We investigated β-lactamase activity determined by the nitrocefin disc method and acidometry disc method.The object bacteria were isolated from infections in the field of oral surgery.A total of 96 samples collected from patients with obstructive purulent infections in their oral cavities were examined, and 385 strains of bacteria were isolated.The β-lactamase activity was positive in 26 (6.8%) of 385 strains.Twenty-six microbes, including 4 strains of Staphylococcus aureus, 2 of Staphylococcus epidermidis, 1 of Staphylococcus haemolyticus, 5 each of Prevotella oralis and Prevotella intermedia, 2 of Prevotella melaninogenica 1 each of Prevotella loescheii, Bacteroides capillosus, Klebsiella oxytoca and Moraxella osloensis, and 3 of Enterobacter cloacae were recovered from 23 patients (24.0%) with oral infections.The β-lactamase activity of isolates from patients with prior antibiotic chemotherapy was higher than that from those without prior chemotherapy.β-lactamase producing bacteria in the field of oral surgery were highly sensitive to clindamycin and ofloxacin.

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The synergistic activities of a combination of arbekacin (ABK) and imipenem/cilastatin (IPM/CS) against mixed cultures of MRSA and Pseudomonas aeruginosa were examined.The bactericidal effect of ABK against MRSA in the mixed culture was decreased as compared with that in the culture of MRSA alone.A good synergistic effect was observed with the combination of ABK and IPM in the mixed culture. On the other hand, the bactericidal effect of ABK against P. aeruginosa in the mixed culture was similar to that in the cuture of P. aeruginosa alone, and a good synergistic effect was observed with combinations of ABK and IPM in the mixed culture.The bactericidal effect of ABK against MRSA was increased when the inoculum size of P.aeruginosa was dcreased in the mixed culture.Synergistic activity was the greatest under simultaneous treatment with ABK and IPM. Greater synergistic activities were obtained by treatment with ABK precedence as compared with the treatment with IPM precedence.In morphological observations with an electron microscope, the thickening of the cell wall of MRSA and filamentous formation in P. aeruginosa were observed after treatment with ABK alone.On the other hand, with the combination of ABK and IPM, the lysis of cells of MRSA and P. aeruginosa as well as abnormal septum formation in MRSA were observed. Finally, with respect to the protective effects on mixed infection of MRSA and P. aeruginosa, the combination of ABK and IPM/CS was more potent than ABK or IPM/CS alone.

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We evaluated the effects of 7 antibiotics combined with rG-CSF and γ-globulin on methicillin-resistant Staphylococcus aureus (MRSA) in cyclophosphamide-treated mice. Antibiotics were chosen by the MIC, which ranged from 0.78 to 1, 600μg/ml against MRSA. The dose of antibiotics administered to mice was calculated from the MIC of each drugs, and amout of MRSA inoculated in the mice was determined by the criterion that rG-CSF did not affect the survival rate of mice.The results indicated that combined therapy using antibiotics with rG-CSF and γ-globulin in which MIC was less than 200μg/ml enhanced the survival rate of neutropenic mice inocculated with MRSA.

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The antitumor effect of 5-fluorouracil (5-FU) was studied experimentally according to the dosage schedule of the drug.Human stomach cancer (SC-1-NU) serially transplanted subcutaneously to nude mice was used for the experiment.5-FU was administered intraperitoneally, daily (5, 10, 20mg/kg) or intermittently (20mg/kg q 2 d, 30mg/kg q 3 d, 40mg/kg q 4 d, 50mg/kg q 5 d and 70mg/kg q 7 d). The minimal T/C ratios when 5-FU was administered daily for 30 days were 54.2%(5mg/kg), 29.6%(10mg/kg) and 3.46%(20 mg/kg). The antitumor effect of 20mg/kg was significantly better than twice of the effect of 10mg/kg (p<0.01). The minimal T/C ratios when 5-FU was administered intermittently were 17.2%(20mg/kg q 2 d), 17.8%(30mg/kg q 3 d), 14.3%(40mg/kg q 4 d), 19.9%(50 mg/kg q 5 d) and 29.1%(70mg/kg q 7d). Relative mean tumor weights at 40mg/kg q 4 d×15 and 50mg/kg q 5 d×12 were significantly smaller than those at 10mg/kg q 1 d×60 (p<0.01, p<0.05 respectively).Moreover, the antitumor effects of 40mg/kg q 4 d×15 weresignificantly stronger than those of other intermittent doses (p<0.05).No toxic death or significant loss of body weight were experienced in any group.It was suggested that 5-FU might be more effective under intermittent administration than daily dosage, and that the dosage interval of the drug was important to obtain the superior effect.

