Pharmacokinetic, bacteriological and clinical studies on SY5555 were performed in children.
The results were as follows:
1. A total of 15 patients considered to have bacterial infections were treated with SY5555. Each dose, 5 mg/kg, was orally administered 3 times daily, for 4-11 days. Clinical efficacies of SY 5555 in 13 patients with bacterial infections (1 with pneumonia, 2 with bronchitis, each 1 with maxillary sinusitis, 2 with otitis media, 5 with pharyngitis, 1 each with gastroenteritis and pyelonephritis) were evaluated as excellent in 10 patients and as good in 3 patients with an efficacy rate of 100%.
Two patients with viral infection and malignant lymphoma were not evaluated.
Thirteen causative strains in 7 species were found in 10 patients. Streptococcus pneumoniae in 1/3, Haemophilus influenzae in 2/2, Streptococcus pyogenes 4/4, Salmonella spp. in 1/1, Escherichia coli in 1/1 were eradicated.
Only one patient developed mild diarrhea as an adverse reaction. Another patient showed elevated GPT (glutamate pyruvate transaminase). The abnormality was mild and the patient recovered after the cessation of SY5555 administration without specific treatment.
2. MICs of SY5555 were examined against 33 clinical isolates. SY5555 has low MICs against Enterococcus faecalis and other Gram-positive cocci.
3. Pharmacokinetic studies
Peak plasma concentrations of SY5555 was 1.15μg/ml at a dose level of 4.9mg/kg orally administered at fasting.
Based on the above results and the broad spectrum of the anti-bacterial activities, SY5555 appears to be a promising antibiotics that is usable as a single agent for the primary therapy of respiratory tract infections, skin soft tissue infections and urinaly tract infections in children.

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A new oral penem antibiotic, SY5555, was evaluated for its safety and efficacy in 35 children with various bacterial infections. SY5555 was effective in 100% of scarlet fever, pharyngotonsillitis, pneumonia, otitis media, bacterial diarrhea, urinary tract infections and skin and soft tissue infections. The etiologic bacteria were eradicated except Salmonella sp. Side effects were observed in 3.5% cases; one was diarrhea and Candida dermatitis, one was loose stool, and one was Candida dermatitis. From these data, SY5555 is thought to be a safe and effective antibiotic in the pediatric field. Regular dose of suspension preparation is 15 mg/kg/day in 3 divided dosages, and when needed the dose may be doubled

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Pharmacokinetic and clinical studies on SY5555, a new oral penem antibiotics, were performed in pediatric infections and the following results were obtained.
1. Pharmacokinetics studies
Pharmacokinetics of SY5555 was studied in 5 children(5y1m-10y11m)using doses of 5mg/kg(n=3)and 10 mg/kg(n=2). The average peak plasma levels were 0.65μg/ml at 1 or 2 hours after administration of 5 mg/kg and 2.12μg/ml at 1 or 2 hours after administration of 10 mg/kg, and the plasma half-lives were 0.81 and 1.08 hours, respectively. Average cumulative urinaryrecovery rates at 0-6 hours were 2.97 and 3.96%, respectively.
2. Clinical studies
SY5555 was administered to 45 patient with various infectious diseases(2 with acute pharyngitis, 8 with acute tonsillitis, 4 with lacunar tonsillitis, 3 each with acute bronchitis, pneumonia and pertussis, 7 with scarlet fever, 3 with impetigo contagiosa, 6 with acute urinary tract infections, 2 with balanoposthitis and 1 each with cervical lymphadenitis, S. S. S. S., vulvitis and acute colitis)at daily doses between 3.4-10mg/kg, t. i. d., for 3-14 days.
Clinical responses were excellent in 27 patients, good in 15 patients, fair in 1 patient, and poor in 2 patients, and the efficacy rate was 93.3%. Causative organisms were examined and 39 strains of 11 species were identified. The eradication rate was 78.9%.
Side effects were observed in 1 patient with diarrhea. An abnormal laboratory test value was observed in 1 patient with elevation of eosinophils.
The above results suggest that SY5555 may be avery useful and safe drugfor the treatment of pediatric infection.

