An ad hoc committee has been organized by members of the Japan Society for Chemotherapy with an aim to establish acceptable methods for determination of minimal inhibitory concentrations (MICs) of sulfamethoxazole (SMX) -trimethoprim (TMP) combination product. The following summary outlines the conclusion derived from investigations by this committee.
1. Sensitivities shall be assayed by the agar plate dilution method and activities shall be expressed in terms of MIC (the minimal concentration at which bacterial growth is completely inhibited).
2. Culture medium for inoculation
MUELLER-HINTON broth (Difco) shall be used without modifying its pH (7. 4 ± 0. 2). For those test organisms which require specific nutrients, appropriate media shall be selected.
3. Dilution of culture broth
Sterilized physiological saline shall be used in general as a diluting medium but other appropriate material may be employed for specific organisms.
4. Culture medium for sensitivity testing
MUELLER-HINTON agar (Eiken) or Medium for Sensitivity Disc Testing (Nissan) shall be employed enriched with 7.5% hemolyzed horse blood (pH 7.4).
5. Method of inoculating test organisms
Culture medium for inoculation purposes shall be incubated at 37°C for 18-20 hours. The culture broth thus obtained shall be diluted 100-fold for gram positive cocci, or 1000-fold for gram negative rods to make inoculating materials for sensitivity testings. A loopful of this culture broth will be streaked over 2 cm on a sensitivity plate.
6. Judgement
After incubating the plate at 37°C for 18-20 hours, the minimal concentration at which the bacterial growth is completely inhibited shall be examined macroscopically to determine MIC. The growth of a single colony, or of a very thin bacterial film shall be judged as bacterial growth (in case the bacterial growth is insufficient after the aforementioned conditions, the judgement shall be made after 48 hours' incubation).
7. Concentrations of drugs
Two-fold dilutions shall be made in the following order : 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39, 0.2, 0.1, 0.05 and 0.025 mcg/ml. When employing concentrations in excess of 100 mcg/m I, concentrations shall be 200, 400 and 800 mcg/ml.
8. Preparation of standard solution of TMP and SMX
Ten mg of TMP are dissolved in a small volume of 4/100 N HCI, to which water is added to make a total volume of 10 ml. Ten mg of SMX is dissolved in a small volume of 1/8 N NaOH, to which water is added to make a total volume of 10 ml. The following alternative may be acceptable for TMP : Ten mg of TMP is dissolved in 0.5 ml of dimethylformamide or 0.5 ml propyleneglycol, to which water is added to make a total of 10 ml.
9. Preparation of plate for sensitivity testing
Hemolyzed horse blood shall be added when the temperature of culture medium is cooled down to approximately 50-60°C. Drugs in prescribed quantities are poured into the plate and the culture medium in 9-fold volume is added while the plate is gently shaken.
10. Test organisms (clinical isolates and standard bacterial strains)
Test organisms must be fresh within 2-3 culture generations after the clinical isolation. As reference standard of organisms, the following 2 strains as recommended by the Japan Society for Chemotherapy shall be employed ;Staphylococcus aureus FDA 209-P JC-1 and Escherichia coli NIHJ JC-2. The MICs of these standard strains as assayed by the foregoing procedures are as follows :
SMX (mcg/ml) TMP (mcg/ml)
Staphylococcus aureus FDA 209-P JC-1 25-50 0.39-0.78
Escherichia coli NIHJ JC-2 3.12-6.25 O.1-0.2

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The presence of anin vitro synergistic effect in the combination of sulfonamides and trimethoprim was investigated using two-fold agar plate dilution method recommended by the Japan Society of Chemotherapy. Each test material was cultured in MUELLER-HINTON broth overnight, and one loopful of an appropriate diluent (100 times dilution for gram-positive bacteria and 1000 times dilution for gram-negative rods) was inoculated into MUELLER-HINTON agar plate enriched with 7.5% lysed horse blood and containing increasing levels of test drugs.
In both sulfamethoxazole-sensitive and-resistant cultures a definite synergistic effect was observed, and in sulfonamide-resistant cultures much lower MIC values of sulfamethoxazole in combination were noted as compared with those of the single use of sulfonamide, whereas the decrease in the MIC values of trimethoprim in combination was not so significant chiefly due to the high antibacterial activity of trimethoprim. The combination was ineffective againstPseudomonas.
In spite of the relatively low activity of sulfadimethoxine, the combination of this and trimethoprim showed nearly the same MIC values as sulfamethoxazole- and sulfamonomethoxine-combination.
The potentiation of the activity of sulfonamide by trimethoprim was also confirmed in the growth curves of Escherichia coli culture with and without either of sulfonamide or trimethoprim and the combinations.

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In vitro and in vivo bacteriological studies on the combination of sulfamethoxazole (SMX) and trimethoprim (TMP) revealed the following results :
1. Antimicrobial activities of SMX and TMP, alone and in combination, were investigated employing the broth dilution method and a checkerboard technic. Activities of the combination of SMX and TMP were markedly enhanced by potentiation against strains of Staphylococcus aureus and Escherichia coli originally sensitive to SMX alone. The growth of Staphylococci highly resistant to SMX alone was also inhibited by SMX-TMP combination through potentiation, however, the degree of potentiation by the combination was not too impressive in Escherichia coli strains highly resistant to SMX alone.
2. Evaluation of the changes of minimal inhibitory concentrations (MICs) of the combination of SMX and TMP in various combination ratios indicated that MICs of the combination mixed in ratios of 1. : 1 to 20 : 1 (SMX : TMP) were enhanced by potentiation or synergism in strains of Staphylococcus aureus and Escherichia coli originally sensitive to SMX. MICs of SMX-TMP combination in a ratio of 1 : 1 against strains highly resistant to SMX were identical with those of TMP alone but MICs of the combination tended toward increase as the ratio of SMX increased.
3. MICs of SMX and TMP alone and 20 : 1 combination were investigated in a number of grampositive and negative laboratory strains according to the method as recommended by an expert group of the Japan Society of Chemotherapy. MICs of the combination were found to be more significantly potentiated than that of SMX alone in all strains but for Pseudomonas. These MICs were comparable to those of currently available antibiotics.
4. Potentiation of the antimicrobial activities by SMX-TMP combination was clearly demonstrated also in a test of 50 strains of Staphylococcus aureus and 37 strains of Escherichia coli isolated from clinical materials. Activities against strains highly resistant to sulfonamide were significantly improved by potentiation.
5. Studies of the influence of SMX-TMP combination on growth curves of Staphylococci revealed that potentiation by the combination was evident in staphylococcal strains sensitive to SMX alone. But the degree of potentiatiation was to a lesser extent in SMX-resistant strains.
6.In vivo studies on experimented infection of mice with Staphylococcus aureus and Escherichia coli confirmed potentiation of activities by SMX-TMP combination in strains both sensitive and resistant to SMX alone. The doses of combination required to treat mice infected with sulfonamide resistant Staphylococcus aureus and Escherichia coli were more than those required to treat animals with sulfonamide sensitive bacterial infection. The survival of mice experimentally infected with Salmonella was also improved by the combination of SMX and TMP.

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Combined activities of trimethoprim (TMP) and sulfamethoxazole (SMX) on clinically isolated strains of Staphylococcus aureus, Escherichia coli and Shigella flexineri were studied by the agar dilution and crossed paper strip methods. The combined drug was shown to have a synergistic action against 48 strains of Staphylococcus aureus tested, without regard to their sensitivities to sulfonamide and to tetracyclin. The synergism of combined drug was also observed in 4 strains of sulfonamide-sensitive Escherichia coli. On the other hand, no synergistic action to 24 strains of sulfonamide resistant Escherichia coli and 14 strains of Shigella flexineri was detected by the methods mentioned above, regardless of existance of R factors in these strains.

