A bacteriological study of enduracidin, a new polypeptide antibiotic which was discovered by Microbiological Research Laboratories of Takeda Chemical Industries, Ltd. has been carried out, and the following findings have so far been obtained:
1. From the standpoint of the a ntibiotic spectrum, enduracidin was found effectively only against Gram-positive cocci and bacilli, and ineffective against Gram-negative cocci and bacilli. Further, the test antibiotic has a slight effect against Myco. tuberculosis which is an acid-fast bacteria.
2. Enduracidin was found to be as effective against about 100 strains of clinically isolated pathogenic Staphylococci (including those resistant to 2 or more antibiotics) as against the standard strains, but there was no cross resistance with the already known chemotherapeutics.
3. Tests on the influence of various factors on the antibiotic activity of enduracidin revealed that the variations in pH value and addition of serum protein did not exert any appreciable effect, but the variations in the amount of inoculum greatly influenced the antibiotic activity of the test antibiotic. Examination of the type of antibiotic activity of the test substance disclosed that it is stro ngly bactericidal but scarcely bacteriostatic.
4. In-vitro experime nt on the effect of enduracidin in combination with the already known antibiotics showed that the test antibiotic was synergistic with streptomycin and kanamycin, which are a glucoside antibiotic, but not synergistic with gramicidin-J, which is a chemically similar polypeptide antibiotic.
5. Enduracidin was found to be very potent in therapeutic effect against experimental infections in mice-Streptococcus hemolyticus and D. pneumoniae in particular, and superior to cephaloridine, an antibiotic of synthetic cephalosporin-C group. The test antibiotic, however, was considerably less active in effect against Staphylococcus, be ing inferior to cephaloridine.
The morphological changes in the cells of Staphylo coccus caused by enduracidin are being electronmicroscopically examined using super-micro slices of the sample at present, and the study on the absorption, distribution in vivo and excretion of enduracidin is under way. The findings will be published later.

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The studies on the absorption, excretion and distribution to organs of enduracidin (EDC) were conducted with rabbits and rats by dilution method. The following results were obtained:
1) The maximum blood level was obtained in rabbits 0. 5-8 hours after a single subcutaneous administration of 10 mg/kg of EDC, and its concentration in 15th day after administration was still 0. 031 mcg/ml.
2) The total urinary recovery for 15 days after a single subcutaneous administration of 10 mg/kg of EDC was 4. 74-5. 03% in rabbits.
3) It was demonstrated by saline extraction that EDC was trasferred to spleen, liver, kidney, lung and heart after subcutaneous administration of 10 mg/kg of EDC in rats and its concentration in the organs after 6 days was still enough to inhibit the growth of Staphylococci, Strept. hemolyticus, Diplo. pneumoniae.
4) Skin concentration was determined with rats administered 10 mg/kg of EDC subcutaneously. The value after 3 hours and 6 days was 320 mcg/0. 3 g and 20 mcg/0. 3 g, respectively.
From these results, low blood concentration and urinary excretion may be considered to be due to slow diffusion from the injected site.

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The growth inhibitory action of enduracidin upon Staph. aureus 209P strain was investigated by analyzing the growth curve automatically registered by Biophotometer (Jouan). The following data were elucidated by the experiment.
1) The growth of 209P strain was inhibite d by EDC at the dosis of 0. 1 m cgfml when given at the beginning of the culture, and the action of EDC was demonstrated not only bactericidal but also bacteriolytic when the antibiotic was given at the beginning of the logarythmic growth phase.
2) The anti-staphylococcal growth inhibitory action after i. m. injection of EDC were also studied by the same method and the activities were evaluated as the prolongation of the lag phase.
The serum level of activities was proved to be highest at 6 hours after injection an d retained for long period. On the contrary the excretion into the urine was proved to be smaller as expected before.

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The effect of enduracidin (EDC) against Staphylococci was examined, and the following was observed.
1) The MIC of EDC against 42 strains of Staphylococci isolated from lesions of various co nditions was under 0. 63 mcg/m1 in 40 strains and no cross resistance was found with streptomycin and kanamycin.
2) A pronounced bactericidal action was found against Staph. aureus 209 P with concen trations of higher than 1. 0 mcg/m1 of EDC.
3) No difference in antib acterial activity of EDC was found between a serum sample and a hemolytic sample.
4) The therapeutic effect of EDC by subcutaneous injection was examined in the mouse, experimentally infected by intravenous inoculation of Staphylococcusu, sing the abscess formation in the kidney and the intrarenal bacterial counts as indices and a marked effect was observed.

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Basic studies were carried out on enduracidin (EDC), a new antibiotic, in the field of urology and the following observed.
1) The bl o od concentration reached a maximum of 1. 9 mcg/ml following a single intramuscular injection of 2 mg/kg of EDC in healthy, mature, male rabbits weighing ca. 3 kg and a level of over 1. 0 mcg/ml was still present after 12 hours.
2) Experimental pyelonephritis w as produced in rabbits by inoculation with Staph. aureus and EDC then administered intramuscularly in a dose of 2 mg/kg/day for 7 days from the day after infection. The bacterial count in urine was followed during treatment and on the 8 th day, the animals were sacrificed and the bacterial count and histological changes in the kidney examined.
3) The bacterial count in the urine was over 10⁵/ml up to the 5 th da y of treatment with EDC in all 5 animals but on the 8 th day, no bacteria could be found in the urine except in one case.
4) Eight kidneys of 5 animals were examined and a bacterial count of 316/g and 36/g was obtained in 2 kidneys but was zero in the remaining 6 kidneys.
5) A prominent histological change was fo und in only 1 of the 8 kidneys examined. The changes in the others were mild.

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Single subcutaneous dose of enduracidin ranging from 1 to 4 mg per kg was effective in reducing the number of bacteria in the kidneys of a intravenous Staphylococcal infection in mice. The result of this study recomfirmed that enduracidin was useful in Staphylococcal infection.

