Quinolone Antibacterials

It has been over 30 years since the first clinically important member of the quinolone class, nalidixic acid, was introduced into medical practice. The modification produced in the quinolone nucleus by introducing a fluorine at the 6-position led to the discovery of the newer fluoroquinolones with enhanced antibacterial activities as compared to nalidixic acid. By now a great deal of preclinical and clinical experience has been obtained with these agents. The intense interest in this class of antibacterial agents by chemists, micro­ biologists, toxicologists, pharmacologists, clinical pharmacologists, and clini­ cians in various disciplines encouraged us to summarize the information on the history, chemistry, mode of action and in vitro properties, kinetics and efficacy in animals, mechanisms of resistance, toxicity, clinical pharmacology, clinical experience, and future prospects in one volume of the Handbook of Experimental Pharmacology. As this series deals predominantly with "experimental" characteristics of drugs, our volume is dedicated specifically to quinolones and emphasizes principally their preclinical and clinical phar­ macological characteristics, despite the existence of several summaries on quinolones. The chemistry of the quinolones is described in detail. The chapter on the mode of action of quinolones reports the conclusive evidence that gyrase is the intracellular target of the quinolones; however, another enzyme, topoisomerase IV, may also be a target for quinolones, and the exact mechanisms by which quinolones act bactericidally are far from being understood.

