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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, …). -
Unsafe €Œcrossover-Use― of Chloramphenicol in Uganda
The Journal of Antibiotics (2021) 74:417–420 https://doi.org/10.1038/s41429-021-00416-3 BRIEF COMMUNICATION Unsafe “crossover-use” of chloramphenicol in Uganda: importance of a One Health approach in antimicrobial resistance policy and regulatory action 1,2 1,2 3 1 1 Kayley D. McCubbin ● John W. Ramatowski ● Esther Buregyeya ● Eleanor Hutchinson ● Harparkash Kaur ● 3 2 1 Anthony K. Mbonye ● Ana L. P. Mateus ● Sian E. Clarke Received: 22 December 2020 / Revised: 2 February 2021 / Accepted: 16 February 2021 / Published online: 19 March 2021 © The Author(s) 2021. This article is published with open access Abstract Since the introduction of antibiotics into mainstream health care, resistance to these drugs has become a widespread issue that continues to increase worldwide. Policy decisions to mitigate the development of antimicrobial resistance are hampered by the current lack of surveillance data on antibiotic product availability and use in low-income countries. This study collected data on the antibiotics stocked in human (42) and veterinary (21) drug shops in five sub-counties in Luwero district of Uganda. Focus group discussions with drug shop vendors were also employed to explore antibiotic use practices in the 1234567890();,: 1234567890();,: community. Focus group participants reported that farmers used human-intended antibiotics for their livestock, and community members obtain animal-intended antibiotics for their own personal human use. Specifically, chloramphenicol products licensed for human use were being administered to Ugandan poultry. Human consumption of chloramphenicol residues through local animal products represents a serious public health concern. By limiting the health sector scope of antimicrobial resistance research to either human or animal antibiotic use, results can falsely inform policy and intervention strategies. -
Danmap 2006.Pmd
DANMAP 2006 DANMAP 2006 DANMAP 2006 - Use of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, foods and humans in Denmark Statens Serum Institut Danish Veterinary and Food Administration Danish Medicines Agency National Veterinary Institute, Technical University of Denmark National Food Institute, Technical University of Denmark Editors: Hanne-Dorthe Emborg Danish Zoonosis Centre National Food Institute, Technical University of Denmark Mørkhøj Bygade 19 Contents DK - 2860 Søborg Anette M. Hammerum National Center for Antimicrobials and Contributors to the 2006 Infection Control DANMAP Report 4 Statens Serum Institut Artillerivej 5 DK - 2300 Copenhagen Introduction 6 DANMAP board: National Food Institute, Acknowledgements 6 Technical University of Denmark: Ole E. Heuer Frank Aarestrup List of abbreviations 7 National Veterinary Institute, Tecnical University of Denmark: Sammendrag 9 Flemming Bager Danish Veterinary and Food Administration: Summary 12 Justin C. Ajufo Annette Cleveland Nielsen Statens Serum Institut: Demographic data 15 Dominique L. Monnet Niels Frimodt-Møller Anette M. Hammerum Antimicrobial consumption 17 Danish Medicines Agency: Consumption in animals 17 Jan Poulsen Consumption in humans 24 Layout: Susanne Carlsson Danish Zoonosis Centre Resistance in zoonotic bacteria 33 Printing: Schultz Grafisk A/S DANMAP 2006 - September 2007 Salmonella 33 ISSN 1600-2032 Campylobacter 43 Text and tables may be cited and reprinted only with reference to this report. Resistance in indicator bacteria 47 Reprints can be ordered from: Enterococci 47 National Food Institute Escherichia coli 58 Danish Zoonosis Centre Tecnical University of Denmark Mørkhøj Bygade 19 DK - 2860 Søborg Resistance in bacteria from Phone: +45 7234 - 7084 diagnostic submissions 65 Fax: +45 7234 - 7028 E. -
