Clinic. suspected nosocomial pneumonia

Diagnostik und Therapie der
Beatmungspneumonien
M. Raffenberg, H. Lode
Zentralklinik Emil von Behring, Berlin-Zehlendorf
Lungenfachklinik Heckeshorn
akadem. Lehrkrankenhaus der FU Berlin
Epidemiologie der
Beatmungspneumonie
 Inzidenz:
7 - 20% bzw. 5-34/1000 Tage
 VAP-Rate:
1-3 % pro Beatmungstag
 ICU-Therapie: +6d - +13d
 Beatmung:
+10d - +23d
 Letalität:
20 - 50 %
Craven DE, Steger KA. Epidemiology of nosocomial pneumonia. Chest 1995:108:1S-16S
Fagon JY et al. Nosocomial pneumonia and mortality among pts in ICU. JAMA 1996;275:866-9
Cook DJ et al. Incid. of and risk factors for VAP in critically ill pts. Ann Intern Med 1998;129:433-40
Fagon JY et. al. Nosocomial Pneumonia. in: Schoemaker. Crit Care Med. 4th Ed. 2000: 1572-98
The Mechanically Ventilated Patient
environment
other patients
catheter, tube
enteral
nutrition
nursing stuff
oropharyngeal
flora
endogenous flora
microaspiration
stomach, bowel
distant focus
of infection
lower respiratory tract
air
blood
pneumonia
mod. Francoli. CMI 1997; 3(1)
Supine Body Position as a Risk Factor for Nosocomial
Pneumonia in Mechanically Ventilated Patients:
A Randomized Trial (I)
Background:
Can the incidence of nosocomial pneumonia
be reduced by a semirecumbent body position
in ICU-patients?
Design:
Prospective randomized study in 130 patients
at 2 ICU in Hospital Clinic Barcelona.
Methods:
Analysis of clinically suspected and microbiologically confirmed nosocomial pneumonia
(clinical + quantitative bacteriological criteria).
Drakulovic MB, Torres A et al. Lancet 1999; 354:1851-58
Supine Position in Mechanically Ventilated
Patients (II)
Results:
Clinic. suspected nosocomial pneumonia
- semirecumbent group:
3/39 (8%)
- supine group:
16/47 (34%); p = 0.003
Microbiologically confirmed pneumonia
- semirecumbent group: 2/39 (5%)
- supine group:
11/47 (23%); p = 0.018
Highest risk: Supine body position plus enteral
nutrition:
14/28 (50%)
Conclusions: Semirecumbent body position reduces
frequency and risk of nosocomial pneumonia
especially in patients who receive enteral
nutrition.
Drakulovic MB, Torres A et al. Lancet 1999; 354:1851
Infektionsraten bei nicht invasiver Beatmung
Pneumonie
%
Ergebnisse randomisierter kontrollierter Studien
30
nicht invasive Beatmung
Kontrollgruppe
25
20
15
10
5
0
Brochard
1995
n=43/42
Kramer
1995
n=16/15
Antonelli
1998
n=32/32
Wood Confalonieri
1998
1999
n=16/11
n=28/28
Antonelli
2000
n=20/20
Nava
1998
n=25/25
Ventilator-Associated Pneumonia
Variables Independently Associated with
VAP by Log. Regress. Analysis
VariableAdjusted
OR
95% Cl
p
OSFI > 3
10.2
4.5 - 23.0
< 0.001
Pat. age > 60 yrs.
