DOCSLIB.ORG

Infectious Diseases, 3D Edition Elsevier/Mosby, 2010 Available on Line At

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Infectious Diseases, 3D Edition Elsevier/Mosby, 2010 Available on Line At Infectious Diseases, 3d Edition Elsevier/Mosby, 2010 Available on line at http://www.expertconsultbook.com/ Chapter 130: Mechanisms of Action Françoise Van Bambeke,1 Youri Glupczynski,2 Marie-Paule Mingeot-Leclercq1 & Paul M Tulkens1 1 Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium 2 Laboratoire de microbiologie, Cliniques universitaires UCL de Mont-Godinne, Yvoir, Belgium MOSBY is an imprint of Elsevier Limited. © 2010, Elsevier Limited. All rights reserved. First published 1999, Second edition 2004, Third edition 2010 ISBN: 978-0-323-04579-7 British Library Cataloguing in Publication Data Infectious diseases.-3rd ed. 1. Communicable diseases2. Communicable diseases - Diagnosis3. Communicable diseases - Treatment I. Cohen, J. (Jon), 1949-616.9 ISBN-13: 9780323045797 Infectious diseases.-3rd ed., Expert consult premium ed. Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress Françoise Van Bambeke Youri Glupczynski Marie-Paule Mingeot- Chapter |130 | Leclercq Paul M Tulkens Mechanisms of action the cyclic amide is similar, and act as a false substrate for D -alanyl- D - ANTIBIOTICS THAT ACT ON THE CELL WALL alanyl transpeptidases. The carbonyl of the beta-lactam ring reacts with a serine residue of the transpeptidases (also called penicillin-binding proteins, PBPs) to give an inactive acyl enzyme (‘suicide inhibition’ by The basis of the bacterial cell wall is peptidoglycan, containing alter- 2 nating residues of N -acetyl-glucosamine and muramic acid in β -1 →4 formation of a covalent bond; Fig. 130.3 ). Transpeptidases, located linkage. The carboxyl groups of muramyl residues are substituted by in the periplasmic space, are directly accessible in Gram-positive bac- teria but protected by the outer membrane in Gram-negative bacteria, short peptides (usually pentapeptides) terminated by a D -Asp- D -Ala- D - which β -lactams must cross (mainly via porin channels). Ala sequence. Cell-wall active antibiotics act by inhibiting the activity β of enzymes involved in the synthesis of the precursors or in the reticu- The impairment of cell wall formation by -lactams explains the lation of peptidoglycan. inhibition of the growth of bacteria, but the bactericidal effect results from indirect mechanisms (mostly the activation of autolytic enzymes). β -Lactams are usually active against rapidly dividing bacteria only. b -Lactams The β -lactam nucleus is the basic building block of an exceptionally Resistance large class of antibiotics that all share a common mode of action but Resistance to β -lactams occurs by three main different mechanisms. have quite distinct properties in terms of spectrum, pharmacokinetics • First, access to the PBPs in Gram-negative bacteria might be and, to some extent, activity against resistant strains. abolished by alteration of porin channels, which affects highly water-soluble β -lactams. • Second, resistance can be conferred through modification of PBPs, Chemical structure in particular PBP2 which is essential for the ‘shaping’ of bacteria. The All antibiotics in this class contain a cyclic amide called β -lactam. With most typical example is found in methicillin-resistant Staphylococcus the exception of the monobactams, this cycle is fused with a five- or aureus (MRSA) that produces an altered protein (called PBP2′ or six-membered cycle. According to the nature of the four-membered PBP2a) with a very low affinity for β -lactams. This makes the bacteria latter and/or of the heteroatom included, the following classes have resistant to all conventional β -lactams. Recent research has shown been described ( Fig. 130.1 ): that PBP2a is insensitive to β -lactams because the protein is in ‘closed’ • penams – β -lactams with a five-membered ring containing a conformation, preventing access of the drug to the reactive serine. This sulfur atom (penicillins); is circumvented if bacteria are exposed to acidic pH, which causes • clavams – β -lactamase inhibitors that contain a five-membered an opening of the enzymatic cavity. 