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The therapeutic effect of enduracidin (EDC) was comparatively examined with potassium penicillin O in rabbits experimentally infected with syphilis. The followings were observed.
1) EDC was given intramuscularly in a dose of 50 mg/day for 10 days in r abbits infected with syphilis by inoculation in the back and testis and the effect appeared to be somewhat superior compared to similarly infected animals treated with PC-G.
2) The histological examination afte r treatment also showed that EDC had the same, if not superior effect compared to PC-G. In the control, the function of the testis was destroyed with no possibility of restoration 50 days after intratesticular infection while in the EDC group, the testicular function appears to be histologically restored normal. The PC-G group showed a gross l y similar picture but some pathological changes still remained.
3) The next day after completion of the therapeutic course, testicular tissue from the exp e rimental animal was implanted in a healthy animal but the results with both EDC and PC-G groups were negative.
4) There appeared no relationship between the therapeutic effect and the changes in antibo d y level of the blood.

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Pharmacological actions of enduracidin, an antibacterial agent were investigated.
The movement of the excised heart of frog and rabbit was stimutated (5 × 10^-8 and 5 × 10^-7 g/ml). The movement of the excised intestine of rabbit and the tonus of the excised intestine of guinea pig were stimulated (5 × 10^-8 g/ml), and inhibited (2 × 10^-5 and 5 x 10^-5 g/ml).
The excised rabbit ear vessels were dilated (10-3 g /m1). Temporary fall and rise of blood pressure (1-5 mg/kg) and acceleration of respiration (1-5 mg/kg) were observed in the urethane anes thetised rabbit. Bradycardia took place at the dose of 20 mg/kg. Enduracidin, therefore, has not remarkable pharmacological actions at the therapeutic doses.

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On a new antibiotic, enduracidin, some laboratory and clinical studies were performed and the results were summurized as follows:
1) Plasma level of endura cidin was assayed to the lower limit of 0. 1 μg/ml by the thin-layer cylinder-plate method.
2) Employin g 86 strains of 19 species of microorganisms, single-disc method was performed in parallel with the two-fold agar dilution method. As the results the standard curves representing the relationship between MICs and sizes of inhibition zones in the single-disc method were constructed.
3) No side effect was observed in 5 cases of intramuscular injections.

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A cylinder thin-layer agar plate method with Bacillus subtilis PCI 219 as test organism was most favourable for assaying enduracidin (EDC) concentration in body fluids. Sensitivities of assay were as follows; in phosphate buffer (pH 8. 0) 0. 25 mcg/ ml, whole blood 1 mg/ml, plasma 0. 5 mcg/ml. Estimates of EDC in bile and urine must be corrected, as these fluid increased sizes of inhibition zones of EDC. EDC was extracted from tissue homogenates by 60% acetone (pH 3---4)and subjected to estim ation by a paper disk method using thin-layer agar plate seeded with same microorganism. About 15 mcg of EDC per one gram of wet tissue can be estimated.

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Several fundamental studies were carried ou t on a new antibiotic, enduracidin (abbreviated as EDC) and the results obtained were as follows.
1. The MIC value of EDC a gainst Staphylococcus aureus measured by two fold dilution plate ranged from 0. 8 to 0. 2 mcg/ml.
2. There wa s the difference of two to sixteen fold dilutions between the minimal inhibitory and bactericidal concentrations.
3. The M IC value was influenced greatly by the size of inoculum.
4. There was moderate red blood corpuscle adsorption to EDC.
5. The marked EDC level reduction was shown immediate ly after mixing with mouse liver homogenate and further this decrease progressed gradually.
6. The protein binding rate using cello p hane bag dialysis was calculated to 32. 9% in average.
7. The organ level determination following intramuscular injection to mice in dose of 10 mg/kg was not successful by buffer dilution, but acetone extraction was essential for this purpose. The peak value ranked in the order as kidney>spleen>lung>liver, though the difference was relatively small. The serum level was equivalent to these organ's ones in general. These level was maintained in longer period and detectable after 24 hours.

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Effects of enduracidin on Gram positive bacterial strains, and the blood levels and urinary recovery of the drug were summarized as follows:
1) The sensitivity to enduracid in was measured by the plate dilution method in 156 strains of Staph. aureus, 10 strains of Str. hemolyticus isolated from patients.
One hundred and fifty one of 156 strains of Sta ph. aureus and all 10 strains of Str. hemolyticuws ere susceptive to the drug of less than 0. 78 mcg/ml.
2) Blood levels following a sin gle i. m. dose of 50 mg were studied in 5 patients with decreased renal function and 10 patients without renal impairment for comparison.
Blood levels were higher in the group with impaire d renal function than the group with normal function.
The urinary recoveries following the administration were also checked in these 5 patients with impaired renal function, and 3 of normal function, giving the result of higher recoveries in normal group.
a) The blood maximum level of enduracidin were obtained at 1-24 hrs. in the 10 patients with normal renal function, and at 1-4 hrs. in the impaired patients (GFR≤58) after intramuscular administration, and the mean values were 1. 81 mcg/ml in the normal patients, and 3. 50 mcg/ml in the impaired patients.
b) Average values of urinary recoveries, 72 hrs. after the administration, were 9. 86% in the normal patients, and 7. 22% in the impaired patients.

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Serum and aquous levels of enduracidin, a new highly inhibitory antibiotic for gram positive organisms, were determined with Bacillus subtilis following systemic or topical administration in rabbits.
A higher intraocular penetration was obtained by topical administration than sys temic, especially in the previously paracenteric eye.

