Antibacterial Agents Antibacterial Agents Chemistry, Mode of Action, Mechanisms of Resistance and Clinical Applications ROSALEEN J ANDERSON Sunderland Pharmacy School, University of Sunderland, UK PAUL W GROUNDWATER Faculty of Pharmacy, University of Sydney, Australia ADAM TODD Sunderland Pharmacy School, University of Sunderland, UK ALAN J WORSLEY Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR This edition first published 2012 Ó 2012 John Wiley & Sons, Ltd Registered office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book This publication is designed to provide accurate and authoritative information in regard to the subject matter covered It is sold on the understanding that the publisher is not engaged in rendering professional services If professional advice or other expert assistance is required, the services of a competent professional should be sought The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose This work is sold with the understanding that the publisher is not engaged in rendering professional services The advice and strategies contained herein may not be suitable for every situation In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read No warranty may be created or extended by any promotional statements for this work Neither the publisher nor the author shall be liable for any damages arising herefrom Library of Congress Cataloging-in-Publication Data Antibacterial agents : chemistry, mode of action, mechanisms of resistance, and clinical applications / Rosaleen Anderson [et al.] p ; cm Includes bibliographical references and index ISBN 978-0-470-97244-1 (cloth) – ISBN 978-0-470-97245-8 (pbk.) I Anderson, Rosaleen J [DNLM: Anti-Bacterial Agents QV 350] 615.70 922–dc23 2012006648 A catalogue record for this book is available from the British Library HB ISBN: 9780470972441 PB ISBN: 9780470972458 Set in 10/12pt Times by Thomson Digital, Noida, India FOR OUR FAMILIES Contents Preface SECTION xiii INTRODUCTION TO MICROORGANISMS AND ANTIBACTERIAL CHEMOTHERAPY 1.1 Microorganisms Key points 1.1.1 Classification 1.1.2 Structure 1.1.3 Antibacterial targets 1.1.4 Bacterial detection and identification 1.1.5 Other than its mode of action, what factors determine the antibacterial activity of a drug? 1.1.6 Bacterial resistance 1.1.7 The ‘post-antibiotic age’? References Questions 25 27 29 31 33 SECTION 35 2.1 AGENTS TARGETING DNA Quinolone antibacterial agents Key points 2.1.1 Discovery 2.1.2 Synthesis 2.1.3 Bioavailability 2.1.4 Mode of action and selectivity 2.1.5 Bacterial resistance 2.1.6 Clinical applications 2.1.7 Adverse drug reactions 2.1.8 Drug interactions 2.1.9 Recent developments References 3 17 37 37 37 39 41 44 45 47 50 55 56 60 viii Contents 2.2 Rifamycin antibacterial agents Key points 2.2.1 Discovery 2.2.2 Synthesis 2.2.3 Bioavailability 2.2.4 Mode of action and selectivity 2.2.5 Bacterial resistance 2.2.6 Clinical applications 2.2.7 Adverse drug reactions 2.2.8 Drug interactions 2.2.9 Recent developments References 63 63 63 65 68 69 71 71 77 78 81 81 Nitroimidazole antibacterial agents Key points 2.3.1 Discovery 2.3.2 Synthesis 2.3.3 Bioavailability 2.3.4 Mode of action and selectivity 2.3.5 Mechanisms of resistance 2.3.6 Clinical applications 2.3.7 Adverse drug reactions 2.3.8 Drug interactions 2.3.9 Recent developments References Questions 85 85 85 86 86 87 89 90 94 95 96 97 101 SECTION 103 2.3 AGENTS TARGETING METABOLIC PROCESSES 3.1 Sulfonamide antibacterial agents Key points 3.1.1 Discovery 3.1.2 Synthesis 3.1.3 Bioavailability 3.1.4 Mode of action and selectivity 3.1.5 Bacterial resistance 3.1.6 Clinical applications 3.1.7 Adverse drug reactions 3.1.8 Drug interactions 3.1.9 Recent developments References 105 105 105 107 108 111 114 115 119 121 123 124 3.2 Trimethoprim Key points 3.2.1 Discovery 3.2.2 Synthesis 127 127 127 128 Contents ix 3.2.3 Bioavailability 3.2.4 Mode of action and selectivity 3.2.5 Bacterial resistance 3.2.6 Clinical applications 3.2.7 Adverse drug reactions 3.2.8 Drug interactions 3.2.9 Recent developments References Questions 130 130 136 136 138 138 139 140 145 SECTION 147 AGENTS TARGETING PROTEIN SYNTHESIS 4.1 Aminoglycoside antibiotics Key points 4.1.1 Discovery 4.1.2 Synthesis 4.1.3 Bioavailability 4.1.4 Mode of action and selectivity 4.1.5 Bacterial resistance 4.1.6 Clinical applications 4.1.7 Adverse drug reactions 4.1.8 Drug interactions 4.1.9 Recent developments References 149 149 149 152 156 158 160 161 165 167 168 168 4.2 Macrolide antibiotics Key points 4.2.1 Discovery 4.2.2 Synthesis 4.2.3 Bioavailability 4.2.4 Mode of action and selectivity 4.2.5 Bacterial resistance 4.2.6 Clinical applications 4.2.7 Adverse drug reactions 4.2.8 Drug interactions 4.2.9 Recent developments References 173 173 173 175 177 180 181 182 187 189 191 193 4.3 Tetracycline antibiotics Key points 4.3.1 Discovery 4.3.2 Synthesis 4.3.3 Bioavailability 4.3.4 Mode of action and selectivity 4.3.5 Bacterial resistance 4.3.6 Clinical applications 197 197 197 200 205 210 213 217 x Contents 4.3.7 Adverse drug reactions 4.3.8 Drug interactions 4.3.9 