nebulized antibiotics for treating ventilator-associated pneumonia
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Nebulized antibiotics for ventilator-associated pneumonia
Multidisiplinary Intensive Care Unit Department of Anesthesiology and Critical Care,
Pitié Salpêtrière hospital, University Pierre and Marie Curie (UPMC) Paris 6
Jean-Jacques Rouby
Paris
http://www.reapitie-univparis6.aphp.fr
Potential benefits of using the inhaled rather than the intravenous route
2 – Increase the bactericidal efficiency by increasing lung
tissue concentrations.
1 – Reach directly the infected lung parenchyma without crossing cell membranes V
en
tilat
or
Nebulizer
3 - Decrease systemic toxicity.
Conditions required to reach the deep lungConditions required to reach the deep lung
Optimisation of aerosol particles size
Extrapulmonary deposition
Specific issues related to antibiotic nebulization
Type of nebulizer
Ultrasonic and vibrating plate nebulizers are more performant than jet nebulizers Ultrasonic and vibrating plate nebulizers are more performant than jet nebulizers (Ferrari et al ICM 34: 1718-1723, 2008(Ferrari et al ICM 34: 1718-1723, 2008 ) )
Ventilator settings should be Ventilator settings should be modified during the nebulization modified during the nebulization period to limit inspiratory flow period to limit inspiratory flow turbulences turbulences ++++++
Patients should be synchronized with the ventilator to avoid turbulences which increase extrapulmonary deposition (propofol)
50 % of the particles should have a diameter < 5
If nebulization is optimized, 40-70% of the dose deposited in the nebulizer chamber reaches the deep lung
Initial dose inserted into the nebulizer’s chamber
Nebulized dose Chamber depositChamber deposit
Upper airways depositUpper airways deposit Pulmonary dose
alveoliBronchiolesExhaled doseExhaled dose
Expiration and tracheal suctioning
Circuits depositCircuits deposit Inhaled dose
Systemic absorption
Urinary excretion
J.J. Rouby, Bouhemad B., Monsel A., Brisson H., Arbelot C., Lu Q. and the Nebulized Antibiotics Study Group. Aerosolized antibiotics for Ventilator-Associated pneumonia: Lessons from experimental studies. ANESTHESIOLOGY 117:1364-1380, 2012
O’Doherty et al, Am Rev Respi Dis, 1992 (146) 383-8
Low respiratory frequency (12 bpm)
Plateau inspiratory pause (20%)
Specific ventilator settings for decreasing inspiratory flow turbulences
High I/E ratio (50%)
Propofol sedation is often necessary to synchronize the patient with the ventilator
Expiratory filter
Ve
ntila
tor
Nebulizer
Rationale for determining the nebulized dose
Dose delivered to the tracheobronchial tree = intravenous dose
Dose in the nebulizer = dose delivered to the tracheobronchial tree + extra-pulmonary deposition
J.J. Rouby, Bouhemad B., Monsel A., Brisson H., Arbelot C., Lu Q. and the Nebulized Antibiotics Study Group. Aerosolized antibiotics for Ventilator-Associated pneumonia: Lessons from experimental studies. ANESTHESIOLOGY 117:1364-1380, 2012
Before clinical use, experimental studies reproducing conditions observed in ventilated critically ill patients
J.J. Rouby, Bouhemad B., Monsel A., Brisson H., Arbelot C., Lu Q. and the Nebulized Antibiotics Study Group. Aerosolized antibiotics for Ventilator-Associated pneumonia: Lessons from experimental studies. ANESTHESIOLOGY 117:1364-1380, 2012
Experimental models should concern big
animals whose cradiopulmonary
physiology is close to humans and a critical care
environment allowing prolonged mechanical
ventilation
Experimental Intensive Care Unit Experimental Intensive Care Unit Département Hospitalo-Universitaire de Recherche Expérimentale Département Hospitalo-Universitaire de Recherche Expérimentale
de Lille (Pr Charles-Hugo Marquette)de Lille (Pr Charles-Hugo Marquette)
Big animals: piglets and pigsBig animals: piglets and pigs
Prolonged mechanical ventilationProlonged mechanical ventilation
Post-mortem pulmonary samplesPost-mortem pulmonary samples
J.J. Rouby, Bouhemad B., Monsel A., Brisson H., Arbelot C., Lu Q. and the Nebulized Antibiotics Study Group. Aerosolized antibiotics for Ventilator-Associated pneumonia: Lessons from experimental studies. ANESTHESIOLOGY 117:1364-1380, 2012