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The experiments in rabbits and adults were made to assess the contents of enduracidin in the blood and the aqueous humor after intramuscular injection.
Four hours after injection of a single dose of 2. 5 mg/kg and 2 hours after injection of a single dose of 5 mg/kg, the highest plasma levels in rabbits were 2. 67 mcg/ml and 2. 91 mcg/ml respectively. The daily levels in the blood in rabbits given in a daily dose of 4 mg/kg for 5 days showed gradual increase and finally reached 1. 60 mcg/ml.
The effective blood lev el in adults was scarcely found after both injection of a single dose of 1 mg/kg and 2 mg/kg.
Eight hours after both injection of a single dose of 2. 5 mg/kg and 5 mg/kg, the highest aqueous humor levels in rabbits were 1. 09 mcg/ml and 2. 09 mcg/ml respectively and declined rapidly. The daily variations in the aqueous humor in rabbits given in a daily dose of 4 mg/kg for 5 days were not assayed bacause of minimal intraocular penetration.

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The present study was made to evaluate the toxic effect of enduracidin on the internal ear in the guinea pig in comparison with kanamycin.

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The antigenicity of enduracidin (EDC) was investigated with the passive cutaneous anaphylaxis and the inhibition of the antibacterial activity by the antiserum produced in rabbit.
The antiserum against EDC was prepared as follows: Two albino rabbits were in j ected with 12. 5 mg of EDC emulsified with complete Freund's adjuvant 4 times a week, and 1 week after boostered with the same dose of EDC. The antiserum was obtained in the 10th day after the last injection.
1) Positive cutaneous reaction was provoked in guinea pig with each antiseru m by the method of OVARY.
2) The inhibition of the antibacterial activity of EDC by the antiserum was observed while no inhibition was observed by the addition of normal rabbit serum or saline solution to EDC soluti on with the vertical diffusion method of TORII and KAWAKAMI. T he grade of inhibition was co rrelated to the concentration of the antiserum.

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This paper concerns the clinico-laboratory evaluation on a new peptide antibi otic, enduracidin, as follows:
1) Sus c eptibility test to 58 strains of Staphylococcus aureus with plate dilution method indicates excellent antibacterial activity of the substance (0. 4 mcg/ml of M. I. C. for the most of strains).
2) In absorption and excretion study in human subjects, low but prolonged blood level and poor urinary excretion were observed following 100 mg intramuscular administration.
3) In tissue level study in the rats following 20 mg/kg i. m. dos e, low tissue concentration was maintained throughout observation with BSS extraction, whereas higher level was observed with acetone extraction. The antibiotic recovered from injected site 24 hours after injection was calculated as 20% of the dose.
4) In absorption and urinary excretion study in the dog, higher blood level and greater urinary output were found in intravenous administration as compared to intramuscular dose. Its half-life (2. 7 hours) was longer than kanamycin, and renal clearance was about one-sixth of GFR. Estimated amount of the antibiotic in extravascular space 6 hours after i. m. and i. v. administr ation were calculated as 97% and 84% of the dose respectively. The difference may be due to the amount of antibiotic remained in injected site.
5) Serum protein binding study was carried out using cellophanebag dialysis and ultracentrifugation. Dialysis study showed low binding rate, whereas higher rate was observed by ultracentrifugation. There was little adsorption with the red blood cell.
6) In in vitro inactivation study by the rat liv er no practical loss of antibacterial activity was found. The data above mentioned seems to indicate that low but prolonged blood level of the sub stance results from poor absorption, strong affinity to but slower degradation by the tissue and poor excretion to urine and bile.
7) Clinica l observation in 10 cases with various infections treated with daily 100-200 mg dose showed 5 good, one fair and 4 poor results. There was no side-effect with the exception of one case with pain in injected sites.

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1) The MIC of nduracidin against coagulase positive staphylococci (25 strains) from various infectious foci determined by the plate dilution method revealed below 0. 8 mcg/ml in all strains and its activity was found to be neither influenced by the pH of culture media nor an addition of human serum.
2) The serum concentration of enduracidin studied in healthy adults ranged from 1 to 1. 5 mcg/ml following an intramuscular injection in a dosage of 50 mg. The rate of absorption of the drug was found to be quite slow with a half life of 11 hours. In patients with chronic renal insufficiency the serum concentration of the drug were also determined with the value at 48 hours following the single intramuscular injection not significantly different from that of peak concentration, indicative of a marked retension of the drug in such condition. The rate of urinary excretion of the drug appeared markedly low when studied in the healthy adults with its urinary recovery rate at 24 hours in the range of 1. 9 to 5. 3%.
3) In the experiment with the rats the organ concentration of the drug disclosed the highest in the kidneys followed by the lungs, liver and spleen respectively.
4) The nephrotoxicity of the drug were eva luated in rats by the daily intramuscular injection in a dosage of 10, 25 and 50 mg/kg for 3 weeks and its toxic effects were interpreted as relatively mild.

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The results of some studies on enduracidin (EDC) were summarized as follows:
1. The levels of EDC in the blood and the urine were determined in two adult men who received 50 mg of EDC by intramuscular injection. The mean peak level of EDC in the blood was 2. 1 mcg per ml and occurred about 3 hours after the injection. The urinary excretion rate was 19. 1% in 24 hours.
2. EDC treatment was effective in 3 of 7 patients with respiratory infections. The bacteria cultured from the sputum of 3 patients who improved were gram-positive cocci; Streptococcus hemolyticusa nd Diplococcus pneurnoniae, a nd disappeared after the treatment.
3. Anti-EDC-antibodies were found in the se ra of rabbits sensitized with EDC. These antibodies were revealed by some immunological methods; agar diffusion method and BDB hemagglutination method, but these antibodies had no influences on the antibacterial activities of EDC. In our experiments, the provocations of anaphylactic shock and the SCHULZ-DALEre action with EDC were not successful in the sensitized guinea pigs.

