Micronomicin is a new aminoglycosidic antibiotic discovered and developed by Kyowa Hakko Kogyo Co., Ltd.It is produced by Micromonospora sagamiensis var.nonreducans.
Investigation of micronomicin performed in134research facilities in Japan led to the following results.
1) Micronomicin showed a broad antibacterial spectrum against Gram positive and Gram negative bacteria.
2) In susceptibility tests of clinical isolates, micronomicin was almost similarly active to GM.
3) Bactericidal activity of micronomicin against Pseudomonas aeruginosa and E.coli was higher than those of TOB and DKB.
4) Micronomicin showed a synergistic antibacterial activity against Pseudomonas aeruginosa and E. coli with CBPC and SBPC.
5) The therapeutic activity of micronomicin in mice infected with Pseudomonas aeruginosa and Serratia sp.was in high correlation with in vitro antibacterial activity similarly to that of GM.
6) Micronomicin was confirmed to be stable against aminoglycoside 6'-acetyltransferase of Pseudomonas aeruginosa and to be not inactivated.
7) Pharmacokinetics of micronomicin was almost similar to those of GM with respect to the concentrations in the serum, urine and tissues.
8) Ototoxicity of micronomicin in guinea pigs was found to be approximately four times lessthan that of GM.
9) Nephrotoxicity of micronomicin in rabbits was estimated to be less than those of GM and DKB. In rats, nephrotoxicity of micronomicin was approximately4times less than that of GM.
10) Micronomicin was effective on 964 cases out of1, 469cases from127research facilities in Japan (65.6%), suggesting its favorable activity against respiratory tract infections and against urinary tractinfections.
11) Side effects with the drug were observed in43cases out of1, 532 cases (2.81%).Abnormalities in laboratory findings were also recognized, but transient without severe cases.
12) In conclusion, micronomicin is a favorable drug having lesser ototoxicity and nephrotoxicity as well as antibacterial and bactericidal activity of aminoglycosidic antibiotics usually used.

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[in Japanese]

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The combination action of ampicillin and dicloxacillin was studied in vitro.
The following conclusions were obtained.
1) When both ampicillin and dicloxacillin were employed, an increase in antibacterial activity was observed against β-lactamase producing E.coli No.106 (clinical isolated strain).
2) A synergistic action of ampicillin and dicloxacillin was proved by chequer board dilution method for E.coli No.106.
3) A same synergistic action of ampicillin and dicloxacillin was also proved by the growth curve for E.coli No.106.
4) Dicloxacillin showed an inhibition in degradation of ampicillin brought about by β-lactamase extracted from E.coli No.106.
5) When the organisms of E.coli No.106 were exposed to the combination of ampicillin and dicloxacillin, spheroplast-like structure and lysis were observed by scanning electron microscope.

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In29patients of infectious diseases associated with acute leukemia, 60 to 160 mg/day of gentamicin was injected intravenously drip infusion.
The results showed that69.0%of the cases were clinically effective (excellent+good+fair), and 31%ineffective.Abnormal GOT and GPT level was temporarily noted in 2 cases and audiovestibular dysfunction in 1 case, which improved after the discontinuation of the injection.
Safety of the intravenous drip administration of gentamicin was discussed.The patients with acute leukemia might easily have opportunistic infection by Gram negative rods and it is more advantageous to administrate intravenously drip infusion than intramuscularly because of hemorrhagic tendency.

