Complicacions infeccioses en el malalt neutropènic

Montserrat Rovira

Servei Hematologia, Hospital Clínic

Barcelona, 27 de gener 2011

VI Conferència d´experts de la SOCMIC

tracte gastro-

intestinal

accessos vasculars

Gram (-)

Gram (+)

Origen principal de les infeccions en el malalt neutropènic

mucosa

decreased cell renewal

epithelial thinning

mucositis

infection

bone marrow

Micro-organisms

myelosuppression

neutropeniathrombocytopenia

discomfortpaindry mouthburning sensationloss of tasteerythemaulceration

Conseqüencies de la quimioteràpia

Cytostatic chemotherapy

infectiousdisease

4

Clinical Infectious Diseases 2009: 49: 1 – 44.

5

Mucositis:

6

Mucositis:

diarrhea

vomiting

nausea

bowel cramps

pain

7

Risc infecciós durant neutropènia i mucositis

Days

0 10 20 30 40

Neutropenia

Mucositis

colonisation

invasion

8

bacteraemi

a

GR

AN

UL

OC

YT

ES

{lo

g(1

09/L

)}

0.1

1

0

1

2

3

Gra

de o

f m

uco

sit

is

Mucositis

Neutropènia

Mucositis i neutropènia després quimioteràpia

bacterièmia

9

Infeccions bacterianes

Febrile episodes in neutropenic patients – EORTC trials–

0

20

40

60

80

100

73-76 77-80 80-83 83-85 86-88 89-91 91-93 94-96

year of EORTC trial

Gram (-ve)

Gram (+ve)

year of EORTC study

withmicrobiological

diagnosis

33%

withoutmicrobiological

diagnosis

67%

Febrile episodes in neutropenic patients *

0

20

40

60

80

100

91-92 93-94 95-96 97-98 99-00 00-04 04-'08

3.3 3.8 2.0 1.9 1.8

Ratio G (+ve) / G (-ve)

Gram (- ve)

Gram (+ ve)

1.7

* Hospital Clínic. Barcelona 1991-2008

1.1

12

Distribution of 275 micro-organisms isolatedin 835 neutropenic patients (PETHEMA study)

Gram positive nº (%) Gram negative nº (%)

SPCN

Strept. viridans

Corynebacterium

S. aureus

Enterococcus

Neumococcus

otros

86 (31)

26 (10)

15 (5)

11 (4)

7 (2,5)

3 (1)

10 (4)

E. coli

P. aeruginosa

Klebsiella spp

Enterobacter spp

Acinetobacter spp

others

62 (23)

16 (6)

15 (5)

7 (3)

6 (3)

11 (4)

W/O microbiological diagnosis

67%

Sanz et al. J Antimicrob Chemother 2002

13

Distribution of 275 micro-organisms isolatedin 835 neutropenic patients (PETHEMA study)

Gram positive nº (%) Gram negative nº (%)

SPCN

Strept. viridans

Corynebacterium

S. aureus

Enterococcus

Neumococcus

otros

86 (31)

26 (10)

15 (5)

11 (4)

7 (2,5)

3 (1)

10 (4)

E. coli

P. aeruginosa

Klebsiella spp

Enterobacter spp

Acinetobacter spp

others

62 (23)

16 (6)

15 (5)

7 (3)

6 (3)

11 (4)

Sanz et al. J Antimicrob Chemother 2002

1491 episodes of bacteriemia inneutropenic patients (<500/mL) *

* Hospital Clínic. Barcelona 1991-2004

Agent Isolates (%)

Staph. coagulase (-ve).

E. coli

P. aeruginosa

Streptococcus viridans

476

283

133

96

(32)

(19)

(9)

(6)

Mortality (%)

(5)

(19)

(21)

(9)

25

54

28

9

Flora changes during severe disease evolution

Healthy

people

Severe

disease

Atb

>72 h

Long term

Atb - ICU

each

epithelium its

flora

flora

redistribution

flora

selection

multi-

resistant

flora

Haemophylus

S Aureus MS

Enterobacteria

Enterobact-R

non-ferm-GNB

S Aureus MR

Multi-R GNB

SPCN

Enterococcus

Candida

JM

16

Infeccions comuns durant neutropènia

39

40

41

Te

mp

era

ture

°C

Gra

nu

locyte

s (

log

10

1x 1

06/L

)

