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INTRODUCTION

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Sulfonamides and trimethoprim are antimetabolites selectively toxic to microorganisms because they interfere with folic acid synthesis. Sulfonamides continue to be used selectively as individual antimicrobial agents, although resistance is common. The combination of a sulfonamide with trimethoprim causes a sequential blockade of folic acid synthesis. This results in a synergistic action against a wide spectrum of microorganisms; resistance occurs but has been relatively slow in development.

Fluoroquinolones, which selectively inhibit microbial nucleic acid metabolism, also have a broad spectrum of antimicrobial activity that includes many common pathogens. Resistance has emerged to the older antibiotics in this class, but has been offset to some extent by the introduction of newer fluoroquinolones with expanded activity against common pathogenic organisms.

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ANTIFOLATE DRUGS

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A. Classification and Pharmacokinetics
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The antifolate drugs used in the treatment of infectious diseases are the sulfonamides, which inhibit microbial enzymes involved in folic acid synthesis, and trimethoprim, a selective inhibitor of dihydrofolate reductase.

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1. Sulfonamides
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The sulfonamides are weakly acidic compounds that have a common chemical nucleus resembling p-aminobenzoic acid (PABA). Members of this group differ mainly in their pharmacokinetic properties and clinical uses. Pharmacokinetic features include modest tissue penetration, hepatic metabolism, and excretion of both intact drug and acetylated metabolites in the urine. Solubility may be decreased in acidic urine, resulting in precipitation of the drug or its metabolites. Because of the solubility limitation, a combination of 3 separate sulfonamides (triple sulfa) has been used to reduce the likelihood that any one drug will precipitate. The sulfonamides may be classified as short-acting (eg, sulfisoxazole), intermediate-acting (eg, sulfamethoxazole), and long-acting (eg, sulfadoxine). Sulfonamides bind to plasma proteins at sites shared by bilirubin and by other drugs.

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2. Trimethoprim
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This drug is structurally similar to folic acid. It is a weak base and is trapped in acidic environments, reaching high concentrations in prostatic and vaginal fluids. A large percentage of trimethoprim is excreted unchanged in the urine. The half-life of this drug is similar to that of sulfamethoxazole (10–12 h).

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High-Yield Terms to Learn
Antimetabolite A drug that, through chemical similarity, is able to interfere with the role of an endogenous compound in cellular metabolism
Sequential blockade The combined action of 2 drugs that inhibit sequential steps in a pathway of bacterial metabolism
DNA gyrase Bacterial topoisomerase responsible for negative supercoiling of double-stranded DNA that balances the positive supercoiling of DNA replication, preventing damage to the DNA strand
Topoisomerase IV Bacterial topoisomerase initiating decatenation, the mechanism by which 2 daughter DNA molecules are separated at the conclusion of DNA replication

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B. Mechanisms of Action
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1. Sulfonamides
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The sulfonamides are bacteriostatic inhibitors of folic acid synthesis. As antimetabolites of PABA, they ...

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