Laboratory investigations conducted in 29 nation-wide laboratories and institutions are summarized as follows. T he antibacterial activity of josamycin (JM) was studied on staphylococci, other Gram positive and negative organisms isolated from clinical materials, and it was observed:
1) JM was inactive against Gram negative bacteria as other usual mac rolide antibiotics were;
2) JM was active against those strains which were sensitive to the usual macrolides;
3) JM was not active against A group strains among macrolide-resistant staphylococci, which were constitutively resistant to all the usual macrolides;
4) JM was active against C group strains of macro lide-resistant staphylococci which showed resistance to all the macrolides only after induction by EM or OM, as JM could not be an inducer in these strains. Some mention w a s made on a mutation from C group staphylococci to A group.

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A total of 164 strains of recently isolated pathogens from clinical materials, i. e. pneunzococci, hemolytic streptococci, enterococci, Staphylococcus aureus and several species of anaerobes, were tested for their in vitro susceptibility to josamycin, erythromycin and lincomycin by a plate dilution method.
To aerobic Gram positive cocci erythromycin was most effective and secondly josamycin was effective, but to anaerobes these three antibiotics were almost equally effective.
Among the strains of Staphylococcus aureus, josamycin-resistant strains were all resistant to erythromycin, but a few were sensitive to lincomycin. Josamycin-sensitive strains of staphylococci were almost all sensitive to erythromycin and lincomycin, but a few were resistant to erythromycin and lincomycin or one of these two antibiotics.

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The bacteriological study was conducted by the authors using josamycin, a new antibiotic which was developed in Japan as a member of the macrolide family. The result showed that josamycin could be fairly compared with other known members of the macrolide family such as erythromycin, leucomycin, oleandomycin and spiramycin, in terms of antibacterial activity as well as antibacterial spectrum. Cross resistance involving josamycin and these macrolide antibiotics was proved in this study. Some strains of erythromycin-resistant organisms were found resistant to josamycin but not the other strains of them. Here was demonstrated the same pattern observed in cross resistance between erythromycin and leucomycin or spiramycin. By the study on various possible factors that could exert influence on antibacterial activity of josamycin, it was shown the drug was more potent at the alkaline side of culture medium pH. In infections induced by staphylococci in mice, josamycin was found almost equal to erythromycin in its therapeutic efficiency. In infections with streptococci in mice, it was found to show better therapeutic effect than erythromycin, tetracycline or chloramphenicol.

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Study was made on the cardiovascular effect of the macrolide antibiotics, josa mycin, spiramycin and oleandomycin.
1) Josamycin showed lasting hypotensive effect in dogs. The effect was due to peripheral vasodilation.
2) Spiramycin and oleandomycin also exhibited marked hypotensive effect, which could be attributed to the liberation of histamine.
3) Josamycin had dilating action o n peripheral blood vessels.

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Josamycin, spiramycin and oleandomycin were compared with respcct to their effect on the smooth muscle, motor nerve, monoamineoxidase and cholinesterase activities.
1) Josamycin inhibited the movement of isolated intestin al segment of rabbit through direct action on the smooth muscle.
2) Spiramycin and oleand omycin stimulated the movement of isolated intestinal segment of rabbit. The effect was due to excitation of the smooth muscle.
3) None of these antibiotics acted on the motor nerve endi ngs.
4) None of these antibiotics affected the activity of mon oamineoxidase and cholinesterase.

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Josamycin aspartate at 2x 10^-4g/m1 inhibited activities of the isolated heart of toad, but it did not affect that of the isolated atrium of guinea-pig. The isolated perfused vessel of the rabbit's ear mussel was dilated at 10^-4 g/ml. Injection (2 mg/kg i. v. ) into rabbit cased fall of the blood pressure and acceleration of respiration. Bradycardia was observed at 50 mg/kg i. v. in the rabbit.
The isolated intestine of rabbit was first stimulated and then inhibited at 2 x1 0^-4g/ml, but that of guinea-pig was not affected even at 10^-3 g/ml.
The base itself acted similarly on the atrium and intestine of guinea-pig and on the perfused vessel of the ear mussel of rabbit, but it stimulated the motility of the isolated heart of toad at 5x10^-4g/ml, and inhibited that of the intestine of rabbit at 10^-4g/ml.
When the drug is used as antibiotic, the above effects d o not count, since they appear only at such high concentrations.