Recent developments References 223 224 224 225 Chloramphenicol Key points 4.4.1 Discovery 4.4.2 Synthesis 4.4.3 Bioavailability 4.4.4 Mode of action and selectivity 4.4.5 Bacterial resistance 4.4.6 Clinical applications 4.4.7 Adverse drug reactions 4.4.8 Drug interactions 4.4.9 Recent developments References 231 231 231 231 232 235 235 236 239 239 240 241 Oxazolidinones Key points 4.5.1 Discovery 4.5.2 Synthesis 4.5.3 Bioavailability 4.5.4 Mode of action and selectivity 4.5.5 Bacterial resistance 4.5.6 Clinical applications 4.5.7 Adverse drug reactions 4.5.8 Drug interactions 4.5.9 Recent developments References Questions 243 243 243 245 247 248 249 251 252 253 254 254 259 SECTION 261 4.4 4.5 5.1 AGENTS TARGETING CELL-WALL SYNTHESIS b-Lactam antibiotics Key points 5.1.1 Discovery 5.1.2 Synthesis 5.1.3 Bioavailability 5.1.4 Mode of action and selectivity 5.1.5 Bacterial resistance 5.1.6 Clinical applications 5.1.7 Adverse drug reactions 5.1.8 Drug interactions 5.1.9 Recent developments References 263 263 263 272 277 284 285 290 296 298 300 301 Contents xi 5.2 Glycopeptide antibiotics Key points 5.2.1 Discovery 5.2.2 Synthesis 5.2.3 Bioavailability 5.2.4 Mode of action and selectivity 5.2.5 Bacterial resistance 5.2.6 Clinical applications 5.2.7 Adverse drug reactions 5.2.8 Drug interactions 5.2.9 Recent developments References 305 305 305 306 307 308 309 313 314 316 316 317 5.3 Cycloserine Key points 5.3.1 Discovery 5.3.2 Synthesis 5.3.3 Bioavailability 5.3.4 Mode of action and selectivity 5.3.5 Bacterial resistance 5.3.6 Clinical applications 5.3.7 Adverse drug reactions 5.3.8 Drug interactions 5.3.9 Recent developments References 319 319 319 320 320 321 323 323 325 325 325 325 5.4 Isoniazid Key points 5.4.1 Discovery 5.4.2 Synthesis 5.4.3 Bioavailability 5.4.4 Mode of action and selectivity 5.4.5 Bacterial resistance 5.4.6 Clinical applications 5.4.7 Adverse drug reactions 5.4.8 Drug interactions 5.4.9 Recent developments References 327 327 327 328 329 329 330 331 333 334 335 335 5.5 Daptomycin Key points 5.5.1 Discovery 5.5.2 Synthesis 5.5.3 Bioavailability 5.5.4 Mode of action and selectivity 339 339 339 340 341 341 xii Contents 5.5.5 Bacterial resistance 5.5.6 Clinical applications 5.5.7 Adverse drug reactions 5.5.8 Drug interactions 5.5.9 Recent developments References Questions 343 343 344 345 345 346 349 Index 351 Daptomycin 347 H S Sader, T R Fritsche, J M Streit, and R N Jones, J Chemother., 2005b, 17, 477–483 J A Silverman, N G Perlmutter, and H M Shapiro, Antimicrob Agents Chemother., 2003, 47, 2538–2544 J A Silverman, L I Mortin, A D G VanPraagh, T Li, and J Alder, J Infect Dis., 2005, 191, 2149–2152 J N Steenbergen, J Adler, G M Thorne, and F P Tally, J Antimicrob Chemother., 2005, 55, 283–288 D L Stevens, A L Bisno, H F Chambers, E D Everett, P Dellinger, E J Goldstein, S L Gorbach, J V Hirschmann, E L Kaplan, J G Montoya, and J C Wade, Clin Infect Dis., 2005, 41, 1373–1406 F P Tally and M F DeBruin, J Antimicrob Chemother., 2000, 46, 523–526 S J van Hal, D L Paterson, and I B Gosbell, Eur J Clin Microbiol Infect Dis., 2011, 30, 603–610 Questions (1) Although the stereochemical configuration at the a-carbon atom of serine does not change during the synthesis of DCS (Scheme 5.3.2), the stereochemical (R) or (S) descriptor does Assign the stereochemistry at this centre in each of the compounds shown in Scheme 5.3.2 and explain why the descriptor changes (2) The stability of the carbanion intermediate provides a strong driving force for the deprotonation of the PLP-L-ala complex in the mechanism for ALR (Scheme 5.3.3) Draw resonance forms for this intermediate (3) Draw the product of the D-ala-D-ser ligase which is produced in VanC- and VanE-type resistance in VRE (4) Why should isoniazid not be used in the management of leprosy? (5) Have a look again at the structure of daptomycin (Figure 5.5.1) and list any amino acids which are nonproteinogenic or have an unusual configuration (6) In Scheme 5.5.1, what is the function of the Boc (ButOCO) group, which is added in the first step by the reaction of A21978C with di-tert-butyl dicarbonate (ButOCO)2O)? (7) Suggest reagents for the conversion of thienamycin to imipenem Index ACE inhibitors see angiotensin-converting enzyme (ACE) inhibitors acetaminophen see paracetamol ACHN-490 168 Acinetobacter baumannii 27, 29, 208, 289 acne vulgaris 137, 217–19 Actinoplanes teichomyceticus 305, 306 Actinoplanes utahensis 340 ADH see alcohol dehydrogenase agranulocytosis 121 AIDS and co-trimoxazole 117 and isoniazid 329 and pneumocystis pneumonia 116 and rifabutin 76 and sulfonamides 119 and toxoplasmic encephalitis 116 and tuberculosis 329, 333 see also HIV alatrofloxacin 42, 43 albendazole 91 alcohol 95–6 alcohol dehydrogenase (ADH) 95–6 alprazolam 190 amadacycline 204, 213, 224 Ambler system 287 American Thoracic Society 73, 76 amikacin 149, 150 clinical applications 163, 164 discovery 151 mode of action and selectivity 158, 160 spectrum of activity 161 synthesis 152, 155 7-aminocephalosporanic acid (7-ACA) 275–6 aminoglycosides 149–68 adverse drug reactions 