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Bacteriological, pharmacokinetic and clinical studies on SY5555 dry syrup (powder which is dissolved before use), a new penem antibiotic for oral use, were performed. The following results were obtained.
1. Antibacterial activities
MICs of SY5555, clavulanic acid/amoxicillin (CVA/AMPC), cefotiam (CTM), cefpodoxime (CPDX), cefaclor (CCL) and cefdinir (CFDN) were determined against clinically isolated Staphylococcus aureus, coagulase negative staphylococci, Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus inflenzae, Moraxella catarrhalis, Escherichia coli and Enterobacter cloacae at a dose of 10⁶ CFU/ml. MICs of SY5555 against S. aureus, CNS, S. pneumoniae, S. pyogenes, H. influenzae, M. catarrhalis, E. coli and E. cloacae were 0.2, 0.2, 0.2, ≤0.025, 0.78, 0.2, 0.78 and 3.13μg/ml, respectively, showing excellent antibacterial effects on these pathogens. Although the effects of SY5555 against H. influenzae and E. coli were slightly inferior to those of CPDX and CFDN, the drug showed the most excellent antibacterial effect on other strains as compared with the control drugs.
2. Absorption and excretion
In this study, plasma concentrations and urinary recovery rates were examined after administration of SY5555 at doses of 5 and 10 mg/kg (potency) after meals. With both 5 and 10 mg/kg doses, peak plasma concentrations were reached 1 hour after administration, at 0.25-2.61μg/ml (mean 1.47μg/ml) and 1.08-2.17μg/ml (mean 1.74μg/ml), respectively. The plasma levels rapidly decreased to 0.06-0.19μg/ml (0.12μg/ml) and 0.0503-0.0637μg/ml (0.057μg/ml) after 6 hours. The half-lives 1.12 hours in the 5 mg/kg group and 1.0 hour in the 10 mg/kg group. The urinary recovery rates were determined in the first 8 hours after administration in the 5 mg/kg and 6 hours in the 10 mg/kg group, and the values were as low as 1.05-12.3% and 1.6-4.33%, respectively.
3. Clinical results
The clinical responses were examined in a total of 73 cases including 4 acute pneumonia, 13 acute bronchitis, 11 tonsillitis, 3 pharyngitis, 12 scarlet fever, 2 pertussis, 6 urinary tract infection, 6 otitis media, 7 lymphadenitis, 2 staphylococcal scalded skin syndrome, 2 phlegmon, 4 impetigo and 1 purulent parotitis. The treatment was effective or better in 66 of 70 cases with an efficacy rate of 94.3% (3 undeterminable cases were excluded). Bacteriological effects were examined during the clinical course for detected or suspected pathogens found before administration of SY5555. The effects were determined in 50 cases including 7 cases of polymicrobacterial infections, 57 strains in total. Eight strains, however, persisted, hence the overall eradication rate was 86.0%. Because of the persistence of eight strains, the bacteriological efficacy rate was 84.0% (42/50). Except for mild watery stool which appeared in 1 case, no adverse reactions or abnormal laboratory test values were observed in any case.

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We assessed the in vitro antimicrobial activity and the clinical efficacy and safety of SY5555 in the field of pediatrics. The results obtained are summarized below.
1. In vitro antibacterial activities of SY5555 against 52 clinical isolates were compared with those of clavulanic acid/amoxicillin (CVA/AMPC), cefotiam (CTM), cefpodoxime (CPDX), cefaclor (CCL) and cefdinir (CFDN). Against Gram-positive bacteria, including Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes, SY5555 displayed antimicrobial activities superior or nearly equivalent to those of the reference agents used in the study. In cases of Gram-negative bacteria, the antimicrobial activity of SY5555 against Haemophilus influenzae was inferior to those of CPDX and CFDN. Against Klebsiella pneumoniae, the antimicrobial activity of SY5555 was less potent than that of CPDX.
2. Forty-seven children with infectious diseases were treated with SY5555 dry syrup (powder dissolved just before use). The clinical results were excellent in 24 and good in 16, with an efficacy rate of 85.1%.
3. Bacteriological screening identified 30 pathogenic organisms, and the eradication rate was 76.7%.
4. Side effects consisted of diarrhea in 12.5% (6 cases), loose stools in 4.2% (2 cases) and urticaria in 2.1 % (1 case) of the patients. The only abnormal laboratory test value observed was an increase in eosinophil count in one child.
5. The palatability of SY5555 dry syrup was very good; it was very easily ingestible or easily ingestible by 32 of the 48 children.
From the above results, SY5555 dry syrup appears to be a useful drug with a preferable safety profile in the treatment of pediatric patients with infectious diseases.