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Agar dilution method was employed to determine antibacterial activity of sulfamethoxazole (SMX) and trimethoprim (TMP) against 53 strains of Staphylococcus aureus, 26 strains of Enterococcus, 36 strains of Escherichia coli, 33 strains of Klebsiella and 8 strains of Enterobacter which had been freshly isolated from clinical materials. Minimum inhibitory concentrations (MIC) of SMX were found to be within the range between 6.25 and >100 mcg/ml, while those of TMP were found to range from 0.05 to 1. 56mcg/ml, except for a single strain of Enterococcus and 2 Klebsiella strains.
The activity of SMX, TMP and their combinations were investigated employing various combinations of SMX and TMP at concentrations of 100 mcg/ml and their 2-fold diluted materials, respectively. Culture materials used were agar plates and liquid media. Combinations of SMX and TMP were found to have marked potentiating activity against microorganisms which were primarily sensitive to both SMX and TMP alone, i. e. the concentration of each drug contained in the combination was less than 1/4 the MIC of the corresponding drug when used alone.
However, when organisms were resistant to SMX with MIC higher than 100 mcg/ml, potentiation was found to be less remarkable.

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Influence of various components of a medium on activities of sulfamethoxazole (SMX) and trimethoprim (TMP) against Escherichia coli NIHJ JC-2 strain was investigated. Yeast extract or p-aminobenzoic acid added to M9 minimum liquid medium competitively antagonized the antibacterial activity of SMX, while lactoalbumin hydrolysate or methionine, glycine, adenine and thymine added to the medium non-competitively antagonized both SMX and TMP. Folic acid and N^{5, 10}-methenyl tetrahydrofolic acid were found to have no antagonizing effect on the activities of both drugs against Escherichia coli.
The replica method was found to be inadequate for assaying antimicrobial activities of SMX-TMP due to the difficulty in controlling inoculum size. Reproducible sensitivity tests were possible by employing a plate dilution method with MUELLER-HINTON agar supplemented with 7.5 % hemolyzed horse blood. Sensitivity levels of some bacterial strains as assessed by this method were found to be significantly higher than those employing a tube dilution method with a minimum liquid medium and a small inoculum size.
A marked potentiation of antimicrobial activity was demonstrated by SMX-TMP combination on drug-sensitive Escherichia coli M48-34 (pab), a sulfonamide-resistant substrain, M48-34 (sul, met, gyl) and a R⁺substrain, M48-34/R 100 (fi⁺, sul, str, tet, cml). The amount of SMX necessary for potentiation, however, was much higher with M48-34/R 100 strain than with the parent strain. Siginificant potentiation was confirmed by the combination on gram-positive bacteria regardless of their sulfonamide sensitivities.

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Bacteriostatic effect has been variously affected against anaerobesly to trimethoprim (TMP) and sulfamethoxazole (SMX) combination drug by inoculum size.
We think that sensitive anaerobes to TMP or SMX have the enhanced activity by the combination of TMP and SMX, while high resistant anaerobes have not.

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This study was undertaken to investigate the antibacterial activities of sulfamethoxazole (SMX) and trimethoprim (TMP), alone and in combination in vitro.
Activities of the 2 drugs, alone and in combination, were found to be dependent on the composition of culture medium, medium pH and inoculum size of the organisms to be tested. SMX and TMP were active against a wide range of gram-positive and gram-negative organisms. The potentiation of the antibacterial activity of SMX by TMP was confirmed. The maximum potentiation by the combination was achieved when the 2 components were combined at the ratio of their respective minimal inhibitory concentrations acting alone. A guiding manual for sensitivity testing was established as follows :
1. In vitro antibacterial activity is determined according to the agar dilution method. The sensitivity is expressed as minimal inhibitory concentration (MIC).
2. MUELLER-HINTON broth (Difco) is recommended for culturing test organisms and MUELLER-HINTON agar (Eiken) with hemolyzed (freeze-thaw) horse blood (7. 5% v/v) is recommended as a medium for sensitivity testing.
3. Test organisms are inoculated in MUELLER HINTON broth and incubated at 37°C for 18-20 hours.
4. The inoculum size is one loopful (inner diameter I mm : weight of wet bacteria ca. 2 mg) of a 10^-2dilution of a gram-positive broth culture or 10^-3dilution of a gram-negative broth culture; the inoculum is streaked over 2 cm in length on the plate.
5. The interpretation is made macroscopically after 18-20 hours of incubation at 37°C and the lowest concentration at which bacterial growth is completely inhibited is designated as MIC.
6. Bacterial strains isolated from clinical materials should be tested while they remain fresh within 2-3 culture generations. For reference strains, Staphylococcus aureus FDA 209-P JC-1 and Escherichia coli NIHJ JC-2 are used.
The following guidelines have been proposed for estimation of potentiation of activities by SMX and TMP.
a) When organisms are sensitive to both SMX (MIC≤800 mcg/ml) and TMP (MIC≤100 mcg/ml) : Potentiation is estimated by calculating FIC (fractional inhibitory concentration) index. FIC values can be calculated by dividing the MICs of SMX and TMP in the combination by the MICs of SMX and TMP when used alone. FIC index is the sum of FIC values. When this index is below 1. 0, potentiation is indicated.
b) When organisms are resistant to either SMX (>800 mcg/ml) or TMP (>100 mcg/ml) : If the MIC of SMX or TMP in the combination against a test organism is less than one fourth that of SMX or TMP when used alone, potentiation is indicated.
c) When organisms are resistant to both SMX (>800 mcg/ml) and TMP (>100 mcg/ml) : If the growth of a test organism is completely inhibited by the combination of SMX-TMP (the range of their combination concentrations : SMX 800, 400, 200 mcg/ml and TMP 100, 50, 25 mcg/ml, respectively), potentiation is indicated.

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Biological Research Laboratory, Tanabe Seiyaku Co., Ltd. Bactericidal activities of SMX, TMP and combinations of SMX-TMP in vitro were investigated with several strains of Staphylococcus aureus and Escherichia coli. Complete viable counts were performed in cultures containing the drugs singly and together according to the chequer-board titration method and bactericidal action was estimated by a decreased rate of survived bacteria.
In the combination, significant bactericidal effects were exerted by the far lower concentrations than the MIC of each drug alone, although they, when acting singly, did not totally eliminate viability. The synergism on bactericidal effect was found to be most pronounced with the combination equal to the ratio of MIC of either drug alone.

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Acquired resistance of Staphylococcus aureus (strain FDA 209P JC-1, strain CN 491) and Escherichia coli (strain NIHJ JC-2, strain CN 314 and strain K-12) to TMP alone, SMX alone and their combinations (SMX-TMP) have been studied by serial transfer of light inoculum (10⁴cells/ml) in increasing concentrations of drugs in MUELLER-HINTON broth (Eiken) or SR medium (Difco).
It was concluded from the results of this investigation that the increases in resistance to combinations (SMX-TMP) were less than those to SMX alone and TMP alone.

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1) The combination of SMX and TMP in the four experimental infections of mice proved more effective than either SMX or TMP alone. Especially in combinations of SMX and TMP in the proportion of 2+1 and 5+1 are proved synergistic in these four experimental infections.
2) When tested against sulfamethoxazole resistant strain of Escherichia coli, 2+1 combination showed a synergistic effect.
3) The synergistic effects were similary observed both on the experimental sepsis and on the experimental foot-pads infections caused by Klebsiella pneumoniae in mice.

