Efficacies of 8 antibiotics against Pseudomonas aeruginosa in the relation to serotypes and clinical sources were investigated on 50 strains isolated from patients at Nagoya Ekisaikai Hospital between August and September, 1986. Disk sensitivity test was carried out simultaneously for 5 antibiotics including piperacillin (PIPC), cefoperazone (CPZ), cefsulodin (CFS), ceftazidime (CAZ) and amikacin (AMK), using the single-disk method. We also examined changes in susceptibilities of P. aeruginosa to 5 antibiotics including PIPC, CFS, fosfomycin, gentamicin (GM) and AMK during last 4 years (1983-1986).
The results are summarized as follows.
1. CAZ and AMK proved to have high antibacterial potencies, and their MIC₈₀'s (concentrations to inhibit growth of 80% of objective bacteria) were both 6.25μg/ml. Following these two the order of potencies were; CFS, cefpiramide (CPM), PIPC, CPZ, netilmicin (NTL), and cefmenoxime (CMX). Sixty two percent of the strains of P. aeruginosa showed high resistances (MIC 50μg/ml) to CPM, CPZ, NTL and CFS, 58% to PIPC, and 2% to AMK.
2. With regard to serotypes, strains belonging to type E were less susceptible than those belonging to types G and I. Type E strains showed high resistance to all antibiotics except CAZ and AMK.
3. Strains obtained from pura and secreta were relatively susceptible, while those from urines were resistant, to these antibiotics tested, in general.
4. Good correlation between MIC's obtained with the agar dilution method (MIC≤12.5μg/ml) and these with the disk sensitivity test (++) was observed. x² statistical analysis showed that the results obtained with the 2 methods were closely related (P<0.01).
5. P. aeruginosa showed fairly high susceptibility to AMK through the recent 4 years (1983-1986). On the other hand, highly resistant strains against CFS, PIPC, FOM and GM increased rapidly during this period.

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We investigated in vitro synergistic activity of astromicin (ASTM) combined with β-lactam antibiotics cefsulodin (CFS), cefoperazone (CPZ), ceftazidime (CAZ), piperacillin (PIPC) and fosfomycin (FOM) against fresh clinical isolated Pseudomonas aeruginosa, which consisted of 13 CFS sensitive (MIC≤3.13μg/ml) and 19 CFS resistant (MIC≥400μg/ml) strains according to the FIC index. Against CFS-sensitive P. aeruginosa, ASTM showed good synergistic activities when combined with PIPC (54%), CAZ (38%), CPZ (23%) and CFS (8%). Against CFS-resistant P. aeruginosa, ASTM also showed high synergistic activities when combined with CAZ (63%), CPZ (47%), PIPC (37%) and CFS (11%). Among the CFS-resistant P. aeruginosa, one clinical isolate showed a high sensitivity (MIC0.78μg/ml) against ASTM alone.

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We described antimicrobial susceptibilities of clinical isolates of Staphylococcus aureus in 1985 and also a 6-year survey of changing patterns of their susceptibilities to ampicillin (ABPC), cefazolin (CEZ), cefmetazole (CMZ) and gentamicin (GM) from 1980 to 1985 in 103 hospitals. The MICs were determined by the standard method of the Japan Society of Chemotherapy.
Among 2,891 isolates in 1985, ratios of resistant strains to ABPC and GM were 24% and 29%, respectively, and those to CEZ and CMZ were 8% and 3%, respectively.
Gradual increases in numbers of resistant strains to ABPC, CEZ and CMZ were observed until 1984 but a trend for decreases in numberes of resistant strains to the above 3 antibiotics was observed in 1985. A continuous rise in numbers of resistant strains to GM until 1985 was noted.
Isolates from clinical materials such as pus, bile, and urine showed higher incidences of resistance to ABPC and GM than those from sputum, secreta and throat swab. Rates of resistant strains to CEZ were the highest in isolates from bile, pus, sputum and urine. Rates of resistant strains to CMZ were the highest in isolates from bile, and decreased in isolates from sputum, urine and pus in this order.
Rates of resistant isolates from inpatients to the 4 antibiotics tested were greater than those from outpatients.