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1. The minimal inhibitory concentrations of EDC for several kinds of bacteria obtained from patients were studied by plate dilution method. The results are as follows;
49 Strains.......... 0. 8 mcg/ml
15 Strains.......... 0. 2- 1 2. 5 mcg/ml
MIC of EDC for 3 strains of Klebsiella, 4 strains of E. coli and 1 strain of Pseudomonas........... not less than 100 mcg/ml.
2. Blood levels and urinary excretions by intramuscular administrations of 1. 5 mg/kg of EDC were studied about 5 adults cases without renal impairment. Results are as follows.
Blood level
1 hr........... 0. 28 mcg/ml 12 hr........... 0. 40 mcg/ml
3 hr........... 0. 39 mcg/ml 24 hr........... 0. 31 m c g/ml
6 hr........... 0. 37 mcg/ml
Urinary excretion
0 - 6 hr........... 0 mg 12-24 hr........... 0. 54 mg
6-12 hr........... 0. 36 mg
3. The therapeutic effect of EDC on experimental Staphylococcal infections of mice were studied. The results indicated more effectiveness of EDC than erythromycin. 4. The binding rates of EDC with serum protein were studied by the method of ultracentrifugation. The results are as follows:. Binding rate:
Human sera ..........67-72% Horse sera ..........84-86%
5. One case of acute bronchopneumonia and the other case of acute urinary infec t ion were treated with EDC and these cases indicated the effectiveness of EDC.

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The mean minimum inhibitory concentration of the new polypeptide antibiotic “ Enduracidin” against the 70 strains of Staphylococcuasu reus was lower than PC-G, TC, SM, CP, EM, SPM, AB-PC and LCM, and of the same order as in MPI-PC and CER.
Although antimicrobial activity of the drug in vit r o was demonstrated, the clinical effectiveness to the five case of infectious diseases including pneumonia, lung abscess and sepsis was not remarkable. Serum levels at 1 to 2, 3, 6 and 12 hours after 50 and 100 mg intramuscular injection of enduracidin ranged from undetectable to 6. 0 mcg/ml and the urinary excretion rate ranged from 1. 7 to 4. 5%.
The low serum levels and urinary excretion obtained suggested poorer absorption than was antic ipated, although rapid degradation or tissue binding of absorbed drug cannot be excluded.

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16Children (8 with scarlet fever, 5 with follicular angina, 1 with acute pharyngitis and 2 with common cold) and 7 adults (4 with lung abcess, 1 with bacterial pneumonia, 1 with empyema thoracis and 1 with bronchiectasis) were treated with new antibiotic enduracidin. Results were as follows:
1. To infectious diseases of children, enduracidin was effective in 14 out of 16 amounti ng to 87. 5%.
On the contrary, only one adult out of 7 was successfully treated with enduracidin.
2. Even in effective case, it needed 3-5 days for improvement of fever. Enduracidin was thought to be slow but long acting antibiotic resulting in cummurative effects.
3. Skin rash, local pain at the site of injection and induration w ere side effects.

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Studies were conducted on enduracidin, a new antibiotic, and the following results were obtained.
1) The agent shows a potent antibacterial action against Gram positive cocci such as Staphylococcus and Streptococcubsu t has little effect against Gram negative bacteria.
2) The hemolytic Streptococcu asppeared to be the most su itable organism for biological determination by the multi layer method.
3) Serum level s of 0. 2-0. 3 mcg/ml and 0. 5-1. 0 mcg/ml are obtained after a single intramuscular injection of 50 mg and 100 mg of EDC, respectively, and these levels are maintained for 2-72 hours. Small amounts are excreted in the urine over an extended period and the recovery after 72 hours is around 27%.
4) Five cases of infections were treated with EDC but these were cases of Gram negative bacillus infection or a mixture of Gram positive cocci and Gram negative bacillus and it was effective in 1 case, somewhat effective in 1 case and ineffective in 3 cases.
5) Noteworthy side effects were not observed.

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1) Enduracidin (EDC) seems to be absorbed by blood cells and released from them by dilution with the physiologic saline solution. The recovery rate of EDC from the five fold diluted emulsions of rat organs is very poor, especially from those of liver, spleen, kidney and muscle.
2) Assay of EDC in rat organs after intramuscular injection revealed that t he antibiotic is distributed in the blood and the lung in the highest concentration, followed by the kidney and the spleen, while, after intravenous injection, the kidney shows the highest activity. The concentration in the liver was very low, and that in the brain was not detectable.
3) The biliary excretion of EDC in r abbits after intravenous injection was found to be rather poor. The concentration in the bile was almost similar as that in the blood.
4) Humans treated with EDC intramuscularly showed low, but long enduring blood levels. Three cases of respiratory infection were treated with EDC (100 mg daily, 10-20 days): The treatment was effective in two of them. No untoward reaction was found.

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The in vitroantibacterial activity of new antibiotic enduracidin against gram positive bacteriae and the clinical therapeutic effect of this antibiotic on gram positive bacterial infections was studied by us.
1. The in vitro sensitivity of enduracidin was measured by serial dilution method with freshly isolat ed strains of Staph. aureus. Most of strains were inhibited by 1. 0 mcg/nil.
2. Seven patients with gram positive 'bacterial infections and mixed infections of gram positive and negative bacteriae were treated with enduracidin. All patients were administered 100 mg of enduracidin intramuscularly once daily and the treatment period was about a week to a month. With respect to the clinical symptoms and clinical examination, enduracidin treatment showed good clinical results. Any side effect was not found by enduracidin therapy.

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The minimum inhibitory concentrations of enduracidin (EDC) against 48 strains of Staphylococcus aureus, most of which were highly resistant to G-penicillin, tetracycline, chloramphenicol or er ythromycin, were 0. 2 mcg/ml in 38 strains and 0. 4 mcg/ml in 10 strains. The pathogenic staphylococci appeared to be highly susceptible to this antibiotic.
Antibiotic activity was detect able in the blood of patients within 30-60 minutes after intramuscular injection of EDC, reached a low peak at 6-8 hours, and declined very slowly. A considerable concentration was still found at 24 hours. Injection of 2 mg and 7 mg per kg body weight gave peak serum levels of 0. 4 and 1. 5 mcg/ml at 6-8 hours. At 24 hours they were 0. 2 and 1. 0 mcg/ml respectively. About 10% of the drug was recovered in urine within 24 hours.
Twenty children with acute infections caused by Gram -positive cocci were treated for 3 to 7 days with intramuscular injections of daily dosis of 50 to 100 mg, according to their body weight. A prompt improvement of laboratory data and clinical signs occurred in 13 patients (65%). No untoward side effects were observed except a transient, slight proteinuria in 4 patients, which was indistinguishable from febrile albuminuria. No abnormality of the urine sediment or no elevation of the blood NPN was observed during the course of treatment.