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Laboratory and clinical studies were performed on9, 3-diacetylmidecamycin (MOM), a new macrolide antibiotic in the field of pediatrics, and the results were as follows.
Antibacterialactivity: For 32 clinically isolated strains of Staphylococcus aureus, the MIC of MOM ranged from 0.78 to 1.56μg/ml for 17 of the 32 strains, and exceeded 100μg/ml for the 15 remaining strains with both inoculum sizes of10⁸cells/ml and 10⁶ cells/ml.For 27 strains of Streptococcus pyogenes, the MIC range was wide, varying from 0.10 to 100≥μg/ml and less than 1.56μg/ml for about 2/3 of all the 27 strains.For 9 strains of Bordetella pertussis, the MIC ranged from0.10 to 0.78μg/ml and 0.10 to 0.39μg/ml with the inoculum size of 10⁸cells/ml and 10⁶cells/ml, respectively.Comparing the antibacterial activity of MOM with that of midecamycin (MDM) and erythromycin (EM) against these 3 bacterial species, MOM was almost comparable to MDM, but about 2 or 3 tubes inferior to EM.
Absorption andexcretion: MOM was administered to5 children (from 5 to 8 years old) at a dose of 10 mg/kg or 20 mg/kg at 30 minutes before breakfast.The peak of serum concentration was observed 30 minutes to 1 hour after administrations of bothdosages: 0.52 to 1.71μg/ml with 10mg/kg and 0.88 to 1.77μg/ml with20mg/kg. 0.09 to1.10% and 0.94 to 1.19% of MOM were excreted in the urine within the first 6 hours, respectively.
Clinicalresults: MOM was administered to 28 pediatric patients with acute respiratory tract infections (acute pharyngitis; 2, acute purulent tonsillitis; 19, acute bronchitis; 4, acute pneumonia; 2 and whooping cough; 1).The overall clinical response was excellent in 10, good in 10, fair in 3 and poor in 5; the efficacy rate was 71.4%.Isolated S.pyogenes strains were eradicated in 6 out of 11 strains, reduced in 3 and unchanged in 2 strains.One strain of S.aureus was eradicated.One strain of non group A β-Streptococcus was reduced. Haemophilusinfluenzae strains were reduced in 1 of the 4 strains and unchanged in 3 strains.The overall eradication rate was 41.2%.No side effects or abnormal laboratory findings were observed, but 1 case complained of a bitter taste.

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1.We had a chance to administer the ‘MOM dry syrup’ (MOM fine granules) to22patients: 6 patients with streptococcal infections and16patients with other respiratory tract infections.The clinical efficacy was good in16cases and its rate was80%.
2.The causative organisms were isolated from 9 cases: 6 cases with S.pyogenes, 2with S. pneumoniae and1case with B.pertussis. All of the clinical isolates were eradicated except for the S.pyogenes strains.
3.Any remarked side effects were not observed but only eosinophilia in2cases.
4.Because of no bitterness of the MOM dry syrup, all the children take it easily.
5.MOM was effective in all the cases of pertussis and Mycoplasma pneumoniae pneumonia.As for streptococcal and pneumococcal infections, it is necessary to administer MOM under the control of bacterial sensitivity.

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The tissue distribution of9, 3-diacetylmidecamycin (MOM) was studied in the pregnant rats and in the rats following repeated administration. After oral administration of MOM (200mg/kg) in the pregnant rats, the levels in the placenta and in the uterus were2-3times higher than that in the blood, however the levels in the amniotic fluid and in the fetus were1/10-1/20 of the blood levels. After the third administration of MOM in the first day (30mg/kg p.o./dose, 3times/day, 4-hour interval), the levels in the liver, kidney, lungs, spleen, salivary glands and thymus were1.5-12times higher than that in the blood;the level in the muscle was almost equal to that in the blood;and the levels in the brain were1/3-1/10of the blood level.The tissue distribution patterns after repeated administrations were found to be similar to those of the first day administrations.

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9, 3-Diacetylmidecamycin (MOM), a new macrolide antibiotic, was administered to 28 patients: 6 with pharyngitis caused by Group A β-Streptococcus, 2with lacunar tonsillitis, 8with upper respiratory tract infection, 6with acute bronchitis, 3 with Mycoplasma pneumonia, 1with primary atypical pneumonia, 1 with pneumonia caused by H.influenzae and1with whooping cough.
MOM in the form of fine granules was administered at a daily dose of about20-30mg/kg divided into3doses.
Isolated group A β-Streptococcus strains were eradicated in only1out of6strain S.One strain of H.influenzae was eradicated.
The clinical results could be obtained with21cases and the response was excellent in1case, good in7, fair in3and poor in10.
Although diarrhea was found in3cases during the administration of MOM, it was not clear whether these phenomena were caused by MOM, because of the prevalence of diarrhea among the children treated by us at that time.

