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Inhibitionof Folate Metabolismin ChemotherapyThe Origins and Uses of Co-trimoxazole

Contributors

J. F. Acar • N. Anand • D. W Barry • R. E. Black • J. J. BurchallS. R. M. Bushby • M. L. Clements • A. D. DayanR. E. Desjardins • F. W. Goldstein • L.T. Gutman • I. HansenG. H. Hitchings • D. T. D. Hughes • G. T. Keusch • D. H. LawsonM. M. Levine • F O'Grady • K. H. Pattishall • I. M. RolloB. Roth • J. K. Seydel • C. W Sigel • T. A. Stamey • W E. StammC. M. Wilfert • G. P. Wormser

Editor

G. H. Hitchings

UNIVERSITATS-BIBLIOTHEK

Springer-Verlag Berlin Heidelberg New York 1983

Contents

Trimethoprim/Sulfamethoxazole: An Overview. G. P. WORMSER andG. T. KEUSCH. With 1 Figure

A. Introduction 1B. Mechanisms of Action 1C. Resistance 3

I. Chromosome-Mediated Resistance 3II. Plasmid-Mediated Resistance 4

III. Thymidine Dependence 4D. Clinical Use of TMP/SMX 5

I. Approved Indications in the United States 5II. Other Important Uses 5

E. Use of TMP or SMX as Single Agents 6F. Adverse Effects 6G. Summary 7References 7

Pharmacology and Biochemistry

CHAPTER 1 -

Functions of Tetrahy drofolate and the Role of Dihydrofolate Reductasein Cellular Metabolism. G. H. HITCHINGS. With 6 Figures

A. General 11B. Occurrence of Folates 11C. Functions of Tetrahydrofolate: Cofactors 12

I. Formate and Equivalents 121. Purine Biosynthesis 13

II. Formaldehyde Equivalents, Hydroxymethyl, and Methyl Derivatives 141. Methionine Biosynthesis 142. Thymidylate Synthesis 153. Vitamins and Other Metabolites 16

D. Origins of Cellular Folates 16E. Transport Systems 17

I. Selective Rescue . 18F. Mechanism of Action of TMP/SMX 18

I. Thymineless Death 20

X Contents

G. Summary 20References 20

CHAPTER 2

Sulfonamides: Structure-Activity Relationships and Mechanism of Action.N. ANAND. With 1 Figure

A. Introduction 25B. Development of Sulfonamides and Sulfones 26

I. Sulfonamides 26II. Sulfones 29

III. Antimicrobial Spectrum 30C. Structure and Biological Activity 31

I. Structure-Activity Relationship 31II. Physicochemical Properties and Antimicrobial Activity 32

1. Water Solubility 342. Lipid Solubility 363. Protein Binding 36

III. Pharmacokinetics and Metabolism 371. Sulfonamides 372. Sulfones 38

IV. Half-Life 38D. Mode of Antimicrobial Action 39

I. Folic Acid Metabolism 39II. Action of Sulfonamides and Sulfones 41

1. Selectivity of Action 44III. Synergism with Dihydrofolate Reductase Inhibitors 45IV. Drug Resistance 45

E. Present Status in Therapeutics 46References 47

CHAPTER 3

Dihydrofolate Reductase. J. J. BURCHALL

A. Introduction 55B. Assay and Kinetic Studies 56C. Mechanism of Action 57D. Basis of Selectivity 58

I. Kinetic Studies 58II. Inhibitor Binding Analysis 59

III. Enzyme Conformation and Cooperativity 62IV. Amino Acid Sequences 63V. Three-Dimensional Structures of DHFR 65

E. Plasmid-Coded Reductases 68F. Genetics of DHFR 69References 70

Contents XI

CHAPTER 4

Antibacterial Activity. S. R. M. BUSHBY. With 4 Figures

A. Introduction 75B. In Vitro Activity 75

I. Effects of Medium and Size of Inoculum 75II. Bacteriostatic Activity 77

III. Bactericidal Activity 80IV. Demonstration of Synergy 80

C. Synergy and Sulfonamide-Resistant Strains 86D. Reversal of Activity of TMP 87E. Development of Resistance 87F. Spectrum of Activity of TMP/SMX 90G. Choice of Sulfonamide 92H. 2,4-Diaminopyrimidines as Single Agents 94J. Susceptibility Testing 96

