We presented a new colorimetric bioassay of aminoglycoside antibiotics, which were represented by netilmicin (NTL) in this study, based on the discoloration of thymolphthalein (TP) in paper (indicator-disc) by carbon dioxide produced by Bacillus subtilis.
To evaluate the amount of the carbon dioxide, the following experiment was carried out.
One milliliter of B. subtilis suspension containing 4.5×10⁷ colony forming units/ml, 1ml of nutrient broth, 0.9ml of 0.1M phosphate buffer (pH 8. 0) and 0.1 ml NTL sample solution were added to an incubation container, which was then placed in a water-bath (37°C) for 3 hours.
The oxygen concentration in the head space of flask was determined using gas-chromatograph. The dose-response curves showed good correlation between amounts of NTL and carbon dioxide produced by B. subtilis. The indicator-disc containing TP and sodium hydroxide was placed into the Reacti-flask and then incubated in the same manner as described above. After incubation, concentration of blue colored TP was determined using a TLC scanner. The discoloration of blue color to white showed the proportionality between NTL concentrations and the degrees of discoloration of TP. The method can accurately measure NTL levels down to 2.5μ g/ml in water using 0.1ml samples, and should be adequate for rapid bioassay.

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Investigations were made on effects of a combination therapy consisting of arbekacin (ABK) and ampicillin (ABPC) against methicillin-resistant Staphylococcus aureus (MRSA). The following conclusions were drawn.
1. A frequency of FIC index to be≤ 50.5 upon a combination therapy consisting of ABK and ABPC against MRSA was 48.7%, hence this therapy showed better antibacterial effects than the other 8 combination therapies consisting of ABK and other antibiotics previously studied.
2. A combination therapy consisting of ABK and ABPC against MRSA was better than any other combination therapy because ABPC had a higher binding affinity with penicillin-binding protein 3 of MRSA, and because a high antibacterial activity of ABPC was maintained during the combination therapy. ABPC did not lose antibacterial activity largely because MRSA dose not produce β-lactamase, or most of MRSA produces little β-lactamase activity.
3. Our data indicate that the success of a combination therapy against MRSA depends upon the effects of the drug under sub MIC concentrations.

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The effects of cefclidin (CFCL), a novel antibacterial agent, on the central nervous system (CNS) were examined in a variety of animal models. The effects of cefazolin (CEZ) were also examined for comparative purposes.
In the animal models used CFCL whilst having some effects at the doses examined, failed to show an overall consistent effect on the CNS.
In contrast CEZ produced changes in the parameters measured which were generally consistent with a proconvulsant ction.

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The penetration of tosufloxacin (TFLX) into the bone and joint tissues of rabbits and its in vitro antibacterial activity were compared with those of lomefloxacin (LFLX) which is a efficacious drug for orthopedic infections.
Serum levels of TFLX at 1, 2, 4 and 6 hours after oral administration (100mg/kg) were 0.41, 0.65, 0.62 and 0.42μg/ml, respectively. Except in synovial fluid and femur, TFLX concentrations in bone and joint tissues were higher than those in serum (0.69-1.92μg/g in bone marrow of sternum, 0.55-1.53μg/g in bone marrow of femur). TFLX concentrations in synovial fluid at 4 and 6 hours after the administration were equal to those in serum, which were lower than those of LFLX, but the ratio of tissue level/serum level of TFLX was similar to that of LFLX.
TFLX was 8-to 64-fold more active than LFLX against Staphylococcus aureus (including methicillin-resistant S. aureus), Streptococcus pyogenes, Haemophilus influenzae, which are major pathogens of purulent osteomyelitis and arthritis. TFLX inhibited the growth of these bacteria at less than 0.39μg/ml.
These results indicate that TFLX is a useful drug for orthopedic infection.

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We studied the penetration of cefuzonam (CZON) into the cerebrospinal fluid (CSF) in 20 patients with neurosurgical diseases. Influences of the presence of meningeal reaction and the intensity of brain damage on CSF penetration of CZON were also examined. Concentrations of CZON in serum and CSF were determined using the thin-layer cup method before and 1, 2, 4, and 6 hours after 2g of CZON was administered intravenously. The serum concentration at 1 hour was 60.4±31.3 (mean±S. D.) μg/ml, then rapidly decreased to 2.1±2.3μg/ml at 6 hours. In contrast, the CSF concentration gradually increased, reached a peak level of 0.319±0.313μg/ml at 4 hours and then slowly decreaced to 0.273-10.249 μg/ml at 6 hours. The CSF penetration ration: CZON ( [CSF]/[serum] ) was 5.6% at 4 hours. The peak CSF concentration in patients with meningeal reaction (0.465±0.364μg/ml at 2 hours) was about 2-fold higher than that in those without the reaction (0.249±0.223μg/ml at 4 hours). The peak CSF concentrations in patients with slight, moderate, and severe brain damage were 0.231±0.133μg/ml at 4 hours, 0.270±0.232μg/ml at 4 hours, and 0.680±0.467μg/ml at 2 hours, respectively. CSF penetration of CZON was augmented in patients with meningeal reaction or severe brain damage. These findings indicate that the concentration of CZON in CSF after intravenous administration is sufficient for treatment of meningitis or infections after neurosurgical operations caused by such bacteria as Escherichia coli., Klebsiella pneumoniae, Haemophilus influenzae, and Streptococcus pneumoniae.