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Isolation patterns and drug susceptibilities of Staphylococcus aureus and Staphylococcus epidermidis were investigated in Kashima Rosai Hospital, a local hospital with 300 beds opened in June, 1981. Our investigation covered 218 Staphylococcus strains isolated from various clinical materials in the Clinical Laboratory during a one year period in 1985.
These isolated strains comprised of 8 species of genus Staphylococcus with S. aureus and S. epidermidis together accounted for 93.6% of all the clinically isolated Staphylococci. S. aureus was detected in materials obtained from outpatients at a higher frequency than S. epidermidis, while the opposite was the case in materials obtained from inpatients. When distributions of these organisms were classified depending on clinical materials from which they were isolated, outpatient sources from which S. aureus were isolated at high frequencies were otorrhea and pus, while inpatient sources with high incidents of S. aureus isolation were sputum and pus. With regards to S. epidermidis, urine and pus from outpatients as well as from inpatients yielded this organism at high frequencies.
Isolation frequency ratios in this hospital of methicillin-resistant S. aureus (MRSA) and S. epidermidis (MRSE) were 8.6% and 30.8%, respectively. These resistant strains were found from a large spectrum of clinical materials. Thus, these strains seemed to have established themselves more or less firmly among bacterial population in the hospital, hence alerting us the risk of hospital infections in compromised hosts. As to the coagulase typing of MRSA, type IV was the most frequent from outpatient sources whereas type II was the most frequent from inpatient sources including a large variety of clinical materials. The coagulase typing has been regarded as useful in epidemiological surveys of nosocomial infections, and as more expedient and rapid than the phage typing. We confirmed these in our investigation.
Among beta-lactam antibiotics we tested against MRSA, flomoxef was found to be superior to the others. Cephalothin and cefamandole proved to be highly active against MRSE. Minocycline and vancomycin showed good activities against MRSE as well as MRSA.

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Hospital acquired infection due to Serratia marcescens, a ubiquitous saprophyte, is significantly increasing1-3, 16, 19). A majority of such S. marcescens strains are highly resistant, and in fact, the emergence of multiple drug resistant strains of genus Serratia is more prevalent than any other commonly occurring members of the family Enterobacteriaceae of clinical origin12). The presence of transferable R plasmids with resistance markers to ampicillin (ABPC), chloramphenicol (CP), gentamicin (GM), nalidixic acid (NA), streptomycin (SM), and/or tetracycline (TC) has been demonstrated in these strains6, 11, 12, 15, 17). In this papers, we describe antibiotic susceptibilities of 101 strains of S. marcescens isolated in our hospital. Mention will also be made on the transferability of their drug resistance properties. The 101 isolates of S. marcescens tested came from various pathological specimens obtained during years 1980 to 1981. Forty three strains were isolated from urine, 37 from sputum and 21 from wound or soft tissue infections. Criteria used for the identification of S. marcescens were as follows: Gram-negative, cytochrome oxidase-negative motile rods that fermented glucose and sorbitol but not arabinose and raffinose. They neither produced indole, hydrogen sulfide (in TSI agar) nor urease. Lysine was decarboxylated. They grew on SIMMONS' citrate agar and excreted gelatinase and extracellular DNase.

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Plasma and urinary antibiotic concentrations measured by 3 different bioassay methods were compared to each other in vitro, after oral administrations of rokitamycin (RKM) tablet, midecamycin acetate (MOM) tablet or josamycin (JM) tablet at a dose of a potency of 600mg to each of nine healthy volunteers.
Method I (RKM bioassay method) was an agar-well method using the agar medium described in the Minimum Requirements for Antibiotic Products of Japan (MRAPJ medium, pH 6.5), method II (MOM bioassay method) was an agar-well method using mycin-assay agar (pH 8.0) and method III (JM bioassay method) was an agar-well method using nutrient agar (pH 7.8). Micrococcus luteus ATCC 9341 was used as the test organism in all the assay method.
With any of the bioassay methods tested, plasma concentrations of RKM were determined to be higher than those of MOM or JM.
When the three different bioassay methods were compared, method II and III gave consistently higher values than method I for plasma concentrations of any of the drugs tested. These higher values obtained by method II and III appeared to be due to their inability to correctly assay potencies of metabolites of these antibiotics. Using in vitro assay method, potencies of metabolites were found to be estimated higher than they should when method II and III were used.
Method I, on the other hand, determined relative potencies of these antibiotics and their metabolites correctly, reflecting differences in MIC values of original antibiotics and their metabolites. Method I, therefore, should be used as the method of preference to determine concentrations of these drugs in body fluids.

