The purpose of this report is to investigate antibacterial activities of sulfamethoxazole (SMX) -trimethoprim (TMP) combination product together with evaluation of its clinical efficacy in obstetrics and gynecological patients. Activities of the combination of SMX-TMP were found to be enhanced by potentiation against clinically isolated Staphylococci, Escherichia coli and Proteus strains. Concentrations of this combination product in specimens of blood, urine and milk were assessed by employing thin layer chromatography. The results indicated that the combination product was absorbed relatively promptly and excreted well through the kidney.
A clinical trial was conducted in a total of 42 patients with bacterial infections. The response in 5/7 patients with pelvic infections, 3/3 of puerperal mastitis, 2/4 patients with abscess of external genitalia and 22/28 patients with urinary tract infections was classified as effective (effective rate 78. 5%).
In view of its pharmacokinetic and bacteriological characteristics, this antimicrobial agent appears to be an effective drug particularly suitable for the treatment of urinary tract infections.

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In vitro anti-microbial activities of SMX and TMP combined at various ratios were investigated. Potentiation of antibacterial activities was demonstrated in the majority of strains tested. Clinical trials of SMX-TMP combination product in patients with infections of the genito-urinary tract confirmed its therapeutic efficacy. Minimal side effects were observed.

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Clinical studies were carried out to investigate the nature of potentiation of antimicrobial activity of sulfamethoxazole (SMX) by trimethoprim (TMP). The results are summarized as follows;
1. FIC indices of the SMX-TMP combination against Escherichia coli isolated from clinical materials ranged 0. 05 to 0. 083.
2. The antibacterial activity of urine collected from patients following administration of SMX-TMP combination product was potentiated by a few times than that of SMX alone, indicating therapeutic efficacy of this combination product in SMX-resistant infections.
3. Detail blood counts and tests of the liver and renal function in healthy volunteers revealed no detectable abnormalities after 7 day treatment of 0. 7 g TMP daily. Further evaluation along the similar line in anemic patients may be of value. No untoward effects on spermatogenesis were detected after 7 to 14 days of treatment with SMX-TMP combination product in an ordinary dosage.
4. The results of SMX-TMP combination product in infections of the female reproductive system confirmed its therapeutic efficacy. The efficacy of the combination of SMX-TMP was found to be clearly superior to that of SMX or TMP alone in a preliminary sequential trial.

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Sulfamethoxazole (SMX) -trimethoprim (TMP) combination product was administered in 23 patients with infections consisting of salpingitis, pyosalpinx, metritis, puerperal fever, pyelonephritis and mastitis. The dosage of the combination product was 4 tablets daily divided in 2 doses given for 5 to 14 days. The overall effective rate of 73.9% was achieved. The antibacterial activities of SMX and TMP, alone and in 20 : 1 combination, were assessed on Escherichia coli strains isolated clinically. The potentiation of activities was clearly demonstrated by the combination of the 2 compounds.

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SMX-TMP combination was administered orally daily 4 tablets for 7 days to 30 female patients with acute cystitis. The therapeutic results were remarkable in 19 patients, fair in 11, with the effectiveness rate of 100 per cent.
FIC index of SMX-TMP combination against Escherichia coli (19 strains) was below. 0.3 in 10 strains, between 0.41 and 0.5 in 8 strains and about 0.6 in 1 strain.
Side effects were found in 4 patients, being in 1 case stomachache, which disappeared after administration was stopped.

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Experimental and clinical studies on sulfamethoxazole (SMX) -trimethoprim (TMP) combination product indicated the following conclusion. The combination ratio of the 2 active principles used throughout this study was 5 to 1 (SMX TMP).
1. Potentiation of anti-microbial activities was demonstrated in 91 % of Escherichia coli strains investigated. Potentiation was particularly marked with FIC index remaining below 0.5 in 90 % of the strains primarily sensitive to SMX alone with MIC below 100 mcg/ml.
2. The anti-microbial activities of SMX-TMP combination against Escherichia coli strains in vitro were more potent than those of TC, CP, SM, KM, ABPC, CER and NA; in particular, MIC of SMX-TMP was lower by 1-2 times than that of CL.
The majority of pathogenic organisms isolated from outpatients with acute cystitis at this urology clinic was Escherichia coli; during the period 1965-1969, 65-78 % of the strains isolated from our outpatients were Escherichia coli. Accordingly, the potential of this combination product in clinical practice is promising.
3. Our clinical experience confirmed its efficacy in patients with acute cystitis and acute gonorrheal urethritis.
4. Untoward dermatological reactions were observed in 2 patients, one of whom developed severe manifestations.