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The results of our studies on josamycin are summarized as follows:
1) The sensitivity was measured by the plate dilution method on 60 strains of Staph. aureus. Thirty eight strains showed MIC's of less than 1. 6 mcg/ml and 14 showed those of higher than 100 mcg/ml. Josamycin was found to show cross resistance to erythromycin and spiramycin.
2) Blood levels, bile levels and urinary recoveries following an oral and intravenous administration were studied in dogs. The bile levels were very high. The results of these stu d ies were calculated as follows: t/2 was 1. 13 hr., Cs 285. 6 ml/min., Cr 61. 5 ml/min and Cb 0. 12 ml/m in.
3) Blood levels and urinary recoveries following an oral administration were studied in adults. Low blood levels and low urinary recovery rates were found.
4) In oral absorption and biliary excretion study in dog, it was shown by thin layer chromatographic analysis that the most of josamycin excreted in bile was in the degradated form.
5) Thirty one cases of infectious disease including 29 respiratory infections and others were treated with josamycin. Fifteen cases were cured excellently, 9 were good, 5 were fair and 2 were failed. Three p a tients have shown the side effects of anorexia and abdominal pain.

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1) Sensitivity 24 strains of coagulase positive staphylococci were used for determination of sensitivity to josamycin. The MIC was found to be 0. 8 mcg/ml in 16 and more than 100 mcg/ml in 3 strains.
2) Blood level The m aximum blood level was 2. 0 mcg/ml one hour after oral administration of josamycin at a dose of 600 mg in normal subjects. The half life was 1. 7 hours.
3) Urinary excretion The uri n a ry level was 24-64 mcg/m1 and the urinary recovery rate 2. 8 % in the first 8 hours.
4) Rat tissue level The distri b u tion of josamycin which was given orally to rats was studied. The highest level of the drug was found in the lung which was followed by the liver, kidney, spleen and serum i n order.
5) Clinical result Josamyc i n was administered to 6 patients with respiratory tract infection, in 4 of whom the drug was found to be effective.

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The results of clinical and bacteriological studies on josamycin were as follows:
1) Susceptibility test to 66 strains of Staphylococcus aures, 13 strains of hemolytic streptococci, 11 strains of Enterococcus and two strains of Diplococcus pneumoniae with plat e dilution method indicate excellent antibacterial activity of new antibiotic, such as 0. 78 mcg / ml of MIC. for the most of the strains of Staphylococcus, 0. 38 for the hemolytic streptococci an d Diplococcus pneumoniae. Five of eleven strains of enterococci showed 100 or more mcg/ml of MIC and remain showed 1. 56 mcg/ml.
2) Comparatively, mean MIC of josamycin tend to be greater than that of erythromycin and less than leucomycin and spiramycin.
3) Clinical evaluation in eight cases with respiratory infections treated with daily doses of 0. 8-2. 4 g for 7 to 20 days revealed four good and four fair results. One case of pelvic peritonitis due to Esch. coli had no respo n c e to josamycin-treatment.

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The fundamental and clinical studies on Josamycin were carried out and the following results were obtained.
1. The sensitivities to josamycin of 49 strains of Staph. aureus, 14 strains of Strept. hemolyticus and 12 strains of Strept. viridans were measured by the plate dilution method. 3 1 strains among 49 strains of Staph. aureus indicated MIC less than 3. 12 mcg/ml, but M I C of these strains by josamycin were from 2 to 8 times inferior to those by EM MIC of Strept. hemolyticus were distributed from 0. 2 to 3. 12 mcg/ml, and those of Strept. viridans from 0. 1 to 1. 6 mcg/ml. MIC of these strains by josamycin were from 2 to 4 times inferior to tho s e by EM. 2. Bloo levels and urinary recoveries following an oral administration of 5 mg/kg of josamycin were measured by dilution method. The maximum blood levels were obtained after 1 hour and the average blood level was 0. 85 mcg/ml. Effective blood levels were retained for 6 hours. The urinary recoveries were 0. 8 mg (0. 3%) in 24 hours.
3. Clinical effects: 35 patients of respiratory infections and 1 patient of colitis acuta were treated by josamycin. It was found that the results were good in 28 cases of 36 (77. 8%) b y oral administration. No significant side effects were observed.

