[in Japanese]

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A new parenteral cephem, cefozopran (CZOP), was evaluated for its safety and efficacy in 21 children with acute infections. A mild side effect or an abnormality in laboratory tests was observed in one case each, but the safety of CZOP was otherwise observed. CZOP was effective in all of the 18 bacterial infections tested including pneumonia, cellulitis and urinary tract infections, and all the causative organisms were eradicated. Serum half-lives of CZOP were 1.5-1.8 hours and the urinary excretion rates were 63-96% in the first 5-8 hours after administration.
These data suggest that CZOP is safe and effective in children with susceptible bacterial infections.

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Pharmacokinetic and clinical evaluations of cefozopran (CZOP) were carried out in pediatric patients.
The following results were obtained:
1. Upon 30-minute intravenous drip infusion at a dose of 20mg/kg, plasma concentrations of CZOP reached their peaks at the end of drip infusion with an average value of 77.1 μg/ml, and the average plasma half-life was 1.78 hours in the β-phase. Upon 30-minute intravenous drip infusion at a dose of 10mg/kg, peak plasma concentration was 40.5 μg/ml and plasma half-life was 1.62 hours.
2. The urinary excretion rates of CZOP after 30-minute intravenous infusion at doses of 20 and 10mg/kg were 53.2% and 56.2%, respectively.
3. CZOP was administered to 17 cases (upper and lower respiratory tract infections, pneumonia, lymphadenitis and urinary tract infections) at daily doses of 60-90mg/kg divided into 3 dosages using 30-minute intravenous drip infusion. Clinical responses were “excellent” in 13 patients, “good” in 3, and “poor” in 1, hence the efficacy rate of 94.1 % was obtained.
4. Bacteria identified from various disease cases included 19 strains of 8 species, and the eradication rate was 94.7%.
5. Soft stool occurred in 1 case as an adverse reaction. Laboratory test results showed abnormalities in 2 cases with elevation of GOT and GPT.

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Cefozopran (CZOP, SCE-2787), a new parenteral cephalosporin antibiotic, was studied for its pharmacokinetics, bacteriological and clinical effects in the field of pediatrics.
The serum and cerebrospinal fluid concentrations 1 hour after a bolus intravenous injection of 50mg/kg were, respectively, 92.1, 10.5, μg/ml, and penetration rate to cerebrospinal fluid of CZOP in patients with purulent meningitis was 11.4%.
25 patients, including those with purulent meningitis, pneumonia, urinary tract infections, staphylococcal scalded skin syndrome (SSSS) etc., were treated with CZOP at dose levels of 16.0 to 50.0mg/kg 3-4 times daily, via intravenous injection and intravenous drip infusion. CZOP gave “excellent” or “good” responses in all the 25 patients. In bacteriological examinations, 25 strains were identified and were eradicated except 1 strain of Staphylococcus aureus and 2 strains of Salmonella sp.
As a side effect, diarrhea was observed in 1 patient among the 27 patients treated with the drug. As for abnormal laboratory findings, eosinophilia was observed in 1 patient, increases of thrombocytes in 3 and GPT in 2.
Influences on blood coagulation parameters were studied. No changes in PIVKA II, HPT or APTT were observed during the treatment.
Based on the above results, it has been concluded that CZOP is a safe and effective drug to use in the treatment of pediatric infections. The normal recommended dosage and administration should be 20 to 50mg/kg of CZOP at a time, using intravenous injection or intravenous drip infusion 3 to 4 times a day.

