Cotrimoxazole is an antibiotically active combination drug composed of the antibiotic trimethoprim and the sulfonamide sulfamethoxazole in a fixed ratio of one to five. The drug inhibits the biosynthesis of tetrahydrofolic acid in bacteria, thereby impeding DNA synthesis. Cotrimoxazole, which is used primarily to treat urinary tract and respiratory tract infections and against typhoid and paratyphoid fever, is also effective against certain protozoa and some types of fungi.
What is cotrimoxazole?
Cotrimoxazole is a combination drug with bacteriostatic activity against a wide range of Gram-positive and Gram-negative bacteria. In addition, the combination drug is also effective against certain protozoa and some types of fungi. It contains the antibiotic trimethoprim and the antibiotically active sulfonamide sulfamethoxazole in a ratio of one to five. The two main active ingredients of the drug largely complement each other and interfere with the folic acid balance of bacteria. Sulfamethoxazole, in its capacity as a sulfonamide, inhibits the enzyme folic acid synthetase. The antibiotic trimethoprim in turn inhibits dihydrofolate reductase, another important enzyme of folic acid metabolism in bacteria. In this way, the combined active ingredients simultaneously inhibit two different enzymes of folic acid metabolism, so that the risk of resistance forming due to the double track is reduced. Cotrimoxazole ultimately impedes the synthesis of tetrahydrofolic acid, which is an essential intermediate (metabolite) required for the synthesis of purine bases and thymidine, building blocks of DNA. An important requirement for combining two or more active ingredients is that their biological half-lives be approximately the same. Cotrimoxazole meets the condition very well, with half-lives of 10-11 hours and 9-11 hours for trimethoprim and sulfamethoxazole, respectively, in the latter case.
Pharmacological action
Pharmacologically, the ingestion of cotrimoxazole has direct and indirect effects on the body and its organs. The bacteriostatic properties of the drug do not extend exclusively to pathogenic bacteria but, because of its broad-spectrum action, also partially affect normal bacterial flora, especially in the digestive tract, so that not infrequently reversible but sometimes serious digestive problems are observed. The two main active ingredients are almost 100 percent absorbed in the intestine and are biologically available. Direct pharmacological effects consist mainly of allergic reactions, which are manifested, for example, in skin irritations and, in rare cases, in vesicular skin scaling (Lyell’s syndrome). The bacteriostatic properties of cotrimoxazole, which are based on the inhibition of folic acid formation, can also affect metabolism to a certain extent, so that general anemia can develop, especially if other drugs with a similar spectrum of action, such as barbiturates, painkillers, and phenytoin or primidone, are taken in parallel. Other indirect effects may result from a direct influence on potassium balance, which may have an impact on cardiac rhythm and sensory nerve sensitivity.
Medical application and use
A typical major use of cotrimoxazole is inflammation of the upper and lower respiratory tract. A major advantage of the combination drug is that it can also control the fungus Pneumocystis jirovecii, causative agent of interstitial pneumonia. Another main area of application is infections of the kidneys and the entire male and female genitourinary tract. Treatable conditions also include inflammation of the prostate and venereal diseases such as ulcus molle (soft chancre) and lymphogranuloma inguinale, an infectious venereal disease more common in the tropics that causes, among other things, swelling of the lymph nodes in the genital and inguinal areas. Similarly, cotrimoxazole is used to treat infections of the gastrointestinal tract, including salmonella poisoning and typhoid and paratyphoid fever. Brucellosis and nocardiosis, as well as other infectious diseases, are also part of the combination drug’s spectrum of use. The reduced risk of pathogenic germs developing resistance allows the combination drug to be used for preventive purposes as well, especially in immunocompromised individuals.Due to its broad spectrum of use, the World Health Organization (WHO) included the drug combination of trimethoprim and sulfamethoxazole in the list of essential medicines as early as 1977. To treat an infection, the dose for adults is normally 2 x 960 milligrams daily. The dose may be increased up to five times if acute Pneumocystis jirovecii is present. For long-term therapy and for preventive measures, the daily dose is reduced to 480 milligrams.
Risks and side effects
As with treatment with other antibiotics, use of cotrimoxazole may be associated with adverse side effects. The most common side effects involve transient disturbances of the digestive system. Symptomatic symptoms include nausea, vomiting, and loss of appetite. In rarer cases, oral mucosal inflammation also occurs. Skin reactions such as rash and hives occur in up to 4 percent of cases. More severe skin irritation or photosensitization has been observed, but is rare. Blood count disorders in the form of anemia or a decrease in leukocytes (leukopenia) may also occur. At high doses of cotrimoxazole, potassium levels may increase and cause hyperkalemia, with symptoms such as cardiac arrhythmias, muscle weakness, and paralysis. Before treatment with the combination drug, the main interactions with other drugs should be considered. For example, the effect of anticoagulants from the 4-hydroxycoumarin group of substances is enhanced. Treatment with cotrimoxazole is contraindicated in cases of known hypersensitivity to sulfonamides or severe renal insufficiency.