[in Japanese]

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The chronic toxicity of potassium clavulanate (CVA-K) and BRL28500 were evaluated using dogs in 26-week intravenous administration studies followed by a 5-week off-dose period. The doses for CVA-K and BRL28500 were 10, 20, 50 and 100mg/kg (p. f. a.), and 80, 160, 320 and 800mg/kg (p. f. a.) respectively.
There were no deaths in either of the groups.
For general condition, dogs dosed with CVA-K at 100mg/kg showed reddening of the skin and mucous membranes, shaking of the head, facial oedema, a decrease in food intake and a reduction in body weight. Also some dogs of the same group showed decreased spontaneous activity, emaciation and signs of dehydration. In the BRL28500 treatment groups, there was reddening of the skin and mucous membranes, vomiting and salivation at 800mg/kg.
Urinalysis of dogs dosed with CVA-K showed occasional dark yellow coloration of the urine. There was also a very weak and equivocal response or positive reaction for protein, occult blood, and urine sugar in some animals at 100mg/kg. Some dogs dosed with BRL28500 also showed either a very weak and equivocal response or slight positive reaction for occult blood at 320 mg/kg and above, and dark yellow coloration of the urine at 800mg/kg. Haematological examination of the CVA-K groups showed increases in leukocyte count and platelet count at the highest dose of 100mg/kg. No haematological abnormalities were noted in any of the BRL28500 groups. Serum biochemical studies of dogs dosed with CVA-K revealed a decrease in total protein at 50mg/kg and above, and increases in Al-P, total bilirubin, GPT, BUN and creatinine at 100mg/kg. In the BRL28500 treatment groups, there were increases in total cholesterol and triglyceride at 160mg/kg and above.
In dogs dosed with CVA-K there was an increase in liver weight at 100mg/kg. Histopathological examination showed a ground glass-like appearance of the hepatocyte cytoplasm and also altered distribution of PAS positive material at 50mg/kg and above. In the BRL28500 groups, there was an increase in liver weight at 320mg/kg and above. There were the same ground glass-like appearance in hepatocytes and altered distribution of PAS positive material at 800mg/kg.
In view of the above results, the maximum non-effect dose levels in the present studies were considered to be 20mg/kg for CVA-K and 80mg/kg for BRL28500.
All the above findings and changes were slight and were reversible either at the end of the dosing period or at the end of the off-dose period.

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Fosfomycin (FOM)(50mg/kg) was administered to burned patients by intravenous bolus injection. Burn blister fluid and serum were taken during 8 hours after injection, and concentrations of FOM in burn blister fluid and serum were determined by bioassay using Proteus sp.(MB-838) as the test organism.
The serum concentrations of FOM were 257±34.6μg/ml at 15 minutes, 222±34.8μg/ml at 30 minutes, 166±34.6μg/ml at 1 hour, 114±43.9μg/ml at 2 hours, 79.5±34.9μg/ml at 3 hours, 63±36.4μg/ml at 4 hours, 44.3±27.6μg/ml at 5 hours, 29.6±20.9μg/ml at 6 hours and 17.9±12.8μg/ml at 8 hours after the injection.
FOM concentrations in burn blister fluid were 64.4±18.1μg/ml at 30 minutes, 77±26.0μg/ml at 1 hour, 71.6±24.7μg/ml at 2 hours, 64.8±23.6μg/ml at 3 hours, 43.2±8.8μg/ml at 4 hours, 24.8±7.9μg/ml at 6 hours and 17.9±10.5μg/ml at 8 hours after the injection.
The obtained data were analysed pharmacokinetically. The serum levels were analysed by a two-compartment model, and the transfer of FOM into burn blister was analysed by a modified deconvolution method. In results,Tmax and Cmax of FOM levels in burn blister fluid were calculated as 1.3 hours and 80.9μg/ml, respectively. The transfer rate constant of FOM from serum to burn blister fluid (K1) and that from burn blister fluid to serum (K2) were calculated as 0.612hr^-1 and 1.10hr^-1, respectively.

