484_bakteriella Infektioner Hos Neutropena m Kalin

7/29/2019 484_bakteriella Infektioner Hos Neutropena m Kalin

1/23

Bakteriella Infektioner

hos Neutropena

Mats Kalin

Infektionsklinken

Karolinska universitetssjukhuset, [email protected]

De viktigaste bilderna
mailto:[email protected]:[email protected]


2/23

First line

of defense

Barrier

function

Non-specific defense

Cytoreductive

chemotherapy

primarily affects cells

with a high rate of

division, like

bone marrow cells and

epithelial cells

Mucous membranes areaffected causing

mucositis,

which may be

especially severe in the

oral cavity, in the lower

oesophagus and in the

perianal region.

Necrotising enterocolitis

may also occur


3/23

Granulocytes

Mucositis severely compromises the barrier

function

Therefore, translocation of bacteria from the

entire GI canal to the blood occurs with

increased frequency

Bacteria translocated to the blood stream are

normally rapidly cleared by granulocytesIn case of granulocytopenia bacteremia with

signs and symptoms of sepsis will develop

Most commonly translocated bacteria causing

bacteremia in neutropenic pts

- Gramneg enteric rods from the lower GI

tract including

- P.aeruginosa

- alpha-streptococci from the oral cavity


4/23

Infection Risk in Relation to Granulocyte Count

B B B BB B

JJ

JJ

JJ

H

H

H

H

H

H

0

10

2030

40

50

6070

80

90

100%

WITH

FEVE

R

5 10 daysBodey et al 1969, AAC 9:386

< 0.1

0.10.5

0.5 - 1


5/23

P

B

CTL

Granulocytes MacrophagesT

Antigen

presentation

Cytokine

regulation

In addition to mucositis and

granulocytopenia cancer chemotherapy

will cause

- T and B cell deficiencies

- for long time periods

implying increased risks for infection w

- intracellular bacteria, herpes viruses,

PCP and other fungi (T-deficiency)- pneumococci (Ig-deficiency)

In addition steroids and other drugs may compromisemacrophage function


6/23

Blood stream Pathogens

at the Center for Haematology, Karolinska hospital

Cherif et al 2004

The Haematology J 4:240

CNS

S.aureus

PneumococciEnterococci

E.coli

Klebsiella

Enterobacter

Pseudomonas

aerugionsa

Stenotrophomonasmaltophilia

OtherGramneg

Alpha-strept

Other

Grampos

1988-2001n=1402


7/23

Bacteria in Single Organism

Bacteremia in EORTC Trials

0

5

10

15

20

25

30

35

1973-78 1980-83 1986-88 1989-91

S.aureus

CNS

Strept

E.coli

P.aerugOther G-


8/23

Course in Neutropenic Patients with

Gramneg Bacteremia who did not receive

Appropriate Therapy

Within % dead

12 h 15

24 h 57

48 h 70

Bodey et al 1985, Arch Intern Med 145:1621


9/23

Infections in Neutropenic Cancer Patients

The risk for bacterial infection is related to depth and lengthof neutropenia

Bacteria are translocated from the GI tract

GI flora may be affected by hospitalisation and ab therapy

The course may be fulminant with septic shock

Symptoms may be subtle due to lack of immune response

Fever is the signal for risk of serious infectionBroad-spectrum antibiotic therapy must be startedimmediately when a neutropenic patient presents with fever:

- Cephalosporin with Pseudomonas activity

- Carbapenem

- Piperacillin/Tazobactam .


10/23

before start of antibiotics 2040 ml in 4-6 bottles - - excluding anaerobic bottles?

>1 venipuncture does not facilitate interpretation

but if CVC or PAC is used a peripheral specimen should alsobe obtained

Time to positive results from CVC/PAC and peripheralsample, respectively, can be used to diagnose line infection

Cultures should also be obtained from urine, wounds andairways

..but only afterblood cultures have been obtained

Lamy 2002, CID 35:842

Ortiz & Sande 2000, Am J Med 108:445

DesJardin 1999, Ann Intern Med 131:641


11/2324 H

Bact.conccfu

/ml

105

- Combination therapy is not superior to

monotherapy

- But the addition of an aminoglycoside

may be of value in septic shock

AG exert concentration-dependent

killing

Single daily dose recommended

0

10

20

30

40

50

60

70

80

% survival

Top level > 7/28vs < 7/28 mg/L

Moore 1984

Am J Med 77:756


12/23

It is of decisive importance to follow the course closely

Therapy may have to be changed as a results of

deteriorating general condition

new signs and symptoms of focal infection

results of cultures, most importantly blood cultures

results of chest X ray or other investigations


13/23

Pulmonary Infiltrates in Neutropenic Patients

Totally 1573 patients 1986-92

295 (17%) developed pulmonary infiltrates

- 29 % microbiologically documented

Complete Response

- 61 % in patients with pulmonary infiltrates

- 83 % in other documented infections

Early deaths (


14/23

Cometta 2003, CID 37:382

Prospective randomized double blind study of

Vancomycin vs Placebo for persistant neutropenic fever

after 48-60 h of Piperacillin/tazobactam (34 C, n=165of tot 763)

Excluded: CVC-inf, Pulm inf, Gramneg and PT-Res Grampos infect

Total case fatality rate 4 Vanco vs 8 placebo


15/23

Indications for Vancomycin

Clinically suspected serious CVC infection

Infection with cephalosporine resistant bacteria

Blood culture reported positive for Gram-pos

bacteria in a patient with deteriorating condition

before final identification and susceptibility report

Hypotension or other evidence of cardiovascularimpairment

and ??

