We studied the activity of 17 antimicrobial agents against 552 strains of Bacteroides fragilis, Porphyromonas asaccharolytica, Fusobacterium spp., Veillonella parvula and others, isolated from clinical specimens sent from countrywide medical facilities during the 5 years from April 1983 through March 1988. B. fragilis, 349 strains of which were isolated from the specimens, was the most frequently isolated anaerobic organism. B. fragilis proved most susceptible to metronidazole, chloramphenicol, and minocycline. Other B. fragilis group organisms were less susceptible to cefoxitin, cefmetazole, cefotetan, and latamoxef, and their susceptibilities were different from that of B. fragilis itself. Although resistance rates of B. fragilis to cefotiam, ampicillin, and tetracycline were higher at their breakpoints, those to chloramphenicol and minocycline were lower. No strains of B. fragilis resistant to metronidazole were isolated. Black pigmented and other Bacteroides spp.(excepting the B. fragilis group and Black pigmented spp.), P. asaccharolytica, Fusobacterium spp., and V. parvula were susceptible to most of the antimicrobial agents. However, a number of isolates of Fusobacterium varium, V. parvula, and P. asaccharolytica were resistant to erythromycin. Annual tests of susceptibility of B. fragilis demonstrated that the MIC₅₀s and MIC₉₀s of most antimicrobial agents were unchanged. The breakpoint resistance rates of B. fragilis to ampicillin, cefazolin, cefoperazone, ceftizoxime, cefoxitin, and cefmetazole demonstrated a steady annual decrease. Clindamycin, conversely, proved less active to recent isolates of B. fragilis than to older isolates.

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Multiple-infusion dosing strategies for netilmicin were established for 10 patients using the Sawchuk-Zaske method (individually calculated values of elimination kinetic parameters). A test dose of netilmicin was adminstered to each patient by constant-rate infusion, usually over a 60-min period.
Serum was drawn at 1, 3 and 6 hours of the postinfusion phase. All samples were immediately analyzed for netilmicin by a fluorescence polarization immunoassay (FPIA).
The serum level-time data from the postinfusion phase were fitted to a single exponential term using linear regression analysis. Serum level-time data obtained after single infusion were used to determine the patient's netilmicin half-life (mean±SD, 2.54±0.92 h) and distribution volume (mean±SD, 15.62±2.72 h). The mean total body clearance was 5.04±1.97l/h and the mean maximum serum level was 7.46±1.00 μg/ml. The trough level was O.40±0.22 μg/ml. Dosing intervals and the infusion rate were calculated based on each patient's kinetic parameters and the desired steadystate peaks and troughs predicted using a one-compartment pharmacokinetic model. The follow-up steady-state peak and trough levels were similarly measured. All peaks and troughs were within the therapeutic range. No patients suffered side effects.
The mean error (ME), mean absolute error (MAE) and root mean squared error (RMSE) served as measures of accuracy and precision. The ME, MAE and RMSE of peaks and troughs were-0.010, 0.180, 0.253 μg/ml, respectively. The Sawchuk-Zaske method proved to be simple and accurate in calculating routine netilmicin dosage adjustments.

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The efficacy of gamma-globulin preparation given as supportive therapy was examined in 4 patients with refractory pneumonia and 8 with chronic respiratory infection.
1. Clinically, body temperature fell to normal in 6 patients (67%), cough and sputum decreased in 4 patients (57%), leukocytosis improved in 3 patients (60%) and the erythrocyte sedimentation rate and C-reactive protein fell to within normal level in 7 patients (58%). Bacteriologically, 11 strains were clinically isolated and 5 of these were eradicated. The overall efficacy rate was 58%.
2. The level of serum IgG rose significantly (P<0.05) after gamma-globulin administration.
3. The mean concentration of Gamma-Venin in serum, sputum and bronchoalveolar lavage fluid (BALF) was 115, 0.075 and 0.28 mg/dl and the correlation of the concentration in serum and in BALF was inverted.
4. The ratio of Gamma-Venin to albumin and IgG in BALF was 2 to 10 times more than in serum and the patients with pneumonia and bronchiectasis showed good penetration of Gamma-Venin into the inflamed lung.
On the basis of the above results, we conclude that Gamma-Venin supportive therapy in refractoryrespiratory infections is effective due to good penetration into the inflammatory lung.

