[in Japanese]

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Activities of antimicrobial agents were examined against Staphylococcus aureus strains isolated in 1990. Strains resistant to benzylpenicillin were isolated at the highest frequency (93.6%), and followed by those resistant to kanamycin (51.5%), erythromycin (49.0%), gentamicin (45.1%), fluoroquinolone (33.4%) and minocycline (12.3%). Most of these drug resistant strains of S. aureus were also resistant to methicillin. It should be noted that the MRSA strains were also resistant to other multiple drugs.
Annual changes of MRSA in clinical isolates have been increasing since 1981. The isolation frequencies of MRSA strains were 18.9%, 44.8% in 1981 and 1990, respectively. Among methicillin susceptible S. aureus (MSSA), however, drug resistance to other antibiotics have been decreasing year by year.
Many strains among both MRSA (73%) and MSSA (86%) were sensitive to typing phages of 100×RTD. 76% of the MRSA strains were phage typed into groups III or mixed, and 60% of the MSSA strains were typed into these two groups, also.

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Antimicrobial activity of cefuroxime axetil (CXM-AX) was compared with those of other cephem antibiotics against clinically isolated strains obtained mainly from outpatients of our center in a period from January to September of 1990 and 1993. Minimum inhibitory concentrations were determined and the following results were obtained.
1. The results suggested that, compared with reports of studies conducted with clinical isolates in early 1980's, MIC of CXM were equal to or lower against Staphylococcus spp., Streptococcus pyogenes, Escherichia coli, Klebsiella spp., Proteus mirabilis, Haemophilus influenzae, Moraxella subgenus Branhamella catarrhalis, Neisseria gonorrhoeae, Peptostreptococcus spp., and Propionibacterium acnes, except for Streptococcus pneumoniae, MIC₈₀ which was slightly higher.
2. MIC₉₀ of comparator drugs reflected those of new resistant organisms recently appeared, such as benzylpenicillin (PCG)-insensitive S. pneumoniae (PISP), cephem-resistant E. coli and Klebsiella spp., new quinolone-resistant H. influenzae and N. gonorrhoeae. Methicillin-resistant Staphylococcus aureus (MRSA) was detected also from specimens of community acquired infections. From the nature of MRSA detected in those situations MRSA appeared to present a continuing problem.
3. MIC₉₀ against strains obtained from patients with community acquired infections was a good index of increases of multidrug-resistant organisms in the past. Therefore, the determination of MIC₉₀ is important in examining changes with time of sensitivities or resistances of clinically isolated strains to antimicrobial drugs.
4. Antimicrobial activities of CXM against recent clinical isolates showed the existence of problems as mentioned above. However, MIC of CXM as well as those of comparator drugs indicated that antimicrobial activities of CXM against Staphylococcus spp., Streptococcus spp., H. influenzae appeared to be relatively strong, and it is concluded that cefuroxime axetil still is one of the clinically useful oral antimicrobial drugs in the 1990's.

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SY5555, a new oral penem, was pharmacokinetically and clinically evaluated in the pediatric field and the following results were obtained:
1. Pharmacokinetics
Pharmacokinetics of SY5555 dry syrup (powder which is dissolved before use) was investigated in 64 children. At a dose level of 3mg (potency)/kg, CmaX, and T1/2 were 0.33μg/ml and 0.95 hours (n=1), espectively, in the non-fasting state. At a dose level of 5mg/kg Cmax and T1/2 were 2.09±1.25μg/ml and 1.20±1.07 hours, respectively, in the fasting state, and were 1.21±0.70μg/ml and 1.33±0.90 hours, respectively, in the non-fasting state. At a dose level of 10mg/kg, Cmax and T1/2 were 2.96±1.89μg/ml and 0.89±0.43 hours, respectively, in the fasting state, and were 2.45±1.37μg/ml and 1.17±0.53 hours, respectively, in the non-fasting state. At a dose level of 15mg/kg, Cmax and T1/2 were 4.30±2.15μg/ml and 0.82±0.09 hours, respectively, in the non-fasting state. Data of Cmax and AUC showed that plasma concentration of the drug depended on dose levels.
Urinary recovery rates in the first 6 hours were 1.71%(n=1) in the non-fasting state at a dose level of 3mg/kg, 4.13±1.40% in the fasting state and 4.17±3.29% in the fasting and the non-fasting state, respectively at a dose level of 5mg/kg, and 6.02%(n=1) and 4.64±2.81%, respectively, at a dose level of 10mg/kg. At a dose level of 15mg/kg, urinary recovery rate in the first 6 hours was 7.97%(n=2) in the non-fasting state.
2. Clinical results
1) Dry syrup
The clinical efficacy of the SY5555 dry syrup was evaluated in 506 cases. SY5555 was administered at daily doses of 15-30mg/kg divided into 3 equal doses to most patients. Daily doses of 12-<18mg/kg were given to 46.6% of the patients.
The overall clinical efficacy rate was 92.9%, and this drug was effective in 93.0% of the 301 patients for whom the causative pathogens were identified, and in 92.7% of the 205 patients with infections for whom the causative pathogens were unknown. The efficacy rate at daily doses of 12-<18mg/kg was 94.5% similar to those obtained at daily doses of 18-< 27mg/kg (91.7%) or 27-<33mg/kg (91.3%).
The bacteriological eradication rate was 82.3%.
The efficacy and eradication rates for 62 patients who had not responded to previous chemotherapy of more than three days were 90.3%(56/62) and 72.4%, respectively.
Side effects occurred in 36 (6.4%) of 566 patients subjected to safety analyses. The primary side effect was diarrhea but no serious side effects were noted. As abnormal laboratory test results, increases of the eosinophils, elevation of GOT or GPT, and others were observed. These abnormalities are also observed with cephems and to a similar extent. No particular and serious problems were associated with administration of this drug.
2) Tablets
Clinical efficacy of SY5555 200mg (potency) tablets was evaluated in 8 cases, and good to excellent clinical responses were obtained in 7 cases. Bacteriological efficacy was good, and all of the 3 identified causative organisms were eradicated.
Neither side effects nor abnormal laboratory test results were observed.
3. Conclusion
Based on the above results, SY5555 in dry syrup or tablets is considered to be useful at the standard dose of 5mg/kg t. i. d. against many infections encountered in the pediatric field. The dosage may be altered according to symptoms (but should not exceed the maximum adult daily dose, 1, 200mg).

