The literature on co-trimoxazole (TMP jSMX) is voluminous, but in the main it consists of research reports. The same can be said of various symposia that have appeared. This volume attempts to present the current status of this antibacterial combination in a series of topical reviews, each of which represents a comprehensive summary of a segment of the field. The editor acknowledges with appreciation the help provided by JACKIE, JENKS, LEE KUYPER, and particularly, RUTH Ross in the preparation of the Subject Index, and thanks Burroughs Wellcome Co. for providing access to library and word processing facilities. Research Triangle Park GEORGE H. HITCHINGS List of Authors Dr. J. F. ACAR, Hospital Saint-Joseph, 7, rue Pierre-Larousse, F-75674 Paris Cedex 14 Dr. N. ANAND, National Information Centre for Drugs and Pharmaceuticals, Central Drug Research Institute, Chattar Manzil, P. O. Box No. 173, Lucknow, 226001jIND Dr. D. W. BARRY, The Wellcome Research Laboratories, Burroughs Wellcome Co. , 3030 Cornwallis Road, Research Triangle Park, NC 27709jUSA Dr. R. E. BLACK, Center for Vaccine Development, University of Maryland, Division of Infectious Diseases, 29 S. Greene Street, Bressler Building, Room 404, Baltimore, MD 21201jUSA Dr. J. J. BURCHALL, Department of Microbiology, The Wellcome Research Laboratories, Burroughs Wellcome Co. , 3030 Cornwallis Road, Research Triangle Park, NC 27709jUSA Dr. S. R. M. BUSHBY, The Wellcome Research Laboratories, Burroughs Wellcome Co. , 3030 Cornwallis Road, Research Triangle Park, NC 27709jUSA Dr. M. L.

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Trimethoprim/Sulfamethoxazole: An Overview.- A. Introduction.- B. Mechanisms of Action.- C. Resistance.- I. Chromosome-Mediated Resistance.- II. Plasmid-Mediated Resistance.- III. Thymidine Dependence.- D. Clinical Use of TMP/SMX.- I. Approved Indications in the United States.- II. Other Important Uses.- E. Use of TMP or SMX as Single Agents.- F. Adverse Effects.- G. Summary.- References.- Pharmacology and Biochemistry.- 1 Functions of Tetrahydrofolate and the Role of Dihydrofolate Reductase in Cellular Metabolism.- A. General.- B. Occurrence of Folates.- C. Functions of Tetrahydrofolate: Cofactors.- I. Formate and Equivalents.- 1. Purine Biosynthesis.- II. Formaldehyde Equivalents, Hydroxymethyl, and Methyl Derivatives.- 1. Methionine Biosynthesis.- 2. Thymidylate Synthesis.- 3. Vitamins and Other Metabolites.- D. Origins of Cellular Folates.- E. Transport Systems.- I. Selective Rescue.- F. Mechanism of Action of TMP/SMX.- I. Thymineless Death.- G. Summary.- References.- 2 Sulfonamides: Structure-Activity Relationships and Mechanism of Action.- A. Introduction.- B. Development of Sulfonamides and Sulfones.- I. Sulfonamides.- II. Sulfones.- III. Antimicrobial Spectrum.- C. Structure and Biological Activity.- I. Structure-Activity Relationship.- II. Physicochemical Properties and Antimicrobial Activity.- 1. Water Solubility.- 2. Lipid Solubility.- 3. Protein Binding.- III. Pharmacokinetics and Metabolism.- 1. Sulfonamides.- 2. Sulfones.- IV. Half-Life.- D. Mode of Antimicrobial Action.- I. Folic Acid Metabolism.- II. Action of Sulfonamides and Sulfones.- 1. Selectivity of Action.- III. Synergism with Dihydrofolate Reductase Inhibitors.- IV. Drug Resistance.- E. Present Status in Therapeutics.- References.- 3 Dihydrofolate Reductase.- A. Introduction.- B. Assay and Kinetic Studies.- C. Mechanism of Action.- D. Basis of Selectivity.- I. Kinetic Studies.- II. Inhibitor Binding Analysis.- III. Enzyme Conformation and Cooperativity.- IV Amino Acid Sequences.- V. Three-Dimensional Structures of DHFR.- E. Plasmid-Coded Reductases.- F. Genetics of DHFR.- References.- 4 Antibacterial Activity.- A. Introduction.- B. In Vitro Activity.- I. Effects of Medium and Size of Inoculum.- II. Bacteriostatic Activity.- III. Bactericidal Activity.- IV. Demonstration of Synergy.- C. Synergy and Sulfonamide-Resistant Strains.- D. Reversal of Activity of TMP.- E. Development of Resistance.