inhaled antimicrobial therapy: pharmacodynamics and risks for … › conferences › 2015 ›...

Inhaled antimicrobial therapy: pharmacodynamics and risks for

development of resistance

Paul M. Tulkens, MD, PhD

Cellular and Molecular PharmacologyLouvain Drug Research InstituteUniversité catholique de Louvain

Brussels, Belgium

27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections” 1

16th International Symposium of KU Leuven - February 26-28, 2015

Leuven“Pulmonary infections”

Disclosures and slides availability

• Research 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 Lectures27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections” 2

Why Inhalation ?


• Novel strategies are required to ‘break’ the vicious cycle created in local pulmonary infections where exacerbations and recurrences are common and cause disease progression1

Geneticpredisposition

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 needed

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 99mTechnetium labelled Amikacin Inhale in one representative subject

An example

with amikacin


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

amik

acin

conc

entr

atio

n, m

g/L

or µ

g/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


Where do we go to now ?


MICs can be very high…

Dalhoff, Clin Microb Rev 2014; 27:753-782


MICs can be very high…

Dalhoff, Clin Microb Rev 2014; 27:753-782

0.125 0.25 0.5 1 2 4 8 16 32 64 128

256

512

1024

2048

0

25

50

75

100

TZP

> 51

2

P. aeruginosa (n = 342)

MIC90

MIC50

MEM

S bkpt TZP & AMK

AMKCIP

S bkpt MEMS bkpt MEM

MICs(mg/L)

% o

f iso

late

s (c

umul

ativ

e)

Drug MIC50 MIC90 % S % RCIP 1 8 49 51MEM 2 16 48 52AMK 32 128 46 54TZP 64 512 31 69

Data from an European (FR, UK, BE; DE)

collection


But here are published concentrations…


Large variations sputum and little in lung/ELF…


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..

-5

-4

-3

-2

-1

0

1

2

3

4

5

brothTHP-1 cells

gentamicin

brothTHP-1 cells

meropenem

-5

-4

-3

-2

-1

0

1

2

3

4

5

-3 -2 -1 0 1 2 3-5

-4

-3

-2

-1

0

1

2

3

4

5

brothTHP-1 cells

ciprofloxacin

-3 -2 -1 0 1 2 3

brothTHP-1 cells

colistin

-5

-4

-3

-2

-1

0

1

2

3

4

5

log extracellular concentration (mg/L)

∆ lo

g C

FU fr

om in

itial

inoc

ulum


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

Would a high concentration help ?Concentration effects relationships (pharmacology)


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

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 detection


Buyck et al. ICAAC 2012 and in preapration

-3 -2 -1 0 1 2 3

-5

-4

-3

-2

-1

0

1

2

3

4

PA256 CIPATCC-PAO1-CIP

extracellular

log10 concentration (mg/L)

∆ lo

g cf

u fr

om ti

me

0 (2

4 h)

-3 -2 -1 0 1 2 3

-5

-4

-3

-2

-1

0

1

2

3

4intracellular

log10 concentration (mg/L)

∆ log cfu from tim

e 0 (24 h)

Strain MIC

PaO1 0.125

PA256 32

High concentration and biofilm (S. aureus)


Adapted from Bauer et al. Antimicrob Agents Chemother. 2013;57:2726-37

m o xiflo xa c in 6 h b io film

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

-0 .5 0 .0 0 .5 1 .0 1 .5 2 .0

v ia b ility

b io m a s s

log 10 c o n c e n tra tio n (X M IC )

% c

on

tro

l v

alu

e

C T

m o x iflo x a c in (2 4 h b io film s)

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

-0 .5 0 .0 0 .5 1 .0 1 .5 2 .0

v ia b ility

b io m a s s

log 10 c o n c e n tra tio n (X M IC )

% c

on

tro

l v

alu

eC T

High concentration and biofilm (S. pneumoniae)


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

-5 -4 -3 -2 -1 0 1 2 3 40

2 0

4 0

6 0

8 0

1 0 0

1 2 0

-5 -4 -3 -2 -1 0 1 2 3 40

2 0

4 0

6 0

8 0

1 0 0

1 2 0

A T C C

R 6

2 -d a y s n a iv e

N 6

-5 -4 -3 -2 -1 0 1 2 3 40

2 0

4 0

6 0

8 0

1 0 0

1 2 0

-5 -4 -3 -2 -1 0 1 2 3 40

2 0

4 0

6 0

8 0

1 0 0

1 2 0

A T C C

R 6

N 6

1 1 -d a y s in d u c e d

m o x iflo xa c in

via

bil

ity

(re

so

rufi

n f

luo

res

ce

nc

e)

% o

f c

on

tro

l

lo g 1 0 M IC in b ro th (m g /L )

bio

ma

ss

(cry

sta

l vio

let O

D5

70

nm

)

% o

f co

ntro

l

We may need antibiofilm strategies

Lebeaux et al. Microb Mol Biol Rev 2014;78:510–543


Will this prevent emergence of resistance ?


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



Lu et al. Am J Respir Crit Care Med Vol 184. pp 106–115, 2011

Wher are we now ?


Kollef et al. Curr Opin Infect Dis 2013, 26:538–544

Will this prevent emergence of resistance ?What are the problems

• Gradient concentrations … – where are the bacteria ?– where is the antibiotic ?

• Specific situations in lungs– Large inocula

• heteroresistance / inoculum effects

– Biofilm formation• sharp decrease in susceptibility• Dormant/persistent bacteria

– Intracellular sheltering









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





– Biofilm formation• sharp decrease in susceptibility

• Dormant/persistent bacteria– Intracellular sheltering


We may need antipersisters strategies



And some antibiotics may trigger a persistence phenotype



And here is the team …


The boss !

The biofilm Experts !

The persistersguy !

The inhalationguy !

The cystic fibrosis fellow

The intracellularinfection experts

See them all on http://www.facm.ucl.ac.be

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

Thank you for your attention!


inhaled antimicrobial therapy: pharmacodynamics and risks for … › conferences › 2015 ›...

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