Netilmicin, a new semisynthetic aminoglycoside antibiotic recently developed by Shering Co., was injected to 5 patients with respiratory tract infection (2 cases of diffuse panbronchiolitis, 2 cases of bronchiectasis and 1 case of bronchial asthma with infection). A daily dose of netilmicin was 200 mg by intramuscular injection and duration of netilmicin therapy was for 7 to 14 days.
Clinical response to netilmicin therapy of respiratory tract infection was good in 3 cases, fair in 1 case and poor in 1 case.
No subjective and objective findings considered as the side effect was observed and laboratory examinations showed no abnormality.
It may be concluded from the above clinical results that netilmicin may be effective for respiratory tract infections and further study may prove its efficacy.

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In the present study, we used netilmicin for the postoperative complications and obtained the following results.
1. Netilmicin was used in totally 29 cases; 23 with localized peritonitis, 4 with generalized peritonetis and 2 with wound infection.Excellent effects were obtained in 2 cases, effective results in 24 cases and ineffective results in 3 cases. The effective rate was 89.7%.
2.Adverse reactions or abnormal clinical laboratory test results which might be attributable to the use of netilmicin were not noticed.

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Netilmicin was intramuscularly injected at a daily dose of 200 mg, divided twice, for 5 to 10 days to 14 patients with complicated urinary tract infection caused by P. aeruginosa.
The clinical results were excellent in 7 cases, good in 5 cases, and fair in 2 cases. Neither side effects nor abnormal values in laboratory findings were reported.
The MIC of netilmicin against 14 strains of P. aeruginosa isolated from the above patients were distributed between 3.13 μg/ml and 12.5 μg/ml except 1 strain at inoculum size 10⁶ cells/ml.

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Netilmicin was administered to 1case of simple acute pyelonephritis and 21cases of complicated urinary tract infections, 22cases in total, and the effects were evaluated clinically.
Total clinical effects of netilmicin evaluated by the UTI standard for evaluation of drug effects showed 61.9%of clinical effectiveness in21cases, and the results are satisfactory because11cases out of21cases were catheterized.
The result was examined bacteriologically;the frequency of detection of particular strains among23strains clinically isolated from complicated urinary tract infections was that10strains of P.aeruginosa (43.5%), 3of S. marcescens (13.0%), and3of E.coli (13.0%), and the ratios of bacteriologically disappeared strains were70%, 33.3% and66.7%, respectively, and the overall disappearance ratio was73.9%.
The MIC's determined for17strains and disappearance of the bacteria were examined;when MIC was less than6.25mcg/ml, 10strains out of12disappeared, that is, 83% of disappearance was obtained.
When MIC was larger than100mcg/ml, 2strains out of5disappeared, that is, 40%of disappearance was obtained. Disappeared2strains of bacteria were isolated from patients who were not catheterized.
Neither subjective symptoms nor abnormal laboratory findings related to the drug were observed.
It may be said from these findings that netilmicin is an effective drug for urinary tract infections.

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The antibacterial activities of Staph. aureus isolated in 1980 and 1981 at all districts in Japan to ABPC, CEZ, CMZ and GM were tested. Numbers of test strains were 587 strains in 1980 and 700 strains in 1981, respectively. The frequencies of ABPC and CEZ resistant strains of Staph. aureus (MIC:≥25μg/ml) were clearly increased in annual variation. The percentage of CEZ resistant strains in 1981 tested by 108 CFU/ml inoculum size was 12.3%, but the same of CMZ was only 0.6%.

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1. Cefmetazole (CMZ) was administered to a total number of 12 patients, 10having acute or chronic osteomyelitis and 2 pyarthrosis in the orthopedic field. The emcacy rate was 91.7%.
2. Patients received an intravenous instillation of 1 to 2 g CMZ daily for an average period of 29.8 days.
3. Causative organisms were identified in 8 of the cases examined.In 7 cases S.aureus wassolated. CMZ showed an extremely strong antibacteriaalc tivitay gainst S.aureusi n a disk testi n support of itse xcellentc linical results.
4. No abnormality was found with respectt o subjectivea nd objectives ymptoms and in laboratory tests.
5. The above resultsa nd migration of CMZ into the bone tissuea t a high concentration4) suggest hat CMZ is an efectivea nd safe drug for bone and joint infectioni n the orthopedic fiel

