Clinical studies were carried out on SY5555, a new oral penem, in the field of pediatrics. The results obtained are summarized below.
The clinical efficacies were examined in a total 31 patients consisting of 4 patients with pharyngitis, 10 with purulent tonsillitis, 4 with scarlet fever, 7 with impetigo, one with balanitis, one with cellulitis and 4 with UTI. The clinical efficacy rate was 96.8% (30/31).
Bacteriological efficacies of SY5555 were examined on identified pathogens including 7 strains of Staphylococcus aureus, 6 of Streptococcus pyogenes, 3 of Enterococcus faecalis, 3 of Haemophilus influenzae, one of Escherichia coli and one of Citrobacter freundii. The bacteriological eradication rate was 81.0%.
As for side effects, loose stool in one patient was noted. Abnormal laboratory findings test results included eosinophilia in 2 patients, eosinophilia and elevation of serum transaminase in one patient, and thrombocytosis in another.

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A clinical study was performed on SY5555, a newly developed penem antibiotic, in children. SY5555 was given orally to 14 patients at 19-29 mg/kg/day in 3 doses for 4 to 12 days. Clinical evaluations were made on the 14 patients including 4 with pharyngitis, 7 with tonsillitis, one with urinary tract infection, and 2 with impetigo. Overall clinical effects were excellent in 2, good in 12, with an efficacy rate of 100%. Causative organisms (Staphylococcus aureus and Streptococcus pyogenes) were all eradicated. As to adverse reactions, mild diarrhea was observed in 4 patients. These data suggest that SY5555 is a useful oral antibiotic for the treatment of bacterial infections in children.

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SY5555 dry syrup (powder to be dissolved before use) was clinically used in pediatric patients. The following results were obtained:
1. The subjects were 6 pediatric patients including 1 case each with pharyngitis, tonsillitis, lacunar tonsillitis and impetigo contagiosa and 2 cases with scarlet fever. The drug was administered at a daily dose of 14.5-29.0 mg/kg divided into 3 dosages. The clinical results were excellent in 5 cases and good in 1 case with an efficacy rate of 100%.
2. Identified bacteria included 3 strains of Haemophilus influenzae, 2 strains of Streptococcus pyogenes and 1 strain of Staphylococcus aureus. Five strains were eradicated but 1 strain still remained with an bacteriological eradication rate of 83.3%.
3. No side effects were observed throughout the study period. In laboratory test results, elevated eosinophil count was observed in only 1 case.
4. Patients' compliance was good in general.
5. Based on the results mentioned above, the drug was considered to be a useful new oral antibiotic in the pediatric field.

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1. SY5555 dry syrup (powder which is dissolved before use) was administered to 25 patients with bacterial infections (6 cases of bronchitis, 2 cases of bronchopneumonia, 1 case of pertussis, 3 cases of scarlet fever, 5 cases of tonsillitis, 3 cases of urinary tract infections, 2 cases of staphylococcal scalded skin syndrome, 1 case of impetigo, 2 cases of purulent lymphadenitis).
2. Clinical efficacies were excellent in 11 patients and good in 13, poor in 1 with an efficacy rate of 96.0%. As pathogenic organisms, 15 strains were identified and 14 of them were eradicated with eradication rate of 93.3%.
3. No side effects were observed. As for abnormal laboratory test results increase in eosinophiles in 2 cases, decrease in filamented neutrophiles in 1 case, elevation of GOT and GPT in 1 case and elevation of GPT and γ-GTP were abserved.
4. There was no rejection incidence of the drug during the therapy.
From the above results, we consider SY5555 in dry syrup form to be a useful and safe drug in the treatment of various bacterial infections in pediatric patients.

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SY5555 in dry syrup (powder which is dissolved before use) or tablet form was given orally to 21 children with acute bacterial infections including 4 with acute pharyngitis, 5 with acute tonsillitis, 7 with acute bronchitis, 2 with acute gastroenteritis, 1 each with scarlet fever, acute lymphadenitis and urinary tract infection.
Good to excellent clinical responses were obtained in all of the 21 patients and 8 of 11 strains found as causative organisms in these cases were eradicated and 3 strains were decreased. Loose stools were observed in 3 cases and eosinophilia was observed in 1 case.
From the above clinical results, it appears that SY5555 is a useful antibiotic for the treatment of pediatric patients with various bacterial infections.

