Uterine infections, particularly myometritis have been shown to be sever ebecause of the difficult passage of the antibiotics into the affected tissues.ConsequentLy, abiochemically novel drug, cefotiam (CTM) was investigated for thedistribution into the uterine body, uterine cervix, ovary and oviduct of 10patients with benign tumor, 1g of CTM in250ml of 5%glucose was infused for 2hours.The mean concentration of the antibiotics in the serum, uterine body, uterine cervix, ovary and oviduct at 30minutes after the in travenous drip infusion was, respectively19.7μg/ml, 10.1μg/g, 12.9μg/g, 10.7μg/g and 11.7μg/g.
The concentration ratio of the tissue to serum was found to be relatively high (51.5-65.5%), as compared to other antibiotics.
In this experiments, no adverse effects, such as laboratory findings wcre found.

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The concentrations of cefotiam (CTM) in the exudate of pericardium were investigated, and determined in 8 patients accompanied open heart surgery after a single intravenous injection or intravenous drip infusion of1or2grams.The peak concentrations of CTM have been appeared after 30 minutes or1hour, and prolonged for 3 hours, these concentrations of CTM showed about 8-30 times of MIC values which inhibit the growth of E.coli, K.pneumoniae, P.mirabilis and S.aureus.
Therefore, it is recommended that CTM will be administered by intravenous infusion just prior to the operation.

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Cefotiam (CTM) was administered to 52 patients with infectious disease associated with respiratory system, hematological malignancy, urinary system and other system.Good clinical responses were obtained in 38 out of 52 cases (73.1%).Neither objective and subjective side effects nor extreme abnormalities of laboratory tests were observed in these patients.
It can be, therefore, concluded that CTM is 1 of the most useful drugs for infectious diseases in respiratory system, hematological malignancy, urinary system and other system.

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There are few report about the concentration of antibiotics in the tissue of intrathoracic organs. At present, it was analized the concentration in serum and tissue of intrathoracic organ and urinary excretion for CTM, and clinical effect against postoperative infection and side effect of CTM were discussed.
1) The peak concentration in serum was 48.7μg/ml and half lives of CTM was about 30 minutes in 1 hour drip infusion of CTM 1 g.
2) The concentration of CTM in lung tissue was about 30-50% of serum level. The concentration of CTM to pulmonary lesion was relatively high.
3) The concentration of CTM to the secretion of normal bronchiole was high as well.
4) The concentration of CTM to the bone marrow of rib was less than lung tissue.
5) Urinary excretion of CTM was 50-77% of total dose by 6 hours after injection.
6) CTM has wide spectrum and is useful to prophylaxis of postoperative infection.
7) It may be ineffective for Pseudomonas aeruginosa infection of lung.

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Laboratory and clinical comparative investigations with cefotiam (CTM) and cefazolin (CEZ) were performed to confirm efficacy and safety in surgical, biliary tract infections.
The following results were obtained.
1) The MICs of CTM against organisms, 20 strains, which were isolated from bile of patients with cholecystitis, were studied, espetially those of CTM against E. coli and Klebsiella were 0.2-≥100μg/ml and 0.1-2.5μg/ml, respectively, considerably lower than those of CEZ.And moreover against CEZ-resistant Proteus morganii and Serratia marcescens, CTM showed potent activities, that is, MIC values, 12.5-50μg/ml and 0.78μg/ml, respectively.
2) In cholecystectomized patients, 2 grams of CTM was injected intravenously, followed by determination of bile concentration in gallbladder, common bile duct and concentration of gallbladder and liver tissue about 2 hours after administration.The mean bile concentrations of CTM in gallbladder and common bile duct were 1,213.2μg/ml and 1,287.8μg/ml, respectively. The peak concentration of CTM was 2,919.0μg/ml. The mean concentrations of CTM in gallbladder and liver tissue were 28.5μg/g and 45.7μg/g, respectively.
On the other hand, the mean bile concentrations of CEZ in gallbladder and common bile duct were 138.7μg/ml and 128.8μg/ml, respectively.
3) Bile concentrations of CTM was compared with those of CEZ by crossover method.The concentration of CTM was 37.7μg/mL even at 5 or 6 hours after 2 grams intravenously administration. CTM showed extremely higher concentration than CEZ in bile.
4) The clinical effect was studied in 6 cases of surgical, biliary tract infections.The results were excellent in 2 cases, good in 3 cases and poor in 1 case, and the clinical efficacy was 83%.
5) CTM was administered to 6 patients who showed negative to intracutaneous reaction test. Nausea, itching, and eruption were observed in each 1 case after intravenously administration of CTM 2g, however these adverse reactions disappeared within several hours.Throughout the course of treatment, any unusual laboratory findings related to CTM were not observed.