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We studied the transfer of astromicin (ASTM) to the bronchoalveolar system using bronchoalveolar lavage (BAL), and compared findings with previous results for cefmenoxime (CMX). The relation between inflammation and bronchoalveolar transfer was investigated. The subjects were 16 patients with various respiratory diseases: 7 with lung cancer, 5 with chronic bronchitis, 3 with interstitial pneumonia, and 1 with diffuse panbronchiolitis. BAL was performed 60 minutes after intramuscular injection of 200 mg of ASTM and the ASTM concentration in serum and BAL fluid (BALF), total protein and albumin were measured. The ASTM concentration was measured by high performance liquid chromatography and the following results were obtained.
1) The concentration of ASTM was 6.04-13.79 μg/ml in serum, and 0.02-0.21 μg/ml in BALF.
2) The mean value±standard deviation of ASTM concentration was 8.96±2.49μg/ml in serum, and 0.10±0.06μg/ml in BALF.
3) The transfer of ASTM to BALF was similar to that of CMX in the previous study, and smooth transfer to the bronchoalveolar system was recognized.
4) The ASTM/albumin ratio was higher in BALF than in serum.
5) In a case of idiopathic interstitial pneumonia, the level of ASTM in BALF was about ten times higher in the acute exacerbation phase than in the stable phase.

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A combination therapy of clindamycin (CLDM) with aztreonam (AZT) was used in 138 institutes in Japan from April through October 1988.
The methods and results obtained were as follows:
1. As a rule, patients with moderate to severe infections were given 1, 200 to 2, 400mg/day of CLDM with 2.0 to 4.0 g/day of AZT for 7 to 14 days.
2. Of the 638 cases treated, clinical efficacy was evaluated in 611 cases.
The side effects and abnormal laboratory findings were analysed in the remaining 27 cases and in 224 other cases in which the drugs were used to prevent post-operative infection.
3. Of the 611 cases, 354 were males and 257 females. Three hundred and eleven patients (50.9%) were aged 60 years or over, and 394 (64.5%) had underlying diseases.
4. Regarding the severity of the infections, 534 cases (91.6%) were judged to be moderate or severe.
5. The combination therapy was found to be effective in 74.0% of 277 cases of respiratory infection including an efficacy rate of 74.8% in 210 cases of pneumonia, 55.0% in 80 cases of septicemia and 88.6% in 70 cases of biliary tract infections, with an overall efficacy rate of 77.7% in the total 611 cases of various bacterial infections.
6. Clinical efficacy rates were different in the presence of underlying diseases. The efficacy rate was 71.6% in 394 cases in the group with underlying diseases and 89.6% in 211 cases without underlying disease. This tendency was also observed in the difference of the severityof diseases with statistical significance.
7. The combination therapy proved to be effective in 76.6% of 47 cases in which Gram-positive aerobic cocci and anaerobic bacteria were isolated, and 74.1% of 54 cases in which Gram-negative bacteria were isolated.
8. The efficacy rate in cases with Enterococcus faecalis and Pseudomonas aeruginosa which had relatively high MICs to the drugs were 33.0% and 50.0%, respectively.
9. Side effects occurred in only 13 (1.5%) out of 862 cases, including rash or skin eruption in 8 cases, which was the most frequent symptom.
10. Abnormal laboratory findings were seen in only 2.1%(18 of 862 cases). Elevation of S-GOT and S-GPT were most frequent, but in almost all cases these abnormalities returned to normal after discontinuation of the drugs.
In conclusion, combination therapy of CLDM with AZT is safe and effective in various kinds of bacterial infections.