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Clinical effects of SY5555 dry syrup, a new oral penem antibiotic, were analysed in 20 children with various bacterial infections. Ages of the patients varied from 8 months to 14 years. Doses of SY5555 were varied from 12.8 mg/kg/day to 30.5 mg/kg/day, and it was administered in 3 divided dosages. Clinical efficacy rates were as follows; 6/7 in acute bronchitis, 5/5 in pharyngotonsillitis, 3/3 in acute otitis media and 2/2 in cystitis and 3/3 in impetigo contagiosa. The overall rate was 95.0% (19/20).
Bacteriologically, eradications were obtained with 1/2 strains of Streptococcus pyogenes, 3/3 of Staphylococcus aureus, 1/1 of Haemophilus influenzae, and each of Staphylococcus epidermidis, Haemophilus parainfluenzae, coagulase-negative staphylococci and Serratia marcescens. Diarrhea was observed in 1 patient. And elevated eosinophiles or GPT was observed in one patient each.
In vivo pharmacokinetics of SY5555 was examined in 2 cases. Peak plasma levels were observed at 1 hour after dosage in one patient and at 2 hours in another upon oral administration of 8.3mg/kg of SY5555, and peak levels were 2.44 and 1.38μg/ml respectively. Half-lives of SY 5555 were 1.39 and 0.59 hr. Concentrations of SY5555 in urine after administration were 70.2 (2-4 hrs.) to 91.0 (0-5 hrs.) μg/ml, respectively.
SY5555 dry syrup is considered as an useful and safe antibiotic in treating the infectious diseases in children.

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Pharmacokinetic, bacteriological and clinical studies on SY5555, a new oral penem, were carried out, and the following results were obtained.
1. MICs were determined for 6 drugs, SY5555, clavulanic acid/amoxicillin (CVA/AMPC), cefaclor (CCL), cefotiam (CTM), cefpodoxime (CPDX), cefdinir (CFDN) against 20 strains of bacteria isolated from patients who were subsequently treated with SY5555. MICs of SY5555 for Gram-positive cocci ranged from 0.05 to 0.10μg/ml against 10 strains of Staphylococcus aureus. The MIC was≤0.025μg/ml against one strain of Streptococcus pyogenes, and MICs were from ≤0.025 to 0.39μg/ml against streptococcus pneumoniae. These MIC values were equivalent or superior to those of the other 5 drugs. MICs of SY5555 for Gram-negative bacilli were 0.39 and 6.25μg/ml against Haemophilus influenzae, and these values were equivalent to those of the other drugs, except CPDX. The MIC of SY5555 was 0.39μg/ml against 2 strains of Escherichia coli, and this value was equivalent or superior to those of CVA/AMPC and CCL, similar or inferior to those of CPDX and CFDN, and inferior to that of CTM. The MICs of several drugs were determined for 10 strains of Bordetella pertussis and 30 strains of Campylobacter jejuni isolated from patients before this clinical study. The MICs of SY5555 against the 10 strains of B. pertussis were compared with those of 7 drugs, CCL, CTM, CPDX, ampicillin (ABPC), piperacillin (PIPC), imipenem (IPM) and erythromycin (EM). The MIC of SY5555 was 0.78μg/ml against all of the strains. This value was superior to those of CCL, CTM and CPDX, similar or inferior to that of IPM and inferior to those of PIPC and EM. The MICs of SY5555 against the 30 strains of C. jejuni were compared with those of 7 drugs. CCL, CTM, CPDX, CFDN, ABPC, IPM and EM, and the MIC of SY5555 was≤0.025μg/ml or 0.05μg/ml and these values were equivalent or superior to those of the 7 reference drugs.
2. SY5555 dry syrup was administered orally at 30 min. after meals, to a total of 5 patients, at doses of 5.0 and 10.0 mg/kg to 2 patients each and at a dose of 15.0 mg/kg to one patient and the plasma concentrations were determined. Peak concentrations were detected 1 to 3 hours after administration in all patients and the peak concentrations were 0.93 and 1.21μg/ml at the 5.0 mg/kg dose, 2.85 and 5.49μg/ml at the 10.0 mg/kg dose and 5.79μg/ml at the 15.0 mg/kg dose. A dose-response relationship was observed among the three dose groups, except one of the patient who received the 10.0 mg/kg dose had a high plasma concentration, and the half-lives in all of the patients ranged from 0.76 to 1.05 hours. AUCs also showed a dose-response relationship in the three dose groups, except for the patient who received the 10.0 mg/kg dose and showed a high plasma concentration level.
3. Urinary concentrations were determined in the above patients and peak urinary concentrations occurred in 0 to 2 hours in one patient and in 2 to 4 hours in 4 patients. Urinary recovery rates in the first 6 hours after administration ranged from 6.0 to 13.8%.
4. SY5555, mainly in dry syrup (powder dissolved just before use), was administered to children with infectious diseases. Clinical efficacies in the 76 evaluable patients were excellent in 20, good in 43, fair in 9 and poor in 4, and the overall efficacy rate was 82.9%.
5. Bacteriologically, 33 causative organisms were identified in the above clinical study, and 30 were eradicated. The eradication rate was 90.9%.
6. Side effects were evaluated in 82 patients and diarrhea was reported in 4.
7. No abnormal changes in laboratory test values were noted, except for an increase in eosinophil count in one patient.