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Basic and clinical studies were conducted on enduracidin (EDC), a new antibiotic in the field of pediatrics and the following results were obtained.
1) The minimal growth inhibiting co ncentration of EDC against 71 strains of coagulase positive Staphylococci, isolated from lesions, was 0. 4 mcg/ml.
2) The blood concentration, 2-6 hours after a single intramuscular injection of 5 mg/kg in 2 infants and 2 children, was 2-5 mcg/ml and a level of 0. 3-0. 6 mcg/ml was still present after 24 hours.
3) The rate of recovery in the urine 24 hours after a single intramuscular injectio n of 5 mcg/kg in 1 infant and 2 children was 2. 5-3. 6%.
4) EDC was administered clinically in 15 children with Staphylococcus infection and was effective in 7 and ineffective in 8 cases.
5) The effect of EDC on the liver and kidney functions was examined in 6 cases and a rise in GOT and GPT was found in 5 cases. Further study, however, is required to determine whether this is a side effect of EDC.

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Our basic and clinical studies on a new polypeptide antibiotic enduracidin have led to the following results.
1) The minimal inhibitory concentration (MIC) of EDC against Staph. aureus, Strept. hemolyticus, D. pneumoniae and C. diphtheriae recently isolated from patients was about 0. 4 mcg/ml and no cross resistance with other antibiotics was found.
2) The blood concentration a fter an intramuscular injection of 50 mg EDC in infants and children was determinable until 12 hours and it was effective clinically.
3) The drug was excreted in urine 10% until 8 ho urs after the injection.
4) In infants, no abnormal changes were observed at the site o f injection, liver and renal function test a daily single injection of 50 mg for a long time was given intramuscularly.
5) It was effective in 26 out of 31 cases of acute infection.
We observed this drug was especially effective ag ainst Staph. aureus and Strept. hemolyticusr esistant to other antibiotics.
No particular side effects were detected in infants and children after a daily single injection of 25-50 mg EDC.

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Enduracidin (EDC) was studied bacteriologically and clinically and the following results obtained.
The MIC of EDC against 56 strains of coagulase positive staphylococci isolated from le sions was under 0. 78 mcg/ml in 98. 2% and growth was completely suppresed with a concentration of less than 1. 56 mcg/ml in all the strains. No cross tolerance was found with other antibiotics such as PC-G, SM, CP, TC, EM, OM and KM.
EDC was tested clinic ally in 8 acute infectious conditions, chiefly due to Staphylococcus aureus and was effective in 4 and ineffective in 4 cases. No side effects attributable to EDC were observed.

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Enduracidin was used in 3 cases of pneumonia and 2 cases of emOyema, among which 2 case were not adequate to evaluate the effect of enduracidin on account of their causative agents, E. call and probably virus. It is impossible, at present, to get accurate evaluation of this new antibiotic.
The existence of local painful induration after intramuscular injection made it di fficult to use this for considerable duration. A study in which blood concentration was measured for 24 hours after the single injection of 5 mg per kg suggested that twice injections of 5 mg per kg were desirable to maintain an effective blood concentration on the first day.

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Antibiotic effects of enduracidin against Staphylococcus aureus Escherichia coli and Pseudomonaso btained from surgical fields were tested by means of plate dilution method, and the MIC's of 222 out of 238 strains of Staphylococcuasu reusw ere distributed in the range of less than 0. 8 mcg/ml of enduracidin, while those of Escherichia coli and Pseudomonas were more than 100 mcg/ml.
Serum concentration of enduracidin in normal adults aft er 100 mg intramuscular injection, which were measured by cup assay using B. subtilis PCI 219, reached their peaks of 0. 4-1. 2 mcg/ml at 1-4 hours following injections, and continued their hight until the end of 24 hours. Urinary levels showed almost similar patterns as those of serum, and the 48 hours urinary recovery were less than 1. 0% of administrated dose.
Clinical results of enduracidin in 82. 3% of 17 patients with surgical infections and 3 with prophylactic use were satisfactory. We used the drug as much as daily 100 mg intramuscularly and continued it for 1-6 days.
Any se rious side effects were not observed, excepting 3 patients complained of pain in injected areas.

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On a new antibiotic substance, enduracidin, derived from Streptomycefsu ngicidicus, several basic experiments and clinical studies were performed in our clinic and the results were as follows.
1) Serum levels: The serum levels of enduracidin after a single dose of 100 m g intramuscularly exhibited their peak at 6 to 8 hours, the value being about 1. 5 mcgiml. The serum levels were determinable even after 24 hours as high as about 1. 0 mcg/ml.
2) Urinary excretions: 24 hours urinary e xcretion of enduracidin after 50 mg intramuscular administration were 1. 8% of the administered dosis. 3) Migration into the pus: Pus level from patient operated upon his liver rupture after a single dose of 100 mg intramuscularly was about 1/2 of serum level.
4) Migration into the bile: Animal experiments wi th rabbits, 2. 5 to 3. 0 kg of body weight, were made by intramuscular injection of 20 mg/kg. The concentration of enduracidin in the bile average about 1/10 serum level.
5) Organ level (determined by acetone-extraction method): The organ levels of rabbit following intramuscular injection of 20 mg per kilogram of body weight were found in kidney, spleen, liver, and muscle at 24 hours in order of higher concentration and gradually tended to increase in course of time respectively. The concentration in the muscles was generally low or not detectable, however concentration at the site of intramuscular injection kept longer period higher level than muscles elsewhere.
6) Sensitivity of organisms clinically isolated: On Staphylococcal strains (80 strains) the peak sensitivity was observed at 0. 8 mcg/ml in 40% of all strains. MIC not higher than 1. 6 mcg/ml was recognized on 90% of all strains.
7) Results of clin ical application: Enduracidin was found effective in 18 of 24 cases of surgical infection and ineffective in 5, uncertain in 1. The ineffective 2 cases were found in Gram-negativebacterial infections. A few side effects such as local pain were noted, but no disturbance of the renal or hepatic functions was found.