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As useful antibiotics for biliary tract infections, smooth transmigration to lesion and potent antibacterial activities will be demanded.Usually the antibiotics having potent antibacterial activities against E.coliand Klebsiella, which are considered to be main causative organisms of biliary tract infections, will be used for treatment.
The concentrations of cefotiam (CTM) in bile and gallbladder wall tissue were investigated, and CTM showed very high concentrations in these tissues for several hours. And very good corelation between concentration of CTM in bile and laboratory findings, especially ICG R₁₅ value, was obtained. CTM showed also very potent antibacterial activities againstE.coli and Klebsiella.
These results suggest that CTM will be useful agent for the treatment of biliary tract infections.

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Clinical investigation of cefotiam and aminoglycosides combination use against infections complicated by acute leukemia was performed, and the results obtained were as follows.
1) Sixteen patients were treated with cefotiam in doses 4-6 grams per day parenterally. The clinical effectiveness were excellent 47.6%, good 14.3%, fair 9.5% and poor 28.6%.No significant differences in therapeutic efficacy was observed between the patients given CTM 4 g/day and CTM 6 g/day.
2) It was considered that the clinical effectiveness of CTM has not been influenced by the difference of a number of maturation granulocyte.CTM has showed a certain, though not distinctive, efficacy compared with CFX.
3) As side effects with CTM, eruption appeared in 1 case, and no remarkable laboratory findings was observed.
Cefotiam is thus considered to be a useful drug for the treatment of infections complicated by acute leukemia.

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Efficiency and safety of cefotiam in 16 serious infections associated with hematological disorders were studied.
Effectiveness was obtained in 10 cases (62.5%).
Efficiency of cefotiam was significantly poor in cases with neutropenia (<500/mm³).
Adverse reactions were not seen except for 2 cases with chronic hepatitis.

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Change in external appearance, pH values and residual antimicrobial potency of cefotiam dihydrochloride (CTM) upon combination with infusion solutions and other injections was investigated.
The combinations of CTM with bromhexine hydrochloride 2mg/ml, 2ml, dipyridamole 5mg/ml, 2ml and gabexate mesilate 100mg/vial respectively were found to be incompatible on account of turbidity produced.
As for 34 other combinations, no change in their appearance, pH and potency was observed.

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Cefotiam of 1 to 2g was intravenously given during 15 to 60 minutes in 10 cases, and blood levels and cerebrospinal fluid (CSF) levels were studied.Following the drip infusion of cefotiam, maximum blood levels of 25.2 to 305μg per ml with an average of 101.2μg per ml were achieved at 15 to 60 minutes in 9 cases.Half life of cefotiam in serum was from 20 to 50 minutes, and mean time was 39.4 minutes.
In contrast, maximum CSF levels of cefotiam were ranged 1.4 to 17.2μg per ml and mean value was 5.7μg per ml in 8 cases.The ratios of CSF levels to blood levels were calculated from 1.7 to 6.6% with an average of 4.6%.The CSF levels of cefotiam showed long delay and long decay.The period between the drip infusion and peak levels of cefotiam in CSF showed 60 to 420 minutes and mean time was 194 minutes.Half life varied between 45 and 270 minutes with an average of 178 minutes.
No side effects were found in all cases.