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Cefmenoxime (CMX, Bestcall®) was administered by drip infusion to 65 patients with various respiratory infections and its effect was evaluated. The rate of effectiveness was 86.2% in all cases including 40 cases of acute pneumonia and 12 cases of chronic bronchitis.
CMX was examined comparatively with other drugs for antibacterial activity on clinically isolated strains of 2 bacterial species, i. e. H. influenzae and B. catarrhalis, each of which has a high frequency of clinical isolation from infected respiratory organs. On H. influenzae CMX exerted the strongest antibacterial activity among test drugs (ampicillin, piperacillin cefoperazone, latamoxef) regardless of the production of beta-lactamase by the organism, while on B. catarrhalis it also exerted an antibacterial activity strong enough to control the proliferation of all strains at a dose level of 0.39μg/ml.
Drip infusion of this drug (2 gram) brought about an average maximum blood concentration of 127.2±21.5μg/ml and an average half-life in blood of 1.10±0.28 hours. However, different values were obtained for different individual cases because these subjects were patients of chronic respiratory infections each having some underlying disease or other.
Side effects of the drug were observed as allergic symptoms such as pyrexia, eruption and the like, but only 5 cases without any serious cases. Increases in transaminase suggestive of abnormal clinical test results were also observed in 5 cases. However, numerical recoveries to the normal values were obtained in all of these 5 cases with the withdrawal of the drug.

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The effect of cefmenoxime (CMX) was evaluated in the abdominal surgery at 18 hospitals on the prevention and the treatment of postoperative infections. The results were summarized as follows.
1. In 179 patients with prophylactic use of 2-4g of CMX a day, no postoperative infection was observed in 94.4%.
2. Using fever index to judge the effect of CMX in prevention of postoperative infections, the value of fever index was higher in the infected group than in the non-infected group. A significant difference was also observed in mean fever index value between the groups given CMX in 2g and 4g daily, being 15.4 degree hours and 1.7 degree hours.
3. The incidence of postoperative infections was higher in cases with intraoperative bleeding of more than 500ml than in cases with less bleeding.
4. Postoperative infection and peritonitis subsided after the administration of 2-4g of CMX/day for more than 8 days in 77.1% of cases.
5. Very few side effects were noted due to CMX.
These results suggest that CMX is safe and effective in the field of abdominal surgery for the prevention of postoperative infections and in the treatment of postoperative infections.

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Since December of 1983, clinical trial was undertaken on the prophylactic use of amikacin sulfate (AMK) and metronidazole (MET) in colonic cancer surgery. Daily dose of AMK 1,600mg and MET 1,000mg was administered orally in 4 divided doses to 17 patients with colonic cancer for 3 days prior to operation. As a result, wound infection was recognized in only one of 17 cases treated (5.9%).
An examination was also performed on bacterial flora in the feces. After the administration of AMK and MET, E.coil and Klebsiella were remarkably decreased, however, E. faecalis and Candida remained unchanged. P. aeruginosa and Bacteroides detected in a few cases were also reduced. These bacteria were restored to the pretreatment level in 1 or 2 weeks after operation.

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T-2588 was used on 55 patients with respiratory tract infections and 44 cases were evaluated; 23 patients with pneumonia, 12 patients with acute bronchitis, 2 patients with chronic bronchitis, 1 patient with diffuse panbronchiolitis and 6 patients with bronchiectasis with infection.
Clinical effects of T-2588 were as follows; excellent in 6 and good in 28 patients. The efficacy rate was 77.3% (34/44). Bacteriological effects of T-2588 were prominent in 8 patients infected with B. catarrhalis, H. influenzae, K. pneumoniae and E. coli, but not in a patient infected with P. putida. The elimination rate was 90.0% (9/10 strains).
As side effects, stomatitis, anorexia, diarrhea·vomiting and pruritus were observed in one patient each. Abnormal laboratory findings were observed in 4 patients with elevated GOT and/or GPT. These side effects and abnormal laboratory findings were not serious.
The usefulness of T-2588 was 68.2% (30/44). Therefore, T-2588 is a useful drug and its effects are promising in clinical management of respiratory tract infections.