3 This can also occur if β -lactams ring with an oxygen as the heteroatom (e.g. clavulanic acid; have a bulky hydrophobic substituent attached to the molecule in sulfur analogues have also been reported); the vicinity of the carboxylate (see Fig. 130.4 for cephalosporins). • carbapenems – five-membered rings without heteroatom and These molecules typically show a loss of activity towards MRSA of with a double bond (e.g. thienamycin, imipenem); only one to eight dilutions (corresponding to the energy needed to • cephems – six-membered unsaturated rings with a sulfur atom open the PBP2a) compared to fully susceptible S. aureus (in contrast (cephalosporins); with often more than 256-fold for conventional β -lactams). Two • oxacephems – the oxygen analogues of cephems (latamoxef); anti-MRSA β -lactam antibiotics (ceftobiprole and ceftaroline) 4 have • monobactams – cyclic amides in a four-membered ring been clinically developed. Penicillin-binding proteins in staphylococci (azetidine) with a methylcarboxylate function in the case or in other organisms (e.g. streptococci) can also show decreased of nocardicins and a sulfonate in the case of the other affinity; in such cases resistance is more specific to some β -lactams monobactams (e.g. aztreonam). but can also be only partial (decreased susceptibility). Other β -lactams include thiacephems, dethiacephems, dethiacephams, • The third and for many years the most frequent mechanism heterocephems and cephams, as well as diverse bicyclic systems. of resistance is the production of hydrolyzing enzymes called β -lactamases. 5 The corresponding genes may be carried either on chromosomes (where their expression may be constitutive or Mode of action inducible) or on plasmids, and their products are secreted out β -Lactams act primarily as inhibitors of transpeptidases (specialized of the cell wall in Gram-positive bacteria and in the periplasmic acyl serine transferases), thereby impairing the synthesis of the cell wall space in Gram-negative bacteria. β -Lactamases are serine proteases ( Fig. 130.2 ). 1 β -Lactams mimic the D -Ala- D -Ala sequence in that the that have a high affinity for β -lactams and cleave the amide bond. distance between the carboxylate or the sulfonate (monobactams) and Although most β -lactamases open the β -lactam ring in the same way 1288 Mechanisms of action Chapter | 130 | to five times the MIC provides little gain in activity, so that frequent Diversity of b-lactam antibiotics dosing is more appropriate than infrequent administration of large doses. Administration of β -lactams by continuous infusion is gaining increasing popularity, 6 but care must be taken regarding the stability of Structure Group Examples the drugs when exposed to room temperature for prolonged periods of time (carbapenems are unstable and cannot be used by continuous S infusion; a ‘prolonged’ infusion time of 3–4 hours has been proposed for doripenem as part of the drug labeling). In general, β -lactams show N Penam Penicillins only a moderate postantibiotic effect. O COOH O Future developments Clavam β-lactamase inhibitors N (clavulanic acid) Efforts continue to develop β -lactams active against MRSA in order O COOH to obtain compounds with increased intrinsic activity (applying the approach used with cephalosporins to penems). In parallel, efforts β Carbapenem (Thienamycin, are being made to develop more effective -lactamase inhibitors N imipenem) (especially for Gram-negative bacteria). Faropenem, an oral penem, O COOH was halted in its development in spite of excellent activity against pneumococci, largely because of fear of triggering resistance to the S whole class of penems if used indiscriminately in the community. Penem (Faropenem) Hybrid molecules combining a β -lactam part and an active antibi- N otic part from a different class (e.g. glycopeptides, fluoroquinolones) O COOH have also been described, with some potentially promising com- S pounds (because of markedly improved activity) in development. N Cephem Cephalosporins O Glycopeptides and lipoglycopeptides COOH Chemical structure O Currently available glycopeptide antibiotics (vancomycin, teicoplanin) contain two sugars and an aglycone moiety made of a relatively highly N Oxacephem (Latamoxef) conserved heptapeptide core, bearing two chloride substituents. The O aglycone fraction is responsible for the pharmacologic activity of the COOH molecule, whereas the sugars are thought to modulate its hydrophilicity and its propensity to form dimers (see below). As a result of their large N Monobactam (Aztreonam) size, glycopeptides are not only unable to cross the outer membrane of Gram-negative bacteria, explaining why they