J.J. Rouby, Bouhemad B., Monsel A., Brisson H., Arbelot C., Lu Q. and the Nebulized Antibiotics Study Group. Aerosolized antibiotics for Ventilator-Associated pneumonia: Lessons from experimental studies. ANESTHESIOLOGY 117:1364-1380, 2012
In 1997 an Experimental Intensive Care UnitExperimental Intensive Care Unit allowing the prolonged mechanical ventilation of piglets with inoculation bacterial pneumonia was set up
Anesthetized intubated piglets weighing 20 kg, mechanically
ventilated
Bronchoscopic inoculation in middle and lower lobes of 40- 60
ml of a solution containing 10 5- 10 6 Escherichia coli or
Pseudomonas aeruginosa
The animals are mechanically
ventilated for 1 to 4 days
J.J. Rouby, Bouhemad B., Monsel A., Brisson H., Arbelot C., Lu Q. and the Nebulized Antibiotics Study Group. Aerosolized antibiotics for Ventilator-Associated pneumonia: Lessons from experimental studies. ANESTHESIOLOGY 117:1364-1380, 2012
Multiple hilar and juxtapleural lung
tissue samples for histologic and bacteriologic
examination and measurement of antibiotic tissue concentrations
At the end of the experiments, animals are sacrified for multiple lung tisssue samplingAt the end of the experiments, animals are sacrified for multiple lung tisssue sampling
Death
SternotomyExsanguination
Did experimental studies confirm the potential benefits of nebulized antibiotics ?
1 – YES, high tissue concentrations in the infected lung parenchyma were demonstrated
Extrapulmonary deposition can be limited to 30-40% if nebulization is optimized
10% to 20 % of the dose inserted into the nebulizer chamber reaches the infected lung parenchyma
2 – YES, potent and rapid bactericidal effect was demonstrated in animals with inoculation pneumonia.
Ferrari et al, Intensive Care Medicine 2009 35: 1792-1800Time-dépendant antibiotics CeftazidimeTonnellier et al, Anesthesiology 102: 995-1000, 2005
Concentration-dependant antibiotics
Amikacin
Colistin
Goldstein I et al , AJRCCM 165 :172-175, 2002
Goldstein I et al , AJRCCM, 166, 1375 - 1381, 2002
Lu et al, Intensive Care Medicine 36: 1147-1155, 2010
Elman et al, Anesthesiology 97: 199-206, 2002
Did experimental studies confirm the potential benefits of nebulized antibiotics ?
Goldstein I et al , AJRCCM, 166, 1375 - 1381, 2002
Piglets with inoculation Escherichia coli pneumonia :comparison between nebulized and IV amikacin ( 45 vs 15 mg.kg -1 )
Piglets with inoculation Escherichia coli pneumonia :comparison between nebulized and IV amikacin ( 45 vs 15 mg.kg -1 )
MIC50
Bactericidal effect ++++ following 24h treatment and 2 nebulizations
amikacin, concentration-dependant antibiotic
Ferrari et al, Intensive Care Medicine 2009 35: 1792-1800
Piglets with inoculation pneumonia caused by Pseudomonas aeruginosa partially resistive to ceftazidime: comparison between
nebulized (/3 h) and continuous IV ceftazidime ( 200 vs 100 mg.kg -1 )
Piglets with inoculation pneumonia caused by Pseudomonas aeruginosa partially resistive to ceftazidime: comparison between
nebulized (/3 h) and continuous IV ceftazidime ( 200 vs 100 mg.kg -1 )
ceftazidime, time-dependant antibiotic
MIC50
Aerosol
IV
Bactericidal effect ++++ following 24h treatment and 9 nebulizations
Aerosol
IV
Piglets with inoculation pneumonia caused by Pseudomonas aeruginosa partially resistive to ceftazidime: : comparison between nebulized and IV colistin ( 56 000 IU vs 40000 IU.kg -1 )
Piglets with inoculation pneumonia caused by Pseudomonas aeruginosa partially resistive to ceftazidime: : comparison between nebulized and IV colistin ( 56 000 IU vs 40000 IU.kg -1 )
colistin, concentration-dependant antibiotic
Bactericidal effect ++++ following 24h treatment and 3 nebulizations
Lu et al, Intensive Care Medicine 36: 1147-1155 2010
Antibiotic tissue concentrations decrease with lung aeration and histological severity of pneumonia
Elman M et al , Anesthesiology, 97, 199-206, 2002
Nebulized amikacin
Lu et al, Intensive Care Medicine 36: 1147-1155 2010
Nebulized colistin
Histological grade of pneumonia
3 - NO, as far as systemic toxicity is concerned.