Inhibition of Peptide Bond Formation by Pleuromutilins: the Structure of the 50S Ribosomal Subunit from Deinococcus Radiodurans in Complex with Tiamulin
Blackwell Science, LtdOxford, UKMMIMolecular Microbiology0950-382XBlackwell Publishing Ltd, 2004? 200454512871294Original ArticleStructure of 50S ribosomal subunit in complex with TiamulinF. Schlünzen et al. Molecular Microbiology (2004) 54(5), 1287–1294 doi:10.1111/j.1365-2958.2004.04346.x Inhibition of peptide bond formation by pleuromutilins: the structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin Frank Schlünzen,1 Erez Pyetan,2,3 Paola Fucini,1 clic nucleus composed of a cyclo-pentanone, cyclo-hexyl Ada Yonath2,3 and Jörg M. Harms2* and cyclo-octane, and a (((2-(diethylamino)ethyl)thio)- 1Max-Planck Institute for Molecular Genetics, D-14195 acetic acid) side-chain on C14 of the octane ring (Fig. 1A). Berlin, Germany. The drug is soluble in water and readily absorbed; it is 2Max-Planck-Research-Unit for Ribosome Structure, D- therefore one of the few antibiotics that can be easily 22607 Hamburg, Germany. administered to animals. So far, pleuromutilin derivatives 3Weizmann Institute of Science, IL-76100 Rehovot, Israel. are only employed in veterinary practice and most fre- quently to treat swine dysentery. However, the increasing number of pathogens resistant to common antibiotics has Summary raised a new interest in pleuromutilin derivatives, which Tiamulin, a prominent member of the pleuromutilin may be suitable for human therapy (Brooks et al., 2001; class of antibiotics, is a potent inhibitor of protein Bacque et al., 2002; 2003; Pearson et al., 2002; Springer synthesis in bacteria. Up to now the effect of pleuro- et al., 2003). mutilins on the ribosome has not been determined Early biochemical and genetic studies of the antimicro- on a molecular level. -
Antibiotics Currently in Clinical Development
A data table from Sept 2014 Antibiotics Currently in Clinical Development As of September 2014, an estimated 38 new antibiotics1 with the potential to treat serious bacterial infections are in clinical development for the U.S. market. The success rate for drug development is low; at best, only 1 in 5 candidates that enter human testing will be approved for patients.* This snapshot of the antibiotic pipeline will be updated periodically as products advance or are known to drop out of development. Please contact Rachel Zetts at [email protected] or 202-540-6557 with additions or updates. Cited for potential Development Known QIDP4 Drug name Company Drug class activity against gram- Potential indication(s)?5 phase2 designation? negative pathogens?3 Approved (for acute Acute bacterial skin and skin structure bacterial skin and skin infections, hospital-acquired bacterial Tedizolid Cubist Pharmaceuticals Oxazolidinone Yes structure infections), pneumonia/ventilator-acquired bacterial June 20, 2014 pneumonia Approved, May 23, Acute bacterial skin and skin structure Dalbavancin Durata Therapeutics Lipoglycopeptide Yes 2014 infections Approved, August 6, Acute bacterial skin and skin structure Oritavancin The Medicines Company Glycopeptide Yes 2014 infections New Drug Application (NDA) submitted (for Complicated urinary tract infections, complicated urinary complicated intra-abdominal infections, Novel cephalosporin+beta- Ceftolozane+tazobactam8 tract infection and Cubist Pharmaceuticals Yes Yes acute pyelonephritis (kidney infection), lactamase -
ARCH-Vet Anresis.Ch
