Bacterial infections in HSCT

Montserrat Rovira, Enric Carreras with the collaboration of Josep Mensa

Hospital Clinic, Barcelona, Spain

Vienna. 8-10 May, 2014

1 3 • physical barriers

• neutrophil

• T lymphocytes

• antibodies

• spleen

100 %

months

bacteria

Aspergillus

CMV

T lymphocytes

antibodies

spleen

Pneumococcus Haemophilus

VZV

antibodies

spleen

bacteria

Candida

HSV

barriers

neutrophil

T lymphocytes

antibodies

spleen

Protective mechanisms

aGvHD cGvHD

JM

Tomblyn et al. BB&MT 2009

Bacterial infections

Early after HSCT

(neutropenic phase)

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

with microbiological

diagnosis

33%

without microbiological

diagnosis

67%

Febrile episodes (positive blood cultures) in neutropenic patients . Hospital Clínic 1991 - 2012

0

20

40

60

80

100

91-92 93-94 95-96 97-98 99-00 00-04 04-'08 08-´12

Gram (+)

Gram (-)

2540 episodes of bacteriemia in neutropenic patients (<500/mL) *

* Hospital Clínic. Barcelona 1991-2009

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

gastro-

intestinal

tract

vascular access

Gram (-ve)

Gram (+ve)

Main sources of infection in neutropenic patients

Clinical Infectious Diseases 2009: 49: 1 – 44.

aerobic / anaerobic

1 / 100-1000

oxide-reduction gradient

translocation

- complement - antibodies

JM

reduction of phagocytosis capacity - neutropenia

increased permeability of the mucosa - mucositis

increased density of aerobic bacteria - treat. antibiotics

primary

bacteraemia

JM

Bacterial infections

Prophylaxis

Gastro-intestinal decontamination (GID) + low bacterial diets

Cooked vs non cooked diets AML - induction therapy

Incidence of major infections

Gardner et al. JCO 2008; 26: 5684

RAW randomized

Higher incidence of Enterococcus

SRV=

RAW no randomized

COOKED randomized

Profilaxis with non-absorbable antibiotics

(GVN) + isolation measures in 95

consecutive severe neutropenic patients

Isolation +

GVN

without

measures

Febrile episodes 40% 80%*

Clinically doc. Infect. 25% 55%*

Bacteriol. doc. Infect. 21% 53%*

Related deaths 8% 26%*

Ribas-Mundó et al. Cancer 1981

* p<0.01

Hospital Clínic Barcelona

Gentamicin

Vancomicin

Nistatin (Aerobic + anaerobic

flora)

HPA rooms

Sterile diets

• van der Vaaij. Resistance to

colonization mechanisms. Infection 1983

Anaerobic flora

Selective

GID

Total

GID

Gram(-ve)

Quinolones era

GID with fluoroquinolones

infections gram (-ve) microbiol. docum. infect. total infections days with fever

= gram (+ve) infections = fungal infections = clinically docum. infect. = infection-related deaths

Quinolone vs. Placebo or TMP-SMZ *

* Engels et al, JCO 1998 **Cruciani et al, JCO 2003

Emergence S. viridans & S. coagulase (-)

18 randomized studies / 1408 patients

Quinolone + gram (+ve) vs. Quinolone**

Same results adverse effects

9 randomized studies / 1202 patients

rifampicin, vancomycin, amoxicillin, roxithromycin, penicillin

Bucaneve et al, NEJM 2005

Patients with acute Leukaemia

Probability of

survival

free

of fever (%) Levo

Placebo

p<0.01

GID with levofloxacin

Imran et al. Eur J Clin Microbiol Infect Dis 2008

Meta-analysis randomized studies (2719 patients)

GID with quinolones

1st European Conference on Infections in Leukemia (ECIL)

ECIL1 Guidelines. EJC supplement 2007: 5(2)

1st European Conference on Infections in Leukemia (ECIL)

ECIL1 Guidelines. EJC supplement 2007: 5(2)

Bacterial infections

Diagnosis

To analyze epidemiologic exposures

1st

To analyze the predominant type of immuno- suppression

2nd

To evaluate preventive measures used

3rd

.