165–6 bacterial resistance 160–1 bioavailability 156–8 clinical applications 161–5 discovery 149–50 dosing schedule 166 drug interactions 167–8, 315 mode of action and selectivity 158–60 recent developments 168 spectrum of activity 161 synthesis 152–5 amoebiasis 91 amoxicillin 274, 279 adverse reactions to 297 and clavulanic acid 292 and methotrexate 299 and warfarin 300 eradication of H pylori 92, 185, 186 spectrum of activity 292 treatment of anthrax 50 treatment of CAP 184 treatment of UTIs 137 treatment of Lyme disease 221 treatment of pancreatitis 95 treatment of RTIs 48 see also co-amoxiclav ampicillin bioavailability 280, 281, 282 spectrum of activity 292 treatment of meningitis 157, 163, 238 Amycolatopsis mediterranei 63, 66 Antibacterial Agents: Chemistry, Mode of Action, Mechanisms of Resistance and Clinical Applications, First Edition Rosaleen J Anderson, Paul W Groundwater, Adam Todd and Alan J Worsley Ó 2012 John Wiley & Sons, Ltd Published 2012 by John Wiley & Sons, Ltd 352 Index Amycolatopsis orientalis 305, 306 anaemia aplastic 121, 238–9 haemolytic 78 sideroblastic 333–4 anaerobic infections 93–4 anaesthetics 167 angiotensin-converting enzyme (ACE) inhibitors anhydrotetracycline 205, 213 antacids and quinolones 55 and tetracyclines 224 anthrax 49–50 anticoagulants 122 see also warfarin antiepileptic drugs 239 antimetabolites 112 Antimicrobial Index Knowledgebase 26 API identification systems 22 aplastic anaemia 121, 238–9 arrythmias 51, 56, 188 aspirin 167 atracurium 168 atropisomerism 305 aureomycin 198–9 see also chlortetracycline avoparcin 29 azithromycin 173, 174 adverse reactions 187 bioavailability 179 clinical applications 183–7 drug interactions 191 spectrum of activity 183 synthesis 176 azole antifungals 80, 95, 239 azomycin 85, 86 aztreonam 267, 269 and warfarin 300 discovery 272 spectrum of activity 292 synthesis 277 Bacillus anthracis 49–50 Bacillus anthrax 135 Bacillus lichenformis 272 Bacillus stearothermophilus 322 Bacillus subtilis 215 bacteria cell shapes 21 cell-wall synthesis 11–17 classification 3–4 122 detection and identification 17–24 DNA replication 6–7 Gram negative 3–4, 11, 13, 17 Gram positive 3–4, 11, 13, 16 metabolic processes 7–9 protein synthesis 9–11 resistance to antibacterial agents 27–31 structure 4–17 bactericidal agents 4, 25–6 concentration- and time-dependent action 26–7 bacteriophage 28 bacteriostatic agents 4, 25–6 Bacteroides fragilis 90, 93, 216 benzodiazepines 190, 334 benzylpenicillin 237, 278, 292, 294 see also penicillin G besifloxacin 37, 38 beta-lactamase inhibitors, 268, 289, 290, 300–1 beta-lactamases 29, 286–90 classification systems 287, 288 extended spectrum (ESBLs) 29, 286 beta-lactams 263–301 adverse drug reactions 296–8 bacterial resistance 285–90 bacterial uptake 284 bioavailability 277–84 clinical applications 290–6 discovery 263–72 drug interactions 167, 298–300 mode of action and selectivity 284–5 pharmacokinetic data 283 recent developments 300–1 spectrum of activity 290–2 synthesis 272–7 blood disorders and quinolones 50–1 and rifampicin 78 and sulfonamides 119, 121 see also anaemia boils see furuncles Bordetella pertussis 186 Borrelia afzelii 221 Borrelia burgdorferi 221, 222 Borrelia garinii 221 brain abscesses 117 BRENDA 130 bronchitis 48 Brotzu, Guiseppe 271 Brucella species 115 BSOP ID identification flowchart 22 Burkholderia cenocepacia 235 Index burn wounds 118 Bush system 287 calcium channel blockers 80–1, 239 Calymmatobacterium granulomatis 181 Campylobacter coli 182 Campylobacter jejuni 114, 182 Candida albicans 294 CAP see community-acquired pneumonia captopril 120 carbamazepine and doxycycline 224 and isoniazid 334 and macrolides 191 and nitroimidazoles 96–7 carbapenemases 287–9 carbapenems 29, 267, 269 adverse reactions 298 bioavailability 277 discovery 272 spectrum of activity 292 synthesis 276 carbenicillin 167 carbuncles 293 Care Quality Commission (CQC) 19 catalase-peroxidase (KatG) 329–30 CATs see chloramphenicol acetyltransferases CDAD see Clostridium difficile-associated diarrhoea CDI see Clostridium difficile infection C difficile see Clostridium difficile cefadroxil 297 cefepime 294 cefixime 49 cefotaxime 237 cefpodoxime 281 ceftazidime 300–1 ceftriaxone 221, 222, 282 cefuroxime 281, 295 cellulitis 292, 293 cell-wall synthesis 11–17 central nervous system (CNS) 54–5, 234, 271 cephalosporinases 287 cephalosporins 29, 265–6, 269 adverse reactions 297 bioavailability 277, 282 discovery 271 drug interactions 299, 300 spectrum of activity 292 synthesis 274–6 Cephalosporium acremonium 271 cethromycin 192, 193 childhood leukaemia 239 children and chloramphenicol 233, 234 and linezolid 248 and quinolones 50, 51 and tetracyclines 208 and trimethoprim 130 see also infants; neonates chlamydia 187, 220–1 Chlamydia trachomatis 220 chloramphenicol 231–40 adverse drug reactions 238–9 bacterial resistance 235 bioavailability 232–4 clinical applications 164, 236–8 discovery 231 drug interactions 239 mode of action and selectivity 235 recent developments 239–40 spectrum of activity 236–7 synthesis 231–2 chloramphenicol