Usage of Antibiotics and Occurrence of Antibiotic Resistance in Bacteria from Humans and Animals in Switzerland Joint report 2013 ARCH-Vet anresis.ch Publishing details © Federal Office of Public Health FOPH Published by: Federal Office of Public Health FOPH Publication date: November 2015 Editors: Federal Office of Public Health FOPH, Division Communicable Diseases. Elisabetta Peduzzi, Judith Klomp, Virginie Masserey Design and layout: diff. Marke & Kommunikation GmbH, Bern FOPH publication number: 2015-OEG-17 Source: SFBL, Distribution of Publications, CH-3003 Bern www.bundespublikationen.admin.ch Order number: 316.402.eng Internet: www.bag.admin.ch/star www.blv.admin.ch/gesundheit_tiere/04661/04666 Table of contents 1 Foreword 4 Vorwort 5 Avant-propos 6 Prefazione 7 2 Summary 10 Zusammenfassung 12 Synthèse 14 Sintesi 17 3 Introduction 20 3.1 Antibiotic resistance 20 3.2 About anresis.ch 20 3.3 About ARCH-Vet 21 3.4 Guidance for readers 21 4 Abbreviations 24 5 Antibacterial consumption in human medicine 26 5.1 Hospital care 26 5.2 Outpatient care 31 5.3 Discussion 32 6 Antibacterial sales in veterinary medicines 36 6.1 Total antibacterial sales for use in animals 36 6.2 Antibacterial sales – pets 37 6.3 Antibacterial sales – food producing animals 38 6.4 Discussion 40 7 Resistance in bacteria from human clinical isolates 42 7.1 Escherichia coli 42 7.2 Klebsiella pneumoniae 44 7.3 Pseudomonas aeruginosa 48 7.4 Acinetobacter spp. 49 7.5 Streptococcus pneumoniae 52 7.6 Enterococci 54 7.7 Staphylococcus aureus 55 Table of contents 1 8 Resistance in zoonotic bacteria 58 8.1 Salmonella spp. -
Pulmonary Disposition and Pharmacokinetics of Minocycline in the Adult Horse
PULMONARY DISPOSITION AND PHARMACOKINETICS OF MINOCYCLINE IN THE ADULT HORSE BY KATE ECHEVERRIA THESIS Submitted in partial fulfillment of the requirements for the degree of Master of Science in VMS - Veterinary Clinical Medicine in the Graduate College of the University of Illinois at Urbana-Champaign, 2017 Urbana, Illinois Master’s Committee: Assistant Professor Kara Lascola, Chair Professor Jonathan Foreman Clinical Assistant Professor Scott Austin ABSTRACT The purpose of this study was to determine the pharmacokinetics and pulmonary disposition of minocycline in horses after a single intravenous (IV) and intragastric (IG) dose and after multiple IG doses. The study hypotheses were that: minocycline would be present in the pulmonary epithelial lining fluid (PELF) and bronchoalveolar lavage (BAL) cells at concentrations exceeding those in plasma within 3 hours of IV or IG administration and achievable trough concentrations in the PELF and BAL cells after administration of IG minocycline would exceed a target concentration of 0.25 µg/mL. Seven healthy adult horses from the resident teaching herd were used for the two part study. For part one of the study, 6 horses received IV (2.2 mg/kg) or IG (4 mg/kg) minocycline in a randomized cross-over design. Plasma samples were collected prior to minocycline administration and 16 times within 36 hours. Bronchoalveolar lavages were performed 4 times within 24 hours for collection of PELF and BAL cells. For part two of the study, minocycline (4 mg/kg) was administered IG every 12 hours for 5 doses to 6 horses. Plasma samples were collected before minocycline administration and 20 times within 96 hours. -
Antibiotics Currently in Clinical Development
A data table from Feb 2014 Antibiotics Currently in Clinical Development As of February 2014, there are at least 45 new antibiotics1 with the potential to treat serious bacterial infections in clinical development for the U.S. market. The success rate for drug development is low; at best, only 1 in 5 candidates that enter human testing will be approved for patients.* This snapshot of the antibiotic pipeline will be updated periodically as products advance or are known to drop out of development. Please contact Rachel Zetts at [email protected] or 202-540-6557 with additions or updates. Cited for Potential Development Known QIDP4 Drug Name Company Drug Class Activity Against Gram- Potential Indication(s)5 Phase2 Designation? Negative Pathogens?3 New Drug Application Acute bacterial skin and skin structure Oritavancin The Medicines Company Glycopeptide Yes (NDA) submitted infections New Drug Application Acute bacterial skin and skin structure Dalbavancin Durata