Lung infection impairs the « barrier effect » of alveolar-capillary membrane and allows systemic diffusion of most nebulized
antibiotics (amikacin and ceftazidime)
A single exception: colistin has a very low systemic diffusion in presence of lung infection
J.J. Rouby, Bouhemad B., Monsel A., Brisson H., Arbelot C., Lu Q. and the Nebulized Antibiotics Study Group. Aerosolized antibiotics for Ventilator-Associated pneumonia: Lessons from experimental studies. ANESTHESIOLOGY 117:1364-1380, 2012
Did experimental studies confirm the potential benefits of nebulized antibiotics ?
Plasma pharmacokinetics following nebulization of amikacin : healthy lungshealthy lungs vs infected lungs
30
Time after nebulization (h)0 5 10 15 20 25
amik
acin
pla
sma
µg/
ml
0
5
10
15
20
25
30
35
Healthy lungs
Infected lungs
Goldstein I et al , AJRCCM 165 :172-175, 2002
Goldstein I et al , AJRCCM, 166, 1375 - 1381, 2002
5858 ± ± 18 %18 % of the administered dose is of the administered dose is eliminated in the urineseliminated in the urines
7474 ± 12 %± 12 % of the administered dose is of the administered dose is eliminated in the urineseliminated in the urines
Plasma and tissue pharmacokinetics following administration of 1 to 4 aerosols of amikacin 45 mg/kg
Ferrari F et al , Anesthesiology, 98, 1016 - 1019, 2003
Plasma elimination
Urinary elimination
Tissue concentrations
Tissue concentrations
Plasma pharmacokinetics following nebulized and intravenous amikacin (45 vs 15 mg/kg)
Goldstein I et al , AJRCCM, 166, 1375 - 1381, 2002
Aerosol
IV
Ferrari et al, Intensive Care Medicine 2009 35: 1792-1800
Plasma pharmacokinetics following nebulized and intravenous ceftazidim ( 200 vs 100 mg.kg -1 )
Lu et al, Intensive Care Medicine 2010 36: 1147-1155
Plasma pharmacokinetics following nebulized and intravenous colistin (56 000 IU vs 40000 IU.kg -1 )
Experimental studies in pigs and piglets are encouraging: high tissue concentrations in the infected parenchyma and rapid and efficient bactericidal activity
Experimental studies: summary
Nebulization should be optimized: doses adapted to extrapulmonary deposition and specific ventilator settings +++
Intravenous colistin does not diffuse in infected lung parenchyma. Nebulized colistin has a very low systemic diffusion that could decrease its renal toxicity.
Aminoglycosides and cephalosporins systemic toxicity is not reduced by nebulization.