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In vitro susceptibilities of bacterial pathogens to β-lactam antibiotics were determined. Bacterial pathogens examined included various isolates from patients of respiratory tract infections at hospitals of KyotoShiga area in 1984. Major organisms isolated from clinical specimens were Pseudomonas spp., Klebsiella spp., Haemophilus spp., Staphylococcus aureus and Streptococcus spp. An increase in the isolation frequency of Pseudomonas spp., a decrease in the isolation frequency of S. aureus, and no change in the isolation frequency of other organisms were observed between the years 1981, 1983 and 1984.
Data from susceptibility tests of clinical isolates confirmed that cefazolin (CEZ), cefamandole and cefotiam (CTM) showed good antibacterial activity against S. aureus and cefmenoxime (CMX) was highly active against Streptococcus spp., but their susceptibilities to CEZ in 1984 were lower than in 1983.Susceptibilities of Klebsiella spp. to CMX, cefbuperazone, latamoxef, CTM, cefoperazone (CPZ) were better than those to other β-lactam antiobiotics tested, but there was a decline in the susceptibility to CEZ, cefmetazole and CTM. Further, CMX, CPZ and LMOX also showed good antibacterial activity against Haemophilus spp. Although gentamicin, cefsulodin, cefpiramide and piperacillin were highly active against Pseudomonas spp., resistant organisms were present for all the β-lactam antibiotics tested.

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Intravenous drip infusion of a new aminoglycoside agent, astromicin (ASTM), was used against various infections in the field of internal medicine, and its clinical efficacy and safety were studied. Clinical effects were evaluated in 105 among 111 patients administered with ASTM. Almost all the patients were given 200mg of ASTM twice a day by intravenous drip infusion for 60 minutes.
1. Among 105 cases, clinical effects of ASTM were excellent in 15, good in 56, fair in 10 and poor in 24. The number of cases who were judged as excellent or good was 71, and the efficacy rate was 67.6%.
Efficacy rates classified by diseases were as follows; 80% (4/5 cases) in sepsis, 55.6% (5/9 cases) in urinary tract infections, and 68.1% (62/91 cases) in respiratory tract infections (RTI). In 91 cases with RTI, clinical effects of ASTM were excellent in 14, good in 48, fair in 9 and poor in 20. The efficacy rates classified by diseases of RTI were 77.3% (34/44 cases) in pulmonary parenchyma infection and 59.6% (28/47 cases) in chronic RTI and others.
2. As subjective and objective side effects, tinnitus and malaise were observed in 5 (4.5%) of 110 patients evaluated for side effects. But, either symptom was mild and disappeared after the end or withdrawal of administration.
Slight elevations of S-GPT, BUN and others were observed in 7 cases (6.4%) as abnormal laboratory test values.
3. Safety and efficacy of intravenous drip infusion of ASTM were confirmed.

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A clinical evaluation of astromicin (ASTM) administered by intravenous drip infusion against infections in the surgical field was made, and the results were summarized as follows.
1. Excellent effect was observed in 19 out of a total of 44 cases, good effect in 19, fair in 1 and poor in 5. The efficacy rate calculated from the 38 cases of “excellent” and “good” was 86%.
2. In stratification by disease, the efficacy rate was 91% in localized peritonitis (31/34 cases) and 63% in diffuse peritonitis (5/8 cases); the overall efficacy rate in peritonitis was 86%.
3. The efficacy rate in 2 cases infected by Gram-positive bacteria was 50%, and that in 16 cases by Gramnegative bacteria was 94%. The disappearance rate of Gram-negative bacteria was 93%, and this drug was especially effective against E. coli.
4. There were no subjective or objective side effects and no abnormal laboratory test values that were related to the administration of ASTM.

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Intravenous drip infusion of a new aminoglycoside agent, astromicin (ASTM), was used for various urological infections, and its clinical efficacy and safety were studied. Each of almost all the patients tested was given 200mg of ASTM twice a day by intravenous drip infusion.
Among 114 cases with complicated urinary tract infections (UTI) evaluated according to the criteria for evaluation of drug efficacy in UTI, clinical response was excellent in 16, moderate in 54 and poor in 44. The efficacy rate was 61.4%.
Among 137 cases who were evaluated for side effects, headache was observed in 1 case (0.7%), which recovered spontaneously the day after the withdrawal of the drug.
Slight elevation in S-GOT, S-GPT, Al-P and others was observed in 12 cases (8.8%) as abnormal labo-ratory test values.

