Transcript Candida Species Causing Invasive Disease

Bakteriella Infektioner
hos Neutropena
Mats Kalin
Infektionsklinken
Karolinska universitetssjukhuset, Solna
[email protected]
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 may be aggravated by reactivation of Herpes simplex virus
infection, which may affect all parts of the GI tract
Also increased yeast colonisation of the GI tract may aggravate
mucositis.
Mucositis severely compromises the barrier function. Therefore,
translocation of bacteria from the entire GI canal to the blood
occurs with increased frequency
In case of granulocytopenia (<0.5) bacteremia with signs and
symptoms of sepsis will develop
Blood stream Pathogens
at the Center for Haematology, Karolinska hospital
Candida spp 1.7 %
1988-2001
n=1402
Other Gramneg
Stenotrophomonas maltophilia
CNS
Enterobacter spp
Pseudomonas aeruginosa
S.aureus
Klebsiella spp
Alpha-strept
E.coli
Cherif et al 2004
The Haematology J 4:240
Enterococci
Other Pneumococci
Grampos
In addition to mucositis and granulocytopenia cancer chemotherapy
will cause
- T cell deficiencies
- - for long time periods
implying increased risks for infection w
- intracellular bacteria, herpes viruses, PCP and other fungi
- Ig-deficiency
With risk for severe pneumococcal ao infections
Steroids
and other drugs may compromise macrophage function
CNS
has become the most common etiology in neutropenic fever
due to the frequent use of CVCs
Alpha-streptococci
- are increasing in frequency as a cause of neutropenic fever
- due to severe mucositis caused by e.g. high dose cytosin
arabinoside.
-The course may be fulminant with septic shock and ARDS
Enterococci
are increasing in many centers, especially E.faecium
Infections in Neutropenic Cancer Patients
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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
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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 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 et al 2002, CID 35:842
Ortiz & Sande 2000, Am J Med 108:445
DesJardin et al 1999, Ann Intern Med 131:641
Treatment of Infections
in Neutropenic Cancer Patients
Broad-spectrum antibiotic therapy
must be started immediately
when a neutropenic patient presents with fever:
-Cephalosporin with Pseudomonas activity
Ceftazidime
(Cefepime)
-Carbapenem
Imipenem
Meropenem
-Piperacillin/Tazobactam
Paul et al, JAC Dec 12, 2005
Monotherapy probably superior to
combination therapy
• Similar if not better survival rate
• Lower treatment failure rate
• Lower rate of adverse events
• Similar rate of secondary infections
(Cochrane 2003;(3):CDOO3038)
Treatment of Neutropenic Fever
• Cephalosporin with Pseudomonas activity
Ceftazidime …………. 1 st choice G- (G+)
(Cefepime)
• Carbapenem ……………… 2 nd choice G- G+
Imipenem
Meropenem
• Piperacillin/Tazobactam …. 1 st choice G- G+
No advantage of combination with aminoglycoside
- except for septic shock (?)
- aminoglycoside alone insufficient Gramneg coverage
Limited advantage of addition of
- vancomycin……………………………
G+
Indications for Vancomycin
• Clinically suspected serious CVC infection
• Infection with multiresistant 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)
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
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
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%
% ultimately
surviving
100
28%
90
bacteremia
22%
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
Neutropenia had
resolved
3 episodes
Fever relapsed
6 episodes
2 patients
died
Success
20 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 tumor 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
Fever relapse
readmission
One patient
• 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
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
14
Quinolone consumption and resistance
in Stockholm and at Karolinska Hospital
120
Per cent resistance
12
10
140
100
Quinolone consumption
Stockholm area
Quinolone resistance, P.aeruginosa
80
8
60
6
40
Quinolone consumption
4 Karolinska hospital
Quinolone resistance, E.coli
2
20
0
0
1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
Years
Sörberg et al 2002, Scand J Infect Dis 34:372
DDD/1000pcd or 1000DDD
16
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 %
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