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The pharmacokinetic behavior of dibekacin was studied in 8 elderly subjects.These subjects had not apparent renal failure, although they were diagnosed as having various diseases such as arteriosclerosis, essential hypertension, etc.
Dibekacin, 50mg/subject, was infused intravenously for 1 hour.Serum and urine concentrations of dibekacin were measured by the bioassay and radioimmunoassay methods.
The peak serum concentration of dibekacin ranged from 3.55 to 5.35μg/ml when measured by bioassay, and from 3.19 to 8.9μ/ml by radioimmunoassay. The biological half-life of dibekacin ranged from 2.13 to 3.45 hours, and from 1.57 to 3.55 hours, with these 2 methods.The area under the curve (AUC) ranged from 14.8 to 25.6μ/ml.hr and from 11.3 to 18.0μg/ml.hr, respectively.
Creatinine clearance showed a positive correlation with the elimination rate constant and a negative correlation with the distribution volume of dibekacin.These relationships were more pronounced when determined by radioimmunoassay.These data suggest that the peak serum concentration of dibekacin decreases with creatinine clearance.The serum and urine concentrations of dibekacin measured by the radioimmunoassay method correlated well with those measured by the bioassay method.Therefore, it was concluded that the radioimmunoassay method is a useful technique for monitoring the serum concentration of dibekacin.

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The concentrations inserum, cancellous and cortical bones of dibekacin sulfate were measured in 16 cases.Dibekacin sulfate rapidly penetrates into bone.The peak concentration in serum and cancellous bone is reached within 1 hour after intramuscular injection and the concentration in cancellous bone parallels that in serum. The concentration in cortical bone increases with time.Cancellous bone has higher concentration than cortical bone.Dibekacin sulfate is suitable for prevention of infection in orthopaedic surgery, because it maintains a bactericidal level in bone for enough time.

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The clinical effect and side effect of micronomicin sulfate were studied in collaboration of 14 univer sities and one public hospital in accordance with the method and evaluation criteria recommended by the Association for Research in Infectious Diseases of the Eye, Japan.
The results were as follows.Among the 397 cases accepted for evaluation the clinical effect was excellent in 166 (47.8%), good in 212 (53.4%), fair or poor in 18 (4.5%), and unidentified due to adverse effect in the last one;thus the effective rate was 95.2%.By the evaluation criteria of the above Association, the drug is judged as ‘excellent’ when the effective rate is over 90% where the excellent clinical effect is 45%.The evaluation criteria of the Association also provides that the treated cases should contain more than 15 cases of infections with 3 kinds of specific bacteria, such as KOCH-WEEKS, MORAX-AXENFELD, Streptococcus pneumoniae and Pseudomonas aeruginosa.The present study contains 78 cases of 4 kinds of specific bacterial infections;excellent clinical effect was seen in 35 (44.9%) of the 78, good effect in 41 (52.6%), and the effective rate was 97.4% in these cases.As they correspond to the over-all results, the said evaluation was applicable.
The safety of micronomicin sulfate eye drops was calculated on the 451 cases including 397 adopted cases and 54 excluded cases from efficacy evaluation due to negative bacteria though continuously treated.No serious side effect was seen in these cases and the safety coefficient was found to be 1.94 (full mark: 2).The drug showing safety coefficient over 1.90 is judged as ‘excellent’ in safety.
Micronomicin sulfate was applied as the aseptic procedure of preoperative conjunctival sac according to the regulatory method, and the aseptizing rate obtained was 77% (admitting line: 70% in more than 30 cases), and the effective coefficient calculated according to the regulatory method was 13.5 (admitting line: 10).In addition, this drug prevented the manifestation of infection after an intensive in oculation with potent Pseudomonas aeruginosa into the rabbit cornea.Thus, micronomicin sulfate was judged ‘passed’ as a drug for prophylaxis of postoperative infections including those due to Pseudomonas aeruginosa.
From the above results, it was concluded that micronomicin sulfate eye drop is one of the first choice eye drops for the treatment of the external bacterial infections of the eye.