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We investigated enzymatic mechanisms of resistance to aminoglycoside antibiotics in methicillin-cephem-resistant Staphylococcus aureus (MRSA) by elucidation of the structures of the enzymatic reaction products.
According to the MIC data, MRSA,(46 strains) can be classified into 3 groups as follows. 1. Group I (35 strains) was highly resistant to gentamicin (GM) and tobramycin (TOB), and produced 2-aminoglycosides phosphotransferase (APH (2)). 2. Group II (8 strains) was sensitive to GM, but was highly resistant to TOB, and produced 4'-aminoglycosides adenylyl-transferase (AAD (4')). 3. Group III (3 strains) was sensitive to GM and TOB, but was highly resistant to kanamycin, and produced 3'-aminoglycosides phosphotransferase (APH (3'))-III.
Arbekacin (HBK) was the most stable antibiotic to all of the inactivating-enzymes produced by MRSA, and all MRSA were sensitive to HBK.

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Antibacterial activity of gentamicin (GM), along with activities of other aminoglycosides and beta-lactams, was studied against clinical isolates collected from pediatric patients during a period of May 1986-April 1987.
1. GM-resistance was noted in 22% of Staphylococcus aureus, 6% of Proteus vulgaris, 8% of Morganella morganii, 40% of Providencia spp., 6% of Enterobacter spp., 14% of Serratia marcescens, and 14% of Pseudomonas aeruginosa isolates. No GM-resistance was observed with isolates of Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis.
2. The antibacterial activity of GM against clinical isolates from pediatric patients was found to be comparable to its activity against clinical isolates from adults studied at the same time.
3. The majority of GM-resistant strains of S. aureus were MCRSA, and the GM-resistant strains of S. marcescens and P. aeruginosa were found also to be resistant to multiple drugs.
4. GM-resistant strains were found at relatively high rates (14-22%) in S. aureus, S. marcescens and P. aeruginosa. These rates did not increase compared to the rates observed in the first half of the 1980's.
5. GM was considered to have poor antibacterial activity against genus Providencia.
It is concluded from above results that GM still maintains effective antibacterial activity against many of causative organisms of infections in both adults and children.

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A multiclinic study of gentamicin (GM) given by intravenous drip infusion was carried out by the Gentamicin Pediatric Study Group. The results are summarized as follows:
1. Upon intravenous drip infusion of GM at a dose range of 2.0-2.5mg/kg over a period of 0.5-1 hour, therapeutically effective serum concentrations of 4-12μg/ml were obtained. These values are similar to reported values in previous studies using GM intramuscular injection.
2. High urinary concentrations were observed up to 6 hours after administration, and the urinary recovery rate was approximately 60%.
3. Of a total of 142 cases collected, 117 cases were evaluated. Efficacy rates by diseases were: 100% in pneumonia (30/30), 98.3% in urinary tract infections (59/60), and 92.3% in other infections (skin and soft tissue)(12/13), with an overall efficacy rate of 94.9% (including 77 “excellent” cases).
4. Bacteriological examinations showed high eradication rates with the use of GM; i.e., 80% with Staphylococcus aureus (8/10), 60% with Pseudomonas aeruginosa (3/5), 100% with Haemophilus influenzae (7/7) and 97.8% with Escherichia coli (44/45), achieving an overall eradication rate of 92.4%. In mixed infections, the eradication rate was 85.7% (6/7).
5. No ototoxicity, nephrotoxicity or allergic reactions was observed. Abnormal laboratory findings observed were: GOT elevation in 3.1% of cases, GPT elevation in 3.9%, platelet increase in 1.5% and eosinophil increase in 0.8%, thus an overall rate of the appearance of abnormality was 5.6%.
The above results indicate that an intravenous drip infusion of GM is a useful method for treating infections in pediatrics.

