Ventilator associated Pneumonia Tobias Welte Department of Respiratory Medicine and Intensive Care

Ventilator associated Pneumonia

Tobias Welte

Department of Respiratory Medicine and Intensive Care

Welte – VAP – Mar del Plata 11.10.2014Welte – VAP – Mar del Plata 11.10.2014

Subgroup analyses - Mortality

0.5 1 2 3 4

Hazard Ratio

0.2

B

Nosocomial infectionCommunity acquired infectionMicrobiologically documentedClinically suspected

Surgical patientsMedical patients

Gram-negative infectionGram-positive infectionBacteremic infection

Non-bacteremic infectionGram-negative bacteremiaGram-positive bacteremia

Pneumonia

IntraabdominalUrogenital

Intention to treatPer protocol set

SOFA score at baseline <= 9 pointsSOFA score at baseline >= 10 pointsStudy treatment >= 4 days

Severe SepsisSeptic Shock

1.09 (0.70; 1.69)

0.84 (0.54; 1.32)

1.54 (0.89; 2.66)0.78 (0.53; 1.15)

1.11 (0.73; 1.71)

0.82 (0.51; 1.32)1.19 (0.75; 1.88)

1.07 (0.69; 1.64)0.88 (0.51; 1.52)

1.10 (0.74; 1.63)

0.79 (0.33; 1.89)

0.88 (0.38; 2.06)

1.07 (0.64; 1.77)

1.15 (0.70; 1.88)

1.48 (0.56; 3.92)

0.710

0.456

0.1250.209

0.618

0.4250.464

0.7670.639

0.652

0.597

0.774

0.799

0.591

0.434

1.00 (0.73; 1.36)

0.94 (0.65; 1.35)

1.05 (0.63; 1.74)

0.90 (0.60; 1.34)1.12 (0.76; 1.66)

0.986

0.720

0.864

0.6040.572

adjustedHR (95% CI) p-value

2.01 (0.98; 4.12)

0.81 (0.57; 1.16)

0.055

0.245

13713697

176

146

127

149

140

90

18340

49

1059939

273199

141

132

206

No.

434232534738

4743

30

5512

14

323714

8559

37

48

57

Death Cases

135141

98

178

162

114

120

155

93

18333

58

119110

25

276214

153

123

209

No.

465028685046

4653

37

59

15

38408

9670

43

53

61

Death Cases

Monotherapy Combination Therapy

74199

1867

84192

2076

19

Adjusted proportional hazard models for the effect of addition of moxifloxacin on overall survival

70 out of 225 patients died= 31.1%

Brunkhorst FM. JAMA 2012; 307: 2390-99


Dalhoff K et al. Pneumologie 2012; 66:707-65

Dt. Ärzteblatt Int. 2013; 110 (38): 634-40• Diagnostics1. Clinical diagnosis and differential diagnosis

2. Imaging procedures in the diagnostic work up

3. The role of scoring in the diagnostics and for risk assessment

4. The role of biomarkers in the diagnostics

5. The role of blood cultures in the diagnostics

6. The role of an antigen test in the diagnostics

7. What microbiological tests should be carried out??

8. Invasive or non invasive diadnostic techniques?

9. Standards in diagnostics

10.Mykological diagnostics


CDC and prevention national healthcare safety network clinical definition for VAP

Klompas. Curr Opin Infect Dis 2012;25:176-82

Two or more serial radiographic, systemic and pulmonary criteria

One of the following

Two of thefollowing

New or progressive and peristent infiltrate

Fever(>38ºC or >100.4ºF)

New onset of purulent sputum or change in character of sputum or

increased respiratory secretions or increased suctioning requirements

ConsolidationLeukopenia (<400 WBC/µl)

or leukocytosis (>12000 WBC/µl)

New onset or worsening cough, or dypsnea, or tachypnea

CavitationFor adults ≥70 years old,

altered mental status with no other recognised cause

Rales or bronchial breath sounds

Worsening gas exchange(eg oxygen desaturation, increased

oxygen requirements, or increased ventilation demand)

Patients must fulfil radiographic, systemic and pulmonary criteria:


Do we have an objective, independent and reliable surveillance system?

