Ten patients (8 with moderate or severe infection s, 2 for prevention of postoperative infections)were treated with cefoxitin.
The patients were given cefoxitin of2-9 g, given once, or in 2-3 divided doses.
Clinical efficacy was good in 7 cases, fair in 2 and poor in1.
Transient nausea and vomiting occured in 1 patient when a direct intrauterine injection (1g of cefoxitin) was given, however, no side effects were observed in the other patients.
The result of this study demonstrates that cefoxitin when given massively is effective in achieving bacteriologic and clinical cure in treatment of infections and for prevention of postoperative infections in the field of obstetrics and gynecology.

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Prior to the operation, 1.0 g of CTM was administered by one-shot intravenous injection to 15 operative cases, and CTM concentration was measured 1-, 2-and 3-hour later by collecting bone marrow and serum.Results were as follows.
1) CTM concentrations in bone marrow averaged 18.60, 8.25 and 4.54.μg/ml in the 1-, 2-and 3-hour groups, respectively.
2) The ratios of CTM concentrations in bone marrow to those in serum were on the average 121.4, 116.5 and 97.2 per cent in the 1-, 2-and 3-hour groups, respectively.

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An antibiotic drug of aminoglycoside group, amikacin (AMK) for parenteral use was used to8 hospitalized patients: 4with acute or subacute cholecystitis and cholangitis, 4with acute peritonitis (3cases were due to acute appendicitis and a case was torsion of right ovarian cyst).AMK in a dose of200mg were administered by intravenous drip infusion for1to2hours, twice a day for 4 to 9 days. To the cases with biliary tract infection, AMK was treated to preoperatively and to the cases with acute peritonitis, AMK was treated to the postoperatively. Clinical response was excellent in2cases, good in6cases, fair and poor in none. No adverse effect was observed.The organisms were isolated in4cases, 4were Escherichia coli, 1was Klebsiella pneumoniae and1was Bacteroides fragilis.The MIC for AMK were 3.131-1.56μg/ml in10⁸and10⁶cells/ml, except Bacteroides fragilis.
Before the operation of above cases, AMK in a dose of200mg were administered by intravenous drip infusion in2cases (acute and subacute cholecystitis and cholangitis with cholelithiasis), 5cases by intramuscularly and1case by intravenously (acute appendicitis with localized peritonitis).The materials of A-bile, B-bile, wall of gallbladder, the appendix, ascites and serum samples were taken during the operation.AMK concentration was measured by bioassay method with Bacillus subtilis ATCC6633as test organism.AMK concentrations in B-bile were higher than those in the A-bile. AMK concentrations in wall of gallbladder were much higher than those in A and B-bile. The concentrations after intravenous drip infusion were higher than those after intramuscularly administration.AMK concentrations in wall of gallbladder and appendix were directly proportional to the degree of pathological changes of inflammation.In a case of gastric ulcer, AMK200mg by intravenous drip infusion was administered, the AMK concentrations of the tissues at25minutes after end of infusion, they were 15.00μg/g in gastric ulcer, 7.20μg/g in normal gastric wall, 9.14μg/g in duodenal wall and 8.12μg/g in the omentum, respectively.Serum concentration of AMK in this case at 58 minutes was 15.7μg/ml.
Therefore, it was supposed that AMK could be used safety and effective by intravenous drip infusion.

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We have studied clinically on9, 3-diacetylmidecamycin (MOM), a new macrolide antibiotic derived from midecamycin. The following results were obtained.
1) Serum concentration
To the same child weighing 15 kg and aged 4 years, the MOM dry syrup was administered orally at single doses of 150 mg (10mg/kg) and 300 mg (20mg/kg) and then the MDM fin e granules at a singled ose of 300mg (20mg/kg). At dosages of 10mg/kg and 20mg/kg of MOM dry syrup and 20mg/kg of MDM fine granules, the serum concentrations were 0.5.μg/ml, 0.8.μg/ml and not detectable (N.D.) respectively, at 45 minutes after administration;0.4, 0.6 and N.D. at 1 hour; 0.12, 0.2 and N.D. at2hours; N.D., <0.1, N.D.at 4 hours;N.D.in all the cases at 6 hours.
2) Clinical results
MOM dry syrup was administered to 25 children. The efficacy rate was 68.75% except for 1 dropout case and the elimination rate of 11 isolated strains of group A Streptococcus was 9.09% in 16 cases of scarlet fever and 1 of acute pharyngitis caused by group A Streptococcus. With 6 cases of pertussis, the efficacy rate was 50% and 2 isolated strains of B. pertussis were eradicated. The clinical response to 1 with acute bronchitis and 1 with Mycoplasma pneumonia were good and poor respectively.
3) Side effect
No clinical side effect and abnormal laboratory findings were observed in any of the 25 cases administered MOM dry syrup.