acetyltransferases (CATs) 235 chloramphenicol palmitate 233–4 chloramphenicol succinate 233–4 chloroquine 37, 39 chlortetracycline 197, 200–1 see also aureomycin cholestasis 78 chromogenic detection 22–3 Churchill, Winston 106 Ciloxin 50 ciprofloxacin 37, 38 adverse effects 51, 52, 53 bioavailability 41–2 clinical applications 47, 48, 49, 50 drug interactions 55 synthesis 39, 40 cisapride 188 clarithromycin 173, 174 bioavailability 179–80 clinical applications 76, 184, 185, 186, 187 drug interactions 190–1 synthesis 176 clavulanic acid 290, 291, 292 see also co-amoxiclav clopidrogel 239 Clostridium difficile 90, 93 Clostridium difficile-associated diarrhoea (CDAD) 307, 313 Clostridium difficile infection (CDI) 93–4, 313 clozapine 190 353 93, 354 Index CNS see central nervous system co-amoxiclav 184, 294, 295 commensal bacteria 280 community-acquired pneumonia (CAP) 184–5, 252, 345–6 complicated skin and soft-tissue infections (cSSTIs) treatment with daptomycin 344 treatment with linezolid 251–2 treatment with tetracyclines 222–3, 224 see also skin and soft-tissue infections (SSTIs) conjunctivitis 237, 238 conteben 327–8 contraceptives 299 corneal ulcers 50 Corynebacterium diphtheria 115 co-trimazine 135 co-trimoxazole 105, 106, 135 drug interactions 121–2, 138 treatment of nocardiosis 118 treatment of pneumocystis pneumonia 116 treatment of toxoplasmic encephalitis 116 CQC see Care Quality Commission Cubicin 339, 344 see also daptomycin CURB65 score 184 cycloserine see D-cycloserine (DCS) cystic fibrosis 51, 163–4 D-alanine 321 dapsone 75 daptomycin 30, 339–46 adverse drug reactions 344–5 bacterial resistance 343 bioavailability 341 clinical applications 343–4 discovery 339–40 drug interactions 345 mode of action and selectivity 341–3 recent developments 345–6 synthesis 340–1 D-cycloserine (DCS) 319–25 adverse drug reactions 325 bacterial resistance 323 bioavailability 320–1 clinical applications 323–5 discovery 319 drug interactions 325 mode of action and selectivity 321–3 recent developments 325 spectrum of activity 323 synthesis 319–20 demeclocycline 199, 205 demethylchlortetracycline 199, 205 deoxythymidine monophosphate 7, dermatological effects see skin reactions DHFR see dihydrofolate reductase DHPP see 6-hydroxymethyldihydropterin pyrophosphate DHPS see dihydropteroate synthase diarrhoea Clostridium difficile-associated (CDAD) 93, 307, 313 traveller’s 50, 76, 81 dibekacin 167 dicloxacillin 274, 300 digoxin 56, 139 dihydrofolate reductase (DHFR) 131–6, 139–40 dihydrofolic acid 7–9, 112 dihydropteroate synthase (DHPS) 112, 114–15, 123 directly observed therapy (DOT) 72, 183 DIVERSOMER technology 39 DNA chance mutations 28 replication 6–7, transcription 9–10 transfer 28 DNA gyrase 45–6 DNA helicase 6,7, 44 DNA polymerase 6, 7, 44 DNA primase 6, 44 dobutamine 316 Domagk, Gerhard 106, 327, 328 Donnan potential 209 donovanosis 183–4 dopamine 316 doripenem 276, 292 DOT see directly observed therapy doxycycline 197, 198 bioavailability 206–8 clinical applications 219–22 discovery 199 drug interactions 224 Duggar, Benjamin M 197–8 ear drops chloramphenicol 237, 240 gentamicin 165 ear infections 164 see also otitis externa; otitis media Ebacterium lentum 56 E coli see Escherichia coli efflux pumps 214–16 Elixir Sulfanilamide 106 encephalitis 116 Index encephalopathy 76, 95 enflurane 167 enoxacin 55 Entamoeba histolytica 91 enteric fever 50 see also typhoid fever Enterobacteriaceae 29, 47, 182, 290 Enterococcus faecalis 342 Enterococcus faecium 29, 213, 248, 313, 317 Enterococcus hirae 342 enterohepatic shunt 299 eperezolid 244–5, 247 epianhydrotetracycline 205 epiglottitis 238 epitetracycline 205 ertapenem 276, 282, 292 erythromycin 173, 174 adverse reactions 187 bacterial resistance 182 bioavailability 177–80 clinical applications 184–7 discovery 173–5 drug interactions 189–91 spectrum of activity 182–3 synthesis 175–7 erythromycin A 175, 179, 180 erythromycin B 179, 180 erythromycin ethyl succinate 179 erythromycin stearate 179 ESBLs see extended spectrum beta-lactamases Escherichia coli 47, 50, 76, 118, 131, 132, 137 and D-cycloserine 323 and linezolid 250 and penicillins 292 and sulfonamides 114–15 and tetracyclines 213 E-test 26 ethambutol 72, 76, 332 ethanol 95 ethionamide 328 eukaryotic cells 3–6 folic acid synthesis RNAP 10 extended spectrum beta-lactamases (ESBLs) 29, 286 extensively drug-resistant tuberculosis (XDR-TB) 49, 332 eye drops gentamicin 164 quinolone 50 eye infections 50 treatment with aminoglycosides 164 treatment with chloramphenicol 237, 240 Fanconi syndrome 205, 223–4 farm animals 29, 213 feedstock 29 fenbufen 55 ferredoxin 88, 89 Fleming, Sir Alexander 27, 263–7, 270 flesh-eating disease see necrotising fasciitis florfenicol 235, 236 flucloxacillin 274 and methotrexate 299 and warfarin 300 clinical applications 293–4 spectrum of activity 292 fluconazole 95 fluorogenic media 23 fluoroquinolones 42 adverse effects 51, 53, 54 bacterial uptake 43 drug interactions 56 structure–activity relationship 39 see also quinolones 5-fluorouracil 113 fluvastatin 191 folid acid cycle 131 