Bonten. Clin Infect Dis 2011;52:115-21;Klompas. Curr Opin Infect Dis 2012;25:176-82


Clinical signs for VAP are subjective and non-specific

Initiatives intended to decrease the occurrence of nosocomial infection can artefactually lower VAP rates


A comparison of VAP rates as identified according to intensivists vs infection

control practitioners

• Prospective comparison of 5 months of VAP surveillance by surgical intensivists vs infection preventionists in a surgical ICU using CDC definitions

• Intensivists found much higher rates of VAP than infection preventionists (28.5% vs 8.3%; p<0.001)

• When compared with BAL, intensivist-VAP had 61% sensitivity and preventionist-VAP had 29% sensitivity

Thomas et al. Am Surg 2011;77:998-1002


Prevention and therapy of HAP using a bundle approach

• Zack JE, et al. Effect of an educational program aimed at reducing the occurrence of ventilator-associated pneumonia. Crit Care Med 2002;30:2407-12.

• Babcock HM, et al. An educational intervention to reduce ventilator-associated pneumonia in an integrated health system: a comparison of effects. Chest 2004;125:2224-31.

• Resar R, et al. Using a bundle approach to improve ventilator care processes and reduce ventilator-associated pneumonia. Jt Comm J Qual Patient Saf 2005;31:243-8.

• Institute for Healthcare Improvement. Implement the ventilator bundle. Available at: http://www.ihi.org .

• Apisarnthanarak A, et al. Effectiveness of an educational program to reduce ventilator-associated pneumonia in a tertiary care center in Thailand: a 4-year study. Clin Infect Dis 2007:45:704-11.

• Bird D, et al. Adherence to ventilator-associated pneumonia bundle and incidence of ventilator-associated pneumonia in the surgical intensive care unit. Arch Surg 2010;145:465-70.

• DePalo VA, et al. The Rhode Island ICU collaborative: a model for reducing central line-associated bloodstream infection and ventilator-associated pneumonia statewide. Qual Saf Health Care 2010;19:555-61.

• Berenholtz SM, et al. Collaborative cohort study of an intervention to reduce ventilator-associated pneumonia in the intensive care unit. Infect Control Hosp Epidemiol 2011;32:305-14.

• Anon. Five years without VAP? Two years without BSI? Hosp Peer Rev 2011;36:42-6.


Type of locationNo.

locationsNo. VAPs

Ventilator days

Pooled mean

Percentile

10% 25%50%

(median)

75% 90%

Critical care units

Burn 21 109 14,703 7.4 0.0 0.0 2.7 10.9 14.2

Medical, major teaching 74 (74) 263 140,784 1.9 0.0 0.0 1.1 2.9 5.6

Medical, all other 97 (92) 178 131,185 1.4 0.0 0.0 0.2 2.2 4.6

Medical cardiac 125 (116) 149 100,768 1.5 0.0 0.0 0.0 2.4 4.8

Medical / surgical, major teaching

116 (115) 398 194,776 2.0 0.0 0.0 1.2 3.1 5.6

Medical / surgical, all other, ≤15 beds

359 (305) 284 209,206 1.4 0.0 0.0 0.0 1.6 5.1

Medical / surgical, all other, >15 beds

154 (152) 348 295,884 1.2 0.0 0.0 0.7 1.9 3.5

Mean VAP rates reported to the national healthcare safety network, data summary for 2009

Dudeck et al. Am J Infect Control 2011;39:349-67 VAP rate


What is the clinical relevance of studies having demonstrated a VAP rate of zero?

• None of them were rigorously evaluated and demonstrated a benefit using relevant endpoints such as:– Antibiotic use– Duration of mechanical ventilation– Length of stay in the ICU and the hospital– Overall mortality




Blood Culture Diagnostics The Reality

• Structured telephone interviews about blood culture diagnostics in Great Britain (Gb), France (F), Italien (I) and Germany (G)– 59 Intensivists– 79 Clinical mikrobiologists

• Time from taking the blood cultures to inkubation of them in Gb 2, F 3, I 4, G 20 hours– If the microbiological lab was inhouse 2h

• Satisfaction with the quality of the blood cultures– Intensivists 62%– Mikrobiologists 47% Schmitz RP et al. Crit Care 2013; 17 (5): R248