Therapeutics Lipoglycopeptide Yes (NDA) submitted infections NDA submitted (for Acute bacterial skin and skin structure acute bacterial skin infections, hospital acquired bacterial Tedizolid Cubist Pharmaceuticals Oxazolidinone Yes and skin structure pneumonia/ventilator acquired bacterial infection indication) pneumonia ACHN-975 Phase 1 Achaogen LpxC inhibitor Yes Bacterial infections Acute bacterial skin and skin structure infections6, methicillin-resistant Fabl inhibitor (AFN-1252 AFN-1720 Phase 1 Affinium Pharmaceuticals Staphylococcus aureus (MRSA) pulmonary pro-drug) infections -
In Vitro Antibacterial Spectrum of BC-7013, a Novel Pleuromutilin Derivative for Topical Use in Humans Nabriva Therapeutics AG Leberstrasse 20 ICAAC 2009 D.J
F1-1521 In Vitro Antibacterial Spectrum of BC-7013, a Novel Pleuromutilin Derivative for Topical Use in Humans Nabriva Therapeutics AG Leberstrasse 20 ICAAC 2009 D.J. BIEDENBACH1, R.N. JONES1, Z. IVEZIC-SCHOENFELD2, S. PAUKNER2, R. NOVAK2 1112 Vienna, Austria Tel.: +43 (0)1 74093 0 1 JMI Laboratories, North Liberty, Iowa, USA Fax.: +43 (0)1 74093 1900 2 Nabriva Therapeutics AG, Vienna, Austria www.nabriva.com Table 1. Antibacterial spectrum of BC-7013 and topical comparator antibiotics tested against Gram-positive bacteria Abstract Methods % susceptible/ % susceptible/ Conclusions Antimicrobial agent MIC MIC Range Antimicrobial agent MIC MIC Range 50 90 resistant a 50 90 resistant a Background: BC-7013 [14-O-[(3-Hydroxymethyl-phenylsulfanyl)-acetyl]-mutilin] is a novel Organism Collection: The activity of BC-7013 was determined against bacterial pathogens • BC-7013 was the most active compound against common Gram- semi-synthetic pleuromutilin derivative that inhibits prokaryotic protein synthesis. BC-7013 is in causing uSSSI. Organisms included strains isolated from patients in either the United States S. aureus (303) CoNS (105) early stage of clinical development for the topical treatment of uncomplicated skin and skin (USA, 52.3%) or European (47.6%) medical centers (n=67) primarily during 2006 to 2007. Less BC-7013 0.015 0.03 0.008 – 0.03 - / - BC-7013 0.03 0.06 0.008 – >8 - / - positive bacterial pathogens such as S. aureus, S. pyogenes and S. structure infections (uSSSI). We assessed BC-7013 activity against a wide range of clinical commonly isolated species and those organisms w ith characterized resistance mechanism were Retapamulin 0.12 0.12 0.03 – 0.12 - / - Retapamulin 0.06 0.5 0.015 – >8 - / - agalactiae when compared with other topical antibiotics. -
Lefamulin the Potential for 1 Antibiotic Rather Than 2 in CABP March 13, 2018
Lefamulin The potential for 1 antibiotic rather than 2 in CABP March 13, 2018 Prof. Mark H. Wilcox Professor of Medical Microbiology Leeds Teaching Hospitals & University of Leeds Confidential Disclosures Mark H. Wilcox has received Consulting fees from Abbott Laboratories, Actelion, Antabio, AiCuris, Astellas, Astra-Zeneca, Bayer, Biomèrieux, Cambimune, Cerexa, Da Volterra, The European Tissue Symposium, Ferring, The Medicines Company, MedImmune, Menarini, Merck, Meridian, Motif Biosciences, Nabriva, Paratek, Pfizer, Qiagen, Roche, Surface Skins, Sanofi-Pasteur, Seres, Summit, Synthetic Biologics, and Valneva Lecture fees from Abbott, Alere, Allergan, Astellas, Astra-Zeneca, Merck, Pfizer, Roche, and Seres Grant support from Abbott, Actelion, Astellas, Biomèrieux, Cubist, Da Volterra, Merck, MicroPharm, Morphochem AG, Sanofi-Pasteur, Seres, Spero, Summit, and The European Tissue Symposium Confidential Pleuromutilin Antibacterial Agents • Pleuromutilin antibiotics inhibit translation and are O OH R O 14 semisynthetic derivatives of the naturally occurring tricyclic H diterpenoid pleuromutilin isolated from an edible mushroom – Veterinary use: tiamulin and valnemulin (oral treatment of dysentery O Pleuromutilin R = OH and respiratory infections in swine and poultry) Pleurotus mutilus (Clitopilus – Human use: retapamulin (topical treatment of uSSSTI caused by scyphoides) MSSA or Streptococcus spp) Source: James Lindsey's Ecology of Commanster Site, 2006 • Lefamulin was discovered by Nabriva and is the first systemic CH2 pleuromutilin for -