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The antimicrobial activities of sulfamethoxazole (SMX) and trimethoprim (TMP), alone and in combination, were tested in 449 strains of micro-organisms freshly isolated from clinical materials. The following results were obtained :
1. Of the 449 strains investigated, approximately 60 % of the organisms were found to have MIC of SMX greater than 100 mcg/ml, whereas MIC of TMP was found to be between 0.2 and 0.78 mcg/ml in 71% of the strains.
2. Antimicrobial activities by the combination of SMX and TMP as assessed by checker board titration method were demonstrated potentiation in 66.6 % of the materials. Of particular interest was the evidence of potentiation in 44.2 % of those microorganisms which were found to have MIC greater than 100 mcg/ml of SMX alone.

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1) Assessment of acute toxicity of SMX and TMP in WISTAR strain rats and dd-strain mice revealed the following LD₅₀ :
Rats male female
SMX
p. o. 8640 8400
i. p. 2790 2690
s. c. >5000 >5000
TMP
p. o. 1670 1670
i. p. 1530 1460
s. c. 5000 5000
ST (5 : 1)
p. o. 7300 7200
i. p. 2450 1840
s. c. >3000 >3000
Mice male female
SMX
p. o. 3900 3471
i. p. 2300 2450
s. c. 5000 5000
TMP
p. o. 5200 5400
i. p. 1870 2200
s. c. 5000 5000
ST (5 : 1)
p. o. 7200 6400
i. p. 2010 2197
s. c. >3000 >3000
No potentiation of acute toxicity was apparent from the combination of the 2 drugs. There was neither difference in the expression of acute toxicity between male and female animals.
2) The study of subacute toxicity of SMX and TMP in rats revealed that all compounds, alone and in combination, were tolerated in relatively high doses. Results of peripheral blood examinations indicated that SMX, TMP and their combination gave inhibitory actions on the hematopoietic system in higher doses.
The histopathological abnormalities were largely confined to dose-dependent enlargement of the thyloid gland in animals given SMX. The morphological pictures in groups given SMX-TMP combination appeared to be also dominated by SMX. Histopathological examinations of animals given TMP and SMX-TMP combination did not reveal significant changes in other tissues including brain, heart, thymus, lung, stomach, intestines, liver, pancreas, spleen, adrenal, kidney, male and female reproductive organs and bone marrow. There was no evidence of the potentiation of subacute toxicities by the combination of SMX and TMP.

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Behavioral and electroencephalographic analyses of the central effects of sulfamethoxazole (5- methy 1-3-sulphanilamido-isoxazole) (SMX), trimethoprim [2, 4-diamino-5- (3, 4, 5-trimethoxy benzyl) pyrimidine] (TMP), and their mixture in a ratio of 5 : 1 (SMX-TMP) were carried out in animal experiments. Each drug was orally administered in a gum-emulsion.
1. SMX-TMP (6000-9000 mg/kg) caused suppression of somatic behavior in mice viz; inhibition of spontaneous locomotor activity, slowing down of movement, and abnormal posture. The animals died under tonic extensor. The behavioral changes caused by 4000-6000 mg/kg of SMX were almost the same as those by SMX-TMP. With 3000-9000 mg/kg of TMP, marked muscle relaxation accompanied by slowing down of movement and abnormal posture was observed. The animals died in respiratory paralysis. In cats, each drug, at doses of 25-50 times the human dosage, caused sedative behavior and inhibition of appetite. Vomitting appeared with 900 mg/kg of SMX-TMP.
2. The LD₅₀ in mice was as follows : SMX-TMP : 5513 mg/kg, TMP : 7000 mg/kg, SMX : 3662 mg/kg.
3. The grip strength test, rotarod performance test and righting reflex in mice were not influenced by 1000 mg/kg of each drug.
4. Neither drug at a dose of 1000 mg/kg possessed analgesic activity when evaluated by the stretching method and the modified HAFFNER'S method, nor anti-convulsive activity on evaluation by the maximal electroshock method and the pentetrazol seizure method in mice.
5. Each drug showed hypothermic activity in mice, the effect of TMP being the most marked. 6. The nondiscriminated avoidance response in rats was remarkably suppressed by TMP and slightly suppressed by SMX-TMP. The effect of SMX on the response was negligibly small.
7. The potentiation of thiopental-Na anaesthesia was the most evident with SMX; the lesser effects of SMX-TMP and TMP were almost the same as each other.
8. SMX-TMP and TMP caused sedate behavior in chronically electrodes-implanted cats and increased the resting pattern for several hours. Even with a large dose of SMX-TMP, no essential changes of EEG pattern were observed in any EEG-leads, except for a slight inhibition of the slow wave components at the amygdala and the hippocampus in the slow wave sleeping state.
9. The sleep-wakefulness cycles of cats were remarkably altered by SMX-TMP and/or TMP, an increase in the waking state, and decrease in the slow and fast wave sleeping states, being observed. These effects were considered to be primarily caused by TMP.

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The effects of sulfamethoxazole (SMX), trimethoprim (TMP) and their mixture in a ratio of 5 : 1 (SMX-TMP) on the circulatory and respiratory systems were studied. They had no noteworthy pharmacodynamic action on the circulatory and respiratory systems of rabbit except for the following effects which were observed after large doses.
1) Blood pressure : A slight and transient hypertensive effect was observed after intravenous administration of SMX. On the other hand, slight and transient hypotensive effects were observed after both oral and intravenous administration of TMP and SMX-TMP.
2) Respiration : TMP and SMX-TMP caused slight and transient acceleration of respiration when administered intravenously.
3) ECG : A slight tachycardia was observed after both oral and intravenous administration of TMP and SMX-TMP.
4) Heart : Movement of heart in situ was slightly suppressed by 'intravenous administration of SMX, TMP and SMX-TMP. The spontaneous beating rate of isolated right atrial strip of guinea-pig was decreased by SMX and TMP, and the amplitude was slightly increased by TMP.
5) Blood vessels : TMP had a slight vasodilator action on the perfused blood vessels of hind leg. The hypotensive effect of TMP may be attributed to this action.

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Pharmacological properties of sulfamethoxazole (SMX), trimethoprim (TMP) and their mixture (SMX-TMP=5 : 1) were investigated, and the following results were obtained.
1. SMX, TMP and SMX-TMP, when administered orally in rats, did not affect urine volume and urinary sugar concentration. TMP and SMX-TMP, but not SMX, increased sodium excretion and decreased potassium excretion. These actions were dose-dependent and are attributed to TMP.
2. On daily administration of TMP and SMX-TMP, the above effects were maintained, and there was no change in the plasma levels of sodium and potassium ions.
3. TMP had no effect on the blood sugar level, but high doses of SMX and SMX-TMP had a hypoglycemic action. This hypoglycemic action is probably due to SMX.
4. SMX, TMP and SMX-TMP did not inhibit the gastrointestinal propulsion of a charcoal meal in mice.
5. When administered intravenously, SMX (sodium salt), TMP (lactate) and SMX+TMP did not affect contraction of skeletal muscle in rabbits.
6. SMX (sodium salt), TMP (lactate) and SMX+TMP did not affect contraction of the isolated smooth muscle preparations.

