Inhaled - PowerPoint Presentation

Slide1

Inhaled antimicrobial therapy: pharmacodynamics and risks for development of resistance

Paul M. Tulkens, MD, PhDCellular and Molecular PharmacologyLouvain Drug Research InstituteUniversité catholique de LouvainBrussels, Belgium

27/02/2015

16th International Symposium of KU Leuven “Pulmonary infections”

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16

th

International Symposium

of

KU Leuven - February 26-28, 2015 Leuven“Pulmonary infections”Slide2

Disclosures and slides availabilityResearch grants Cerexa/Forest, AstraZeneca, Bayer, GSK, Trius, Rib-X, Eumedica, Cempra

Belgian Science Foundation (F.R.S.-FNRS), Ministry of Health (SPF), and Walloon and Brussels Regions Speaking fees Bayer, GSK

Decision-making and consultation bodies (current)

General Assembly of EUCAST

European Medicines Agency (external expert)US National Institutes of Health (grant reviewing)

Slides: http://www.facm.ucl.ac.be

 Lectures

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16th International Symposium of KU Leuven “Pulmonary infections”

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Why Inhalation ?

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16th International Symposium of KU Leuven “Pulmonary infections”

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Novel strategies are required to ‘break’ the vicious cycle created in local pulmonary infections where exacerbations and recurrences are common and cause disease progression

1

Genetic

predisposition

External insult (infectious or toxic)

Ineffective mucus clearance

Bronchial wall inflammation and destruction

Ciliary dyskinesia or altered bronchial dynamics

Chronic or recurrent infection

Impaired immune system

Figure adapted by kind permission of Dr Diane Bilton, Royal Brompton Hospital, London

1. Smith MP.

J R

Coll

Physicians

Edinb

2011;41:132

Deliver the drug

where its is neededSlide4

Trying to reach deep in lung …

Deposition of nominal dose, [%]: mean (SD)

Amikacin

Inhale 400 mg (n=13*)

Lung

43.1 (6.1)

Oropharyngeal

29.4 (7.4)

Remaining in device

16.1 (4.8)

Exhaled air

11.5 (5.5)

Corkery K et al. ATS 2008 Poster 517

Scintigraphy

scans after administration of a single dose of 400 mg

99m

Technetium labelled

Amikacin

Inhale in one representative subject

An example with

amikacin

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16th International Symposium of KU Leuven “Pulmonary infections”

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Can you achieve high local concentrations ?

Amikacin lung (predicted by

scintigraphy

) and

mean serum-time profiles after single doses of Amikacin Inhale

(Amikacin Inhalation Solution 400 mg administered via the PDDS hand-held device) and IV amikacin 400 mg infusion in healthy volunteers. *Evaluable subjects

Lung

predicted:

Amikacin

Inhale 400 mg (

n=14*)

Serum

observed

: Amikacin Inhale 400 mg (

n=14*)

Serum

observed

:

i.v

amikacin

400 mg (

n=14*)

0

20

40

60

80

100

0

4

8

12

16

20

24

amikacin

concentration,

mg/L or µg/g

Time relative to administration, h

120

0

40

60

80

100

120

20

1. Corkery K et al. ATS 2008. Poster 517; 2. Eldon M et al. ISICEM 2008. Poster A135

This is what is predicted

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16th International Symposium of KU Leuven “Pulmonary infections”

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Where do we go to now ?27/02/201516th International Symposium of KU Leuven “Pulmonary infections”6Slide7

Where do we go to now ?27/02/201516th International Symposium of KU Leuven “Pulmonary infections”7Slide8

MICs can be very high…Dalhoff, Clin Microb Rev 2014; 27:753-78227/02/201516th International Symposium of KU Leuven “Pulmonary infections”

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MICs can be very high…Dalhoff, Clin Microb Rev 2014; 27:753-782

Drug

MIC

50

MIC

90

% S

% R

CIP

1

8

49

51

MEM

2

16

48

52

AMK

32

128

46

54

TZP

64

512

31

69

Data from an European

(FR, UK, BE; DE)

collection

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16th International Symposium of KU Leuven “Pulmonary infections”

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But here are published concentrations…27/02/2015

16th International Symposium of KU Leuven “Pulmonary infections”10Slide11

Large variations sputum and little in lung/ELF…27/02/201516th International Symposium of KU Leuven “Pulmonary infections”

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Would a high concentration help ?Concentration effects relationships (P. aeruginosa)Concentration--response curves of selected antibiotics against extracellular and intracellular P. aeruginosa. The graphs show the change in the number of CFU (∆log CFU from the initial inoculum) per mL of broth (extracellular, open symbols, dotted lines) or per mg of cell protein (intracellular, closed symbols; plain lines) in THP-1 cells after 24 h incubation at the increasing extracellular concentrations expressed in mg/L (total drug). The plain horizontal line corresponds to a bacteriostatic effect (no change from initial inoculum).

The vertical dotted lines show the serum MIC-Cmax range of concentrations..

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16th International Symposium of KU Leuven “Pulmonary infections”

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Buyck et al. Antimicrob Agents Chemother. 2013;572310-8.Slide13

Would a high concentration help ?Concentration effects relationships (pharmacology)27/02/201516th International Symposium of KU Leuven “Pulmonary infections”13

Flume & Klepser, Pharmacotherapy 2002;22(3 Pt 2):71S–79S.Slide14

Would a high concentration help ?Concentration effects relationships (pharmacology)27/02/201516th International Symposium of KU Leuven “Pulmonary infections”14

Flume & Klepser, Pharmacotherapy 2002;22(3 Pt 2):71S–79S.Slide15

High concentration and resistant organismsConcentration effects relationships (P. aeruginosa – ciprofloxacin)Concentration--response curves of selected antibiotics against extracellular and intracellular P. aeruginosa. The graphs show the change in the number of CFU (∆log CFU from the initial inoculum) per mL of broth (extracellular, left) or per mg of cell protein (intracellular, right) in THP-1 cells after 24 h incubation at the increasing extracellular concentrations expressed in mg/L (total drug).