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SY5555 is a new oral penem antibiotic. Pharmacokinetic and clinical studies using SY5555 dry syrup (powder which is dissolved before use) were performed in pediatric patients.
1. Pharmacokinetic investigation
Peak plasma concentrations of SY5555 after dose of 5 mg/kg, 10 mg/kg and 15 mg/kg were, respectively, 1.58±0.37μg/ml, 2.78±0.54μg/ml and 5.28μg/ml at 1 hour. The average half-life with 5 mg/kg administration was 0.94±0.05 hours, that with 10 mg/kg was 1.46±0.31 hours and that with 15 mg/kg was 0.88 hours.
2. Clinical investigation
Enrolled in the study were 15 patients including 5 with acute otitis media, 5 with urinary tract infections and 1 each with pharyngitis, tonsillitis, bronchitis, pneumonia and subcutaneous abscess. Responses were excellent in 4 patients, good in 8 patients, fair in 2 patients and poor in 1 patient. In the assessment of the bacteriological efficacy, 8 out of 10 strains of organism identified previous to treatment were eradicated and 2 strains were unchanged, hence the eradication rate was 80.0%.
3. No adverse reactions attributable to the drug were observed and good drug compliance were obtained. From the above results, it has been concluded that SY5555 is a highly effective andsafe agent for mild to moderate respiratory and urinary tract infections in children.

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The clinical effectiveness of a combination treatment using imipenem/cilastatin sodium (IPM/CS) with G-CSF was studied in neutropenic patients (<500/mm³) with hematological malignancies and secondary infections. Thirty seven patients were entered in the trial, and 30 patients were eligible. This combination was effective in 20 patients, thus the overall efficacy rate was 66.7 parcent. The combination was effective in all 6 cases with septicemia, in 10 case out of 15 cases with fever after chemotherapy (efficacy rate; 66.7%), in 3 out of 8 cases with respiratory infections including 7 cases with pneumonia (efficacy rate; 37.5%), and a case with laryngopharyngitis. According to the order of the administration, the efficacy rates were 60.0% in 5 cases in whom G-CSF treatment was started before IPM/CS, 66.7% in 21 cases given both G-CSF and IPM/CS simultaneously, and 75.0% in 4 cases in whom IPM/CS was started before G-CSF. The difference was statistically not significant on the efficacy rates in the three groups. The efficacy in 18 cases treated with monotherapy on antibiotic was 72.2% and that in 12 cases treated with IPM/CS in combination with other antibiotics was 58.3%, and the difference in the efficacy rates in these two groups was not statistically significant. According to the neutrophil counts before and after the treatment, high response rate (60.0%) was obtained in cases of severe neutropenia (less than 100/mm³). Bacteriological examinations showed that all of bacteria detected as pathogens (10 strains of Gram-positive bacteria and 6 strains of Gram-negative bacteria) were eradicated, though 3 strains were replaced by other pathogens. As adverse reactions, there was a case who had restlessness (2.7% of 37 cases), and also 5 cases who had slight abnormal values in liver function tests (13.5% of 37 cases). No clinical or laboratory adverse reactions induced by G-CSF were observed.