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On a new macrolide group antibiotic, josamycin (abbreviated as JM), several investigations were carried out and the following results were obtained.
1) In the sensitivity test against Staphyloc occus aureus, JM showed nearly comparable MIC values to lincomycin and leucomycin which were inferior to erythromycin and superior to spiram y cin and oleandomycin. Thirty five of 42 erythromycin resistant strains showed cross resi s t ance to JM as well.
2) Antibact erial action of JM was considered chiefly to be bacteriostatic and the difference between bacteriostatic and bactericidal levels was five to seven or more grades of two-fold dilutio n.
3) JM showed slight adsorption to red blood corpuscles, and the serum protein bind ing rate of 15% on the average using cellophane bag dialysis.
4) The peak serum level after oral administrati on to rabbit in dose of 30 mg per kg was as low as 0. 4 to 0. 8 mcg/ml.
5) The peak tiss ue level following oral administration to mice in dose of 400 mg per kg was found at 30 minutes after starting. Height of the level ranked i n the order of lung, spleen, serum, kidney and liver. Mixing of JM with organ homogenates resulted in reduction of JM concentration, which was so great i n liver and kidney homogenates that only about a half was recovered.

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Josamycin, a new macrolide antibiotic, were used against 50 strains of Staphylococcus (coagulase positive) for minimum inhibitory concentration and exhibited in vitro antimicrobial activity which was greater than spiramycin but smaller than erythromycin.
Josamycin produced relatively low serum le vels after oral administration of 400 mg, the peak ranging from 0. 46 to 1. 56 mcg/ml (average: 1. 08 mcg/ml) in 4 subjects.
Josamycin was administered 400 mg three times daily for 5 t o 21 days orally to 18 patients with a variety of respiratory infections. Fifteen patients responded clinically and/or bacteriologically, to the treatment: the diagnosis included lung abscess (4 cases), chronic bronchitis (3 cases) and others. The same doses of the drug were also given to 8 patients with late latent syphilis for one month.
Fall of the titer of the quantitative serological reactions did not become evident in mo st cases after treatment except in three cases.
In none of them the reaction became negative.
No side effect was seen except in one case who developed gastro-intestinal disturbance.
It was concluded that josamycin would be promising for the treatment of respiratory tract and others but not much for late syphilis.

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Clinical application and some basic studies were performed of josamycin, a new macrolide. The results obtained were as follows:
1) Serum concentration and urinary excretion in human volunteers. Each adult volunteer took 600 mg of josamycin by m o uth. Serum concentration of josamycin ranged from 0. 24 t o 1. 2 mcg/ml on average 1 to 2 hours after administration. Urin a r y recovery of josamycin for 12 hours was 3. 1 % on average.
2) St. viridans, St. hemolyticus and Staph. aureus were found out to be susceptible to josamycin. MIC of these strains were under 0. 195 mcg/ml. MIC of Enterococcus, only 4 stra i ns, were about 0. 78 mcg/ml. Gram N. b a c illi were resistant to even over 100 m cg/ml of josamycin.
3) MIC of josamycin for the Staph. aureus was 3. 125-0. 39 mcg/ml.
4) 23 cases of infectious diseases (i. e. bacterial pneumonia, bronchitis and tonsillitis) were treated with the agent, 17 of them exhibited satisfactory therapeutic response.
5) 25 cariers of bacillary dysentery were treated with josamycin. Culture revealed no growth of bacilli in 2 days af t e r treatment in 10 cases (40 %) and 5 days in 12 cases (48 % ). 3 cases in thi s series showed continuous possitive culture or reapperance of the bacilli.
6) No remarkable side effects include hepatic disorder were noted in our trial.