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1. The serum concentration of cefmetazole (CMZ) was 56.8±13.3μg/ml at 1 hour after one-shot intravenous injection of 2g Half-lifewas 1.1 hours, indicating that.the drug is adsorbed rapidly. In addition, CMZ was detected at high concentrations inthe endometrium, myometrium, ovary, uterine tube and cervix uteri. The concentration was especially high in the uteline tube and ovary. It was also demonstrated in the fbtus and fetal membrane, though at low concentration.
2. Clinically one-shot intravellous injection of 1 to 2g of CMZ were given 2 times daily to 15 patients with intrauterine infection, adnexitis, intrapelvic infbction or postoperative wound infbction. The drug was evaluated to be effective in 15 or 80% of them. No special side effects were found.

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Cefmetazole was studied experimentally in the field of dermatology. The following results were obtamed.
1. The in vitro antibacterial activities of cefmetazole against S.aureus and S.epidermidis were studied. Most strains of both staphylococci were inhibited by 1.56μg/ml or less of cefmetazole.
2. Serum and skin concentrations of cefmetazole in rats were studied after intramuscular administration of 20mg/kg of cefmetazole.
Mean serum concentrations were 40.3, 21.5, 7.1, 0.56μg/ml respectively at 0.25, 0.5, 1 and 2hours, and the corresponding skin concentrations were 12.5, 6.1, 0.62, 0.61μg/g (n=4).

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Recently, a new antibiotic of cephamycins, cefmetazole (CMZ) has been developed.In our clinic, CMZ was used to examine its clinical effect and adverse reactions, and the results were herein reported.
The CMZ was administered to 8 patients for the prevention of postoperative infections, 7 with genitourinaryi nfections and 1 with maxillitis complicated with uremia.
For these patients, a daily dose of 1 to 6 g of CMZ was intravenously given for a period of 4 to 12 days. Among the 8 patients who received CMZ for the prevention of postoperative infections, there were 1 case with urinary tract infection, 1 with wound infection and 2 with fever of over 38°C, but they had no serious infections. I n the clinical observations on 3 cases with pyelonephritis, the CMZ showed marked effectiveness in 2 cases and effectiveness in 1 case.It must be noted that CMZ was proved to be markedly effective for pyelonephritis caused bySerratia marcescens.
In the cases with acute epididymitis and prostatitis, a good effect of CMZ was obtained. Similarly in the case with maxillitis complicated with uremia, the maxillitis was improved by the effect of CMZ and hemodialysis. No cases with hepatic or renal dysfunction were observed after using CMZ.It is concluded that satisfactory effect of CMZ was obtained clinically.

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A new mitomycin derivative, 7-N-(p-hydroxyphenyl)-mitomycin C (KW 2083), was labeled with ¹⁴C at 3 and 5 position of p-hydroxyphenyl moiety.Its radioactive purity and specific radioactivity were 97.6% and 3.42, μCi/mg, respectively. The labeled drug was administered intravenously to male rats or pregnant rats. Radioactivity was rapidly cleared from the plasma and transfered to the peripheral tissues. However low and sustained level of radioactivity was maintained in the plasma, even 48 to 72 hours after administration.
About 29% of the radioactivity was recovered from the urine and 58% from the feces by 72 hours after administration. In the bile, 45% of the dose was excreted until 48 hours after administration, and the enterohepatic circulation was observed.The tissue levels of ¹⁴C-KW 2083 given to male rats were highest in the kidney, liver and intestinal contents. In the brain, eyes and spinal cord the radioactivity was very low. Autoradiography with ¹⁴CK-W 2083 in male or pregnant rats demonstrated that radioactivity distributed in kidney, liver and intestinal con-tents. The transfer of radioactivity was very low in the fetuses of rats. Radioactivity was observed to some extent in the fetal membrane.
Plasma concentrations of KW 2083 or mitomycin C in dogs were determined by means of bioactivity and could be best described by a two-compartment open model. The total clearance of KW 2083 was higher than mitomycin C and hence the biological half life of KW 2083 was shorter. The result may suggest less toxicity of KW 2083 to the host cells.