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Cefditoren pivoxil (CDTR-PI, ME1207) granules, a new oral cephem, was given to pediatric patients with infectious diseases to evaluate antibacterial activities against clinical isolates, pharmacokinetics, clinical efficacy and safety, and the following results were obtained.
1. In sensitivity test, 30 strains were used comprised of 5 species, isolated from the patients before administered with CDTR-PI. Against Staphylococcus aureus, MICs of 7 agents, cefditoren (CDTR), cefaclor, cefixime, cefteram, cefotiam, cefpodoxime and methicillin, were determined. Against other 4 species, MICs of the above 6 agents excluding methicillin were determined. Among Gram-positive cocci tested, the MICs of CDTR were 0.78 to 100μg/ml or higher against S. aureus (16 strains),≤0.025μg/ml against Streptococcus pyogenes (5 strains), and 0.10 or 0.39μg/ml against Streptococcus pneumoniae (2 strains). These values were equal to or lower than those of conventional cephems and of methicillin. Among Gram-negative rods tested, the MICs of CDTR were R0.025μg/ml against Haemophilus influenzae (3 strains), and 0.10 or 0.20μg/ml against Escherichia coli(4 strains). Also, these values were equal to or lower than those of conventional cephems.
2. When CDTR-PI granules was orally administered in a single dose of 3.0mg/kg to 1 patient and that of 6.0mg/kg to 2 patients 30 minutes after meal, plasma CDTR concentrations reached their maxima 4 hours after administration in the former patient and 1 or 2 hours after administration in the latter 2 patients, and the peak plasma concentrations were 1.91, 3.46 and 4.82μg/ml with half-lives of 1.01, 0.81 and 0.88 hours and AUCs of 8.62, 9.89 and 13.52μg·hr/ml, respectively. Dose-dependency was observed for the peak plasma concentrations and AUCs also tended to depend on dose excepting for the AUC in one 6.0mg/kg patient.
3. The urinary concentrations in the above patients reached their peaks at 4 to 6 hours after administration in one 3.0mg/kg patient and at 4 to 6 hours and 2 to 4 hours after administration in two 6.0mg/kg patients, and the corresponding values were 126.0, 195.0 and 234.0μg/ml, respectively. Recovery rates in the first 8 hours after administration were 18.2, 24.6 and 21.3%, respectively.
4. Of 53 patients with 13 diseases, CDTR-PI was clinically judged “excellent” in 32 (60.4%) and “good” in 21 (39.6%), showing excellent efficacy.
5. Bacteriologically, excellent results were obtained, i. e., 29 (96.7%) of 30 strains from 5 species were eradicated.
6. Side effects were observed in none of the 54 patients treated.
7. Laboratory tests revealed eosinophilia in peripheral blood in 3 (10.3%) of 29 patients examined and abnormal elevation of GOT in 1 (5.9%) of 17 patients examined.

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A combined therapy using miconazole (MCZ) and G-CSF was evaluated in clinical patients who developed deep-seated mycoses and fever of unknown etiology following chemotherapy for malignant gyneco-obstetrical tumors.
1. Combined administration of 100 to 250 & g/day of G-CSF, 400 to 800mg/day of MCZ, and various antibiotics (Group I) was evaluated in 7 patients with mycoses (fungemia and fungal infections of the digestive and respiratory systems). The efficacy of the treatment was found to be 3/3. When 200 to 1,200mg/day of MCZ was combined with various antibiotics (Group III), the therapy was found to be slightly effective (2/4). The rate of fungal eradication was 3/5.
2. The efficacy of combined administration of 400 to 800mg/day of MCZ, 100 to 250μg/day of G-CSF, and various antibiotics (Group II) in patients with fever of unknown etiology (n=8) was 4/4.
The efficacy of combined administration of 400 to 800mg/day of MCZ and various antibiotics (Group III) was 3/4.
3. Leukocyte counts were recorded in the 7 patients who had received G-CSF (Groups I and II). The counts rose from <1,000/μl before the chemotherapy to>5,000/μl in 6 patients (6/7) in 5 to 8 days following drug administration. The favorable clinical efficacy was recorded in all who received MCZ and antibiotics.
4. The objective or subjective adverse effects of this therapeutic modality were limited to mild nausea in a single case. No deviations from norm were noted in clinical or other tests.

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