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10 th Symposium on Infections in the critically ill patient
Porto – January 29th, 2005
Antibiotic Resistance per se
Causes Attributable Mortality
in VAP
Jean-François TIMSIT MD, PhD
Medical ICU
CHU Grenoble, France
No!
• Fitness of bacterias
• Positive studies biased
• Well designed recent studies are negative
What is antibiotic resistant bacterias?
• Multiple resistant bacterias?
– MRSA, P.aeruginosa, A. baumannii, ESBL, ERV
• Pan resistant bacterias? (tuberculosis)
If
panresistance
Not
treated
 Risk of death
When bacterias are panresistant, infectious diseases
always cause some degree of increase in the risk
of death
Antibiotic resistant bacteria are
less virulent…
« when resistance occurs as a consequence of a genetic alteration
in a housekeeping gene (ribosome function, cell wall
construction, biosynthetic pathway, DNA machinery)…an
evolutionary mechanism has deviated from its functional
optimum. Resistance should have a direct cost in bacterial
fitness.
The location of antibiotic resistance in accessory gene elements
probably reduces the « direct » costs, but at the expense of the
indirect costs of the elements themselves.
In both cases, antibiotic resistance should have a fitness cost
which might reduce bacterial virulence »
Martinez & Baquero – Clinical Microbiology reviews – 2002; 647-679
Virulence and resistance
MSSA
N=7
MRSA
N=13
p
Infecting dose 50
4.7
7.1
0.001
LD 50
8.2
9
0.001
Mizobuchi S- Microbiol Immunol 1994;38(8):599-605
The rate of complications associated with VAP is
not different between MRSA and MSSA
MRSA
N=32
Septic shock
43%
Acute renal failure
50%
Neurological alteration 22%
Hepatic alteration
13%
Respiratory distress
21%
DIC
3%
MSSA
N=54
33%
37%
17%
11%
37%
2%
Gonzalez et al – CID 99
Increase in the morbi/mortality?
MSSA VAP
MRSA VAP
Age> 25
23/38 (60%)
10/11 (91%)
APACHE II
?
?
MV
8.1 d
11.9
<0.005
Septic shock
3/38 (8%)
3/11 (27%)
NS
Mortality
11/38 (30%)
8/11 (72%)
NS
Mortality related
to VAP
1/38 (3%)
6/11 (55%)
<0.01
<0.05
Rello et al – AJRCCM 1994; 150:1545
Confounding factors
Risk factors
of
NI
Risk factors
of
MRB
Severity
Procedures
Antimicrobials
Duration of MV
Inappropriate ABx
Risk factors
of
death
Duration of stay before VAP
LOS (days)
MSSA
MRSA
Gonzalez 1999
7.2
24.3
<.01
Rello 1994 (MV)
8.1
11.9
<.05
Pujol 1998 (MV)
6
18.7
<0.001
Pujol 1998 (Hopital)
9.7
26.2
<0.001
Combes 2004 (MV)
10
19
<0.0001
Zahar 2005 (MV)
6
12
0.002
In all these studies the crude mortality was higher in the MRSA group…
Duration of ICU stay
• Length of stay before S. aureus bacteremia is a
risk factor of MRSA recovery and of death
LOS (days)
MSSA
MRSA
Blot 2002
10
29
Craven 83
28
40
French 90
8.4
21.4
Harbarth 98
8
32
Hershow 92
8
18
Lewis 85
19
20
Marty 93
15
23
Misushima 94
23
43
Mylotte 96
3.2
15.3
Pujol 94
14
27
Romero-Vivas 95
14
32
Selvey 2000
6
16
Soriano 2000
8.3
18
P<0.005
Length of stay before bacteremia
Hurley JC – Clin Infect Dis 2003; 37:866-868
Duration of MV before VAP is an
independent outcome predictor
Factor
OR (95% CI)
P value
Age
1.03 (1.01-1.05)
0.004
MV duration
prior VAP
1.04 (1.01-1.06) 0.02
Day 1 ODIN
score
1.91 (1.35-2.71)
0.0003
Methicillin
resistance
1.36 (0.66-2.82)
0.4
Hospital mortality (Table E7 – electronic supplement)
AJRCCM 2004; 170:786
The aim of the matching or adjustment process ..Is to
obtain exposed and unexposed patients similar in
everything except in the resistance profile of the bacteria….
I’m
twent
y.!!!