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Clinical studies on 9, 3-diacetylmidecamycin (MOM) was carried out in 31 patients with respiratory tract infections (acute pharyngitis 6, acute purulent tonsillitis 5, scarlet fever 1, acute bronchitis 6, pneumonia 13 cases), in dose of 12-34 mg/kg divided 3 per day for 3-19 days.
The ovarall efficacy rate was 74.2%.
As to adverse reaction, exanthema and diarrhea with abdominal pain were observed in each 1 patient. Eosinophilia and elevation of serum GPT were noted in each 1 patient.

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The effects of netilmicin (NTL) on the central nervous, cardiovascular, respiratory and muscular systems were studied and compared with those of gentamicin (GM). The following results were obtained.

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Immunogenicity of netilmicin (NTL) was studied and following results were obtained.
The antisera obtained from rabbits immunized with both NTL alone and NTL-I-ISA mixture did not shown positive response in the heterologous 3-hour PCA reaction and the passive hemagglutination test against the challenge of either NTL alone or NTL-OVA mixture.
Guinea pigs immunized with NTL alone did not exhibit systemic anaphylaxis when elicited with NTL alone.
The antisera obtained from BALB/c mice immunized with NTL-OVA conjugate adsorbed to Al (OH) ₃gel gave positive response in the 24-hour PCA reaction by the method described by MOTA, whereas did not respond to intact NTL in the same system.
Similar responces were also obtained in the animals immunized with either gentamicin or gentamicin protein mixture used as control.

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The absorption, distribution and excretion of netilmicin (NTL) in rats were examined by the microbiological assay method. Plasma level and urinary excretion of NTL in rats after intramuscular administration were compared with those of S other aminoglycoside antibiotics, gentamicin, sisomicin, dibekacin, amikacin and tobramycin.
1.After intravenous administration, plasma level of NTL declined rapidly with a half-life of about 18minutes.In the cases of intramuscular, intraperitoneal and subcutaneous administrations, plasmal evels reached maximum at 15 minutes and declined with similar half-life as intravenous administration.
2.When20mg/kg of NTL was administered intramuscularly, NTL was highly distributed into the kidney, while poorly into the brain.The disappearance rates of NTL from the tissues except the kidney were almost same as that from the plasma.Concentration of NTL in kidney was about 3 times higher than that in plasma at 15 minutes after administration and declined with a half-life of about 7 days.
3.NTL excreted in the bile within 24 hours was only 0.2% of the dose administered (20 mg/kg, i.m.).An average concentration of bile during the first 2 hours was 3 mcg/ml.
4.Irrespective of the route of administration (i.v., i.m., i.p.and s.c.), NTL was excreted rapidly in the urine and 70.0-81.0% of the dose was recovered within 6 hours.
5.Plasma level and urinary excretion of NTL after intramuscular administration (20 mg/kg) were almost similar to those of 5 other aminoglycoside antibiotics.
6.There was no difference between NTL and GM in plasma level after high dose (100 mg/kg, i.m.)

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Repeated administration of netilmicin (NTL), a new aminoglycoside antibiotic, to rats at daily intramuscular dose of10or20mg/kg for22days did not affect the plasma level and the plasma halflife of the drug.The concentrations of NTL in the kidney increased markedly after repeated administration, and reached peak level after8and15doses for 10 an 20mg/kg, respectively.Cumulative effect of NTL after repeated dose was also observed in the liver, spleen and lung, although the peak concentrations of NTL in these organs were below 1/50 of that in the kidney.
Blood and tissue levels of NTL in rats were determined after a single intramuscular administration of<USP>14<USP>C-NTL at a dose of20mg/kg following21repeated intramuscular administrations of NTL at daily dose of20mg/kg.The repeated dose of NTL had no effect on the blood level-time curve of radioactivity.
The concentration of NTL in the kidney determined by radioassay was about1/3of that determined by bioassay, whereas the half-lives in the tissue levels determined by these two assays were nearly identical with each other.The half-life in the lung determined by bioassay was almost identical to that determined by radioassay, whereas the former was rather shorter than the latter in the liver and spleen.

