A simple method has been developed for the determination of the aminoglycoside antibiotic isepamicin (ISP) in whole blood, using dried blood spots (DBSs) on filter-paper. ISP in the DBSs were recovered most effectively in 0.5 M Na2HPO4-NaH2PO4 buffer (pH 7) by incubation for 30 minutes at 35°C in an ultrafiltration tube. The eluates from the DBS papers were centrifuged at 3,000×g for 10 minutes. The clear, colorless filtrates were transferred to an Abbott TDx cartridge for measurement by the fluorescence polarization immunoassay. The lower limit for the quantitative determination of ISP in the DBS was 2.5μg per ml of whole blood. The method permits a simple collection of blood at a microliter level and should prove particularly useful for therapeutic drug monitoring of ISP in blood at effective levels in pediatric and geriatric patients.

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An in vitro study was done to evaluate combination use of aspoxicillin (ASPC) with each of β-lactam preparations, ceftazidime (CAZ), cefmetazole (CMZ) and aztreonam (AZT). The results obtained are summarized as follows:
1. ASPC has strong activity against Gram-positive bacteria and anaerobic bacteria, while CMZ and CAZ have strong activity against Gram-negative bacteria.
2. Rates of β-lactamase producing strains among the isolated bacteria (a total of 383 isolates) were 4.4% among Gram-positive bacteria, 71.6% among Gram-negative bacteria and 89.3% among anaerobic bacteria. The overall rate of β-lactamase secreting strains among all isolates was 46.5%.
3. Efficacies of combination uses were studied using the FIC index. Combination of ASPC and CAZ was effective against 95.0% of the isolates, ASPC and AZT against 85.7%, and ASPC and CMZ against 83.5%. Combination of ASPC and CMZ showed antagonism in 12.8% of the isolates.
In conclusion, combination use of ASPC with any one of CMZ, AZT or CAZ proved to be highly effective. In particular, combination of ASPC and CAZ appeared to be the best in view of complementing antibacterial spectra.

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Anitibiotic activities (MICs) of ceftriaxone (CTRX) against 1,210 strains of bacteria including 28 spp. isolated in 1987 and 1990 were compared with those of other cephems.
1. When compared to data on clinically isolated strains reported in the early 1980s, strains of the following species isolated in 1990 showed extremely elevated MIC9os of CTRX: Staphylococcus spp., Streptococcus pneumoniae, Escherichia coli, Citrobacter spp., Enterobacter spp., Serratia spp., Proteus vulgaris, Morganella morganii and Providencia spp. No changes were observed in MIC9os between the 2 periods for microorganisms such as Streptococcus pyogenes, Haemophilus influenzae, Klebsiella pneumoniae, Proteus mirabilis and Peptostreptococcus spp.
2. The MIC90 of CTRX to S. pneumoniae was high because a large number of benzylpenicillin (PCG)-insensitive S. pneumoniae (PISP) was present among this species. The MIC80 to Bacteroides fragilis group was also high because highly resistant B. fragilis and B. thetaiotaomicron were isolated in large proportions among the bacteria of this group. Other oxime-type cephems also had high MICs against the above mentioned bacteria. Therefore, a further evaluation has to be made with regard to activities of oxime-type cephems such as CTRX against PISP and B. fragilis group.
3. Sample strains included, in high ratios, methicillin-resistant Staphylococcus aureus-(MRSA), cephamycin-resistant as well as oxime-type cephem-resistant intestinal bacteria, Gram-negative bacteria, and new-quinolone-resistant bacteria. Some of there resistant bacteria are also CTRXresistant, and CTRX had insufficient activities against them.
4. With regard to the assessment of changes of frequencies of specific drug-resistant bacteria, including those with CTRX-resistance from year to year, the authors would like to point out the following comment of theirs made in 1989 and 1991, which appears to be increasing its significance, Subjects of future studies should include dose on the mechanisms for the acquisition of bacterial resistance to entire β-lactam antibiotics and the social circumstances in which resistant bacteria appear.
5. It appears that those strains resistant to cephems including CTRX are increasingly found among clinically isolated strains in recent years. CTRX, however, was found still effective against most clinical pathogens. Furthermore, considering that CTRX is one of the few drugs which sustain high blood concentrations of active forms we concluded that CTRX is a useful cephemgroup antibiotic.