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1) E. coli and Klebsiella were highly resistant to josamycin (JM) showing the minimal inhibitory concentrations of 100 mcg/ml or more, while in Staphylococcus aureus some stra i n s were resistant with the MIC values of more than 100 mcg/ml, but others were sensitive to JM showing the MIC's of 0. 39-3. 13 mcg/ml.
2) The serum levels, sputum and urinary recoveries were studied after a single intravenous administration of 200 mg of JM in a patient. The maximum serum level was 0. 6 9 mcg/ml after one hour, and the maximum sputum level was 17. 4 mcg/ml after three hours w i t h the sputum recovery of only 0. 38% during 24 hours. The maximum urinary level was 240 mcg/ m l after one hour, and the urinary recovery during 24 hours was 23. 9%. 400 mg of JM administrated orally every six hours in a patien t gave the peak of serum level of 1. 4 mcg/ml after one hour, the peak of urinary level of 41. 3 mcg/ml after two hours and the urinary recoveries of 4. 5-7. 8% during every six hours.
3) In clinical application of JM in 17 cases, results were proved to be effective in 13. Among them, especially in respiratory infections, 9 out of 12 cases had good therapeutic effect.
4) The side effects were quite minimal, only nausea, anorexia and itching being observed in each one case.

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Laboratory and clinical investigations were made on josamycin (JM), and the following results were obtained.
1) 21 of 48 staphylococcal strains isolated from clinical materials were sensitive to 0. 78 to 3. 12 mcg/m1 of JM, but remaining 27 strains were resistant to JM, showing MIC of 100 m cg/ml or more. All E. coil, Klebsiella and Shigella strains were not sensitive to 100 mcg/ml.
2) Blood levels of JM after oral administration were relatively low, reaching 1. 2 and 2. 6 mcg/m1 in each one of three cases given a single oral dose of 200 and 400 mg respectively. U r i nary excretion was found in a small quantity.
3) Results of oral administration of JM were excellent in 3 and good in 3 of 12 infection cases in internal medicine. No side effects were observed.

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1) Tissue concentration of Josamycin (JM) in rats:
a) Recovery from tissue emulsions: Recovery of added JM in vitro from tissue emulsions, especially from liver emulsion, was very poor. Other macrolides were not so inact i v ated by emulsions as JM, while carbomycin was in activated similarly to JM.
b) Distribution of JM into rat organs: Concentrations of JM in organs (corrected by in vitro recovery rate) after oral administration in dose of 250 mg per kg were generally very l o w, similarly to concentration of carbomycin, which was previously reported.
2) Biliary excretion of JM in rabbits: Intravenously injected JM in dos e of 20 mg per kg was excreted into bile in markedly higher concentration than serum level. 1-2 % of the administered JM was recovered from bile i n 2 to 2. 5 hours.
3) Blood level and urinary recovery in a human adult: Blood level of JM in a human adult after single o r al dosage of 600 mg was found to be very low; i. e. 0 mcg/ml (1 hr. ), 0. 34 (2 hrs) and O. 3 2 (4 hrs). Only O. 6 % was recovered from his u rine in 4 hrs.
4) In vitro sensitivity of staphylococci to JM: In vitro sensitivity of 28 strains of Staphylococcus aureus to JM was examined and compared with the sensitivity of the same strains to other antibiotics, i. e. spiramycin, olean d omycin, triacetyl-oleandomycin, erythromycin, tetracycline, doxycycline, lincomycin, clinimyc in, kanamycin and kanendoamycin. Generally speaking, the sensitivity of staphylococci to JM was qui t e similar to that to triacetyl-oleandomycin, higher than that to spiramycin, but lower than those t o the other antibiotics.
5) Clinical trials: Five cases of b ronchitis, pneumonia or tonsillitis were treated with oral JM (1200 to 2400 mg daily) administration, which was effective in one case of bronchitis. Nausea was the only adve r s e effect, of which one of the five cases complained.

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The results of studies on josamycin are summarized as follows:
1. In a greater number of staphylococci included in this study, josamycin inhibited their growth at the concentration of 0. 63-2. 5 mcg/ml.
2. Josamycin achieved the highest blood level which was 1. 04 mcg/ml one hour after 400 mg of the drug and 2. 2 mcg/ml two hours after 800 mg were given. In one patient who received 800 mg of josamycin and li m onada hydrochlorica in combination, the josamycin blood level was found higher than if the drug was given singly.
3. Josamycin was found as good as or slightly better than erythromycin in infections induced by staphylococci in mice.
4. Josamycin was found effective in 6 of 7 out patients with Gram positive organism infections.
5. No side effects were observed in all patients included in this study except for one who had mild rash seemingly accounted for by the drug.