91


•SeptiFast®, Roche, Basel, Switzerland – Multiplex real-time PCR that simultaneously detects a pre-defined panel of the most important

sepsis pathogens by species- or genus-specific fluorescent probes

•SepsiTestTM, Molzym, Bremen, Germany – Eubacterial and pan-fungal real-time PCR that is able to detect nearly all known bacterial and

fungal pathogens by a 16S and 18S rRNA gene-based universal PCR, followed by sequencing of the amplification product for species identification

•VYOO®, SIRS Lab, Jena, Germany – Multiplex PCR that detects a predefined panel of the most important sepsis pathogens by

microarray-based detection of target-specific amplicons

•Plex-IDTM, Abbott, Wiesbaden, Germany – Eubacterial and pan-fungal PCR that is able to detect nearly all known bacterial and fungal

pathogens by genome-specific targets followed by mass spectrometry for species identification

PCR diagnostics in blood cultures

Pletz MW et al. Intensive Care Med 2011;37:1069-76Pletz MW et al. Intensive Care Med 2011;37:1069-76PCR, polymerase chain reaction; rRNA, ribosomal ribonucleic acid

11


PCR diagnostics in blood culturesSeptifast®

• 142 patients with severe sepsis and 63 surgical control individuals

• Presence of microbial DNA was assessed by multiplex PCR (SeptiFast®) on enrolment and each time a BC was obtained

• Control individuals had ~4% positive PCRs and BCs

• In severe sepsis, 34.7% of PCRs were positive vs 16.5% of BCs (p<0.001)

• 70.3% of BCs had a corresponding PCR result, while only 21.4% of PCR results were confirmed by BC

• Patients with positive PCRs had higher SOFA scores (12 vs 9; p=0.023) and a trend towards higher mortality (PCR negative 25.3%; PCR positive 39.1%; p=0.115)

Bloos F et al. Intensive Care Med 2010;36:241-7

32 6

8915

18(7 not on PCR

panel)

289(75 not on PCR panel)

Specimen321 microorganisms from 135 samples

PCR BC

61 microorganisms from 47 samples

41 microorganisms from 39 samples


• Observational study in a 50-bed ICU

• 311 concomitant blood cultures and blood for multiplex PCR (VYOO®) were obtained from patients with suspected sepsis (n = 245)

– 14.5% of blood cultures and 30.1% of PCRs were were positive

– Median time to positivity was 24.2 hours for the PCR and 68 hours for BC

– In 34% of patients with positive PCRs, antimicrobial therapy was considered inadequate

• 5 patients with VRE

• 3 patients with multi-resistant Staphylococci

• 4 patients with fungi

PCR diagnostics in blood culturesVyoo ®

Bloos F et al. PLoS One 2012;7:e46003

85 18

7107

22797 not on target list

297 not on target list

BC

PCR MiBi


Impact of the rapid multiplex PCR-based UPA in detecting aetiological pathogens and resistance markers in patients with NP

•49 patients with NP – 27 (55.1%) and 4 (8.2%) harboured multiple bacteria by UPA and conventional

culture, respectively

– A single pathogen was detected in 8 (16.3%) and 4 (8.2%) patients, respectively

– 13 different genes were detected from 38 patients, including the ermB gene (40.8%),the blaOXA-51-like gene (28.6%), the sul1 (28.6%) and int1 (20.4%) integrase genes, and the mecA and blaCTX-M genes (12.3% each)

– The time from sample testing to results was 4 hours by UPA vs 48–96 hours by culture

– Initial empirical treatment was changed within 5–6 hours in 33 (67.3%) patients based on the availability of UPA results

Jamal W et al. J Clin Microbiol 2014;52:2487-92

PCR diagnostics in Sputum / BAL

14


PCR diagnostics in Sputum / BAL

Microorganism (no. of isolates)

Patientsa infected according to indicated detection type, n

Group 1 (n=8) Group 2 (n=26) Group 3 (n=15)