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In an open, multicenter trial, we investigated the clinical efficacy of a combination therapy of ceftazidime (CAZ) and tobramycin (TOB) for intractable pulmonary infections mainly caused by Pseudomonas aeruginosa.
Evaluated for the utility of the combination therapy were 33 cases with pneumonia (Group I: pneumonia caused by P. aeruginosa 15, Group II: pneumonia caused by other Gram-negative bacilli 4 and pneumonia which causative organism was not determined 14) and 23 cases with chronic respiratory tract infection caused by P. aeruginosa.
The results obtained are summarized as follows.
1. In Group I pneumonia, included 11 severe cases and 4 moderate cases, with a mean age of 69.3 years. Significant underlying diseases were present in 14 out of the 15 (93.3%): they included 10 cases of pulmonary diseases and 4 cerebrovascular diseases. The overall efficacy rate in these cases was 60.0%: but the efficacy rate in moderate cases was 100% and that in severe cases was 45.5%.
2. In Group II pneumonia included 16 severe cases and 2 moderate cases with a mean age of 68.2 years. Significant underlying diseases were present in 15 out of 18 (83.3%, all of the underlying diseases were pulmonary diseases) and the overall efficacy rate was 72.2% with 100% efficacy rate among moderate cases and 68.8% among severe cases.
3. In the cases with chronic respiratory tract infections caused by P. aeruginosa, the efficacy rate was 82.6% and the eradication rate was 65.2%.
We consider the combination therapy of CAZ and TOB is useful for intractable pulmonary infections caused by P. aeruginosa.

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The transferability of meropenem (MEPM) to cereblospinal fluid (CSF) was studied employing rabbits with experimental meningitis caused by Staphylococcus aureus.
The mean serum concentration was 93.1±13.5μg/ml at 15 minutes after intravenous administration of MEPM at a dose level of 100 mg/kg. The mean concentration in CSF was maximum at 15 minutes after administration at 4.42±2.24μg/ml.
Pharmacokinetic parameters calculated from these values were as follows: Cm.(CSF/serum) 4.75%, AUC (CSF/serum) 10.4% between 15 and 60 minutes, 13.9% between 15 and 120 minutes and 15.7% between 15 and 180 minutes, T 1/2 for MEPM in CSF: 50.9 minutes, T 1/2 (CSF/serum): 2.19.
In comparison to those of imipenem which were obtained in the same way, the transferability of MEPM was similar and in consideration of the antimicrobial potency against the main pathogens of meningitis, it appears worth-while of running clinical trials for this drug.

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Twenty-five children were treated with meropenem (MEPM, SM-7338) and the clinical efficacy and side effects were evaluated. Ages of the patients ranged from 9 months to 11 years. Dose levels of MEPM ranged from 50.4 to 108 mg/kg/day for 4 to 8 days. The 25 patients included 11 pneumonia cases, 4 bronchitis, 6 tonsillitis, 3urinary tract infections and 1 gingivitis, and they were evaluated for the clinical efficacy of MEPM. Results were excellent in 13 and good in 12 patients. No side effects nor abnormal clinical laboratory test results were observed.
The pharmacokinetics of MEPM was studied in 7 patients with ages ranging from 9 to 15 years. The mean plasma peak concentration of MEPM in 5 patients was 36.7 lug/ml after dosing 10 mg/kg, and that of 2 patients was 70.0, ug/ml after administering 20mg/kg. These data showed that plasma concentrations of drug depended on dose levels. Average half-life values for the 2 groups (10 and 20mg/kg) were 0.83 and 0.85 hour, respectively. Urinary recovery rates for the 2 groups (10and 20mg/kg) were 64.3% and 81.3%, respectively, in the first 5 hours after administration.

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A clinical study on a new carbapenem antibiotic, meropenem (MEPM), was carried out in acute pediatric infections. MEPM was administered to 8 patients including 3 patientswith acute pneumonia, 2 with cervical lymphadenitis, 1 with acute tonsillitis, and 1 with cellulitis and 1 with sepsis.
The overall efficacy rate was 100%. As an adverse reaction, diarrhea was observed in 1 patient.
In clinical laboratory tests 1 patient was found to have S-GPT elevation which normalized after discontinuation of MEPM.
MEPM appears to be effective and safe drug for pediatric acute infections.