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1) The sensitivity of 89 strains of coagulase positive Staphylococcus aureus, isolated from patients, was studied by means of plate dilution method. Most of test strains was inhibited in 1. 56 mcg/ m l and 3. 12 mcg/ml, and only four strains was showed more than 100 mcg/ml in MIC.
2) When 250 mg of josamycin were administered orally in three children, maximum blood level was 0. 5 mcg/ml (at the 1st hour) in two cases and 3. 60 mcg/ml (at the 4th hour) in o t her one case Urinary recovery rate is reported.
3) Josamycin was administered to 27 patients with acute infections, in 17 of whom the drug was found to be effective.

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We titrated the concentration of josamycin in each tissue of such organs as muscle, kidney, spleen, lung, cardiac valvus (Tricuspid and mitral valvus), cardiac muscle, aorta, pericardial effusion and so on, by the capillary agar diffusion method utilizing β-hemolytic streptococci (Cook strain) as the test organism and human blood as the indicator, giving intravenously 100 mg/kg weight.
The extremely high concentration of josamycin was recognized especially in the tissues of lung and spleen, and still showing a reasonable amount of concentration in those organs even in the stage of that of the serum being decreased.
In contrast with this, the con centration in the tissues of kidney showed always below the josamycin concentration in the serum. Referring to the side effects, as far as we know, josamycin is free from harmful after-effects using regular amounts of dosages.

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A series of laboratory and clinical studies using josamycin (JM), a new macrolide antibiotic discovered in Japan, revealed the following results.
1) Pneumococci, hemolytic streptococci and coagulase-positive Staphylococcus aureus strains recently isolated from patients showed high sensitivity to JM, and staphylococci resistant to com m only used antibiotics were also sensitive. Further many of staphylococci resistant to EM, b e longing equally to macrolides, showed sensitivity to JM.
2) Detectable blood levels were demonstrated as long as 6 to 7 hours after oral administration of ca. 10. 0 to 20. 0 mg/kg, and their peaks were observed at the 3rd hour.
3) JM levels in mother's milk showed similar values to those in blood.
4) JM was, shown to be excreted into urine in its active state.
5) Good therapeutic results were obtained in most of 57 infantile acute infections belonging to 8 different diseases by daily oral dose of ca. 20 to 40 mg/kg, mostly of 30 mg/kg. JM wa s suggested to be effective in lung mycoplasmosis. The rate of effectiveness amounted to ab o u t 87% in total cases treated. Pneumococci and hemolytic streptococci isolated from medic a t ed patients were highly sensitive to JM. The cases infected with staphylococci showing M I C of as high as 3. 12 mcg/ml or less responded well to JM.
6) Oral administration of ca. 20 to 30 mg/kg p er day for 10 days in children revealed no recognizable change in blood findings or liver function suspected to be due to medication.

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Clinical observations were performed in 21 cases of pyogenic skin disorders treated with a new macrolide antibiotic, josamycin. Remarkable effects were revealed in 9 of 21 cases. It was especially effective in these of furuncle and furunculosis given large oral daily doses ranging between 1200 and 1600 mg. Whereas no improvement was achieved in both of adult cases of impetigo given small daily doses ranging between 600 and 800 mg.
No data suggesting untoward effe cts were obtained in cases which underwent urinary examination, blood counts and GOT-and GPT-estimations. No gastrointestinal disturbances skin eruptions were encountered. The MIC's of josamycin estimated by agar plate dilution method were 1. 56 megimi or less in 30 of 40 strains of staphylococci.