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Our research group was engaged for 3 years (1979-1981) in a study on sensitivities to antibiotics of 4 bacterial groups including representative pathogenic bacteria found in cases of urinary tract infections; i.e. E. coli, Klebsiella spp., Citrobacter spp., and Proteus spp. Since 1982, all the bacterial strains isolated by our group from patients with urinary tract infections and deemed by doctors in charge as pathogens were sent to the Laboratory of Clinical Pathology of Juntendo University, where they were refixed and subjected to MIC determination. This is the third year of the new study. E. coli was detected most frequently from patients with urinary tract infections and the detection frequency was 28% (323/1, 153) this year (1984), whereas it was 35.3% (304/860) last year, showing a 7% decline from last year to this year. E. faecalis was next frequent organism (12.7% or 147/1, 153) followed by P. aeruginosa (10.8% or 124/1, 153). This order, however, was reversed from last year. Other pathogens, in a decreasing order of isolation frequencies following the above three, were as follows: Proteus spp.(9.5% or 109/1, 153), S. marcescens (6.2% or 71/1, 153), S. epidermidis (5.4% or 62/1, 153), K. pneumoniae (4.9% or 56/1, 153), Enterobacter spp.(2.4% or 28/1, 153) and Citrobacter spp.(2.3% or 27/1, 153).
The results of the determination of the sensitivity of bacterial strains to the antibiotics are described below.
1. Of all the oral antibacterial and antibiotic agents used against E. coli, mecillinam (MPC), cefaclor (CCL) and pipemidic acid (PPA) proved to have high antibacterial potency, and their MIC₉₀ (the concentration to inhibit growths of 90% of the objective bacteria) was 3.13μg/ml. The MIC₉₀'s of cefotiam (CTM), cefotaxime (CTX), ceftizoxime (CZX), cefmenoxime (CMX) and latamoxef (LMOX) were less than 0.39μg/ml. The MIC₉₀'s of cefmetazole (CMZ) and cefoperazone (CPZ) were invariably 1.56μg/ml.
2. K. pneumoniae was not sensitive to ampicillin (ABPC) and did not show much sensitivity to other oral antibacterial and antibiotic agents also. Of all the injectable preparations of antibiotics, cephem antibiotics of the third generation showed the most potent antibacterial effects against K. pneumoniae, and their MIC₉₀'s were lower than 0.10μg/ml for CZX, 0.20μg/ml for CTX, 0.39μg/ml for CMX, and 0.78μg/ml for LMOX, while MIC₉₀'s of CPZ was 6.25μg/ml, which was equal to that of CMZ. The MIC90, of CTM was 0.78μg/ml which was identical to that of LMOX.
3. The sensitivity of Citrobacter spp. to the objective antibacterial and antibiotic agents was low, but showed some sensitivity to MPC, nalidixic acid (NA), PPA and sulfamethoxazole-trimethoprim (ST). Of all the injectable antibiotics, LMOX and CMX were the most effective against Citrobacter spp., showing MIC₈₀ of 6.25μg/ml and 12.5μg/ml, respectively.
4. Fairly strong antibacterial activity was shown by MPC to Enterobacter spp. and its MIC₈₀ was 12.5μg/ml. The Enterobacter spp. showed low sensitivity to the injectable preparations of cephem antibiotics of the first and the second generations except for CTM, and the MIC₈₀ was invariably higher than 200μg/ml. The MIC₈₀ of CTM was 6.25μg/ml. The MIC₈₀'s of the cephem antibiotics were 12.5μg/ml for CMX, 25μg/ml for both LMOX and CTX, and 50μg/ml for both CZX and CPZ.
5. P. mirabilis was very sensitive to cephem antibiotics of the third generation. The MIC₉₀'s of CZX, CTX and CMX were lower than 0.10μg/ml, while that of LMOX was 0.20μg/ml.
6. P. vulgaris was less sensitive to cefazolin (CEZ) and CTM than to cefoxitin (CFX) or CMZ.

