Antibacterial Agents Antibacterial Agents Chemistry, Mode of Action, Mechanisms of Resistance and Clinical Applications ROSALEEN J. ANDERSON Sunderland PharmacySchool,University of Sunderland, UK PAUL W. GROUNDWATER Facultyof Pharmacy, Universityof Sydney, Australia ADAM TODD Sunderland PharmacySchool,University of Sunderland, UK ALAN J. WORSLEY Department ofPharmacology andPharmacy,TheUniversity of Hong Kong, Hong Kong SAR Thiseditionfirstpublished2012 (cid:2)2012JohnWiley&Sons,Ltd Registeredoffice JohnWiley&SonsLtd,TheAtrium,SouthernGate,Chichester,WestSussex,PO198SQ,UnitedKingdom Fordetailsofourglobaleditorialoffices,forcustomerservicesandforinformationabouthowtoapplyforpermissiontoreusethecopyrightmaterialin thisbookpleaseseeourwebsiteatwww.wiley.com. TherightoftheauthortobeidentifiedastheauthorofthisworkhasbeenassertedinaccordancewiththeCopyright,DesignsandPatentsAct1988. 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LibraryofCongressCataloging-in-PublicationData Antibacterialagents:chemistry,modeofaction,mechanismsofresistance, andclinicalapplications/RosaleenAnderson...[etal.]. p.;cm. Includesbibliographicalreferencesandindex. ISBN978-0-470-97244-1(cloth)–ISBN978-0-470-97245-8(pbk.) I. Anderson,RosaleenJ. [DNLM:1. Anti-BacterialAgents. QV350] 615.70922–dc23 2012006648 AcataloguerecordforthisbookisavailablefromtheBritishLibrary. HBISBN:9780470972441 PBISBN:9780470972458 Setin10/12ptTimesbyThomsonDigital,Noida,India. FOR OUR FAMILIES Contents Preface xiii SECTION 1 INTRODUCTIONTO MICROORGANISMS AND ANTIBACTERIAL CHEMOTHERAPY 1 1.1 Microorganisms 3 Keypoints 3 1.1.1 Classification 3 1.1.2 Structure 4 1.1.3 Antibacterial targets 6 1.1.4 Bacterial detectionand identification 17 1.1.5 Other than itsmode ofaction, what factors determinethe antibacterial activity of adrug? 25 1.1.6 Bacterial resistance 27 1.1.7 The ‘post-antibiotic age’? 29 References 31 Questions 33 SECTION 2 AGENTS TARGETINGDNA 35 2.1 Quinolone antibacterialagents 37 Keypoints 37 2.1.1 Discovery 37 2.1.2 Synthesis 39 2.1.3 Bioavailability 41 2.1.4 Mode ofaction andselectivity 44 2.1.5 Bacterial resistance 45 2.1.6 Clinical applications 47 2.1.7 Adversedrug reactions 50 2.1.8 Drug interactions 55 2.1.9 Recent developments 56 References 60 viii Contents 2.2 Rifamycinantibacterialagents 63 Keypoints 63 2.2.1 Discovery 63 2.2.2 Synthesis 65 2.2.3 Bioavailability 68 2.2.4 Mode of action and selectivity 69 2.2.5 Bacterial resistance 71 2.2.6 Clinical applications 71 2.2.7 Adverse drugreactions 77 2.2.8 Drug interactions 78 2.2.9 Recent developments 81 References 81 2.3 Nitroimidazole antibacterialagents 85 Keypoints 85 2.3.1 Discovery 85 2.3.2 Synthesis 86 2.3.3 Bioavailability 86 2.3.4 Mode of action and selectivity 87 2.3.5 Mechanisms ofresistance 89 2.3.6 Clinical applications 90 2.3.7 Adverse drugreactions 94 2.3.8 Drug interactions 95 2.3.9 Recent developments 96 References 97 Questions 101 SECTION 3 AGENTS TARGETING METABOLIC PROCESSES 103 3.1 Sulfonamide antibacterialagents 105 Keypoints 105 3.1.1 Discovery 105 3.1.2 Synthesis 107 3.1.3 Bioavailability 108 3.1.4 Mode of action and selectivity 111 3.1.5 Bacterial resistance 114 3.1.6 Clinical applications 115 3.1.7 Adverse drugreactions 119 3.1.8 Drug interactions 121 3.1.9 Recent developments 123 References 124 3.2 Trimethoprim 127 Keypoints 127 3.2.1 Discovery 127 3.2.2 Synthesis 128 Contents ix 3.2.3 Bioavailability 130 3.2.4 Mode ofaction andselectivity 130 3.2.5 Bacterial resistance 