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A comparative clinical study of lomefloxacin hydrochloride (LFLX) was performed to confirm the optimal dose of LFLX for treatment of respiratory tract infections. Daily dosages of LFLX, 400 mg (200 mg b.i.d.) and 600 mg (200 mg t.i.d.) were allocated by the randomization method. Treatment period was 7-14 days. Of a total of 136 cases, 14 cases were excluded from evaluation of clinical efficacy and 4 cases from evaluation of safety. There were no differences in the background factors of the patients between the 2 dosage groups. The clinical efficacy rates, judged by a committee, were 76.4% (42/55) for the 400 mg group and 74.6% (50/67) for the 600 mg group. No significant difference was observed between the 2 groups (P 1.000). Incidences of adverse effects were 1.6% (1/64) for the 400 mg group and 2.9% (2/68) for the 600 mg group. Incidences of abnormal laboratory test values were 3.4% (2/58) for the 400 mg group and 1.6% 1.6% (1/63) for the 600 mg group. No significant differences were found between the 2 groups. These adverse effects and abnormal laboratory test values improved with the cessation of the administration of the drug. From these results, a dose of 400 mg (200 mg b.i.d.) LFLX seems to be better than that of 600 mg (200 mg t.i.d.) LFLX in the treatment of respiratory tract infections.

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Cefpodoxime (CPDX-PR) was evaluated clinically in respiratory tract infections. The results obtained are summarized as follows;
1. The total number of the patients who were treated with CPDX-PR was 61, out of whom 53 cases were evaluated for clinical efficacy and 55 cases were investigated for the safety of the drug. CPDX-PR was given orally twice a day at 100-200 mg for 5-21 days.
2. Clinical efficacies were exellent in 9 patients, good in 36, fair in 4 and poor in 4. The overall clinical efficacy was 84.9%. In paticular, CPDX-PR showed satisfactory efficacy for acute respiratory infections and mild chronic respiratory infections, with efficacy rates of 88.6% (31/35) and 100% (8/8), respectively.
3. No adverse reactions was observed, but slight and transient elevation of BUN was noted. In conclusion, it has been confirmed that CPDX-PR is an exellent and safe drug for the treatment of the respiratory tract infections.

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Forty patients with chronic respiratory infections were randomly assigned to 2 groups to compare the effect of once daily administration of 300mg each and 3 times daily administration of 600mg each of ofloxacin (OFLX).
Twenty patients were administered with 300mg OFLX a day and 18 cases received 600mg. The number of underlying diseases in the 300mg group was greater than that in the 600mg group. The ratios of general amelioration of clinical symptoms were 80.0% in the 300mg group and 88.9% in the 600mg group. For bacteriological effects, the eradication rate was 80.0% in the 300mg group and it was 84.6% in the 600mg. The incidence of side effects in the 300 mg group was 0% and that of the 600mg group was 5.6% (1 patient) but the symptom was mild. The incidence of abnormal laboratory test results was 15.0% in the 300mg group and it was 11.2% in the 600mg group, but all of these abnormalities were slight and trasient. The safety rates in the 300mg and the 600mg groups were 95.0% and 94.4%, respectively. Efficacy rates in the 300mg and the 600 mg groups were 80.0% and 88.9%, respectively. There was no statistically significant difference in all the results between the 2 treatment groups, and the both treatments were highly effective.
From the above results, we consider that once daily administration of 300mg is a useful therapy in respiratory tract infections.