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Sulfamethoxazole-trimethoprim combination (abbrv : ST) showed satisfactory antibacterial activity against Gram negative enteric bacteria and some strains belonging to Pseudomonacea. Potentiating property of this combination drug was found especially against moderately or highly resistant organisms.
When employed for the treatment of complicated urinary tract infections, ST was shown to be useful in long-term management of chronic infections, though recurrence rate was not appreciably low. Efficacy of ST was almost comparable to gentamicin or carbenicillin in short-term response. An episode of gastro-intestinal discomfort with vomitting and another incidence of skin eruption were the untowards reactions among the 16 adults and 19 children, the latter patients showed positive skin reaction on patch test.

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Sulfamethoxazole (SMX) -trimethoprim (TMP) combination product was given in a trial of 22 outpatients comprising 13 females with acute cystitis, 4 females with other urinary tract infections and 5 males with prostatitis. The drug was administered for a period of 5 days and the response was followed every 5 days.
In acute cystitis, the response was classified as markedly effective in 1, effective in 10, fair in 1 and undetermined in 1. In other varieties of female urinary tract infections, the drug therapy was judged as effective in 3 and fair in 1. For the treatment of prostatitis, the combination product was markedly effective in 1, effective in 2, fair in 1 and undetermined in 1. The overall effective rate was 77%. Two patients with allergic diathesis developed untoward reactions and the drug administration was therefore discontinued.
Side effects, mainly those of gastro-intestinal disturbance, were observed in 6 patients. Although the memler of treated cases is small, the effect of this combination preparation in prostatitis was impressive.

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Thirty-seven patients suffering from genitourinary infections were treated with combination of sulfamethoxazole and trimethoprim in ratio 5 : 1. Good clinical and bacteriological responses were observed in 35 of the 37 patients.
In 15 patients bacteriological investigation was done along with the clinical observation. Seven out of 8 patients with Escherichia coli infection, all of 4 patients with Cloaca infection and each one patient with Staphylococcus aureus, Proteus and Klebsiella infection responded satisfactorily to sulfamethoxazole-trimethoprim combination therapy as evidenced by a negative urine culture following treatment.

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In order to test the value in the treatment of urinary tract infection, 72 patients with infections of varying severity and due to a wide range of organisms were treated with SMX-TMP combination product.
SMX-TMP combiation product was administered orally 2 tablets two times daily.
Satisfactory results were obtained in 95. 8% of 48 non-specific urinary tract infection cases, whereas 58.5% of 24 complicated cases. In total, satisfactory results were 83. 8%. No side effect was obtained except 4 cases.
It is evaluated that SMX-TMP combination product is a useful antibacterial agent for the urinary tract infection.

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Experimental and clinical investigations of a new antimicrobial agent, sulfamethoxazole (SMX) -trimethoprim (TMP) combination product, were carried out. The peak serum levels were recorded 4 hours after oral administration, whereas urinary concentrations reached at peak at 4 to 6 hours post-dose. Thirty-five patients with urinary tract infections were treated by SMX-TMP combination product. The effective rate in acute inflammation was 100%, that in chronic infection 61.5%, that in uncomplicated infection 82.3% and that in complicated infection 55.5%. Four patients complained of gastro-intestinal disturbance.

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We presented some fundamental and clinical studies on the combined drug of sulfamethoxazole and trimethoprim. MIC was measured with total of 45 strains ; Escherichia coli NIHJ, Staphylococcus aureus 209P and others.
Escherichia coli, Staphylococcus and Klebsiella revealed sensitivity against trimethoprim, while Proteus showed relative sensitivity.
However, Pseudomonas and Alcaligenes were resistant to trimethoprim as well as sulfamethoxazole. No synergistic action was observed between trimethoprim and sulfamethoxazole.
Clinical studies showed that urinary tract infection caused by Escherichia coli and Staphylococcus were satisfactorily controlled with the drug.
No side effect on subjective symptom, liver and kidney function, except a case with gastric disorder, was marked with the administration of this combined drug.

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Authors have questioned for years why sulfonamides are ineffective in vitro despite their frequent clinical efficacy. The advent of sulfamethoxazole (SMX) -trimethoprim (TMP) combination product has provided an occasion to study this problem again. A significant number of isolated organisms were found to be sensitive to SMX alone whereas practically all strains were sensitive to the SMX-TMP combination in vitro. Untoward reactions, such as exanthem and photosensitivity, which are not infrequently encountered with sulfonamide drugs alone appeared to be as common with this new combination preparation.

