1. Biliary excretion
Cefoperazone (CPZ) in a dose of 1g was intravenously injected to each of 13 cases with obstructive jaundice. Entire bile was collected through percutaneous transhepatic cholangiodrainage (PTCD) catheter in every 1 hour for 6 hours.
(1) The mean concentration of CPZ in serum was 112.1±17.8μg/ml (mean±S.E.) at 1 hour and 55.1±19.2μg/ml at 6 hours after injection.
(2) The mean recovery of CPZ in bile within 6 hours was 1.13±0.60%. Average CPZ concentrations in bile were 64.0±45.8μg/ml in the 1 hour fraction, 142.7±78.4μg/ml in the 2 hours fraction and 72.2±34.0μg/ml in the 6 hours fraction.
(3) Biliary excretion of CPZ was low in cases where the serum concentration of total bilirubin was high, but maximum CPZ level in bile in patients with higher serum bilirubin concentrations than 30mg/dl was still more than 3μg/ml.
2. Clinical evaluation
CPZ was administered to 43 patients with biliary tract infections.
(1) The efficacy ratio was 88.4% (excellent and good cases) in all cases, and especially high in cases with cholecystolithiasis. But no difference in efficacy ratio was observed among cases with cholecystolithiasis, choledocholithiasis without gallstone and cases subjected to PTCD.
(2) In 10 patients examined by ultrasonography, 8 cases showed reduced diameters of gallbladder.
(3) No adverse effect of CPZ was noted in any cases.
These results suggest that a fairly large portion of CPZ was excreted through bile and that CPZ is a very useful drug for the treatment of biliary tract infections.

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Ceftizoxime (CZX) were administered and tested for the efficacy and safety in 80 eldery patients who were older than 65 years of age with infections. The sensitivity of bacteria found in these infections to CZX was examined before the administration of the drug. Serum concentrations and the rate of urinary output of the drug were examined in 3 cases.
1. The clinical effect of CZX was as follows: 29 cases (36.3%) of excellent effectiveness and 31 cases (38.8%) showed moderate effectiveness. The patients were divided into 2 groups depending on the presence or the absence of other diseases in their backgrounds. Effectivenesses of CZX for patients with and without other diseases were 74.0% and 85.7%, respectively. The effectiveness of CZX in patients with other diseases in their background was lower than the group without other diseases.
2. Other antibiotics were used in 16 cases before the use of CZX. The effectiveness of CZX for these patients was 62.5%.
3. Infecting bacteria were detected in a total of 46 cases (19 cases of respiratory infections and 27 cases of urinary tract infections). Among the respiratory cases, 8 were due to Gram-positive bacteria and 11 were due to Gram-negative bacteria. No Gram-positive organisms were detected from urinary tract infections, which were all due to Gram-negative bacteria. Sensitivities of isolates of these infecting bacteria to CZX were very sensitive (+++) 37 isolates, sensitive (++) 8 and slightly sensitive (+) 1 isolate.
It was found that CZX was effective against 39 of 46 cases from which causative organisms were identified. The effectiveness ratio was 84.8%.
4. Serum concentration of CZX was determined after a drip injection of 1g CZX for 1 hour. The half-lives of CZX in plasma in healthy subjects and aged patients were 1.33 hours and 2.15 hours, respectively. The rate of urinary output of CZX during 6 hours after the injection was 76.4% in healthy subjects. Delayed urinary output which was 58.2% during 7 hours after injection was observed in aged patients.
5. Fever in 1 patient and eosinophilia in 3 cases were observed after administration of CZX.