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Four hundred strains (13species, 8 genera) were obtained from patients with complicated and intractable infections. The antibiotic sensitivities of these isolates were detemined in relation to aminoglycoside (AGs)(GM, DKB, AMK, HBK), β-lactam (SBPC, PIPC, CMZ), and FOM.
1. The frequency of clinical isolates that were resistant to GM and DKB in this study was high level in the case of S.aureus, Enterobacter spp., S. marcescens, Proteus spp.(indole positive) and P.aeruginosa.And some of them were also resistant to AMK and HBK.However HBK had potent antibactorial activity to S.aureus. The inactivating enzyme contributing to AGs resistance was AAC for almost Gram-negative bacilis and APH+AAC for S.aureus.But AGs was not permeable only to P.maltophia.
2. Almost similar resistant patterns were seen to SBPC and PIPC.However, the frequency of resistantstrains of S. aureus to SBPC was less than one of PIPC, while that of Citrobacter spp. to PIPC was less than SBPC. Among of other bacteria, P. aeruginosa and Proteus spp.(indole positive) had moderate sensitivity to SBPC and PIPC.
3. CMZ had poor antibacterial activity to Enterobacter spp. and S. marcescens and no activity to P. aeruginosa. It ht, d moderate activity to Citrobacter spp. and potent activity to S. aureus, E. coli, K. pneumoniae and Proteus spp.(indole positive).
4. FOM had antibacterial activity to all the bacteria tested. Almost FOM-sensitive bacteria had moderate MICs (6.25-25 μg/ml).

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A total of 24 patients who was hospitalized in the Internal Medicine Wards of Yamaguchi University attached Hospital and the university's 3 related hospitals were administered with cefoxitin.
The breakdown of the patients treated with cefoxitin was 7 with cholecystitis, 7 with choledochitis and the remaining 10 for the prevention of infections with obstructive jaundice.
Daily doses of 2-6g of cefoxitin were administered for 6-40 days by intermittent intravenous drip infusion in divided doses.
Results:
1. Of 14 patients with biliary tract infections, 10 (71.4%) responded favorably with cefoxitin.
2. Of 10 patients with obstructive jaundice used for the prevention of infections, 8 (80%) responded favorably with cefoxitin.
3.No untoward side effects were observed.
4. Cefoxitin proved to be a safe and effective antibiotic in the treatment of biliary tract infections and for the prevention of infections in patients with obstructive jaundice.

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A total of 20 hospitalized patients underwent orthopedic surgery in the Tokyo Metropolitan Police Hospital during the period from December 1981 to March 1982.These patients were treated with cefoxitin, mainly, for the prevention of postoperative infections.
The following clinical findings were obtained.
1. Out of the 20 patients, 14 were judged ‘good’ and 6 ‘fair’.
2. No side effects were reported by the patients or were evident in the clinical data.
3. These clinical results indicated that cefoxitin is a very effective antibiotic for the prevention of postoperative infections in orthopedic surgery.

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Spiramycin (SPM) and acetylspiramycin (ASPM) have been known to be potent macrolide antibiotics in vivo, although spiramycins had rather mild antimicrobiol activities in vitro. The physiological disposition of SPMand ASPM could participate in their in vivo activities.
¹⁴C-labeled SPM-I or ⁸H-labeled ASPM was admini1s4tered intravenously in rats (20mg/kg), and plasma levels, excretion and tdistribution have been studied.The plasma levels of. SPM-I and ASPM were low both, in radioactivity and bioactivity. After intravenous administration, ¹⁴C-SPM-I was excreted by 48 hours into urine, bile and faeces at the rates of 39.6, 31.4%, and 37.1%, respectively. And 27.8% of the dose was recovered into urine by 48 hours after administration, of ⁸H-ASPM. Higher radioactivities were detected in the spleen, kidney cortex, submaxillary gland, liver and lung by whole body autoradiography 1 hour after intravenous administration, andth e levels tended to be retained until 24 hours.
After intravenous administration at the dose rate of 50mg/kg, the biological half-lives (T 1/2) of ASPM, SPM-I, josamycin and Mideeamycin were 151, 103, 71 minutes and 54 minutes, respectively, and the apparent volumes ofdi stibution (VβA) were 9.2, 8.9, 3.6 L/kg and 7.7 L/kg, respectively.
From these results, it was suggested that the highest activity observed for ASPM in experimental mice infec-tions might be correlated with high affinity for the tissues and the long biological half-life of ASPM.

