Diagnostik und Therapie der Beatmungspneumonien

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Diagnostik und Therapie der Beatmungspneumonien
M. Raffenberg, H. Lode Zentralklinik Emil von
Behring, Berlin-Zehlendorf Lungenfachklinik
Heckeshorn akadem. Lehrkrankenhaus der FU Berlin
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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 19951081S-16S Fagon JY et al.
Nosocomial pneumonia and mortality among pts in
ICU. JAMA 1996275866-9 Cook DJ et al. Incid. of
and risk factors for VAP in critically ill pts.
Ann Intern Med 1998129433-40 Fagon JY et. al.
Nosocomial Pneumonia. in Schoemaker. Crit Care
Med. 4th Ed. 2000 1572-98
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The Mechanically Ventilated Patient
enteralnutrition stomach, bowel air

• environmentother patients
• nursing stuff
• endogenous flora
• distant focusof infection
• blood

catheter, tube oropharyngealflora microaspiration
lower respiratory tract pneumonia
directcontact
mod. Francoli. CMI 1997 3(1)
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Supine Body Position as a Risk Factor for
Nosocomial Pneumonia in Mechanically Ventilated
PatientsA 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
  micro-
• biologically confirmed nosocomial pneumonia
• (clinical quantitative bacteriological
  criteria).

Drakulovic MB, Torres A et al. Lancet 1999
3541851-58
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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
3541851
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Infektionsraten bei nicht invasiver Beatmung
Pneumonie

Ergebnisse randomisierter kontrollierter Studien

Brochard 1995 n43/42
Kramer 1995 n16/15
Antonelli 1998 n32/32
Wood 1998 n16/11
Confalonieri 1999 n28/28
Antonelli 2000 n20/20
Nava 1998 n25/25
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Ventilator-Associated PneumoniaVariables
Independently Associated with VAP by Log.
Regress. Analysis

• VariableAdjusted OR 95 Cl p
• OSFI gt 3 10.2 4.5 - 23.0 lt
  0.001
• Pat. age gt 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 2701965
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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. bacteria
• 58 VAP by other organisms

Trouillet JL, Chastre J et al. AJR CCM 1998
157531
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Ventilator-associated Pneumonia

• Results Potentially-resistant bacteria
• S. aureus (MRSA), P.
  aeruginosa,
• A. baumannii, S. maltophilia
• Riskfactors Duration of MV (gt 7d/OR6.0)
• Prior antibiotic use (OR13.5)
• Prior use of broad - sp. ant. (OR4.1)
• 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 157531
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Characteristics of Patients Who Died from VAP

• Case/Ageyr/ 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 1041230
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Ventilator-Associated Nosocomial Pneumonia
Recommendations for Diagnostic Bronchoscopic
Techniques

• 1. Protected specimen brushing (PSB)
• - No wedging into a peripheral position - gt103
  CFU/ml significant bacterial level

2. Bronchoalveolar lavage (BAL) - Total amount
of fluid gt140 ml - gt104 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
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Evaluation of Diagnosis of Pneumonia
Operative values of protected specimen brush
(PSB) and broncho-alveolar lavage (BAL) in four
recent studies systematically referring to
histology

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
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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 Bronchoscop
y 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 132621-30
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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
132621-30
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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 132621-30
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Nosokomiale PneumonieDiagnose und Therapie nach
Singh et al (2000)
Klinischer Verdacht auf Infektion
Chastre J, Fagon JY (2002) AJRCCM 165867-903
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Nosokomiale PneumonieDiagnose und Therapie
invasive Strategie
Klinischer Verdacht auf Infektion
ja
ja
sofort gezielte AB-Therapie
Chastre J, Fagon JY (2002) AJRCCM 165867-903
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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
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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
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Diagnosis of Nosocomial Pneumonia
Nosocomial Pneumonia
moderate
severe
VAP
(sputum), serology, blood cultures,
Legionella-antigen
therapy

• BronchoscopyPSB or BALquantitative

progress
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Bacteriology of Hospital-Acquired Pneumonia

• Early-Onset Late-Onset
• Pneumonia 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

Francioli et al.Clin Microbiol Infect 1997
3(suppl 1)61-76 in patients with risk factors,
including methicillin-resistant S. aureus
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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)

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Stenotrophomonas-Infektionen auf der
Intensivstation - Epidemiologie

• ACourt 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 pneumonia
• P. aeruginosa (38,4) ORSA (21,1)
• S. maltophilia (11,4) OSSA (10,8)
• Gesamtletalität 41

Chest 2000,117,1434-42
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Antibiotic Therapy in Nosocomial Pneumonia
versus

• 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

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Antibiotic Monotherapy in HAP

• Reference Drugs Results
  Comments
• (Cure/Improv.)
• R.D. Manji et al Cefoperazone
  Cefoper. 87 Lower costs
• AJM 1988 versus
  Combin. 72 for monotherapy
• Cefazol/Gentamycin
• M.P. Fink et al Ciprofloxacin
  Ciprofloxacin 64 Imipenem 6 seizures
• AAC 1994 versus
  Imipenem 56 Ciprofloxacin 1
• Imipenem
• A. Cometta etal Imipenem
  Imipenem 80 Combination 11
• AAC 1994 versus
  Combination 86 nephrotoxic reaction
• Imipenem/Netilmicin
• E. Rubinstein, Ceftazidime
  Ceftazidime 85 Combination 9
• H. Lode et al versus
  Combination 77 nephrotoxic reaction
• CID 1995 Ceftriaxone/Tobramycin

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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
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Mean Change (log values) of MIC for Ceftazidime
of Pseudomonas aeruginosa During Monotherapy or
Combined With Tobramycin in a in vitro
Pharmacokinetic Model
8 6 4 2 0
ceftazidime ceftazidime tobramycin
mean increase factor MIC
8 h
0 h
24 h
16 h
Mouton JW. 1999
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Clinical Indications of Combinations
Enterobacter Pseudomonas Acinetobacter

• 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
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PK/PD Parameters A First Sight
SerumConcentration varying with time

• Peak
• Through
• Area under the curve

peak
concentration
area under the curve
through
time
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AUIC Prediction of Clinical and Microbiological
Outcome in RTI
Forrest A et al. Antimicrob Agents Chemother
1993371073-1081
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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 42521-27
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AUIC versus Resistance
Thomas JK et al. AAC 1998
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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 1561040
35
Kollef et al.AJRCCM 19971651040-48
36
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 1561040
37
Classifying Patients With Hospital-acquired
Pneumonia
Severity of illness
severe
mild to moderate
no risk factors
with risk factors
with risk factors
no risk factors
onset any time
onset any time
onset any time
early onset
late onset
Group 1
Group 3
Group 1
Consensus Statement of the American Thoracic
Society Am J Respir Crit Care Med 1996
1531711-1725
38
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 or
• Enterobacter spp. Nonpseudomonal third
  generation E. coli
• Klebsiella spp. Beta-lactam / beta-lactamase-
• Proteus spp. inhibitor combination
• Serratia marcescens
• Haemophilus influenzae If allergic to penicillin
• S. aureus (Methicillin-sensitive) Fluoroquinolone
  or
• Streptococcus pneumoniae Clindamycin aztreonam

Excludes patients with immunosuppression
Consensus Statement of the American Thoracic
Society Am J Respir Crit Care Med 1996
1531711-1725
39
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
1531711-1725
40
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 ciprofloxacin
• Acinetobacter spp. plus one of the following
• Consider MRSA 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
1531711-1725