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Pharmacokinetic and clinical studies on DQ-2556, a new cephem antibiotic, in obstetrics and gynecology were performed and following results were obtained.
Concentrations of DQ-2556 were determined in serum, internal genital organs and retroperitoneal exudate after single intravenous administration (i. v.) or drip infusion (d. i. v.) of 1.0g. Serum levels following i. v. were approximately 30μg/ml at 1 hour, 14μg/ml at 3 hours 30 minutes, and concentrations in internal genital organs including oviduct, ovary, endometrium, myometrium, cervix uteri and portio vaginalis reached approximately 50% to 70% levels of serum concentration. The mean concentration (n=6) in the retroperitoneal exudate after d. i. v. of 1.0g following radical hysterectomy were about 20μg/ml, 23μg/ml, 14μg/ml and 8μg/ml at 1 hour, 2 hours 30 minutes, 4 hours 30 minutes and 6 hours 30 minutes, respectively.
In clinical trials, DQ-2556 (2.0g b. i. d. for daily dose) was given in 5 patients with gynecological infections such as pyometra (1 case), salpingitis (1), retroperitoneal space infection (2), pelvic peritonitis (1). The clinical results were evaluated as good in 3 cases and poor in 2 cases including a case with salpingitis infected by Pseudomonas aeruginosa and the other with pelvic peritonitis caused by Methicillin-resistant Staphylococcus aureus. Bacteriologically, 11 organisms were isolated from patients, and eradication rate was 54.5%. Neither side effect nor abnormal laboratory test result was observed.
Thus, DQ-2556 appears to be effective for gynecological infections, and the good results were supported by good penetration of the compound into tissues of internal genital organs and retroperitoneal exudate after i. v. or d. i. v.

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The penetration of tosufloxacin (TFLX) into the bone and joint tissues of rabbits and its in vitro antibacterial activity were compared with those of lomefloxacin (LFLX) which is a efficacious drug for orthopedic infections.
Serum levels of TFLX at 1, 2, 4 and 6 hours after oral administration (100mg/kg) were 0.41, 0.65, 0.62 and 0.42μg/ml, respectively. Except in synovial fluid and femur, TFLX concentrations in bone and joint tissues were higher than those in serum (0.69-1.92μg/g in bone marrow of sternum, 0.55-1.53μg/g in bone marrow of femur). TFLX concentrations in synovial fluid at 4 and 6 hours after the administration were equal to those in serum, which were lower than those of LFLX, but the ratio of tissue level/serum level of TFLX was similar to that of LFLX.
TFLX was 8-to 64-fold more active than LFLX against Staphylococcus aureus (including methicillin-resistant S. aureus), Streptococcus pyogenes, Haemophilus influenzae, which are major pathogens of purulent osteomyelitis and arthritis. TFLX inhibited the growth of these bacteria at less than 0.39μg/ml.
These results indicate that TFLX is a useful drug for orthopedic infection.

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Cefditoren pivoxil (ME1207) in granules, a new oral cephalosporin, was pharmacokinetically and clinically evaluated in the pediatric field and the following results were obtained:
1. Pharmacokinetics
In infants administered single oral doses of 3 mg (potency) /kg and 6mg/kg, the C_max. was 1.54±0.68 and 2.85±1.03μg/ml; Tmax 2.27±1.08 and 2.06±1.16 hours; T 1/2, 2.22±1.95 and 1.68±0.66 hours; and AUC (0-∞), 7.43±3.68 and 11.90±4.51μg·hr/ml, respectively. These values have indicated that the drug has a dose-dependent pharmacokinetic behavior. Urinary concentrations peaked in 2-4 hours after administration. Urinary recovery rates in the first 8 hours were 19.4±6.6% at 3mg/kg and 17.1±5.2% at 6mg/kg.
2. Clinical results
The clinical efficacy of the drug was evaluated in 445 patients with various infections.
Cefditoren pivoxil was administered at daily doses of 9-18mg/kg divided into 3 equal doses to most patients. Daily doses of >7.5-10.5mg/kg were given to 48.8% of the patients.
The overall clinical efficacy rate was 97.3%, and this drug was effective in 97.5% of the 319 patients for whom the causative pathogens were identified and in 96.8% of the 126 patients with infections for whom the causative pathogens were unknown. The efficacy rate at daily doses of >7.5-10.5mg/kg was 97.2%, similar to that obtained at daily doses of >10.5-19.5mg/kg (97.0%).
The bacteriological eradication rate was 90.4%.
The efficacy and eradication rates for 66 patients who had not responded to previous chemotherapy were 95.5% (63/66) and 89.4%, respectively.
Side effects occurred in 19 (4.2%) of 456 patients subjected to safety analyses. The primary side effect was diarrhea but no serious side effects were noted. As abnormal laboratory test results, moderate increases of the eosinophils and platelets counts as well as moderate elevations of thetransaminases were observed. These abnormalities are also seen with other cephems and to a similar extent. No particular and serious problems were associated with administration of this drug.
Based on the above results, cefditoren pivoxil is considered to be very useful at a dose level of 3mg/kg t. i. d. against most infections encountered in the pediatric field.

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