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The activity against staphylococci obtained from pyoderma lesions was studied by the plate dilution method. The distribution of minimum inhibitory concentration was as follows; 0. 8 mcg/ml for 1 strain, 1. 56 mcg/ml for 20 strains, 3. 13 mcg/ml for 1 strain and 100 mcg/ml for 10 strains. The anti-staphylococcal activity of josamycin was similar to that of lincomycin.
Serum concentrations of the antibiotics after oral administration of 400 mg to the fasting three adult human males were studied. The assay was performed by the cup method with B. subtilus PCI 219. The peak levels showed in the conc. of 0. 88 to 1. 0 mcg/ml at 2 to 3 hours.
The clinical use of the antibiotics was tried in 16 cases of pyoderma. 7 cases showed excellent results, 6 cases fair fesults and 3 cases poor results. No remarkable side effects were seen except heart burn in 1 case.

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Following results were obtained by our fundamental and clinical studies on josamycin (JM). 1) The in vitro antibacterial activity of JM against 68 strains of staphylococci isolated from boils and other skin diseases was similar to that of erythromycin (EM). However as to 9 resistant strains to EM, 5 of them were al s o resistant to JM but other 4 strains were inhibited by 3. 12 mcg/ml of JM.
2) JM was less effective than EM against the experimental rabbit syphiloma but its efficacy was enough recognized.
3) JM was clinically applied to 19 cases of pyoderma. Effective therapeutic results were obtaine d in 12 of 19 cases, particularly, satisfactory results in many cases of furuncles, furunculosis and other follicular infection diseases, but no effect in each of 2 impetigo cases. No noticeable side effec t was observed except one case who complained a burning sensation in the epigastrium.

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Josamycin is a new macrolide antibiotic with high in vitro activity against Gram-positive bacteria. The following results were obtained. Antibacterial effect of josamy cin was intensified at pH 7. 0-8. 0 of media, it was stable at 105-101 of inoculum size and no influence Was observed in coexistence of serum. 2. 2-3. 6 mcg/ml of blood level and 390-460 mcg/ml of maximal concentration in the urine were obtained after oral dose of 1. 0g in healthy adults. Urinary recovery rate was 5. 8% in the first 6 hours.
Josamycin sensitivity of 34% of staphylococci cultured from surgical infections in inpatients was ranged in 0. 1-1. 56 mcg/ml, and of 60% in outpatients was 0. 4-1. 56 mcg/ml.
In the open clinical test of the drug it was found that the results were good in 8 cases of 12, and failed in 4 cases, and no side effects were observed.

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Following results were obtained by our fundamental and clinical studies on a new macrolide antibiotic, josamycin.
1) Josamy cin was clinically applied to 21 cases of various surgical infections. In 18 cases, josamycin was found to be effective. As to the side effects, a case showed nausea and epiga s t r ic discomfort but tolerated continuous administration.
2) Three hours after a single oral admin istration of 200 mg to healthy adults, blood levels of josamycin averaged as high as 0. 535 mcg/ml, and the urinary excretion rate was 0. 65% within 12 hours.
3) Josa mycin sensitivity of staphylococci (20 strains) and E. coli (26 strains) isolated from infected lesions in surgical field was studied. Staphylococci were sensitive to josamycin in the ra n g e of 0. 8-6. 3 mcg/ml, 55 % of which were at 1. 6 mcg/ml, and E. coli at more than 100 mcg/ml.
4) Remarkable high concentration of this antibiotic was detected in the bile, i. e. 19 2. 5 mcg/ml on the average (about 200 times) of blood level 1 to 2 hours after administration (20 m g/kg in rabbit).