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The metabolic fate of<USP>14</USP>C-netilmicin (<USP>14</USP>C-NTL) was studied in rats after intramuscular administration (20 mg/kg).
1.Binding ratio of<USP>14</USP>C-NTL to rat plasma protein, determined by the ultracentrifugal method, was 15-20% during the first 1 hour after intramuscular administration.
2.Binding ratio of<USP>14</USP>C-NTL to HSA, determined by the equilibrium dialysis method, was 15-23%. Binding constant (K) and maximum binding number (n) were calculated as 1.48 x 10<USP>4</USP>m and 3.3 mole/mole, respectively.Half of<USP>14</USP>C-NTL bound to HSA was dissociated from HSA by gel-filtration.
3.The radioactivity in tail vein blood reached peak level at 10 minutes after intramuscular administration and declined rapidly.
4.Since the distribution rate of<USP>14</USP>C-NTL into the blood cells was low during the first 2 hours, the plasma level at that time was about 1.5 times higher than whole blood level.
5.The recovery of radioactivity in the bile (0-24 hours) was only 0.13% of the dose administered. An average concentration during 2 hours after intramuscular injection was 2.5 mcg/ml.
6.Within 2 hours after administration, approximately 40% of the dose was recovered in the urine. Within 24 hours, 87.8% of the dose was excreted in the urine, 2.6% in the feces, 0.3% in the cage washing and 8.8% in the carcass.Total recovery ratio was 99.5% of the dose.
7.The radioactivity was widely distributed in the tissues, especially high in the kidney and bone, low in the brain.A high concentration of radioactivity was found in the renal cortex at 24 hours after administration.
8.Netilmicin was excreted into the urine unchanged and no metabolites were detected by TLC at all.

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Distribution in kidney and transmigration to fetus or suckling in rats were studied in male, pregnant or lactating rats after intramuscular administration of<USP>14</USP>C-netilmicin (20mg/kg).
1.After administration to male rats, the radioactivity in the kidney declined slowly with a halflife of approximately6days.
2.The radioactivity in the kidney was distributed in the renal cortex.The distribution pattern was further investigated by means of microautoradiography.
The radioactivity was specifically observed in lysosomal granules of the proximal tubules at6 hours after administration and reached maximum at24hours after administration, then declined gradually.On the other hand, the radioactivity in the distal tubules was lower than that of the proximal tubules.The highest radioactivity in the distal tubles was detected later than24hours after administration.
3.In pregnant rats (20th day of gestation), the distribution of radioactivity in the tissues were almost the same as those in the male rats.The small amount of radioactivity was detected in the fetal kidney and bone.
4.In mother rats (14 days after parturition), the radioactivity in the milk was3-4mcg equivalent of netilmicin/ml during24hours after administration.The small amount of radioactivity (0.13% of dose) was observed in the gastrointestinal contents of a suckling within6hours after administration.

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Pharmacokinetics of netilmicin (NTL), a new aminoglycoside antibiotic, injected intramuscularly to Beagle dogs were compared with those of gentamicin (GM), and the relationship between NTL dosage administered and plasma level and urinary excretion was examined.
1.When administered to6male Beagle dogs at a dose of10mg/kg, the plasma level showed a broad peak (ca.23mcg/ml) at10to45minutes after administration and declined thereafter with halflife of65minutes.On the other hand, the plasma level of GM administered at a dose of10mg/kg showed a peak (ca.24mcg/ml) at15to45minutes after administration and the elimination halflife was75minutes.Both of the urinary concentrations of NTL and GM administered at a dose of 10mg/kg were highest in the4-to6-hour urine, whereas NTL and GM recovered in the 24-hour urine were51.7%and57.7%of the dose administered, respectively.The pharmacokinetic profile of NTL administered intramuscularly to Beagle dogs appeared to be almost identical to that of GM.
2.The peak plasma level of ca.50mcg/ml was obtained at10to 60minutes after administration of NTL at20mg/kg, and the half-life was74minutes.NTL recovered in the24hour urine was69.7% of the dose administered. 3.TLC-bioautograms showed no biologically active metabolites of NTL in the urine collected from Beagle dogs given the antibiotic intramuscularly.

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Antibacterial activities of cefotiam (CTM) cefazolin (CEZ) and cefmetazole (CMZ) against various causative organisms isolated from clinical materials were investigated.
CTM showed excellent antibacterial activities against Gram negative bacilli.Especially against E. coli and Klebsiella, CTM showed superior antibacterial activities to other antibiotics, CMZ and CEZ. The MICs of CTM against Serratia and Enterobacter dispersed very widely, but showed small values comparing with CMZ and CEZ.The antibacterial activity of CTM against P.mirabilis was slightly superior to that of CMZ, but against P.vulgaris was rather inferior to that of CMZ.However, these 3 antibiotics, CTM, CMZ and CEZ, showed slightly less active against non-glucose-fermentation bacilli.

