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NEW ANTIBACTERIAL DRUGS Drug Pipeline for Gram-Positive Bacteria

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NEW ANTIBACTERIAL DRUGS Drug Pipeline for Gram-Positive Bacteria NEW ANTIBACTERIAL DRUGS Drug pipeline for Gram-positive bacteria Françoise Van Bambeke, PharmD, PhD Paul M. Tulkens, MD, PhD Pharmacologie cellulaire et moléculaire Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium http://www.facm.ucl.ac.be Based largely on presentations given at the 24th and 25th European Congress of Clinical Microbiology and Infectious Diseases and the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 1 Disclosures Research grants for work on investigational compounds discussed in this presentation from • Cempra Pharmaceuticals • Cerexa • GSK • Melinta therapeutics • The Medicine Company • MerLion Pharmaceuticals • Theravance • Trius 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 2 Belgium 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 3 Belgium 10 millions inhabitants … 10 Nobel prizes (10/850) • Peace - Institute of International Law, Ghent (1904) - Auguste Beernaert (1909) - Henri Lafontaine (1913) - Father Dominique Pire (1958) • Literature - Maurice Maeterlinck, Ghent (1911) • Medicine - Jules Bordet, Brussels (1919) - Corneille Heymans, Ghent (1938) - Christian de Duve, Louvain (1974) - Albert Claude, Brussels (1974) • Chemistry - Ilya Prigogyne, Brussels (1977) - Physics - François Englert, Brussels (2013) 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 4 The Catholic University of Louvain in brief (1 of 4) • originally founded in 1425 in the city of Louvain (in French and English; known as Leuven in Flemish) 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 5 The Catholic University of Louvain in brief (2 of 4) • It was one of the major University of the so-called "Low Countries" in the 1500 – 1800 period, with famous scholars and discoverers (Vesalius for anatomy, Erasmus for philosophy, …). Teaching was in Latin, Greek, and Hebrew (College of the 3 languages…) The University in the 1500's Erasmus Vesalius 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 6 The Catholic University of Louvain in brief (3 of 4) • In the 19th century, teaching was in French but in the early 1900's, a Flemish- speaking section was opened. Courses were given in both languages, attracting many students and celebrities… Professor C. de Duve, Professor of Biochemistry, obtained the Nobel Prize (Physiology and Medicine) in 1974 for his work on Prof. G. Lemaitre, professor of Physics intracellular organelles and Mathematics at the University who, (lysosomes, peroxisomes…) in the 1930's, made the first suggestion of the continuous expansion of the (here in front of a centrifuge) Universe (“big bang”) (here in conversation with A. Einstein) • in 1968, the University was divided into – a French-speaking Université catholique de Louvain – a Flemish-speaking Katholieke Universiteit Leuven… 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 7 The Catholic University of Louvain in brief (4 of 4) • The Flemish-speaking Katholieke Universiteit Leuven has remained in Louvain (Leuven) and is named in English "Catholic Universiteit Leuven". • The French-speaking Université catholique de Louvain has moved about 25 km South in a place called "Louvain-la-Neuve, with the "Health Sciences Sector" located in Brussels (Woluwé) Université catholique Katholieke de Louvain Universiteit Leuven http://www.uclouvain.be 10 km http://www.kuleuven.be • Together, the two Universities have about 55,000 students 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 8 What do we do ? • Teaching of Pharmacology and • Toxicity, medicinal chemistry, and Pharmacotherapy improved schedules of aminoglycosides • Post-graduate training on Drug Development • novel antibiotics • Launching of Clinical Pharmacy in Europe • beta-lactams (ceftaroline…) • Web-based courses on anti-infective • fluoroquinolones (finafloxacine…) Pharmacology • kétolides (solithromycin…) • 30 graduating students, doctoral fellows and • oxazolidinones (tedizolid …) post-graduate fellows working on anti- infective therapy (laboratory and clinical applications) www.facm.ucl.ac.be • Editorial board of AAC and IJAA • Member of the General Committee of EUCAST (for ISC) and of its Steering committee (2008-10) • Member of the Belgian Antibiotic Policy Coordination Committee • Founder and Past President of the International Society of Antiinfective Pharmacology (ISAP) A partial view of our University Clinic (900 beds) and the Education and Research buildings (5,000 students), in the outskirts of Brussels, Belgium www.isap.org 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 9 New antibiotics: what is your own view of the pipeline ? 