References 99

CHAPTER 5

Selective Inhibitors of Bacterial Dihydrofolate Reductase: Structure-ActivityRelationships. B. ROTH. With 2 Figures

A. Introduction 107B. Historical Perspective 109C. Some General Requirements for DHFR Inhibition and Antibacterial

Activity I l lD. Inhibitors of Specific DHFRs I l l

I. The 5-Phenyl Derivatives and Related Compounds I l lII. 5-Benzyl-2,4-Diaminopyrimidines and Close Relatives 112

1. The 6-Unsubstituted Derivatives . 1122. 6-Substituted Derivatives 1153. Substitution of a Heterocyclic Ring for the Benzene Moiety . . 1164. Variations in the Bridge Between the Pyrimidine and Benzene

Rings 116III. The 1,2-Dihydro-1,3,5-Triazines 117IV. Bicyclic Analogs of the Diaminopyrimidines 117

E. Discussion 118F. Conclusion 121References 122

CHAPTER 6

Kinetics of Antibacterial Effects. J. K. SEYDEL. With 19 Figures

A. Introduction: Bacterial Growth Kinetics in the Presence of FolateInhibitors 129

B. Sulfonamides (Synthetase Inhibitors) 131I. Effect of Sulfonamides on Generation Rates of E. coli 131

XII Contents

C. Trimethoprim (TMP): Dihydrofolate Reductase Inhibitor 133I. Effect of TMP on Generation Rates of E. coli 133

II. Influence of TMP Concentration and Inoculum Size on the"Bactericidal" Effect of TMP 135

III. Reversibility of TMP Action 137IV. Influence of Culture Broth Constituents on Biphasic Inhibition . . 138V. Development of Resistance Against Dihydrofolic Acid Reductase

Inhibitors 142D. Combined Action of Sulfonamides and Trimethoprim (Folate Inhibitors) 143

I. Effect of TMP/SMX on Generation Rates of E. coli 143II. Influence of Inhibitory Power and Concentration of Sulfonamides

or Sulfones on the Degree of Synergism 145III. Influence of Inhibitory Power of TMP Derivatives on the Degree

of Synergism and Maximal Possible Effect 151IV. Selection Criteria for Combination of TMP and TMP Derivatives

with Sulfonamides 151V. Mode of Action of Sulfonamides, TMP, and Their Combinations 155

1. Sulfonamides 1552. TMP 1563. Combinations of Sulfonamides and TMP 158

References 158

CHAPTER 7

Disposition and Metabolism of Trimethoprim, Tetroxoprim, Sulfamethoxazole,and Sulfadiazine. C. W. SIGEL. With 4 Figures

A. Introduction 163B. Drug Disposition 163

I. Drug Absorption 163II. Distribution into Biologic Fluids and Tissues . . . . . . . . . . 164

1. Physicochemical Properties that Influence Distributions . . . . 1642. Relationship Between Plasma and Tissue Concentrations . . . 164

III. Excretion 168IV. Metabolism 169

1. Trimethoprim 1692. Tetroxoprim 1733. Sulfamethoxazole 1744. Sulfadiazine 175

C. Drug Assay Methods 177I. Trimethoprim and Related Benzylpyrimidines 177

1. Spectrofluorometric Methods 1772. Quantitative Thin Layer Chromatography 1773. High Pressure Liquid Chromatographic Methods 1784. Gas-Liquid Chromatographic Analysis 1785. Microbiologic Procedures 1786. Other Methods 179

Contents XIII

II. Sulfonamides1. Spectrophotometric Methods 1792. Quantitative Thin Layer Chromatography 1793. High Pressure Liquid Chromatography Methods 180

D. Conclusion 180References 180

CHAPTER 8

Preclinical Toxicity Testing of Co-trimoxazole and Other Trimethoprim/Sulfonamide Combinations. A. D. DAYAN