5.1
1.9 - 4.1
0.002
Prior antibiotics
3.1
1.4 - 6.9
0.004
Pat. head position
2.91
.3 - 6.8
0.013
Kollef MH. JAMA 1993; 270:1965
Ventilator-associated Pneumonia Caused by
Potentially Drug-resistant Bacteria
Design:
Risk factor analysis of 135 consecutive
episodes of VAP in a single ICU over 25
months in terms of potentially drugresistant bacteria
Technique: VAP was diagnosed by PSB and BAL
Results:
77 VAP by potent. resist. bacteria
58 VAP by “other” organisms
Trouillet JL, Chastre J et al. AJR CCM 1998; 157:531
Ventilator-associated Pneumonia
Results:
Potentially-resistant bacteria:
S. aureus (MRSA), P. aeruginosa,
A. baumannii, S. maltophilia
Riskfactors:
Duration of MV (> 7d/OR=6.0)
Prior antibiotic use (OR=13.5)
Prior use of broad - sp. ant. (OR=4.1)
Conclusions: Considering these risk factors may provide
a more rational basis for selecting the
initial therapy of VAP
Trouillet JL et al. AJR CCM 1998; 157:531
Characteristics of Patients Who Died from VAP
Case/Age[yr]/ Sex
Diagnosis
pATB
Microorganisms
1 / 43 / M
Heart transplant
Yes
Aspergillus species, Candida sp.
2 / 59 / M
COPD
Yes
Pseudomonas aeruginosa
3 / 33 / M
Heart transplant
Yes
P. aeruginosa, S marcescens
4 / 76 / M
CET
Yes
P. aeruginosa
5 / 75 / M
Cardiogenic shock
Yes
Aspergillus species
6 / 62 / M
CAP
Yes
P. aeruginosa, S. marcescens
7 / 70 / M
COPD
Yes
Acinetobacter, A. calcoacetius
8 / 74 / M
COPD
Yes
P. aeruginosa
9 / 71 / F
COPD
Yes
A. calcoacetius
10 / 46 / M
Asthma
Yes
P. aeruginosa
11 / 65 / M
Cardiac surgery
Yes
P. aeruginosa
12 / 72 / F
Pancreatitis
Yes
P. aeruginosa
13 / 54 / M
Septic shock
Yes
Proteus mirabilis
17 / 51 / M
Multiple trauma
No
S. marcescens
18 / 71 / M
Thoracic surgery
No
P. aeruginosa
Rello J et al. Chest 1993; 104:1230
Ventilator-Associated Nosocomial Pneumonia
Recommendations for Diagnostic Bronchoscopic Techniques
1. Protected specimen brushing (PSB)
- No wedging into a peripheral position
- >103 CFU/ml significant bacterial level
2. Bronchoalveolar lavage (BAL)
- Total amount of fluid >140 ml
- >104 CFU/ml significant bacterial level
Controversy: Diagnostic value of PSB/BAL in
patients receiving antibiotics
International Consensus Conference, Memphis, May 1992. Chest 102(1) 1992
Evaluation of Diagnosis of Pneumonia
Operative values of protected specimen brush (PSB) and bronchoalveolar lavage (BAL) in four recent studies systematically referring
to histology
Sensitivity [%]
PSB
BAL
Specificity [%]
PSB
BAL
authors
year
Torres
1994
36
50
50
45
Marquette 1995
58
47
89
100
Chastre
1995
82
91
89
78
Papazian
1995
42
58
95
95
Lode H et al. Crit Care Clinics 1998; 14(1):119-133
Invasive and Noninvasive Strategies
for Management of Suspected
Ventilator-associated Pneumonia (I)
Background:
Optimal management of patients with clinically
suspected VAP is a controversial issue
Design:
Multicenter, randomized trial in 31 french ICU
including 413 patients
Interventions: - Invasive Management
Bronchoscopy with quantitative cultures
of BAL or PSB
- Noninvasive Management
Clinical criteria and nonquantitative
analysis of endotracheal aspirates
Fagon JY et al. Ann Intern Med 2000; 132:621-30
Actuarial 28-day Survival Among 413 Patients Assigned to the
Invasive (solid line) or Clinical (dashed line) Management Strategy
Fagon JY et al. Annals of Internal Medicine 2000; 132:621-30
Invasive and Noninvasive Strategies
for Management of Suspected
Ventilator-associated Pneumonia (II)
Measurements:
- Death from any cause
- Quantification of organ failure
- Antibiotic use at 14 / 28 days
Interventions: - Reduced mortality at day 14
(16.2% vers. 25.8%; p = 0.02)
- Decreased Sepsis-related Organ Failure
Assessm. Score on day 3 / 7
- Decreased antibiotic use on day 14 / 28
(11.5 vers. 7.5 antib.-free days on day 28)
Fagon JY et al. Ann Intern Med 2000; 132:621-30
Nosokomiale Pneumonie
Diagnose und Therapie nach Singh et al (2000)
Keine weitere
Untersuchung,
beobachten
nein
Klinischer Verdacht auf
Infektion
ja
ja
CPIS (clinical pulmonary infection
score): > 6
Antibiotika für
10-21 Tage
nein
3 Tage Ciprofloxacin
Erneute Bewertung am 3. Tag:
CPIS > 6
nein
Ciprofloxacin absetzen
Chastre J, Fagon JY (2002) AJRCCM 165:867-903
ja
Als Pneumonie
behandeln
Nosokomiale Pneumonie
Diagnose und Therapie „invasive Strategie“
Keine weiteren
Untersuchungen
beobachten
Beobachten,
anderen Herd
suchen
nein
Klinischer Verdacht auf Infektion
ja
sofort PSB/BAL
Beobachten,
anderen Herd
suchen
nein
Bakterienkultur
positiv?