Inhalt
1 History and Introduction.- A. Chemistry.- B. Antibacterial Activity.- C. Oxygen and 4-Quinolones.- D. 4-Quinolone Kinetics and Distribution in Humans.- E. Outlook.- References.- 2 The Chemistry of the Quinolones: Methods of Synthesizing the Quinolone Ring System.- A. Introduction.- B. Methods of Synthesizing the Quinolone Ring System.- I. Gould-Jacobs Reaction.- II. Dieckmann Cyclization of Diesthers.- III. Cycloaracylation Procedure.- IV. Biere and Seelen Approach.- V. Isatoic Anhydride Procedure.- VI. Camps Quinolone Synthesis.- VII. Meth-Cohn Quinolone Synthesis.- VIII. Synthesis of Quinolone Analogues.- IX. Synthesis of 4-Cinnolone-3-carboxylic Acids.- X. Synthesis of 4-Pyridone-3-carboxylic Acids.- References.- 3 The Chemistry of the Quinolones: Chemistry in the Periphery of the Quinolones.- A. Introduction.- B. 1-Position.- C. 2-Position.- D. 3-Position.- E. 4-Position.- F. 5-Position.- G. 6-Position.- H. 7-Position.- I. Synthesis of Specific Amines.- 1. Bicyclic Piperazine Derivatives.- 2. Aminopyrrolidine and Aminomethylpyrrolidine Derivatives.- 3. 3,4-Bridged Pyrrolidine Derivatives.- 4. Mixed Derivatives.- II. C-N Linkage.- III. C-S Linkage.- IV. C-O Linkage.- V. C-C Linkage.- I. 8-Position.- References.- 4 Mode of Action.- A. Introduction.- B. Effects on Bacteria.- C. Effects on DNA Gyrase.- I. Reactions of Gyrase.- II. Mechanistic Steps.- 1. DNA Binding.- 2. DNA Cleavage.- 3. ATPase.- III. Illegitimate Recombination.- IV. Summary.- D. Mode of Binding.- I. Binding of Quinolones to DNA.- II. Effect of DNA Gyrase on Quinolone Binding.- III. Cooperative Quinolone-DNA Binding Model.- IV. DNA Cleavage is not an Absolute Requirement for Quinolone Binding to a Gyrase-DNA Complex.- V. A Role for Magnesium Ions in the Binding of Quinolones to DNA.- VI. Binding of Quinobenzoxazines to DNA.- VII. Quinolone Binding to Quinolone-Resistant Mutants of DNA Gyrase.- VIII. Mode of Binding of Topoisomerase II-Targeting Drugs.- IX. Problems with Current Models.- X. Conclusions.- E. Mechanism of Cell Killing.- I. Paradoxical Effects of Quinolones.- II. Poison Hypothesis.- III. Polymerase Blocking.- F. Conclusions and Future Prospects.- References.- 5 The In Vitro Antibacterial Activity of Quinolones: A Review.- A. Introduction.- B. In Vitro Activity.- C. The Future.- References.- 6 Pharmacokinetics of Fluoroquinolones in Experimental Animals.- A. Introduction.- B. Norfloxacin.- C. Pefloxacin.- D. Enoxacin.- E. Ofloxacin.- F. Ciprofloxacin.- G. Temafloxacin.- H. Tosufloxacin.- I. Fleroxacin.- J. Lomefloxacin.- K. Sparfloxacin.- L. Penetration of Quinolones at Sites of Infection.- References.- 7 Pharmacodynamics of Fluoroquinolones in Experimental Animals.- A. Introduction.- B. Bacterial Killing In Vivo.- C. In Vivo Postantibiotic Effects.- D. Pharmacodynamic Parameters Determining Efficacy.- E. Emergence of Resistance to Fluoroquinolones.- I. P. aeruginosa Experimental Infections.- II. Staphylococcal Infections in Experimental Animals.- III. Miscellaneous Infection Models.- IV. Factors Contributing to the Emergence of Resistance In Vivo.- References.- 8 Interaction of Quinolones with Host-Parasite Relationship.- A. Introduction.- B. Effect on Adherence.- C. Effect Against Slowly Growing Bacteria.- D. Effect on Exoenzyme Production.- I. E. coli.- II. P. aeruginosa.- E. Quinolone-Induced Endotoxin Release.- F. Summary.- References.- 9 Mechanisms of Resistance to Fluoroquinolones.- A. Introduction.- B. Target Site Modification.- I. Mutations in gyrA.- II. Mutations in gyrB.- III. Mutations in Other Topoisomerase Genes.- C. Reduced Intracellular Accumulation.- I. Decreased Uptake.- II. Increased Efflux.- III. The mar Operon.- D. Reduced Killing.- E. Prevalence of Fluoroquinolone Resistance.- I. Community Acquired Pathogens.- II. Nosocomial Pathogens.- III. Impact of Fluoroquinolone Use in Agriculture.- F. Distribution of Resistance Mechanisms.- G. Summary.- References.- 10 Toxicology and Safety Pharmacology of Quinolones.- A. Introduction.- B. Arthropathy.- C. Achilles Tendinitis and Rupture.- D. Nephropathy.- E. Effects on Central Nervous System.- F. Ocular Toxicity.- G. Impairment of Spermatogenesis.- H. Cardiovascular Effects.- I. Possible Mutagenic and Carcinogenic Effects.- J. Phototoxicity.- K. Photocarcinogenicity and Photomutagenicity.- L. Drug Interactions.- M. Metabolic and Nutritional Effects.- N. Conclusion.- References.- 11 Clinical Pharmacology.- A. Introduction.- B. Pharmacokinetics of Fluoroquinolone Antibiotics.- I. Healthy Subjects.- 1. Absorption.- 2. Intravenous Administration.- 3. Bioavailability.- 4. Distribution.- 5. Disposition.- II. The Elderly.- III. Patients with Various Degrees of Renal Failure.- 1. Ciprofloxacin.- 2. Norfloxacin.- 3. Ofloxacin.- 4. Enoxacin.- 5. Fleroxacin.- 6. Pefloxacin.- 7. Lomefloxacin.- 8. Summary.- IV. Patients with Hepatic Failure.- V. Fluoroquinolones in Pediatric Patients.- C. Interactions of Fluoroquinolone Antibiotics with Other Drugs.- I. Interactions During the Absorption Process.- 1. Food and Dairy Products.- 2. Al3+-, Ca2+- and Mg2+-Containing Antacids.- 3. Sucralfate.- 4. Didanosine.- 5. Other Metal Cations.- 6. Chemotherapy Treatment.- 7. Activated Charcoal.- II. Interactions of Fluoroquinolones Due to Alterations in Metabolism.- 1. Theophylline, Caffeine and Structurally Closely Related Substances.- 2. Antipyrine.- 3. Phenytoin.- 4. H2-Receptor Antagonists.- 5. K+/Na+-ATPase Inhibitors.- 6. Warfarin.- 7. Cyclosporine.- 8. Rifampin.- 9. Oral Contraceptive Steroids.- 10. Benzodiazepines (Diazepam, Temazepam).- III. Alterations in Renal Excretion.- 1. Probenecid.- 2. ?-Lactam Antibiotics.- IV. Pharmacodynamic Interactions.- 1. Nonsteroidal Anti-inflammatory Drugs.- 2. Metronidazole.- V. Conclusions.- D. Adverse Reactions of Fluoroquinolones.- I. Gastrointestinal Tract.- II. Central Nervous System.- III. Skin and Allergic Reactions.- 1. Photosensitivity.- 2. Photoallergy.- IV. Nephropathy and Crystalluria.- V. Arthropathy and Musculoskeletal Disorders.- VI. Body Systems.- VII. Others.- References.- 12 Concentration-Effect Relationship of the Fluoroquinolones.- A. Introduction.- B. Pharmacodynamic Data of Antimicrobials as a Basis for Clinical Use.- I. ?-Lactams: Concentration-Independent Killing Rate.- II. Aminoglycosides: Concentration-Dependent Killing Rate.- III. Fluoroquinolones.- 1. …

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