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Clinical bacteriological studies on cefotiam and cefsulodin in the field of otorhinolaryngology were carried out and the following results were obtained.
1) Aerobic and anaerobic Gram-positive bacteria were dominantly isolated from the clinical materials sent to the center from the clinical institutes.
2) It was considered that Streptococcus pneumoniae, Haemophilus influenzae and β-Streptococcus played an important role in the primary infections in the field of otorhinolaryngology.Staphylococcus aureus was also frequently isolated from the primary infections. Peptostreptococcus spp.was dominantly isolated from peritonsillar abscess. Gram-negative bacilli (GNB) were mainly isolated from the chronic secondary infections. Among GNB, Pseudomonas aeruginosa and Proteus spp.were more frequently isolated. Staphylococcus aureus was also constantly detected in the secondary infections together with GNB.Anaerobic bacteria were isolated from20.1%of the patients with chronic otitis media and27.1% of sinusitis.
3) Cefotiam showed potent antibacterial activities against most isolates of Gram-positive and Gramnegative bacteria.
4) Cefsulodin showed potent antibacterial activities against clinically isolated Pseudomonas aeruginosa. Staphylococcus aureus and β-Streptococcus were also susceptible to cefsulodin.

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The authors have carried out laboratory and clinical studies of9, 3-diacetylmidecamycin (MOM) and obtained the following results.
1. Absorption and excretion of MOM
MOM was administered orally to4patients at a dose of10mg/kg in the fasting condition. The peak of serum levels was found at30minutes after administration. The mean values were 1.3±0.5μg/ml, and1.1±0.9μg/ml after30minutes and1hour respectively. The serum levels were deteuctable in 2 cases after2hours (1.0and0.78μg/ml), in1case after4hours (0.78μg/ml) and were not detectable in all cases after6hours. Half-life was able to calculate in2cases (2.5and1.5hours).The mean urinary recovery rate examined in3cases was0.33%for initial6hours.
2. Clinical result
MOM was administered to35children at a daily dose of16.7-51.5mg/kg divided into3or4doses for4to19days: 18cases with bacterial infection (9cases with tonsillitis, 7cases with scarlet fever and each 1 case with bronchitis and pneumonia) and 17 cases with Mycoplasma infection (5cases with bronchitis and12cases with pneumonia).The overall clinical response was good in28cases (80.0%), fair in6cases and poor in1case.The efficacy rate in bacterial infections and Mycoplasma infections were66.7and94.1%respectively. Eight strains of S.pyogenes and 1 strain of S.pneumoniae were isolated from9cases.One strain of S.pyogenes was eradicated and the others were unchanged.The eradication rate was11.1%.The MIC of MOM against S.pyogenes was above50μg/ml in3strains out of measured 5 isolated strains.
3. Side effect
Side effects were examined with all the54cases involving19drop-out cases.Although clinical side effects were not observed in2cases and1case respectively.

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Some studies were carried out on the use of 9, 3-diacetylmidecamycin (MOM) dry syrup, a new macrolide antibiotic preparation, in the treatment of children.The results are summarized below.
1) A single oral dose of10mg/kg of the MOM dry syrup was administered to1child at2hours after a meal.The peak concentration of the antibiotic in the blood was0.88μg/ml and occurred at1 hour after administration.At2hours the concentration had fallen to0.59μg/ml, and after4hours the blood level was already below the minimum detectable concentration (0.5μg/ml).During the first6 hours after the administration, 6.7%of the MOM was recovered in the urine.
2) The MOM dry syrup was orally administered to4pneumonia patients (including2cases of mycoplasmal pneumonia) for7days at a daily dosage of15.2-20.5mg/kg (divided into3equal doses). The therapeutic results were excellent in2cases, good in2cases and poor in none.
3) No side effects such as exanthema were observed to occur.In1case only, there was a mild and temporary elevation in the laboratory test values for total bilirubin, GOT and GPT.
4) All4of the pneumonia patients found the MOM dry syrup to be easy to ingest.The taste and odor of this antibiotic preparation were judged to be sufficiently palatable to permit convenient use in the treatment of children.