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This report is based on the studies of pharmacokinetic studies of sulfamethoxazole (SMX) with particular reference to the effect of coexistence of trimethoprim (TMP).
Methods :
Each group of animals comprises 6 Sprague-Dawley strain male rats weighting approximately 200 g. SMX was given either 100 mg/kg alone or combined with TMP 20 mg/kg. Drugs were given orally as suspensions in 5% gum arabic in volume of 2 ml/100 g animal weight. Animals were sacrificed in 0.5, 1, 2, 4, 6, 16, 24 and 48 hours after drug administration by exsanguination from cervical vein. Each organ was immediately excised. Brain, lung, liver, kidney, spleen, fatty tissues and contents of the rectum were processed by 0.4 N HClO₄ to make a 10% homogenate. SMX present in the filtered supernatant was assessed for its concentration. The assay of SMX was made according to the method of BRATTON-MARSHALL. Glucuronide fractions of SMX were determined employing ethyl acetate extraction as described by KOECHLIN et al.
Results :
Plasma concentration : Table 1 demonstrates changes in plasma levels of SMX after oral administration of SMX alone or SMX with TMP. Figure 1 illustrates concentrations of free SMX. The acetyl form of SMX corresponded approximately to 8 % of the total SMX and this relation remained practically identical when TMP was given together. As shown in Figure 1, the absorption of SMX was rapid reaching peak levels in the first 4 hours followed by a gradual decrease. No significant changes of plasma SMX concentration were detected whether SMX was given alone or combined with TMP; if any, the rats of SMX absorption appeared to be slightly retarded when TMP was given together.
Intra-organ distribution : Table 2 and Figure 2 present concentrations of SMX at different hours after dosing in the brain, lung, liver, kidney, spleen, fatty tissues and feces. The peak values in these organs roughly coincided with the maximum plasma concentration 4 hours post-administration. SMX in the kidney, liver, spleen, lung, brain and fatty tissues, in the order of decreasing concentration, was present mostly as the free form and acetyl form accounted less than 10% of the total. The concentrations in rectal contents were relatively elevated particularly at 6 hours after administration. These concentrations did not differ significantly between the animals which were given SMX alone and those given the combination of SMX and TMP.
Urinary excretion : Data relative to urinary excretion of SMX after SMX alone and SMX with TMP are tabulated in Table 3. The administered SMX was found at 72-82 % to be excreted in the urine during the first 48 hours after administration. Most of the SMX was excreted in the first 24 hours. N⁴-acetylated SMX was major metabolite followed by free-SMX and glucuronide. The amount of SMX excreted was found to be slightly more when SMX was given with TMP than that when SMX was given alone. The effect of combined administration was also detectable in the quantity of free-SMX in the urine. The free-SMX in the urine was found to be larger in quantity when SMX was given together with TMP.

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Absorption, distribution, excretion and metabolism of trimethoprim were studied in rats. Trimethoprim was absorbed rapidly and almost completely from the digestive tract, the half-life for absorption being 18 minutes.
The concentration of the drug in blood and tissues attained maximum at 20 minutes after oral administration, and thereafter decreased rapidly. The highest concentration was found in the kidney. Appreciable levels were found in the bone marrow, thyroid, liver and lung. The lowest drug concentration was noted in the brain.
Approximately 95 % of the radioactivity after oral administration of ¹⁴C-trimethoprim was recovered from the urine and feces within 72 hours. The urinary excretion is the major excretory route since more than 85 % of the total radioactivity recovered appeared in the 72 hour urine.
Metabolic pathways of trimethoprim consisted of O-demethylation, ring N-oxidation, α-hydroxylation and glucuronic acid conjugation. Intact trimethoprim accounted for about 30% of the radioactivity excreted in 8 hour urine.
The simultaneous administration of sulfamethoxazole did not influence the absorption, distribution, excretion and metabolism of trimethoprim in rat.

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The distribution and antibacterial effect of trimethoprim orally administered to rats or mice were studied by means of whole body autoradiography and autobacteriography.
When administered alone in a dose of 20 mg/kg, ¹⁴C-trimethoprim was rapidly and easily absorbed from the digestive tract and distributed to almost all tissues or organs except the central nervous system. The radioactivity in the various tissues or organs reached at their maximum levels within 30 minutes, and then decreased gradually, and was almost diminished at 24 hours after the administration.
The highest radioactivity was found in the kidney, liver, salivary gland, adrenal medulla, pituitary gland, pineal body and the next higher radioactivity was observed in the spleen, pancreas, adrenal cortex, thyroid, bone marrow, lymph nodes and prostate.
¹⁴C-trimethoprim and/or its metabolites were excreted into the urine, bile and saliva.
When ¹⁴C-trimethoprim (20 mg/kg) was administered in the combination with sulfamethoxazole (100 mg/kg), the distribution pattern was not essentially different from that of ¹⁴C-trimethoprim alone.
When trimethoprim, in the dose from 3.14 to 200 mg/kg, or its combination with sulfamethoxazole, in the dose from 1.87 to 120 mg/kg, was administered to mice infected intraperitoneally with Staphylococcus aureus, the numbers of viable organisms in various tissues of mice were apparently less in the latter than in the former.

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Sulfamethoxazole (SMX) 400mgとtrimethoprim (TMP) 80mgを含有する錠剤を6人の健康成人男子に空腹時投与し両薬剤の血中濃度および尿中排泄量を検索した。SMXおよびTMPともに血中濃度は, 内服後2-4時間で最高に達し, その値は2錠1回投与の場合はfree-SMXで平均50.2mcg/ml, TMPは平均1.9mcg/mlで, その後両者は20 : 1ないし40 : 1の濃度比を保ちつつ, ともに約9時間の半減期で漸減した。投与量に対する尿中排泄量は, 内服後はじめの24時間で, SMXは約60%, TMPは約50%が排泄された。一方, 投与後24時間以内における尿中のfree-SMXとTMPの濃度は, 血中濃度にくらべSMXは5-8倍, TMPは20倍前後の高い濃度であつた。
なお, 本研究で, TMPの血中濃度同時定量に用いたSCHWARZらの分光螢光光度法および微生物学的定量法は, その測定値が互いに近似し, 尿中濃度測定に用いた紫外部吸収法, NIMMO-SMITHの分光螢光光度法および微生物学的定量法による測定値間にもすぐれた相関性を認めた。
[この研究は, 塩野義製薬, 田辺製薬, 日本ロシユ3社の共同企画にもとついて実施されたものである。]

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Minimum inhibitory concentrations (MICs) of sulfamethoxazole (SMX) and trimethoprim (TMP), alone and in 20 : 1 combination were studied employing agar plate dilution method with MUELLER-HINTON agar (pH 7.4) in 22 laboratory strains of Escherichia coil. Lysed horse blood was added to the assay medium. In the majority of strains MICs of SMX were higher than 200 mcg/ml of SMX, however, MICs of TMP, were always within the range between 0.8 and 0.05 mcg/ml, with the mode at 0.02 mcg/ml. MICs of the combination of SMX and TMP ranged between 6.3 and 0.4 mcg/ml. Potentiation of antimicrobial activities was clearly demonstrated by combining the 2 drugs in some strains but in others the degree of potentiation was slight or absent.
Concentrations of SMX and TMP in serum and urine following 2 and 4 tablets of SMX-TMP combination preparation (1 tablet contains 400 mg SMX and 80 mg TMP) were determined in human subjects known to have no renal impairment. The peak plasma level of TMP after 2 tablets was attained in 4 hours, averaging 2. 7 mcg/ml and that of SMX in 6 hours, averaging 62 mcg/ml for free-SMX and 78 mcg/ml for total SMX. Concentration in the urine varied between 10 and 50 mcg/ml for TMP, and between 40 and 300 mcg/ml for free-SMX. Levels obtained in a patient given 4 tablets were correspondingly higher. Concentration ratios of SMX and TMP in the serum ranged between 20-40 : 1 while those in urine specimen 4-10 : 1, indicating different metabolic pathways of the 2 drugs in vivo.
Concentrations of SMX and TMP in rat tissues following oral application of SMX-TMP were determined. The results indicated higher extravascular distribution of TMP while tissue concentrations of free-SMX were approximately similar to serum levels.
The binding of TMP to serum proteins was found to be less than 10% whether existing alone or in combination with SMX.

