Transcript Candida Species Causing Invasive Disease

Bakteriella Infektioner
hos Neutropena
Mats Kalin
Infektionsklinken
Karolinska universitetssjukhuset, Solna
[email protected]
De viktigaste bilderna
Non-specific defense
First line
of defense
Barrier
function
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
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
Granulocytes
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
Infection Risk in Relation to Granulocyte Count
%
W
I
T
H
100
H
90
80
H
70
60
F
E
V
E
R
< 0.1
H
50
40
30
H
20
10
0
0.1 – 0.5
JB
H
H
J
B
J
B
5
Bodey et al 1969, AAC 9:386
J
B
J
J
B
10
B
0.5 - 1
days
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
Granulocytes
Macrophages
Cytokine
regulation
T
B
In addition steroids and other drugs may compromise
macrophage function
Blood stream Pathogens
at the Center for Haematology, Karolinska hospital
Stenotrophomonas Other
Gramneg
maltophilia
CNS
1988-2001
n=1402
Enterobacter
Pseudomonas
aerugionsa
S.aureus
Klebsiella
Alpha-strept
E.coli
Cherif et al 2004
The Haematology J 4:240
Enterococci
Other Pneumococci
Grampos
Bacteria in Single Organism
Bacteremia in EORTC Trials
35
S.aureus
CNS
Strept
E.coli
P.aerug
Other G-
30
25
20
15
10
5
0
1973-78
1980-83
1986-88
1989-91
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
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 ….
..but only after blood cultures have been obtained
•
•
•
•
•
•
before start of antibiotics
20 – 40 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 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 35:842
Ortiz & Sande 2000, Am J Med 108:445
DesJardin 1999, Ann Intern Med 131:641
Bact.conc cfu / 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
% survival
80
70
60
50
40
30
20
10
0
Top level > 7/28
vs < 7/28 mg/L
Moore 1984
Am J Med 77:756
24 H
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
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 (<21 days): 22 %
_________________________________________
Meschmeyer et al 1994,
Medizinische Klinik 89:114
Cancer 73:2296
Annals Hematol 69:231
Prospective randomized double blind study of
Vancomycin vs Placebo for persistant neutropenic fever
after 48-60 h of Piperacillin/tazobactam (34 C, n=165 – 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 37:382
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 alphastreptococci
Hughes 2002 CID 34:730 (IDSA Guidelines)
GI epithelial damage
Bacteremia
Increased GI yeast
colonisation /focal infection
Antibiotic
therapy
Yeast translocation
Invasive yeast infection
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
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
Clinical Condition after 72 h of Antibiotic Therapy
Relation to Ultimate Outcome,
n=1085
IMPROVING
25 %
STABLE
65 %
10%
15%
46%
18%
DETERIORATING
10 %
Gbacteremia
FUO
20%
39%
23%
33%
CDI
25% G+
21%
28%
bacteremia
22%
% afebrile
after 5 days
100
33
5
% ultimately
surviving
100
90
11
De Pauw & Intercontinental Study Group, Ann Intern Med 1994
FUO
89 episodes
Afebrile after ab therapy
60 episodes
antibiotics stopped
48h after defervescence
31 episodes
Neutropenic when
ab stopped
23 episodes
Neutropenia
resolved
8 episodes
Fever relapsed
3 episodes
Fever relapsed
2 episodes
Success
20 episodes
Success
6 episodes
Cherif 2004, SJID 36:593
Failure
29 episodes
antibiotics continued
> 48h after defervescence
29 episodes
Neutropenic when
ab stopped
26 episodes
Fever relapsed
6 episodes
2 patients
died
Success
20 episodes
Neutropenia had
resolved
3 episodes
Success
3 episodes
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
8-16 17-18 19-20 21
n=71 67
67
172
22
52
23
102
24 25-26
127 98
Klastersky et al 2000, J Clin Oncol 18:3038
Characteristic
Points
Age < 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
Outpatient status
3
Prospective
evaluation of
MASCC at
Hem C
Karolinska
Low risk patients (105 episodes)
Ineligible for oral therapy
(38 episodes)
eligible for oral therapy
(67 episodes)
Excluded
Discherged with oral antibiotics
24 hours after defervescence
Infection related mortality
2 patients
Clinical assessment after 3 days
• 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 facts
precluded oral therapy
Fever relapse
readmission
One patient
Continued afebrile
66 episodes
Final evaluation
after 4 weeks
Fever relapse
2 patients
one aspergillosis
one pneumocyctis
Afebrile (success)
64 patient
No mortality
Thus, a total of 24% of haematological patients with neutropenic
fever could be discharged with oral therapy 24 h after
Cherif et al 2006
defervescence, essentially w/o complications
Haematologica
Resistance problems according to ICU-”STRAMA”
 Gramneg enterobacteria
Quinolones
ESBL

Enterobacter
Cephalosporin
Quinolones

inducable resistance in high frequency
5-10 %
Pseudomonas aeruginosa
Imipenem
Quinolones
Ceftazidime
Piperacillin

5-10 %
rare findings
25 %
12 %
10 %
17 %
Stenotrophomonas maltophilia
Imipenem
Quinolones
Ceftazidime
100 %
30 %
10 %
Hahnberger: http://e.lio.se/ivastrama/