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Basic experiments to determine body fluid levels, blood levels, urinary excretion, antibiotic activity against organisms isolated from lesions, clinical effect and side effects of enduracidin (EDC) were conducted.
Studies of the conditions for blood fluid level determinations reveal that the suppressive curve is greater in ordinary agar medium than in brain-heart infusion agar, the optimum pH is 7-8 and the effect of blood serum is almost nil.
The blood levels 4 and 24 h ours after a single intramuscular injection of 100 mg of EDC are 0. 70 mg/m1 and 0. 58 mcg/ml, respectively. There is a further rise in the blood level with successive ad ministration indicating that accumulation takes place. A higher level is obtained by administration in divided doses than by a single injection even when the total dosage is the same.
The total recovery rate in the urine was 2. 54% 24 hours after a single intr amuscular injection of 100 mg.
Sensitivity tests with 66 strains of Staphylococcus aureus isolated from lesions revealed a peak at 0. 4 mcg/ml and growth Was completely suppressed in all the strains by 1. 6 mcg/ml and under. E. coli, Klebsiella pneurnoniae, Proteus and Pseud. aeruginosa were not sensitive to EDC.
Clinical tests in 21 cases of infectious conditions in the surgical field showed that EDC was effective in 16, ineffective in 4 and indefinite in 1 case.
The liver function, renal function and b lood picture were followed in all the cases but no abnormalities were found. However, pain and induration at the site of injection were reported with a considerable number of cases.

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Enduracidin (EDC) was tested clinically in 23 cases of infection, chiefly due to Staphylococcus aureus It was markedly effective in 15, effective in 6 and ineffective in 2 cases. The dosage was 1-2 mg/kg/day for 2-27 days. Administration was intramuscular for the most part but was applied locally in 2 cases.
Except for pain at the site of injection report in 5 of 26 instances, side effects were not observed. The sensitivity of 15 causative strains isolated from the lesions was tested against EDC, TC, CP, SM, EM and MPI-PC. EDC had the greatest effect. The clinical effect of EDC is verified bacteriologically by these results.

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Enduracidin, a new antibiotic, was examined and the following results obtained.
1) The MIC of enduracidin was less than 0. 78 mcg/ml in 44 strains o f coag. positive Staphylococci isolated from lesions of surgical cases in a period of 6 months from Jan. 1967.
2) The blood concentration was determined after intramuscular inject ion into the gluteal muscle of a female weighing 58. 5 kg and values of 4 mcg/m1 at 1 hour, 7 mcgiml at 2 hours, 6 mcg/m1 at 3 hours, 1 mcg/ml at 6 hours and 0. 5 mcg/ml at 12 hours were obtained. The results suggest that a fairly high blood level is maintained over a considerable length of time,
3) Administration in 8 clinical cases resulted in a satisfactory effe ct in all the 8 cases.
4) A slight decrease in urinary volume occurred in 1 of the cases but this is at tributable to an underlying diabetes mellitus and no other side effects were found. An urticarial rash occurred after termination of the agent but it could not be definitely determined that the agent was the cause. The liver function was not affected in any of the cases.
5) From the suppression of growth of co ag. positive Staphylococci with low concentrations in vitro, the prolonged effective blood concentration following intramuscular injection, the high efficacy in clinical cases and the low incidence of side effects it is considered that enduracidin is a highly effective substance against coag. positive Staphylococci.

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The antibacterial activity of a new polype tpide antibiotic enduracidin against Staphylococcus and Streptococcus was excellent.
The peak leve l in blood concentration following an intramuscular injection of 5 mg/kg in infants was 2. 6 mcgiml and determinable highly even at 24 hours after injection.
Excretion of EDC into urine was good.
Seven cases of various infection inc luding 3 cases of resistant staphylococcal infection in obstetrics and gynecology were treated by daily dosis 100-200 mg of EDC.
Six patients were cured.

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Basic clinical studies were carried out in the field of obstetrics and gynecology with enduracidin (EDC), a new antibiotic substance. The following results were obtained.
1) The MIC of EDC in 20 strains of clinically isolated Stap hylococci was under 6. 25 mcg/ml and the 50% MIC was 0. 78 mcg/ml.
2) The blood concen tration following a single intramuscular injection of 50 mg, 100 mg and 250 mg in the adults was maximal at 4. 4 mcg/ml and a sustained low peak was found over a period of 4-24 hours.
3) The urinary excretion 24 hours a single intramuscular injection of 50-250 mg was 2. 6-8. 5 %.
4) The blood concentration and urinary excretion in the newborn showed a trend sim ilar to that in the adult.
5) The transfer of EDC to breast milk was about one-half that in the blood with continuous injection of 100 mg but there was almost no transfer to the umbilical blood, amniotic fluid and newborn blood, with a single intramuscular injection of 100-250 mg.
6) In the pelvic organs, EDC concentration in the uterus and tubes was found to be 80-90% of that in the blood, but transfer of EDC to the ovaries was extremely slight with a single intramuscular injection of 200 mg.
7) The clinical results in 20 cases of Staphylococcal infection were as follows: 13 were effective, 5 ineffective and 2 unknown.
8) Side effects consisted of pain in 3 cases and induration in 1 case out of 20 cases. Liver function and renal function were unaffected.