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1. Antibacterial activities of sulfamethoxazole (SMX), trimethoprim (TMP) and SMX-TMP combination (5 : 1) were investigated against 26 strains of Hemophilus influenzae isolated from patients with chronic respiratory tract infections. The distribution of sensitivities as determined by a modified LEVINTHAL method indicated that the bacterial sensitivities were largely dependent upon their sensitivity to TMP under the tested conditions.
2. The potentiation of antibacterial activities by SMX-TMP combination mixed at a ratio of 5 : 1 was clearly confirmed in an experiment employing subcutaneous infection with Hemophilus influenzae in mice.
3. A clinical trial of SMX-TMP combination product (SMX 400 mg and TMP 80 mg per tablet) in dosages 4-6 tablets daily in 7 patients with respiratory tract infections, 7 patients with urinary tract infections and 1 patient with Salmonella carriers demonstrated that this preparation is effective as long as pathogenic organisms isolated from the clinical materials were sensitive to the combination in vitro. Aside from a single case of drug examthem, no adverse reaction has been recorded.
Further experience is required to confirm the effect of this combination product in Salmonella carriers.

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The following results have been obtained from our experimental and clinical investigations of sulfamethoxazole (SMX) -trimethoprim (TMP) combination product.
1. Antibacterial activity :
The antibacterial activities of SMX were found to be significantly potentiated by the addition of TMP combined at a ratio of 20 : 1 (SMX-TMP) against coagulase-positive Staphylococci and Klebsiella strains. No potentiation was detectable in Pseudomonas strains tested.
2. Absorption :
Two healthy volunteers were given 4 tablets of SMX-TMP combination product (sulfamethoxazole 1600 mg + trimethoprim 320 mg) and blood levels of the 2 active principles were determined during the first and 6 th hour post-dose. Blood levels of free SMX ranged between 50-84 mcg/ml and those of trimethoprim between 3.5-5.3 mcg/ml.
3. Clinical results :
SMX-TMP combination product was given to 6 patients with respiratory tract infections (acute tonsillitis 1, acute pharyngitis 1, acute bronchitis 3, and bronchiectasis 1) and 4 patients with urinary tract infections (acute cystitis 3 and chronic pyelonephritis 1). The therapy was effective in 4 of the patients with respiratory tract infections and 2 of the patients with urinary tract infections. No untoward reaction has been encountered.

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1. Potentiation of in vitro antimicrobial activities of sulfamethoxazole (SMX) and trimethoprim (TMP) combined at ratios of 10 : 1 and 20 : 1 were demonstrated in Staphylococcus aureus FDA 209P JC-1, Escherichia coli NIHJ JC-2 and other strains of Staphylococcus aureus and Escherichia coli isolated from clinical materials.
2. This combination product is well absorbed after oral dosing followed by satisfactory renal excretion. Concentrations of 2 active drugs were maintained over a relatively long period of time and concentrations in the urine were high.
3. Studies on the distribution of the 2 drugs in rat revealed that SMX concentrations in the blood were higher by several times than those found in the liver, kidney and lung, whereas those of TMP in the blood were lower by several times than those in the liver, kidney and lung, indicating an extensive extra-vascular distribution of the latter compound. The ratio of SMX and TMP concentrations varied according to the kind of tissue, organ and the time interval after drug administration.
4. The in vitro antimicrobial activity of 4-demethyl-TMP, a metabolite of TMP, was found to be essentially similar to that of the parent compound. Thin layer chromatography failed to detect this metabolite in 10-fold concentrated human urine specimens collected 8 hours after a dose of 800 mg SMX and 160 mg TMP. It was assumed that concentrations of this metabolite in the urine were not probably exceeding 10 mcg/ml.
5. SMX-TMP combination products were given to 6 patients with urinary tract infections. In 5 patients urine cultures became sterile and a significant reduction of bacterial count was recorded in another. However, bacteriological relapse and superinfections were observed in 3 patients after cessation of the drug therapy. Fever and eruption possibly related to therapy were encountered in a single patient.

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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.

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Sulfamethoxazole-trimethoprim combination product was given to 3 patients with blood dyscrasias (2 patients with acute granulo myeloid leukaemia and 1 patient with aplastic anemia) complicated by bacterial infections and 2 patients with rheumatoid arthritis and cystic kidney complicated by urinary tract infections in a dosage of 2 to 8 tablets daily for 8 to 20 days. Two of the 3 patients with blood dyscrasias responded by defervescence and both patients with urinary tract infections underwent bacteriological cure. Isolated pathogenic organisms were Escherichia coli, Klebsiella and Pseudomonas. A mild skin eruption was recorded on the 11th treatment day in a patient.

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Ten ambulatory patients with infections of the respiratory and urinary tracts were given a trial with sulfamethoxazole-trimethoprim combination product. The treatment was successful in 6 patients. This combination product appears to be a new addition to the group of effective antimicrobial agents.

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Sulfamethoxazole-trimethoprim combination product has been tried in 18 patients with infections of the urinary tract, respiratory tract and other organ systems. Therapeutic response was classified as effective in 7, fair in 6 and ineffective in 5 patients.
Mild gastrointestinal disturbance was observed in 3 cases. This product appears to deserve further extended clinical evaluation.

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A trial of sulfamethoxazole (SMX) -trimethoprim (TMP) combination product was conducted in 14 patients, mainly consisting of cases with respiratory tract infections. The drug was given 4 tablets daily for 4-23 days. Bacteriological cure followed in all of the 6 patients, in whom bacteriological studies were possible before and after the treatment. Of 12 clinically evaluable cases, 8 patients were classified as good responders and 4 as fair.
One patient complained of nausea and another developed probable sulfa-sensitivity manifested by fever, skin eruption and emesis. No hematological or hepato-renal disturbance was observed.

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This report is based on the results of studies on anti-microbial activities of sulfamethoxazole (SMX) -trimethoprim (TMP) combination product against clinically isolated strains and therapeutic efficacy of SMX-TMP combinations in various infections.
1. Minimum inhibitory concentrations (MICs) of SMX and TMP in 20 : 1 combination were clearly potentiated in comparison with those of SMX alone against 17 strains of coagulase-positive Staphylococcus aureus, 58 strains of Escherichia coli and 8 strains of Proteus. MICs of the combinatoin in Pseudomonas strains were similar to those of SMX alone.
2. A clinical trial of SMX-TMP combinations was conducted in 203 patients with infection of the fields of internal medicine, pediatrics, surgery, orthopedics, gynecology, urology and otorhinolaryngology. The daily dosage for adults was 4 to 6 tablets, for children 2 tablets and for infants 1 tablet. The overall effective rate was 63%.
3. Side effects were registered in 12 patients. These included drug exanthema in 6, gastro-intestinal disturbance (diarrhea, epigastralgia, vomiting, anorexia) in 4 and giddiness and restlessness in 1 patient, respectively.

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Laboratory and clinical studies on sulfamethoxazole (SMX) -trimethoprim (TMP) combination have been performed. Laboratory studies are based on the determination of minimal inhibitory concentrations (MICs) of SMX and TMP, alone and in combination ratio of 20 : 1 (SMX : TMP) in 33 clinically isolated strains of Staphylococcus aureus. MICs of the combination of SMX and TMP ranged from 0.4-12.5 mcg/ ml, which were lower by 2-3 folds than those of SMX alone and higher by 1-2 folds than those of TMP alone.
A clinical trial of SMX-TMP combination product included 12 patients with bacterial infections in the field of internal medicine. The effective response was obtained in 83.3% of the clinical material. This preparation appeared to have antipyretic activity as evidenced by defervescence in 5 of 6 patients with high-fever of unknown origin. Obvious clinical improvement followed a little later than the beginning of defervescence. No untoward clinical reactions to the medication were recorded, and examinations of blood counts, liver and renal function did not reveal anormalities ascribable to the drug administration. Because of its unique mechanism of action, this preparation appears to be a useful addition to the armamentrium of chemotherapeutic agent. The prompt antipyretic effect appears to warrant further studies.