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a. Antibacterial activities of sulfamethoxazole (SMX) and trimethoprim (TMP) alone and in 20 : 1 combination, have been studied against 14 strains of Staphylococcus epidermidis, 14 strains of Corynebacterium acnes and 28 strains of Staphylococcus aureus isolated from pyodermic lesions. In vitro antibacterial activities were assessed by the agar dilution method. Minimal inhibitory concentrations (MICs) for strains of Staphylococcus epidermidis and Staphylococcus aureus were found to be similarly distributed, i. e., SMX exhibiting low activity while TMP registering marked activities. The potentiation of antimicrobial activities by the combination of SMX and TMP was demonstrated in these strains. A similar tendency has also been found in the sensitivity pattern of Corynebacterium acnes against SMX and TMP alone and in combination.
b. A clinical trial in 4 cases of acne vulgaris and 8 cases of acne pustulosis revealed that SMX-TMP combination product was effective in 4 of the 10 evaluable cases. Two patients complained of subjective s.de effects, i. e., epigastric pain in 1 and epigastric discomfort associated with nausea in another.

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The following results were obtained by our clinical studies on sulfamethoxazole-trimethoprim combination :
1) The combination of sulfamethoxazole and trimethoprim was effective in vitro to Staphylococci isolated from infectious skin lesions.
2 ST tablets were given to 56 cases of pyoderma. The therapeutic results were effective in 27 cases, moder tely effective in 14 cases and not effective in 15 cases, but were effecctive in 13 cases of 19 cases of primary pyoderma.
3) Side effects were observed in 4 cases, that is, gastrointestinal symptom in 3 cases and fixed drug eruption in 1 case.

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The following report is based on a clinical trial of the combination product of sulfamethoxazole (SMX) and trimethoprim (TMP) in a total of 32 patients, 18 males and 14 females, with infections in otorhinolaryngology. Clinical materials are composed of 9 cases of acute purulent otitis media, 8 cases of furuncle of the ear, 12 cases of acute lacunar tonsillitis and 3 cases of peritonsillar abscess. SMX-TMP combination product was administered orally in daily doses of 3 to 6 tab., according to the age of the patient, divied in 2 doses. The drug therapy was markedly effective in 12, moderately effective in 15, slightly effective in 2 and ineffective in 2 cases. The effective rate including marked and moderate totaled 87. 5%. No significant adverse reactions have been recorded during the study.

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Bacteriological and clinical experiments on ophthalmic use of the combination of Sulfamethoxazole (SMX) and Trimethoprim (TMP) were performed, and the following results were obtained.
1) The MICs of SMX and TMP against 34 strains of 8 species, bacteria causing ocular infections were measured ; 3. 13, 0.19 mcg/ml for Koch-Weeks bacilli, 0.78, 0.19 mcg/ml for Morax-Axenfeld diplobacilli, 25->100, 0.19-50 mcg/ml for Pneumococci, 6.25-50, 0.19-3.13 mcg/ml for C. diphtheriae, 12.5, 0.19 mcg/ml for Gonococci, 1.56->100, 0.19->100 mcg/ml for Streptococci, 6.25-25, 0.19-0.78 mcg/ml for Staphylococci, >100, >100 mcg/ml for Pseudomonas aeruginosa and 25, 0.78 mcg/ml for Staphyl coccus aureus 209P.
2) The MICs of the combination of SMX and TMP when combined 16 : 1 were tested ; 0.2/0.0125 mcg/ml for Koch-Weeks bacilli, <0.1/<0.00625 mcg/ml for Morax-Axenfeld diplobacilli, 6.25-100/0.39-6.25 mcg/ml for Pneumococci, >100/>6.25 mcg/ml for Streptococci, <0.1/<0.00625 mcg/ml for Gonococci and 0.39/0.025 mcg/ml for Staphylococcus aureus 209P.
3) MICs of SMX for 40 strains of Staphylococcus aureus ranged 1. 56-≥100 mcg/ml and those of TMP 0.19-1.56 mcg/ml.
The MICs of the mixture of 16 SMX and 1 TMP were 0.2-0.39 mcg/ml of SMX and 0.0125-0.025 mcg/ml of TMP.
4) The distribution of the sensitivities for 10 strains of Pseudomonas aeruginosa was in the range of 50->100 mcg/ml of SMX and ≥100 mcg/ml of TMP. The combination of SMX and TMP (16 : 1) inhibited Pseudomonas aeruginosa in <12.5->100 mcg/ml of SMX and <0.78->6.25 mcg/ml of TMP.
5) After an oral administration of the mixture of 200 mg/kg SMX and 40 mg/kg TMP in rabbits, the aqueous humor levels were recognized for 2-24 hours, and the peak level (33.4 mcg/ml of SMX and 1.67 mcg/ml of TMP) was obtained 3 hours later.
Aqueous humor-serum ratio was about 50%.
6) Oral administration of 1-2 tablets twice daily revealed good effects in 14 out of 20 cases ; 7 out of 8 cases of external hordeolum caused by Staphylococcus aureus, 3 out of 4 cases of inner hordeolum, one case of corneal infiltration, and all of 3 cases of prevention of posttraumatic infection.
7) No severe side effects were noticed in any of the 20 cases.

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