are inactive against these O SO3H organisms, but are also unable to penetrate inside bacteria, limiting them to an extracellular target. Lipoglycopeptides are semisynthetic Fig. 130.1 Diversity of β -lactam antibiotics: main ring structures names derivatives characterized by the addition of a hydrophobic moiety, and representative antibiotics. The figure highlights the fact that all drugs which confers additional properties to the drugs. share a common four-piece β -lactam ring and a carboxylate (or sulfonate) function at an appropriate, similar distance. (Clavams are weak antibiotics Mode of action but efficient β-lactamase inhibitors.) Glycopeptides inhibit the late stages of cell wall peptidoglycan synthe- sis (see Fig. 130.2
Load more

Recommended publications
  • A Small Outbreak of Third Generation Cephem-Resistant Citrobacter
    Jpn. J. Infect. Dis., 57, 2004 Laboratory and Epidemiology Communications A Small Outbreak of Third Generation Cephem-Resistant Citrobacter freundii Infection on a Surgical Ward Toshi Nada*, Hisashi Baba, Kumiko Kawamura2, Teruko Ohkura, Keizo Torii1 and Michio Ohta1 Department of Clinical Laboratory, Nagoya University Hospital, Nagoya 466-8560, 1Department of Bacteriology, Nagoya University Graduate School of Medicine, Nagoya 466-8550 and 2Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya 461-8673 Communicated by Yoshichika Arakawa (Accepted June 11, 2004) Citrobacter freundii is a member of family Enterobacteri- from those of type a and b strains. aceae and has been associated with nosocomial infections As previous studies have indicated, third generation in the urinary, respiratory, and biliary tracts of debilitated cephem-resistance of Gram-negative bacteria are due to the hospital patients. C. freundii has an inducible chromosomally hydrolysis of β-lactams by β-lactamases. These β-lactamases encoded cephalosporinase that can inactivate cephamycins include extended spectrum β-lactamase (ESBL), metallo- and cephalosporins. However, most clinical isolates are β-lactamase, and plasmid-encoded AmpC cephalosporinase sensitive to new third generation cephems and carbapenems. (1-3). ESBL confers variable levels of resistance to cefotaxime, We report here a small outbreak of infection caused by ceftazidime, and other broad-spectrum cephalosporins and third generation cephem-resistant C. freundii on a surgical to monobactams, but has no detectable activity against ward of a university hospital in 2002. We identified four cephamycins and carbapenems, and is relatively sensitive patients with biliary infection and two carrier patients during to sulbactam (1). Plasmid-encoded metallo-β-lactamase July and October.
    [Show full text]
  • Sepsis Caused by Newly Identified Capnocytophaga Canis Following Cat Bites: C
    doi: 10.2169/internalmedicine.9196-17 Intern Med 57: 273-277, 2018 http://internmed.jp 【 CASE REPORT 】 Sepsis Caused by Newly Identified Capnocytophaga canis Following Cat Bites: C. canis Is the Third Candidate along with C. canimorsus and C. cynodegmi Causing Zoonotic Infection Minami Taki 1, Yoshio Shimojima 1, Ayako Nogami 2, Takuhiro Yoshida 1, Michio Suzuki 3, Koichi Imaoka 3, Hiroki Momoi 1 and Norinao Hanyu 1 Abstract: Sepsis caused by a Capnocytophaga canis infection has only been rarely reported. A 67-year-old female with a past medical history of splenectomy was admitted to our hospital with fever and general malaise. She had been bitten by a cat. She showed disseminated intravascular coagulation and multi-organ failure because of severe sepsis. On blood culture, characteristic gram-negative fusiform rods were detected; therefore, a Capnocytophaga species infection was suspected. A nucleotide sequence analysis revealed the species to be C. canis, which was newly identified in 2016. C. canis may have low virulence in humans; however, C. canis with oxidase activity may cause severe zoonotic infection. Key words: Capnocytophaga canis, Capnocytophaga canimorsus, sepsis, oxidase activity (Intern Med 57: 273-277, 2018) (DOI: 10.2169/internalmedicine.9196-17) Introduction Case Report The genus Capnocytophaga consists of gram-negative A 67-year-old woman was admitted to our hospital with rod-shaped bacteria that reside in the oral cavities of humans general malaise and fever for 3 days starting the day after and domestic animals. Capnocytophaga formerly comprised being bitten by a cat on both her hands. She had a medical eight species (1, 2).
