tok

• formiranje abscesa u organima

• smrtni ishod bez brzog lečenja

Hronična

• Sporoprogresivna

• kod bolesnika koji su se oporavili od neutropenije

• tipično hepatosplenična (hepatosplenomegalija, bol u abdomenu, patološki jetreni testovi)

Diseminovana kandidijaza

PATOGENEZA: embolizacija malih k.s., stvaranje

mikroapscesa

Hepatosplenična kandidijaza, N Engl J Med, 2007

Diseminovana kandidijaza

(crvene papule bez eshare i nekroze)

Mays et al. Am J Clin Dermatology, 2006

Patogeneza Zygomycose

Kod zdravih osoba-makrofagi ubijaju intracelularne spore oksidativnim mehanizmom; Neutrofilni granulociti-oštećuju hife gljiva ekstracelularnih mehanizmom.

Neutropenija nakon hemioterapije ili oštećena funkcija neutrofila kod d.mellitusa ili steroidne terapije pogoduju razvoju Zygomycose

Serumsko gvožđe stimuliše rast gljiva (uloga helatora gvožđa u terapiji Zygomycose)

Angioinvazija- glavni faktor u brzoj progresiji infekcije Zygomycetama→nekroza tkiva,uz tromboziranje krvnih sudova

Dijagnostika

high level of laboratory skill for their identification.“Klinički znaci nedovoljno karakteristični, dif. Dg Invazivna aspergilosa

Dijagnoza često tek na autopsiji

Nepostojanje specifičnih seroloških testova (za sada nema spec. biomarkera bolesti)

CT→karakteristične multiple nodularne promene, >10; uz pleuralnuefuziju

Neophodna je biopsija zahvaćenog tkiva, uz pravilnu interpretacijuhistopatološkog nalaza. “The causative fungi are members of the order Mucorales and individual species within this group require a high level of laboratory skill for their identification.“

Lass-Flore, Clin Infect Dis;2007;45:101-4.

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

Radiografska i CT dijagnostika IZ

Cryptococcus

Kriptokokoza

skok incidencije sa pojavom AIDS-a

pad incidencije sa upotrebom HAART

DANASIncidencija 5 obolelih/milion

31

Nivoi dijagnostike IGI

Moguća infekcija “possible”- specifičan CT nalaz - Da, ali Galactomannan/ Mannan test- negativan

Verovatna infekcija “probable”- jasna radiografskapotvrda infekcije +2 ili više pozitivnih uzorka na Galactomannan/ Mannan test

Dokazana- “documented” infekcija - pozitivanhistopatološki pregled tkiva na Aspergilus ili pozitivnakultura dobijena invazivnom procedurom (otvorena biopsija pluća, traheobronhijalna ili perkutana iglena biopsija)- retko izvodljivo kod hematoloških bolesnika zbog trombocitopenije ili lošeg opšteg stanja bolesnika

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

Dijagnostikovanje IGI

33

Metode laboratorijske dijagnoze IGI

MIKOLOŠKE

(KONVENCIONALNE

METODE)

1. MIKROSKOPSKI

PREGLED BOLESNICKOG

MATERIJALA

direkni mikroskopski preparat

(DMP)

patohistologija (PH)

2. IZOLACIJA GLJIVA IZ

BOLESNICKOG MATERIJALA

mikološka kultura (MK)-"zlatni

standard"

IMUNOLOŠKE

DOKAZIVANJE ANTITELA

(At)

DOKAZIVANJE

ANTIGENA (Ag)

DOKAZIVANJE

BIOMARKERA

MOLEKULARNE

DOKAZIVANJE DNK

(PCR)

DOKAZANA VEROVATNA GI

34

Nivoi terapije IGI

Kontinium 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-emtivne terapija

Započinje 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

Pre-emptive Antifungal Therapy (ECIL3)

• Pre-emptivna antigljivična strategija je “izvodljiva”– Klinički znaci + GM/CT-scan bazirana strategija: ukupno

preživljavanje kao sa empirijskom terapijom- samo u centrima sa brzom dg IGI

– Smanjenje obima antigljivične terapije u odnosu na empirijsku (↓ toksičnost, interakcije, rezistencija, troškovi?)

– Rizik od povećanja incidence IFI (Aspergillus, Candida)u odnosu na empirijsku terapiju, posebno kod bolesnika sa neutropenijom > 15 dana: uticaj na prognozu IFI?

– Mogućnost rane terapije IFI u odsustvu febrilnosti, pre-emptivnim pristupom (propušteno kod empirijske terapije koja je dirigovana febrilnošću)

– Nema gradiranja pouzdanosti/preporuka za pre-emptivnu terapiju usled nepostojanja definisanih standardnih kriterijuma i usled varijabilnosti rezultata u različitim studijama

UPDATE ECIL-3 2009

9,0%

*2.7%

0%

5%

10%

15%

20%

Empirical, n=150 Pre-emptive, n=143

% o

f p

ati

en

ts

97,0% 95,0%

0%

20%

40%

60%

80%

100%

Empirical, n=150 Pre-emptive, n=143

% o

f p

ati

en

ts

Empirijska v. Preemptivna antigljivičnaterapija

(n =293)

*p<0.02p=ns

Ukupno preživljavanje Dokazana i verovatna IGI

Cordonnier et al. CID 2009; 48: 1042-1051

SVI PACIJENTIPrimena

antimikotika tokom

perioda postojanja

rizika infekcije

SPECIFIČNA

TERAPIJA

FEBRILNI

PACIJENTI

Posle 48h

primene

antibiotika

POZITIVNI

DG.

TESTOVIDOKAZANO

NIJE

PRISUTNANIJE

ISKLJUČENASUSPEKTNA PRISUTNA

GM esej ili CT;

bez simptoma

IFI/EORTC/MSG

PROFILAKSA EMPIRIJSKA TERAPIJA PREEMPTIVNA Th

Terapijske strategije u IGI

IZGLEDI DA OBOLJENJE POSTOJI

42

Vodiči/strategija lečenja

hematoonkoloških bolesnika sa IGI u

2017.godini (NCCN i ECIL 6) i

raspoloživi antimikotici

1950~ 1970~80 1997~ 2002~ 2004

Early AzolesClotrimazoleMiconazole

Ketoconazole

AmbisomeAbelcet

Amphocil

2nd Tri-azole: VfendEchinocandins: Cancidas

PolyenesNystatin

Amphotericin B

1st Tri-azolesFluconazoleitraconazole

Micafungin

Posaconazole

1990~

Antigljivični lekovi

-(1,3)-D-glukan

Analozi nukleozida

Ergosterol

Polieni

Azoli

Fosfolipidni dvosloj

Ćelijske membrane

Ćelijski zid

-(1,6)-glukan

Sintaza -(1,3)-D-glukana

Inhibitor sinteze glukana

(ehinokandini)

jedro

Mehanizmi delovanja antimikotika

45

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

neutropenia

INTERMEDIATE

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

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

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

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

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

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

Aspergillus infections

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

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

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

ECIL-6 recommendations for salvage therapy of invasive aspergillosis

ECIL-6 recommendations for first-line therapy of mucormycosis

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