Gram Positive Cocci (GPC) Gram Neg (Rods = GNR) Anaerobes
Gram Positive Cocci (GPC) Gram Neg (rods = GNR) Anaerobes Atypicals Classification Antibiotic Cluster Streptococcus Entero- Resp Enteric Non- Bacteroides, Mycoplasma = Staph β↓ & α-hemolytic↓ coccus (cocci) GI flora enteric Clostridium Legionella Beta-Lactams General Spectrum MSSA Group pneumo, faecalis H. flu, E. coli, Pseud- (non-dfficile) Chlamydia Penicillins of Activity → only A / B Viridans only M. cat Klebsiella omonas Peptostrep. (pneumonia) Natural Penicillin G IV/ PenVK PO +/- ++ + + 0 0 0 + 0 Anti- Oxacillin/Nafcillin IV, ++ ++ + 0 0 0 0 0 0 Staphylococcal Dicloxacillin PO Aminopenicillins Amp/Amoxicillin IV/PO 0 ++ + ++ +R +/- 0 + 0 Anti-Pseudomonal Piperacillin/Ticarcillin IV 0 + + + + + ++R + 0 Beta-Lactamase Clavulanate IV/PO, sulbactam Increase Inc by Increase Increase Inhibitor added tazobactam, vaborbactam IV by + + by + by + Cephalosporins Cefazolin IV/ ++ ++ +/- 0 +/- + 0 0 0 1st Generation Cephalexin PO 2nd Generation Cefuroxime IV/PO + ++ + 0 + + 0 +/- 0 Cephamycins Cefoxitin/Cefotetan IV 0 + 0 0 + + 0 + 0 3rd Generation Ceftriaxone/Cefotaxime IV + ++ ++ 0 ++ ++R 0 +/- 0 (PO in between 2nd Ceftazidime IV (+ Avibactam 0 + 0 0 ++ ++R ++R 0 0 and 3rd gen) for Carb-Resistant Enterics) 4th Generation Cefepime IV + ++ ++ 0 ++ ++ ++R 0 0 Novel Ceftolozane-tazo/Cefiderocol 0 + + 0 ++ ++ ++ +/- 0 Carbapenems Imipenem, Meropenem IV + + + +/- ++ ++ ++R ++ 0 (+rele/vaborbactam for CRE) Ertapenem IV + ++ ++ 0 ++ ++ 0 ++ 0 Monobactam Aztreonam IV 0 0 0 0 ++ ++R + 0 0 Non β-Lactams Includes MRSA Both sp. Aminoglycosides Gentamicin, -
Recent Advances in the Development of Antibacterial Agents
ISSN: 0975-8585 Research Journal of Pharmaceutical, Biological and Chemical Sciences Recent Advances in the Development of Antibacterial Agents. Avin S, A Avinash, Navin Patil, Sushil Kiran Kunder, Anurag Pathak, and KL Bairy*. Department of Pharmacology, Kasturba Medical College, Manipal, Karnataka, India. ABSTRACT Antibacterials are one of the most commonly prescribed groups of medications, especially in developing nations, owing to the vast number of microbial diseases prevalent in the community. Ever since the discovery of the phenomenal antibacterial, penicillin, there has been a great rise in the number of antibacterials in the market. In this era, where roadblocks like chemo-resistance and mutations plague medicine, scientists across the world are looking to adapt lateral approaches in encountering diseases. This review article brings to limelight, the recent advances in the field of antibacterial drug development, from the year 2007 till date. Keywords: Oritavancin, Tedizolid, Dalbavancin, Raxibacumab, Bedaquiline, Ceftaroline *Corresponding author September - October 2015 RJPBCS 6(5) Page No. 1220 ISSN: 0975-8585 INTRODUCTION Infectious diseases are among the leading causes of mortality worldwide, especially in developing nations where second line antibacterial drugs against resistant bacteria are generally either unavailable or unaffordable. The emergence of multi-drug resistance (MDR) in both community-acquired and hospital- acquired infections has outpaced the development and delivery of new drugs to the clinic. While the market potential for new antibacterial drugs is estimated to be several billions of dollars, the discovery pipelines of most major pharmaceutical companies are running near empty. The paucity of new antibacterial drugs has led the Infectious Disease Society of America (IDSA) and other bodies to call for action in rebuilding the infrastructure and efforts to develop next generation drugs [1].