folic acid synthesis 7–9, 112 Fourneau, Ernest 107 furosemide 119 and gentamicin 167 and vancomycin 316 furuncles 293 Fusobacterium necrophorum 90, 93 Fusobacterium nucleatum 93 29, Gardnerella vaginalis 93 gastric cancer 91–2 gastritis 92, 93 gastroduodenal disease 92 gastroenteritis 182 gastrointestinal (GI) effects and macrolides 187–8 and rifamycins 77–8 gatifloxacin 51, 52 gemifloxacin 51 gentamicin 149, 150, 158, 160 adverse effects 166 clinical applications 162–5 discovery 151, 168 355 356 Index gentamicin (Continued ) drug interactions 167, 168 spectrum of activity 161 gentamicin C 151 Giardia lamblia 90, 91 giardiasis 91 gliclazide 239 glycopeptide-resistant enterococci (GRE) 18, 20 glycopeptides 305–17 adverse drug reactions 314–15 bacterial resistance 311–13 bioavailability 307 clinical applications 313–14 discovery 305 drug interactions 315–16 mode of action and selectivity 308–11 recent developments 316–17 spectrum of activity 313 synthesis 305–7 glycylcyclines 217 gonorrheal conjunctivitis 237, 238 gonorrhoea 48 Gram, Hans Christian Joachim Gram negative bacteria 3–4, 11, 13, 17 Gram positive bacteria 3–4, 11, 13, 16 Gram positive infections 314 GRE see glycopeptide-resistant enterococci grepafloxacin 51, 52, 53 grey baby syndrome 239 gut flora 56, 287, 299 HACEK organisms 162 haemolytic anaemia 78 Haemophilus influenzae, 48, 184, 222, 263, 267 and beta-lactams 277 and chloramphenicol 235, 236–7 and penicillin 267 type B (Hib) 74, 157, 238 HAIs see health-care associated infections haptens 296 health-care associated infections (HAIs) 18 hearing loss 165, 187, 189 see also ototoxicity Helicobacter pylori and macrolides 185–6 and nitroimidazoles 90, 91–3 eradication of 185–6 hepatitis 76, 77, 121, 223, 333 hepatotoxicity and isoniazid 333 and quinolones 51 and rifampicin 77 and sulfonamides 121 and tetracyclines 223 HERG channel blockade 51–2 histamine 335 Hitchings, George H 127 HIV and Mycobacterium avium complex 76 and pneumocystis pneumonia 116 and rifabutin 73, 76 and rifampicin 69 and sulfonamides 120 and toxoplasmic encephalitis 116 and trimethoprim 138 and tuberculosis 73, 79, 333 see also AIDS HMGCoA inhibitors see hydroxymethylglutaryl coenzyme A (HMGCoA) inhibitors hOAT see human organic anion transporters Hodgkin, Dorothy 270, 271 H€ orlein, Heinrich 105 hospital-acquired pneumonia (HAP) 48, 252, 295 human organic anion transporters (hOAT) 224 hydantoins 122 6-hydroxymethyldihydropterin pyrophosphate (DHPP) 123 hydroxymethylglutaryl coenzyme A (HMGCoA) inhibitors 79 hydroxymethylgutaryl coenzyme A reductase inhibitors (HMG CoA inhibitors) 191 see also statins hyperkalaemia 122 hypoglycaemic agents 123 IE see infective endocarditis imipenem 276, 292, 294, 298 IMP-1 289 impetigo 293 indinavir 79 indomethacin 167 infants and aminoglycosides 167 and azithromycin 186 and chloramphenicol 233, 234, 239 and erythromycin 186 and linezolid 248 see also children; neonates infective endocarditis (IE) 162, 163 right-sided 344 insulin 123 integrons 28 Index isatin derivatives 335 isoniazid 327–35 adverse drug reactions 333–4 bacterial resistance 330–1 bioavailability 69, 329 clinical applications 331–3 discovery 327–8 drug interactions 334–5 mode of action and selectivity 329–30 recent developments 335 spectrum of activity 331–2 synthesis 328–9 itraconazole 95 Ixodes ticks 221, 222 kanamycin 151, 161, 164 kanamycin A 152, 155, 156 KatG see catalase-peroxidase KEGG database see Kyoto Encyclopedia of Genes and Genomes database ketoconazole 95 ketolides 191–3 Klarer, Josef 105 Klebsiella granulomatis comb nov 181 Klebsiella pneumoniae 27, 29, 136, 289, 300 KPC-1 289, 290 Kyoto Encyclopedia of Genes and Genomes database 130 Lactobacillus casei 127 lamivudine 138 Legionella pneumophila 184 Legionella species 184–5 legionnaires’ disease 184–5 leprosy 74–6 leukaemia 239 levofloxacin 37, 38 adverse effects 51–3 bioavailability 41, 42 clinical applications 47–9 limecycline 199, 200, 206–8 linear IgA bullous dermatosis 314 linezolid adverse drug reactions 252–3 bacterial resistance 249–51 bioavailability 247–8 clinical applications 251–2 discovery 30, 243–5 drug interactions 253–4 mode of action and selectivity 248–9 spectrum of activity 251 synthesis 245–7 lipopolysaccharide 11, 14 lipoteichoic acid 11, 13 listeria meningitis 162–3 Listeria monocytogenes 162–3 lovastatin 191 lupus erythematosus 333 Lyell’s syndrome 53–4 Lyme disease 221–2 lymecycline 198, 206 MAC see Mycobacterium avium complex macrolides 173–93 adverse drug reactions 187–9 bacterial resistance 181–2 bioavailability 177–80 clinical applications 182–7 discovery 173–5 drug interactions 189–91, 239 mode of action and selectivity 180–1 recent developments 191–3 spectrum of activity 182–3 synthesis 175–7 MALDI-TOF 24 Marshall, Barry 92 mass spectrometry 24 MBC see minimum bactericidal concentration MBLs see metallo-beta-lactamases MDR-TB see multidrug-resistant tuberculosis MDT see multidrug therapy mebendazole 91 mecillinam 281–2 memantine 139 meningitis listeria 162–3 treatment with aminoglycosides 157 treatment with beta-lactams 282 