    [Show full text]
  • Criteria for Use of Dalbavancin for Acute Bacterial Skin/Soft Tissue Infection (Abssti)
    Criteria for Use of Dalbavancin for Acute Bacterial Skin/Soft Tissue Infection (abSSTI) 1. Patients meeting any of the following are NOT ELIGIBLE for dalbavancin therapy: a. History of hypersensitivity reaction to lipoglycopeptide antibiotics (vancomycin, televancin, dalbavancin, oritavancin). b. Patients with acute bacterial skin or skin structure infections such as superficial/simple cellulitis/erysipelas, impetiginous lesion, furuncle, or simple abscess that only requires surgical drainage for cure. c. Infection thought to be caused by gram-negative bacteria d. Infection due to an organism suspected or known to be resistant to dalbavancin or vancomycin 2. For outpatient use (i.e. ED) a. Contact infectious disease for authorization: ABX approval pager (see ON-CALL schedule) b. The following clinical criteria must be met: i. Pre-antibiotic blood cultures must be drawn. ii. Clinical condition expected to require ≥ 24 hours of IV antibiotics – must not qualify for oral antibiotic therapy. iii. Presence of cellulitis, major abscess or a wound infection associated with at least 75cm2 of erythema highly suspected or known to be caused by gram-positive bacteria. iv. The size of the infection must be clearly documented and/or outlined prior to leaving the ED, preferably with a photograph. v. Patient to be discharged to home ± home health (not to skilled nursing facility). c. Required follow up must be set up prior to leaving the ED: i. Must document patient contact info for follow up, preferably reliable cell phone number. ii. Must have follow up within 48-72H with Dr. Turnipseed (916-765-0196) or Rominski. 1. Email patient name, MRN, and phone number.
    [Show full text]
  • Infant Antibiotic Exposure Search EMBASE 1. Exp Antibiotic Agent/ 2
    Infant Antibiotic Exposure Search EMBASE 1. exp antibiotic agent/ 2. (Acedapsone or Alamethicin or Amdinocillin or Amdinocillin Pivoxil or Amikacin or Aminosalicylic Acid or Amoxicillin or Amoxicillin-Potassium Clavulanate Combination or Amphotericin B or Ampicillin or Anisomycin or Antimycin A or Arsphenamine or Aurodox or Azithromycin or Azlocillin or Aztreonam or Bacitracin or Bacteriocins or Bambermycins or beta-Lactams or Bongkrekic Acid or Brefeldin A or Butirosin Sulfate or Calcimycin or Candicidin or Capreomycin or Carbenicillin or Carfecillin or Cefaclor or Cefadroxil or Cefamandole or Cefatrizine or Cefazolin or Cefixime or Cefmenoxime or Cefmetazole or Cefonicid or Cefoperazone or Cefotaxime or Cefotetan or Cefotiam or Cefoxitin or Cefsulodin or Ceftazidime or Ceftizoxime or Ceftriaxone or Cefuroxime or Cephacetrile or Cephalexin or Cephaloglycin or Cephaloridine or Cephalosporins or Cephalothin or Cephamycins or Cephapirin or Cephradine or Chloramphenicol or Chlortetracycline or Ciprofloxacin or Citrinin or Clarithromycin or Clavulanic Acid or Clavulanic Acids or clindamycin or Clofazimine or Cloxacillin or Colistin or Cyclacillin or Cycloserine or Dactinomycin or Dapsone or Daptomycin or Demeclocycline or Diarylquinolines or Dibekacin or Dicloxacillin or Dihydrostreptomycin Sulfate or Diketopiperazines or Distamycins or Doxycycline or Echinomycin or Edeine or Enoxacin or Enviomycin or Erythromycin or Erythromycin Estolate or Erythromycin Ethylsuccinate or Ethambutol or Ethionamide or Filipin or Floxacillin or Fluoroquinolones
    [Show full text]
  • B-Lactams: Chemical Structure, Mode of Action and Mechanisms of Resistance
    b-Lactams: chemical structure, mode of action and mechanisms of resistance Ru´ben Fernandes, Paula Amador and Cristina Prudeˆncio This synopsis summarizes the key chemical and bacteriological characteristics of b-lactams, penicillins, cephalosporins, carbanpenems, monobactams and others. Particular notice is given to first-generation to fifth-generation cephalosporins. This review also summarizes the main resistance mechanism to antibiotics, focusing particular attention to those conferring resistance to broad-spectrum cephalosporins by means of production of emerging cephalosporinases (extended-spectrum b-lactamases and AmpC b-lactamases), target alteration (penicillin-binding proteins from methicillin-resistant Staphylococcus aureus) and membrane transporters that pump b-lactams out of the bacterial cell. Keywords: b-lactams, chemical structure, mechanisms of resistance, mode of action Historical perspective Alexander Fleming first noticed the antibacterial nature of penicillin in 1928. When working with Antimicrobials must be understood as any kind of agent another bacteriological problem, Fleming observed with inhibitory or killing properties to a microorganism. a contaminated culture of Staphylococcus aureus with Antibiotic is a more restrictive term, which implies the the mold Penicillium notatum. Fleming remarkably saw natural source of the antimicrobial agent. Similarly, under- the potential of this unfortunate event. He dis- lying the term chemotherapeutic is the artificial origin of continued the work that he was dealing with and was an antimicrobial agent by chemical synthesis [1]. Initially, able to describe the compound around the mold antibiotics were considered as small molecular weight and isolates it. He named it penicillin and published organic molecules or metabolites used in response of his findings along with some applications of penicillin some microorganisms against others that inhabit the same [4].