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Eighteen children with urinary tract infection were treated with intravenous drip infusion of gentamicin (GM), and clinical efficacy and pharmacokinetics were studied. Ages of the patients ranged from 2 months to 12 years. Doses of GM ranged 1.0 to 2.5mg/kg every 8 to 12 hours, and treatment continued for 4 to 10 days.
Among 18 patients treated, clinical results were excellent in 12, and good in 6. Values of BUN and creatinine remained within normal range in all patients during and after the GM treatment. One child had an eosinophilia. There were no cases that showed signs and symptoms of oto-and nephrotoxicity.
Twenty eight time-serum level curves were studied in 16 patients during and after intravenous infusion of GM over 30 minutes. Doses were 1.0mg/kg in 4, 1.9-2.0mg/kg in 14, and 2.2-2.5mg/kg in 10. Peak serum levels at 30 minutes after the start of infusion were 2.66-7.38μg/ml (average 5.45μg/ml) in cases receiving 1.0mg/kg, 4.67-10.8μg/ml (7.26 μg/ml) in 1.9-2.0mg/kg, and 6.16-16.5μg/ml (8.86μg/ml) in 2.2-2.5mg/kg. Elimination half-lives were 1.75-2.48 hours (average 2.10 hours) in cases with ages less than 1 year, 1.58-2.58 hours (2.01 hours) with 1 to 6 years, and 1.20-3.07 hours (1.66 hours) with 7 to 12 years who were given doses of 1.9-2.5mg/kg. There were no significant differences in pharmacokinetic parameters between first and last administration in these patients, suggesting that no accumulation occurred with above mentioned doses. Urinary recovery of GM ranged from 21.9 to 99.2 percent (average 62.48%) within 6.5 hours after the initiation of drip infusion.

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A 3-day-old, 3,413g, 38-week gestated male infant developed neonatal meningitis due to Flavobacterium meningosepticum. Treatment with cefmetazole and cefotaxime led him to a complete recovery without neurologic deficit.
Of 82 previously published cases under 1 year old, 41 cases died and 16 of survivors developed hydrocephalus because the organism was resistant to many antibiotics.
Therapy of meningitis due to the organism has not been standarized but the early laboratory identification and the choice of effective and safe antibiotics determined by antimicrobial sensitivity test improve the outcome.

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1. Cefmetazole (CMZ) and netilmicin (NTL) were administered by one-shot intravenous and intramuscular injection, respectively, and measurements were made on their concentrations in the serum as well in the cerebrospinal fluid (CSF) which was collected using a drainage tube inserted into the cisterna basalis after the operation of ruptured cerebral aneurysm.
2. Concentrations of CMZ and NTL in the CSF changed nearly in parallel to those in the serum.
3. A one-shot intravenous injection of these drugs seemed to achieve their high concentrations in the CSF, though high concentrations may not last very long.

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Twenty-five adult female patients with acute cystitis were treated with 500mg fosfomycin tablets, at a dose of 6 tablets per day for 7 days. The clinical effects were evaluated on the 3rd day, and the treatment was found effective in all the 18 patients evaluated. The cystitis recurred in 1 patient, one week after the treatment. As for the side effects, three patients complained gastric discomfort and/or diarrhea.

