Quinolones, Antifolate Drugs, and Other Antimicrobial Agents

Quinolones, Antifolate Drugs, and Other Antimicrobial Agents

Antifolate Drugs

There are two types of antifolate drugs used in chemotherapy. Members of the first group, the sulfonamides, inhibit the synthesis of dihydrofolate in some bacteria and parasites. Members of the second group, the folate reductase inhibitors, block the action of dihydrofolate reductase and the formation of tetrahydrofolate in various organisms. This second group includes the following: pyrimethamine, which inhibits folate reduction in some protozoa and is primarily used to treat toxoplasmosis and malaria (see Chapter 44); methotrexate, which inhibits folate reduction in mammalian cells and is used in the treatment of neoplastic and autoimmune diseases (see Chapter 45); and trimethoprim, which selectively blocks folate reduction in bacteria as described later in this chapter (see section on trimethoprim).

Mechanisms of Action

Bacterial synthesis of folate begins with the fusion of pteridine and p-aminobenzoic acid (PABA) to form dihydrofolate. This step involves the enzyme dihydropteroate synthase. Dihydrofolate is then converted to tetrahydrofolate by folate reductase.

In bacteria, the sulfonamides and trimethoprim inhibit sequential steps in the synthesis of folate (Fig. 40-1). The sulfonamides are structural analogues of PABA and competitively inhibit dihydropteroate synthase. Hence their effects can be counteracted by the administration of PABA. Trimethoprim inhibits bacterial folate reductase.

Mammals must obtain folic acid in their diet because they are unable to synthesize dihydrofolate. Once absorbed, dihydrofolate is converted to tetrahydrofolate and active folate derivatives (methyl, formyl, and methylene tetrahydrofolate) that donate single-carbon atoms during the synthesis of purine bases and other components of DNA (see Chapter 17). Although folate reductase is found in both microbial and mammalian cells, the affinity of trimethoprim for the enzyme in bacteria is about 100,000 times greater than its affinity for the mammalian enzyme.


In the 1930s, sulfanilamide was found to be the active metabolite of PRONTOSIL, a dye that had been developed in the search for bacterial stains with antimicrobial properties. This discovery led to the synthesis and development of a large number of sulfonamide compounds to treat bacterial infections. Only a few of these are still used today.

Chemistry and Pharmacokinetics

The sulfonamides are benzene sulfonic acid amide derivatives. Most sulfonamides are adequately absorbed from the gut and are widely distributed to tissues and fluids throughout the body, including the cerebrospinal fluid. The half-lives of sulfonamides vary greatly (Table 40-1), but the most widely used compounds for treating human infections, such as sulfacetamide and sulfamethoxazole, have half-lives ranging from 6 to 10 hours.

TABLE 40-1

Pharmacokinetic Properties of Selected Antifolate Drugs, Fluoroquinolones, and Other Agents*

Antifolate Drugs
Sulfacetamide Topical ocular NA 10 Metabolism; renal excretion
Trimethoprim Oral Approximately 100 10 Metabolism; renal excretion
Trimethoprim-sulfamethoxazole Oral or IV Approximately 100 10 Metabolism; renal excretion
Ciprofloxacin Oral, IV, or topical ocular 75 4 Metabolism; renal excretion
Levofloxacin Oral or IV 99 8 Metabolism; renal excretion
Norfloxacin Oral 35 3.5 Metabolism; renal excretion
Moxifloxacin Oral or IV 90 12 Metabolism; renal excretion
Gatifloxacin Topical ocular NA NA Metabolism; renal excretion
Gemifloxacin Oral 71 7 Metabolism, renal excretion
Other Antibacterial Drugs
Nitrofurantoin Oral 87 0.5 Metabolism; renal excretion
Polymyxin B IV or topical NA 5 NA
Daptomycin IV NA 9 Renal excretion


IV, Intravenous; NA, not applicable.

*Values shown are the mean of values reported in the literature.

Sulfonamides are converted to inactive compounds by N-acetylation, and the parent drug and its metabolites are excreted in the urine. The acetylated metabolites are less soluble than the parent compound in urine, and they can precipitate in the renal tubules, causing crystalluria. Therefore it is important for patients who are being treated with a sulfonamide to consume adequate quantities of water.

Spectrum, Indications, and Bacterial Resistance

The sulfonamides were the first drugs used in the treatment of systemic bacterial infections. They were once active against a wide variety of organisms, including streptococci, gonococci, meningococci, many gram-negative bacilli, and chlamydiae. Over the years, however, significant resistance to sulfonamides has developed in many bacterial species, and the antimicrobial spectrum of these drugs has been greatly reduced. Today, sulfonamides are primarily used to prevent or treat urinary tract infections (Table 40-2).

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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Quinolones, Antifolate Drugs, and Other Antimicrobial Agents

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