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 10 New antibiotics: where are we ? Approvals by FDA/EMA – systemic antibiotics telavancin ceftaroline 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 11 New antibiotics: where are we ? Approvals by FDA/EMA – systemic antibiotics Shall we succeed ? dalbavancin oritavancin tedizolid ceftazidime/avibactam ceftolozane/tazobactam telavancin ceftaroline 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 12 Anti Gram-positive recently approved drugs company drug class indications MRSA MDRSP VRE lipoglyco- cSSSI / VanB Theravance Telavancin peptide HABP/VABP only lipoglyco- VanB Durata Ther. Dalbavancin ABSSSI peptide only lipoglyco- The MedCo Oritavancin ABSSSI peptide MSD Tedizolid oxazolidinone ABSSSI Forrest Ceftaroline β-lactam ABSSSI / CABP Astra-Zeneca Basilea Ceftobiprole* β-lactam CAP / HAP * licensed in 13 countries: AT, BE, CH, DE, DK, ES, FI, FR, IT, LU, NO, SE, UK; reimbursement and pricing authorization ongoing in most of them 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 13 Lipoglycopeptides prolonged half-life dimerization • prolonged half-life • membrane anchoring Van Bambeke, decreased Cur. Op. Pharmacol. half-life 2004, 4:471–478 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 14 Lipoglycopeptides: dual mode of action Cl D-Ala oritavancin (lipoglycopeptide) Lipid II D-Ala L-Lys D-Glu HO HO L-Ala O OH O O HN CH3 N-acetylmuramic acid - H2N O Cl HO OH N-acetylglucosamine H3C O O H3C O Pyrophosphate CH3 O OH Lipid carrier Cl O O O H H N N N N NH H H HN O O NHCH3 CONH2O HOOC OH HO OH transpeptidase • highly bactericidal transglycosylaseX • activity on VR strains Van Bambeke et al, TIPS 2008, 29:124-134 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 15 Lipoglycopeptides: pharmacokinetics parameter VAN ORI TLV TEC DAL Dosage 15 mg/kg 1200 mg 10 mg/kg 6 mg/kg 1000 mg Cmax 20-50 138 93 43 287 (mg/L) AUC 1110 (24h) 3185 (24h) 260 668 600 (mg.h/L) 2800 (tot) 23443 (tot) (%) prot. 55 85 95 88-94 99 binding 1 (β) 14 (β) 10 (β) T ½ (h) 8 346 (γ) 3-9 (γ) 245 (γ) 168 (γ) single dose once-a-week dose treatment treatment (2 doses) Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 16 Oritavancin: a unusual development … N Engl J Med 2014;370:2180-90. Participants underwent randomization in a 1:1 ratio to receive either • a single intravenous dose of 1200 mg of oritavancin followed by intravenously administered placebo, or • an intravenous dose of vancomycin (1 g, or 15 mg per kilogram of body weight) every 12 hours for 7 to 10 days 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 17 Oritavancin: a unusual development … N Engl J Med 2014;370:2180-90. 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 18 Oritavancin: a unusual development … N Engl J Med 2014;370:2180-90. 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 19 Oritavancin: a unusual development … N Engl J Med 2014;370:2180-90. 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 20 oritavancin vancomycin Oritavancin: a unusual development … N Engl J Med 2014;370:2180-90. 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 21 Tedizolid 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 22 Dong-A pharmaceuticals and tedizolid: step #1 Replacing the morpholinyl by a pyridinyl and adding a methyl-tetrazolyl moiety • increases activity • prolong half-life 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 23 Tedizolid has more interactions with the ribosome… tedizolid 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 24 Tedizolid is systematically 3-4-x more active than linezolid against LSDS strains O O O N N H N O F O N O N N OH N N N F potential role of the tetrazolyl moiety Lemaire et al. JAC 2009; 64:1035–1043 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 25 And even for S. aureus of different epidemiological origin… 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 26 Dong-A pharmaceuticals and tedizolid: step #2 O N O N N OH N N N F 2. replacing the acetamido by an hydroxyl maintains the increased activity vs. linezolid ! 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 27 Tedizolid and linezolid resistance 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 28 Oxazolidinones: 1st mechanism of resistance full to 16 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 29 Activity against Cfr+ resistant strains … (cfr+ bacteria) Locke et al. AAC 2010;54:5337-5343 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 30 Why is tedizolid active against LZDR strains (cfr) ? O O O N N H N O F LZD O N O N N OH N N N F TR700 Locke et al.
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