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Groups of bacteria were isolated from patients with infections of urinary tracts, and backgrounds of these isolates and patients have been studied in terms of the sexual distribution, and distributions of sexes versus age of the patients relationships between bacterial types and sexual and age distribution of the patients from whom the isolates were obtained correlation between ages of patients and types of infections, the association of certain types of bacteria with certain infections and the effect of antibacterial treatments on these types of bacteria, approximately 20% of simple infections of urinary tracts occurred in males and approximately 80% in females on average from 1981 to 1984. This ratio showed hardly any changes during this period. Likewise, male patients comprised approximately 60-70% of all the cases with complicated infections of urinary tracts regardless of indwelling or without indwelling of catheters. In terms of age, the ratio of urinary tract infections was almost universally observed, e.g., for patients in 40's: 10.0% in 1981, 11.0% in 1984, while in those in 70's: 25.5% and 21.2%, respectively. Consequently, background factors of the cases with infections of urinary tracts, such as sexes, age, or simple or complicated, remained almost stable, whereas bacteria involved showed considerable variations.
In 1982 and 1983, the frequency of isolations of Enterococcus spp. was approximately 8% in both males and females. However, in 1984, the frequency of isolation of Enterococcus spp. was 22.5% in the males 17.9% in the females. The frequency of isolation of Enterococcus spp. increased in all age groups, but the frequency was not particularly high among the aged.
A study on variations and isolation frequencies of bacteria before the administration of antibiotic agents revealed that isolation frequencies of Enterococcus spp. sharply increased in 1983, and this high frequency remained in 1984. The frequency of isolation of E. coli tended to decrease year after year. This finding represents that the frequency of isolations of E. coli from materials of cases with simple infections of urinary tracts has decreased, showing that pathogenic bacteria from simple infections of urinary tracts were becoming similar to that of the complicated infections of urinary tracts. These findings seem to be worth mentioning here.
In cases receiving administrations of antibacterial and antibiotic agents for more than 8 days. Frequencies of isolation from cases without catheter retention and from those with catheter retention were similar. Also in these cases, the frequency of isolations of Enterococcus spp. was approximately 34-38%, followed by that of P. aeruginosa and Serratia spp. It was seemed also to be noteworthy that S. aureusm was isolated at a frequency of 4.8% from those with retention of catheter. In 1982, the isolation of S. aureus was 4 strains (4/781), while it was 12 strains (12/724) and 17 strains (17/989) in 1983 and 1984, respectively, showing a steady increase.
Furthermore, E. coli used to be approximately 90% of all the pathogenic bacteria in cases with simple urinary tract infections, but decreased to 50%, showing yearly decrease, and, in its stead, pathogenic bacteria found in complicated infections of urinary tracts increased, and urinary tract infections are becoming more complicated.