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Nineteen episodes of infection in 17 children (one had 3 episodes) were treated with imipenem/cilastatin sodium (MK-0787/MK-0791), and the clinical efficacy and side effects were evaluated. The ages of patients ranged from 1 month to 8 years 1 month and their body weights ranged from 3.9 to 25.2kg. The MK-0787/MK-0791 was administered intravenously by a 30-60 minutes infusion, in doses ranging from 8-42 mg/8-42mg/kg every 6 to 12 hours for 3 to 40.5 days. Among 18 episodes in 16 patients (one patient proved to have rubella meningoencephalitis and was excluded from evaluation of the clinical efficacy) with bacterial infections including sepsis, pneumonia, acute suppurative thyroiditis and urinary tract infections, the results were excellent in 10, good in 5, fair in 2, and poor in 1 episode. Some side effects were noted; among all 19 episodes in the 17 patients diarrhea was noted in 3, rash in 1, slightly elevated serum transaminases in 1 and thrombocytosis in 1 episode.
Pharmacokinetic studies were done in 7 patients whose ages ranged from 3 years 2 months to 13 years 1 month. Plasma concentrations of MK-0787 in 2 children were 19.6 and 20.0μg/ml at 15 minutes and 5.6 and 2.1μg/ml at 2 hours after a 10mg/10mg/kg intravenous 30-minute drip infusion of MK-0787/MK-0791. Plasma half-lives of MK-0787 were 1.52 and 0.74 hour, and total urinary recoveries were 54.6 and 71.4% during 0-6 hours. After a 20 mg/20mg/kg intravenous 30-minute drip infusion into 2 other children, plasma concentrations of MK-0787 were 46.8 and 44.0μg/ml at 15 minutes and 7.8 and 7.4μg/ml at 2 hours. Plasma half-lives were 0.82 and 0.83 hour, and total urinary recoveries were 110.2 and 80.5% during 0-6 hours. Plasma concentrations of MK-0787 were <0.2, 0.2 and 1.2μg/ml just before the next doses in 3 patients given 11-20 mg/11-20mg/kg of MK-0787/MK-0791 every 6-8 hours. The time course of the plasma levels and urinary excretion in these patients were similar to those noted in the previous 4 patients following a single dose.
Plasma concentrations of MK-0787 in a girl were 0.3μg/ml just before the next dose and 8.2μg/ml at 2 hours after multiple doses of 14 mg/14mg/kg every 6 hours for 3 days and then 28mg/28mg/kg every 6 hours for 35 days.
Cerebrospinal fluid levels of MK-0787 at 195 and 180 minutes after drug administration were 0.5 and 2.4μg/ml on the 2nd and 4th days of treatment in a boy with rubella meningoencephalitis who was given 42mg/42mg/kg of MK-0787/MK-0791 every 6 hours. Concentrations of MK-0787 in the cerebrospinal fluid were 2.7 and 23.5% of those in the plasma.

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Nine pediatric patients with moderate or severe bacterial infections (3 septicemia or bacteremia, 2 pyelitis, 2 tonsillitis, 1 pneumonia and 1 pyothorax) in hospital were treated with MK-0787/MK-0791. The drug was administered intravenously by 30 or 60 minutes drip infusion in 3 or 4 divided doses totalling 24mg/24mg-70.2mg/70.2mg per kg/day. Clinical effectiveness were excellent in 4 cases, good in 2 cases, poor in 2 cases and not evaluated in 1 case. The overall efficacy rate was 75%.
A slight decrease of WBC was observed in 1 case.
It was concluded that MK-0787/MK-0791 was a useful antibiotic for the treatment of infections in pediatric practices.
Pharmacokinetics of intravenously administered MK-0787/MK-0791 was studied in 2 other cases.
The MK-0787/MK-0791 was administered intravenously by 30 or 60 minutes drip infusion to 2 cases at a dose of 10mg/10mg/kg. The mean half-life (T 1/2) of MK-0787 was 1.03 hours and MK-0791, 0.69 hour. The mean urinary recovery rate of MK-0787 within 6.5-7 hours after administration was 62.5% and MK-0791, 76.7%.

