“Pulmonary infections”

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Volume 151, Issue 4, Pages (April 2017)

Presentation transcript:

“Pulmonary infections” Inhaled antimicrobial therapy: pharmacodynamics and risks for development of resistance Paul M. Tulkens, MD, PhD Cellular and Molecular Pharmacology Louvain Drug Research Institute Université catholique de Louvain Brussels, Belgium 16th International Symposium of KU Leuven - February 26-28, 2015 Leuven “Pulmonary infections” 27/02/2015 16th International Symposium of KU 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  Lectures 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

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 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 1. Smith MP. J R Coll Physicians Edinb 2011;41:132 Deliver the drug where its is needed Figure adapted by kind permission of Dr Diane Bilton, Royal Brompton Hospital, London 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

Trying to reach deep in lung … An example with amikacin 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) Scintigraphy scans after administration of a single dose of 400 mg 99mTechnetium labelled Amikacin Inhale in one representative subject Corkery K et al. ATS 2008 Poster 517 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

Can you achieve high local concentrations ? This is what is predicted 20 40 60 80 100 4 8 12 16 24 amikacin concentration, mg/L or µg/g Time relative to administration, h 120 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*) 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 1. Corkery K et al. ATS 2008. Poster 517; 2. Eldon M et al. ISICEM 2008. Poster A135 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

16th International Symposium of KU Leuven “Pulmonary infections” Where do we go to now ? 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

16th International Symposium of KU Leuven “Pulmonary infections” Where do we go to now ? 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

16th International Symposium of KU Leuven “Pulmonary infections” MICs can be very high… Dalhoff, Clin Microb Rev 2014; 27:753-782 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

Data from an European (FR, UK, BE; DE) collection MICs can be very high… Data from an European (FR, UK, BE; DE) collection Dalhoff, Clin Microb Rev 2014; 27:753-782 Drug MIC50 MIC90 % S % R CIP 1 8 49 51 MEM 2 16 48 52 AMK 32 128 46 54 TZP 64 512 31 69 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

But here are published concentrations… 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

Large variations sputum and little in lung/ELF… 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

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.. Buyck et al. Antimicrob Agents Chemother. 2013;572310-8. 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

Would a high concentration help ? Concentration effects relationships (pharmacology) Flume & Klepser, Pharmacotherapy 2002;22(3 Pt 2):71S–79S. 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

Would a high concentration help ? Concentration effects relationships (pharmacology) Flume & Klepser, Pharmacotherapy 2002;22(3 Pt 2):71S–79S. 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

High concentration and resistant organisms Concentration effects relationships (P. aeruginosa – ciprofloxacin) Strain MIC PaO1 0.125 PA256 32 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 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

High concentration and biofilm (S. aureus) Adapted from Bauer et al. Antimicrob Agents Chemother. 2013;57:2726-37 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

High concentration and biofilm (S. pneumoniae) Vandevelde et al. J Antimicrob Chemother. 2015 Feb 23. pii: dkv032. [Epub ahead of print] 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

We may need antibiofilm strategies Lebeaux et al. Microb Mol Biol Rev 2014;78:510–543 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

Will this prevent emergence of resistance ? Palmer & SmaldoneAm J Respir Crit Care Med Vol 189, Iss 10, pp 1225–1233, May 15, 2014 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

Will this prevent emergence of resistance ? Palmer & SmaldoneAm J Respir Crit Care Med Vol 189, Iss 10, pp 1225–1233, May 15, 2014 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

Will this prevent emergence of resistance ? Palmer & SmaldoneAm J Respir Crit Care Med Vol 189, Iss 10, pp 1225–1233, May 15, 2014 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

Will this prevent emergence of resistance ? Palmer & SmaldoneAm J Respir Crit Care Med Vol 189, Iss 10, pp 1225–1233, May 15, 2014 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

Will this prevent emergence of resistance ? Lu et al. Am J Respir Crit Care Med Vol 184. pp 106–115, 2011 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

Will this prevent emergence of resistance ? Lu et al. Am J Respir Crit Care Med Vol 184. pp 106–115, 2011 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

Will this prevent emergence of resistance ? Lu et al. Am J Respir Crit Care Med Vol 184. pp 106–115, 2011 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

16th International Symposium of KU Leuven “Pulmonary infections” Wher are we now ? Kollef et al. Curr Opin Infect Dis 2013, 26:538–544 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

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

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

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

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

We may need antipersisters strategies Lebeaux et al. Microb Mol Biol Rev 2014;78:510–543 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

And some antibiotics may trigger a persistence phenotype Lebeaux et al. Microb Mol Biol Rev 2014;78:510–543 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

16th International Symposium of KU Leuven “Pulmonary infections” And here is the team … The boss ! The biofilm Experts ! The persisters guy ! The inhalation The cystic fibrosis fellow The intracellular infection experts See them all on http://www.facm.ucl.ac.be 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”

Thank you for your attention! And ask questions 27/02/2015 16th International Symposium of KU Leuven “Pulmonary infections”