Febril neutropeni hur agera

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Febril neutropeni- hur agera?

• Mats Kalin
• Department of Medicine
• Infectious Disease Unit
• Karolinska Universitetssjukhuset, Solna
• mats.kalin_at_karolinska.se

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Non-specific defense
Cytoreductive chemotherapy will affect all
cells with a high rate of division, like
bone marrow cells and epithelial
cells, especially those in the GI tract
First line of defense Barrier function
skin
Second line of defense
CTL
P
B
T
Granulocytes
Macrophages
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Mucous membranes are affected causing mucositis,
which may be especially severe in the oral
cavity, in the lower oesophagus and in the
perianal region. Mucositis severely compromises
the barrier function Therefore,
translocation of bacteria from the entire GI
tract to the blood is increased
Non-specific defense
First line of defense Barrier function
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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
Non-specific defense
First line of defense Barrier function
Second line of defense
Granulocytes
Macrophages
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Infection Risk in Relation to Granulocyte Count
100
W I T H F E V E R
H
lt1000
B
90
lt500
J
80
H
lt100
H
70
60
H
50
40
30
H
J
20
J
J
10
J
H
B
J
B
B
B
B
B
J
H
0
5 10
days
Bodey et al 1969
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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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• Translocated bacteria
• causing bacteremia
• in neutropenic patients are
• Gramneg enteric rods
• from the lower GI tract
• including P.aeruginosa
• alpha-streptococci
• from the oral cavity
• S.aureus

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Blood stream Pathogens at the Center for
Haematology, Karolinska hospital 1988-2001
n1402
Other Gramneg
Stenotrophomonas maltophilia
The distribution of bacteria isolated in blood
cultures are similar in children at the oncology
unit ALB, Karolinska
Enterobacter
CNS
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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Course in Neutropenic Patients with Pseudomonas
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
  the depth and length of neutropenia
• Bacteria are translocated from the GI tract
• The GI flora may be affected by
  hospitalization 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 patient presents with fever
  with
• Cephalosporin with Pseudomonas activity or
• Carbapenem or
• Piperacillin/Tazobactam

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Betalaktamantibiotika - koncentrations-o-beroende
avdödning liksom flertalet andra
antibiotika Aminoglykosider - snabb baktericid
effekt - koncentrations-beroende
avdödning liksom kinoloner och några andra prep
Bakterie-konc cfu / ml
105
Betalaktamantibiotikum 4 x MIC
Betalaktamantibiotikum 10 x MIC
Aminoglykosid 10 x MIC
Aminoglykosid 4 x MIC
24 H
Vid septisk chock eftersträvar man snabb
baktericid effekt
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Aminoglykosider

• Mycket snabb baktericid effekt
• Ökar trol chansen för överlevnad vid svår sepsis
• men nefrotox kan vara svårhanterat
• Doseras för maximal effekt
• en gång per dygn
• Endosering ger något lägre toxicitet
• Vid endosering bör dalvärdet vara nära 0
• Toppvärdet har ingen betydelse för tox, men ett
  bra toppvärde är pos korrelerat till överlevnad
  vid svår sepsis

survival
AG top level gt 7/28 vs lt 7/28 mg/L Moore 1984,
Am J Med 77756
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• CNS has become the most common
• etiology in neutropenic fever
• - due to the frequent use of CVCs
• - CNS are usually multiresistant, but
• - the course is most often not fulminant
• - CNS therefore not covered from start
• Focal symptoms may be missing
• Also enterococci are isolated with increasing
  frequency
• Addition of Vancomycin is the most common
  modification in neutropenic fever not responding
  to the initial regimen
• seems to be well gounded
• nb, if the patient has continued fever and is
  not improving when continued therapy with started
  regimen is recommended

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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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Cherif 2004, SJID 36593
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Neutropenic Children with Cancer Chemother

• Patients not suitable for outpt ther
• Leukemia induction therapy
• BMT
• Clin unstable
• Hypotension
• Respiratory distress
• Haemorrhage
• Soft tissue infection
• Pneumonia
• Sever mucositis
• Socially unstable

• Death rate 1
• ICU admittance 1
• Average no of fever days 3
• Neutropenia 4-5 d after fever
• Bacteremia 15-20
• Low-risk patients identifiable w very low risk
  of bacteremia or death. Hospital readmittance
  4-22 in 8 studies (494 pts)
• Therapy with ceftriaxone, genta/cloxa/ticar, po
  quinolone OK
• Mullen 2001 Brit J Haematol 112832
• Oral Cefixime vs Ticar/Amika/Vanco 28 vs 27
  failure, no death
• Shenep 2001 CID 3236

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Invasive Candidiasis

• Incidence probably ?
• Diagnosis difficult
• Clin pres nonspecific
• Blood cult often neg
• Skin lesions uncommon - biopsy for micro and
  culture if present
  
  
• Retinal infiltrates specific, very uncommon due
  to neutropenia
• Empiric therapy used, but unclear indications,
  when to start, when to stop and total benefit
  
  

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Empiric AmB O.6 mg/kg / day after 4 d of
neutropenic fever
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In Vitro Susceptibility of Fungal Species
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Viral infections in neutropenic hosts

• T-cells decisive for defense
  against viruses w a latent
  phase
• Herpes simplex reactivation common cause of
  fever
• VZV reactivation rather common, may be severe
• CMV reactivation less common. Very important in
  allo-BMT PCR diagnosis and preemptive therapy
  for control. In other hosts occasionally fever,
  colitis, hepatitis, but most often reactivation
  of unknown significance.
  
• Adenovirus may also be latent. Occasional severe
  cases
• Influenza, RSV, parainfluenza may cause severe
  pneumonia

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Causes of fever in cancer patients
Bacterial translocation from GI tract Focal
bacterial infections including CVC-related
infection Mycobacterial infection Fungal
infection, Yeast, Mold, PCP Viral infection
Bleeding / haematoma Tromboembolic events Tumor
related fever Drug fever