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Pharmacokinetic, bacteriological and clinical studies on meropenem (MEPM) were performed in children.
The results are summarized as follows:
1.A total of 16 patients was treated with MEPM.Each dose was 20 mg/kg, and administration was made 3 times daily using 30-minute intravenous drip infusion for 5-28 days. Clinical efficacies of MEPM in 16 patients with bacterial infections (1 with purulent meningitis, 1 with suspected subdural abscess, 2 with suspected sepsis, 4 with pneumonia, 1 with acute maxiller sinusitis, 2 with cervical abscess, 1 with acute gastroenteritis, 2 with skin soft tissue infection and 2 with urinary tract infection) were evaluated as excellent in 7 patients, good in 8 patients and fair in 1 patient with an efficacy rate of 93.8%. Fourteen causative organisms found in 11 patients (Streptococcus peumoniae in 4, Branhamella catarrhalis in 3, Staphylococcus aureus in 3, Group B Streptococcus in 1, Escherichia coli in 3) were all eradicated.
No adverse reactions were observed in any of the 16 patients.
2. MICs of MEPM against 6 clinically isolated bacteria (B.catarrhalis 2, S.pneumoniae 3 and S.aureus 1) from children with bacterial infections were examined.MEPM showed good antibacterial activities.
3. Pharmacokinetic studies
Peak plasma concentrations of MEPM averaged 43.07, ug/ml (37.20-46.30fig/ml) at dose of 20mg/kg administered by 30-minute drip infusion.
In the first 8 hours after administration, the urinary excretion rates of MEPM averaged 39.9% of the administered dose. CSF concentration/plasma concentration of MEPM were 4.22/16.6 on Day 2 and 1.77/11.1 on Day 5, 1.5 and 2.0 hours after administration of a dose of 40 mg/kg by 30-minute drip infusion to a child with purulent meningitis (case1).
The average plasma half-life of MEPM in the β-phase was 0.79 hours (0.56-1.12 hours).
Based on the above results and the extremely broad spectrum of antibacterial activities of MEPM, it appears that MEPM is a promising antibiotic usable as a single agent for the primary therapy of severe infections in children and immunocompromized hosts.

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Pharmacokinetic and clinical evaluations of meropenem (SM-7338, MEPM) were carried out in pediatric patients.
The following results were obtained.
1. After 30-minute intravenous drip infusion at a dose of 20 mg/kg, plasma concentrations of MEPM reached their peaks at the end of drip infusion with an average value of 48.8±3.64μg/ml, and the average plasma half-life was 0.93±0.21 hour in theβ-phase.Afrer 30-minute intravenous drip infusion at a dose of 10mg/kg, the average peak plasma concentration was 27.7±4.33μg/ml and the average plasma half-life was 0.78±0.20hour.
2. Urinary excretion rates of MEPM after 30-minute intravenous drip infusion at doses of 20 and 10 mg/kg were 44.8±4.54% and 40.9±1.78%, respectively.
3. MEPM was administered to 13 cases (upper and lower respiratory infections, pneumonia and lymphadenitis) at daily doses between60-90mg/kg/day divided into 3 dosages using 30-minute intravenous drip infusion.Clinical responses were excellent in 12 patients, good in 1, hence an efficacy rate of 100% was obtained.
4. Bacteria identified in various disease cases incuded 12 strains of 5 species, and the eradication rate was 100%.
5. No side effects were observed in any children.Laboratory test results showed abnormalities in 2 cases with elevations of GOT and GPT.
These results suggest that MEPM may be a very useful and safe drug for the treatment of pediatric infections.

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We studied clinical effects of meropenem (MEPM, SM-7338), a newly developed parenteral carbapenem β-lactam drug, and following results were obtained.The patients were administered with 16-20 mg/kg of MEPM every 8 hours using 1 hour drip infusion.
1. Clinical effects of MEPM were studied in 10 children with various infectious diseases: 1 with acute bronchitis, and 2 each with acute tonsillitis, acute bronchopneumonia, acute pneumonia, acute urinary infection, and 1 with pertussis pneumonia.The case of pertussis pneumonia later developed bronchiolitis obliterans, hence a steroid and 7-globulin were used. This case was excluded from the clinical evaluation. The efficacy rate was 100% (9/9), and the bacteriological eradication rate was 100% (6/6).
2. No side effects were noted.Clinical laboratory test values were investigated in 10 patients. There was a case of abnormal laboratory test findings with mild elevations of liver functions such as GOT, GPT, and γ-GTP.These abnormalities disappeared in 1 week after the end of therapy.

