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
Hvala na pažnji