Pseudomonas free specific pathogen free (SPF) mice were orally inoculated with Pseudomonas aeruginosa D-4m strain via drinking a 0.45% NaCl solution containing P.aeruginosa. The animals also received ampicillin (ABPC) to promote indigenous colonization. The Pseudomonas colonized mice, rendered neutropenic by cyclophosphamide injection, developed fatal P.aeruginosa bacteremia. Using this model, a comparison of mortality due to P. aeruginosa endogenous septicemia was made between C3H/HeN (endotoxin-sensitive) and C3H/HeJ (endotoxin-resistant) mice. C3H/HeJ mice were hypersusceptible to P. aeruginosa endogenous septicemia, while C3H/HeN mice were resistant. P. aeruginosa levels in the livers were high enough to cause death in C3H/HeJ mice, while the bacteria were eliminated from the livers of C3H/HeN mice. When both strains of mice were also inoculated with P. aeruginosa intravenously, the 50% lethal doses (LD₅₀) of P. aeruginosa D-4m strain were 10^2.4 and 10^2.8 CFU/mouse in C3H/HeJ and C3H/HeN mice, respectively. The clearance rate of P. aeruginosa from blood was similar in the two groups of mice. These results suggest an important difference between endotoxin-sensitive and -resistant mice in endogenous infection.

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Tazobactam/piperacillin (TAZ/PIPC), an injectable combination antibiotic consisting of tazobactam (TAZ), a new β-lactamase inhibitor, with piperacillin (PIPC), an injectable penicillin antibiotic, in a ratio of 1: 4 (potency) was studied with regard to its effect on the intestinal flora of mice inoculated with four types of bacteria. A comparison was made with the efficacy of PIPC alone. In mice inoculated with four species of bacteria (Escherichia coli, Kitaken M, Enterococcus faecalis, Kitaken M, Bacteroides fragilis GKP 0001, and Bifidobacterium breve YIT 4006) in the intestinal lumen, TAZ/PIPC was administered i. m. at 100 mg/kg once daily for 5 consecutive days. From the day after the beginning of treatment, the cell counts of all species of bacteria examined began to decrease, and from the third day thereafter the cell counts were below detectable limits except for E. faecalis. Comparable results were obtained when PIPC alone at 100mg/kg was administered in a similar manner. At 4 hours after completion of the final dose, the viable cell counts in the contents of various segments of the gastrointestinal tract (stomach, upper, middle and lower intestine, and large intestine) were lower for groups treated with TAZ/PIPC or PIPC than the control group for all segments examined. The PIPC levels in feces from the day after the beginning of treatment, and thereafter in large intestinal contents upon completion of the final dose, were 8.30-75.3 μg/g for the TAZ/PIPC group (excluding one sample in which the PIPC level was below the detectable limit) and 3.62-32.4 μg/g for the PIPC group (excluding one sample in which the PIPC level was below the detectable limit). The PIPC level in gastrointestinal contents was highest in the middle and lower segments of the intestine for both the TAZ/PIPC and the PIPC group. No detectable amount of TAZ was found in feces or in the gastrointestinal contents of each segment, with the exception of 2 samples. The minimum inhibitory concentrations (MIC) of TAZ/PIPC and PIPC were 6.25 μg/ml and 3.13 μg/ml for E.coli kitaken M, 3.13-6.25 μg/ml and 3.13 μg/ml for E. faecalis Kitaken M, 0.78-1.56 μg/ml and 3.13μg/ml for B. fragilis GKP 0001, and 0.78 μg/ml and 0.39 μg/ml for B.breve YIT 4006. Neither the TAZ/PIPC nor the PIPC dosing group showed an increasing effect on the MIC of the 4 species tested.