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Sulfamethoxazole-trimethoprim combination product was used orally 4-8 tablets daily for 5-67 days, in 10 patients (empyema 1, pneumonia 2, acute pharyngitis 1, co-infection of pulmonary tuberculosis 1, lymphadenitis colli simplex 1, chronic pyelonephritis 1, cholecystitis 2, typhoid fever carrier 1).
(1) The results were excellent in 1 patient (empyema), good in 6 patients, fair in 1 patient (typhoid fever carrier), poor in 1 patient (lymphadenitis colli simplex) and uncertain (because of simultaneous use of CET) in 1 patient (pnenumonia).
(2) Side effects were observed in 4 patients, nausea 1, poor appetite 1, glossitis 1, skin rush, fever and iridocyclitis (maybe the side effects of sulfamethoxazole) 1.
(3) Two patients showed leucopenia, one became soon normal after the finish of the treatment, another became also normal in spite of using the drugs.
(4) No disturbance of liver and renal function was detected.

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1. Antibacterial activities of sulfamethoxazole (SMX) and trimethoprim (TMP) alone and in combination, were investigated against 7 bacterial strains including Staphylococcus aureus, Escherichia coli and Shigella employing MUELLER-HINTON medium.
In vitro activities against tested organisms were not significantly influenced whether lysed horse blood was added or not to the medium, when the size of inoculum was adjusted to 10³-10⁴/cm².
2. Minimum inhibitory concentrations (MIC) of SMX and TMP, alone and in combination (mixture ratio 19 : 1) were determined on 63 bacterial strains by the agar plate dilution method.
1) MIC of TMP was found to be lower than that of SMX in 55 strains.
2) MIC of SMX-TMP combination was lower than that obtained by either one of the single agents in the following strains tested, all of 4 Salmonella strains, all of 5 Proteus-providence strains, 1 Cloaca strain, 1 Citrobacter strain, 2 Serratia strains, 8 of 26 Staphylococcus aureus strains and 4 of 8 Pseudomonas strains.
3) MIC of the combination was identical with or higher than the lower MIC of the two single agents in 18 of 26 strains of Staphylococcus aureus (including 7 SMX resistant strains), all of 7 Escherichia coli, 4 Klebsiella and 5 Shigella strains; and 4 of 8 Pseudomonas strains.
4) FIC index calculated on the results mentioned above indicated the synergism in 62 of all 63 tested strains.
3. Rapidly growing acid-fast bacillus, M. fortuittum 238, was selected as a test organism for the bioassay of SMX in body fluids. This Mycobacterium was primarily resistant to TMP and sensitive to SMX. The technique developed enabled bioassay of SMX in concentrations exceeding 3. 12 mcg/ml using the agar diffusion method.
4. Plasma and urine concentrations of SMX and TMP were determined in 3 volunteers after a single oral administration of 800 mg SMX and 160 mg TMP. SMX levels were determined chemically by BRATTON-MARSHALL method and biologically by the cup diffusion method as described above. TMP concentrations were bioassayed using the technique reported by REEVES and CHILDE.

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The present study revealed that minimum inhibitory concentrations (MICs) of trimethoprim (TMP) alone against various strains of Staphylococci and Gram-negative rods (except for Pseudomonas) in vitro were significantly superior to those of sulfamethoxazole (SMX) alone. Few strains were found to be resistant to TMP, however. When SMX was combined with TMP in a ratio of 20 : 1, MICs were found to be 1 to 2 fold higher than that of TMP alone, but its antibacterial spectrum became broader. The implication of this phenomenon was discussed in relation to the therapeutic practice.
Clinical trials with this combination product revealed that 21 out of 26 patients with respiratory tract infection, and 4 out of 6 patients with urinary tract infection responded, efficacy rates of 80.8% and 66.7%, respectively. All responders belonged to infections of less than moderate severity. Although further clinical experience is in order, this product seems to be indicated for infections of moderate and mild severity. It was of particular interest to note that 6 of 8 non-responders to SMX alone were classified as responders after the therapy with SMX-TMP combination product. Six out of 35 cases complained of gastro-intestinal disturbance; all but I were mild and necessitated no interruption of the treatment. No haematological side effects have been observed.

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This investigation evaluated bacteriological activities, human pharmacokinetic profile and therapeutic effects of sulfamethoxazole (SMX) and trimethoprim (TMP) in combination.
Bacteriological : Antibacterial activities of SMX and TMP, alone and in combination were studied in clinically isolated strains; Staphylococcus aureus, Escherichia coli, Klebsiella and Proteus organisms. The potentiation of activities by combination in vitro was demonstrated in 29 of the 30 strains of Staphylococcus aureus, 22 of the 24 strains of Escherichia coli, 14 of the 18 strains of Klebsiella and 5 of the 9 strains of Proteus organisms.
Pharmacokinetic : Three healthy adults received a single oral dose of 2 tablets of SMX-TMP combination product (400 mg SMX and 80 mg TMP per tablet). Drug concentrations in the serum specimens, 2-6 hours following the drug administration ranged between 40 and 50 mcg/ml for free SMX and 1. 24-4.5 mcg/ml for TMP. The concentrations of free SMX in the serum was approximately 20 mcg/ml and that of TMP averaged 0.47 mcg/ml at 12 hour post-dosing. The concentrations of free SMX in the urine during the first 12 hours remained approximately 250-300 mcg/ml and those of TMP in the range of 95-100 mcg/ml.
Clinical : SMX-TMP combination product was therapeutically tried in 16 patients. Of these 16 patients, excellent response was achieved in 5, effective response in 7 and no response in 3. A trial in 1 patient was judged as not evaluable. Of interest was the response of 3 patients with serious pulmonary infections, 1 of these achieved remarkable response and the remaining 2 were satisfactory responders. Unwanted reactions included exanthema in 2 and anorexia in 1 patient.

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1) The in vitro anti-bacterial activity of trimethoprim (TMP) against clinically isolated organisms (Staphylococcus aureus, Klebsiella, Proteus and Escherichia coli) was found to be markedly intensified by the coexistence of sulfamethoxazole (SMX).
2) Some studies were made on the biological assay of TMP using the “band culture method” (test organism : Bacillus pumilus). PABA added to the assay media in order to eliminate the activity of coexistent SMX was found to affect the length of the inhibition zones produced by TMP.
3) Clinical trials : Thirty-five cases, including 16 of respiratory tract infections, 9 of urinary tract infections, two each of toxoplasmosis, colitis and lymphadenitis, one each of phlebitis, oto-furuncle, gingivitis and common cold, were treated with SMX-TMP combination product (2 tab.×2 daily, each tablet containing 400 mg SMX and 80 mg TMP). The treatment yielded satisfactory results in 9 cases of respiratory tract infections, 9 of urinary tract infections as well as in 4 of the remainder; while it failed in 6 cases. The clinical results were undeterminable in 7 cases, although, in two toxoplasmosis cases among them, antibody titer of their sera lowered after the treatment.
As for the side effects of the drug, glossitis and perleche were found in two patients who received the treatment more than 20 days. Three complained of anorexia. Although two patients showed anemia after the treatment, it was explainable as due to the infection.

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The growth inhibitory activity of sulfamethoxazole (SMX) against Escherichia coli in vitro was potentiated by the addition of trimethoprim (TMP). The growth inhibitory activity (Escherichia coli) of sera of a patient following oral administration of SMX-TMP combination product was similar to that of the same patient after a dose of SMX alone. However, the effect of the sera on Escherichia coli reproduction curve was more potent with those following administration of SMX-TMP combination product than with those after SMX alone, indicating potentiation of the bactericidal activity by the combination.