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Laboratory and clinical studies were performed on SY5555, the first penem oral antibiotic developed in Japan, in the pediatric field. The following results were obtained.
1. Antibacterial activities of the drug against 42 strains of Streptococcus pneumoniae clinically isolated in 1993 were compared to those of 13 other drugs mainly composed of β-lactam preparations. Minimum inhibitory concentration (MIC) values of SY5555 were below 0.39μg/ml for all strains examined, thus the drug showed an excellent activities against benzylpenicillin (PCG)-resistant strains as well. When the antibacterial effects of individual drugs were compared using MIC₅₀ and MIC₉₀ as indices, SY5555 was the most effective against PCG-sensitive strains and sim ilar to cefazolin (CEZ), cefotaxime (CTX), cefuzonam (CZON), amoxicillin (AMPC) and imipenem (IPM). It also showed excellent antibacterial effects against moderately PCG-resistant strains, and the activities were similar to IPM. Activities of SY5555 on highly PCG-resistant strains were similar to those of CTX, CZON and IPM.
2. SY5555 at a dose of 5 mg/kg or 10 mg/kg was administered to 16 pediatric patients in the fasting state or after meal to examine its plasma concentration and urinary excretion rate.
The fecal excretion was measured in 5 affected children treated with this drug.
When the drug at a dose of 5 mg/kg was administered to 11 older children, 5 with ages 5-12 years and 6 with ages 10-13 years in the fasting state and after meal, respectively. Peak plasma levels were reached at 1 hour after administration in the two groups, and they were 0.93±0.25 and 2.44±1.25μg/ml, respectively. The plasma levels then decreased gradually with half-lives of 1.95±1.09 and 0.72±0.21 hours, respectively. Urinary recovery rates in the first 6 hours after administration were 1.98±0.82 and 4.13±1.40%, respectively. In 3 cases (6-9 years) treated with the drug at a dose of 10 mg/kg after meal, a peak of 1.58±0.81μg/ml appeared 1 hour after administration with a half-life of 1.08±0.30 hours and with the urinary recovery rate in the first 6 hours after administration of 3.46±1.03%. When the drug at a dose of 10 mg/kg was administered to 2 infants (2-3 months post partum) after meal, a peak plasma level of 3.74μg/ml appeared 1 hour after administration with a half-life of 1.19 hours.
Fecal concentrations of the drug determined for 5 infected older children (2-9 years) under treatment with 5-10 mg/kg three times a day ranged from<0.05μg/g to 47.8μg/g.
3. Thirty-five children with various infections were examined for the clinical efficacy, bacteriological effect, safety and patient's compliance. In 31 of 35 cases (4 undeterminable cases were excluded), the drug was administered at doses ranging 4.4-14.6 mg/kg, three times a day for 3-14 days (total dose 0.75-8.10g).
The clinical effect was evaluated in 29 cases including 1 scarlet fever, 12 acute purulent tonsillitis, 4 acute bronchitis, 6 acute pneumonia, 1 pertussis, 3 acute urinary tract infections and 2 impetigo. The results were excellent in 17 cases and good in 12 cases with an efficacy rate of 100.0%. As for the bacteriological effects on suspected pathogens including 4 strains of Staphylococcus aureus, 4 of Streptococcus pyogenes, 1 of Streptococcus pneumoniae, 1 of Moraxella (Branhamella) catarrhalis, 4 of Haemophilus influenzae, 2 of Escherichia coli and 1 of Bordetella pertussis, all strains were eradicated except 2 strains of H. influenzae that were judged as decreased or persisted and B. pertussis of which bacteriological examination was not performed after administration, thus the eradication rate was 87.5%. In addition, no bacterial alternation was observed in any case examined.

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Clinical studies on SY5555 dry syrup, a new oral penem antibiotic, were carried out in the field of pediatrics. The following results were obtained.
1. SY5555 was administered to 10 children with various bacterial infections (2 patients with acute tonsillitis, 2 with acute bronchitis, 1 with pharyngitis, 2 with scarlet fever, 1 with pertussis and 2 with urinary tract infections).
The overall clinical efficacy rate was 90%.
2. Side effects or abnormal laboratory test values were not observed except for loose stool in 1 and eosinophilia in 1.