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Pharmacokinetic and clinical studies on meropenem (MEPM, SM-7338), a new developed carbapenem, were performed and the following results were obtained.
1. Absorption/excretion
Pharmacokinetics of MEPM was studied in 9 children using doses of 10 mg/kg and 20mg/kg by a 30 minute-drip infusion.
Peak plasma levels and plasma half-lives of the 2 doses were 28.4 and 43.0μg/ml, and 0.70 and 0.80 hours, respectively.
Their urinary recovery rates were 42.5 to 67.6% and 29.9 to 62.6%, respectively.
Cerebrospinal fluid levels and penetration rates of MEPM in a patient with prulent meningitis were 0.66 to 4.01μg/ml and 1.6 to 12.2%, respectively.
2. Clinical study
Forty-nine patients were treated with MEPM at doses exceeding 100mg/kg/day with prulent meningitis and 30 to 60mg/kg/day with other infections.
MEPM gave excellent or good responces in 48 cases, an efficacy rate of 98.0%. Only one patient with subdural abscess showed fair response.
Diarrhea and rash were observed in 1 case each. Abnormal laboratory test results were noted in 5 patients including elevation of GOT, GPT and eosinophils. In no cases the treatment had to be discontinued.

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A new carbapenem antibiotic, meropenem (MEPM), was evaluated for its safety and efficacy in 33 infants and children. MEPM was effective in all the 32 evaluable cases including 4 cases of bacterial meningitis and 5 cases of Pseudomonas aeruginosa infections.
The mean half life of plasma concentrations of MEPM was 0.84±0.09 hours after 30 minutes intravenous drip infusion. Mild diarrhea (2 cases), transient elevation of transaminases (8 cases), and transient eosinophilia (2 cases) were associated with the MEPM therapy, but none of them was problematic.
These data suggest that MEPM is safe in infants and children and could be one of the therapeutic agents for severe infections or infections in compromised hosts.

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Laboratory and clinical studies on meropenem (MEPM), a new carbapenem antibiotic, were carried out in the field of pediatrics.
The results obtained are summarized below.
1. The antibacterial activities of MEP1M against clinically isolated organisms in our department were generally high.
2. After 30 minutes intravenous drip infusion ofMEPM at a dose of 20mg/kg to 2 children, the mean peak plasma level of MEPM was 32.7μg/ml at the end of infusion with a mean half-life of 1.45hours.The mean cumulative urinary recovery rate in the first 6 hours after infusion was 43.6%.
3. Fifteen patiens with various bacterial infections were treated with MEPM. The clinical efficacy rate was 100% and the bacteriological efficacy rate was 95.2%.
4. No side effects were observed except in 1 case of mild diarrhea.Some abnormal laboratory test results were obtained, but they were mild with slight elevations of GOT and GPT in 2 cases.

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We have carried out clinical studies on meropenem (MEPM, SM-7338), the results are summarized as follows.
Treatment with MEPM was made in 13 cases of pediatric bacterial infections including 9 cases of pneumonia and 2 cases of colitis and 1 case each of purulent tonsillitis, and pharyngitis. Results obtained were excellent in 10 cases, good in 3 cases.
No significant side effects due to the drug were observed in any cases, expect in 1 case each of eosinophilia, elevated β-GTP, elevated total bilirubin and elevated GPT.

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The pharmacokinetics and the clinical effectiveness of meropenem (MEPM) were examinied in the field of pediatrics. The results are summerized as follows.
1.A 4-year-6-month-old girl with suppurative meningitis (Haemophilus influenzae) was treated by intravenous drip infusion of MEPM in a daliy dose of 29 mg/kg which was divided into 4 dosages, each dosage being infused over 30 minutes, and the drug concentration in cerebrospinal fluid was determined. Upon completion of infusion on the 2nd day of treatment, the drug concentration was 2.52μg/ml, which corresponded to 3.6% of the drug concentration in the blood.
2.MEPM was used in 10 patients, including 3 with suppurative lymphnoditis, 2 with staphylococcal scalded skin syndrome (SSSS) and 1 each with pneumonia, suppurative meningitis, suppurative knee arthritis, facial phlegmon and pyelonephritis.The daily doses ranged from 30 to 117.6 mg/kg, divided into 3 to 4 dosages and administered via intravenous drip infusion over 30 minutes.Clinical responses were evaluated as very good in 7 patients, good in 2 patients and fair in 1 patient, with an efficacy rate of 90%.
3.Isolated pathogens were 2 strains of Staphylococcus aureus, 1 strain of Klebsiella pneumoniae and 3 strains of Haemopilus influenzae.All of the 6 strains were eradicated, with an eradication rate of 100%.
4.In the safety evaluation, none of the patients was observed to have any side effects. Furthermore, no abnormal variations were found in laboratory test data possibly attributable to administration of MEPM.

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