Antitumor activity of peplomycin (PEP) against 7, 12-dimethylbenz (a) anthracene (DM BA)-induced rat mammary tumors was compared with activities of bleomycin (BLM) and doxorubicin (adriamycin, ADM). Drugs were administered subcutaneously 3 times weekly (24 times in total) starting on 75 days after an intravenous administration of DMBA. PEP strongly inhibited the growth of mammary tumors detected at the start of the treatment, and some of the tumors disappeared and regressed upon the administration of PEP. The number of stable tumors was larger and the number of progressed tumors smaller in the PEP-treated group than in the control group. Moreover, PEP exhibited strong growth inhibitory effect with slight delay of tumor appearance against mammary tumors appeared during the treatment period. These antitumor effects of PEP were greater than those of BLM, a parent compound of PEP, and almost comparable to those of ADM.

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Effects of imipenem/cilastatin sodium (IPM/CS), a new parenteral carbapenem combination antibiotic, on the excretion of urinary peptides were investigated by amino acid analysis of these peptides from 12 patients with varying degrees of impairment of renal function, after single or multiple doses (9 doses) of 500 mg/500 mg of the combination drug administered by 30-minute drip infusion.
In a single dose study, slight increase in glycine (Gly) were observed in patients with mildly impaired renal function (group I). On the other hand, several amino acids including aspartic acid (Asp), glutamic acid (Glu), Gly and alanine (Ala) were increased in patients with moderately (group II) and severely (group III) impaired renal function. Gly showed the greatest increase, 1.029μm/mg creatinine. 2 hours, and the value was 2.4 times as high as the control collected before drug administration. These values were reduced to the control levels within 10 12 hours after the drug administration for amino acids showing small increases and within 12-24 hours after drug administration even for those showing greater increases.
In a multiple-dose study employing 3 patients with moderately impaired renal function, Asp and Gly were found to increase after the 1st, 5th and 9th doses. The increased amino acids were reduced to preadministration levels within 10-2 hours or faster, and no tendency for accumulation was observed.
From the above results, CS, as a dehydropeptidase-I inhibitor apparently caused increases in some peptides consisting mainly of Asp, Glu, Gly and Ala in patients with impaired renal function. A careful selection of dose levels and frequency of administration will be required in patients with moderately or severely impaired renal function.

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Norfloxacin (NFLX), a synthetic oral antibacterial agent of quinolone carboxylic acid, was given orally for 5 full days at a dose of 200 mg, three times daily after each meal to healthy normal men with ages between 22 and 25 years weighing 53.0 to 84.0 kg (average 67.0 kg). The actual regimen followed was that the drug was administered twice after lunch and supper on the rst day of dosing, and once after breakfast on the last day of dosing. On the 5th day beforefi the start of dosing, on the first, 3rd and 5th days (last dosing day) of dosing, and on the 3rd, 5th, 10th and 20th days after the end of dosing, effects of the drug on the fecal flora were examined and its fecal levels were determined. Susceptibilities against NflX and nalidixic acid (NA) of various fecal isolates from 7 men were determined. Adverse effects and influences on clinical laboratory tests were also examined. The results obtained are summarized below.
1. Following the drug administration, a transient decrease or disappearance of Escherichia coli, Klebsiella sp., Citrobacter sp. and Enterobacter sp. of Enterobacteriaceae was noted. The 3 strains other than E. coli were isolated from increasing number of cases after the end of dosing. No constant trend was observed in the isolation of Proteus sp. Organisms belong to Enterobacteriaceae were isolated only in 4 and 2 cases after 3 and 5 days of the start of dosing, respectively, but then gradually increased to the predose level. Among other Gram-negative bacteria, no constant trend was noted in the isolation frequency of Plesiomonas sp. Pseudomonas sp. was isolated from 6 and 5 cases on the 3rd day after dosing and on the 3rd day after the end of dosing, respectively; the frequency of isolation increased after dosing. Gram-positive bacteria such as Staphylococcus sp. were isolated with a reduced frequency on the 3rd day of dosing. However, the number of isolates increased in all cases both on the 5th day of dosing and on the 3rd day after the end of dosing, and then decreased. No change was noticed in the number of isolates of Enterococcus sp., and no constant trend was observed for Micrococcus sp. and YLO. The average count of the whole aerobic bacteria did not change. Some strains decreased significantly after the start of dosing.
2. Among anaerobes, Bacteroides fragilis and other Bacteroides were isolated on every test day. Although their average counts did not change, in some cases significant decreases were noted in numbers of both groups of bacteria after the start of the dosing. Average counts of Bifidobacterium were significantly lower than normal in 3 and 5 days after the start of dosing and 3 days after the end of dosing, but no change was noted on other days of testing. In some cases, significantly lower counts were noted for Bifidobacterium. No consistent change was seen in the isolation of Lactobacillus. Lecithinase (?) Clostridium strains except Clostridium difficile were not isolated until 5 days after the end of dosing; they were isolated from 4 and 3 cases at 10 and 20 days after the end of dosing, respectively. Lec.(-I-) Clostridium strains were isolated more frequently at 3 days after the start of dosing and 5 days after the end of dosing than those before dosing. C. difficile was not isolated from any case until 5 days after the start of dosing nor at 10 and 20 days after the end of dosing. They were isolated from 4 and 5 cases on the 3rd and 5th day after the end of dosing, respectively. From the feces of these cases, C. difficile D-1 toxin was detected. From 1 of the 2 cases from which C. difficile was not isolated, D-1 toxin was detected in the feces at 20 days after the end of dosing. C. difficile and its D-1 toxin were detected in the feces of a number of cases, but the significance of their presence is not known, at this time.