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Flomoxef (FMOX, 6315-S), a newly developed oxacephem drug, was administered to 6 patients with chronic respiratory tract infections. Bacteriological examination of these infections using quantitative sputum cultures revealed that 2 patients had Haemophilus infiuenzae, 2 had Branhamella catarrhalis and 2 had mixed pathogens (one was with H. influenzae+B. catarrhalis and the other with Streptococcus pneumoniae+B. catarrhalis). The administration of the drug was done by drip infusion, twice daily, with a daily dose of 1 to 2g. As results, all the above mentioned pathogenic organisms were eradicated in 5 to 10 days after the initiation of the drug therapy. No undesirable symptoms were observed in these patients during the course of the chemotherapy.
Serum drug concentrations after an intravenous administration of the drug reached their peak values averaging 134.32±40.32μg/ml immediately after a single dose of 2 g of FMOX in 5 patients with chronic respiratory tract infections. Drug concentration in the sputum was at highest 1.86μg/ml.
Susceptibilities to FMOX of clinically isolated 49 strains of H. influenzae and 35 strains of B. catarrhalis from our clinic in the year of 1986 were compared to those to ampicillin and to latamoxef (LMOX). The study revealed that MICs of FMOX against H. influenzae were 0.10 to 1.56μg/ml, hence H. influenzae strains seemed to be sensitive to FMOX regardless of β-lactamase activities. LMOX had higher activities against H. influenzae than FMOX, however. Activities of FMOX against B. catarrhalis, on the other hand, were distributed from less than 0.05 to 0.39μg/ml which were also not as good as LMOX activities.

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A combination of cefmenoxime (CMX) and cefsulodin (CFS) which has a broad spectrum on various bacteria including Pseudomonas aeruginosa was evaluated for severe infections associated with hematological malignancies.
Seventy one patients were treated with the combination therapy. Among them, 57 patients were evaluable for the effectiveness. Fourteen patients were not evaluable because 10 patients were subjected to additional therapy such as γ-globulin, interferon, radiation and pulse therapy of a large dose of methylprednisolone, 3 were prophylactically treated and the remaining one was a patient with disseminated bone marrow metastasis of prostatic cancer and not a patient with a hematologic malignancy.
Excellent responses were obtained in 24 (42.1%) patients and good response in 12 (21.1%) patients, with a total rate of effectiveness of 63.2%.
Three patients who were treated prophylactically and one patient who suffered from prostatic cancer with metastasis to bone marrow, were included in the final evaluation of side effects.
Side effects were observed in only one patient (1/61, 1.6%). Mild neutropenia was identified in a patient of 78 years of age in 4 days after the combined regimen was started. Neutropenia disappeared soon after the cessation of the treatment.
These results showed that a combination of CMX and CFS was an effective and safe regimen for the treatment of severe infections in patients with hematological disorders.

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1. The bacteria isolated from pelvic dead space drainage well reflect the characteristics of prophylactic drugs. As drugs advance from penicillin (PC) to tetracycline (TC) to the first, second and third generation cephems, detection rates for Gram-negative bacilli, mainly Escherichia coli, decrease remarkably, while those for Gram-positive cocci, mainly Enterococcus faecalis, increase.
2. The bacteria isolated from the drainage and those which later caused parametritis and purulent lymphocyst were closely related. It is therefore very important to identify bacteria present in the drainage.
3. Judging from changes occurred in blood levels of ceftriaxone (CTRX) and its effective transfer to the pelvic dead space when CTRX 2 g was administered once daily, this administration regimen is considered to control even parametritis and purulent lymphocyst satisfactorily.
4. CTRX 2g was administered once daily for 5 consecutive days to each of 4 patients with parametritis, and it was observed that the general efficacy was good in 3 of the 4 cases.

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In vitro synergistic interaction between cefotaxime (CTX) and its main metabolite, desacetyl-cefotaxime (DCTX), against 7 species of clinical isolates (23-27 strains per species) was examined. Complete or partial synergy was noted with a 1:1 combination of CTX and DCTX against 22-78% of the Bacteroides fragilis, Staphylococcus aureus, Citrobacter freundii, Pseudomonas cepacia and Enterobacter cloacae isolates examined. Antagonistic effects of the drugs appeared against 11% of Proteus vulgaris and 4% of Serratia marcescens. When combined at various ratios by the checkerboard method and tested against B. fragilis, CTX and DCTX were found to act synergistically, and no antagonism occurred. The combined use of CTX and DCTX exhibited strong bactericidal activity against B. fragilis and inhibited bacterial regrowth. An experiment with concentrations of CTX and DCTX simulating human serum levels after intravenous administration also showed that the coexistence of DCTX augmented bactericidal activity of CTX against B. fragilis and brought inhibitory effects on bacterial regrowth.
It is presumed from the present results that clinically applied CTX would have more potent effects than expected from in vitro sensitivity test data.

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