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The existence of methicillin-resistant Staphylococcus aureus (MRSA) is an important clinical problem. Staphylococcus aureus strains were isolated from 101 patients (19 outpatients and 82 inpatients) during the one-year period from July 1993 to June 1994. The mecA gene and the spa gene of these strains were analyzed by the polymerase chain reaction, and the strains were classified according to susceptibility to antibiotics, coagulase type, and phage type. Five of the 40 MRSA strains isolated produced type-5 protein A, 34 produced type-4 protein A and one produced type-3 protein A. In contrast, 38 of 61 methicillin-susceptible S. aureus (MSSA) strains produced type-5 protein A, 21 produced type-4 protein A, 2 produced type-3 protein A. The rate of expression of type-4 protein A by MRSA was significantly higher than in MSSA (p<0.001, X²=22.92). Coagulase type-H strains were the most common among the 8 serotypes (46 of 101 strains [45.5%]). Thirty coagulase type-II strains were detected among the type-4 protein A producing MRSA, but their phage types varied: 16 were untypable, 3 were type I, 1 was type I and M, 1 types I, II, and HI, 5 type HI, 2 type M and M, 1 types M and V. and 1 type V, suggesting that these strains were not of the same origin. The strains that produced type-4 protein A showed high resistance to other antibiotics. The results of this study indicated that most MRSA strains have type-4 protein A, which is uncommon in MSSA strains.

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Tazobactam/piperacillin (TAZ/PIPC), a new injectable combination antibiotic consisting of tazobactam (TAZ), a new β-lactamase inhibitor, and piperacillin (PIPC), an injectable penicillin, in a ratio of 1: 4 (potency) was studied with regard to its effect on the intestinal flora of pediatric patients. Five children with infections (2 boys and 3 girls; ages: 4 months to 9 years 10 months; body weights 8.14-28.0 kg) were given TAZ/PIPC at 43-53.6 mg/kg 4 times daily for 5-15 days. Before, during and after administration, fecal samples were collected and bacterial contents per gram of feces were assessed and viable cells counted for each bacterial species. At the same time, fecal levels of TAZ and PIPC, β-lactamase activity and contents of Clostridium difficle D-1 antigen were also determined. With regards to changes in fecal bacterial flora during administration of TAZ/PIPC, slight individual differences were seen. A decreasing tendency was seen in Enterobacteriaceae among major aerobes in feces. The cell count of this species of bacteria decreased remarkably, falling below the detectable limit in 3 of 5 cases. The cell count of Enterococcus also fell below the detectable limit in 3 of 5 cases. In the 2 remaining cases, changes in bacteria occurred within the genera of the bacterial species examined. As a result, the total cell count of aerobes decreased remarkably in 1 case and slightly in 1 other case. Among anaerobes in feces, Bifidobacterium, Eubacterium and Bacteroides, which had been prevalent, showed a remarkable decrease in cell count during treatment. In 3 cases, the total cell count of anaerobes decreased remarkably. In all 3 of these cases the patients were infants. An increasing tendency was seen in glucose-nonfermentative gram-negative rods, fungi and Bacillus in 1, 4 and 4 cases, respectively, during treatment. In 2 infants in whom remarkable decreases were seen in Enterobacteriaceae, Enterococcus and the main fecal anaerobes, diarrhea was observed, and Candida became the most predominant organism during treatment. C. difficile and C.difficile D-1 antigen were isolated in 1 and 2 cases, respectively, and no relation was found between changes in these counts and fecal characteristics. In 2 cases, TAZ was detected in feces during administration and the fecal concentration ranged from 27.4 to 41.8μg/g. On the other hand, PIPC was detected in feces during treatment in 3 infants in whom marked changes were seen in the intestinal flora. These cases had fecal concentrations of 34.7 to 238μg/g. Before treatment, β-lactamase activity was positive in 4 cases. In 3 of these cases, conversion to negativity was obtained during treatment. From these results, TAZ/PIPC is considered to have a marked in fluence on the intestinal flora in childeren. Caution should thus be exercised as the development of diarrhea, along with changes in gastrointestinal bacteria, may occus during the use of TAZ/PIPC.

