Sulphonamide-trimethoprim combinations

As on date, there exist a few typical sulphonamides and partieularly the sulphonamide-trimethoprim combinations which find their applications exclusively and most extensively for the management and treatment of the opportunistic infections in humans having AIDS. A few typical examples are as illustrated below ... 

Co-lrimoxazcde (trimethoprim combined with suUamethoxazule). Because the side-effecLs of co-trimoxazole are mainly the same us those of the sulphonamides, its use is now largely restricted to treating patients w ith PneunuKystis carinii (meumonia. nocardiasis and t[Pg.81]

Noli, C., Koeman, J.P., andWillemse, T., A retrospective evaluation of adverse reactions to trimethoprim-sulphonamide combinations in dogs and cats. Vet. Q., 17, 123-128, 1995. 

Sulphonamides, amongst the first successful chemotherapeutic agents, now have their place in medicine mainly in combination with trimethoprim. Because of the risks of adverse drug reactions associated with their use, this is generally restricted to specific indications where other therapeutic agents have clearly inferior efficacy. Many sulphonamide compounds have been withdrawn from the market. Their individual names are standardised in the UK to begin with sulfa-. ... 

Co-trimoxazole, at first, very largely replaced the use of a sulphonamide alone. In turn, trimethoprim on its own is now used in many conditions for which the combination was originally recommended, and it may cause fewer adverse reactions (see below). The combination is, however, retained for ... 

Proguardl (t) 17 h) inhibits dihydrofolate reductase which converts folic to folinic acid, deficiency of which inhibits plasmodial cell division. Plasmodia, like most bacteria and unlike humans, cannot make use of preformed foUc acid. Pyrimethamine and trimethoprim, which share this mode of action, are collectively known as the antifols. Their plasmod-icidal action is markedly enhanced by combination with sulphonamides or sulphones because there is inhibition of sequential steps in folate synthesis (see Sulphonamide combinations, p. 231). 

Gruneberg RN. The microbiological rationale for the combination of sulphonamides with trimethoprim. J Antimicrob Chemother 1979 5(B) 27-36. 

Co-trimoxazole is a mixture of sulphamethoxazole (five parts) and trimethoprim (one part). The reason for using this combination is based upon the in vitro finding that there is a sequential blockade of folic acid synthesis, in which the sulphonamide is a competitive inhibitor of dihydropteroate synthetase and trimethoprim inhibits DHFR (see Chapter 12). The optimum ratio of the two components may not... 

A most interesting and useful development concerning DHR inhibitors was the selectivity of inhibition observed between different classes of compounds against dihydrofolate reductases from mammals, protozoa and bacteria, which was found to be due to marked differences in binding affinity to the enzyme methotrexate binds very tightly to all reductases tested and is lethal to any cell it can enter, while trimethoprim and pyrimethamine have selectively strong affinity for bacterial and plasmodial reductases, respectively. This helped to rationalise the clinical use of DHFR inhibitors alone or in combination with sulphonamides and sulphones while trimethoprim is used mainly for bacterial infections, pyrimethamine is used for protozoal infections [58a]. 

Trimethoprim inhibits another enzyme, dihydrofolate reductase, in the same folic acid metabolic pathway. Folic acid is converted into folate, which then has to be converted into an activated form by dihydrofolate reductase. In this way, trimethoprim interferes with the conversion of folate into its activated form, which is a cofactor in the synthesis of bacterial DNA. Dihydrofolate reductase also occurs in host cells, but it is less sensitive to trimethoprim. Trimethoprim is used to treat urinary tract infections. It is also formulated in combination with a sulphonamide, when it is known as co-trimoxazole, to treat pneumonia in patients with HIV (see page 170). Due to the synergistic effect of the two drugs, this combination is more effective than either drug alone. 

Not established. The pharmaeokinetie and pharmacodynamic evidence in-dieates that eo-trimoxazole is not likely to reduce the effectiveness of combined oral eontraeeptives. Although there are a number of reports of contraceptive failure attributed to co-trimoxazole, these are anecdotal and unconfirmed, whereas the studies suggest increased contraceptive efficacy (but see below). It is possible that the cases are coincidental, and fit within the normal failure rate of combined oral contraceptives. The UK Family Planning Authority considered that it was almost certain that co-trimoxazole and sulphonamides did not interact with combined oral contraceptives. However, the Faculty of Family Planning and Reproductive Health Care (FFPRHC) Clinical Effectiveness Unit has issued guidance on the use of antibacterials with hormonal contraceptives. Although they recognise that there is poor evidence for contraceptive failure, they recommend that additional contraceptives, such as condoms, should be used for short courses of antibacterials, see Hormonal contraceptives + Antibacterials Penicillins , p.981, for more detailed information. This applies to both the oral and the patch form of the combined contraceptive. This advice has usually been applied to only broad-spectrum antibacterials that do not induce liver enzymes but the FFPRHC notes that some confusion has occurred over which antibacterials are considered to be broad-spectrum , and thus they recommend that this advice is applied to all antibacterials that do not induce liver enzymes, which would include co-trimoxazole, sulfonamides and trimethoprim. ... 

The combination of a sulphonamide with trimethoprim (Wellcome and Roche, 1968), an inhibitor of microbial dihydrofolate reductase, blocks two steps in the synthesis of tetrahydrofolate and leads to a synergistic antibacterial effect. Trimethoprim sulphamethoxazole combinations (Figure 4.22) continue to play an important role in antibacterial therapy (Table 4.4) but as a... 

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