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We conducted pharmacokinetic and clinical studies on cefozopran (CZOP, SCE-2787), an aminothiadiazolmethoxyiminoacetamido cephalosporin, and obtained the following results.
1. Concentrations in serum/excretion in urine
We studied pharmacokinetic in children upon intravenous bolus injection and 30-minute intravenous drip infusion in single doses of 10 and 20mg/kg. Upon intravenous bolus injection, mean serum concentrations 30 minutes after administration of 10 and 20mg/kg were 27.8 and 52.3μg/ml, respectively, and half-lives were 2.01 and 2.02 hours, respectively. Upon 30-minute intravenous drip infusion, mean serum concentrations on completion of the drip infusions of 10 and 20mg/kg were 36.8 and 70.3μg/ml, respectively, and half-lives were 1.74 and 4.11 hours, respectively. Their urinary recovery rates in the first 8 hours after administration were higher than 67.0% in the fomer regimen and between 23.2 to 98.0% in the latter.
2. Clinical results
54 patients were treated with CZOP for 32 cases of pneumonia, 11 cases of bronchitis, 3 cases of cervical lymphadenitis, 1 case of purulent tonsillitis, 2 cases of phlegmon, 2 cases of entero-gastritis and 3 cases of urinary tract infections. CZOP gave “excellent” or “good” responses in 53 cases. 1 case of urinary tract infection showed fair response.
Diarrhea was observed in 1 case. Abnormal laboratory test results were noted in 9 patients including elevations of eosinophils, GOT and GPT. In no cases the treatment had to be discontinued.

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Pharmacokinetic and clinical studies on cefozopran (CZOP, SCE-2787), a new cephalosporin antibiotic, were carried out in the field of pediatrics.
The results obtained are summarized below.
1. Serum concentrations and urinary excretion rates were determined after intravenous bolus injection of CZOP at a dose of 20mg/kg for 5 minutes in 3 cases. The mean serum concentration of CZOP was 45.9μg/ml at 30 minutes with the serum half-life of 1.77 hours. The mean cumulative urinary excretion rate in the first 8 hours after administration was 71.4%.
2. Fourteen patients with bacterial infections (pneumonia 9 cases, urinary tract infection 4 cases and lymphadenitis 1 case) were treated with CZOP at a daily dose of 55.8-65.7mg/kg. The overall clinical efficacy and bacteriological eradication rates were both 100%.
3. No adverse reactions were observed. Abnormal laboratory test results were mild, slight elevation of GOT and GOT, GPT & LDH in 1 each and eosinophilia and thrombocytosis in 2 cases each.

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We conducted a pharmacokinetic and clinical studies on cefozopran (CZOP), a new cephem antibiotic for injection.
1. Changes in serum levels of the agent after intravenous bolus injection at a dose of 20mg/kg to 4 pediatric patients (age: 5-10 years) were observed. The levels at 30 minutes after injection were 32.9-73.4μg/ml average: 55.4±18.1μg/ml), then the levels gradually decreased with half-lives of 1.67-2.24 hours (average: 1.85±0.27 hours) to 0.8-1.8μg/ml (average: 1.2±0.4μg/ml) at 8 hours after injections. Urinary levels reached at the maximum as, 1,773-3,450μg/ml (average: 2,693±698μg/ml) within 0-2 hours or 2-4 hours after injection, and recovery rates from urine in the first 8 hours after injection were 55.4-91.1% (average: 71.6±16.8%).
2. Transition to cerebrospinal fluid was examined in cases with purulent meningitis and aseptic meningoencephalitis. In the meningitis case, the level in cerebrospinal fluid 1 hour after administration was 8.8μg/ml in the second day after the start of 4 times a day intravenous bolus injections with 42.5mg/kg at each dose; The ratio of the drug level in cerebrospinal fluid to that in serum was 24.0%. In the meningoencephalitis, the levels in cerebrospinal fluid 1 hour after administrations were 1.1μg/ml and 1.5μg/ml in the second and the sixth days respectively, after the start of 4 times a day intravenous bolus injections with 50mg/kg at each dose; the ratio of the levels in cerebrospinal fluid to those in sera were 0.93% and 2.41% respectively, at the second and the sixth day.
3. CZOP was clinically evaluated in 29 cases (ages: 2 months to 15 years) of pediatric infectious diseases. The agent was administered 3-4 times daily with 17-50mg/kg at each dose, continued for 5-13 days. Total does were 1.95-24.05g.
Clinical efficacy was evaluated in a total of 28 cases (1 case of purulent meningitis, 2 cases of acute purulent tonsillitis, 20 cases of acute pneumonia, 3 cases of urinary tract infections, 1 case of purulent lymphadenitis in cervical part and 1 case of cellulitis in face); The efficacies were “excellent” in 22 cases and “good” in 6 cases. The efficacy rate including “excellent” and “good” responses was 100.0%. Bacteriological effects of the agent on 3 strains of Streptococcus pneumoniae, 1 strain of Moraxella (Branhamella) catarrhalis, 2 strains of Escherichia coli, 4 strains of Haemophilus influenzae and 1 strain of Acinetobacter calcoaceticus, all of which were considered to be causative bacteria, were evaluated as eradicated except 1 strain of H. influenzae for which the effect was evaluated as decreased. Eradication rate was 90.9%. No side effects were observed. In laboratory tests, elevation of GOT and GPT activities were observed in 1 case and thrombocytosis in another; In the former case, normalization of the activities were observed in the follow-up examination.
From these results, CZOP is expected to have high effectiveness and with reasonable safety.