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Cefuzonam (CZON, L-105), a cephem type antibiotic, was clinically studied in the field of obstetrics and gynecology. The results are summarized as follows:
CZON 1-2 g was administered by injection twice daily to 11 cases of infections (4 of endometritis, 2 of pyometra, 3 of adnexitis and peritonitis, 1 of abdominal abscess, and 1 of puerperal fever). Clinical efficacy was excellent in 2 cases and good in 9 cases, with a very high overall efficacy rate of 100%. Slight elevations of GOT and GPT in 1 case were noted in clinical laboratory tests. No side effects attributable to the drug were noted.
CZON is considered to be a useful drug for obstetric and gynecological infections.

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Fundamental and clinical studies on cefuzonam (CZON, L-105), a new cephem antibiotic, were carried out.
The results obtained are summarized as follows:
1. Upon drip infusion of 1 g CZON, a good transfer of the drug into female genital organ was observed. The transfer of CZON into exudates of the pelvic dead space was also good.
2. Clinical efficacy of CZON was good in 1 case we tested. No side effect was observed.

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Twenty-six patients who underwent pulmonary resection for the lung disease were administered 1 g of cefmenoxime (CMX) by intravenous drip infusion just before the operation. The CMX levels in the serum, lung tissue and pleural fluid were measured using the agar-well technique. The effect of the drug on the prophylaxis of postoperative infections was investigated. The obtained results are summarized as follows;
1. The peak concentration of CMX in the serum was 58.23μ 1 hour after starting the drip infusion of 1 g of CMX. The serum half-life of CMX (β-phase) was 2.15 hours.
2. The ratio of the CMX concentration in lung tissue to the peak serum level was 14.9% 202 minutes after starting the drip infusion. In the pulmonary lesion, the ratio was 9.72% at the 201 minutes. In the bronchiole, the ratio was 20.7% 191 minutes after starting the drip infusion.
3. The concentration of CMX in the pleural fluid was 2.53 μg/ml 12 hours after starting the drip infusion.
4. CMX is useful as a prophylaxis of postoperative infections after thoracotomy, because no postoperative infectious complications were observed.

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Cefoperazone (CPZ) was used for the treatment of 20 febrile episodes in 18 patients with hematological malignancies and polymyxin B (PL) was applied to the antimicrobial decontamination of the digestive tract in 9 patients with acute leukemia during remission induction therapy.
The clinical evaluation of effectiveness was as follows: Excellent in 9 patients (45%), good in 6 patients (30%) and poor in 5 patients (25%). In neutropenic patients the overall efficacy rate was 70%.
Side effects were recognized in 3 patients. Allergic reactions such as eruption and eosinophilia were seen and transient liver dysfunction was recognized. This study indicates that CPZ is effective for the treatment of infections in patients with hematological malignancies.