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1. Antimicrobial activities in vitro : The effect of combination treatment with SMX and TMP against Staphylococcus aureus and Escherichia coli was remarkable.
2. Experimental treatment of Staphylococcus infection in mice : Effective results of combination treatment with SMX and TMP were obtained, but its effect was weak compared with in vitro studies.
3. Serum antimicrobial activity test (SAAT) : The level of SAAT in the single treatment with SMX as well as the combination treatment with SMX and TMP was low of less than four times.
4. Clinical results : Effective results were obtained in five cases out of thirteen cases of chronic respiratory infection treated with ST drugs.

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A total of 150 patients, consisting of cases with bacterial dysentery, typhoid fever, salmonellosis, enteritis from pathogenic Escherichia coli, and stool culture-negative enteritis, were treated with sulfamethoxazole (SMX) -trimethoprim (TMP) combination product.
A comparison of therapeutic indices between SMX-TMP combination product and available antibiotics was made in 80 patients with bacterial dysentery, in whom 38 patients were accompanied with clinical symptoms and the rest were carriers. The clinical materials were comparable in terms of pathogenic organisms, age and sex of the patients in both groups.
The effect of SMX-TMP preparation appeared to be somewhat superior in improving the frequency of defecation and shortening the period of days required for recovery of facal properties to other antibiotic groups. In patients with clinical symptoms, the therapeutic results from SMX-TMP preparation appeared to be slightly inferior to the control antibiotic treated groups in terms of the rapidity at which stool cultures were converted to negative, the rate of re-excretion of pathogenic organisms and the duration of febrile period after the therapy. In carrier patients, SMX-TMP preparation was more effective than the compared antibiotics.
Of 11 patients with Salmonellosis, stool cultures became negative in 2 of the 4 clinically infected and in 3 of the 7 carriers after the treatment. The results in 10 patients with manifest typhoid fever and 5 carriers were classified as effective in 1 and probably effective in 3.
Bacterial strains isolated from hospitalized patients, consisting of 43 strains of Shigella, 7 strains of Salmonella typhosa, a single strain of Salmonella paratyphi, 12 strains of other Salmonella groups, 3 strains of Escherichia coli and 2 strains of Pseudomonas, were tested in vitro to assess their sensitivity to chloramphenicol, tetracycline, nalidixic acid, ampicillin, SMX alone, TMP alone, and SMX-TMP combination mixed at a ratio of 20 : 1.
SMX-TMP combination demonstrated higher antibacterial activities than the other agents in the majority of bacterial strains except for Pseudomonas. In all strains tested the activities of SMX-TMP combination were improved by marked potentiation over those of the drugs when they were used alone.

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Good therapeutic results were obtained in most of 13 infantile infections belonging to 4 different diseases by daily oral dose of 1 to 2 tablets of SMX-TMP (1 tab. were included 400 mg of SMX and 80 mg of TMP). SMX-TMP was suggested to be effective in urinary tract infection. The rate of effectiveness amounted to about 76.9% in total cases treated.
No significant side effects were observed.

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1. In vitro antimicrobial activities of sulfamethoxazole (SMX) -trimethoprim (TMP), alone and in combination, were studied in Staphylococcus and Escherichia coli strains isolated from pediatric patients. Potentiation of activities was demonstrated by combinations of SMX and TMP against both SMX-resistant and sensitive strains. The minimal inhibitory concentrations of SMX-TMP combination against SMX-resistant strains were found to be higher than those presumed to be attainable in vivo. The bactericidal activities of SMX-TMP combination, although significantly superior to those of either drug alone, were thought to be moderate. It was also found that the bactericidal effect of TMP was more marked in strains resistant to SMX rather than in those originally sensitive to the sulfonamide.
2. A new bioassay method for SMX and TMP applicable in pediatric patients was proposed. Determination of antimicrobial activities in serum and urine from an 8-year-old patient indicated somewhat lower values than those expected from previous reports. Whether this discrepancy was due to the difference in methods applied or patients' age remains to be studied.
3. SMX-TMP combination product was given to a pediatric patient with pyelonephritis caused by Klebsiella (MIC : SMX>800 mcg/ml, TMP>0. 78 mcg/ml), who had shown resistance to various chemotherapeutic agents including chloramphenicol, tetracycline, ampicillin, kanamycin and nalidixic acid. Changes in urine bacterial counts were followed while concentrations of SMX and TMP were also determined. Bacteriuria was cleared in 24 hours and no recurrence ensued 2 weeks' treatment with the combination preparation.

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The following results were based on our recent clinical studies on sulfamethoxazole (SMX) and trimethoprim (TMP) combination product in the pediatric field.
1. The majority of freshly isolated Staphylococcus aureus strains including those resistant to tetracycline was found to be sensitive to this combination product.
2. After oral administration, both SMX and TMP were well absorbed through the intestinal tract. Plasma levels of the compounds reached peak during the 2nd and 5th hours post-administration. Concentrations of bacteriologically active substances excreted in urine was found to be markedly high.
3. The clinical effect of the combination product in acute respiratory infections was excellent.
4. In the treatment of scarlet fever, this combination product rapidly normalized temperature and β-hemolytic streptococci in the throat cultures promptly disappeared. Positive conversion of throat culturesafter the cessation of treatment was relatively frequent, however.
5. In the treatment of diarrhea in infants and children, this combination product normalized the fecal findings within 3 to 4 days.
6. Patients with quasi-dysentery symptomatology without positive stool cultures were promptly responsive to the combination. Patients infected with Shigella sonnei which was resistant to streptomycin, tetracycline and chloramphenicol, clinically improved by normalization of fecal findings and frequency of defecation, but eradication of pathogenic organisms was difficult in most cases.
7. This combination product was highly effective in cystitis caused by Escherichia coli.

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The following results have been obtained from our studies of sulfamethoxazole (SMX) -trimethoprim (TMP) combination product in children with bacterial infections :
1. Ten out of 13 cases responded favorably, an effective rate being 77%.
2. This combination product gave particularly impressive results in acute urinary tract infections caused by Escherichia coli.
3. In patients with bacterial infection of the respiratory tract, clinical response started with a prompt normalization of fever followed by an improvement in other clinical features and laboratory findings. The foregoing experience encourages further trial of this combination product in various infections of bacterial origin in the pediatric field including more serious infections.

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A syrup preparation of sulfamethoxazole-trimethoprim combination was given to a total of 24 pediatric patients, consisting of 3 children with acute upper respiratory tract infection, 4 patients with acute bronchitis, 3 patients with pyoderma, 1 patient with periproctal abscess, 6 patients with infantile diarrhea, 1 patient with acute infantile diarrhea and 6 patients with acute urinary tract infection. The overall effective response was seen in 18 patients, an effective rate being 75%. No significant untoward reactions have been seen clinically. Tests of the liver and kidney function and blood counts remained within the normal limits throughout the therapy.