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Bacteriological evaluation was made on cefotiam (CTM), a new broard-spectrum cephalosporin antibiotic, and the following results were obtained.
1) CTM has showed very potent antibacterial activities against Staphylococcus aureus, Escherichia coli, Edwardsiella tarda, Citrobacter intermedius, Salmonella, Klebsiella, Proteus mirabilis, Proteus rettgeri, Proteus inconstans, Yersinia enterocolitica, Aeromonas hydrophila, Plesiomonas shigelloides and Pseudomonas putrefaciens.
2) Streptococcus faecalis, Enterobacter and Proteus morganii isolated from urine, Serratia and glucose non fermentative Gram-negative bacilli except Pseudomonas putrefaciens, were almost insusceptiblet o cefotiam.

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The antibacterial activities of cefotaxime (CTX), cefoperazone (CPZ), ceftizoxime (CZX), cefmenoxime (CMX), latamoxef (LMOX), cefotiam (CTM), cefazolin (CEZ), gentamicin (GM) and cefsulodin (CFS) were investigated.
All causative organisms were isolated from patients with urinary tract infections treated in Tokai University Hospital.
The results were as follows.
1) The MICs of CMX, CTX and CZX against most of clinically isolated strains of E.coli, K. pneumoniae, Indole (-) Proteus sp. were0.1μg/ml and lower. And then CTM, LMOX and CPZ showed similar antibacterial activities.
2) LMOX and GM showed potent antibacterial activities against C. freundii which was considered to be causative organisms of infections in rare cases.
3) Against S.marcescens, CMX, CTX, CZX and LMOX showed very potent antibacterial activities.
4) Against P.aeruginosa, CFS, GM and CPZ showed moderate antibacterial activities.
5) Against Enterobacter sp., GM and CMX showed potent antibacterial activities.

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In vitro activities of antibacterial agents against. E.coli, Klebsiella, Citrobacter and Proteus which were isolated from patients urinary tract infections at8hospitals in Japan, were investigated by agar dilution method from July to October in 1979.
The summarized results are as follows.
1.Among oral antibacterial agents, MPC and PPA have showed potent antibacterial activities against. E.coli and Klebsiella. Among parenteral antibiotics, CTM was the most active against E.coli and Klebsiella. However, ABPC-resistant. E.coli and Klebsiella have appeared to occupy about40% and 96% of bacteria isolated from urinary tract infections, respectively.
2.In vitro activities of antibacterial agents against Proteus and Citrobacter showed not so potent.
3.Causative organisms in female patients with simple urinary tract infections were mainly E.coil and Klebsiella.<USP>*<USP>
4.Among oral antibacterial agents, PPA have showed similar antimicrobial activities againts E. coli isolated from simple and complicated urinary tract infections.ABPC and MPC have been influenced in some degree by these factors.However, parenteral antibiotics are not influenced by these factors.On the other hand, in vitro activities of antibacterial agents against Klebsiella isolated from simple and complicated urinary tract infections were similar.

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Cefotiam (CTM) was administered to rabbits and human, and the serum and tissue levels of CTM were investigated.The results were as follows.
1) The cefotiam levels in serum and tissue of rabbits in the dehydration were higher than those of rabbits in the overhydration.
2) The cefotiam concentrations in the rabbit's testis were low in both experimental conditions.
3) The cefotiam levels in the tissue of human testis were 1.9-27.4.μg/ml or g, those of kidney were4.5-57.1.μg/g.