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Cefozopran (CZOP) was administered intravenously to 22 infants (aged 3 months to 15 years) with infections excluding suppurative meningitis in doses of 10 to 40mg/kg 3 to 4 times daily for periods of 3 to 16 days and its efficacy and safety in infantile infections as well as pharmacokinetic parameters were determined.
The half-lives of CZOP after intravenous administration at doses of 10, 20 and 4.0mg/kg were 2.84, 2.36±0.67, and 2.48 hours, respectively. The rates of recovery in the urine within 6 hours of administration were 83.6%, 62.9±23.1%, and 77.3%, respectively.
The subjects for whom drug responses were evaluable consisted of 1 case of suppurative meningitis, 8 cases of respiratory tract infection, 2 cases of urinary tract infection, 2 cases of oral infection, 2 cases of pharyngotonsillitis, 1 case of skin soft tissue infection, and 1 case of external otitis, totaling 17 cases.
The efficacy rate was 88.2%. The drug proved so effective on suppurative meningitis in particular that the patient was healed without leaving any sequela behind. Seven strains were identified as causative pathogens (5 strains of Haemophilus influenzae, 1 strain of Staphylococcus aureus, 1 strain of group B Streptococcus) isolated from 6 patients. All but 1 strain were eradicated (the rate of eradication 83.3%). In the patients with suppurative meningitis the bacterial count of spinal fluid was markedly decreased 6 hours after drug administration and the organism was eradicated in 45 hours.
Eruption was noted in 1 patient as a side effect of CZOP, but disappeared soon after discontinuation. The eosinocyte counts were elevated in 2 patients, but these values were normalized after discontinuation.

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We carried out clinical studies on cefozopran (CZOP, SCE-2787). The results are summarized as follows.
Treatment with CZOP was made in 17 cases of pediatric bacterial infections including 2 cases of purulent tonsillitis, 11 cases of acute pneumonia and 2 cases each of urinary tract infections and enteritis. Results obtained were excellent in 12 cases, good in 2 cases, fair in 2 cases and poor in 1 case.
All of 9 isolated bacteria were eradicated by the treatment.
As side effects and laboratory test results, rash was observed in one case and transient increase of platelets in one case, slight increase of eosinophil in 2 cases and transient elevation of GPT and GOT·GPT in one case.

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Cefozopran (CZOP, SCE-2787), a new parenteral cephem, was evaluated for its antibacterial activity and clinical efficacy. CZOP, 24.0-78.0mg/kg/day, was given to 11 pediatric patients in 3 dose a day via 30-minute drip infusion.
Clinically evaluated were nine patients including 4 with acute pneumonia, 2 with urinary tract infections, 2 with lymphadenitis and 1 with sepsis. Two patients were excluded because of possible non-bacterial infections. Clinical efficacies were excellent in 5, good in 3 and fair in 1.
Bacteriological responses were confirmed for 5 strains in 5 patients. Four strains were eradicated, but one strain was not. MICs of CZOP were equal to those of ceftazidime.
Side effects or abnormal laboratory test results were observed in 3 patients; diarrhea in 1, elevated GPT in 1 and thrombocytosis in 1, but none of them was significant.