Schwere Sepsis?
nein
nein
Direktpräparat:
Bakterien?
ja
ja
gezielte
AB-Therapie
ja
sofort gezielte AB-Therapie
Bakterienkultur positiv?
ja
Antibiotika anpassen
Chastre J, Fagon JY (2002) AJRCCM 165:867-903
nein
AB fortsetzen od.
anpassen,
anderen Herd
suchen
Invasives Vorgehen: Vorteile
 Höhere Sicherheit bei der Diagnosestellung
 Durch Erregernachweis zielgerichtete
Antibiotikatherapie möglich
 Kontaminationen mit der Flora aus den
oberen Atemwegen werden vermieden
 Bewirkt restriktiven Einsatz von Antibiotika und
dadurch eine geringere Resistenzentwicklung
 Weniger Todesfälle
 Schnellere Normalisierung von
Organdysfunktionen,
 Geringerer Antibiotikaverbrauch
Fagon et al (2000) Ann Intern Med
Invasives Vorgehen: Nachteile
 Invasive Methoden mit Risiken behaftet
 Kosten
 Technische Grenzen der Kulturverfahren
 Verzögerung der initialen Antibiotikatherapie
 Bei einem negativen Resultat, das evtl. falsch
ist, erhält der Patient keine Therapie
 Ergebnis erst verfügbar, wenn der Verlauf
der Infektion nicht mehr beeinflusst werden kann
Fagon et al (2000) Ann Intern Med
Diagnosis of Nosocomial Pneumonia
Nosocomial Pneumonia
moderate
severe
VAP
(sputum), serology, blood cultures, Legionella-antigen
therapy
progress
Bronchoscopy:
PSB or BAL
quantitative
Bacteriology of Hospital-Acquired Pneumonia
Early-Onset
Pneumonia
Late-Onset
Pneumonia
Other
S. Pneumoniae
P. aeruginosa
Anaerobic bacteria
H. Influenzae
Enterobacter spp.
Legionella pneumophila
Moraxella catarrhalis
Acinetobacter spp.
Influenza A and B
S. aureus
K. pneumoniae
Respiratory syncitial virus
S. marcescens
E. coli
Fungi
Aerobic
gram-negative bacilli*
Other
gram-negative bacilli
S. aureus**
Francioli et al.Clin Microbiol Infect 1997; 3(suppl 1):61-76
*in patients with risk factors, **including methicillin-resistant S. aureus
Stenotrophomonas maltophilia Studie
Kennzahlen
• Untersuchungszeitraum: Juli 1997 bis Juni 1998
• 273 Aufnahmen auf die ITS (8 Betten)
• 111 Pat. in die Studie eingeschlossen (31 w, 80 m, 58
±13,3 J.)
• 65/111 Pat. (59%) mit signifikantem Nachweis
pathogener Erreger in den Untersuchungsmaterialien.