136 3.2.6 Clinical applications 136 3.2.7 Adversedrug reactions 138 3.2.8 Drug interactions 138 3.2.9 Recent developments 139 References 140 Questions 145 SECTION 4 AGENTS TARGETINGPROTEIN SYNTHESIS 147 4.1 Aminoglycoside antibiotics 149 Keypoints 149 4.1.1 Discovery 149 4.1.2 Synthesis 152 4.1.3 Bioavailability 156 4.1.4 Mode ofaction andselectivity 158 4.1.5 Bacterial resistance 160 4.1.6 Clinical applications 161 4.1.7 Adversedrug reactions 165 4.1.8 Drug interactions 167 4.1.9 Recent developments 168 References 168 4.2 Macrolide antibiotics 173 Keypoints 173 4.2.1 Discovery 173 4.2.2 Synthesis 175 4.2.3 Bioavailability 177 4.2.4 Mode ofaction andselectivity 180 4.2.5 Bacterial resistance 181 4.2.6 Clinical applications 182 4.2.7 Adversedrug reactions 187 4.2.8 Drug interactions 189 4.2.9 Recent developments 191 References 193 4.3 Tetracycline antibiotics 197 Keypoints 197 4.3.1 Discovery 197 4.3.2 Synthesis 200 4.3.3 Bioavailability 205 4.3.4 Mode ofaction andselectivity 210 4.3.5 Bacterial resistance 213 4.3.6 Clinical applications 217 x Contents 4.3.7 Adverse drugreactions 223 4.3.8 Drug interactions 224 4.3.9 Recent developments 224 References 225 4.4 Chloramphenicol 231 Keypoints 231 4.4.1 Discovery 231 4.4.2 Synthesis 231 4.4.3 Bioavailability 232 4.4.4 Mode of action and selectivity 235 4.4.5 Bacterial resistance 235 4.4.6 Clinical applications 236 4.4.7 Adverse drugreactions 239 4.4.8 Drug interactions 239 4.4.9 Recent developments 240 References 241 4.5 Oxazolidinones 243 Keypoints 243 4.5.1 Discovery 243 4.5.2 Synthesis 245 4.5.3 Bioavailability 247 4.5.4 Mode of action and selectivity 248 4.5.5 Bacterial resistance 249 4.5.6 Clinical applications 251 4.5.7 Adverse drugreactions 252 4.5.8 Drug interactions 253 4.5.9 Recent developments 254 References 254 Questions 259 SECTION 5 AGENTS TARGETING CELL-WALL SYNTHESIS 261 5.1 b-Lactamantibiotics 263 Keypoints 263 5.1.1 Discovery 263 5.1.2 Synthesis 272 5.1.3 Bioavailability 277 5.1.4 Mode of action and selectivity 284 5.1.5 Bacterial resistance 285 5.1.6 Clinical applications 290 5.1.7 Adverse drugreactions 296 5.1.8 Drug interactions 298 5.1.9 Recent developments 300 References 301 Contents xi 5.2 Glycopeptide antibiotics 305 Keypoints 305 5.2.1 Discovery 305 5.2.2 Synthesis 306 5.2.3 Bioavailability 307 5.2.4 Mode ofaction andselectivity 308 5.2.5 Bacterial resistance 309 5.2.6 Clinical applications 313 5.2.7 Adversedrug reactions 314 5.2.8 Drug interactions 316 5.2.9 Recent developments 316 References 317 5.3 Cycloserine 319 Keypoints 319 5.3.1 Discovery 319 5.3.2 Synthesis 320 5.3.3 Bioavailability 320 5.3.4 Mode ofaction andselectivity 321 5.3.5 Bacterial resistance 323 5.3.6 Clinical applications 323 5.3.7 Adversedrug reactions 325 5.3.8 Drug interactions 325 5.3.9 Recent developments 325 References 325 5.4 Isoniazid 327 Keypoints 327 5.4.1 Discovery 327 5.4.2 Synthesis 328 5.4.3 Bioavailability 329 5.4.4 Mode ofaction andselectivity 329 5.4.5 Bacterial resistance 330 5.4.6 Clinical applications 331 5.4.7 Adversedrug reactions 333 5.4.8 Drug interactions 334 5.4.9 Recent developments 335 References 335 5.5 Daptomycin 339 Keypoints 339 5.5.1 Discovery 339 5.5.2 Synthesis 340 5.5.3 Bioavailability 341 5.5.4 Mode ofaction andselectivity 341 xii Contents 5.5.5 Bacterial resistance 343 5.5.6 Clinical applications 343 5.5.7 Adverse drugreactions 344 5.5.8 Drug interactions 345 5.5.9 Recent developments 345 References 346 Questions 349 Index 351