A double blind study against placebo combining intravenous
and nebulized antibiotics
Clinical studies
Palmmer et al, Critical Care Medicine 2008 36: 2008-2012
1. VA-Tracheobronchitis 2. Vanco or genta acoording to BGN or Cocci +
2. IV Ab in both groups (IV: 89%, Aerosol: 63%)
Crit Care Med 2008, 36: 2008-12
1. VA-Tracheobronchitis 2. Vanco or genta acoording to BGN or Cocci +
2. IV Ab in both groups (IV: 89%, Aerosol: 63%)
Crit Care Med 2008, 36: 2008-12
Resistive micoorganisms at the end of treatment:
A double blind study against placebo combining intravenous and nebulized antibiotics
Clinical studies
A randomized phase II trial compa-ring nebulized and IV antibiotics in Pseudomonas aeruginosa VAP
AJRCCM 2011, 184: 106-115
Re
spira
teu
r
Nébuliseur
Dose delivered to the tracheobronchial tree = intravenous dose
Dose in the nebulizer = dose delivered to the tracheobronchial tree + extra-pulmonary deposition
Aerosol (n=25)
Randomization
Intravenous (n=25)
ceftazidime15 mg/kg/3h
ceftazidime (continuous)or imipenem (I species)
amikacin25 mg/kg/24h
amikacinou cipro/ fosfo (I species)
D 9
D 1
D 4
D 3
D 2
D 6
D 8
Patients with ventilator-associated pneumoniaPatients with ventilator-associated pneumoniacaused by Pseudomonas aeruginosa
Exclusion criteria
- positive blood cultures
- extrapulmonary infection
- Pseudomonas aeruginosa resistive to ceftazidime
and/or amikacin
Aims
Resolution of lung infection:
- clinical and biological signs
- CT lung re-aeration
- CT decrease in lung tissue
Duration of MV
D 14 BAL 5
TDM Day 0Pharmaco AMK
BAL 1
Pharmaco AMK
Pharmaco CeftaMiniBAL 2
BAL 3
TDM Day 7Pharmaco Cefta
BAL 4
Randomized monocenter
study Phase II
Randomized monocenter
study Phase II
46 patients with ventilator-associated pneumonia caused by Pseudomonas aeruginosa were included
(11 were secondary included)
Following randomisation, 20 patients were treated by intravenous amikacin + ceftazidime
Following randomisation, 20 patients were treated by intravenous amikacin + ceftazidime
IV amikacin
30-min continuous administration
Daily dose 15 mg.kg-1 +
IV ceftazidimeIV ceftazidime
24-hr continuous administration
Daily dose 90 mg.kg-1
Bolus dose = 30 mg.kg-1
Following randomisation, 20 patients were treated by nebulized amikacin + ceftazidime
Following randomisation, 20 patients were treated by nebulized amikacin + ceftazidime
+
Nebulized amikacin
30-min nebulization / 24 hr
Daily dose 25 mg.kg-1
-optimization of ventilatory settings (sedation by propofol during the nebulization)
Nebulized ceftazidimeNebulized ceftazidimeDaily dose 120 mg.kg-1
30-min nebulization / 3 hr
-optimization of ventilatory settings (sedation by propofol during the nebulization)-optimization of ventilatory settings (sedation by propofol during the nebulization)
vibrating plate nebulizervibrating plate nebulizer
Comparative efficiency of intravenous and inhaled antibiotics
Aerosoln=20
Intravenousn=20
p Value
Cure of P aeruginosa VAP at day 9 (n, %) 14 (70) 11 (55) 0.33
Persisting P aeruginosa VAP at day 9 (n, %) 3 (15%) 6 (30%) 0.26
VAP caused by superinfection at day 9 (n, %) 3 (15%) 3 (15%) NS
In the 6 patients of the IV group with persisting VAP, 3 were infected by P aeruginosa intermediate to amikacin and/or
ceftazidime
Temperature
Blood leucocytes
Tracheal secretions
Oxygenation: PaO2/FiO2
Progression of pulmonary infiltrates
Culture of mini-BAL
Evolution of Clinical Pulmonary Infection Score (CPIS)
p < 0.01
p < 0.01
CPIS
Period of Treatment
D0 D3 D5 D7 D9
0
2
4
6
8
10
IV (n =18)Aero (n =17)
Computed Tomography aeration and tissue changes in infected lung regions
Volume of gas in infected lung regions (ml)