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The patient we report here is a 71 year-old female.After hospitalization, she had clouding of consciousness as an accompanying symptom of DIC (disseminated intravascular coagulation) complicated by septicemia.Her clouding of consciousness caused aspiration pneumonia which developed into pulmonary abscess.Furthermore, she had a large decubital ulcer on the gluteal region.Sputum cultures revealed P.aeruginosa, Serratia and Klebsiella and those from decubital pus grew Proteus, showing to be a mixed infection due to Gram-negative bacilli which brings on medical discussion at present.To the patient, repeated intramuscular AMK was administered at a daily dose of200mg (Duration: 124days, Total amount: 24,800mg).Chest X-P showed a marked improvement. Similarly, the large decubital ulcer was improved.No side-effects were observed in the kidney and eighth nerve though she was a patient with the advanced age of71.It is thought, therefore, that patients can tolerate long-term treatment with AMK.

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Susceptibilities to fosfomycin of216strains of28bacterial species were determined by the 2-fold agar dilution method in parallel with the diameter of inhibition zone by the single-disc method, under the experimental condition establish by KANAZAWA.
The experiments demonstrated significant correlation between MIC by the dilution method and diameter of inhibition zone in each of conventional assay of the over-night (about16hours) incubation, delayed assay (about24hours incubation), thus confirming applicability of the single-disc assay for fosfomycin.
Analysis of the data obtained by using fosfomycin disc containing200pg revealed the primary regression equation to be: D (diameter, mm) =42.73 13.85 log MIC (μg/ml) in conventional assay, D=56.51-18.18 log MIC (μg/ml) in delayed assay, respectively.
The range of variations in MICs estimated from the diameter of inhibition zone by the disc test was then calculated in comparison with that in MIC determined by the2-fold agar dilution assays, as reference for the experimental errors which may be involved in the estimation of MIC of fosfomycin by the single-disc assay.

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The basic studies of cefotiam (CTM) were performed, and the following results were obtained. 1.One shot intravenous injection of 40mg/kg of CTM
(1) Serum levels:
The mean serum levels of CTM in 3 children were 133.9μg/ml after 15 minutes, 71.5μg/ml after 30 minutes, 32.6μg/ml after 1 hour, 9.2μg/ml after 2 hours, 2.5μg/ml after 4 hours, 0.9μg/ml after 6 hours.The serum half life of CTM was approximately 1.2 hours on β-phase.
(2) Urinary excretion:
The mean urinary excretions were 39.4% over 2 hours, 44.7% over 4 hours, 45.7% over 6 hours. 2.1 hour-drip infusion of 40 mg/kg of CTM
(1) Serum levels:
The mean serum levels of CTM in 4 children were 140.1μg/ml at immediately after drip infusion was completed, 10.6μg/ml after 1 hour, 3.8μg/ml after 2 hours, 1.4μg/ml after 3 hours, 0.5μg/ml after 5 hours.The serum half life of CTM was approximately 1.0 hour on beta;-phase.
(2) Urinary excretions:
The mean urinary excretions were 42.9% over 2 hours, 48.0% over 4 hours, 48.7% over 6 hours. 3.Bioactive metabolite in serum and urine:
No bioactive metabolites were observed in either serum or urine after administration of 40mg/kgof CTM.