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Cefoxitin (CFX) was administered to15hospitalized patients with postoperative infections mainly caused by Gram negative rods.
Out of 15 cases treated with CFX, 11cases showed excellent or good response.CFX was ineffective in only 1 case infected with P.mirabilis, Enterobacter and S.faecalis.
Bacteriological findings revealed that CFX was highly effective against E.coli, Klebsiella, P. morganii and Neisseria, and antibacterial activity of CFX was equal or slightly superior than those of ABPC and CEZ, however, CFX was less effective against Enterobacter and S.faecalis.
No side effect was observed during the course of therapy with CFX.

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To assess an enzyme multiplied immunoassay technique (EMIT) for determination of gentamicin, comparison was done with a microbiological bioassay. Twenty-nine samples from 5 patients and 1 volunteer were assayed by both EMIT and bioassay methods.
Concentrations of gentamicin obtained with EMIT were compared with those with bioassay.Statistical calculation resulted in a regression linewith a correlation coefficient of 0.9496, a slope of 0.735 and an ordinate intercept of 0.878.
To test the specificity of EMIT, serum controls which contain a constant quantity of gentamicin and a variable quantity of ampicillin concomitantlywere assayed for gentamicin concentrations by both EMIT and bioassay.This test demonstrated that EMIT is free from interference of ampicillin while bioassay is vulnerable to interference.
To conclude, EMIT proved to be a practical alternative to current bioassays for determination of serum gentamicin concentrations.

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Pseudomonas aeruginosa has attracted much attention through its role in hospital outbreaks of disease. However, other members of the genus Pseudomonas,particularly
Pseudomonas maltophilia and Pseudomonas cepacia, may be isolated as opportunistic pathogens of man, and can be found in hospital materials.These organisms have been less susceptible to the commonly used antibiotics.
This report deals with the in vitro sensitivity of Pseudomonas strains except for P.aeruginosa to aminoglycosides and tetracyclines.
The following bacteria were tested:P.maltophilia(50strains),P.fluorescens (29strains),P.putida (52strains),P.cepacia(49strains),P.putrefaciens(18strains),P.acidovorans(12strains).
All of the strains for this study were isolated from routine cultures of infected clinical materials which sent to the Clinical Laboratories,Juntendo University Hospital during the1year period of 1980.The tests for susceptibility of the strains to the3aminoglycosides(gentamicin, tobramycin,amikacin) and3tetracyclines (tetracycline,doxycycline,minocycline)were all performed by the serial 2-fold agar plate dilution method on heart infusion agar, standardized by the Japan Society of Chemotherapy, using the microplanter apparatus with an inoculum size of approximately 108 CFU/ml.There were similar sensitivity patterns for the aminoglycosides tested; most of the strains of P.maltophilia, P.cepacia and P. acidovorans were resistant to the aminoglycosides, while most of P. fluorescens, P. putida and P. putrefaciens were sensitive.Minocycline and doxycycline were extremely active to the Pseudomonas species studied. Tetracycline was almost ineffective against P.maltophilia and P.cepacia.

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Antimicrobial activities of3aminoglycoside antibiotics, including gentamicin (GM), amikacin (AMK) and tobramycin (TOB), were determined against1,714 Pseudomonas aeruginosa strains isolated from clinical specimens in this hospital during3years since April of 1976 to March of 1979. From these results, some discussions were made as followes.
1) MIC ranges,to which about70%of strains tested distributed,were3.13-6.25μg/ml of GM, 3.13-12.5μg/ml of AMK, and 0.78-3.13μg/ml of TOB in each year.
2)Frequency of drug-resistant strain, which showed12.5μg/ml or more MIC value in any drug, was highest in AMK and lowest in TOB in each year.
3)Drug-resistant strain-frequency to any one of3drugs tested was lowest in 1977,and higher in1976than in 1978.It was not supposed that this phenomenon should be undoubtedly caused by the amount of drugs used in each year in this hospital.
4)Frequency of highly TOB-resistant strain increased year by year during the period studied, unlike both cases of other2antibiotics.
5)Cross resistance was most frequently observed between GM and TOB, and more between GM and AMK than between TOB and AMK.
6)It was considered that anti-Ps.aeruginosa-activity was highest in TOB followed by GM and by AMK.
7)It was suggested that there seemed to be some qualitative difference between antimicrobial activity of AMK and those of GM and TOB.