0.1

1

10

0 7 14 21 28 35 42 49 56 63

Days

bacteraemia skin lung

17

Infeccions comuns durant neutropènia

39

40

41

Te

mp

era

ture

°C

Gra

nu

locyte

s (

log

10

1x 1

06/L

)

0.1

1

10

0 7 14 21 28 35 42 49 56 63

Days

bacteraemia skin lung

• Bact gram(-):

E.coli, Klebsiella.,

pseudomona

• Staph. Aureus

•Aspergillus, mucor

18

Profilaxis

19

Profilaxis

39

40

41

Te

mp

era

ture

°C

Prophylaxis

Gra

nu

locyte

s (

log

10

1x 1

06/L

)

0.1

1

10

0 7 14 21 28 35 42 49 56 63

Days

quinolones

cotrimoxazole + colistin

nonabsorbable

none

Gram-negative

fluconazole

polyene

none

yeast

Posa/Itra/vori

amphotericin B

none

mould

Candins Candins

20

Bucaneve et al, NEJM 2005

Patients with acute Leukaemia

Probability of

Survival

free

of fever (%) Levo

Placebo

p<0.01

GID with levofloxacin

21

Imran et al. Eur J Clin Microbiol Infect Dis 2008; 27: 53–63

Meta-analysis randomized studies (2719 patients)

GID with quinolones

22

1st European Conference on Infections in Leukemia (ECIL)

ECIL1 Guidelines. EJC supplement 2007: 5(2)

1986

The life cycle of fluoroquinolone prophylaxis

Gram-negative bacillary bacteremia

Gram-positive coccal bacteremia

fever

Infectious mortality

reduction no reduction

Gram-positive coccal bacteremia

fever

Infectious mortality

reduction no reduction

penicillin

macrolide+

Stop?

Escherichia colifluoroquinolone resistant

Gram-positive cocciresistant

Fluoroquinolones

ciprofloxacin

ofloxacin

norloxacin

pefloxacin

15 years

Courtesy JP Donnelly

Infeccions bacterianes

Tractament

25

A, B, C of treatment of febrile neutropenia

• It must be:

• Started immediately after onset of fever

• Based in an empirical approach

• Adapted to the flora usually observed in each

centre

• Adapted to the type of patient

• Adapted to the clinical situation

1

2

3

26

Distribution of 275 micro-organisms isolatedin 835 neutropenic patients (PETHEMA study)

Gram positive nº (%) Gram negative nº (%)

SPCN

Strept. viridans

Corynebacterium

S. aureus

Enterococcus

Neumococcus

otros

86 (31)

26 (10)

15 (5)

11 (4)

7 (2,5)

3 (1)

10 (4)

E. coli

P. aeruginosa

Klebsiella spp

Enterobacter spp

Acinetobacter spp

others

62 (23)

16 (6)

15 (5)

7 (3)

6 (3)

11 (4)

Sanz et al. J Antimicrob Chemother 2002

1

Flora changes during severe disease evolution

Healthy

people

Severe

disease

Atb

>72 h

Long term

Atb - ICU

each

epithelium its

flora

flora

redistribution

flora

selection

multi-

resistant

flora

Haemophylus

S Aureus MS

Enterobacteria

Enterobact-R

non-ferm-GNB

S Aureus MR

Multi-R GNB

SPCN

Enterococcus

Candida

JM

2

JM

Level of bacterial burden

pneumonia

meningitis

empiema

septic arthritis

endocarditis

osteomielitis

peritonitis, abscess

high > 107 UFC/mLlow < 105 UFC/mL

(urinary infection)

primary bacteraemia

catheter infection

B-lactamic B-lactamic + aminoglucoside

3 Adapted to clinical situation

29

• possible catheter infection

• severe mucositis

• colonization by MRSA

Summary: Initial empirical antibiotherapy in neutropenic patients with fever

antibioticclinical situation

- meropenem (AI)

- imipenem (AII)

- pipera.-tazo (AII)

- cefepime (AII)

• fever withoutclinical focality

- vancomycin

+AII

BIII

AII

JM

30

Initial empirical antibiotherapy in neutropenic patients with fever

antibioticclinical situation

- meropenem (AI)

- imipenem (AII)

- pipera.-tazo (AII)

- cefepime (AII)

• fever withoutclinical focality

• focality (tiphlytis, pneumonia,..)