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Among cases of infantile acute pharyngolaryngitis with cough as a chief complaint, 21 cases that the involvement of bacterial infections has been demonstrated were given minocycline (MINO) and the effectiveness and safety of MINO were investigated.
1. Regarding the clinical effectiveness, the number of cases assessed as markedly effective was 9 (43%) and that as effective was 8 (38%), so that the effectiveness rate was 81%, and particularly, in the infections caused by Haemophilus influenzae, MINO showed a high effectiveness.
2. Five strains of Streptococcus pneumoniae, 2 strains of Streptococcus pyogenes and 16 strains of H. influenzae, a total of 23 strains of pathogenic bacteria were isolated, and MINO showed high activities against not less than 80% of these strains.
3. The bacteriological effect in terms of the rate of eradication was 71%, and that of H. influenzae was as high as 88%, while S. pneumoniae remained in 3 of 5 cases.
4. Adverse reactions were observed in 2 cases (10%), 1 case each of abdominal pain and stomatitis, and both of them were improved after the treatment termination.
5. Regarding the usefulness, which was comprehensively assessed using clinical effectiveness and safety as criteria, the number of cases evaluated satisfactorily useful was 8 (38%) and that as useful was 8 (38%), so that the overall usefulness rate was 76%.
From the above results, it was confirmed that MINO is a drug having high efficacy and safety against infantile acute pharyngolaryngitis with cough as a chief complaint caused by H. influenzae. On the other hand, the rates of eradication of causative bacteria in cases infected with S. pneumoniae and S. pyogenes were not so high as that in cases with H. influenzae. And, since cases complicated with acute tonsillitis or acute otitis media were observed in those that S. pneumoniae was found after the use of MINO. MINO was considered a difficult drug to use in cases infected with S. pneumoniae and S. pyogenes.

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We investigated the bactericidal activity and postantibiotic effect (PAE) of arbekacin (ABK) and fosfomycin (FOM) on clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) strain 1936, and the morphological changes of the bacterium. Both antibiotics were used in combination at concentrations lower than their respective MICs. The following results were obtained.
1. When the bacterium was simultaneously exposed to ABK and FOM, growth inhibition and a PAE longer than that effected by ABK alone were observed.
2. When exposed to ABK after treatment with and removal of FOM, bactericidal activity was stronger than that obtained when exposed to ABK alone. However, no increase in bactericidal activity was obtained when exposed to FOM after pretreatment with ABK.
3. Transmission electron microscopy revealed that, when the bacterium was exposed to ABK after treatment with and removal of FOM, large bacterial cells with cross walls at irregular sites and lysed cells showing destruction of the cell wall at the site of bacterial segmentation caused by ABK and FOM.
These results demonstrated that ABK in combination with FOM shows stronger bactericidal activity against MRSA in vitro than ABK alone.

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Clinical isolates from patients with otitis media and/or otitis externa were collected at otorhinology clinics nationwide and sent to us during 1989, 1991 and 1993. Minimum inhibitory concentrations (MICs) of fosfomycin (FOM) and of reference drugs against these strains were determined to investigate year-to-year antibacterial activity of FOM. A comparative analysis of the results revealed trends described below.
1. The MIC₉₀ of FOM against Staphylococcus aureus subsp. aureus increased 4 times by 1993 as compared to those measured for strains isolated in 1984 and 1985, when FOM for otic use was under development. This was thought to be due to the recent increase in the detection frequency of methicillin-resistant S. aureus (MRSA) which is also resistant to FOM.
2. No annual changes were seen for MIC distribution of FOM against Proteus group and Pseudomonas aeruginosa.
3. Since there was no large annual change in the antibacterial activity of FOM against recent clinical isolates obtained from patients with otitis media and/or otitis externa, FOM may be considered as one of the useful drugs even now, in the mid-1990's.

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