抗微生物剤の生体内動態に関する研究

Sulfamethoxazole-Trimethoprim合剤について

抄録

The following results have been obtained from our investigations on a new chemotherapeutic agent, sulfamethoxazole (SMX) -trimethoprim (TMP) combination product :
1. A marked potentiation of activities against Staphylococcus aureus, Enterobacteriaceae and other strains has been demonstrated in vitro by the combination of SMX-TMP. Pseudomonas strains were resistant to the combination.
2. The mode of action of TMP was considered to be principally bacteriostatic.
3. Among other antimicrobial agents tested, no drug potentiated the activity of TMP or that of SMX-TMP combination.
4. Antibacterial activities of mice serum against Escherichia coli 055 were evaluated following oral administration of SMX and TMP singly or in combination. When combined, the serum diluted 32-fold was inhibitory on the growth of Escherichia coli, whereas after SMX alone the serum was bacteriostatic up to the dilution of 16 : 1 and after TMP alone up to 4 : 1, respectively.
5. The standard curve for bioassay of TMP was drawn by thin-layer cup method employing Bacillus pumilus as a test organism or by vertical superposing method using Escherichia coli 055. In both instances MUELLER-HINTON agar was used as a test medium.
6. The serum protein binding capacity of TMP as determined by cellophane bag dialysis averaged 42%.
7. Adsorption rate of TMP onto sheep red blood cell averaged 2. 72%.
8. Following intramuscular injection of TMP in a dose of 100 mg/kg to rabbits, TMP concentrations in the bile were about 10 times higher than those in the serum and concentrations in the urine reached 10 to 20 times higher than those in the serum.
9. After an oral dose of 60 mg/kg of TMP and 300 mg/kg of SMX in mice tissue concentrations of TMP 30 minutes post-dose ranked, in the order of decreasing concentrations, kidney, lung, spleen and liver. All of these tissue levels exceeded serum levels. TMP was undetectable at any time in the brain.
10. The activity of TMP was markedly reduced when the material was mixed with homogenates of mouse bowel contents and liver, the remaining activity being 32 and 43 % of the original values, respectively. No significant reduction of activity was detectable with other organs.
11. Concentrations of TMP in the urine collected from clinical materials during the first 24 hours after usual daily dose ranged from 70 to 240 mcg/ml. Based on these observations excretion rate was calculated to be 60 to 80 % of the given dose. Concentrations of TMP in the feces varied markedly ranging from 9 to 150 mcg/g. Serum levels 2 hours after administration of 2 tablets of SMX-TMP combination product gave values ranging from 1. 8 to 3.9 mcg/ml.
12. Concentration ratios of SMX-TMP fluctuated considerably from a specimen to another. In various organs of mice the ratio ranged from 5 : 1 to 18 : 1, whereas in human urine it ranged from O. 55 : 1 to 2. 2 : 1.
13. SMX-TMP combination product was given to a case of bacillary dysentery. A prompt bacteriological effect followed but loose stools persisted for several days. Leucopenia of 2800 was recorded in a single patient after treatment with SMX-TMP for influenza probably complicated by bacterial infections. Another patient with cholecystitis manifested drug exanthem and facial edema associated with pruritus and eosinophilia after a single dose of 2 tablets and the treatment was discontinued.