- F. Spectrum of Activity of TMP/SMX.- G. Choice of Sulfonamide.- H. 2,4-Diaminopyrimidines as Single Agents.- J. Susceptibility Testing.- References.- 5 Selective Inhibitors of Bacterial Dihydrofolate Reductase: Structure-Activity Relationships.- A. Introduction.- B. Historical Perspective.- C. Some General Requirements for DHFR Inhibition and Antibacterial Activity.- D. Inhibitors of Specific DHFRs.- I. The 5-Phenyl Derivatives and Related Compounds.- II. 5-Benzyl-2,4-Diaminopyrimidines and Close Relatives.- 1. The 6-Unsubstituted Derivatives.- 2. 6-Substituted Derivatives.- 3. Substitution of a Heterocyclic Ring for the Benzene Moiety.- 4. Variations in the Bridge Between the Pyrimidine and Benzene Rings.- III. The 1,2-Dihydro-1,3,5-Triazines.- IV. Bicyclic Analogs of the Diaminopyrimidines.- E. Discussion.- F. Conclusion.- References.- 6 Kinetics of Antibacterial Effects.- A. Introduction: Bacterial Growth Kinetics in the Presence of Folate Inhibitors.- B. Sulfonamides (Synthetase Inhibitors).- I. Effect of Sulfonamides on Generation Rates of E. coli.- C. Trimethoprim (TMP): Dihydrofolate Reductase Inhibitor.- I. Effect of TMP on Generation Rates of E. coli.- II. Influence of TMP Concentration and Inoculum Size on the "Bactericidal" Effect of TMP.- III. Reversibility of TMP Action.- IV. Influence of Culture Broth Constituents on Biphasic Inhibition.- V. Development of Resistance Against Dihydrofolic Acid Reductase Inhibitors.- D. Combined Action of Sulfonamides and Trimethoprim (Folate Inhibitors).- I. Effect of TMP/SMX on Generation Rates of E. coli.- II. Influence of Inhibitory Power and Concentration of Sulfonamides or Sulfones on the Degree of Synergism.- III. Influence of Inhibitory Power of TMP Derivatives on the Degree of Synergism and Maximal Possible Effect.- IV. Selection Criteria for Combination of TMP and TMP Derivatives with Sulfonamides.- V. Mode of Action of Sulfonamides, TMP, and Their Combinations.- 1. Sulfonamides.- 2. TMP.- 3. Combinations of Sulfonamides and TMP.- References.- 7 Disposition and Metabolism of Trimethoprim, Tetroxoprim, Sulfamethoxazole, and Sulfadiazine.- A. Introduction.- B. Drug Disposition.- I. Drug Absorption.- II. Distribution into Biologic Fluids and Tissues.- 1. Physicochemical Properties that Influence Distributions..- 2. Relationship Between Plasma and Tissue Concentrations.- III. Excretion.- IV. Metabolism.- 1. Trimethoprim.- 2. Tetroxoprim.- 3. Sulfamethoxazole.- 4. Sulfadiazine.- C. Drug Assay Methods.- I. Trimethoprim and Related Benzylpyrimidines.- 1. Spectrofluorometric Methods.- 2. Quantitative Thin Layer Chromatography.- 3. High Pressure Liquid Chromatographic Methods.- 4. Gas-Liquid Chromatographic Analysis.- 5. Microbiologic Procedures.- 6. Other Methods.- II. Sulfonamides.- 1. Spectrophotometric Methods.- 2. Quantitative Thin Layer Chromatography.- 3. High Pressure Liquid Chromatography Methods.- D. Conclusion.- References.- 8 Preclinical Toxicity Testing of Co-trimoxazole and Other Trimethoprim/ Sulfonamide Combinations.- A. Introduction.- B. General Pharmacodynamic Actions.- I. Trimethoprim.- II. Trimethoprim and Sulfamoxole.- C. Acute Toxicity.- I. Trimethoprim, Sulfamethoxazole, and Co-trimoxazole.- II. Trimethoprim and Sulfamethoxypyridazine.- D. Subacute and Chronic Toxicity Tests.- I. Trimethoprim.- 1. Rats.- 2. Monkeys.- 3. Other Species.- II. Trimethoprim and Sulfamethoxazole.- 1. Rats.- 2. Rabbits.- 3. Monkeys.- E. Combinations of Trimethoprim and Other Sulfonamides.- I. Trimethoprim and Sulfafurazole.- II. Trimethoprim and Sulfadiazine.- III. Trimethoprim and Sulfamoxole.- IV. Trimethoprim and Sulfamethoxypyrazine.- F. Special Studies of the Thyroid and Trimethoprim/Sulfonamide Combinations.- G. Other Actions of Trimethoprim Alone or Combined with Sulfonamides.- I. Co-trimoxazole and Immunosuppression.- II. Local Effects of Intramuscular Injection of Trimethoprim and Various Sulfonamides.- III. Co-trimoxazole and Renal Failure.- H. Reproductive Toxicology.- I. Fetal …