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We investigated the effect of commonly used drugs containing metal cations, e. g., precipitated calcium carbonate, magnesium oxide, and sodium ferrous citrate on the gastrointestinal absorption of tosufloxacin tosilate (TFLX) in healthy adult male volunteers, and also investigated the effect of TFLX on the absorption of sodium ferrous citrate. TFLX 150mg was given orally to non-fastingsubjects with and without 1g of precipitated calcium carbonate, 1g of magnesium oxide or 100mg of iron as sodium ferrous citrate. An analysis of C_max and AUC_0-24h, obtained from blood pharmacokinetic parameters and urinary excretion volume over a 0-24h period (UR_0-24h) showed that concurrent administration of TFLX with precipitated calcium carbonate, magnesium oxide, or sodium ferrous citrate decreased the bioavailability of TFLX. Under these conditions, C_max AUC_0-24h, and UR_0-24h were decreased to 52.6%, 57.6%, and 63.2% respectively, when administered with precipitated calcium carbonate, to 37.4%, 45.8% and 51.2% with magnesium oxide, and to 68.9%, 84.1% and 67.6% with sodium ferrous citrate. No particular decreases in mean C_max or AUC_0-24h values. Were noted at the concentrations of serum iron measured after administration of sodium ferrous citrate alone and after coadministration with TFLX. Therefore, we concluded that TFLX has little influence on sodium ferrous citrate absorption.

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A dose range study on cefoselis (FK 037, CFSL), a parenteral cephalosporin, was conducted in patients with bacterial pneumonia.
1) Patients with bacterial pneumonia were intravenously infused with CFSL at a dose of 0.5g (0.5g group), 1.0g (1.0g group) or 2.0g (2.0g group), twice daily, for 14 days as a rule. Of 92 patients, 79 were evaluated for clinical efficacy and usefulness of this drug, and 90 patients for its safety.
2) The clinical efficacy rates were 84.6%(22/26) in the 0.5 g group, 90.0%(27/30) in the 1.0g group and 91.3%(21/23) in the 2.0 g group.
3) In the bacteriological evaluation, the eradication rates were 90.9%(10/11) in the 0.5g group, 6/7 in the 1.0g group and 8/9 in the 2.0g group.
4) As for adverse reactions, diarrhea was observed in only 1 patient in the 1.0g group.
5) Abnormal changes in laboratory tests were observed in 6 patients (20.0%) in the0.5g group, 11 patients (34.4%) in the 1.0 g group and 5 patients (19.2%) in the 2.0g group. None of the abnormal laboratory findings was serious or associated with clinical symptoms.
6) Clinical usefulness rates were 80.8%(21/26), 86.7%(26/30) and 91.3%(21/23) in the 0.5g, 1.0g and 2.0g groups, respectively.
We considered a twice daily dose of 1.0g of CFSL to be the most appropriate clinical dosage for bacterial pneumonia.
This paper reports clinical results excluding cases violating Good Clinical Practice (GCP) found after publication of our previous paper in “CHEMOTHERAPY” (Vol.42, No.10, 1994).

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We found that long-term clarithromycin (CAM) treatment prologed the survival times of primary inoperable non-small-cell lung cancer patients. In the present study, we examined changes in clinical parameters including serum total protein, albumin, cholinesterase, hemoglobin, lymphocyte counts and body weight during CAM treatment. The study included 54 patients with primary inopelable non-small-cell lung cancer. They received chemotherapy, radiotherapy or both. After discharge, they were allocated randomly into the CAM-group and the non-CAM group on the fi rst visit to the outpatient clinic. The CAM-group consisted of 28 cases (24 males and 4 females), with an age distribution of 41-77 years old (66.0 ± 9.0) and the non-CAM group included 26 cases (22 males and 4 females), with an age distribution of 49-84 (64.0 ± 11.0). There were no significant differences between the two groups in age, sex, clinical stage, tissue type, basic treatment or response rate. Four out of 28 patients in the CAM group died within 6 months of treatment, while 10 out of 26 patients in the non-CAM group expired. In the CAM group, serum total protein, albumin, cholinesterase and hemoglobin were elevated to a significant extent as compared to the non-CAM group. The patients in the CAM group put on weight during treatment. These results indicate that treatment with CAM prolongs survival times and improves quality of life for inoperable non-small cell lung cancer patients.

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