ciprofloxacin

cotrimoxazole

fluconazole

aciclovir

ganciclovir

. . .

isolation

measures . . .

vaccines

Exogenous infection (epidemic outbreaks, contact w child or other patients, isolation measures)

Mucosa flora status (previous Atb and infections)

Reactivation (travel, tuberculosis, serologies)

neutropenia

mucositis

T lymphocytes

antibodies

spleen

JM

To analyze epidemiologic exposures

1st

To analyze the predominant type of immuno- suppression

2nd

To evaluate preventive measures used

3rd

.

ciprofloxacin

cotrimoxazole

fluconazole

aciclovir

ganciclovir

. . .

isolation

measures . . .

vaccines

Exogenous infection (epidemic outbreaks, contact w child or other patients, isolation measures)

Mucosa flora status (previous Atb and infections)

Reactivation (travel, tuberculosis, serologies)

neutropenia

mucositis

T lymphocytes

antibodies

spleen

Culture:

- Blood, urine & stools + any other focus

Imaging:

- Chest x-ray + CT/MRI/US (focus)

Biochemistry

- Basic + PCR + blood gasses

JM

blood obtained through the catheter

> 100 UFC / mL

blood obtained from a peripheral vein

< 10 UFC / mL

difference between growing time > 2 h

catheter colonized or infected

JM

W/O microbiological

diagnosis 65-70%

60% of remaining

Gram (+ve)

Bacterial infections

Treatment

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

1491 episodes of bacteraemia / fungemia

in neutropenic patients (< 500 / mL). 1991-2004*

Incidence and mortality by microorganisms

Microorganism (%)

• S. coag. neg. (32)

• E. coli (19)

• P. aeruginosa (9)

• Strept. Viridans (6)

• Enterococcus (6)

• S. aureus (5)

• Candida spp (4)

Death (%)

(5)

(19)

(21)

(9)

(18)

(21)

(40)

25 / 476

54 / 283

28 / 133

9 / 96

15 / 84

15 / 71

23 / 58

* Hospital Clínic. Barcelona JM

1 Adapted to centre

Enterobact-BLEAs

non-ferm-GNB

S Aureus MR

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

Multi-R GNB

SPCN

Enterococcus

Candida

JM 2 Adapted to patient

JM

Level of bacterial burden

pneumonia

meningitis

empiema

septic arthritis

endocarditis

osteomielitis

peritonitis, abscess

high > 107 UFC/mL low < 105 UFC/mL

(urinary infection)

primary bacteraemia

catheter infection

B-lactamic B-lactamic + aminoglucoside

3 Adapted to clinical situation

• B-lactamic active against G(+ve) and G(-ve) including P. aeruginosa

- cefepime (8h), - piperacil.-tazobac., - imipenem o - meropenem - doripenem

JM

• aminoglucoside

- amikacin

+/-

To add an aminoglucoside?

2 meta-analyses >4600 patients (Furno et al. Lancet Infect Dis 2002; Paul et al. Cochrane 2003)

+ 9 trials

Monotherapy = Betalactam + AG?

Betalactam + AG more toxic?

AG in initial regime (empirical or if G-ve documented)?

YES (AI)

YES (AI)

NO

(CIII)

ECIL conclusions 2007

ECIL1 Guidelines. EJC supplement 2007: 5(2)

Eskape pathogens:

Enterococus faecium

Staphylococcus aureus

Klebsiella pneumoniae

Acinetobacter baumanii

Pseudomona aeruginosa

Enterobacter spp

2011

Center with a high

incidence of

ESBL? (extended spectrum

beta-lactamases)

• B-lactamic active against G(+ve) and G(-ve) including P. aeruginosa

- cefepime (8h), - piperacil.-tazobac., - imipenem o - meropenem - doripenem

JM

• aminoglucoside

• anti-gram(+ve)

- amikacin

- glucop./daptom./linezo.