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Seven CEPs agents (CEX, CXD, CDX, CEZ, CTM, CMZ and CXM) were examined for their MIC'sagainst 240 strains of S.aureus isolated from superficial abscesses in infants.
1) Oral agents of CEPs, CEX, CXD and CDX gave similar results in MIC₅₀, MIC₈₀ and MIC₉₀. Eight to 10% of the strains had high MIC's considered to be resistant at an inoculum size of 10³ CFU/ml.
2) In injectable agents of CEPs, CEZ, CTM, CMZ and CXM, MIC₅₀ showed MIC reflecting their antibacterial activity and MIC₈₀ covered MIC which was considered as clinically effective.However, MICH reflected the presence of bacteria considered to be resistant to some degree and differed from one agent to another.The proportion of the strains which gave 50μg/ml or higher MIC at an inoculum size of 10⁸ CFU/ml was 5.8% for CEZ, 4.6% for CTM, and 7.1% for CXM, suggesting the presence of resistant bacteria at a proportion of 5-7%. In contrast, it was as low as 0.8% for CMZ.
3) These results indicate that strains resistant to CEPs tend to increase and take root in bacteria existing in quite usual and general living environment such as S.aureus isolated from superficial abscess in infants.This is a serious situation.Various studies on bacteria resistant to CEPs are being expected to be performed in each field.

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Clinically isolated 741 strains of 10 bacterial genus (except for Pseudomonas aeruginosa) which are frequent causal pathogens of infection in the otorhinolaryngological field were examined fortheir sensitivity to second-generation cephem agents, CTM, CXM and CMZ using the first-generation agent, CEZ, as a control.
1) The antibacterial activity of CTM, CXM, and CMZ was expanded to H.influenzae and Proteus spp.(indole positive) as compared with the first-generation agent, CEZ.CTM and CXM had strong antibacterial activity against H.influenzae. CMZ was slightly inferior to them in this activity. In contrast, against Proteus spp.(indole positive) CMZ was most effective and CTM was more effective than CXM.
2) The proportion of strains of S.aureus resistant to CEPs was6.5% in CEZ, 4.8% in CTM, 8.1% in CXM, and as low as1.6% in CMZ.

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Cefmetazole (CMZ) is an antibiotic agent belonging to the cephamycin group, which is resistant to β-lactamase and has a broad antibacterial spectrum covering from Gram-negative to-positive organisms.Although this agent has been proved to have an antibacterial activity against Staphylococcusspp., it has not been used for treatment of the infections caused by the organism.Thus, 62strains of S.aureus isolated clinically were compared for their sensitivity to CMZ, cefoxitin (CFX), cefuroxime (CXM), cefazolin (CEZ), and ampicillin (ABPC).In addition, 5children suffering from septicemia due to S.aureus were treated with CMZ158mg/kg at a mean daily dose for a mean period of14days.The dose was used after dividing into3and4equal parts in1and4children, respectively.One old patient with septicemia was given2,000mg of CMZ twice daily for4days and once daily for subsequent3days. Another child with bacterial meningitis was treated with50mg/kg of CMZ4times daily for63days. The drug was given intravenous injection by one-shot or drip infusion in all cases under observation of clinical effects, bacteriological effects and side effects.
The MIC of CMZ against S.aureus at inoculum sizes of10⁸ and 10⁸ cells/ml was1.56mcg/ml in 72.6and56.5%of the strains, respectively.When5drugs were compared on the basis of the MIC to which the largest number of strains were sensitive, CEZ was most active, and CMZ was ranked in the next place and similar to CXM in activity.However, when the whole range of the MIC was considered, CMZ was more excellent than CXM, its MIC was lower than those of CEZ, CFX and ABPC in a greater number of strains.It was considered from the results that the serum level of CMZ was ffective against 100 and 93.5% of strains at an inoculum size of106cells/ml and against 100and 83.9%of strains at an inoculum size of 10⁸ cells/ml until4and6hours after a one-shot intravenous injection of 50mg/kg of Moni-trol I standard, respectively in the children.Thus, CMZ is expected to manifest a sufficient effect on septicemia caused by S.aureus in children who receive a one-shot intravenous injection of50mg/kg of it 4 times daily
Treatment with CMZ was clinically evaluated to be excellent in3, good in3and poor in none of 6 patients with septicemia due to S.aureus, and fair in the1with Staphylococcal meningitis.The bacteriological result was excellent, since the causal organisms were eradicated in all cases.
With regard to side effects, abnormal eosinophilia was found in2cases, but it was no ascribable to this drug in 1 of them.GOT showed an abnormal rise in1case and both GOT and GPT in1, although they were considered not to be related to this drug in either case.It is considered from these results that CMZ is a valuable drug in treatment of septicemia due to S.aureus.