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Amikacin was studied for clinical effect in7patients with acute leukemia, 1 patient with chronic myelogenous leukemia-blastic crisis, 1patient with malignant lymphoma and1patient with aplastic anemia, who were suffered from severe infection such as sepsis, pneumonia or subcutaneous abscess. Most of these patients had bleeding tendency, so amikacin was administered by intravenous drip infusion in a dosis of 200mg-400mg for1hour. Total dosis of amikacin were between3.2g and12.6g. These dosis of amikacin gave good response to 3patients with sepsis, 1patient with subcutaneous abscess and1patient with pneumonia. We didn tobserve any side effect most likely associated with amikacin.
Therefore, intravenous drip administration of amikacin might be useful drug for management of severe infections in patients of hematological disorder, and seemeed to be as safe as intramuscular administration.

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In order to know the amount of sulbenicillin (SB-PC) transported to the maxillary sinus through the blood supply after injecting by intravenous drip infusion, the authors measured SB-PC content of the exudate which was gathered from the exploratory operative maxillary sinus.This measurement was performed3times at2, 4and6hours after injecting 5g of SB-PC by intravenous drip infusion.
From results of these measurements, it became obvious that the SB-PC content reached to the maximum value (24.5+16.69mcg/ml) at2-4hours after the injection.
Next, the preventive and therapeutic effect on the postoperative maxillary infection was evaluated for13patients of maillary cancer.
The effect was excellent in2cases (16.7%), good in8cases (66.7%) and fair in2cases (16.7%). So, the ratio of effectiveness was83.3%.
The side effect of SB-PC was observed only in1patient who complained of palpitation, but it wasnot severe.

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Cefmetazole (CMZ), a new cephamycin preparation, has been investigated to give following results.
1) Pharmacokinetics: Serum and tonsil concentration of CMZ were determined by micropore method in humans.The mean concentrations in 5 cases about 30 minutes after administration of 0.5-1.0g intravenously were 55.4μg/ml in serum, 2 1.7μg/g in tonsil.
2) Clinical studies: Seventy-one patients with ear, nose and throat infections were treated with CMZ receiving 1 to 6g per day intravenously (one shot and drip infusion). Thirty-eight of 70 patients were cured excellent, 19 were good, 8 were fair and 6 were failure and effective rate was 80.3%.Adverse reaction was observed in 4 cases. Three cases showed exanthema and 1 case showed fever elevation.

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The following results were obtained from the bacteriological evaluations of netilmicin (NTL), a newly developed antibiotic agent, with gentamicin (GM), dibekacin (DKB) and amikacin (AMK) as the controls.
(1) NTL demonstrated broad antibacterial spectra against both Gram-positive and Gram-negative bacteria, but its antibacterial potency against streptococci was not very strong among other Gram-positive bacteria.
(2) In terms of distribution of sensitivity of clinically isolated bacterial strains, NTL proved to have antibacterial potency comparable to that of GM and higher potency than that of DKB or AMK against E.coli, K.pneumoniae, Enterobocter sp., or H.influenzae.However, its efficacy was inferior to GM against Proteus sp., S.marcescens and P.aeruginosa.
(3) In conjunction with the influences of pH of culture media or of addition of horse sera upon the antibacterial efficacy, NTL showed an inclination similar to that of GM, DKB and AMK.Its antibacterial efficacy was fortified on the alkaline side or by addition of sera.In connection with the influences of the amounts of inoculated bacteria upon antibacterial efficacy, there were hardly any appreciable influences on it by any of the tested bacterial strains.
(4) The interactions of NTL with carbenicillin were evaluated with the chequerboard titration method to find remarkable cooperative actions in any of E.coli, K.pneumoniae, S. marcescens, A.calcoaceticus and P.aeruginosa.
(5) The results of evaluation on the patterns of its antibacterial effects revealed that it acted bactericidal in any tested bacterial strains.
(6) As to the therapeutic effects against experimental infections in mice, it was found out that NTL=GM>DKB and AMK against E.coil, GM>NTL=DKB and AMK against K.pneumoniae and GM and DKB>NTL_AMK against A.calcoaceticus and P.aeruginosa in the decreasing order of efficacy.

