Generality
Trimethoprim is a synthetic antibacterial drug with bacteriostatic activity, ie it is not able to kill bacterial cells, but it is able to inhibit its growth.
It was developed in 1969 by the American doctor George Hitchings and by the American pharmacologist and biochemist Gertrude Elion.
Trimethoprim - Chemical Structure
Generally, trimethoprim is administered in combination with various types of sulfonamides (other antibacterial drugs).
The combination of these two types of antibacterials is able to exert bactericidal action on bacterial cells. Furthermore, the association induces less resistance than that induced by the two drugs used individually. However, if the bacteria treated with the trimethoprim-sulfonamide combination already possess resistance against one of the two antimicrobials, the advantage of the combination in administration is thwarted.
There are various associations between trimethoprim and sulfonamides, the most famous and the most used is probably the one that gives rise to cotrimoxazole.
Co-trimoxazole is nothing but an antibacterial consisting of the combination of sulfamethoxazole and trimethoprim in a fixed 5: 1 ratio.
Indications
For what it uses
Trimethoprim can be used alone to treat uncomplicated urinary tract infections caused by Escherichia coli or other Gram-negative bacteria.
When trimethoprim is administered in combination with sulphonamides, it may be useful for the treatment of:
- Urinary infections;
- Medium ear plugs;
- Shigellosis;
- Diarrhea of the traveler;
- Legionellosis;
- Bronchitis;
- Infections caused by methicillin-resistant Staphylococcus aureus (MRSA infections);
- Infections with Pneumocystis jirovecii (formerly known as Pneumocystis carinii ) that cause pneumonia in AIDS patients.
Action mechanism
Trimethoprim performs its antibacterial action by interfering with the synthesis of tetrahydrofolic acid within bacterial cells.
Tetrahydrofolic acid is an essential compound for the synthesis of purine and pyrimidine bases that will then go to make up bacterial DNA.
More in detail, trimethoprim is able to inhibit the enzyme involved in the last stage of the synthesis of tetrahydrofolic acid, this enzyme is dihydrofolate reductase .
Sulfa drugs, on the other hand, inhibit dihydropteroate synthetase, an enzyme involved in the first stages of the aforementioned synthesis.
With the association of the two types of antibacterials, therefore, we are witnessing a sequential block of two fundamental passages of the same metabolic pathway, in this way, it is very difficult for microorganisms to survive.
Side effects
Trimethoprim can induce undesirable effects such as:
- Allergic reactions in sensitive subjects;
- Skin hypersensitivity reactions;
- Stevens-Johnson syndrome;
- Skin rash;
- Gastrointestinal disorders, such as nausea and vomiting;
- Blood dyscrasias.
Furthermore, the use of trimethoprim can favor the development of superinfections with resistant bacteria or fungi. Such as, for example, infections with Clostridium difficile, the bacterium responsible for the onset of pseudomembranous colitis manifested by severe diarrhea, sometimes accompanied by blood.
Resistance to trimethoprim
Unfortunately, many bacteria have developed and continue to develop resistance to trimethoprim.
The mechanisms by which microorganisms develop this resistance seem essentially two:
- Mutation of one of the amino acids that make up dihydrofolate reductase, thus making the enzyme resistant to inhibition by antimicrobial;
- Overexpression of the same dihydrofolate reductase. It seems that this mechanism is a peculiarity of some resistant strains of Staphylococcus aureus .