D 0 D 8-100
0
100
200
300
400
500
600
700 Aero (n =17)IV (n =16)
} nsp < 0.01
D 0 D 8100
200
300
400
500
600
700
800
900 Aero (n =17)IV (n 16)
} ns
p < 0.01
Volume of tissue in infected lung regions (ml)
Before neb (D0 )
Pulmonary re-aeration ( ) and decrease in lung tissue ( ) following
nebulization of ceftazidime (8 days) and amikacin (3 days) in a patient with VAP caused by
sensitive Pseudomonas aeruginosa
53-year old patient with VAP 53-year old patient with VAP following aortic surgeryfollowing aortic surgery
53-year old patient with VAP 53-year old patient with VAP following aortic surgeryfollowing aortic surgery
After neb (D8 )
Changes of Gas and TissueVolumes (ml)
-200
0
200
400
600
800
1000
Nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa Qin Lu et al. Am J Resp Crit Care Med 2011
Changes of Gas and TissueVolumes (ml)
-200
0
200
400
600
800
1000
Before neb (D0 )
Pulmonary re-aeration ( ) and decrease in lung tissue ( ) following
nebulization of ceftazidime (6 days) and amikacin (3 days) in a patient with
VAP caused by partially resistant Pseudomonas aeruginosa (MIC 16 /ml)
32-year old patient suffering 32-year old patient suffering from multiple traumafrom multiple trauma
32-year old patient suffering 32-year old patient suffering from multiple traumafrom multiple trauma After neb (D8 )
Nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa Qin Lu et al. Am J Resp Crit Care Med 2011
No difference concernant in amikacin toxicity
Amikacin trough concentrations (mg/L)
IV Aerosol
0
2
4
6
8
10
D 1NS
IV Aerosol
0
2
4
6
8
10
D 3NS
Amikacin trough concentrations (mg/L)
Bacteriological results
Patients n = 20 (Intravenous antibiotics) D0 D3 D5 D7 D9 D14
Number of mini-BAL 20 16 15 10 11 4
Nb of BAL Pseudomonas aeruginosa + 20 8 8 5 6 1Pseudomonas resistant to Ceftazidime and/or amikacin 0 0 33 44 3 0
Relapse due to P aeruginosa Cefta/Amk R - - - 4 0
Patients n = 20 (Nebulized antibiotics) D0 D3 D5 D7 D9 D14
Number of mini-BAL 20 17 16 12 12 11
Nb of BAL Pseudomonas aeruginosa + 17 1 0 2 5 4
Pseudomonas resistant to Ceftazidime 0 0 00 00 0 1
Relapse due to Ps aeruginosa Cefta S - - - 2 3
Nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa Qin Lu et al. Am J Resp Crit Care Med 2011
Conclusions of the Phase II trial
Antibiotic nebulization
More efficient and rapid eradication of Pseudomonas aeruginosa from distal pulmonary samples
Prevention of per-treatment acquisition of antibiotic resistance
Nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa Qin Lu et al. Am J Resp Crit Care Med 2011
Efficient treatment of VAP caused by Pseudomonas aeruginosa with decreased sensitivity to ceftazidime and/or amikacin
A double blind study against placebo combining IV and nebulized antibiotics
Clinical studies
A randomized phase II trial comparing nebulized and IV antibiotics in Pseudomonas aeruginosa VAP
Many observationnal studies reporting the efficiency of nebulized antibiotics for treating VAP caused by multidrug resistive Pseudomonas aeruginosa or Acinetobacter baumanïi.
http://www.reapitie-univparis6.aphp.fr/
ANESTHESIOLOGY. 117:1335-1347, 2012
Rationale for using high doses colistin
http://www.reapitie-univparis6.aphp.fr/
Colistin 100 00 UI/kg
http://www.reapitie-univparis6.aphp.fr/
Monocenter prospective, non-randomized observational study performed during 4 years in the 26-bed multidiciplinary ICU of La Pitié-Salpêtrière hospital
Noninferiority study on cure rate of VAP caused by multidrug resistive microorganims. Noninferiority of nebulized colistin was demonstrated if the lower limit of the one-sided 95% CI for difference in clinical cure rate was more than −16%.
