Clinical pharmacokinetics of co-trimoxazole (trimethoprim-sulphamethoxazole).

The combination trimethoprim-sulphamethoxazole (co-trimoxazole) is used clinically for the treatment of a variety of infections due to Gram-positive and Gram-negative organisms; particularly for urinary and respiratory tract infections. While both trimethoprim and sulphamethoxazole are mainly bacteriostatic when used alone, their combined effect tends to be bactericidal. Synergism is due to sequential blockade at two separate steps in bacterial folate metabolism, resulting in inhibition of deoxyribonucleic acid synthesis. The optimum concentration ratio of trimethoprim sulphamethoxazole for a bactericidal effect varies between 1:5 and 1:40, which is consistent with their relative minimum inhibitory concentration (MIC) values against susceptible organisms. The combination is administered principally by the oral route, although it is also given parenterally and rectally. A single oral dose of 160mg trimethoprim and 800mg sulfamethoxazole gives peak serum levels at approximately 4h of 1.2 to 2μg/ml trimethoprim and 26 to 63μg/ml sulphamethoxazole. After repeated 12-hourly doses, minimum serum levels are 1.3 to 2.8μg/ml and 32 to 63μg/ml for trimethoprim and sulphamethoxazole respectively. The high concentration of sulphamethoxazole in serum relative to that of trimethoprim is due to the greater tissue penetration of trimethoprim. The high sulphamethoxazole:trimethoprim concentration ratio in serum does not always occur in extravascular tissues. However, this is partially compensated for by the high bacteriostatic activity of trimethoprim alone in tissues. The 2 compounds are bound to plasma proteins to similar extents. Both trimethoprim and sulphamethoxazole obey first order absorption, distribution, and elimination kinetics. The disposition of sulphamethoxazole in the body after oral doses has been described in terms of one-compartment model kinetics, while both one-compartment and two-compartment model kinetics have been used to describe the disposition of trimethoprim. Both compounds are cleared from the body predominantly via the kidneys, sulphamethoxazole being excreted mainly in the acetylated form. Average elimination half-lives of trimethoprim and sulphamethoxazole are 11 and 9h respectively, although there is considerable individual variation in these values. The clearance of both compounds is not markedly affected by declining renal function until creatinine clearance falls below 30ml/min. In severe renal failure, the elimination half-lives of both drugs may increase to 45 to 60h and adjustment of dosage is necessary to avoid renal toxicity. Both trimethoprim and sulphamethoxazole appear in bile at concentrations similar to those observed in serum, although the sulphamethoxazole:trimethoprim concentration ratio in bile is somewhat less than that in serum. Trimethoprim and sulphamethoxazole give rise to only occasional side effects, which are characteristic of the individual compounds. Principal reactions are those associated with sulphonamide sensitivity, and renal toxicity in patients with impaired renal function. Anaemia due to impaired folate metabolism may be a problem in some patients.