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A total of 10 episodes in 7 patients with leukemia or related disorders was treated with oral amphotericin B (AMPH). In 8 episodes AMPH were used prophylactically for severe neutropenia, and in the remaining 2 it was given when the patients were feverish. A daily dose of 2,400 mg of AMPH was given orally once a day and serum concentrations of AMPH were determined serially with bioassay.
Two hours after administration, the mean serum concentration of AMPH rose to 0.15μg/ml, and reached 0.27μg/ml after 24 hours. The concentration was maintained between 0.23μg/ml and 0.39μg/ml through the follwoing 7 days. These concentrations exceed the minimal inhibitory concentrations of most strains of Candida albicans.
In 8 occasions of prophylactic use, no fungal infection was encountered. In a patient with pneumonia, chest X-ray and physical findings improved with administration of oral AMPH.
Side effect of AMPH was seen in 1 patient, which was mild proteinuria and was eased rapidly after the withdrawal of AMPH. Clinical laboratory tests showed 1 case of proteinuria and disorder of kidney but did not clear under influence of AMPH.
These results suggest that oral administration of AMPH is clinically and therapeutically effective and relatively safe for the prophylaxis or the treatment of fungal infection in patients with leukemia or related disorders.

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Since the efficacy and the safety of aspoxicillin (ASPC, TA-058) have been established on adult patients and the need of ASPC use on pediatric patients was anticipated, we performed a 16 center study on the clinical utility of ASPC in pediatric patients.
1. Pharmacokinetics
ASPC was intravenously administered to 45 patients at a dose of 10, 20 or 40 mg/kg by one shot. Serum concentrations of ASPC were dependent of dose levels, and maximum levels of 58.4-230.8μg/ml and half-lives (A) of 1.08-1.16 hours were observed. Urinary recovery rates were 62.7-67.2% in 6 hours. Results obtained upon drip infusions (0.5 1 hour) were similar to one shot injections.
2. Clinical results
(1) Clinical effectiveness Of 318 evaluable patients including 175 boys and 143 girls, 18.2% were nurslings and 61% were young children under 4 years of age. One hundred eighty six patients from whom causative organisms were isolated were classified as A group. Among them were 5 patients suffered with sepsis, but the ASPC treatment eradicated all the bacteria but Salmonella java in 1 case. All of 4 patients with meningitis were cured and all causative organisms (3 cases with Haemophilus influenzae and 1 case with Gram-positive coccus) were eradicated. Cure rates were 90% for 130 patients with respiratory tract infection, 88.6% for 35 with urinary tract infection, 85.7% for 7 with skin soft tissue infection and 89.8% for all the A group patients. Meanwhile, no causative organisms were isolated from 132 patients (B group patients) but cure rate of 91.7% was obtained for this group. No statistical difference was observed between A and B groups. For all the patients (318), the cure rate was 90.6%.
(2) Bacteriological effects
Of 63 Gram-positive bacteria isolated as pathogens, 58 strains were eradicated. Of 117 Gram-negative bacterial, 101 were eradicated. The eradication rate on all 180 strains was 88.3%. Overall, ASPC showed excellent effects against Streptococcus. Among strains of Staphylococcus aureus, 18 of 20 strains were eradicated. Of 59 strains of H. influenzae, 52 were eradicated and 3 decreased. Among strains of Escherichia coli, 25 of 28 strains were eradicated. Of Pseudomonas aeruginosa, 2 strains were decreased and one was unchanged.
(3) ASPC was effective in 93.3% of 30 patients with serious infections and 79.2% of 72 patients with underlying diseases. Cure rates for patients with and without underlying disease were significantly different statistically (x2: P<0.005).
(4) Of 89 patients not cured by treatments with other antibiotics used for more than 3 days, 81 patients were cured with ASPC with the cure rate of 91.0%. Clinical responses were judged excellent for 46 patients and good for 35. All of 8 strains of S. aureus, 3 strains of Streptococcus pneumoniae, 1 Streptococcus pyogenes, 1 13-Streptococcus, 12 of 13 H. influenzae and 5 of 6 E. coli were eradicated in these patients, thus eradication rate was 88.9%.
(5) Side effects and abnormal laboratory values caused by ASPC were not apparent, thus similar to recent β-lactam antibiotics.
Based on our study for dose levels and methods, we suggest a standard dose level of 20 mg/kg/dose 3 to 4 times daily via intravenous injection or drip infusion with the double dose permissible depending on the severity of symptoms.