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A part of our continuous investigation of the clinical effect of PMPC against urinary tract infections was reported. PMPC has been applied for the treatment of 49 cases of simple urinary tract infections and complicated urinary tract infections, and the total rate ofeffectiveness was 84%, which was similar results of out first (84%) investigations. Side effects were noted in 2 cases (3, 2%).

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Two to 6 g of CMX was administered daily to 9 patients who were admitted to ICU, i. e. 5 cases with pneumonia and 4 with sepsis. In all cases, CMX was administered concomitantly with aminoglycosidewhich had been administered, and additional administeration of other antibiotics was avoided. Bacteriologically, P. aeruginosa was isolated from 4 cases, K. pneumoniae from 4 cases, S. marcescens, P. mirabilis and P.cepacia respectively from 1 case. The CMX treatment was considered effective in 4 of 5 pneumonia cases and in 3 of4 sepsis cases. In total, 7 of 9 cases responded effectively. The clinical effective rate was 77.8%. Elevation of GOT and GPT values was noticed in 1 case, however, the causality with CMX administration was unclear.

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Five infants were administered 9, 3-diacetylmidecamycin (MOM), a newly-developed antimicrobial agent, between meals in a dose of 5 or 10 mg/kg. Then, for the following 6-hour period, RIA was employed to measure the concentration of Mb-12, the principal metabolite of MOM in the serum of the subjects.In addition, in these same subjects, the metabolites and the recoveryrate of the drug in the urine we re determined by the thin-layer chromatography method.
In addition, 40 children, ranging in age from 6months to 10 years and 11 months and diagnosed as having whooping cough, were administered MOM in a meandaily dose of 25.6 mg/kg. This was given in 3 divided doses after meals, for a mean period of 14 days. These patients were analyzed for the clinical efficacy, bacteriological efficacy and side effects resulting from this MOM therapy.
The following results were obtained in these various studies.
1. Three subjects were administered MOM at 5 mg/kg. The peak concentration of Mb-12 in the serum occurred at 2 hours after the dosing; the mean value of the peak concentration was 88.4 ng/ml.MOM was administered in a dose of 10 mg/kg to 2 subjects; in these subjects the peak concentration in the serum occurred at 1 hour, and showed a mean value of 336.4 ng/ml.A dose response was thus seen, with the peak serum concentration being approximately 3 times higher in the 10 mg/kg group than in the 5 mg/kg group. The mean half-lives of MOM in the serum in these subjects was calculated to be 0.86 hour in the 5 mg/kg groupand 0.76 hour in the 10 mg/kg group; they were thus quite similar.
2. In both of these dosage groups, Mb-12 was found to be the most prevalent metabolite of MOM in the urine during the first 6 hours after the administration. In the 5 mg/kg group, Mb-12 accounted for 37.1% of the excreted MOM metabolites, and the corresponding figure in the 10 mg/kg group was 37.9%.
3. The 6-hour urinary recovery rate was found to be 1.33% in the 5 mg/kg group and 2.01% inthe 10 mg/ kg group, which are rather low values.
4. Concerning the MOM treatment of the whoopingcough patients, the evaluation of the clinical efficacy by the physician in charge found the efficacy rate to be low, i.e., 57.9%; the reason for this is that all except 1 of the patients were in the coughing stage of the disease. There was no difference in the resultsbetween the patients who received MOM at 20 mg/kg/day or less and those who were administered the drug at a dosage rate of 21 mg/kg/ day or more.
5.The evaluation of the clinical efficacy by the Committee was carried out on days 3, 7 and 10 as well as the final day of the MOM administration. The efficacy rates found on those days for the 20 mg/kg/day or less patient group were 0, 46.7, 60.0 and 68.8%, whereas the corresponding value for the 21 mg/kg/day ormore patient group were 8.3, 34.8, 52.4 and 66.7%. There was thusno striking difference between these 2 groups. It is, however, apparent that the efficacy rate rose steadily as the number of days of MOM administration increased. These clinical results were, nevertheless, basically the same as those noted above for the evaluation by the physician in charge.
6.It was possible to evaluate the bacteriological efficacy of the MOM therapy in 3 of the patients: the bacterium had been eradicated in 2 of the patients, but it persisted in the third.
7. None of the patients were found to develop side effects to the MOM therapy. Concerning abnormalities in the laboratory tests, 1 patient was found todevelop an elevated GOT level, but there were no abnormal values recorded for any of the other patients.