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In order to evaluate the efficacy of cefmetazole (CMZ) against osseous and articular infections fundamentally, the sensitivity of clinically isolated strains of Staphylococcus aureus to the drug and its concentration in serum and bone marrow of tibia were determined.
1.The clinically isolated strains of S.aureus was found to be sensitive to 0.78μg-6.25μg CMZ per milliliter when inoculated at10⁶cells/ml and to0.78μg-12.5μg CMZ per milliliter when inoculated at10⁸cells/ml.No strains were resistant to CMZ.
2.One gram of CMZ was injected intramascularly before operation.Blood samples were collected from the bone marrow and the vein and measured for the concentration of CMZ.The mean concentration in the bone marrow of tibia were30.5μg/ml, 16.8μg/ml and8.9μg/ml1, 2, and 3 hours later, respectively, and the mean transfer rate from serum to bone marrow was104.8, 92.8 and 101.1% respectively.
3.CMZ concentration in bone marrow of tibia attained following an intramuscular injection of 1g of CMZ were higher than the MIC values for most of the clinically isolated strains of S.aureus, suggesting the effectiveness of CMZ in clinical practice.

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1.Sixteen patients with purulent osteomyelitis were given intravenous instillation of2g cefmetazole (CMZ) twice a day.The effect of the treatment were excellent in2cases (12.5%), good in11 (68.8%), fair in1 (6.3%), and poor in2 (12.5%).
2. S.aureus was detected in 6 of16cases.The organism was eradicated in all of these positive cases.
3. No side effects to be specially mentioned were noted.

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We studied cefoxitin (CFX) concentration of oro-maxillary tissues in rats and in18patients by means of bioassay method.In rats, the highest peak concentrations were observed in the gingiva and buccal mucosa followed by the tongue, submaxillary gland, lower jaw bone and the masseter muscle in the order listed.
In patients, the highest peak concentrations were observed in the maxillary sinus mucosa and peak concentrations in oro-maxillary tissues were froml/5to2/3of the corresponding serum concentrations. Further study is needed to elucidate the reason for the high peak CFX concentration in the maxillary sinus mucosa and the apparent delayed peak concentration in the salivary gland.

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The effects of cefotetan (CTT, YM09330) and cefmetazole (CMZ) on the morphological changes of Escherichia coli NY-17 and Serratia marcescens IID 620 were examined with scanning electron microscope.
1) CTT caused E.coli NY-17 filamentous forms at0.024μg/ml but CMZ showed same morphological changes at0.2μg/ml which is about10fold higher concentration than that of CTT.Spheroplast like structures and cell lysis were observed at lower concentrations than those of CMZ.
2) In case of Serratia marcescens IID 620, filamentous forms, spheroplast like structures and cell lysis were also observed at lower concentrations than those of CMZ.
The action of CTT against the both strains was bactericidal.

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The changes in the fecal flora and their correlation with the fecal drug concentrations were studied, employing4volunteers (healthy adult males) to whomlg of cefotetan was intravenously administered daily for 6 days.
1.In all of the subjects, the total counts of fecal organisms were slightly decreased1day after administration of cefotetan, then showed gradual increase, and recovered to the normal level on8day after the withdrawal of the drug.
2. Cefotetan caused drastic suppression of normal aerobic and anaerobic flora during the administration period, except streptococci that remained unchanged at all.The bacterial groups suppressed were bacteroidaceae, eubacteria, bifidobacteria, peptococcaceae, lactobacilli, enterobacteriaceae, lecithinasepositive clostridia, and staphylococci.Yeasts were found to increase during the administration period.
3. The changes in flora well correlated with the fecal level of the drug concentrations.This is in accordance with the in vitro antibacterial activity of the drug.
4. A period of more than15days was required after the withdrawal of cefotetan to recover the normal fecal flora.
5.Loss of body weight and diarrhoea were not observed in any of the subjects.

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