A. Introduction 185B. General Pharmacodynamic Actions 185

I. Trimethoprim 185II. Trimethoprim and Sulfamoxole 186

C. Acute Toxicity 186I. Trimethoprim, Sulfamethoxazole, and Co-trimoxazole 186

II. Trimethoprim and Sulfamethoxypyridazine 187D. Subacute and Chronic Toxicity Tests 188

I. Trimethoprim 1881. Rats 1882. Monkeys 1893. Other Species 190

II. Trimethoprim and Sulfamethoxazole 1901. Rats 190.2. Rabbits 1923. Monkeys 192

E. Combinations of Trimethoprim and Other Sulfonamides 192I. Trimethoprim and Sulfafurazole . . 192

II. Trimethoprim and Sulfadiazine .192III. Trimethoprim and Sulfamoxole 193IV. Trimethoprim and Sulfamethoxypyrazine 194

F. Special Studies of the Thyroid and Trimethoprim/SulfonamideCombinations 194

G. Other Actions of Trimethoprim Alone or Combined with Sulfonamides 195I. Co-trimoxazole and Immunosuppression 195

II. Local Effects of Intramuscular Injection of Trimethoprim andVarious Sulfonamides 195

III. Co-trimoxazole and Renal Failure 196H. Reproductive Toxicology 196

I. Fetal Toxicity Tests 1961. Rats 1962. Rabbits 198

II. Fertility Tests 1981. Rats 1982. Rabbits 199

XIV Contents

3. Hamsters 1994. Conclusions 1995. Other Related Information 200

III. Reproductive Toxicity of Trimethoprim Combined with OtherSulfonamides 2001. Trimethoprim and Sulfamoxole 2002. Trimethoprim and Sulfamethoxypyrazine 201

J. Mutagenicity 201I. Point Mutation Tests in Bacteria 201

II. Human Cytogenetic Studies 201References 202

Clinical Pharmacology

CHAPTER 9

Adverse Effect of Co-trimoxazole. D. H. LAWSON. With 5 Figures

A. Introduction 207B. Gastrointestinal Disorders 209

I. Upper Gastrointestinal Symptoms 209II. Lower Gastrointestinal Symptoms 210

C. Skin Disorders 210I. Toxic Erythema 214

II. Other Skin Reactions 215III. Sulfamethoxazole or Trimethoprim? 216

D. Renal Disorders 216E. Haematological Disorders 218

I. Folic Acid Deficiency '•. . . . 218II. Leucopenia/Agranulocytosis 218

III. Thrombocytopenia 220IV. Haemolytic Anaemia 220

F. Jaundice 221I. Liver Damage 221

II. Hyperbilirubinaemia of the Newborn 221G. Pregnancy 221H. Miscellaneous 222J. Drug Interactions 222

I. Pyrimethamine 222II. Azathioprine 223

III. Warfarin 223IV. Phenytoin 223V. Hypoglycaemic Agents 224

K. Conclusions 224References 224

Contents XV

CHAPTER 10

Clinical Pharmacokinetics of Co-trimoxazole. I. HANSEN

A. Introduction 229B. Absorption and Biologic Half-Lives 229C. Distribution 231

I. Plasma 231II. Cerebrospinal Fluid 232

III. Aqueous Humor 232IV. Breast Milk 232V. Prostatic and Seminal Material 233

VI. Vaginal Fluid 233VII. Placental and Fetal Material 233

VIII. Bile Fluid 233IX. Erythrocytes 234X. Bone 234

XI. Other Tissues and Organs 234D. Metabolism 234E. Elimination 235F. Interactions 238References 238

CHAPTER 11

Resistance: Genetics and Medical Implications: J. F. ACAR and F. W. GOLDSTEIN

A. Introduction 243B. Resistance to Sulfonamides 243

I. Definition 243II. Natural Resistance 243

III. Acquired Resistance 243C. Resistance to Trimethoprim \ . 243

I. Definition 243II. Natural Resistance 244

III. Acquired Resistance 244D. Mechanisms of Acquired Resistance to Sulfonamides 244

I. Results of Mutations 2441. Decreased Permeability 2442. Hyperproduction of p-Aminobenzoic Acid 2443. Altered Dihydropteroate Synthase 245

II. Acquisition of R Factors 245E. Mechanism of Acquired Resistance to Trimethoprim 245

I. By Mutation 2451. Thymineless Organisms 2452. Modification of Dihydrofolate Reductase 246

II. Plasmid-Mediated Resistance 2471. Transferable 2482. Nontransferable 248

XVI Contents

F. Medical Implications 248I. Sulfonamide-Resistant Strains 248

II. Sulfonamide-Sensitive, Trimethoprim-Resistant Strains 249III. Emergence of Resistant Strains During Therapy 249

G. Epidemiologic Overview of Resistance to Trimethoprim 250I. Gram-Positive Bacteria 250

II. Gram-Negative Bacteria 250References 252

Clinical Studies

CHAPTER 12

Trimethoprim Alone: Clinical Uses. D. W. BARRY and K. H. PATTISHALL.