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Cases with infections of urinary tracts were divided into 3 groups of the simple infections, and complicated infections without indwelling of catheter, and complicated infections with indwelling of catheter. Susceptibilities to antimicrobial agents of Escherichia coli, Klebsiella spp., Proteus spp., Citrobacter spp., Enterobacter spp., Pseudomonas aeruginosa and Serratia marcescens which were isolated from patients with these infections were determined.
There was no tendency of decline in the susceptibilities of E. coil isolated from the patients with simple urinary tract infections (UT!). Susceptibilities of E. coli isolated from the patients with complicated UTI without and with indwelling of catheter to cephem antibiotics of the third generation were examined. The susceptibility of E. coli strains isolated from patients with complicated UTI without and with indwelling of catheter remained the same. More specifically, cefmenoxime (CMX) at a concentration of less than 0.10μg/ml inhibited the growth of E. coli isolated from cases without: with catheter at 74.1%: 78.3% in 1982, 75.4%: 73.3% in 1983, and 81.3%,: 84.8% in 1984. Also, ceftizoxime (CZX) at a concentration of less than 0.10μg/ml inhibited the growth at 83.3%: 95.7% in 1982, 89.2%: 86.7% in 1983, and 91.7%: 97.0% in 1984. Latamoxef (LMOX) at less than 0.10μg/ml inhibited the growth at 59.3%: 43.5% in 1982, 47.7%: 40.0% in 1983, and 47.9%: 42.4%in 1984.
The antibacterial effect of penicillin against Klebsiella spp. was found to be poor, while those of oral cephem antibiotics, cephalexin (CEX), cefaclor (CCL), and cefazolin (CEZ)which is the cephem antibiotics of the so-called first generation and cefotiam (CTM) among other cephem antibiotics of the so-called second generation were relatively good. A study of susceptibilities of Klebsiella spp. isolated from patients with complicated UTI without and with indwelling of catheter revealed inhibition of growth by CTM at a concentration of 0.39μg/ml at 84.0%: 75.9% in 1982, 70.6%: 75.0% in 1983, and 95.8%: 77.8% in 1984. Cefmetazole (CMZ) at a concentration of 0.39μg/ml showed a relatively lower rate of growth inhibition of Klebsiella spp., while at 0.78μg/ml it inhibited the growth at 88.0%: 72.4% in 1982, 52.9%: 50.0% in 1983, and 70.8%: 66.7% in 1984. The antibacterial effects of both CTM and CMZ against Klebsiella spp. isolated from patients with indwelling of catheter were found to be poor, and some of the bacterial strains showed a MIC over than 100μg/ml.
Likewise, a study of susceptibilities of the cephem antibiotics of the so-called third generation revealed that CMX at a concentration of less than 0.10μg/ml inhibited the growth of Klebsiella spp. from cases without: with catheter at a ratio of 84.6%: 72.4% in 1982, 73.7%: 68.8% in 1983, and 83.3%: 72.2% in 1984. CZX at less than 0.10μg/ml inhibited the growth at 92.3%: 75.9% in 1982, 78.9%: 81.3% in 1983, and 100%: 94.4% in 1984. LMOX at less than 0.103 g/ml inhibited the growth at a ratio of 73.1%: 55.2% in 1982, 63.2%: 25.0% in 1983, 37.5%: 44.4% in 1984, indicating slight decline over the period in the susceptibility in comparison to CZX or CMX.
The antibacterial effects of penicillins, oral cephem antibiotics and cephem antibiotics of the first generation were not appreciable against Proteus spp.
The susceptibilities of Proteus spp. strains isolated from the patients with complicated UTI with indwelling of catheter was found to be low to the cephem antibiotics of the second generation. CMZ at a concentration of 1.56μg/ml inhibited the growth of the strains at a frequency of 70.8%: 58.3% in 1982, 71.4%: 20.0% in 1983, and 73.1%: 45.5% in 1984. CTM at 0.78μg/ml inhibited the growth at a ratio of 45.8%: 29.2% in 1982, 28.6%: 32.0% in 1983, and 84.6%; 38.6% in 1984.

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We studied the antimicrobial susceptibility of E. coli isolated in 1983 and 1984 and also the yearly changes of the susceptibility of E. coli from 1980 to 1984 isolated in 103 hospitals in Japan. Antibiotics used for MIC determination were ampicillin (ABPC) as a penicillin, cefazolin (CEZ) as a cephalosporin, cefmetazole (CMZ) as a cephamycin and gentamicin (GM) as an aminoglycoside. Numbers of isolates tested were 2,321 strains in 1983 and 1,965 strains in 1984.
CMZ was the most effective agent among the 4 antibiotics tested, followed by GM and CEZ in this order. A large number of the isolates were inhibited by 1.56 μg/ml on CMZ and GM and by 6.25μg/ml of CEZ. About two-thirds of the isolates were inhibited at a concentration of 12.5μg/ml or less of ABPC. The susceptibility of E. coli against the 4 antibiotics changed little year by year and the tendency of the appearance of resistant strains did not increase in the last 5 years.

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We have reported the antimicrobial susceptibility of clinical isolates of Escherichia coli in 1983 and 1984 to 4 antibiotics, ampicillin (ABPC), cefazolin (CEZ), cefmetazole (CMZ) and gentamicin (GM), in the previous report. In this paper, we described the antimicrobial susceptibility of Klebsiella sp. to the same antibiotics during the same period reported for E. colt before. Numbers of isolates tested were 1,671 strains in 1983 and 1,374 strains in 1984. We determined MICs of the 4 antibiotics against isolates by the standard method of the Japan Society of Chemotherapy.
The most effective agent was GM among the 4 antibiotics. CMZ had a similar antimicrobial activity to GM. Resistance rates were low for both agents. CEZ had a fairly good antimicrobial activity, but it was less active than GM and CMZ. ABPC was not effective. There was neither significant annual change of antimicrobial activity of each agent against isolates nor an increasing tendency of resistant strains in the last 5 years. Depending on isolates from clinical materials, differences in the susceptibility were noted and there was a high ratio of resistant organisms among isolates from urine.

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