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The concentration of serum and intraperitoneal exudate after dripping intravenous administration of CTM were measured.
Four male cases of the emergent laparotomy, a CUSHING'S ulcer, a hemorrhagic gastric ulcer, an adhesive ileus and acute terminal ileitis were investigated on this study. Two grams of CTM dissolving into100ml of physiological saline solution were prepared and administered in a period of1hour by intravenous drip (i.v.d.) for all cases after operation. The measurement of CTM-concentration in serum and intraperitoneal exudate were made at30minutes, 60 minutes following administration by i.v.d.and at30minutes, hourly intervals over a6-hour period after total administration. The intraperitoneal exudate for this study were collected through a drain which provided at the operation. These samples were measured by Agar-well method at Takeda Central Reserch Laboratory, Takeda Co., Ltd.
The mean value of serum CTM at30minutes after the beginning of i.v.d.administration was65.7μg/ml and the maximam value, 79μg/ml was obtained at60minutes. The following mean uvalues at 30minutes, 1hour, 2hours, 3hours, 4hours, 5hours and6hours after total administration were39.1, 26.4, 14.6, 8.9, 4.7and0.6μg/ml. On the other hand, the mean values of CTM intraperitoneal exudate at the same time intervals were4.9, 20.7, 32.0, 34.3, 22.4, 13.9, 11.2, 8.7and3.3μg/ml. These results showed that there were much transfer of CTM between serum and intraperitoneal exudate corresponding to the amount of administration.

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The preoparative administration of cefotiam (CTM) 1 g by intravenous drip infusion for 30 minutes was performed. And the concentration of CTM in peripheral blood, bone marrow fluid and bone tissue was investigated. CTM was smoothly transmigrated from blood to bone tissue, and kept on the concentration in bone tissue over MIC values for several hours. These preliminary results encourage us to think that CTM may be as useful in prophylaxis against postoperative infections.

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In 12 patients undergoing operation, 1 g of cefotiam (CTM) was administered intravenously and CTM levels in gallbladder tissue and gallbladder bile were examined. CTM concentration in gallbladder bile was high in patients with patent cystic duct, while very low in those with cystic duct obstruction. CTM concentration in gallbladder tissue was low in patients with chronic inflammatory gallbladder.
CTM activities of T-tube bile were compared with those of CMZ by cross over method in 2 cases.CTM showed extremely higher concentration in bile than CMZ.
In a case with excessive output of bile, CTM activity, total bile acids concentration and canalicular flow/ductal flow ratio were low.It can be presumed that CTM was diluted by incresed ductal secretion.

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It is well recognized that only very low concentration of antibiotics is obtained from cerebrospinal fluid (CSF) despite its high blood concentration. It has been attributed to the blood-brain and blood-CSF barriers. Penetration of CTM into CSF was studied in 7 patients. Two of them were complicated with septic meningitis, and others were not infected. CTM was administered intravenously and samples were obtained from both serum and CSF from 15 minutes to 4 hours for determination of concentration of the antibiotics.
In 2 patients with meningitis, the peak level of CTM in CSF after intravenous injection of 2 g and 1 g of CTM was 197mcg/ml (46% of peak serum concentration), and 17.3mcg/ml (38% of peak serum level), respectively.In noninfected patients the peak level of CTM in CSF after intravenous injection of lg of CTM was from 0.3mcg/ml to 1.9mcg/ml (0.84%-3.64% of peak serum concentration). We conclude that the percent penetration of CTM into CSF increases in the presence of the inflamed meninges and that prophylactic dosage of CTM for postoperative meningitis will be intravenous administration of 2g of CTM in adults.

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Cefotiam (1g) was administered by one-shot intravenous injection to the patients proceeding a brain surgery. The cerebrospinal fluid (CSF) and serum were taken as a specimen, and the concentration CTM was assayed by agar-well method using Proteus mirabilis ATCC 21100.
The most high concentration of CTM was 2,273 μg/ml in serum, and 2.3 μg/ml in CSF, respectively.
The concentration of CTM in serum, CSF, and CSF/serum ratio were determined at the indicated time.
It appears likely that CTM can pass into CSF more easily than other cephalosporins.

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Neurological surgeon must select the effectiveantibiotics to bacterium, that which penetrated enough to the intracranial organ through the blood-brain barrier. In this study, we measured the concentration of cefotiam (CTM), cephalothin (CET), cephacetrile (CEC) and sulbenicillin (SBPC) into the cerebrospinal fluid in the non inflammatory cases with V-P shunt.
1.Antibiotic concentrations in CSF and CSF/serum ratio (%) were evaluated at 2 hours after an intravenous administration of antibiotics. CTM; 0.543 μg/ml (3.66%), CET; 1.84 μg/ml (7.45%), CEC; 1.77μg/ml (7.5%), SBPC; 6.15μ g/ml (5.58%).
2.The peak of antibiotic concentration in CSF appeared from 2 hours after administration and gradually decreased.
In cerebellar tumor cases, the penetration of antibiotics into CSF showed similar levels as the cerebrovascular disease cases.
3.Concentration of CTM in CSF was higher than MIC of CTM to S. pyogenes and E.coli.

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