PCR Culture PCR Culture PCR Culture p valueb

A. baumannii (13) 1 0 4 2 8 1 0.007

H. influenzae (2) 0 0 1 0 1 0 0.24

K. pneumoniae (10) 0 0 4 1 6 0 0.0013

K. oxytoca (2) 0 0 2 0 0 0 0.24

Legionella pneumophila (2) 0 0 2 0 0 0 0.24

Moraxella catarrhalis (1) 0 0 0 0 1 0 0.5

Proteus spp. (1) 0 0 0 0 1 0 0.5

P. aeruginosa (12) 1 0 4 1 5 1 0.015

S. marcescens (3) 0 0 1 0 2 0 0.12

S. aureus (2) 0 0 1 0 1 0 0.24

MRSA (3) 0 0 1 0 2 0 0.12

S. maltophilia (12) 2 0 3 0 6 1 0.0027

S. pneumoniae (12) 6 2 2 0 2 0 0.015

Jamal W et al. J Clin Microbiol 2014;52:2487-92

14


Etiology of Infections in the ICUEPIC II Vincent et al. JAMA 2009; 302:2323–9

8 May 2007, 667 Western European ICUs




Aspergillus: not only in neutropenic and immunosuppressed pts Meerssman, CID, 2007


RadiologyHERBRECHT ET AL: SEMINARS IN RESPIRATORY AND

CRITICAL CARE MEDICINE/VOLUME 25, NUMBER 2 2004

• Chest X-Ray: in early stages often normal• CT-Thorax (HR-CT) Nodules, even in early stages (AII)• Halo-Sign (dd: Bleeding, Embolus,..), Air crescent sign


Reverse Halo-Zeichen: EtiologyMarchiori, Chest, 2012

• Retrospective CT-Study

• 15 Pts. with invasive fungal infection

Organising Pneumonia Aspergillosis Zygomycosis


Serology

1. Haynes K, Rogers TR (1994) Eur J Clin Microbiol Infect Dis 13:670–6742. Machetti M, Feasi M, Mordini N, Van-Lint MT, Bacigalupo A, Latge JP, Sarfati J, Viscoli C (1998). Bone Marrow Transplant 21:917–9213. Maertens J, Verhaegen J, Lagrou K, Van-Eldere J, Boogaerts M (2001). Blood 97:1604–16104. Sulahian A, Boutboul F, Ribaud P, Leblanc T, Lacroix C, Derouin F (2001). 91:311–338 5. Musher B, Fredricks D, Leisenring W et al. J Clin Microbiol 2004;42: 5517–5522.6. Becker MJ, Lugtenburg EJ, Cornelissen JJBr J Haematol 2003; 121: 448–4577. Meersseman W, Lagrou K, Maertens J, Am J Respir Crit Care Med 2008; 177: 27–34

1. Galaktomannan-Assay (Pastorex® Aspergillus) 1, 2

Specifity 90-100%, Sensitivity 26-76%

2. Galaktomannan ELISA (Platelia® Aspergillus) 3, 4

Specifity 80-100%, Sensitivity 70-90% (PPV 87,5%)

Galactomannan in neutropenic pts 2x/week (AII), cave: Tazobactam or Amoxyclav.

Negative predictive Value 95– 98%

3. Galaktomannan BAL

Specifity 94–100%, Sensitivity 76–85% 5, 6, 7

4. G-Test: Beta-D-Glucan (Fungitec®G) Sensitivity+Specifity ?


Aspergillosis: Galactomannan in BAL

•Design•Retrospective, Leuven

•Patients (n=241)•3 proven

•56 probable

•63 possible

•129 none

•Results (OD)•<0,5 rule out

•>=0,8 (Sens. 86%, Spez. 91%)

•> 3,0 rule in

D`Haese, JCM, 2012


• Therapy– When should the antibiotic therapy starts?– Calculated therapy in patients without risk for MDR pathogens– Calculated Therapie in patients with risk for MDR pathogens– Combination therapy – Early stop of therapy– Evaluation of treatment success – Deescalation therapy– Duration of treatment– Treatment failure– Ventilator Tracheobronchitis– Inhaled antibiotic therapy– Targeted therapy for special therapies

Dalhoff K et al. Pneumologie 2012; 66:707-65

Dt. Ärzteblatt Int. 2013; 110 (38): 634-40



Sepsis Mortality Delay of antibiotic treatment

• Retrospective analysis (1/2005 - 2/2010) of a large dataset collected prospectively for the Surviving Sepsis Campaign

• A total of 28,150 patients with severe sepsis and septic shock

• A total of 17,990 patients received antibiotics after sepsis identification

• In-hospital mortality was 29.7%

• Statistically significant increase in the probability of death associated with the number of hours of delay for first antibiotic administration.