I’m 6 days
old…
Outcomerea study group
(65 MSSA, 69 MRSA VAP)
Length of ICU stay before SA-VAP
Frequency of patients with SA-P
18
16
MRSA
MSSA
Polynomial (MRSA)
Polynomial (MSSA)
14
12
10
8
6
4
2
0
3-4
5-6
7-8
9-10
11-12
13-14
15-16
17-18
19-20
21-22
23-24
25-27
28-30
31-34
>=35
Day of the S. aureus - VAP
MRSA-VAP
MSSA-VAP
p
Duration of MV before VAP
12 (8-21)
6 (4-14)
0.0002
ICU death
34 (49.3)
19 (29.2)
0.0177
Hospital death
41 (59.4)
26 (40.0)
0.0246
Zahar et al; 2005- Submitted
In studies in which previous duration of ICU stay
was taken into account MRSA VAP was not
associated with an increase in the risk of death
ICU death:
Hospital death:
OR= 1.51 (0.56-4.08), p=0.42
OR=0.98 (0.36-2.66), p=0.96
Zahar et al – 2005
Another important confusion factor:
Adequacy of antimicrobial therapy
Inadequacy
of Abx
?
MRB
Risk of
death
MRB is associated with a higher rate
of inadequate therapy
35
30
« Most episodes of inadequate
antibiotic treatment were attributed to
potentially antibiotic-resistant gramnegative bacteria…S aureus was the
second most cause of inadequate
treatment, with most strains being
methicillin resistant »
25
20
15
10
5
0
PA
SA
AS
Other
KP
ES
SP
Ranking of bacterial pathogens associated with
inadequate antibiotic treatment (from Luna 1997,
Alvarez Lerma 1996, Rello 1997, Kollef 1998)
Kollef M – Clin Infect Dis 2003; 31:S131
Clin Infect Dis 1999; 29:1171
32 MRSA-P
22 Abx
appropriate
10 Abx
inapproriate
11 deaths
(50%)
10 Deaths
(100%)
54 MSSA-P
41 Abx
appropriate
14 deaths
(34%)
Mortality
is associated with Inappropriate therapy
but not with methicillin resistance
13 Abx
inapproriate
12 Deaths
(93%)
Clin Infect Dis 1999; 29:1171
32 MRSA-P
22 Abx
appropriate
54 MSSA-P
10 Abx
inapproriate
41 Abx
appropriate
10 Deaths
(100%)
13 Abx
inapproriate
12 Deaths
(93%)
63 episodes appropriately treated
22 glycopeptides
17 glycopeptides
24 other
8 deaths (47%)
6 deaths (25%)
11 deaths (50%)
P=0.17
Vancomycin less effective in S.
aureus pneumonia?
63 patients treated appropriately
aOR*
CI 95 %
Septic shock
61,5
5,7 – 672
Vancomycin treatment
14,5
1,4 – 146
Respiratory distress
8,3
1,5 – 46
Risk factor of death at the last step of the logistic regression
Gonzalez C et al. Clin Infect Dis 1999; 29: 1171-1177.
Vancomycin in the BAL fluid
E
L
F
v
a
n
c
o
from Lamer et al AAC 1993
It might be difficult to reach sufficient
concentration of vancomycin in MRSA VAP
If we want 2 to 4 MIC in the ELF
MIC (µg/ml)
[C] pulm
Serum
0,5
1-2
7-15
1
2-4
15-30
2
4-8
30-60!
4
8-16
60-120!!!
Use trough level > 15 µg/ml or plateau level > 25 µg/ml +++,
and gentamycin in case of susceptible strains
Resistance: no magic bullets anymore…
•
Use of the overall information (gram stain,
ecology of the patients, of the unit, previous
antimicrobial therapy)
Timsit et al – Intensive Care Med 2001; 27:640
– Appropriateness of Abx not significantly reduced:
MSSA: 86.1% vs MRSA: 76.8, p=0.2
Zahar et al – 2005 submitted
•
Infectious diseases specialists could be consulted
Byl et al – Clin Infect Dis 1999; 29:60
•
Consider initial bi (tri) antibiotic therapy and
subsequent desescalation
Trouillet et al – AJRCCM 1998; 157:531
•
When highly resistant strains are suspected, use
PK/PD knowledge Schentag JJ – Crit Care Med 2001; N100
In studies in which treatments followed
these guidelines Methicillin resistance
was not associated with an increase in
the risk of death
28-day mortality: OR=1.72 (0.73-4.05) p=0.22
(appropriate treatment only)
Combes et al 2004
ICU death OR=0.82 [0.1-6.95] p=0.85
hospital death OR=0.506 95%CI [0.06-4.13] p=0.52
(appropriately treated subgroup only)
Zahar et al – 2005
Severity
Underlying illness
Case-mix
Procedures
Workload
Previous LOS
?
ABx
Death
Nosocomial
infections
MRB
Multiresistance and mortality of VAP
• Inadequate therapy kill
patients
• In case of pan-resistance
• Resistant bacteria is less
virulent
• Patients with MRB are
different
• With different medical
history
• Pan-resistance is a very
rare issue
• Optimization of Abx
therapy is possible
Association true
Slides are available on http://www.outcomerea.org
Association false