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Clinical tests were conducted on enduracidin, a new polypeptide antibiotic extracted from Streptomyces fungicidicus, and following results were obtained.
1) The sensitivity of 40 strains of Staphylococci isolated from lesions against various antibiotics was tested and the value obtained with enduracidin was 0. 39-12. 5 mcg/ml and growth of 87. 5% of the 40 strains was inhibited in the range of 0. 78-1. 56 mcg/ml.
2) Concentration of enduracidin in body fluids of 3 female patients administered 100 mg intramuscularly was examined by the multilayer method. The blood level, 1-8 hours after inject i on, was 0. 79-0. 66 mcg/m1 and 12 and 24 hour values were 0. 54, 0. 29 mcg/ml, respectively. The 24 hour urinary excretion was 6. 3%.
3) Enduracidin was administered to 10 patients in the field of ob stetrics and gynecology. Clinically, enduracidin was effective in 3, somewhat effective in 2, ineffective i n 4 and indefinite in 1 case.
4) It is believed that enduracidin is clinically an interesting new antibiotic.

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Studies were conducted on clinical effect and blood concentration of enduracidin (EDC) and sensitivity of gonococcus to the substance. The following results were obtained.
1) A single intramuscular injection of 250 mg of EDC had a highly satisfactory clinical effect in non-gonorrheal conditions but it was ineffective in gonorrheal urethritis.
2) The sole side effect of EDC was pain at the site of injectio n.
3) The maximum blood concentration following a sing le intramuscular injection of 250 mg of EDC was 1. 85 mcg/ml and was 1. 10-1. 85 mcg/ml even after 24 hours.
4) The sensitivity of 25 strains of gonococcus isolated from patients to EDC was tested using the paper disk method. A suppressive zone of more than 1 mm was found with the 2 mcg disk with all the strains.

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Enduracidin was administered to patients with various urinary tract infection and observations on clinical effects as well as basic experiments were performed.
1) Blood concentration and urinary excretion rate. With 50 mg of intramuscular injection, the b lood concentration was low for many hours. The urinary excretion rate after 50 mg intramuscular injection was 1. 75% in case 1 and 0. 54% in case 2 in 8 hours. In p a tients after nephrectomy, same results were obtained.
2) Antibacterial effects. Sensitivity of Staphylococci and E. coli against enduracidin was measured. The sensitive levels of concentration of enduracidin were s een in low concentration areas for Staphylococci tested, whereas the sensitive levels of concentration of E. coli were found in very high concentration areas.
3) Clinical effects. Among 22 ca ses (21 cases of Staphlococci infection, 1 case of other coccal infection), given enduracidin including 2 cases of acute pyelonephritis, 7 acute cystitis, 1 chronic pyelonephritis, 7 chronic cystitis, 1 chronic prostatitis, 1 fistula after nephrectomy, 1 urethral fistula and 1 urethritis nongonorr hoica, remarkable effect, good effect and no effect were seen in 8, 9 and 5 cases respectively, making 77. 3% effectiveness showing a distinguished result.
4) Side effects. Pain was observed in 3 cases. In one case unpleasant feeling was observed.

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Basic and clinical studies were carried out on enduracidin (EDC) and the following observed.
1) For determination of the concentration in body fluids, a modification of the ToR n-KAwAKAmr multi-layer cup method was used.
2) The blood concentratio n showed a maximal level of 3. 8 mcg/ml, 3 hours after intramuscular injection of 50 mg of EDC and with intramuscular injection of 100 mg, a low peak was maintained over a prolonged period.
3) The urinary excretion showed a recovery rate of 1. 8-3. 4%.
4) Concentration in the liver and kidney was obse rved following intramuscular injection in the Wistar rat.
5) T he effect of rat liver homogenate on EDC was examined and it was found that EDC is inac-, tivated by the liver cells.
6) EDC was teste d clinically in 8 cases of postgonorrhoic urethritis, 4 cases of postsurgical cystitis and 2 cases of acute cystitis and was very effective in 7, somewhat effective in 3, indefinite in 3 and. ineffective in 1 case.
7) Side effec ts consisted of anaphylactoid reaction in 2 cases, headache anthralgia and vomiting in 1 case and pain at the site of injection in 11 cases.

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Enduracidin (EDO), a new polypeptide antibiotic, isolated from Streptomyces fungicidicus No. B5477, was tried in various pyodermic conditions such as furuncle, phlegmone, and infectious impetigo and the following results were obtained. EDC injection was used in 7 cases and was effective in 1, somewhat effective in 1 and ineffective in 5 cases. EDC ointment was used in 14 cases and was very effective in 10, somewhat effective in 2 and ineffective in 2 cases.
EDC was tested bacteriologically by examinin g the sensitivity of 30 strains of Staphylococci maintained in the laboratory. The heart infusion agar and trypto-soy agar were used for the medium and the stepwise dilution method was used for the determinations. The minimal growth suppressing concentration of EDC was 0. 5 mcg/ml in 11 strains and 0. 25 mcg/ml in 19 strains in the trypto-soy agar medium. and 0. 5 mcg/ml in 1 strain and 0. 25 mcg/ml in 24 strains in the heart infusion agar medium.

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Basic and clinical studies were conducted on enduracidin (EDC), a new antibiotic, and the followings were observed.
1) The sensitivity of 78 strains of pathological Staphylococci isolated from pyodermic lesions to EDC was 1. 56 mcg/ml or lower and 91% showed sensitivity of 0. 78 mcg/ml.
2) The maximal blood concentration 30 minutes to 1 hour after a single intramuscular injection of 100 mg in 5 healthy adults was 1-2. 9 mcg/ml and a level of 1 mcg/ml was maintained over a prolonged period.
3) The serum concentration and the level in the skin were measured after a single intramuscular injection of 20 mg of EDC in 3 rabbits. The level in the serum followed a course similar to that observed in the human subject and the level per gram of skin was 1. 5-3. 4 mcg after 1 hour and 1. 3-5 mcg after 2 hours.
4) Transfer to the skin when EDC ointment was applied was examined in the rabbit but with the method of 0. 1 M phosphate buffer extraction, could not be determined.
5) Clinical administration of EDC injection in 7 cases o f infective conditions in the field of dermatology resulted in a marked effect in 2 cases, and an effect in 2 cases. The EDC ointment was very effective in 4, effective in 3, somewhat effective in 5 and ineffective in 1 case out of a total of 13 cases.
6) Noteworthy side effects were not observed with either the injection or the ointment.