• Adjusted hospital mortality increased steadily after 1 hour of time to antibiotic administration.

• Results were similar in patients with severe sepsis and septic shock, regardless of the number of organ failure

Ferrer R. CCM 2014; 42: 1749-55


Sepsis Mortality Delay of antibiotic treatment

Ferrer R. CCM 2014; 42: 1749-55


• Retrospective review of adult admissions for CAP for 2 periods

– group 1 (255 pts), when the core quality measure was a TFAD of less than 8 hours

– group 2 (293 pts), when the TFAD was lowered to less than 4 hours.

• Accuracy of diagnosis of CAP were assessed by ED physicians

• At admission, group 2 patients were 39.0% less likely to meet predefined diagnostic criteria for CAP than were group 1 patients (odds ratio, 0.61; 95% confidence interval, 0.42-0.86) (P=.004).

• At discharge, there was agreement between the ED physician’s diagnosis and the predefined criteria for CAP in 62.0% of group 1 and 53.9% of group 2 patients (P=.06)

CAPDelay of Antibiotic Therapy

Welker JA. Arch Intern Med. 2008;168(4):351-356


Lancet Infect Dis 2012; 12: 774–80

• Pre-/post study in a surgical ICU in the US– Aggressive therapy (01.09.2008-31.08.2009)

• If an infection was suspected antibiotic treatment was initiated immediately

– Conservative therapy (01-09.2009-31.08.2010)• Initiation of an antibiotic therapy only, when an infection has been

confirmed by diagnostic results

4


Standard Treatmentgram positive infections

• S. pneumoniae– Beta-Laktam-Macrolid combination therapy

• A and B-Streptococci– Penicillin-/Clindamycin combination therapy

• Staph. Aureus– Sensibel: Oxacillin or 1. Gen. Cephalosporin– MRSA: Vancomycin/Linezolid/Daptomycin/Rifampicin

• Enterococci– E. faecalis: Ampicillin or Ampicillin/Inhibitor Combination– E. faecium: Vancomycin/Linezolid


Standard Treatmentgram negatives

• E. coli/Enterobakteriacae– Ampicillin/Inhibitor Combinations– 2. and 3. Generation Cephalosporines– Ertapenem

• Pseudomoas aeruginosa/Acinetobacter– Piperacillin/Tazobaktam– 4. Generation Cephalosporines– Carbapenemes

• St. maltophilia– Fluorquinolones– Cotrimoxazol


FM Brunkhorst, M Oppert, G Marx and coauthors

Effect of Empirical Treatment With Moxifloxacin and Meropenem vs Meropenem on Sepsis-Related Organ Dysfunction in Patients With Severe Sepsis: A Randomized Controlled Trial

Published online May 21, 2012


SO

FA

Sco

re (

Po

ints

) –

mea

n a

nd

95%

CI

1 3 5 7 9 11 13

Study Day

0

2

4

6

8

10

12

14Monotherapy

Combination therapy

t-test p=0.36 *

1 3 5 7 9 11 13

0

2

4

6

8

10

12

14

SO

FA

Sco

re (

Po

ints

) –

mea

n a

nd

95%

CI

Study Day

Monotherapy

Combination therapy

t-test p=0.37 *

249 212 167 137 124 103 89

255 209 179 153 125 95 81

Patients evaluable:

Monotherapy

Combination therapy

181 156 122 96 88 71 63

198 165 141 119 96 71 57

Patients evaluable

Monotherapy

Combination therapy

Organ Dysfunction (SOFA Score)

Intention-to-treat population Per-protocol population


0

10

20

30

40

50

60

70

80

90

100

0 14 28 42 56 70 84

Days

Ov

era

ll S

urv

iva

l (%

)

log rank p=0.42

Monotherapy

Combination therapy

Patients at risk:

273 222 211 193 188 184 179

276 224 210 193 186 180 177

Monotherapy

Combination therapyO

ve

rall

Su

rviv

al

(%)

0

10

20

30

40

50

60

70

80

90

100

0 14 28 42 56 70 84

Days

log rank p=0.59

Monotherapy

Combination therapy

Patients at risk:

199 164 156 143 138 137 132

214 176 166 155 150 146 144

Monotherapy

Combination therapy

Overall Survival

Intention-to-treat population Per-protocol population


ß-Lactam Monotherapy vs. ß-Lactam-Aminoglycosid Combination Therapy in Sepsis: A

Metaanalysis

Total MortalityTreatment FailureBakterial SuperinfectionAdverse EventsNephrotoxicity

43632739

45

5527661630854945

5213

0,90 (0,77 - 1,06)0,87 (0,78 - 0,97)0,79 (0,59 - 1,06)0,91 (0,80 - 1,04)

0,36 (0,28 - 0,47)

Paul M.BMJ 2004; 328: 668

N Studies N Patients ß-Mono vs. ß-AG Combi


Mono- vs. Combination Therapy for VAP• Randomised controlled

trial in 740 pts– Mechanical ventilated– VAP suspected after 4 days

in the ICU– Pts. with known

Pseudomonas or MRSA excluded

• Meropenem 1g tid + Ciprofloxacin 400 mg bid

• vs. Meropenem alone• Outcome Parameters:

– No difference in 28-day mortality (RR 1.05, p=0.74) Heyland D. CCM 2008; 36: 737-44


Mono- versus Combination Therapy• Metaanalysis of RCTs or observational studies comparing mono- and combination therapy

in patients with sepsis• no overall mortality/clinical response benefit with combination therapy (odds ratio, 0.856)• substantial benefit in the most severely ill subset (monotherapy risk of death >25%; odds

ratio of death, 0.51)• Meta-regression indicated that efficacy of combination therapy was dependent only on the

risk of death in the monotherapy group.

Kumar A. Crit Care Med 2010; 38:1651–1664

30


Pseudomoas aeruginosaCombination Therapy

• If combination therapy is required then combine with – + Aminoglycosid

• Gentamycin/Tobramycin 6 mg/kg BW per day as a single dosage (Through Level < 2 mg/L)

• Amikacin 20-25 (-30) mg/kg KG BW per day as a single dosage

– + Fluorquinolones• Ciprofloxacin (800-1200 mg tgl.)• Levofloxacin (1000 mg tgl.)


AntibioticsPharmacokinetics in severly ill patients

• Charakteristic of severly ill patients

– High Cardiac Index

– Increased distribution volume

– Altered plasma protein binding


AntibioticsPharmacokinetics in severly ill patients

• Consequences

– Dosage of antibiotics at the highest approved level (and above)

– Take pentrtaion properties into the tissue were the infection is suspected, into account

– Combination therapy for MDR pathogenes


Mean tigecycline (TGC) serum concentrations in subjects with hospital-acquired pneumonia after intravenous infusions.

2000 HAP- TGC Serum concentration 2000 HAP- TGC Serum concentration Ramirez J et al. 2013 Apr;57(4):1756-62.


Clinical response in phase 2 Clinical response in phase 2 (study 2000) (study 2000) vs. vs. phase 3 phase 3 (study 311) (study 311) HAP trialsHAP trials

Ramirez J et al. 2013 Apr;57(4):1756-62.


Proportion of 3rd gen. cephalosporins Resistant (R) Klebsiella pneumoniae Isolates in Participating Countries in 2012

http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/, 19.11.13


ESBL Treatment

• Carbapenems, Carbapenems, Carbapenems …..


Proportion of Carbapenems Resistant (R) Klebsiella pneumoniae Isolates in Participating Countries in 2012

http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/, 19.11.13


Revival of „old“ drugs Tigecyclin

• Phase II-Study in patients with hospital acquired pneumonia– Tigecyclin 75 mg twice daily – Tigecyclin 100mg twice daily– Imipenem/Cilastatin 1g three times a day

• Primary Endpoint: Advers Events– No significant difference between the groups

• Secondary Endpoint: Clinical Cure– Both tigecyclin groups were non inferior to Imipenem/Cilastatin– High dose tigecyclin was in trend more effective than low dose tigecyclin

and imipenem/cilastatin

Ramirez J et al. 2013 Apr;57(4):1756-62.

10


Revival of „old“ drugsColistin

• Combination Therapy (?) with– Colistin

• 9 Mill. E Loading Dose• 4.5 Mill E twice daily as maintenance

therapy• + inhaled colistin ???


Documents

Ventilator associated Pneumonia Tobias Welte Department of Respiratory Medicine and Intensive Care