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Cefozopran (CZOP) was administered via intravenous injection to 9 patients (ages ranging from 1 month to 13 years) with pediatric bacterial infections, at daily dose levels between 56.7 and 200mg/kg, divided into 3 or 4 doses. The following results were obtained.
1. Eight patients, including 1 with purulent meningitis, 1 with sepsis, 3 with acute pneumonia and 3 with lymphadenitis, were treated and subjected to clinical evaluation. Clinical effects were excellent in 6 cases and good in 2, with an overall efficacy rate of 100%. One case with pyoderma was not evaluated because of a combined use of an external antibiotic.
2. Organisms suspected as pathogens included 5 strains: 3 strains of Haemophilus influenzae, 1 strain of Staphylococcus aureus and 1 of Escherichia coli. Bacteriologically, all the strains were eradicated.
3. Side effects or abnormal laboratory test results were observed in 4 cases; wheal in 1 case, elevated GOT and GPT in 2 cases and eosinophilia in 1 case.
4. From the results described above, we considered that CZOP would be an effective drug for use in pediatric bacterial infections.

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Blood and urine levels of cefozopran (CZOP) were determined, and its efficacy and safety profile was evaluated in the field of pediatrics. The results of this study are summarized as follows.
1. Blood levels of CZOP peaked in 30 minutes to 1 hour (initial blood collection) after intravenous administration at a dose of 20 or 40mg/kg. Its blood levels at 6 hours after intravenous administration were 1.6μg/ml (HPLC) or 1.9μg/ml (bioassay) at a dose of 20mg/kg and 2.9 to 9.1μg/ml (HPLC) or 2.9 to 8.4μg/ml (bioassay) at a dose of 40mg/kg. The half-lives were 1.58 to 2.27 hours (HPLC) and 1.53 to 1.85 hours (bioassay), respectively. The rate of recovery of CZOP in the urine in the first 8 hours after intravenous administration at a dose of 20mg/kg was 61.5% (HPLC) or 54.6% (bioassay), and urine levels of CZOP at 6 to 8 hours after administration were 157.3μg/ml (HPLC) and 129.7μg/ml (bioassay).
2. When CZOP was administered to 16 patients with respiratory tract infections, 2 patients with urinary tract infections, 2 patients with acute enteritis, 1 patient with skin soft tissue infection, and 1 patient with purulent lymphadenitis, the responses were excellent in 68% of patients and good in 32% with an overall efficacy rate of 100%.
3. Bacteriological effect of CZOP was excellent and the rate of bacterial eradication was 100% (9/9).
4. MICs of CZOP against clinical isolates (Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Streptococcus pneumoniae, Escherichia coli, Moraxella (Branhamella) catarrhalis) were compared to those of other injectable cephems ceftazidime (CAZ), cefuzonam (CZON), flomoxef (FMOX), cefmetazole (CMZ). The MICs of cefozopran (CZOP) against Gram-positive organisms, S. aureus, MRSA, and S. pneumoniae, were nearly as low as those of CZON and were clearly lower than those of CAZ. MICs of CZOP against Gram-negative organisms were examined and the MIC against E. coli was as low as those of other antibiotics but the MIC of CZOP against M.(B.) catarrhalis was higher, at 1.56μg/ml, than those of CAZ, FMOX, and CMZ.
5. Diarrhea was experienced by 1 of 22 patients as a side effect from CZOP, and abnormal laboratory tests including increases of eosinophil counts in 2 patients (9.1%), a decrease of neutrophil counts in 1 patient (4.5%), thrombocytosis in 1 patient (4.5%), and an elevation of GPT in 3 patients (13.6%). These events were all so mild that they had no clinical implications.
Based on the results presented, it may be reasonably concluded that CZOP has high efficacy and safety when used in the treatment of various types of bacterial infections and that it can be a drug of first choice for bacterial infections in the field of pediatrics.

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We conducted clinical studies on cefozopran (CZOP), a newly developed parenteral cephalosporin, for its clinical application in the field of pediatrics.
1. A clinical study was performed on 16 children with infections, including 9 with pneumonia, 1 each with acute bronchitis, enterocolitis, purulent lymphadenitis, 4 with skin and soft tissue infections.
CZOP was administered by 30 minutes intravenous drip infusion. Doses varying from 20 to 35mg/kg body weight were given t. i. d. Lengths of treatment ranged from 4 to 14 days.
2. Clinical efficacies were excellent in 10 and good in 6 cases, with an efficacy rate of 100%.
The overall bacterial eradication rate for the pathogenic bacteria was also 100%.
3. Side effect was noted in 1 case with skin rash. Abnormal laboratory test data were found in 5 cases including slight elevations of GPT in 4 cases and GOT in 2 cases.