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Eight patients with NSCLC and three with metastatic colon cancer of the lung were entered into a phase I study of 5-FU plus high-dose LV. The starting dose of 5-FU was 600 mg/m²/week, which was increased to 800mg/m²/week. The administration schedule was a 2-hour infusion of LV (500 mg/m²) and an IV bolus of 5-FU (600 or 800mg/m²), given 1 hour after the beginning of LV infusion. This regimen was repeated 5-6 times weekly. Five patients received 600 mg/m² of 5-FU with no doselimiting toxicity. Six patients subsequently received 800 mg/m² of 5-FU. One patient with NSCLC who was resistant to CDDP achieved a PR at 800 mg/m² of 5-FU plus high-dose LV. At 800 mg/m² of 5-FU, severe diarrhea (2/6), myelosuppression (2/6), mucositis (2/6), and dermatitis (1/6) were observed. This dose of 5-FU plus high-dose LV was considered intolerable. Based on this study the recommended dose of 5-FU with high-dose LV for a phase II study was 600 mg/m²/week.

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We studied the influence of cefpimizole (CPIZ) or latamoxef (LMOX) treatment on human neutrophil functions in healthy volunteers and cancer patients.
In healthy volunteers, the bactericidal activity of neutrophils against Escherichia coli was enhanced at 2 h and 7 h after CPIZ injection. This tendency was more marked in the senior group (50-60 years old) than the younger group 20-30 years old). Chemiluminescence (CL) and NBT reduction of neutrophils were also examined at 2 h after CPIZ injection in the senior group, and enhancement of both was observed.
In cancer patients, CPIZ or LMOX was given during and after operation for 6-10 days. Enhancement of CL and of bactericidal activity was observed during CPIZ-treatment, whereas these decreased during LMOX-treatment. Chemiluminescence correlated highly with bactericidal activity, with a coefficient of 0.78. No marked changes were observed in the phagocytic and chemotactic activities of neutrophils during CPIZ or LMOX treatment, except for transient elevation in LMOX-treated patients.
We conclude that CPIZ enhances neutrophil functions, especially killing activity, during treatment.

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The safety and efficacy of cefotetan (CTT) were compared to those of latamoxef (LMOX) for prophylaxis in patients undergoing elective colorectal surgery. Eighty-eight patients were randomised to receive either CTT or LMOX. An initial dose of 2 g i. v. was given in the operating room at the bigining of surgery, followed by 1 g i. v. 8-hourly for 4 days. Forty-three cases (including 3 subsequently withdrawn) were given CTT and 45 cases LMOX. The groups were comparable in age, sex, type of intervention and diagnosis. Eight patients (20.2%) in the CTT group and 8 (17.8%) in the LMOX group developed postoperative infections. The rate of postoperative infection was not significantly different. There was one patient with diarrhea and one with eruption in the CTT group, but none with side effects in the LMOX group. In the early postoperative period, abnormal liver function was noted in 30 patients (15 in each group). Postoperative renal dysfunction was observed in 1 patient in the CTT group and 2 in the LMOX group. The rates of side effects and abnormal laboratory findings were also not significantly different between the groups. This study suggests that CTT and LMOX are equally safe and effective prophylactic antibiotics for patients undergoing elective colorectal surgery.

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We investigated the therapeutic efficacy of lenampicillin (LAPC) in the treatment of 112 cases of male gonorrheal urethritis. The following results were obtained.
1) The peak of MICs of LAPC against Neisseria gonorrhoeae was 0.39 μg/ml.
2) The isolation rate of PPNG was 7.1%.
3) The eradication rate of Neisseria gonorrhoeae was 93% with both 3-day and 7-day treatment.
4) The efficacy rate was 91.7% on day 3 and 90.5% on day 7 according to the Japanese UTI Committee's criteria and 78.1% on day 3 and 82.4% on day 7 according to the doctor's evaluation.
5) Eighteen percent of the cases were associated with Chlamydia trachomatis and the efficacy rate in these was the same as in cases without.
6) As to adverse effects, 1 case each of nausea, headache and eruption were observed. Transient elevation of GOT was also observed in one case.

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