Bakteriella Infektioner hos Neutropena

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Bakteriella Infektioner hos Neutropena

• Mats Kalin
• Infektionsklinken
• Karolinska universitetssjukhuset, Solna
• mats.kalin_at_karolinska.se
• De viktigaste bilderna

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Cytoreductive chemotherapy primarily affects
cells with a high rate of division, like bone
marrow cells and epithelial cells Mucous
membranes are affected 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
Non-specific defense
First line of defense Barrier function
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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
granulocytes In 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 - S.aureus
Granulocytes
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Infection Risk in Relation to Granulocyte Count
100
W I T H F E V E R
lt 0.1
H
90
80
H
70
60
H
50
40
0.1 0.5
30
H
J
20
J
J
0.5 - 1
10
J
H
B
J
B
B
B
B
B
J
H
0
5 10
days
Bodey et al 1969, AAC 9386
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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)
CTL
P
Antigen presentation
Cytokine regulation
B
T
Granulocytes
Macrophages
In addition steroids and other drugs may
compromise macrophage function
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Blood stream Pathogens at the Center for
Haematology, Karolinska hospital
Other Gramneg
Stenotrophomonas maltophilia
1988-2001 n1402
CNS
Enterobacter
Pseudomonas aerugionsa
S.aureus
Klebsiella
Alpha-strept
E.coli
Enterococci
Cherif et al 2004 The Haematology J 4240
Pneumococci
Other Grampos
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Bacteria in Single Organism Bacteremia in EORTC
Trials
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Course in Neutropenic Patients with Gramneg
Bacteremia who did not receive Appropriate Therapy
Bodey et al 1985, Arch Intern Med 1451621
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Infections in Neutropenic Cancer Patients

• The risk for bacterial infection is related to
  depth and length of 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
  infection

Broad-spectrum antibiotic therapy must be started
immediately when a neutropenic patient presents
with fever - Cephalosporin with Pseudomonas
activity - Carbapenem - Piperacillin/Tazobactam
.
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..but only after blood cultures have been
obtained

• before start of antibiotics
• 20 40 ml in 4-6 bottles - - excluding
  anaerobic bottles?
• gt1 venipuncture does not facilitate
  interpretation
• but if CVC or PAC is used a peripheral
  specimen should also be obtained
• Time to positive results from CVC/PAC and
  peripheral sample, respectively, can be used to
  diagnose line infection
• Cultures should also be obtained from urine,
  wounds and airways

Lamy 2002, CID 35842 Ortiz Sande 2000, Am J
Med 108445 DesJardin 1999, Ann Intern Med 131641
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- 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
survival
Bact.conc cfu / ml
105
Betalaktamantibiotikum 4 x MIC
Betalaktamantibiotikum 10 x MIC
Aminoglycoside 10 x MIC
Top level gt 7/28 vs lt 7/28 mg/L Moore 1984 Am J
Med 77756
Aminoglycoside 4 x MIC
24 H
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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
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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 (lt21 days) 22
• _________________________________________
• Meschmeyer et al 1994, Cancer 732296
• Medizinische Klinik 89114 Annals Hematol 69231
  

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Prospective randomized double blind study of
Vancomycin vs Placebo for persistant neutropenic
fever after 48-60 h of Piperacillin/tazobactam
(34 C, n165 of tot 763) Excluded CVC-inf,
Pulm inf, Gramneg and PT-Res Grampos infect
Total case fatality rate 4 Vanco vs 8 placebo
Cometta 2003, CID 37382
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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
  cardiovascular impairment
• and ??
• Severe mucositis
• Quinolone prophylaxis
• due to risk of infection with penicillin
  resistant alpha-streptococci

Hughes 2002 CID 34730 (IDSA Guidelines)
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GI epithelial damage
Bacterial translocation
Bacteremia
Antibiotic therapy
Increased GI yeast colonisation /focal infection
Yeast translocation
I n v a s i v e y e a s t i n f e c t i o
n
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Invasive Fungal Infections in Cancer Patients

• intensity of chemotherapy and
• improved antibiotic therapy

More patients surviving for longer periods with
severe immune defects
? (?) Invasive Candidiasis
? Pneumocystis J Pneumonia (PCP)
Improved Fungal Therapy, Prophylaxis, Other
factors (?)
? mortality rate invasive candidiasis, especially
C.albicans ? ?non-albicans Candida ? more
patients with invasive aspergillosis ? more
patients with uncommon fungal infections
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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 for prolonged 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
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Clinical Condition after 72 h of Antibiotic
Therapy Relation to Ultimate Outcome, n1085
DETERIORATING 10
IMPROVING STABLE 25
65
10
G- bacteremia 33
FUO 20
15
39
23
46
18
CDI 25
G bacteremia 22
21
28
afebrile after 5 days 100
33
5
ultimately surviving 100
90
11
De Pauw Intercontinental Study Group, Ann
Intern Med 1994
20
Cherif 2004, SJID 36593
21
Observed and Predicted Rates of Fever Resolution

• without serious complications
• as a response to adequate ab therapy for
  neutropenic fever
• in relation to points by the MASCC risk index
  score

Characteristic Points Age lt 60 y 2 No
COPD 4 Solid tumour or no previous fungal
dis 4 Burden of illness none or mild 5 or
moderate 3 No dehydration 3 No hypotension 5 Outpa
tient status 3
8-16 17-18 19-20 21 22 23
24 25-26 n71 67 67 172
52 102 127 98
Klastersky et al 2000, J Clin Oncol 183038
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Prospective evaluation of MASCC at Hem C
Karolinska
MASCC risk-index score lt 21 (high risk) 176
pts (63) w serious medical complications in
63 gt 21 (low risk) 105 pts w serious
medical complications in 15 - and in
an additional 21 other facts precluded oral
therapy Thus, a total of 24 of haematological
patients with neutropenic fever could be
discharged with oral therapy 24 h after
defervescence, essentially w/o complications
Cherif et al 2006 Haematologica
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Resistance problems according to ICU-STRAMA

• Gramneg enterobacteria
  Quinolones 5-10
• ESBL rare findings
• Enterobacter
  Cephalosporin inducable resistance in high
  frequency
• Quinolones 5-10
• Pseudomonas aeruginosa
  Imipenem 25
  Quinolones 12
  Ceftazidime 10
• Piperacillin 17
• Stenotrophomonas maltophilia
  Imipenem 100
  
  Quinolones 30
  Ceftazidime 10

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