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SY5555, a new oral penem, in the form of dry syrup (powder which is dissolved before use) was evaluated for its pharmacokinetics and clinical efficacy in pediatric patients.
Oral administration of 5 mg/kg and 10 mg/kg of SY5555 in dry syrup resulted in respective maximum plasma concentrations of 1.08±0.38μg/ml (n=4) and 2.50±1.81μg/ml (n=4), half-lives (T 1/2) of 2.72±1.86 hours (n=3) and 1.14±0.88 hours (n=4), and urinary excretion until 6 hours of 4.7% (n=1) and 3.86±2.01% (n=4).
Clinical efficacy was evaluable in 22 patients, and the overall efficacy rate was 100%. As for bacteriological efficacy, all 5 strains of pathogenic organisms identified were eradicated (eradicationrate, 100%).
No remarkable adverse reactions or abnormal laboratory values were observed.

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In vitro antifungal activities of lanoconazole (LCZ) against 9 stock cultures and 10 clinical isolates of Candida albicans were determined using three different testing media, SABOURAUD'S glucose broth (SGB), SABOURAUD'S glucose agar (SGA) and casitone agar (CA). MIC values of LCZ against both the stock cultures and clinical isolates measured on CA distributed in a range of 0.63-5μg/ml. The values were 8-64-fold lower than those obtained in SGB and on SGA. MIC ranges and the geometric mean MIC values of LCZ against stock cultures were virtually the same as those against clinical isolates, no matter which assay techniques were used.
These results suggest that there is no difference in the LCZ susceptibility between stock cultures and clinical isolates of C. albicans, although anti-Candida activity of LCZ was determined to be greater on CA than that in SGB or on SGA.

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In vitro studies with a new imidazole antifungal agent lanoconazole (LCZ) were carried out to confirm its fungicidal property of the anti-dermatophytic activity and unlikeliness of dermatophytes to acquire secondary resistance to this drug. Minimal cidal concentration (MCC) values of LCZ against 6 strains each of Trichophyton mentagrophytes and T. rubrum determined by the cellophane membrane method were in a range of 0.063 to 0.5μg/ml, and much lower than those of bifonazole (16-32μg/ml). The LCZ-sensitivity of both of the two testing strains of T. mentagrophytes did not decrease to less than one-fourth of the initial level during 15 subcultures on LCZ-containing agar. These results suggest that LCZ potently inhibits dermatophytes in a fungicidal manner and that secondary resistance to LCZ is not easily developed in the dermatophytes tested.

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The therapeutic efficacy of ointment and cream preparations of lanoconazole in a guinea pig model of tinea corporis was compared on the basis of degrees of improvement in local symptoms and negative culture rates. When infected animals were treated once daily with 0.25%, 0.5% and 1% lanoconazole ointments, significant improvement of the symptoms and mycological curative effects were observed as compared to those of non-treated control and vehicle-treated control groups of animals. Particularly, in animals treated with 0.5 or 1% lanoconazole ointment, no fungus was recovered from any infected loci. Comparing these results with those obtained with comparable concentrations of lanoconazole cream, no significant difference was found. These studies, therefore, suggested that ointment and cream preparations of lanoconazole on topical application would show basically equivalent therapeutic efficacy in the tinea corporis model.

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Dip-slides are used as semiquantitative microbial sampling devices that are simple to use in routine testing of urine to detect the presence of bacteria, and are recommended for use in “Standard evaluation of drug efficacy in UTI”. Bacterial growth on currently available dip-slides, however, may conceivably be influenced by the presence of antibacterial agents in urine. We studied clinical performance of, and effects of antibacterial agents on, such dip-slides, using two types of dip-slides, URICULTE® and DIASLIDE ®, both of which are newly developed urine culture devices. The quantitative conventional culture method was also used as the control.
1. When single species of bacteria are present in urine specimens of patients, results obtained using URICULTE® and DIASLIDE® agreed very well, and they, in turn agreed well with results obtained using the quantitative, conventional culture method, also.
2. When urine specimens were spiked with Gram-negative rods and Gram-positive cocci together, URICULTE ® fail to provide quantitative results because colonies were not well separated and confluent growth often resulted because of a large sample volume this device employs. DIASLIDE® which used a smaller amount of sample, on the other hand, provided quantitative results with adequate separation of colonies.
3. When three antibacterial agents were added to urine specimens that were spiked with bacteria, DIASLIDE® produced significantly higher numbers of colonies than URICULTER. The difference probably are due to the difference in volumes of specimens used in the two devices, the former device employs approximately 1/100 as much volume of specimen as the latter. When the volume used is large, inhibitory effect of antibiotics present in the urine may be high enough to adversely affect the growth of bacteria, thus DIASLIDE® may provide false-negative results.

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[in Japanese]

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