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Cefozopran (CZOP, SCE-2787), a new parenteral cephalosporin antibiotic, was studied for its effect on the intestinal bacterial flora of pediatric patients.The subjects were children admitted for infections (6 males, 4 months to 3 years 2 months old, weight 5.6 to 19.0 kg). CZOP was intravenously administered at a dose from 19.8 to 52.6 mg/kg, 3 to 4 times daily.The feces from these children were collected before, during and after administration, and bacteria were identified and counted.The CZOP concentration, β-lactamase activity and Clostridium difficile D-1 antigen were also assayed, and the MICs of various isolated bacteria were mesured. Changes of bacterial flora in feces during CZOP administration showed some variation. Among aerobic bacteria, 5 of the 6 cases showed a decrease in Enterobacteriaceae, but no significant change was observed in Enterococcus, and as a result, the total count of aerobic bacteria did not show a large change.Regarding anaerobic bacteria, no significant change was observed in Bifidobacterium or Bacteroides, and the total count of anaerobic bacteria did not show a large change.In no case, were glucose non-fermentative Gram-negative bacilli or fungi dominant.Although C.difficile and C.difficile D-1 antigen were detected in 2 and all cases, respectively, there was no clear relationship between the number of C.difficile and the characteristics of the feces.CZOP was detected in fecal samples from 4 cases during and after administration at concentrations ranging from 1.4 to 29.6 μg/g. Drug sensitivities of the bacteria isolated from feces did not change before, during and after the administration of CZOP.The above results suggest that CZOP is a drug with an extremely small influence on the intestinal bacterial flora of children among the new parenteral cephalosporin antibiotics.

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The clinical efficacy and safety of FK 037, a new parenteral cephem antibiotic, in patients with urinary tract infections (UTI) were preliminarily evaluated.The subjects consisted of inpatients, aged 15 to 79 years, with complicated UTI, underlying urinary tract diseases and no indwelling catheter.The drug was intravenously infused at doses of 0.5, 1.0 and 2.0 g (potency), twice daily (in the morning and evening), for 5 to 9 days.Clinical efficacy was evaluated using the criteria proposed by the Japanese UTI Committee.Of 32 patients who met the inclusion criteria, the overall clinical efficacy of FK 037 was “excellent” in 15 patients, “moderate”in 15 and “poor” in 2, an efficacy rate of 93.8%.Only 1 patient showed a clinical adverse reaction (rash), and only 1 patient showed a laboratory adverse reaction (mild increase in GPT).These results showed that FK 037 provided a good clinical effect, reflecting its activity against a wide range of gram-positive and gram-negative organisms, and that the drug might present no significant problems concerning safety.This drug, therefore, could be useful for the treatment of UTI.

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To find the optimal dose of FK 037, a novel parenteral cephem antibiotic, in the treatment of complicated urinary tract infections, we performed a prospective randomized trial.The subjects consisted of inpatients, aged 16 to 79 years, with complicated urinary tract infections underlying urinary tract disease, and no-indwelling catheter.FK 037 was intravenously infused at doses of 0.25 g (L group), 0.5g (M group) or 1.0 g (H group) twice daily for 5 days.The overall clinical efficacy was evaluated on the basis of the criteria proposed by the Japanese UTI Committee.The overall clinical efficacy was 85.0% of 20 patients in the L group, 88.5% of 26 patients in the M group and 95.0% of 20 patients in the H group.The differences were not statistically significant.The bacteriological eradication rate was 97.0% of 33 strains in the L group, 93.0% of 43 strains in the M group and 97.1% of 35 strains in the H group, with no statistically significant differences.The effect on pyuria on day 1 in the H group was significantly better than that in the M group (p<0.01).Clinical adverse reactions were not observed.Laboratory adverse reactions were experienced in 4 of 28 patients (eosinophilia: 1, abnormal liver function values: 3) in the L group, 2 of 31 patients (abnormal liver function values: 2) in the M group and none of 28 patients in the H group, showing no statistically significant differences.Thus, there was no safety problem and we observed dose related clinical efficacy, although there were no statistically significant differences.We concluded that the optimal dose of FK 037 is 1.0 g twice daily in the treatment of complicated urinary tract infections.

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We evaluated the clinical efficacy of ceftriaxone (CTRX) once daily in community-acquired pneumonia in a multicenter comparative study of two CTRX dosage methods: 2 g once daily (group A) and 1 g twice daily (group B).The 39 patients in group A, had a mean age of 55.1 years, and included 6 mild cases, 31 moderate cases and 2severe cases.The organism was identified in 23 cases (59.0%).The principal organisms were Haemophilus influenzae 13 cases and Streptococcus pneumoniae 7 cases.The 33 patients in group B had a mean age of 60.8 years, and included 5 mild cases, 26 moderate cases and 2 severe cases.The causative organism was identified in 13 cases (39.4%).The principal organisms were S.pneumoniae 7 cases and H.influenzae 3 cases.The clinical efficacy rate of CTRX was 87.2% in group A and 84.8% in group B.Among the patients above 60 years of age, mean age and principal organisms were much the same in both groups, and the clinical efficacy rate was 82.3% in group A and 80.0% in group B.We consider a dose of CTRX, 2 g once daily, to be highly effective in community-acquired pneumonia.

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The intracellular β-lactamase activity of Enterobacter cloacae H-27 which produces an inducible β-lactamase was determined after exposure to 1, 10 and 100 μ/g of 56 β-lactam agents per ml for 2 h.Methicillin, mezlocillin, piperacillin, piperacillin/tazobactam, cephalexin, cefroxadin, cefadroxil, aztreonam, carumonam, sulbactam, and tazobactam induced hardly any intracellular β-lactamase production at the concentrations tested.Most of the other β-lactams increased the β-lactamase activity in a dose-dependent manner.Ceftriaxone, cefoxitin, cefmetazole, cefotetan, cefbuperazone, cefminox, latamoxef, flomoxef and imipenem showed high inducer activity for β-lactamase production even at low drug concentrations. Distinct differences in β-lactamase inducer activity were observed.

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