ANESTHESIOLOGY. 117:1335-1347, 2012
http://www.reapitie-univparis6.aphp.fr/
Inclusion and exclusion flow chart
Q. Lu, Luo R., Bodin L., Yang J., Zahr N., Aubry A., Golmard J.L., Rouby J.J.; the Nebulized Antibiotics Study Group. Efficacy of high-dose nebulized colistin in Ventialator-associated pneumonia caused by Multidrug-resistant Pseudomonas aeruginosa et Acinetobacter Baumanïi ANESTHESIOLOGY. 117:1335-1347, 2012
Colistin 220 00 UI/kg
http://www.reapitie-univparis6.aphp.fr/Q. Lu, Luo R., Bodin L., Yang J., Zahr N., Aubry A., Golmard J.L., Rouby J.J.; the Nebulized Antibiotics Study Group. Efficacy of high-dose nebulized colistin in Ventialator-associated pneumonia caused by Multidrug-resistant Pseudomonas aeruginosa et Acinetobacter Baumanïi ANESTHESIOLOGY. 117:1335-1347, 2012
Patients included in the study
IV β
Patients with multidrug resistive VAP are more severe
http://www.reapitie-univparis6.aphp.fr/
Similar cure rate at day 14: 67 % for Pseudomonas aeruginosa
100 % for Acinetobacter baumaniï
http://www.reapitie-univparis6.aphp.fr/
http://www.reapitie-univparis6.aphp.fr/
Frequent recurrence for VAP caused by Pseudomonas aeruginosa 26 % not observed for Acinetobacter baumaniï 0 %
Q. Lu, Luo R., Bodin L., Yang J., Zahr N., Aubry A., Golmard J.L., Rouby J.J.; the Nebulized Antibiotics Study Group. Efficacy of high-dose nebulized colistin in Ventialator-associated pneumonia caused by Multidrug-resistant Pseudomonas aeruginosa et Acinetobacter Baumanïi ANESTHESIOLOGY. 117:1335-1347, 2012
http://www.reapitie-univparis6.aphp.fr/
Success Failure
Q. Lu, Luo R., Bodin L., Yang J., Zahr N., Aubry A., Golmard J.L., Rouby J.J.; the Nebulized Antibiotics Study Group. Efficacy of high-dose nebulized colistin in Ventialator-associated pneumonia caused by Multidrug-resistant Pseudomonas aeruginosa et Acinetobacter Baumanïi ANESTHESIOLOGY. 117:1335-1347, 2012
Colistin renal toxicity
http://www.reapitie-univparis6.aphp.fr/Q. Lu, Luo R., Bodin L., Yang J., Zahr N., Aubry A., Golmard J.L., Rouby J.J.; the Nebulized Antibiotics Study Group. Efficacy of high-dose nebulized colistin in Ventialator-associated pneumonia caused by Multidrug-resistant Pseudomonas aeruginosa et Acinetobacter Baumanïi ANESTHESIOLOGY. 117:1335-1347, 2012
Conclusions
2 – Cure rate of VAP caused by multidrug resistive Pseudomonas aeruginosa reaches 67 %, a result similar to that obtained in VAP caused by sensitive strains.
4 – Recurrence rate reaches 30 % for Pseudomonas aeruginosa and is unfrequently observed withAcinetobacter baumanï
1 – High doses colistin can be nebulized with good clinical acceptance and without renal toxicity
http://www.reapitie-univparis6.aphp.fr/
3 – Cure rate of VAP caused by multidrug resistive Acinetobacter baumanï reaches 100%, a result similar to that obtained in VAP caused by sensitive strains.
Q. Lu, Luo R., Bodin L., Yang J., Zahr N., Aubry A., Golmard J.L., Rouby J.J.; the Nebulized Antibiotics Study Group. Efficacy of high-dose nebulized colistin in Ventialator-associated pneumonia caused by Multidrug-resistant Pseudomonas aeruginosa et Acinetobacter Baumanïi ANESTHESIOLOGY. 117:1335-1347, 2012
General conclusions
General conclusions
1) Inhaled antibiotics provide mare rapid bacterial killing and similar clinical efficiency for treating ventilator-associated pneumonia.
2) Intravenous antibiotics often induce rapid resistance to various microorganisms, particularly Pseudomona aeruginosa
3) Inhaled antibiotics prevent per-treatment acquisition of resistance
5) Ventilator-associated pneumonia caused by resistive Pseudomonas aeruginosa or Acinetobacter baumanii can be efficiently treated by nebulized colistin
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