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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Increased Resistance to One Drug Used in HIV Patients. - trimethoprim-sulfamethoxazole TMP-SMX
From American Family Physician, 4/15/00 by Karl E. Miller

One of the most effective agents used for preventing pneumocystic infections in patients with human immunodeficiency virus (HIV) infection is trimethoprim-sulfamethoxazole (TMP-SMX). However, long-term use of this antibiotic may increase the risk for creating resistant organisms. If the risk for developing resistant organisms is high, an alternative treatment strategy may be necessary. Martin and associates studied the impact of TMP-SMX on the incidence of resistant organisms before and during the widespread use of this antibiotic in HIV patients.

The study consisted of evaluating the incidence of resistance to TMP-SMX in patients at a general hospital. From 1988 through 1995, each culture sample that was submitted to the clinical microbiology laboratory was recorded. For each sample, the date and site of collection, demographic information, and microbiologic and antimicrobial susceptibility data were noted. All inpatients and outpatients who were infected with Staphylococcus aureus or one of seven Enterobacteriaceae species and who had TMP-SMX susceptibility testing were included in the study.

Resistance of all isolates to TMP-SMX increased from less than 5.5 percent before 1988 to 20.4 percent in 1995. HIV-infected patients had a significantly higher incidence of resistance than the general population. The largest increase was in Escherichia coli and S. aureus in patients with HIV. During the same period, a rapid rise in TMP-SMX use occurred in relation to pneumocystic infection prevention.

The authors conclude that in an area with a high incidence of HIV infection, the use of TMP-SMX for empiric pneumocystic infection prevention should no longer be an option. Because of the increase of resistant organisms, the use of this broad-spectrum antibiotic in HIV patients may select for multiresistant organisms and complicate future therapeutic options.

KARL E. MILLER, M.D.

Martin JN, et al. Emergence of trimethoprim-sulfamethoxazole resistance in the AIDS era. J Infect Dis December 1999;180:1809-18.

COPYRIGHT 2000 American Academy of Family Physicians
COPYRIGHT 2000 Gale Group

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