Nebulized antibiotics for treating Ventilator-Associated Pneumonia

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
Ventilator
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 nebulizersUltrasonic 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 beVentilator settings should be
modified during the nebulizationmodified during the nebulization
period to limit inspiratory flowperiod to limit inspiratory flow
turbulencesturbulences ++++++
Patients should be synchronized with
the ventilator to avoid turbulences
which increase extrapulmonary
deposition (propofol)
50 % of the particles should have a diameter < 5 µ

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
alveoliBronchioles
Exhaled 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
Ventilator
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

Before clinical use, experimental studies reproducing
conditions observed in ventilated critically ill patients
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 UnitExperimental Intensive Care Unit
Département Hospitalo-Universitaire de Recherche ExpérimentaleDépartement 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

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

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 sampling
At the end of the experiments, animals are
sacrified for multiple lung tisssue sampling
Death
Sternotomy
Exsanguination

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: 1792-1800
Time-dépendant antibiotics Ceftazidime
Tonnellier 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

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

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
)
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
aeruginosa partially resistive to ceftazidime: : comparison
between nebulized and IV colistin ( 56 000 IU vs 40000 IU.kg -1
)
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

Plasma pharmacokinetics following nebulization of
amikacin : healthy lungshealthy lungs vs infected lungs
30
Time after nebulization (h)
0 5 10 15 20 25
amikacinplasmaµg/ml
0
5
10
15
20
25
30
35
Healthy lungs
Infected lungs
Goldstein I et al , AJRCCM 165 :172-175, 2002
5858 ±± 18 %18 % of the administered dose isof the administered dose is
eliminated in the urineseliminated in the urines
7474 ± 12 %± 12 % of the administered dose isof 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)
Aerosol
IV

intravenous ceftazidim ( 200 vs 100 mg.kg -1
)

Lu et al, Intensive Care Medicine 2010 36: 1147-1155
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
Respirateur
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)
ceftazidime
15 mg/kg/3h
ceftazidime (continuous)
or imipenem (I species)
amikacin
25 mg/kg/24h
amikacin
ou cipro/ fosfo (I species)
D 9
D 1
D 4
D 3
D 2
D 6
D 8
Patients with ventilator-associated pneumonia
caused 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 0
Pharmaco AMK
BAL 1
Pharmaco AMK
Pharmaco Cefta
MiniBAL 2
BAL 3
TDM Day 7
Pharmaco Cefta
BAL 4
Randomized
monocenterstudy
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
IV amikacin
30-min continuous administration
Daily dose 15 mg.kg-1
+
IV ceftazidime
24-hr continuous administration
Bolus dose = 30 mg.kg-1

Following randomisation, 20 patients were
treated by nebulized amikacin + ceftazidime
+
Nebulized amikacin
30-min nebulization / 24 hr
-optimization of ventilatory settings
(sedation by propofol during the nebulization)
Nebulized ceftazidime
30-min nebulization / 3 hr
-optimization of ventilatory settings
(sedation by propofol during the nebulization)
vibrating plate nebulizervibrating plate nebulizer

Comparative efficiency of intravenous and inhaled antibiotics
Aerosol
n=20
Intravenous
n=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 8
100
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 VAP53-year old patient with VAP
following aortic surgeryfollowing aortic surgery
After neb (D8 )
Changes of Gas and Tissue
Volumes (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 Tissue
Volumes (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 µ/ml)
32-year old patient suffering32-year old patient suffering
from multiple traumafrom multiple trauma After neb (D8 )

No difference concernant in amikacin toxicity
Amikacin trough concentrations (mg/L)
IV Aerosol
0
2
4
6
8
10
D 1
NS
IV Aerosol
0
2
4
6
8
10
D 3
NS
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 1
Pseudomonas 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

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
Colistin 100 00 UI/kg

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%.

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

Colistin 220 00
UI/kg
Patients included in the study
IV β

Patients with multidrug resistive VAP are more severe

Similar cure rate at day 14: 67 % for Pseudomonas aeruginosa
100 % for Acinetobacter baumaniï

Frequent recurrence for VAP caused by Pseudomonas aeruginosa
26 % not observed for Acinetobacter baumaniï 0 %

Success Failure

Colistin renal toxicity

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
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.

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

Nebulized antibiotics for treating Ventilator-Associated Pneumonia

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