    [Show full text]
  • Dead Bugs Don't Mutate: Susceptibility Issues in the Emergence of Bacterial Resistance
    PERSPECTIVES Dead Bugs Don’t Mutate: Susceptibility Issues in the Emergence of Bacterial Resistance Charles W. Stratton*1 The global emergence of antibacterial resistance among and macrolides (the antibacterial agents used most frequently common and atypical respiratory pathogens in the last decade for pneumococcal infections) have become prevalent through- necessitates the strategic application of antibacterial agents. out the world. Indeed, rates of S. pneumoniae resistance to The use of bactericidal rather than bacteriostatic agents as penicillin now exceed 40% in many regions, and a high pro- first-line therapy is recommended because the eradication of portion of these strains are also resistant to macrolides. More- microorganisms serves to curtail, although not avoid, the devel- over, the trend is growing rapidly. Whereas 10.4% of all S. opment of bacterial resistance. Bactericidal activity is achieved with specific classes of antimicrobial agents as well as by com- pneumoniae isolates were resistant to penicillin and 16.5% bination therapy. Newer classes of antibacterial agents, such resistant to macrolides in 1996, these proportions rose to as the fluoroquinolones and certain members of the macrolide/ 14.1% and 21.9%, respectively, in 1997 (9). A more recent lincosamine/streptogramin class have increased bactericidal susceptibility study conducted in 2000–2001 showed that activity compared with traditional agents. More recently, the 51.5% of all S. pneumoniae isolates were resistant to penicillin ketolides (novel, semisynthetic, erythromycin-A derivatives) and 30.0% to macrolides (10). have demonstrated potent bactericidal activity against key res- The urgent need to curtail proliferation of antibacterial- piratory pathogens, including Streptococcus pneumoniae, Hae- resistant bacteria has refocused attention on the proper use of mophilus influenzae, Chlamydia pneumoniae, and Moraxella antibacterial agents.
    [Show full text]
  • Rifalazil | Medchemexpress
    Inhibitors Product Data Sheet Rifalazil • Agonists Cat. No.: HY-105099 CAS No.: 129791-92-0 Molecular Formula: C₅₁H₆₄N₄O₁₃ • Molecular Weight: 941.07 Screening Libraries Target: DNA/RNA Synthesis; Bacterial Pathway: Cell Cycle/DNA Damage; Anti-infection Storage: 4°C, sealed storage, away from moisture * In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture) SOLVENT & SOLUBILITY In Vitro DMSO : 8.33 mg/mL (8.85 mM; Need ultrasonic) Mass Solvent 1 mg 5 mg 10 mg Concentration Preparing 1 mM 1.0626 mL 5.3131 mL 10.6262 mL Stock Solutions 5 mM 0.2125 mL 1.0626 mL 2.1252 mL 10 mM --- --- --- Please refer to the solubility information to select the appropriate solvent. In Vivo 1. Add each solvent one by one: 10% DMSO >> 40% PEG300 >> 5% Tween-80 >> 45% saline Solubility: ≥ 2.2 mg/mL (2.34 mM); Clear solution 2. Add each solvent one by one: 10% DMSO >> 90% (20% SBE-β-CD in saline) Solubility: ≥ 2.2 mg/mL (2.34 mM); Clear solution BIOLOGICAL ACTIVITY Description Rifalazil (KRM-1648; ABI-1648), a rifamycin derivative, inhibits the bacterial DNA-dependent RNA polymerase and kills bacterial cells by blocking off the β-subunit in RNA polymerase[1]. Rifalazil (KRM-1648; ABI-1648) is an antibiotic, exhibits high potency against mycobacteria, gram-positive bacteria, Helicobacter pylori, C. pneumoniae and C. trachomatis with MIC values from 0.00025 to 0.0025 μg/ml[3]. Rifalazil (KRM-1648; ABI-1648) has the potential for the treatment of Chlamydia infection, Clostridium difficile associated diarrhea (CDAD), and tuberculosis (TB)[2].