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Cefozopran (CZOP, SCE-2787) was given intravenously to 12 children with acute bacterial infections including 9 with acute pneumonia, 1 each with acute pyothorax, impetigo and staphylococcal scalded skin syndrome.
Good or excellent clinical responses were obtained in all of the 12 patients and bacterial eradications were achieved for all 10 strains identified in these cases.
No side effects were noted. Eosinophilia was observed in one case, however.
From the above clinical results, it appears that CZOP is a useful antibiotic for treatment of pediatric patients with various bacterial infections.

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Cefozopran (CZOP, SCE-2787), a newly developed parenteral cephem antibiotic, was administered to children with bacterial infections. We determined its antibacterial activity, pharmacokinetics, efficacy and safety in these patients.
1. Antibacterial activity
MICs of cefmetazole, ceftazidime, cefuzonam, flomoxef and CZOP were determined against a total of 19 strains. For Gram-positive cocci, MICs of CZOP ranged from 0.39 to 0.78μg/ml against Staphylococcus aureus(3 strains), from 0.05 to 6.25μg/ml against Streptococcus pneumoniae(5 strains), and 12.5μg/ml against Enterococcus faecalis(1 strain). These MICs were generally similar to those of other cephems, but the MIC of CZOP against E. faecalis was lower than those of the other cephems examined. For Gram-negative bacilli, MICs of CZOP were 25μg/ml against Citrobacter freundii(1 strain), and 6.25μg/ml against Pseudomonas aeruginosa(1 strain). These values were similar to or lower than those of other cephems, MICs of CZOP against Haemophilus influenzae(7 strains) ranged from 0.1 to 0.39μg/ml. However, the MIC of CZOP against Serratia marcescens(1 strain) was higher than 100μg/ml, and CZOP was as ineffective as the other cephems against this organism.
2. Pharmacokinetics
CZOP was administered to children at 20 or 40mg/kg via intravenous injection, and determinations were made for its serum concentrations, urinary concentrations and concentrations in cerebrospinal fluid (CSF) using the bioassay.
Serum concentrations at 30 minutes after administration were 60.4μg/ml with a dose of 20mg/kg to one patient and 93.9 and 99.0μg/ml with 40mg/kg to two patients. The corresponding half-lives were 1.55 hours for 20mg/kg administration, and 1.10 and 3.41 hours for 40mg/kg, while the AUCs were 136.5μg·hr/ml for 20mg/kg, and 194.4 and 264.5μg·hr/ml for 40mg/kg.
The rates of urinary recovery in the first 8 hours after administration were 45.0% in the patient receiving 20mg/kg, and 84.6 and 97.6% in the two patients receiving 40mg/kg.
The concentrations in the CSF determined in 3 patients with purulent meningitis ranged from 2.6 to 16.0μg/ml 1 hour after administration, and the CSF/serum concentration ratio ranged from 6.5 to 39.0%.
These values for pharmacokinetic parameters obtained in the bioassay were similar to those obtained using HPLC.
3. Clinical evaluation
Forty-eight patients were clinically evaluated. Of these patients, 75% were less than 3 years of age and there were slightly more male children than female children. Most of the patients were administered with about 20mg/kg of CZOP 3 or 4 times per day, and were treated for 6 to 10 days. Forty-six of the 48 patients including 2 with purulent meningitis showed excellent or good clinical responses, yielding an efficacy rate of 95.8%. One patient with pharyngo-laryngitis, 3 with sinusitis, 2 with purulent meningitis, 7 with urinary tract infections, 1 with impetigo, 3 with staphylococcal scalded skin syndrome and 2 with phlegmon were rated as having excellent or good clinical responses to the treatment. The efficacy rate was 96.2%(25/26) against pneumonia, and 2 of 3 patients with purulent lymphadenitis were rated as showing good clinical responses. Causative organisms were detected in 18 cases and 22 strains were isolated. With regard to Gram-positive cocci, one strain each of S. aureus, Staphylococcus epidermidis and E. faecalis that were identified, and 5 detected strains of S. pneumoniae were all eradicated. One strain of Enterococcus faecium was decreased in number upon treatment. With regard to Gram-negative bacilli, eight of 9 H. influenzae strains were eradicated, but 1 strain was unchanged in number upon treatment.

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