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1) Average blood levels after a single oral administration of 1. 0 g of josamycin (JM) showed a peak at 2. 62 mcg/ml in one hour, decreasing to 2. 33 mcg/ml in 2 hours, 1. 49 mcg/ml in 4 hours a nd 0. 77 mcg/ml in 6 hours. Twelve hours after the administration, JM was detected in the blo od of 2 of 7 cases, but not recognized in all the cases 24 hours after.
2) Total urinary excretion after a single oral dose of 1. 0 g of JM was 20. 0 to 94. 7 mg (55. 3 mg on the average) during the first 24 hours, and the urinary recovery was 5. 5 %.
3) Antibacterial activity of JM was studied on stock strains of bacteria isolated from clinical materials. The MIC distribution of 82 Staphylococcus aurens strains showed bimodal p attern with peaks at 0. 8 mcg/ml and more than 100 mcg/ml respectively, and 76 of the 82 strains (92. 7 %) were sensitive to 3. 13 mcg/ml or less of JM. However, almost all Gram negative bact eria were resistant, showing MIC of 50 mcg/ml or more. Among 82 strains of Staphylococcus aurens, the highly sensitive strains showing MIC of 6. 25 mcg/ml or less, were sensitive the m o st to EM, and then to JM, OM and LM in the order. However regarding to resistant strains showing MIC of 100 mcg/ml or more, 16 strains were resistant to EM, 12 to LM and 7 to OM, b u t only 6 strains were resistant to JM.
4) Of 106 cases treated orally with JM, results were effective in 82, failed in 21 and doubtful in 3. The rate of effectiveness was 77. 4 %.
5) Among these 106 cases, JM was effective to 42 of 49 Staphylococcus aureus infections (85. 7 f4).
6) JM was effective to most of Staphylococcus aureus infections from which there were isolated cocci highly sensitive (_??_ and _??_) to EM in sensitivity disc assay.
7) Among these staphylococcal infections, JM was not effective to one case infected with cocci showing MIC of more than 100 mcg/ml and to 2 of 4 infected with those with MIC of 3. 13 mcg/ml. However, all of 11 cases infected with cocci sensitive to 1. 6 mcg/ml or less respond e d well to JM with good therapeutic results.
8) Therapeutic results of JM were effective in 38 of 43 surgically treated (88. 4 %) and 17 of 21 not surgically treated cases (81. 0 %), showing marked therapeutic results singly by JM admini stration.
9) Of 106 medicated cases, 9 complained of gastrointestinal disturbances (8. 5%) such as anorexia or gastric disconfort, but no other side effects were observed in any of them. And also, in any of these cases, no abnormal findings were found in liver and kidney functions examined befo r e and after the medication.

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From the study on blood levels, urine levels, antibacterial activity of josamycin (JM) and its clinical trials, the following results were obtained.
1) Coagulase-positive staphylococci isola ted from urinary infection cases showed bimodal MIC distribution with two peaks at lower and higher JM concentrations. Regarding antibacteri a l activity, JM was found about a half as active as EM.
2) Detectable blood levels lasted for 6 hours after a single oral dose of 800 or 1400 mg, the peaks being observed in one to two hours. Urinary recoveries were 5 to 10 %
3) JM was applied to urinary and genital infections, and the results were excellent in 10, good in 5 and failed in 8 cases. The rate of effectiveness was 65. 2 %.
4) No side effects were noted in 23 medicated cases.

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The maximum blood level of josamycin was reached at 2 hours after oral administration and the highest excretion rate in urine was showed at 6 hours in normal human.
The organ concentration of josamycin in rats was the highest in liver, kidney and blood in order.
Minimum inhibitory concentration of josamycin against pathologenic Staphylococcus aureus was in the range of 0. 19 mcg/ml to 100 mcg/ml.
Josamycin was administered to 13 patients with urinary tract infections, and exhibited excellent therapeutic effects.

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In our clinic, josamycin (JM)-a new macrolide antibiotic-was administered to patients with various gynecological infections, and evaluation on its clinical effects was performed. Furthermore, basic experiments were carried out. The results of the above studies are found below:
1) MIC of JM against many strains of Staphyl ococcus aureus was 0. 78-1. 56 mcg/ml and this sensitivity was almost equal to that of other macrolide antibiotics. Further, JM was proved to be sensitive against staphylococci which was resistant to many other antibiotics.
2) The blood concentration after oral administration of 500 mg of JM was 0. 56-3. 24 mcg/ml after 1-2 hours. Transition of JM into milk was found similar to that into blood in te r m s of concentration, and JM reached 1/2-1/5 of mother's blood concentration at the time of i t s transition into umbilical blood.
3) Transition into uterus, ov ary, uterine tube and placenta was observed a little.
4) Total urinary excretion after oral administration of 500 mg of JM was ab out 4, 4 within 6-8 hours.
5) Clinically, JM was given in 24 cases of gynecological infections such as utero-infection, adnexitis etc., and JM was effective in 87 %. This efficiency corresponded with t h e sensitivity of strains isolated from infected lesions.
6) No side effect was observed but 2 cases of mild anorexia.