treatment with chloramphenicol 237–8 treatment with rifamycins 73–4 6-mercaptopurine 113 meropenem 276, 292, 294 messenger RNA (mRNA) metallo-beta-lactamases (MBLs) 29, 289–90 methionine 10–11 methotrexate 113, 133 and penicillin 299 and sulfonamides 121 and trimethoprim 138 meticillin-resistant Staphylococcus aureus (MRSA) 18–20 and amadacycline 224 and daptomycin 344 357 358 Index meticillin-resistant Staphylococcus aureus (MRSA) (Continued ) and linezolid 251, 252 detection methods 23–4 drug resistance 29 vancomycin-resistant 313 meticillin-susceptible Staphylococcus aureus (MSSA) 24, 292, 294 metronidazole 85, 86 adverse drug reactions 94–5 bacterial uptake 87 bioavailability 86–7 clinical applications 90–5 drug interactions 95–7 mode of action and selectivity 87–9 selective toxicity 89 spectrum of activity 90 synthesis 85 MIC see minimum inhibitory concentration Micromonospora inyoensis 151 Micomonospora species 151 midazolam 190 minimum bactericidal concentration (MBC) 26 minimum inhibitory concentration (MIC) 26 minocycline 197, 198 bioavailability 206–7 clinical applications 217, 218 discovery 199 mitemcinal (GM-611) 187 Modified Jones Criteria 119 molecular beacons 23–4 molecular diagnostic methods 23 monobactams 267, 272, 277, 292 motilides 187–8 motilin 187 moxifloxacin 37, 38, 42 adverse reactions 51–3 clinical applications 47, 48 mRNA see messenger RNA MROs see multiresistant organisms Mrp2 see multidrug-resistance-associated protein MRSA see meticillin-resistant Staphylococcus aureus MSSA see meticillin-susceptible Staphylococcus aureus MTC see Mycobacterium tuberculosis complex multidrug-resistance-associated protein (Mrp2) 224 multidrug-resistant tuberculosis (MDR-TB) 20, 29, 49, 332 treatment with aminoglycosides 164 treatment with D-cycloserine 324 treatment with rifabutin 73 multidrug therapy (MDT) 75–6 multiresistant organisms (MROs) 17–19 see also glycopeptide-resistant enterococci (GRE); meticillin-resitant Staphylococcus aureus (MRSA); vancomycin-resistant enterococci (VRE) mutations 28 mycobacteria 3, 11, 15 Mycobacterium avium 76, 135 Mycobacterium avium complex (MAC) 76, 187 Mycobacterium intracellulare 76 Mycobacterium leprae 74, 75, 332 Mycobacterium lepromatosis 74–5 Mycobacterium smegmatis 323 Mycobacterium tuberculosis 49, 149, 161 and isoniazid 329–30, 332 and rifamycins 71–3 Mycobacterium tuberculosis complex (MTC) 332 mycolic acids 11, 15, 329 Mycoplasma pneumoniae 184 nalidixic acid 37, 38, 41 NASH see nonalcoholic steatohepatitis NDM-1 29, 290 necrotising fasciitis 251, 252 necrotising pneumonia 93 necrotising soft-tissue infections 251 Neisseria gonorrhoeae 48, 237 Neisseria meningitidis 73-4, 114, 217, 292 neoglycoside 168 neomycin 149, 150, 158 neonates and aminoglycosides 157 and beta-lactams 282–4 and chloramphenicol 234, 237, 239 and linezolid 248 see also children; infants nephrotoxicity and aminoglycosides 165–6 and glycopetides 315 and imipenem 276, 298 netilmicin 155 neuroleptics 190 neuromuscular blocking agents 167–8 nifedipine 80 nitrofurantoin 47 2-nitroimidazole 85, 86 nitroimidazoles 85–97 adverse drug reactions 94–5 bioavailability 86–7 clinical applications 90–4, 185 discovery 85 drug interactions 95–7 Index mechanisms of resistance 89–90 mode of action and selectivity 87–9 recent developments 97 spectrum of activity 90 synthesis 86 Nocardia asteroides 115, 117 Nocardia brasiliensis 71, 72, 117 Nocardia mesenterica 85 Nocardia species 71, 117 nocardiosis 117 nonalcoholic steatohepatitis (NASH) 223 non-steroidal anti-inflammatory drugs (NSAIDs) and aminoglycosides 167 and daptomycin 345 and quinolones 55 norfloxacin 37, 38, 50 and theophylline 55 bioavailability 41, 42 NSAIDs see non-steroidal anti-inflammatory drugs NXL104 300–1 ofloxacin 37, 38, 41 adverse effects 51, 52, 53 and theophylline 55 clinical applications, 47, 48, 50 Oftaquix 50 osteomyelitis 93, 294 otitis externa 164–5, 237 otitis media 50, 165 ototoxicity and aminoglycosides 156, 164–5, 167 and glycopeptides 314, 315 see also hearing loss OXA-23 289 oxacillinases 287 oxazolidinones 243–54 adverse drug reactions 252–3 bacterial resistance 249–51 bioavailability 247–8 clinical applications 251–2 discovery 243–5 drug interactions 253–4 mode of action and selectivity 248–9 recent developments 254 spectrum of activity 251 synthesis 245–7 oxytetracycline 198 bacterial resistance 216, 217 bioavailability 207 discovery 199 synthesis 200 PABA see para-aminobenzoic acid pancreatitis 95 para-aminobenzoic acid (PABA) 7, 111–15 paracetamol 334 paromycin 151 patent ductus arteriosus 167 PBSs see penicillin binding proteins PCR method 23–4 penems 298, 300 penicillamine 120 penicillinases 287 penicillin binding proteins (PBPs) 15, 17, 284, 285 penicillin G 270, 273, 279, 282, 287 see also benzylpenicillin penicillins adverse reactions 296–8 benzathine 282 bioavailability 277–82 discovery 263–70 drug interactions 299–300 procaine 282 spectrum of activity 292 structure elucidation 270–1 synthesis 272–4 penicillin V 119, 122, 272–3, 287 see also phenoxymethylpenicillin Penicillium notatum 266–7 peptic ulcer