• previous Atb treatment (>5-7d)

• colonization with resistant G(-ve)

• high incidence of ESBL

AII

BIII

BIII

+- aminoglucoside

JM

31

fever w/ofocality

severe sepsis shock or ARDS

amikacin

carbapenem, (cefepime opiperaciline-tazobactam)

glucopeptideor daptomycin

focalinfection catheter

JM

32

imip.112

Elting L, et alTime to clinical response: An outcome of antibiotic therapy offebrile neutropenia with implications for quality and cost of care

J Clin Oncol 2000; 21: 3699-3706

cefta.112

imip.+vanco.

166

cefta.+vanco.

98P P

• time clinical resp.*

• response at 72 h

• days w Atb.

• days hospital.

5

33%

7

9

.003

.01

.04

.04

7

18%

9

12

5

29%

8

9

6

16%

9

13

.09

.03

.05

.02

* 24 h w/o fever and clinical improvementJM

33

Infeccions fúngiques

34

Pre-emptiveantifungal

based on lab or imagine

tests

Therapeutic approaches to IFI in neutropenic patients

Prophylaxisantifungal to all patients (primary or secondary)

Empiricalantifungal due

to fever unresponsive to

antibact.

Treatmentantifungal based on proven IFI

Probability of IFI0% 100%

Anticipated

Early treatment

~ 80% unnecessary treat. (IFI incidence <20%)

35

0

5

10

15

20

25

30

Pizzo EORTC Pizzo EORTC

No therapy AmB-d

Empirical Ampho-d vs no therapyPizzo et al, Am J Med 1982 / EORTC, Am J Med 1989

4/16

1/18 4/64

3/16

1/18 4/64

0/68

Incidence IFI Mortality IFI

%

1/68

36

Empirical antifungal therapy

Double-blind clinical trialsAuthor,

year

Drugs

compared

Composite

Endpoint

Outcome

baseline

IFI

Break-

trough

IFI

Nephro-

toxicity

White

1998

ABCD

vs AmB-dNS NS NS Less

Walsh,

1999

Lipo-AmB

vs. AmB-dNS NS Less Less

Wingard,

2000

ABCD vs.

Lipo-AmBNS NS NS More

Walsh,

2002*

Vori vs.

Lipo-AmBNS NS Less NS

Walsh,

2004

Caspo vs.

Lipo-AmBNS Better NS Less

* open trial

38

ECIL recommendations

Empirical antifungal therapy in persistent febrile neutropenic patients

BII

Early therapy

Most patients do not have an IFIAdverse effects

Development of resistancesCosts

Better lab + imaging techniques

Neutropenia - bridging the gap with supportive care

Mucosal barrier injury

Antimicrobial agents

Other medication

Diagnosis

Blood products

Nutrition

Nursing

Courtesy JP Donnelly

40

Neutropènia /

Disf. Neutr.

Inmunodef.

Cel.lular

Inmunodef.

Humoral

Leucèmies agudes +++ / + + / - -

Mielodisplasies ++ / +++ + / - -

Linfoma – LLC-

Mieloma múltiple

+ / - ++ ++

Trasplant autòleg ++ / - ++ +

Trasplant

al.logènic

+++ / - +++ +++

No tots els pacients hematològics a risc

d´infeccions estàn neutropènics!!!!!

41

Impaired T-cell function: responsible agents

Bacteria

Listeria

Mycobacteria

Legionella

Nocardia

Brucella

Salmonella

Fungi

Pneumocystis j.

Cryptococcus

Histoplasma

Candida

Aspergillus

Blastomyces

Zygomicosis

Virus

Herpes

Respiratory virus

JC, EBV

Parasites

Toxoplasma

Giardia

42

• Capsulated bacteria

Streptococcus pneumoniae

Haemophilus influenzae

Neisseria meningitidis

• Parasites

Babesiosis

Impaired B-cell function: responsible agents

43

Agraïments:

• Dr E. Carreras

• Dr J. Mensa

• Dr JP. Donnelly

Moltes gràcies per la seva atenció!!!!

mrovira@clinic.ub.es