+/-

Glycopeptides in neutropenic patients –main doubts -

1.- Upfront in the empirical therapy? Vardakas et al. Lancet Infect Dis 2005 (meta-analysis)

Paul et al. JAC 2005 (meta-analysis)

Lancet Infect Dis 2005; 5: 431-439

odds ratios of treatment success without modification of the initial regimen

(1812 patients)

OR 1,63 95% CI 1,2-2,2

JM

odds ratios of mortality

(1073 patients)

OR 0,67 95% CI 0,4-1,05

Lancet Infect Dis 2005; 5: 431-439

odds ratios of all adverse effects

(883 patients)

OR 4,98 95% CI 2,9-8,5

odds ratios of nephrotoxicity

(1508 patients)

OR 2,1 95% CI 1,1-3,9

JM

Glycopeptides in neutropenic patients –main doubts -

1.- Upfront empirical therapy? Vardakas et al. Lancet Infect Dis 2005 (meta-analysis)

Paul et al. JAC 2005 (meta-analysis)

2.- In case of persistent fever after

initial broad spectrum empirical

antibiotic therapy? Cometta et al. CID 2003 (placebo controlled)

Erjavec et al. JAC 2000 (placebo-controlled)

placebo

vanco

Glycopeptides if persistent fever after initial broad spectrum empirical Atb?

Cometta et al. CID 2003

To add a glycopeptide?

At onset of fever

Persistent fever

MARSA colonization, hypotension or shock,

skin, soft tissue, catheter related

NO (DI)

NO (DI)

YES

(CIII)

ECIL conclusions 2007

ECIL1 Guidelines. EJC supplement 2007: 5(2)

Role of the less toxic and more

effective anti-gram (+ve) agents

- Linezolid

- Daptomycin ?

• possible catheter infection

• severe mucositis

• colonization by MRSA

Summary: Initial empirical antibiotherapy in neutropenic patients with fever

antibiotic clinical situation

- meropenem (AI)

- imipenem (AII)

- pipera.-tazo (AII)

- cefepime (AII)

• fever without clinical focality

- glycopeptide or

- daptomycin

+ AII

BIII

AII

JM

Initial empirical antibiotherapy in neutropenic patients with fever

antibiotic clinical situation

- meropenem (AI)

- imipenem (AII)

- pipera.-tazo (AII)

- cefepime (AII)

• fever without clinical focality

• focality (tiphlytis, pneumonia,..)

• previous Atb treatment (>5-7d)

• colonization with resistant G(-ve)

• high incidence of ESBL

AII

BIII

BIII

BIII

+ - aminoglucoside

JM

Initial empirical antibiotherapy in neutropenic patients with fever

antibiotic clinical situation

- meropenem (AI)

- imipenem (AII)

- pipera.-tazo (AII)

- cefepime (AII)

• fever without clinical focality

• sepsis, shock, ARDS

• worsening after first days

of treatment

+ - aminoglucoside

- glycopeptide or

- daptomycin

+ AII

JM

imip. 112

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

J Clin Oncol 2000; 21: 3699-3706

cefta. 112

imip.+ vanco.

166

cefta.+ vanco.

98 P 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 improvement JM

Bacterial infections

Late infections - capsulated bacteria -

Capsulated bacteria (S. pneumoniae, H. influenzae, N meningitidis)

cGvHD

GvHD treat.

Functional

asplenia

Hypogammaglob

Absence of specific Ab

Infections

Bacterial infections late after HSCT

Probability of pneumococcal sepsis

Capsulated bacteria (S. pneumoniae)

Kulkarni, et al. Blood 2000

Bacterial infections late after HSCT

Chronic GVHD

Allograft w/o chronic GVHD

Allo or TBI

non Allo non TBI

Bacterial infections Remember!

When evaluating a HSCT receptor with fever always think in other possible “rare” bacterial infections:

–Mycobacteria (de la Cámara et al, BMT 2000)

–Nocardia (Torres et al, Medicine (Balt.) 2002)

– Listeria (Rivero et al, Diagn Microbiol Infect Dis 2003)

–Legionella (Roig et al, Curr Opin Infect Dis 2003)

–Endemic diseases (travel, globalization!!)