Diagnostik und Therapie der Beatmungspneumonien

M. Raffenberg, H. Lode

Zentralklinik Emil von Behring, Berlin-Zehlendorf

Lungenfachklinik Heckeshorn

akadem. Lehrkrankenhaus der FU Berlin

Inzidenz: 7 - 20% bzw. 5-34/1000 Tage

VAP-Rate: 1-3 % pro Beatmungstag

ICU-Therapie: +6d - +13d

Beatmung: +10d - +23d

Letalität: 20 - 50 %

Epidemiologie der Beatmungspneumonie

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

mod. Francoli. CMI 1997; 3(1)

environmentother patients

nursing stuff

endogenous flora

distant focusof infection

blood

catheter, tube

oropharyngealflora

microaspiration

lower respiratory tract

pneumonia

enteralnutrition

stomach, bowel

air

direct

contact

Supine Body Position as a Risk Factor for Nosocomial Pneumonia in Mechanically Ventilated Patients:

A Randomized Trial (I)

Background: Can the incidence of nosocomial pneumoniabe reduced by a semirecumbent body positionin ICU-patients?

Design: Prospective randomized study in 130 patientsat 2 ICU in Hospital Clinic Barcelona.

Methods: Analysis of clinically suspected and micro-biologically 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

0

5

10

15

20

25

30

nicht invasive Beatmung Kontrollgruppe

Infektionsraten bei nicht invasiver Beatmung Pneumonie

% Ergebnisse randomisierter kontrollierter Studien

Brochard 1995

n=43/42

Kramer 1995

n=16/15

Antonelli 1998

n=32/32

Wood 1998

n=16/11

Confalonieri 1999

n=28/28

Antonelli 2000

n=20/20

Nava 1998

n=25/25

Ventilator-Associated PneumoniaVariables 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 drug-

resistant bacteria

Technique: VAP was diagnosed by PSB and BAL

Results: 77 VAP by potent. resist. bacteria58 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

1. Protected specimen brushing (PSB)- No wedging into a peripheral position- >103 CFU/ml significant bacterial level

International Consensus Conference, Memphis, May 1992. Chest 102(1) 1992

Recommendations for Diagnostic Bronchoscopic Techniques

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

Evaluation of Diagnosis of Pneumonia

Sensitivity [%] Specificity [%]authors year PSB BAL PSB BAL

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

Operative values of protected specimen brush (PSB) and broncho-alveolar lavage (BAL) in four recent studies systematically referring

to histology

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 ManagementBronchoscopy with quantitative cultures

of BAL or PSB

- Noninvasive ManagementClinical 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 PneumonieDiagnose und Therapie nach Singh et al (2000)

Chastre J, Fagon JY (2002) AJRCCM 165:867-903

Klinischer Verdacht auf Infektion

Klinischer Verdacht auf Infektion

Erneute Bewertung am 3. Tag:CPIS > 6

Erneute Bewertung am 3. Tag:CPIS > 6

Antibiotika für 10-21 Tage

ja

Ciprofloxacin absetzenCiprofloxacin absetzen

nein

3 Tage Ciprofloxacin3 Tage Ciprofloxacin

nein

Keine weitere Untersuchung,

beobachten

nein

Als Pneumonie behandeln

ja

CPIS (clinical pulmonary infection score): > 6

CPIS (clinical pulmonary infection score): > 6

ja

Nosokomiale PneumonieDiagnose und Therapie „invasive Strategie“

Klinischer Verdacht auf InfektionKlinischer Verdacht auf Infektion

ja

sofort gezielte AB-Therapiesofort gezielte AB-Therapie

Keine weiteren Untersuchungen

beobachten

nein

Direktpräparat: Bakterien?

Direktpräparat: Bakterien?

sofort PSB/BALsofort PSB/BAL

ja

nein

Beobachten, anderen Herd

suchen

Bakterienkultur positiv?

Bakterienkultur positiv?

nein

ja

Beobachten, anderen Herd

suchen

gezielte AB-Therapie

gezielte AB-Therapie

ja

Schwere Sepsis?Schwere Sepsis?nein

Bakterienkultur positiv?Bakterienkultur positiv?