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Absorption, excretion and distribution of amikacin sulfate (AMK) obtained following administration by drip intravenous infusion (d.i.v.) were studied in dogs, rabbits and rats, and were compared with those obtained after one shot intravenous infusion (i. v.) and intramuscular injection (i.m.).
1. The plasma concentration and urinary excretion of AMK following d.i.v. were comparedwith those after i.v. and i.m. in dogs and rabbits.
The peaks of plasma concentration following d.i.v. were obtained at the end of d.i.v. and it was clearly observed a linear dependence between the peak values andthe doses both in dogs and in rabbits.
There were no significant differences in the peak plasma concentrations between 1 hour d.i.v. and i.m. at the doses of 25 mg/kg and 50 mg/kg in dogs and ateach dose in rabbits. At the higher dose (100 mg/kg) in dogs, the peak plasma concentration following 1 hour d.i.v. was slightly higher than that after i.m.
The plasma concentrations at 10 minutes after i.v. were elevated about twice as high as the peak plasma concentrations following 1 hour d.i.v. both in dogs and in rabbits
The urinary recoveries following d.i.v. and i.v. were more than 90% and those after i.m. were about 85%.
2. The tissue and organ concentrations of AMK following 1 hour d.i.v. were studies in rats and rabbits. The peak concentrations were obtained at the end ofd.i.v. in any tissue and organ. Kidney was the highest and plasma, lungs, heart, stomach and so on were followed. The concentration in kidney was remained but those in other tissues and organs were decreased soon.
3. The plasma concentrations following d.i.v. in dogs were well agreed with the pharmacokinetic analysis in the two-compartment model, as the means of relative errors (¹Xm-Xc^l÷Xc) between the measured plasma concentration (Xm) and the calculated one (Xc) were less than 10% and the deviations of the pharmacokinetic parameters were in little ranges. The plasma concentrations during and just after d.i.v. were also agreed enough with the pharmacokinetic analysis in the one-compartment model.

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Acute toxicity of amikacin sulfate (AMK) was studied in rats, rabbits and dogs following 1 hour drip intravenous infusion (1 hour d.i.v.), and compared with those after intravenous injection (i.v.).
Subacute toxicity was studied in rabbits following 1 hour d.i.v. of AMK at doses of 400,200, 100 and 25 mg/kg for 36 days.
Acute toxicity:
Acute toxicity of AMK by 1 hour d.i.v. was extremely diminished as compared with that by i.v.judging from LD₅₀, the toxicity was approximately 1/6 in rats and approximately 1/2 in rabbits and dogs. No difference was observed between males and females.
Subacute toxicity:
1. No death was found in all rabbits.
2. At the doses of 25 mg/kg and 100 mg/kg, there were no significant changes or signs recognized as toxicological effects of AMK.
3. At the dose of 200 mg/kg, very slight renal damages were observed histopathologically in all the 5 rabbits.
4. At the dose of 400 mg/kg, slight or moderate renal damages were observed in all the rabbits. Those were mainly dilatation of renal proximal tubules, hydropic swelling and degeneration of renal proximal tubular epithelium. No significant impairment effect of AMK was found in heart, lung, liver and other organs.
5. From these results, it is considered that the maximum no effect dose from a view point of safety is about 100 mg/kg in this study.