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We have recently obtained the result describ ed below through the experimental and clinical studies on new antibiotic.
1) T h e minimum inhibitory concentration of enduracidin was measured by agar plate dilution method. Enduracidin inhibited Staphylococcusa ureus 21 strains (including standard 209P strain) with 1. 56-<0. 19 m cg/ml. Enduracidin showed higher sensitivity than other antibiotics, and also c ross resistance was not recognized. Enduracidin, however, could not inhibit with 100 mcg/ml against 6 strains of Pseudomonasa eruginosa.
2) The level of bl ood concentration of enduracidin was determined by the average of 3 cases for adult. The maximal level reached 0. 56 mcg/ml 4 hours after injection, as the result measured by single dose of intramuscular injection of 100 mg. And blood level still maintained 0. 26 mcg/m1 12 hours after injection.
3) The pus concentration showed 0. 25 mcg/ml 10 hours after intramuscular injection of 100 mg in the operation of maxillary sinuititis.
4) Urinary excretion conc entration was determined by the average of 3 cases for adult. The urine concentration showed 0. 95-36 mcg/ml between 8 and 12 hours after injection 100 mg. Urinary recovery rate showed extremely low average, 1-9%.
5) By intramuscular injection (50-100 mg ) or local application (5 mg/ml solution) on 40 cases in 6 types of infections in otorhinolaryngologic field, enduracidin produced a good result of 80% (32 cases).
6) Enduracidin showed no side effect at all, by intramuscular injection and local application.

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Enduracidin (EDC) was applied clinically in the treatment of otorhinolaryngological infections and the following results obtained.
1) EDC showed a MIC value of under 0. 78 mcg/ml against Gram positive bacteria isolated from infectious conditions in the field of otorhinolaryngology.
2) EDC showed bactericidic an d bacteriolytic effect with a concentration of 1. 0 m cg/ml in in-vitro tests. The blood serum 2-12 hours after intramuscular injection of 100 mg of EDC showed a pronounced suppressive effect against growth of Staphylococcus aureus 209 P. The urine showed only a weak growth suppressing effect indicating that urinary. excretion was low.
3) The therapeutic effect in 30 cases was: very eff ective-19 (63. 3%), effective-6 (20. 0%).
4) Side effects attributable to the agent were observed in 4 cases with drug eruption s in 2 and loss of hearing of high frequency waves in 2 cases.

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From the clinical application of enduracidin for otorhinolaryngological infections, the following results were obtained.
33 patients including 3 cases of acute tonsillitis, 5 cases of acute otitis media and 25 cases of chronic otitis media were treated with enduracidin and it was effective in 60. 6% of them.
Minimal inhibitory concentration study was done in 15 strains isolated from these patients and a standard strain of Staphylococcus aureus 209P.
All Staphylococcus strains were inhibite d to grow by the presence of enduracidin at the concentration of 1. 56 mcg per ml or less, but all gram negative bacillus strains were highly resistant to this antibiotic.
These results suggest that enduracidin has an excellent therapeutic effect on gram positiv e coccus infection.

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An experimental and clinical study was conducted over the possible use of enduracidin in ophthalmology. Enduracidin has been claimed to have bacteriocidal action against gram-positve organisms.
Experiments in rabbits have shown that sufficient plasma concentration can be achieved w ith intramuscular injection of a relatively small amount of enduracidin. Enduracidin showed excellent intraocular penetration when administrered subconjunctivally and intramuscularly.
Sensitivity study of enduracidin against 20 pathogenic strain s isolated from infected focus in the eye showed that the bacterial growth was inhibited in 70% of the strains at the concentration of 3. 12 mcg/ml.
Nine cases with ulcus corneae serpens and holdeolum were effectively cured with intram u scular injection of 100 mg daily.

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Bacterial and clinical studies for ophthalmi c use of enduracidin (EDC) were performed and the results summarized as follows.
1) Minimum growt h inhibitory concentration of EDC was 0. 78 mcg/ml for K-W bacillus, 1. 56 mcg/ml for M-A bacillus, 0. 18-3. 12 meg/nil for Pneumococcus, 0. 36-0. 78 mcg/ml for C. diphth eriae, 1. 56 m cg/ml for Gonococcus, 0. 18-3. 12 mcg/ml for Streptococcus, 0. 78-1. 56 mcg/ml for Staphylococcus and >100 mcg/ml for Pyocyaneus.
2) The distribution of the sensitivity for 100 strains of Staph. aur. isolated in 1967 was in the range of ≤0. l2. 5 mcg/ml, and majority of them (52 strains, 52%) was in 0. 5 mcg/ml.
3) The concentration in the blood by intramuscular injection of a sin gle dose 100 mg reached the highest after 4 hours and maintained measurably until 24 hours.
4) After instillation, or subconjunctival injection of EDC, the concentration was found in the tissuse of the outer parts of the rabbit eye. After the intramuscular injection of EDC in a dose of 50 m g/kg, the concentration was recognized both in the outer and inner parts of the eye.
5) Intramuscular injection of 25-100 mg EDC once or twice daily revealed excellent effects on 10 cases out of 13 hordeolums caused by Staphylococcus, 3 cases of 4 lid abscess, 1 case of orbital phle gmone, and 2 cases of 4 corneal ulcers caused Staphylococcus and Pneumococcus.
6) Side effects: Some of patients complained slight pain on injection but any other severe side effects were not noticed.

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