Molecular structure of trimethoprimTetrahydrofolate synthesis pathway
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Trimethoprim

Trimethoprim is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections (cystitis). It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors. Trimethoprim was formerly marketed by GlaxoWellcome under trade names including Proloprim®, Monotrim® and Triprim®; but these trade names have been licensed to various generic pharmaceutical manufacturers. more...

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Mechanism of action

Trimethoprim acts by interfering with the action of bacterial dihydrofolate reductase, inhibiting synthesis of tetrahydrofolic acid. Folic acid is an essential precursor in the de novo synthesis of the DNA nucleosides thymidine and uridine. Bacteria are unable to take up folic acid from the environment (i.e. the infection host) thus are dependent on their own de novo synthesis - inhibition of the enzyme starves the bacteria of two bases necessary for DNA replication and transcription.

Co-trimoxazole

Trimethoprim is commonly used in combination with sulfamethoxazole, a sulfonamide antibiotic, which inhibits the an earlier step in the folate synthesis pathway (see diagram above). This combination, known as co-trimoxazole, results in a synergistic antibacterial effect by inhibiting successive steps in folate synthesis. Its use has been declining due to reports of sulfamethoxazole bone marrow toxicity.

Clinical indications

Trimethoprim, used as monotherapy, is indicated for the prophylaxis and treatment of urinary tract infections (cystitis). Co-trimoxazole, owing to its greater efficacy, is indicated for a wider range of infections. For example, it is used as prophylaxis in patients at risk for Pneumocystis jiroveci pneumonia (e.g. AIDS patients and those with some hematological malignancies), as therapy in Whipple's disease and certain other infections.

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Potassium hazard seen in AIDS drug - trimethoprim may elevate potassium levels in blood - Brief Article
From Science News, 12/5/92 by Daniel Pendick

Physicians often administer large doses of the drug trimethoprim (TMP) to combat pneumocystis carinii pneumonia, a common opportunistic infection in AIDS patients. TMP, however, can also elevate potassium in the blood, creating a condition called hyperkalemia. As many as 53 percent of hospitalized AIDS patients treated with TMP develop mild to moderate hyperkalemia.

Researchers Michael J. Choi, Thomas R. Kleyman, and Pedro C. Fernandez of the Veterans Administration Medical Center in Philadelphia report that they have discovered the cellular mechanism that causes this side effect. But more important clinically, they have observed an AIDS patient treated with TMP whose hyperkalemia reached the point of "medical emergency," says Choi.

This case should alert physicians to the possible life-threatening consequences of using massive doses of TMP to treat pneumocystis carinii pneumonia, he suggests.

TMP does not generally elevate potassium concentrations to harmful levels. But a significant number of AIDS patients already suffer hyperkalemia caused by kidney failure or hormone deficiencies. For these patients, treatment with TMP could boost the potassium in their blood to dangerous levels, causing heart cells to fire erratically and even bringing on cardiac arrhythmia, Choi says.

COPYRIGHT 1992 Science Service, Inc.
COPYRIGHT 2004 Gale Group

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