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Subacute toxicity of amikacin sulfate (AMK) was investigated with 50 Beagle dogs (male25, female 25). As a substitute for drip intravenous infusion (d.i.v.), AMK was administered by intravenous injection (i.v.) twice a day, 1 hour apart, for 38days at daily doses of 400,200, 100mg/kg and 25mg/kg.
1. At the doses of 25mg/kg and 100mg/kg, there were no significant changes or signs recognized as toxicological effects of AMK.
2. At the dose of 200mg/kg, slight renal damages were observed in 3 of 5 males and 2 of 5 females. These were slight elevation of urea N and creatinine, and slight degeneration or regeneration of the renal proximal tubules.
3. At the dose of 400mg/kg, renal damages were noted in all the dogs.Two males and 1 female died after 14-17days'treatment and the remainders were sacrificed for inspection after 18-20 days' treatment. In any dogs, the adverse findings were mainly observed in the renal proximal.tubules but not in the glomeruli. In the other organs, there were no significant impairments.
4. From these results, it is considered that the maximum no effect dose of AMK is 100mg/kg.

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Fertility study on amikacin sulfate (AMK) was carried out in Wistar rats. AMK was administeredintraperitoneally at the doses of 0, 25, 100mg/kg/day and 200mg/kg/day in males for 60days prior to mating and mating period and in females for 14 days prior to mating, mating period and day 0-7 of gestation. The drug induced no significant changes or signs in parent animals, except that soft feces was occasionallyfound at the 100mg/kg/day and 200mg/kg/day and the impairment in kidneys was recogniged only at the 200mg/kg/day. There were no adverse effects on mating, fertility or reproduction indices in males and females.And there were no evidences of teratogenic or embryotoxic effects in at anydoses of AMK.

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Pharmacokinetic and clinical studies on amikacin (AMK) by intravenous drip (i.v.d.) infusion were performed, and the following results were obtained.
1. Serum concentrations of AMK were determined in 4 patients with normal renal function after 1hour i. v. d. infusion of 200mg of AMK. The mean peak serum concentration was 14.20±0.88 μg/ml at the termination of i. v. d. infusion and declined to 2.30±0.79 μg/ml at 4 hours later. The half-life was 1.55±0.28 hours.
2. Twenty-three patients with severe pulmonary infection received 1 hour i. v. d. infusion of 200 mg of AMK 2 to 3 times a day. Clinical response was good in 17 cases, fair in 4 and poor in 2. Thus, 73.9% of the patients responded to AMK.
3. No adverse effects were observed with the exception of tinnitus and hearing loss in 1 case. Therefore, it is thought that the i. v. d. infusion of AMK will be useful for treatment of severe infectious patients with bleeding tendency and emaciation.

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The effect of paromomycin sulfate on Diphyllobothrium latum in vivo in man was examined morphologically with a scanning and a transmission electron microscope. The worm used for this study was expelled from a man by treatment with paromomycin sulfate at 1 dose of 50 mg/kg. The surface of the neck region suffered great damage. The effect of paromomycin sulfate resulted in the progressive breakup of the microtriches and thetegument. Even the basal lamina was lost in some parts. As a result, the muscle layers wereexposed directly to the air.In the immature proglottid, the basal lamina remained as an outermost surface, although paromomycin sulfate caused a great loss of the tegument. The mature proglottid was lacking microtriches in some parts. However, most of the tegument was covered with microtriches. The gravid proglottid remained without any loss of microtriches.

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Thirty-one patients with primary atypical pneumonia (16 patients diagnosed as Mycoplasma pneumonia) who visited our Department of Pediatrics between March and December, 1981 were treated with 200 mg tablets of acetylspiramycin.Clinical effects were studied, and the results were as follows.
1. Acetylspriramycin, in principle 30 mg/kg/day, was given to 31 patients with primary atypical pneumonia. The effective rate was 87.1%.(As for the patients with Mycoplasma pneumonia, the effective rate was 93.8%).
2. There was 1 ineffective case and it was judged as a case of other viral pneumonia by the results of clinical laboratory tests.
3. The only side effect observed was eruption which occurred on the 6th day of administration in 1 case and disappeared after the change of administration.
From the above results, acetylspiramycin is thought to be an effective antibiotic on primary atypical pneumonia.

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