disease 91–2 peptidoglycan 11, 13–15, 284–5, 308 Peptostreptococcus anaerobius 90 pertussis 186–7 P-glycoprotein (Pgp) 224 P-glycoprotein efflux system 191 Pgp see P-glycoprotein pharmaceutical companies 30 Phenobarbital 224 phenoxymethylpenicillin 274, 279, 280, 292, 299 see also penicillin V phenytoin and doxycycline 224 and isoniazid 334 and nitroimidazoles 96–7 and sulfonamides 122–3 phototoxicity 53, 56 pimozide 190–1 pioglitazone 138 piperacillin 274, 278, 292, 294, 295, 299 pivampicillin 281 pivmecillinam 274, 282, 292 plasmids 28 Plasmodium falciparum 110 359 360 Index Pneumocystis carinii 135, 183 Pneumocystis jirovecii 114, 116 pneumocystis pneumonia 116–17 pneumonia community-acquired (CAP) 184–5, 252, 345–6 hospital-acquired (HAP) 48, 252, 295 necrotising 93 pneumocystis 116–17 scoring systems 184, 295 treatment with beta-lactam antibiotics 295–6 ventilator-associated (VAP) 295 porins 11, 46–7 pravastatin 79, 191 pregnancy and metronidazole 89, 93 and quinolones 50 and trimethoprim 137 pregnane X receptor (PXR) 78 Priftin 73 primidone 224 prodrugs 280 prokaryotic cells 3–6 folic acid synthesis 7–8 shapes 21 prontosil 105–7 Propionibacterium acnes 218 propranolol 239 prostatitis 48, 137–8 protease inhibitors 79 protein synthesis 9–11 Proteus mirabilis 136, 137 proton pump inhibitors 185, 239 protozoan infections 90–1, 115–17 prulifloxacin 42, 43, 44 pseudoephedrine 253 Pseudomonas aeruginosa 27, 289 and aminoglycosides 161, 163, 164 and beta-lactams 294 and chloramphenicol 235 and quinolones 46–8 and trimethoprim 136 PXR see pregnane X receptor Pycazide 328 pyrazinamide 328 pyrimethamine 116, 133–4 QT wave and macrolides 188 and metronidazole 95 and quinolones 51–3, 56 quinidine 191 quinolones 37–59 adverse drug reactions 50–5 bacterial resistance 45–7 bioavailability 41–4 clinical applications 47–50, 185 discovery 37–9 drug interactions 55–6 mode of action and selectivity 44–5 prodrugs 42–3 recent developments 56–9 spectrum of activity 47 synthesis 39–41 red man syndrome 314 renal toxicity 121, 167, 223, 345 resistance determinant 214 respiratory tract infections (RTIs) 48 rheumatic fever 118–19, 187 rheumatic heart disease 119 ribosomal protection proteins 214, 216 ribosome 10–11 ribostamycin 167 rifabutin 63, 64 bioavailability 68 clinical applications 73, 76 drug interactions 79, 80 rifampicin 63, 64 adverse effects 77–8 bacterial resistance 71, 72 bioavailability 68, 69 clinical applications 72–6 drug interactions 78–81, 224 syntesis 66 rifamycins 63–81 adverse drug reactions 77–8 bacterial resistance 71 bacterial uptake 69 bioavailability 68–9 clinical applications 71–6 discovery 63–4 drug interactions 78–81 mode of action and selectivity 69–71 prodrugs 69 synthesis 65–8 rifapentine 63, 64 bioavailability 68, 69 clinical applications 73 synthesis 66 Rifater 72 rifaximin 63, 64, 68, 76 RNA polymerase (RNAP) 9–10, 69–71 Index RNAP see RNA polymerase Robinson, Robert 270 rosacea 94, 218–19 roxithromycin 173, 174, 176, 178 RTIs see respiratory tract infections (RTIs) Saccharopolyspora erythreus 173, 175 Salmonella paratyphi 50 Salmonella typhi 50, 238 Salmonella typhimurium 213, 235 sancycline 202 SCCmec see staphylococcal cassette chromosome Schatz, Albert 150 secnidazole 95 selective serotonin reuptake inhibitors (SSRIs) 239, 253 septicaemia 93 serotonin syndrome 95, 253 sexually transmitted infections (STIs) 48–9 sideroblastic anaemia 333–4 silver sulfadiazine 118 simvastatin 191, 345 sinusitis 222 sisomicin 151, 156 skin and soft-tissue infections (SSTIs) treatment with telavancin 316 treatment with tigecycline 222 uncomplicated 251, 293–4 see also complicated skin and soft-tissue infections (cSSTIs) skin reactions and D-cycloserine 325 and glycopeptides 314–15 and macrolides 188–9 and penicillin 297 and quinolones 53–4 and sulfonamides 121 and trimethoprim 138 solithromycin 192sparfloxacin 53 Sphingobacterium species 216 SSRIs see selective serotonin reuptake inhibitors SSTIs see skin and soft-tissue infections staining technique 3–4 staphylococcal cassette chromosome (SCCmec) 23–4 Staphylococcus aureus 251 and beta-lactams 286, 293–4 and daptomycin 342–4 and penicillin 267 and quinolones 46 and sulfonamides 114 and trimethoprim 136 and vancomycin 313 361 emergence of resistant forms 27 meticillin-susceptible (MSSA) 24, 292, 294 vancomycin-intermediate (VISA) 313, 316, 343 vancomycin-resistant (VRSA) 313, 343 see also meticillin-resistant Staphylococcus aureus (MRSA) Staphylococcus saprophyticus 136, 137 statins 79, 191 Stevens–Johnson syndrome 53–4, 120 STIs see sexually transmitted infections strep throat 118, 119 Streptococcus pneumoniae 48, 74, 115, 182, 184, 192, 222, 343 Streptococcus pyogenes 293 Streptomyces aureofaciens 198, 199, 200 Streptomyces cattleya 272 Streptomyces clavuligerus 290 Streptomyces erythreus 173 Streptomyces eurocidicus 85 Streptomyces fradiae 150 Streptomyces garyphalus 319 Streptomyces griseus 149 Streptomyces kanamyceticus 151 Streptomyces lavendulae 319 Streptomyces orchidaceus 319 Streptomyces orientalis 305 Streptomyces rimosus 151, 199, 202 