With 2 Figures

A. Introduction 261B. Microbiologic and Pharmacokinetic Properties 261C. Relation of Sensitivities and Pharmacokinetics to Therapy of Urinary

Tract Infections 264I. General 264

II. Uncomplicated Urinary Tract Infections 267III. Complicated Urinary Tract Infections 271

D. Prophylaxis 273I. Recurring Urinary Infection in Women and Children 273

II. Immunosuppressed Patients 275E. Adverse Reactions and Safety 276

I. General 276II. Dermatologic 277

III. Gastrointestinal , 280IV. Hematologic 280

F. Bacterial Resistance 281I. General 281

II. Finnish Experience 282III. Effect on Fecal Flora 286

G. Conclusion 286References 287

CHAPTER 13

Inhibitors of Dihydrofolate Reductase as Antiprotozoal Agents. I. M. ROLLO.

With 4 Figures

A. Introduction 293B. Points of Possible Therapeutic Attack 295

Contents XVII

C. Antimalarial Therapeutics 296I. Early Trials 297

II. Clinical Cure with Pyrimethamine 298III. Causal Prophylaxis 299IV. Suppression and Mass Prophylaxis 300V. Gametocyticidal Effects 301

VI. Radical Cure 302VII. Drug Resistance 303

VIII. Combination with Sulfonamides and Sulfones 3031. Suppressive and Clinical Cure 3032. Effect on Other Sporozoa 305

References 306

CHAPTER 14Pediatric Uses of Sulfonamides, Trimethoprim, and the Combination.L. T. GUTMAN and C. M. WILFERT

A. Introduction 309B. Hemophilus influenzae Infections 309

I. Otitis Media 3101. Acute 3102. Serous and Chronic 311

II. Sinusitis 311III. Prophylaxis to Prevent Secondary Infection 312

C. Meningitis 314D. Urinary Tract Infections 315

I. Acute 315II. Structural Defects of the Urinary System . 315

III. Prevention . 315IV. Therapy of Periurethral and Rectal Flora . 316V. Chlamydial Infections 316

E. Pneumocystis carinii Pneumonia 318I. Therapy 318

II. Prevention 319F. Enteric Diseases 320

I. Salmonellosis 320II. Shigellosis 321

III. Yersinia Infections 3221. Acute Enteritis 3232. Chronic Enteritis 3233. Mesenteric Adenitis 323

G. Miscellaneous Conditions 324I. Chronic Granulomatous Disease 324

II. Osteomyelitis 324III. Ascending Cholangitis 324

References 325

XVIII Contents

CHAPTER 15

Use of Co-trimoxazole in Urinary Tract Infection. F. O'GRADY. With 2 Figures

A. Introduction 331B. Co-trimoxazole in Acute Urinary Tract Infection 331

I. Epidemiology of Resistance 3321. Types of Resistance 332

II. Effects of Carriage Sites 3331. Effect on Gut Flora 3332. Effect on Urethral Colonisation 334

III. Overtreatment 334C. Control of Recurrent Infection 335D. Role of the Combination 337

I. Contrasting Effects of Trimethoprim and Sulfonamide in the Urine 337II. Toxicity 339

References 339

CHAPTER 16Treatment of Genital Infections with Trimethoprim, Sulfonamides, andCombinations. W. E. STAMM

