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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 ?
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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 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
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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
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
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Where do we go to now ?
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Where do we go to now ?
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MICs can be very high…
Dalhoff, Clin Microb Rev 2014; 27:753-782
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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
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But here are published concentrations…
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Large variations sputum and little in lung/ELF…
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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..
-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
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Buyck et al. Antimicrob Agents Chemother. 2013;572310-8.
Would a high concentration help ?Concentration effects relationships (pharmacology)
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Flume & Klepser, Pharmacotherapy 2002;22(3 Pt 2):71S–79S.
Would a high concentration help ?Concentration effects relationships (pharmacology)
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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
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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)
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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)
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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
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Will this prevent emergence of resistance ?
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Palmer & SmaldoneAm J Respir Crit Care Med Vol 189, Iss 10, pp 1225–1233, May 15, 2014
Will this prevent emergence of resistance ?
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Palmer & SmaldoneAm J Respir Crit Care Med Vol 189, Iss 10, pp 1225–1233, May 15, 2014
Will this prevent emergence of resistance ?
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Palmer & SmaldoneAm J Respir Crit Care Med Vol 189, Iss 10, pp 1225–1233, May 15, 2014
Will this prevent emergence of resistance ?
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Palmer & SmaldoneAm J Respir Crit Care Med Vol 189, Iss 10, pp 1225–1233, May 15, 2014
Will this prevent emergence of resistance ?
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Lu et al. Am J Respir Crit Care Med Vol 184. pp 106–115, 2011
Will this prevent emergence of resistance ?
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Lu et al. Am J Respir Crit Care Med Vol 184. pp 106–115, 2011
Will this prevent emergence of resistance ?
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Lu et al. Am J Respir Crit Care Med Vol 184. pp 106–115, 2011
Wher are we now ?
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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
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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
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Andrade et al. Advanced Drug Delivery Reviews 65 (2013) 1816–1827
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
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Andrade et al. Advanced Drug Delivery Reviews 65 (2013) 1816–1827
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
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We may need antipersisters strategies
Lebeaux et al. Microb Mol Biol Rev 2014;78:510–543
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And some antibiotics may trigger a persistence phenotype
Lebeaux et al. Microb Mol Biol Rev 2014;78:510–543
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And here is the team …
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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
Thank you for your attention!
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