    [Show full text]
  • Title Antimicrobial Therapy for Acute Cholecystitis: Tokyo Guidelines
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by HKU Scholars Hub Title Antimicrobial therapy for acute cholecystitis: Tokyo Guidelines Yoshida, M; Takada, T; Kawarada, Y; Tanaka, A; Nimura, Y; Gomi, H; Hirota, M; Miura, F; Wada, K; Mayumi, T; Solomkin, JS; Author(s) Strasberg, S; Pitt, HA; Belghiti, J; de Santibanes, E; Fan, ST; Chen, MF; Belli, G; Hilvano, SC; Kim, SW; Ker, CG Journal Of Hepato-Biliary-Pancreatic Surgery, 2007, v. 14 n. 1, p. Citation 83-90 Issued Date 2007 URL http://hdl.handle.net/10722/84203 Rights J Hepatobiliary Pancreat Surg (2007) 14:83–90 DOI 10.1007/s00534-006-1160-y Antimicrobial therapy for acute cholecystitis: Tokyo Guidelines Masahiro Yoshida1, Tadahiro Takada1, Yoshifumi Kawarada2, Atsushi Tanaka3, Yuji Nimura4, Harumi Gomi5, Masahiko Hirota6, Fumihiko Miura1, Keita Wada1, Toshihiko Mayumi7, Joseph S. Solomkin8, Steven Strasberg9, Henry A. Pitt10, Jacques Belghiti11, Eduardo de Santibanes12, Sheung-Tat Fan13, Miin-Fu Chen14, Giulio Belli15, Serafin C. Hilvano16, Sun-Whe Kim17, and Chen-Guo Ker18 1 Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan 2 Mie University School of Medicine, Mie, Japan 3 Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan 4 Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan 5 Division of Infection Control and Prevention, Jichi Medical University Hospital, Tochigi, Japan 6 Department of Gastroenterological
    [Show full text]
  • Nature Nurtures the Design of New Semi-Synthetic Macrolide Antibiotics
    The Journal of Antibiotics (2017) 70, 527–533 OPEN Official journal of the Japan Antibiotics Research Association www.nature.com/ja REVIEW ARTICLE Nature nurtures the design of new semi-synthetic macrolide antibiotics Prabhavathi Fernandes, Evan Martens and David Pereira Erythromycin and its analogs are used to treat respiratory tract and other infections. The broad use of these antibiotics during the last 5 decades has led to resistance that can range from 20% to over 70% in certain parts of the world. Efforts to find macrolides that were active against macrolide-resistant strains led to the development of erythromycin analogs with alkyl-aryl side chains that mimicked the sugar side chain of 16-membered macrolides, such as tylosin. Further modifications were made to improve the potency of these molecules by removal of the cladinose sugar to obtain a smaller molecule, a modification that was learned from an older macrolide, pikromycin. A keto group was introduced after removal of the cladinose sugar to make the new ketolide subclass. Only one ketolide, telithromycin, received marketing authorization but because of severe adverse events, it is no longer widely used. Failure to identify the structure-relationship responsible for this clinical toxicity led to discontinuation of many ketolides that were in development. One that did complete clinical development, cethromycin, did not meet clinical efficacy criteria and therefore did not receive marketing approval. Work on developing new macrolides was re-initiated after showing that inhibition of nicotinic acetylcholine receptors by the imidazolyl-pyridine moiety on the side chain of telithromycin was likely responsible for the severe adverse events.
    [Show full text]
  • Gatifloxacin for Treating Enteric Fever Submission to the 18Th Expert
    Gatifloxacin for enteric fever Gatifloxacin for treating enteric fever Submission to the 18th Expert Committee on the Selection and Use of Essential Medicines 1 Gatifloxacin for enteric fever Table of contents Gatifloxacin for treating enteric fever....................................................................................... 1 Submission to the 18th Expert Committee on the Selection and Use of Essential Medicines . 1 1 Summary statement of the proposal for inclusion........................................................... 4 1.1 Rationale for this submission................................................................................... 4 2 Focal point in WHO submitting the application ............................................................... 4 3 Organizations consulted and supporting the application ................................................ 5 4 International Nonproprietary Name (INN, generic name) of the medicine..................... 5 5 Formulation proposed for inclusion ................................................................................. 5 5.1 Prospective formulation improvements.................................................................. 6 6 International availability................................................................................................... 6 6.1 Patent status ............................................................................................................ 6 6.2 Production...............................................................................................................