• 16 Pat. (14%) mit Stenotrophomonas-Nachweis (2 w,
14 m) im Bronchialsekret (68%), Sputum (19%),
Pleuraexsudat (13%)
Stenotrophomonas-Infektionen auf der
Intensivstation - Epidemiologie
A´Court et al. :
SMA verantwortlich für 5% der
nosokomialen Pneumonien auf der ITS
Thorax 1992,47,465-473
Ibrahim EH, Ward S, Sherman G, Kollef MH.:
Vergleichende Analyse von Intensivpatienten mit early-onset und
late-onset Pneumonien.
 3.668 Intensivpatienten (internistisch und chirurgisch)
 420 nosokomiale Pneumonien (11,5%)
 235 early onset
Chest 2000,117,1434-42
185 late onset pneumonia
P. aeruginosa (38,4%) ORSA (21,1%)
S. maltophilia (11,4%) OSSA (10,8%)
Gesamtletalität:
41%
Antibiotic Therapy in Nosocomial Pneumonia
Monotherapy
versus
Antibiotic combination
Lower cost
Higher cost
Lower risk of side-effects
Possible lower risk of
emergence of resistance?
No antagonistic effect
of antibiotics
Synergistic effect
No pharmacologic interactions
Wider spectrum
Equal efficacy?
Lower antibiotic dose
Antibiotic Monotherapy in HAP
Reference
Drugs
Results
(Cure/Improv.)
Comments
R.D. Manji et al
AJM 1988
Cefoperazone
versus
Cefazol/Gentamycin
Cefoper.: 87%
Combin.: 72%
Lower costs
for monotherapy
M.P. Fink et al
AAC 1994
Ciprofloxacin
versus
Imipenem
Ciprofloxacin: 64% Imipenem: 6% seizures
Imipenem: 56%
Ciprofloxacin: 1%
A. Cometta etal
AAC 1994
Imipenem
versus
Imipenem/Netilmicin
Imipenem: 80%
Combination: 11
Combination: 86% nephrotoxic reaction
E. Rubinstein,
H. Lode et al
Ceftazidime
versus
Ceftazidime: 85%
Combination: 9
Combination: 77% nephrotoxic reaction
CID 1995
Ceftriaxone/Tobramycin
Combination Therapy as a Tool to Prevent
Emergence of Bacterial Resistance
Design:
Overview of experimental data
analysing antimicrobial mono-versus
combination therapy.
Results:
In vitro Pk and animal data indicate that
emergence of resistance with
combination therapy is less common.
Problems:
- Demonstrated only in P. aeruginosa
infections
- No strong clinical trials
Mouton JW. Infection 1999
Mean Change (log values) of MIC for Ceftazidime of
Pseudomonas aeruginosa During Monotherapy or Combined
With Tobramycin in a in vitro Pharmacokinetic Model
mean increase factor
MIC
8
6
4
2
0
0h
Mouton JW. 1999
8h
16 h
24 h
Clinical Indications of Combinations
 Difficult to treat
Gram-nagatives
Enterobacter
Pseudomonas
Acinetobacter
 Clinical Arguments
 Avoid mutation
 Obtain synergistic effect
 Possible prevention of the emergence of
resistance
 Extend the spectrum of antibacterial activities:
 against enterococci (using penicillin)
 against anaerobes (using metronidazole)
Bergogne-Bérézine. Phoenix 1995
PK/PD Parameters: A First Sight
• Peak
• Through
• Area under the curve
concentration
Serum
Concentration
varying with time
peak
area under
the curve
through
time
AUIC Prediction of Clinical and
Microbiological Outcome in RTI
Forrest A et al. Antimicrob Agents Chemother 1993;37:1073-1081
Pharmacodynamic Evaluation of Factors Associated
With the Development of Bacterial Resistance in Acutely
Ill Patients During Therapy
Design:
Analysis of 107 pat. suffering
from LRTI; 128 pathogens and
5 antimicrobial regimes.