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It has been more than 4 years since third-generation cephems were introduced into clinical practice. The range of our drug selection definitely tends to increase, because we today have more antibiotics with wider spectrum, antibiotics with strong activities only against Gram-negative strains, such as monobactams, and those with tremendously high activities such as quinolone carboxylic acid derivatives, in comparison to those we had in the past.
Among isolates obtained mainly from sputa of 567 patients with lower respiratory tract infections at 16 institutions throughout Japan between September of 1985 and March of 1986, 741 strains were determined to be causative organisms. MIC's of various antimicrobial agents were determined against 67 strains of Staphylococcus aureus, 100 strains of Streptococcus pneumoniae, 199 strains of Haemophilus influenzae, 92 strains of non-mucoid Pseudomonas aeruginosa, 40 strains of mucoid P. aeruginosa, 29 strains of Klebsiella pneumoniae, 10 strains of Escherichia coli and for 42 strains of Branhamella catarrhalis out of the above 741 strains to determine their drug sensitivities.
As for types of lower respiratory tract infections found in 1981-1983, 57.9-64.5% of the infections were chronic respiratory infections; i.e., chronic bronchitis, chronic bronchiolitis and bronchiectasis. These chronic infections, including diffuse panbronchiolitis (DPB), were found in 63.1% of lower respiratory tract infections in 1984. Their incidence dropped to 54.0% in 1985, even through DPB was included; i.e., the incidence of chronic bronchiolitis was 5.5%, that of DPB was 7.1%, and that of bronchial asthma associated with lower respiratory tract infections in 1985 was 8.8% which was twice as much as that found in 1981-1984.
Although bacterial pneumonia was found in 24.8% of all the cases in 1981, its incidence was reduced to 11.0% in 1983, 15.1% in 1984, and 17.6% in 1985. This reduction seemed to have resulted from gradual decreases in the occurrence of bacterial pneumonia among the young population. As with usual years, a high incidence rate in a total lower respiratory tract infections in 1985 was found among older patients; namely, 73.5% was at the age of 50 or over (417/567).
Next, we determined relationships between clinical isolates and isolates from respiratory infections, including chronic bronchitis, chronic bronchiolitis, bronchiectasis and DPB. H. influenzae was isolated from 50.5% of patients with these infections in 1981; however, the detection rate decreased by about 20% to 29.7% in 1985. P. aeruginosa was consistently isolated, between 24.1% and 30.4% every year. S. aureus and S. pneumoniae were isolated from 15.5% in 1981 and 20.3% in 1985, indicating a tendency toward increases. The detection rate for other Gram-negative bacteia also increased to 14.0% from 0%; Although B. catarrhalis was included in the groups of Gram-negative bacteria in 1981, its single detection was counted to be 5.1% in 1984 and 5.9% in 1985.
These results suggested that clinical isolates were more diversified in species year by year.
The trend was similar in bacterial pneumonia, the detection rate of Gram-positive cocci, including S. aureus and S. pneumoniae, being 32.4%.
The relation of antibiotic treatments to the number of isolates, which were then determined to species was examined. A total of 534 strains, mainly consisting of H. influenzae at 35.4% and S. pneumoniae at 17.4%, were isolated before treatment. The number of isolates decreased to 27 strains within 3 days after the start of treatment due to the presence of strong antibiotic effects, as we expected. However, when the treatment was prolonged to over 15 days, 92 strains were isolated and resistant strains increased in number, because infections might have become chronic. P. aeruginosa was isolated from as high as 51.1% of cases treated for a long period of time, proving the intractable nature of this organism.

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In vitro activities of 7 antimicrobial agents against organisms (474 strains) isolated from patients with various infections in Ehime University Hospital from May to July 1986 were investigated.
Summarized results are as follows:
1. Aztreonam (AZT) showed potent activities against Escherichia coli, Citrobacter sp., Klebsiella pneumoniae, Serratia marcescens, Proteus sp., Pseudomonas aeruginosa and Haemophilus influenzae.
2. Antimicrobial activities of AZT were especially superior against Proteus sp. to the third generation cephem antibiotics.
3. Enterobacter sp. seemed more susceptible to AZT than to cephem antibiotics, but minimum inhibitory concentrations of AZT against many isolates of Enterobacter sp. were in wide ranges.

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