Antibiotika anpassenAntibiotika anpassen

ja

AB fortsetzen od. anpassen,

anderen Herd suchen

nein

Chastre J, Fagon JY (2002) AJRCCM 165:867-903

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

Bronchoscopy:PSB or BALquantitative

moderate severe VAP

(sputum), serology, blood cultures, Legionella-antigen

therapy

progress

Nosocomial Pneumonia

Bacteriology of Hospital-Acquired Pneumonia

Early-Onset Late-OnsetPneumonia 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

Aerobic gram-negative bacilli* S. marcescens Fungi

E. coli

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

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 maltophilia Studie

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 185 late onset pneumoniaP. aeruginosa (38,4%) ORSA (21,1%)S. maltophilia (11,4%) OSSA (10,8%)Gesamtletalität: 41%Chest 2000,117,1434-42

Antibiotic Therapy in Nosocomial Pneumonia

Monotherapy Antibiotic combination

Lower cost Higher cost

Lower risk of side-effects Possible lower risk of emergence of resistance?

No antagonistic effect Synergistic effectof antibiotics

No pharmacologic interactions Wider spectrum

Equal efficacy? Lower antibiotic dose

versus

Antibiotic Monotherapy in HAP

Reference Drugs Results Comments (Cure/Improv.)

R.D. Manji et al Cefoperazone Cefoper.: 87% Lower costsAJM 1988 versus Combin.: 72% for monotherapy

Cefazol/Gentamycin

M.P. Fink et al Ciprofloxacin Ciprofloxacin: 64% Imipenem: 6% seizuresAAC 1994 versus Imipenem: 56% Ciprofloxacin: 1%

Imipenem

A. Cometta etal Imipenem Imipenem: 80% Combination: 11AAC 1994 versus Combination: 86% nephrotoxic reaction

Imipenem/Netilmicin

E. Rubinstein, Ceftazidime Ceftazidime: 85% Combination: 9H. Lode et al versus Combination: 77% nephrotoxic reactionCID 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

Mouton JW. 1999

24 h16 h8 h0 h

mea

n in

cre

ase

fa

cto

r M

ICceftazidime

ceftazidime + tobramycin8

6

4

2

0

Clinical Indications of Combinations

Difficult to treat

Gram-nagatives

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

Enterobacter

Pseudomonas

Acinetobacter

PK/PD Parameters: A First Sight

SerumConcentration

varying with time

• Peak• Through• Area under the curve

time

con

cen

trat

ion

peak

through

area under

the curve

Forrest A et al. Antimicrob Agents Chemother 1993;37:1073-1081

AUIC Prediction of Clinical and Microbiological Outcome in RTI

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)

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

A strategy to decrase the incidence of ventilator-associated pneumonia

11,6

4

6,7

0,90

2

4

6

8

10

12

Before-Period After-Period

VAP (all etiologies)

VAP (due to ARGNB)

Kollef et al.AJRCCM 1997:165:1040-48

Scheduled Change of Antibiotic Classes (II)

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

Results

Group 1 Group 3Group 3Group 2

mild to moderate

Classifying Patients With Hospital-acquired Pneumonia

Consensus Statement of the American Thoracic Society: Am J Respir Crit Care Med 1996; 153:1711-1725

Severity of illness

severe

no risk factors

no risk factors

with risk

factors

with risk factors

Group 1

late onset

early onset

onset any time

onset any time

onset any time

Patients with mild to moderate hospital-acquired 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 Cephalosporin(Non-Pseudomonal) second generation orEnterobacter spp. Nonpseudomonal third generation E. coliKlebsiella spp. Beta-lactam / beta-lactamase-Proteus spp. inhibitor combinationSerratia marcescens

Haemophilus influenzae If allergic to penicillin:S. aureus (Methicillin-sensitive) Fluoroquinolone orStreptococcus pneumoniae Clindamycin + aztreonam

Group 1

*Excludes patients with immunosuppression

Consensus Statement of the American Thoracic Society: Am J Respir Crit Care Med 1996; 153:1711-1725

Patients with mild to moderate hospital-acquired pneumonia,

with risk factors, onset any time*

Core organisms plus: Core antibiotics plus:

Anaerobes Clindamycin

(recent abdomial surgery) or beta-lactam / beta-lactamase-

witnessed aspiration) inhibitor (alone)

Staphylococcus aureus +/- Vancomycin

(coma, head trauma, diabetes (until methicillin- resistant

mellitus, renal failure) S. aureus is ruled out)

Legionella Erythromycin +/- Rifampicin **

(high dose steroids)

Pseudomonas aeruginosa Treat as severe hospital-acquired

(prolonged ICU stay, steroids, pneumonia (Group 3)

antibiotics, structural lung disease)

*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 2

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 Aminoglycoside or ciprofloxacinAcinetobacter spp. plus one of the following:Consider MRSA Antipseudomonal penicillin

beta-lactam / beta-lactamase inhibitorCeftazidime or cefoperazoneImipenemAztreonam**

+/- 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

Group 3