-Severe mucositis

- Quinolone prophylaxis

- due to risk of infection with penicillin resistant alpha-

streptococci

Hughes 2002 CID 34:730 (IDSA Guidelines)


16/23

GI epithelial damage

Bacteremia

I n v a s i v e y e a s t i n f e c t i o n

Antibiotictherapy

Increased GI yeastcolonisation /focal infection

Yeast translocation


17/23

mortality rate invasive candidiasis, especially C.albicans

non-albicans Candida more patients with invasive aspergillosis more patients with uncommon fungal infections

intensity of chemotherapy and

improved antibiotic therapy

(?)Invasive Candidiasis

Improved Fungal Therapy, Prophylaxis, Other factors (?)

Pneumocystis J Pneumonia (PCP)

Invasive Fungal Infections in Cancer Patients

More patients surviving for longer periods

with severe immune defects


18/23

Pneumocystis carinii

Patients with T-cell-defects primarily affected- incidence related to degree of immunosuppression

High dose (median max.dose 80 mg / d) steroid therapy forprolonged time periods (median 3 mo)is the other important

predisposing factor, tapering of dose especial risk

Diagnosis by - Clin presentation: dry cough, dyspnea, CXR, CT

- IFL and PCR from sputum or BAL

Cotrimoxazole drug of choice for therapy, very high doses


19/23

Clinical Condition after 72 h of Antibiotic Therapy

Relation to Ultimate Outcome, n=1085

% ultimately

surviving 100 90 11

% afebrileafter 5 days 100 33 5

10%

23%

28%

39%

DETERIORATING

10 %

G-bacteremia

33%

G+

bacteremia

22%

CDI25%

FUO

20%

IMPROVING STABLE

25 % 65 %

15%

18%

21%

46%

De Pauw & Intercontinental Study Group, Ann Intern Med 1994


20/23

Fever relapsed

3 episodes

Success

20 episodes

Neutropenic whenab stopped

23 episodes

Fever relapsed

2 episodes

Success

6 episodes

Neutropeniaresolved

8 episodes

antibiotics stopped

48h after defervescence

31 episodes

2 patients

died

Fever relapsed

6 episodes

Success

20 episodes

Neutropenic whenab stopped

26 episodes

Success

3 episodes

Neutropenia hadresolved

3 episodes

antibiotics continued

> 48h after defervescence

29 episodes

Afebrile after ab therapy

60 episodes

Failure

29 episodes

FUO

89 episodes

Cherif 2004, SJID 36:593


21/23

Observed and Predicted Rates of Fever Resolution

Characteristic Points

Age < 60 y 2

No COPD 4Solid tumour or no

previous fungal dis 4

Burden of illness

none or mild 5

or moderate 3

No dehydration 3

No hypotension 5

Outpatient status 3

- without serious complications

- as a response to adequate ab therapy for neutropenic fever

- in relation to points by the MASCC risk index score

Klastersky et al 2000, J Clin Oncol 18:3038

8-16 17-18 19-20 21 22 23 24 25-26

n=71 67 67 172 52 102 127 98


22/23

Prospective

evaluation of

MASCC at

Hem C

KarolinskaInfection related mortality

2 patients

Excluded

Ineligible for oral therapy

(38 episodes)

Fever relapsereadmission

One patient

Fever relapse2 patients

one aspergillosisone pneumocyctis

Afebrile (success)64 patient

No mortality

Final evaluation

after 4 weeks

Continued afebrile66 episodes

Clinical assessment after 3 days

Discherged with oral antibiotics

24 hours after defervescence

eligible for oral therapy

(67 episodes)

Low risk patients (105 episodes)

MASCC risk-index score

< 21 (high risk): 176 pts (63%)w serious medical complications in 63%

> 21 (low risk)105 pts

w serious medical complications in 15%

- and in an additional 21% other factsprecluded oral therapy

Thus, a total of24% of haematological patients with neutropenic

fever could be discharged with oral therapy 24 h after

defervescence, essentially w/o complications Cherif et al 2006Haematologica

R i bl di ICU STRAMA


23/23

Resistance problems according to ICU-STRAMA

Gramneg enterobacteriaQuinolones 5-10 %

ESBL rare findings Enterobacter

Cephalosporin inducable resistance in high frequency

Quinolones 5-10 %

Pseudomonas aeruginosaImipenem 25 %

Quinolones 12 %

Ceftazidime 10 %

Piperacillin 17 %

Stenotrophomonas maltophiliaImipenem 100 %

Quinolones 30 %Ceftazidime 10 % Hahnberger: http://e lio se/ivastrama/

Documents

484_bakteriella Infektioner Hos Neutropena m Kalin