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Josamycin, a newly developed macrolide antibiotics, was administered to patients with various gynecological and obstetrical infect ions.
In the present study, 0. 9-1. 9 mcg /ml of blood concentration and 35. 2 mg of total excretion in 24 hrs. urine were obtained after oral 400 mg administration.
Excretion amount in milk, umbilical blood and amnion-water was very low.
In the clinical trial of this drug, 7 out of 9 cases had good therapeutic effect.
The cases were 3 adnexitis, 4 acute cystitis, 1 post-operative bronehitis, 1 puerperal infection.
Isolated pathogenes were 5 Staphylococcus aureus and one Streptococcus faecalis.
No significant side effects such as gastrointestinal disorders were observed.

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We have recently obtained the result described below through the clinical and experimental studies on josamycin.
1) The minimal inhibitory concentration of josamycin was measured by an agar plate dilution method. Josamycin inhibited the growth of 40 strains of coagulase positive Staphylococcus aureus at 0. 39-3. 12 mcg/ml and 25-100 mcg/ml.
2) The blood level of josamycin was dete rrhined in 3 adult cases. The maximal level reached 1. 71 mcg/ml on the average one hour after a single oral administration of 800 mg, a n d the level was still 0. 04 mcg/ml in 6 hours after the administration.
3) The urinary excretion of josamycin was studied i n 3 adult cases. The average urinary recovery was 184 mg in the first 8 hours by a single oral administration of 800 mg, and the r ate of urinary recovery was extremely low ranging in 3. 2-5. 93 %.
4) Recognizable amount of josamycin was not detected i n the pus collected from a case of maxillary sinuitis operation who was given an 800 mg oral dose.
5) The tissue concentration in rats given oral josamycin wa s found the highest in lungs, and lower in spleen, kidneys, heart and liver in order.
6) In the clinical test of josamycin in otorhinola ryngological infections, it was found that the results were good in 41 cases of 46 (89%) by oral administration of 400-1200 mg per day or b y local application of 10 mg/ml solution.
7) Josamycin showed no side effec t at all in oral and local medication.

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Josamycin, a new macrolide antibiotic, were studied to evaluate its possible use in ophthalmology.
1) While JM was proved, in general, to be effective against pathogenic staphylococci in in vitro studies, it was shown that 7 were resistant to JM out of 41 strains of pyogenic organi s m s isolated from clinical materials.
2) JM showed good penetration into the aqueous humor in rabbits both by oral administration and by eye drop instillation (5% solution of JM).
3) 27 patients with external ocular infections and 6 patients with corneal infections were treated with JM at oral doses of 1200 mg per day. Satisfactory therapeutic effects were ob t ained in all cases thus treated.
4) No noticeable side effects were observed in all cases.

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Bacterial and clinical experiments concerning ophthalmic use of josamycin (3M) revealed following results.
1) The minimum growth inhibitory concentration of JM were 0. 1 mcg/ml for Koch-Weeks bacillus, 0. 5-1. 0 mcg/ml for Morax-Axenfeld bacillus, 0. 25-1. 0 mcg/ml for Pneumo c occus, 0. 5 mcg/ml for Corynebact. diphtheriae, 0. 5 mcg/ml for Gonococcus, 0. 25-1. 0 mcg/ml for Streptococcus, 0. 25-2. 5 mcg/ml for Staphylococcus and>100mcg/m1 for Ps. aeruginosa.
2) The distribution of sensitivity for 100 strains of Staph. aur. were in the range of 0. 5-50 mcg/ml, and 68 strains of which were in <1. 0 mcg/ml.
3) Cross-resistance was recognized between JM a nd the other macrolide drugs: erythromycin, oleandomycin, spiramycin and lincomycin.
4) Maximum serum level was at tained at 2 hours after oral administration of 1 gm JM in a single dose. The level decreased gradually until 6 hours.
5) After oral administration of 500 mg JM in rabbit, the concentration in the aqueous humor was recognized for 1 to 6 hours, and peak was reached after 2 hours. The tissue concentrations at 2 hours were high in extraocular m u scles, retina and choroid, lid, conjunctiva, cornea and iris and ciliary body, and low sclera, aqueous, vitreous body and crystalline lens.

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