Streptomyces roseosporus 339, 341, 345 Streptomyces species 27 Streptomyces tenebrarius 151 Streptomyces venezuelae 231, 235 streptomycin 149, 150 bacterial resistance 160 clinical applications 164 discovery 149–50 spectrum of activity 161 synthesis of 152–5 sulbactam 290 sulfa allergy 119–20, 123 sulfadiazine 105, 106 bioavailability 110 clinical applications 116, 117, 119 combined with trimethoprim 135 silver 118 sulfadimethoxine 110 sulfadoxine 110 sulfamethoxazole 105, 106 bioavailability 110–11 combined with trimethoprim 110, 135 see also co-trimoxazole 362 Index sulfanilamide 106, 107, 112 sulfapyridine 106, 110 sulfasalazine 110, 119 sulfathiazole 106, 109, 114, 327 sulfonamides 105–24 adverse drug reactions 119–21 bacterial resistance 114–15 bacterial uptake 111 bioavailability 108–11 clinical applications 15–19 discovery 105–7 drug interactions 122–3 mechanism of toxicity 120–2 mode of action and selectivity 111–14 recent developments 123 spectrum of activity 115–16 synthesis 107–8 sulfonylureas 119, 123 syphilis 219–20 tazobactam 290, 292, 294, 295 teicoplanin adverse drug reactions 314, 315 bioavailability 307 clinical applications 313, 314 discovery 305 spectrum of activity 313 synthesis 305–6 telavancin 316 telithromycin 179, 188, 192–3 temazepam 190 temocillin 278, 292 tendon disorders 51 terizidone 325 tetracycline 197, 198 bacterial resistance 213 bioavailability 208, 209 discovery 199 mode of action 213 synthesis 200 see also tetracycline antibiotics tetracycline antibiotics 197–24 adverse drug reactions 223–4 atypical 213 bacterial resistance 213–17 bioavailability 205–10 clinical applications 217–23 discovery 197–200 drug interactions 224 mode of action and selectivity 210–13 recent developments 224 spectrum of activity 217 synthesis 200–4 tetrahydrocannabinol 239 theophylline 55–6, 190 thienamycin 272, 276 thrombocytopenia 78, 314–15 ticarcillin 274, 278, 292 tigecycline 197, 198 bacterial resistance 216, 217 bioavailability 206, 207, 209 clinical applications 222–3 discovery 199 mode of action 213 synthesis 200 tinidazole 85, 86 bioavailability 86–7 clinical applications 90–2, 95 drug interactions 96–7 spectrum of activity 90 tobramycin 151 clinical applications 163–4 drug interactions 167, 168 mode of action and selectivity 158–60 spectrum of activity 161 tolbutamide 122 topoisomerases 7, 44–5 torsade de pointes 51, 52, 188 toxic epidermal necrolysis 121 Toxoplasma gondii 115, 135, 183 toxoplasmic encephalitis (TE) 116 toxoplasmosis 116 transposons 28 traveller’s diarrhoea 50, 76, 81 Treponema pallidum 219 Trichomonas vaginalis 88, 90 trichomoniasis 90–1 tricyclic antidepressants 239 trimethoprim 127–40 adverse drug reactions 138–9 bacterial resistance 136 bacterial uptake 130 bioavailability 130 clinical applications 47, 136–8 combined with sulfonamides 110, 135 discovery 127–8 mode of action and selectivity 130–5 recent developments 139–40 spectrum of activity 136 synthesis 128–40 see also co-trimoxazole trovafloxacin 42, 43 Index tuberculosis (TB) 29, 149, 332–3 and D-cycloserine 323–5 and isoniazid 332–3 and quinolones 49 and rifamycins 72–3 extensively drug-resistan (XDR-TB) 29, 49, 332 see also multidrug-resistant tuberculosis (MDR-TB) tubocurarine 167 typhoid fever 50, 187, 238 tyramine 335 ulifloxacin 42–3 urinary tract infections (UTIs) and quinolones 47–8 and trimethoprim 136–7 lower (LUTIs) 136–7 upper (UUTIs) 136–7 UTIs see urinary tract infections (UTIs) vaginosis 93 valproic acid 298 vancomycin adverse drug reactions 314–15 bacterial resistance 18, 311–13 bioavailability 307 clinical applications 313–14 discovery 305 drug interactions 315–16 mode of action and selectivity 309–10 spectrum of activity 313 synthesis 305–7 363 vancomycin-intermediate Staphylococcus aureus (VISA) 313, 316, 343 vancomycin-resistant enterococci (VRE) 20, 24, 311–13, 250, 251 vancomycin-resistant MRSA 313 vancomycin-resistant Staphylococcus aureus (VRSA) 313, 343 vecuronium 168 venlafaxine 253 ventilator-associated pneumonia (VAP) 295 verapamil 80, 168 Vitamin D 334–5 VRE see vancomycin-resistant enterococci Waksman, Selman 149–50 warfarin and beta-lactams 299–300 and daptomycin 345 and nitroimidazoles 96 and rifampicin 79–80 and sulfonamides 122 Warren, Robin 92 Watkins, Harold Cole 106 Wernicke’s encephalopathy (WE) 95 whooping cough see pertussis Woodward, R.B 174, 175, 202 World Health Organization (WHO) guidelines for management of MDR-TB leprosy elimination campaign 75 73 XDR-TB see extensively drug-resistant tuberculosis .. .Antibacterial Agents Chemistry, Mode of Action, Mechanisms of Resistance and Clinical Applications ROSALEEN J ANDERSON Sunderland Pharmacy School, University of Sunderland, UK PAUL... herefrom Library of Congress Cataloging-in-Publication Data Antibacterial agents : chemistry, mode of action, mechanisms of resistance, and clinical applications / Rosaleen Anderson [et al.]... explaining the known mechanisms of action of these drugs We believe that knowledge of the mode of action and pharmacology of antibacterial agents is essential to our understanding of the multidrug