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Experimental and clinical studies of sulfamethoxazole (SMX) -trimethoprim (TMP) combination product have revealed the following results :
The assessment of bacterial sensitivity to SMX-TMP combination was made according to agar plate dilution method employing MUELLER-HINTON agar (pH 7.4) added with 7. 5% hemolyzed horse blood. The sensitivity of most of coagulase-positive Staphylococcal strains was 400 mcg/ml or more. Twenty-six out of 36 strains demonstrated minimum inhibitory concentrations (MICs) in exess of 200 mcg/ml of SMX. The peak distribution of TMP sensitivity ranged in the area of 0.2 mcg/ml. Twenty of 23 Escherichia coli strains demonstrated MICs higher than 400 mcg/m1 of SMX but the growth of all strains was inhibited by TMP concentrations less than 0.78 mcg/ml. The peak MIC distribution of SMX was found at 0. 1 mcg/ml. The activity of SMX-TMP combination against Staphylococci was enhanced as the ratio of TMP content within the combination increase. For SMX-sensitive Staphylococci the activity of SMX was potentiated by 2³-2⁴ times by combination with TMP in a ratio of 20 : 1. The growth of SMX-resistant Staphylococci were also inhibited by potentiation by the combination in the order of 2⁶-2⁷ times. The activity of TMP in the combination was reduced by 2^1/4-2^1/5 times in comparison with that of TMP when employed alone. The activities against Escherichia coli strains are subject to greater fluctuations than those seen with Staphylococci. The combination of SMX-TMP demonstrated potentiated activities against SMX-sensitive Escherichia coli greater by 2³-2₄ times than those of SMX alone. The activity against SMX-resistant strains was also strengthened by an average of 2¹⁰ times, while the activity of TMP in the combination was reduced by 2^1/3-2^1/4 times than that of TMP alone.
A clinical trial of SMX-TMP combination product in 17 pediatric patients with bacterial infection (ages ranging from 8 months to 10 years and 2 months) revealed 11 effective and 6 ineffective cases, an effective rate of 64.7%. The correlation between in vitro sensitivity of clinically isolated strains and therapeutic response was studied in 11 instances. All 3 patients from whom SMX-sensitive Staphylococcus aureus had been isolated responded to the combination. Two cases infected with SMX-resistant Staphylococci strains were classified as non-responders. Two strains of β-hemolytic Streptococci were snesitive to SMX and 1 of them was a responder and the other a nonresponder. SMX-TMP combination product was effective in all 4 patients with Streptococcus viridans infection, only one of which was sensitive and the other 3 were resistant to SMX. No untoward reactions were recorded.

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The following conclusions could be drawn from experimental and clinical studies of sulfamethoxazole (SMX) -trimethoprim (TMP) combination product.
1. Antimicrobial activity :
Minimal inhibitory concentrations (MICs) of SMX alone against 5 standard strains of Staphylococcus aureus ranged from 0.8 to over 100 mcg/ml and those of TMP alone were 0.8 to 1.56 mcg/ml. In contrast, activities of the combination of SMX and TMP mixed in a ratio of 20 : 1 recorded MICs of 0.8-1.56 mcg/ml MICs of SMX alone, TMP alone and SMX-TMP combination (20 : 1) in 4 strains of Escherichia coli were greater than 100, 0.05-0.2 and 0.2-0.8 mcg/ml, respectively.
2. Sensitivities of 52 strains of Staphylococcus aureus isolated from clinical materials gave, in term of MIC, greater than 100 mcg/ml for SMX alone in all strains, 0.4-3.12 mcg/ml for TMP alone and 1.6-25 mcg/ml for SMX-TMP combination.
3. MIC's of 51 strains of clinically isolated Escherichia coli were greater than 100 mcg/ml for SMX, 0.2-6.25 mcg/ml for TMP and 1.6-50 mcg/ml for the combination.
4. Blood concentration and renal excretion :
Investigations in 3 adult male volunteers indicated that peak blood levels of TMP 1/2 to 6 hours following a dose of 2 tablets of SMX-TMP combination product (800 mg of SMX and 160 mg of TMP) to empty stomach reached 0.87-1.07 mcg/ml as assessed by a bioassay employing a culture medium containing PABA. Blood levels of TMP 12 hours after a single oral dose averaged 0.4 mcg/ml. Urinary concentrations reached peak values of 116-360 mcg/ml during the period of 2-6 hours post-dose and the recovery in the urine up to 12 hours ranged 36-68 % of the administered dose. Blood levels of SMX determined chemically indicated that the compound reached peak values of 30-40 mcg/ml of free-SMX in 2-4 hours; total SMX-TMP concentrations were higher by 2-5 mcg /ml than those of free-SMX.
5. Thirty-five patients with infections of surgical field were given a trial with SMX-TMP combination product. Effective response was recorded in 24 patients, no effect in 8 and undetermined effect in 3. No significant untoward reactions were observed except for mild epigastralgia in 1 patient.

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Pharmacokinetic profiles, antibacterial properties and clinical effects of sulfamethoxazole (SMX) -trimethoprim (TMP) combination preparation were studied. Plasma concentrations of SMX as determined by BRATTON MARSHALL method reached a peak in 2 hours in adult patients given a single SMX-TMP combination tablet containing 400 mg SMX and 80 mg TMP : peak values for free SMX averaged 33.3 mcg/ml and that for total SMX averaged 39.3 mcg/ml. Peak plasma values for both free and total SMX were recorded 4 hours after oral ingestion in patients with 2 tablets dose; average free SMX concentration being 54.2 mcg/ml and that of total SMX 60. 0 mcg/ml. Plasma concentrations of TMP assessed by fluorimetry were found to scatter markedly and no uniform correlation was observed between peak plasma levels and hours after drug intake. The excretion of TMP in the urine ranged from 8.6 to 29.1% in the first 6 hours and that of total SMX 7.1-21.0%.
Minimum inhibitory concentrations of SMX-TMP combination mixed at a ratio of 20 : 1 against 42 strains of pathogenic Staphylococci, as determined by agar disc dilution method, ranged 1. 56-0. 045 mcg/ml. This antibacterial activity was stronger by 2 dilution tubes than those of kanamycin and streptomycin.
Fifteen patients mainly consisting of soft part superficial infections due to Staphylococcus aureus were given SMX-TMP combination preparation; 11 patients responded favorably. A mild diarrhea was observed in a single patient and no other untoward reactions have been experienced.

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The anti-microbacterial activity of the combination of sulfamethoxazole (SMX) and trimethoprim (TMP) combined in a ratio of 20 : 1 was studied in 20 strains of Staphylococcus aureus, 20 strains of Escherichia coli, 10 strains of Proteus, 9 strains of Klebsiella and 4 strains of Pseudomonas aeruginosa. All strains of Staphylococcus aureus, Escherichia coli, Proteus and Klebsiella were found to be sensitive to the combination. Pseudomonas strains were found to be all resistant to the combination, however, FIC indices were less than 1 in practically all of these strains demonstrating a potentiation of activities by the combination.
A clinical efficacy of SMX-TMP combination product was assessed in total of 26 patients with superficial infections of the soft tissues. The results were classified as markedly effective in 1, effective in 17, ineffective in 7 and undetermined in 1 : an effective rate of 72%. Anorexia and drug eruption were observed in a single patient, respectively. Another patient manifested some increase in preexisting anemic finding, which was thought to be possibly related to the medication.

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We have attempted to assess the therapeutic efficacy of sulfamethoxazole (SMX) -trimethoprim (TMP) combination product according to the criteria established by the Japan Society of Chemotherapy for the evaluation of antimicrobial agents. It was difficult, however, to follow up the changes in leukocyte counts and results of bacteriological studies because the clinical materials were limited to anbulatory out-patients. The therapeutic response may also be significantly influenced by such factor as surgical incision. Accordingly, our clinical assessment had to largely rely upon the improvement in local inflammatory manifestations. Our clinical experience indicates that SMX-TMP combination product is a new effective antimicrobial agent for the treatment of acute soft part infections.

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A total of 55 bacterial strains freshly isolated from clinical materials were investigated as to their sensitivity to sulfamethoxazole (SMX), trimethoprim (TMP) and their 5 : 1 combination mixture. The tested organisms comprised 11 strains of Staphylococcus aureus and Proteus, respectively, 18 strains of Escherichia coli, 5 strains of Klebsiella and 10 strains of Pseudomonas. The SMX-TMP combination was highly active against Staphylococcus aureus, Escherichia coli, Proteus and Klebsiella; the activity was potentiated by the combination.
A total of 24 patients mainly with surgical soft tissue infections has been treated with SMX-TMP combination preparation. The response was classified as markedly effective in 12, effective in 9, fair in 1 and ineffective in 2; an effective rate of 87. 5%. No significant untoward reactions have been encountered.

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