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 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

http://www.ncbi.nlm.nih.gov/pubmed/23135264

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



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 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




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 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



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


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


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

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


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)


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 )


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


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


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%.

ANESTHESIOLOGY. 117:1335-1347, 2012


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


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

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


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

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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