The upper dotted horizontal line corresponds to a bacteriostatic effect (no change from initial inoculum).The lower dotted horizontal line corresponds to the limit of detection27/02/201516th International Symposium of KU Leuven “Pulmonary infections”

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Buyck et al.

ICAAC 2012 and in preapration

Strain

MIC

PaO1 0.125PA256

32Slide16

High concentration and biofilm (S. aureus)27/02/201516th International Symposium of KU Leuven “Pulmonary infections”16Adapted from Bauer et al.

Antimicrob Agents Chemother. 2013;57:2726-37Slide17

High concentration and biofilm (S. pneumoniae)27/02/201516th International Symposium of KU Leuven “Pulmonary infections”17Vandevelde

et al. J Antimicrob Chemother. 2015 Feb 23. pii: dkv032. [Epub ahead of print] Slide18

We may need antibiofilm strategiesLebeaux et al. Microb Mol Biol Rev 2014;78:510–54327/02/2015

16th International Symposium of KU Leuven “Pulmonary infections”18Slide19

Will this prevent emergence of resistance ?27/02/201516th International Symposium of KU Leuven “Pulmonary infections”19Palmer & SmaldoneAm

J Respir Crit Care Med Vol 189, Iss 10, pp 1225–1233, May 15, 2014Slide20

Will this prevent emergence of resistance ?27/02/201516th International Symposium of KU Leuven “Pulmonary infections”20Palmer & SmaldoneAm

J Respir Crit Care Med Vol 189, Iss 10, pp 1225–1233, May 15, 2014Slide21

Will this prevent emergence of resistance ?27/02/201516th International Symposium of KU Leuven “Pulmonary infections”21Palmer & SmaldoneAm

J Respir Crit Care Med Vol 189, Iss 10, pp 1225–1233, May 15, 2014Slide22

Will this prevent emergence of resistance ?27/02/201516th International Symposium of KU Leuven “Pulmonary infections”22Palmer & SmaldoneAm

J Respir Crit Care Med Vol 189, Iss 10, pp 1225–1233, May 15, 2014Slide23

Will this prevent emergence of resistance ?27/02/201516th International Symposium of KU Leuven “Pulmonary infections”23Lu et al. Am J Respir Crit Care Med Vol

184. pp 106–115, 2011Slide24

Will this prevent emergence of resistance ?27/02/201516th International Symposium of KU Leuven “Pulmonary infections”24Lu et al. Am J Respir Crit Care Med Vol

184. pp 106–115, 2011Slide25

Will this prevent emergence of resistance ?27/02/201516th International Symposium of KU Leuven “Pulmonary infections”25Lu et al. Am J Respir Crit Care Med Vol

184. pp 106–115, 2011Slide26

Wher are we now ?27/02/201516th International Symposium of KU Leuven “Pulmonary infections”26Kollef et al. Curr Opin Infect Dis 2013, 26:538–544Slide27

Will this prevent emergence of resistance ?What are the problemsGradient concentrations … where are the bacteria ?where is the antibiotic ?Specific situations in lungsLarge inoculah

eteroresistance / inoculum effectsBiofilm formationsharp decrease in susceptibilityDormant/persistent bacteriaIntracellular sheltering 27/02/201516th International Symposium of KU Leuven “Pulmonary infections”27Slide28

Will this prevent emergence of resistance ?What are the problemsGradient concentrations … where are the bacteria ?where is the antibiotic ?Specific situations in lungsLarge inoculah

eteroresistance / inoculum effectsBiofilm formationsharp decrease in susceptibilityDormant/persistent bacteriaIntracellular sheltering 27/02/201516th International Symposium of KU Leuven “Pulmonary infections”28

Andrade

et

al. Advanced Drug Delivery Reviews 65 (2013) 1816–1827Slide29

Will this prevent emergence of resistance ?What are the problemsGradient concentrations … where are the bacteria ?where is the antibiotic ?Specific situations in lungsLarge inoculah

eteroresistance / inoculum effectsBiofilm formationsharp decrease in susceptibilityDormant/persistent bacteriaIntracellular sheltering 27/02/201516th International Symposium of KU Leuven “Pulmonary infections”29

Andrade et

al. Advanced Drug Delivery Reviews 65 (2013) 1816–1827Slide30

Will this prevent emergence of resistance ?What are the problemsGradient concentrations … where are the bacteria ?where is the antibiotic ?Specific situations in lungsLarge inoculaheteroresistance / inoculum effectsBiofilm formationsharp decrease in susceptibility

Dormant/persistent bacteriaIntracellular sheltering 27/02/201516th International Symposium of KU Leuven “Pulmonary infections”30Slide31

We may need antipersisters strategiesLebeaux et al. Microb Mol Biol Rev 2014;78:510–54327/02/2015

16th International Symposium of KU Leuven “Pulmonary infections”31Slide32

And some antibiotics may trigger a persistence phenotypeLebeaux et al. Microb Mol Biol Rev 2014;78:510–54327/02/2015

16th International Symposium of KU Leuven “Pulmonary infections”32Slide33

And here is the team …27/02/201516th International Symposium of KU Leuven “Pulmonary infections”33

The boss !

The biofilm

Experts !

The

persisters

guy !

The inhalation

guy !

The cystic fibrosis fellow

The intracellular

i

nfection

experts

See them all on

http://www.facm.ucl.ac.beSlide34

Thank you for your attention!27/02/201516th International Symposium of KU Leuven “Pulmonary infections”34

And ask questions