Parameters:
- MIC - before/after treatment
- AUC 0-24
- PK/PD model (Hill equation)
Thomas JK et al. AAC 1998; 42:521-27
AUIC versus Resistance
Thomas JK et al. AAC 1998
Scheduled Change of Antibiotic Classes (I)
A strategy to decrase the incidence of ventilator-associated pneumonia
Study design: Prospective before - after study
Patients:
680 with cardiac surgery
Location:
ICU-St. Louis, Missouri
Barnes-Jewish Hospital (900 beds)
Intervention: During 12-months period (8/95-8/96)
empiric treatment
- first 6-months period: ceftazidime
- second 6-months period: ciprofloxacin
Kollef MH. AJRCCM 1997; 156:1040
VAP (all etiologies)
12
10
VAP (due to ARGNB)
11,6
8
6
4
6,7
4
2
0,9
0
Before-Period
Kollef et al.AJRCCM 1997:165:1040-48
After-Period
Scheduled Change of Antibiotic Classes (II)
Results
Incidence of VAP:
Before 11.6% (n = 327)
After 6.7% (n = 353)
VAP with resist. GNB:
4.0% versus 0.9%
Bacteremia due to
ARGNB:
1.7% versus 0.3%
Conclusion:
These data suggest that a scheduled change
of antibiotic classes can reduce the
incidence of VAP attributed to ARGNB.
Kollef MH. AJRCCM 1997; 156:1040
Classifying Patients With Hospital-acquired Pneumonia
Severity of illness
severe
mild to moderate
no risk
factors
with
risk
factors
with risk
factors
onset
any time
onset
any time
early
onset
late
onset
onset
any time
Group 1
Group 2
Group 1
Group 3
Group 3
no risk
factors
Consensus Statement of the American Thoracic Society: Am J Respir Crit Care Med 1996; 153:1711-1725
Patients with mild to moderate hospital-acquired
Group 1 pneumonia, no unusual risk factors, onset any time or
patients with severe hospital acquired pneumonia with
early onset*
Core organisms
Core antibiotics
Enteric gram-negative bacilli
(Non-Pseudomonal)
Enterobacter spp.
generation
E. coli
Klebsiella spp.
Proteus spp.
Serratia marcescens
Haemophilus influenzae
S. aureus (Methicillin-sensitive)
Streptococcus pneumoniae
Cephalosporin
second generation or
Nonpseudomonal third
Beta-lactam / beta-lactamaseinhibitor combination
If allergic to penicillin:
Fluoroquinolone or
Clindamycin + aztreonam
*Excludes patients with immunosuppression
Consensus Statement of the American Thoracic Society: Am J Respir Crit Care Med 1996; 153:1711-1725
Group 2
Patients with mild to moderate hospital-acquired
pneumonia,
with risk factors, onset any time*
Core organisms plus:
Core antibiotics plus:
Anaerobes
(recent abdomial surgery)
lactamasewitnessed aspiration)
Staphylococcus aureus
(coma, head trauma, diabetes
mellitus, renal failure)
Legionella
(high dose steroids)
Pseudomonas aeruginosa
(prolonged ICU stay, steroids,
antibiotics, structural lung disease)
Clindamycin
or beta-lactam / betainhibitor (alone)
+/- Vancomycin
(until methicillin- resistant
S. aureus is ruled out)
Erythromycin +/- Rifampicin **
Treat as severe hospital-acquired
pneumonia (Group 3)
*Excludes patients with immunosuppression;
** Rifampicin may be added if Legionella species is documented
Consensus Statement of the American Thoracic Society: Am J Respir Crit Care Med 1996; 153:1711-1725
Group 3
Patients with severe hospital-acquired pneumonia,
with risk factors, early onset or patients with severe
hospital acquired pneumonia with late onset*
Core organisms plus:
Therapy
P. aeruginosa
Acinetobacter spp.
Consider MRSA
Aminoglycoside or ciprofloxacin
plus one of the following:
Antipseudomonal penicillin
beta-lactam / beta-lactamase
inhibitor
Ceftazidime or cefoperazone
Imipenem
Aztreonam**
+/- Vancomycin
*Excludes patients with immunosuppression
** Aztreonam efficacy is limited to enteric gram-negative bacilli and should not be used in
combination with aminoglycoside if gram-positive or H. influenzae infection is of concern
Consensus Statement of the American Thoracic Society: Am J Respir Crit Care Med 1996; 153:1711-1725