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 topisomerase responsible for negative supercoiling of double-stranded DNA that balances the positive supercoiling of DNA replication and acts as a “swivel,” preventing damage to the DNA strand Topoisomerase IV Bacterial topisomerase initiating decatenation, the mechanism by which 2 daughter DNA molecules are separated at the conclusion of DNA replication

Antifolate Drugs

Classification and Pharmacokinetics

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.

Sulfonamides

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.

Trimethoprim

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).

Mechanisms of Action

Sulfonamides

The sulfonamides are bacteriostatic inhibitors of folic acid synthesis. As antimetabolites of PABA, they are competitive inhibitors of dihydropteroate synthase (Figure 46-1). They can also act as substrates for this enzyme, resulting in the synthesis of nonfunctional forms of folic acid. The selective toxicity of sulfonamides results from the inability of mammalian cells to synthesize folic acid; they must use preformed folic acid that is present in the diet.

FIGURE 46-1

Inhibitory effects of sulfonamides and trimethoprim on folic acid synthesis. Inhibition of 2 successive steps in the formation of tetrahydrofolic acid constitutes sequential blockade and results in antibacterial synergy.

Trimethoprim

Trimethoprim is a selective inhibitor of bacterial dihydrofolate reductase that prevents formation of the active tetrahydro form of folic acid (Figure 46-1). Bacterial dihydrofolate reductase is 4-5 orders of magnitude more sensitive to inhibition by trimethoprim than the mammalian enzyme.

Trimethoprim Plus Sulfamethoxazole

When the 2 drugs are used in combination, antimicrobial synergy results from the sequential blockade of folate synthesis (Figure 46-1). The drug combination is bactericidal against susceptible organisms.

Resistance

Bacterial resistance to sulfonamides is common and may be plasmid-mediated. It can result from decreased intracellular accumulation of the drugs, increased production of PABA by bacteria, or a decrease in the sensitivity of dihydropteroate synthase to the sulfonamides. Clinical resistance to trimethoprim most commonly results from the production of dihydrofolate reductase that has a reduced affinity for the drug.

Clinical Use

Sulfonamides

The sulfonamides are active against gram-positive and gram-negative organisms, Chlamydia, and Nocardia. Specific members of the sulfonamide group are used by the following routes for the conditions indicated:

Simple Urinary Tract Infections

Oral (eg, triple sulfa, sulfisoxazole).

Ocular Infections

Topical (eg, sulfacetamide).

Burn Infections

Topical (eg, mafenide, silver sulfadiazine).

Ulcerative Colitis, Rheumatoid Arthritis

Oral (eg, sulfasalazine).

Toxoplasmosis

Oral sulfadiazine plus pyrimethamine (a dihydrofolate reductase inhibitor) plus folinic acid.

Trimethoprim-Sulfamethoxazole (TMP-SMZ)

This drug combination is effective orally in the treatment of urinary tract infections and in respiratory, ear, and sinus infections caused by Haemophilus influenzae and Moraxella catarrhalis. In the immunocompromised patient, TMP-SMZ is used for infections due to Aeromonas hydrophila

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