A. Introduction 343B. Treatment of Gonorrhea with Trimethoprim/Sulfamethoxazole . . . . 343

I. Uncomplicated Anogenital Infection 343II. Rectal Infection 348

III. Pharyngeal Infection 348IV. In Vitro Studies and Treatment of Gonorrhea with Trimethoprim/

Sulfamethoxazole 348C. Infections Due to Chlamydia trachomatis 350

I. Postgonococcal Urethritis 350II. Nongonococcal Urethritis 351

III. Lymphogranuloma Venereum 352D. Chancroid 352E. Syphilis 354References 354

CHAPTER 17

Treatment of Enteric Infections and Combinations. M. L. CLEMENTS,

R. E. BLACK, and M. M. LEVINE

A. Escherichia coli Diarrhea 357I. Introduction 357

II. Trimethoprim/Sulfamethoxazole Treatment of E. coli Diarrhea . . 3571. In Vitro Studies 3572. Clinical Studies 358

III. Summary 358

Contents XIX

B. Isospora belli Infections 358I. Introduction 358

II. Trimethoprim/Sulfamethoxazole Treatment of an Isospora belliInfection 359

C. Salmonella Infections 359I. Introduction 359

1. Typhoidal and Paratyphoidal Salmonella Infections 3592. Non-Typhoidal Salmonella Infections 360

II. Trimethoprim/Sulfamethoxazole in the Treatment of Salmonellatyphi Infections 3611. Therapeutic Studies in Antibiotic-Sensitive S. typhi Infections . 3612. Studies in Infections Due to Chloramphenicol-Resistant S. typhi

Strains 3633. Trimethoprim/Sulfamethoxazole Treatment of Typhoid Carriers 3644. Adverse Effects 3655. Summary 365

III. Trimethoprim Alone in Treatment of Enteric Fever 366IV. Trimethoprim/Sulfamethoxazole Therapy in Non-Typhoidal

Salmonellosis 3661. In Vitro Studies 3662. Clinical Studies 3673. Summary 368

D. Shigella 368I. Introduction 368

II. Trimethoprim/Sulfamethoxazole Treatment in Shigellosis . . . . 3691. In Vitro Studies 3692. Clinical Studies 3703. Summary 371

E. Vibrio cholerae Infections 371I. Introduction : . 371

II. Trimethoprim/Sulfamethoxazole Treatment in Cholera . . . .'• . 3721. In Vitro Studies . 3722. Clinical Studies 3723. Summary 373

F. Yersinia enterocolitica Infections 373I. Introduction 373

II. Trimethoprim/Sulfamethoxazole and Yersinia enterocolitica . . . 3741. In Vitro Studies 3742. Clinical Report 3753. Summary 375

References 375

CHAPTER 18

Prostatitis. T. A. STAMEY. With 1 Figure

A. Introduction 379B. Classification and Description of Patient Categories 379

XX Contents

C. Acute and Chronic Bacterial Prostatitis 382I. Diagnosis 382

II. Pathology 384III. Prostatic Immunoglobulins 384IV. The Antibacterial Factor in Prostatic Fluid 385V. Treatment 386

D. Nonbacterial Prostatitis 390References 392

CHAPTER 19

Co-trimoxazole in Chest Infections Including its Long-Term Use in ChestDisease. D. T. D. HUGHES

A. Introduction 397B. Exacerbations of Chronic Bronchitis 397

I. Levels of Two Components in Sputum 399II. Comparative Trials 400

C. Other Acute Conditions 402I. Pneumocystis carinii Pneumonia 403

D. Long-Term Treatment 404E. Parenteral TMP/SMX 406F. Alternative Drugs 406G. Trimethoprim Alone 407H. Future Developments 408References 409

CHAPTER 20

Treatment of Miscellaneous and Unusual Infections with Trimethoprim andTrimethoprim/Sulfonamide Combinations. R. E. DESJARDINS

A. Introduction 411B. Brucellosis 411C. Toxoplasmosis 414D. Nocardiosis 417E. Atypical Mycobacteria 421F. Mycoses 422

I. Histoplasmosis 422II. Paracoccidioidomycosis 423

III. Phycomycosis 424IV. Chromomycosis 425

G. Pseudomonas Infections 425I. Pseudomonas pseudomallei 426

II. Pseudomonas cepacia and Pseudomonas maltophilia 427H. Other Infections 428

I. Bubonic Plague 429

Contents XXI

II. Rickettsiosis 4291. Boutonneuse Fever 4302. Q Fever 430

III. Legionella pneumophila and Pittsburgh Pneumonia Agent Infections 430IV. Isospora belli Infections 430V. Malakoplakia 431

VI. Pediculosis 431References 431

Subject Index 441