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Experimental and clinical studies were carried out on cefmetazole (CMZ), a synthetic antibiotic of cephamycin group, and the following results were obtained.
1)The minimal inhibitory concentrations(MICs)of CMZ against Gram ositive cocci(30 strains)isolated from the patients with oral infections showed slightly inferior to those of ABPC,CEZ,while MICs against Gram negative bacilli(166 strains)of CMZ exhibited stronger activity than ABPC,CEZ.
2)The mean serum concentration of CMZ at60minutes after drip infusion showed 65.6μ/ml. The concentration of CMZ in oral tissues ried in4-60%of serum level at60minutes after drip infusion.
The concentration in pus showed15.2μ/g at60minutes after drip infusion.
3)CMZ was administered by the drip infusion to22patients with various infections in the oral surgical field. The efficacy rate was90.9%.
4)No side effect was observed.

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C-AMOX-long acting amoxicillin preparation (gastro coating3, enterocoating7)-has been investigated to give following results.
A pharmacokinetic study of C-AMOX was conducted in6healthy male volunteers in postprandial state (30minutes after light meal).
The levels of1.8-2.5μg/ml in blood was detected for6hours after500mg dose orally. It was seemed to be long acting amoxicillin in blood levels.And, the calculated data of AUC of C-AMOX was15.17μμg hr/ml administered500mg dose, and14.33μg hr/ml of AMPC twice250mg doses, respectively.
The urinary excretion rate was56.1%of the dose during 10 hours.
Sixty-six patients with respiratory tract infections, urinary tract infections and others were treatedwith C-AMOX0.5g twice daily for4-7days mainly.
Thirty one patients of all were cured excellent, 27were good, 4were fair and4were poor. The global efficacy rate was87.9%.
Only1patient was occured diarrhea, and no abnormal laboratory finding was observed.

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C-AMOX, a new prolonged acting preparation of amoxicillin was administered to122cases by oral administration of daily dosage500mg twice.
Clinical effectiveness of C-AMOX was evaluated in115out of122cases (acute simple cystitis87 cases, acute pyelonephritis6cases, complicated urinary tract infection19cases and others3cases), and the following results were obtained.
1.The clinical effect for87cases of acute simple cystitis was excellent in54cases(62%), moderate in24cases(27.6%)and poor9cases(10.3%),overall effective rate being89.7%.
2.The clinical effect for19cases of complicated urinary tract infection was excellent in6cases (31.6%),good8cases(42.1%)and poor5cases(26.3%),overall effective rate being73.7%.
3.Adverse reaction occured in2patients, one gastric discomfort and the other one slight diarrhoea. No laboratory abnormalities attributable to C-AMOX were observed in the present study.

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Fundamental and clinical evaluations of a new continual penicillin, C-AMOX, were performed.
The results obtained were as follows.
1.Concentration in serum: The level of serum concentration after giving500mg of oral C-AMOX was determined in3cases of health adult.The maximal level measured4.8μg/ml at4hours after oral administration.Even8hours after oral administration, clinically effective serum C-AMOX concentration1.6μg/ ml was still demonstrable.
2.Concentration of tissues: At4hours after a single oral dose of500mg, the concentration in the tissues of palatine tonsilla was0.6μg/g as against4.9μg/ml in the serum, and the concentration in the tissues of mucous membrane of maxillary sinus was0.5μg/g when measured4.6μg/ml in the serum.
3.Results of clinical treatment: C-AMOX of oral administration was tested in46cases of usually encountered acute and chronic infections in the otorhinolaryngologic field, the results being excellent in25cases, good in14cases and fair in6cases.When the excellent and good were bracketed together, it amounts to39cases (84.8%).It can be considered as high effective ratio.No side effect was shown with the oral administration of C-AMOX.

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