    [Show full text]
  • EMA/CVMP/158366/2019 Committee for Medicinal Products for Veterinary Use
    Ref. Ares(2019)6843167 - 05/11/2019 31 October 2019 EMA/CVMP/158366/2019 Committee for Medicinal Products for Veterinary Use Advice on implementing measures under Article 37(4) of Regulation (EU) 2019/6 on veterinary medicinal products – Criteria for the designation of antimicrobials to be reserved for treatment of certain infections in humans Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged. Introduction On 6 February 2019, the European Commission sent a request to the European Medicines Agency (EMA) for a report on the criteria for the designation of antimicrobials to be reserved for the treatment of certain infections in humans in order to preserve the efficacy of those antimicrobials. The Agency was requested to provide a report by 31 October 2019 containing recommendations to the Commission as to which criteria should be used to determine those antimicrobials to be reserved for treatment of certain infections in humans (this is also referred to as ‘criteria for designating antimicrobials for human use’, ‘restricting antimicrobials to human use’, or ‘reserved for human use only’). The Committee for Medicinal Products for Veterinary Use (CVMP) formed an expert group to prepare the scientific report. The group was composed of seven experts selected from the European network of experts, on the basis of recommendations from the national competent authorities, one expert nominated from European Food Safety Authority (EFSA), one expert nominated by European Centre for Disease Prevention and Control (ECDC), one expert with expertise on human infectious diseases, and two Agency staff members with expertise on development of antimicrobial resistance .
    [Show full text]
  • Process to Increase the Production of Clavam
    Europäisches Patentamt *EP000832247B1* (19) European Patent Office Office européen des brevets (11) EP 0 832 247 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C12N 15/54, C12P 17/18, of the grant of the patent: C12N 1/20 24.11.2004 Bulletin 2004/48 // (C12N1/20, C12R1:465) (21) Application number: 96921954.2 (86) International application number: PCT/EP1996/002497 (22) Date of filing: 06.06.1996 (87) International publication number: WO 1996/041886 (27.12.1996 Gazette 1996/56) (54) PROCESS TO INCREASE THE PRODUCTION OF CLAVAM ANTIBIOTICS VERFAHREN ZUR ERHÖHUNG DER PRODUKTION VON CLAVAM-ANTIBIOTIKA PROCEDE POUR AUGMENTER LA PRODUCTION D’ANTIBIOTIQUES CLAVAM (84) Designated Contracting States: (56) References cited: AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC EP-A- 0 349 121 WO-A-94/18326 NL PT SE Designated Extension States: • FEMS MICROBIOLOGY LETTERS, vol. 110, 1993, SI pages 239-242, XP000601357 J.M.WARD AND J.E.HODGSON: "The biosynthetic genes for (30) Priority: 09.06.1995 GB 9511679 clavulanic acid and cephamycin production occur as a ’super-cluster’ in three (43) Date of publication of application: Streptomyces" cited in the application 01.04.1998 Bulletin 1998/14 • MICROBIOLOGY, vol. 140, no. 12, December 1994, pages 3367-3377, XP000601913 H.YU ET (73) Proprietors: AL.: "Possible involvement of the lat gene in the • SmithKline Beecham plc expression of the genes encoding ACV Brentford, Middlesex TW8 9GS (GB) synthetase (pcbAB) and isopenicillin N synthase • THE GOVERNORS OF THE UNIVERSITY OF (pcbC) in Streptomyces clavuligerus" cited in ALBERTA the application Edmonton, Alberta T6G 2E1 (CA) • MALMBERG ET AL: ’Precursor flux control through targeted chromosomal insertion of the (72) Inventors: lysine epsilon-aminotransferase (LAT) gene in • HOLMS, William, Henry Bioflux Limited Cephamycin C biosynthesis.’ JOURNAL OF 54 Dumbarton Road Glasgow G11 6AQ (GB) BACTERIOLOGY vol.
    [Show full text]