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A clinical study on imipenem/cilastatin sodium (MK-0787/MK-0791) was carried out and the following results were obtained.
1. MK-0787/MK-0791 was used for treatment of a total of 33 patients and clinical effectiveness, bacteriological efficacy and adverse reactions were evaluated.
2. The clinical effects were excellent in 1 case, good in 21 cases and fair in 2 cases in a total of 24 cases with respiratory tract infections, were excellent in 5 cases and good in 1 case in a total of 6 cases with urinary tract infections, and were good in 2 cases and fair in 1 case in a total of 3 cases with gastroenteritis.
3. Causative organisms isolated from 11 patients were 1 strain of Gram-positive cocci and 10 strains of Gram-negative bacilli. Ten out of 11 strains were eradicated for an eradication rate of 91%. The clinical efficacy was confirmed in 11 cases for an efficacy rate of 100%. The bacteriological study has shown that MK-0787/MK-0791 has a strong antimicrobial activity.
4. No side effects were observed. There was only one abnormal laboratory finding, i.e., a case of eosinophilia.

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Clinical studies on imipenem/cilastatin sodium (MK-0787/MK-0791) was carried out in 12 patients in pediatric field.
The overall efficacy rate was 83.3%. As for adverse reaction, soft stool was observed in 1 patient.
In clinical laboratory findings, there was 1 patient with granulocytopenia.

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Imipenem/cilastatin sodium (MK-0787/MK-0791) was evaluated for its safety, efficacy and pharmacokine-tics in children. Thirty cases of bacterial infections were treated with MK-0787/MK-0791 at a daily dose of 40 to 222mg/kg for 2.25 to 13 days. Clinical cure rate was 93% and bacteriological efficacy rate was 88%. Treated diseases included severe tonsillitis due to mixed anaerobic infections, pneumonia, sepsis, brain abscess and soft tissue infections. Two cases, one with periosteomyelitis due to methicillin-resistant S. aureus and the other with pulmonary abscess due to Haemophilus influenzae (other than type b), failed to respond to the MK-0787/MK-0791 therapy.
The serum half-life of MK-0787 was 0.892 hour in children with normal renal functions. An episode of convulsions in a case of sepsis with bacterial croup and brain edema was considered to be associated with the MK-0787/MK-0791 therapy.
From the present study, MK-0787/MK-0791 appears a safe and effective anitibiotic when used in children with a variety of bacterial infections.

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Imipenem/cilastatin sodium (MK-0787/MK-0791) was evaluated for its safety and efficacy in 7 pediatric patients with infections.
The clinical efficacy ratio was 100 percent.
No side effect was observed except for elevations of S-GOT and S-GPT and eosinophilia in 1 patient.
It may be considered that MK-0787/MK-0791 is a safe and useful antibiotic for the treatment of pediatric infections.

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Fundamental and clinical evaluations of imipenem/cilastatin sodium (MK-0787/MK-0791) were carried out in pediatric patients.
The following results were obtained:
1. After intravenous drip infusion of single doses of 10mg/10mg/kg to 20mg/20mg/kg of MK-0787/MK-0791 in children, peak plasma levels of MK-0787 ranged from 32.0 to 82.0μg/ml at the end of the infusion. The half-life was 49.9 to 64.0 minutes.
2. The cumulative urinary recovery at 6 to 7 hours after the 1 hour drip infusion ranged from 65.5 to 88.9%.
3. Fecal levels of MK-0787 were 4.2 and 23.1μg/g at 6 hours after a 30-minute intravenous drip infusion of 200mg/200mg of MK-0787/MK-0791.
4. MK-0787/MK-0791 was administered by intravenous drip infusion to patients with purulent meningitis. Penetration into the cerebrospinal fluid was satisfactory, as were the clinical responses.
5. MK-0787/MK-0791 was administered clinically in doses of 30mg/30mg/kg/day to 200mg/200mg/kg/day by intravenous drip infusion 3 or 4 times a day for 3 to 22 days to 26 patients with acute pediatric infections. The clinical response was excellent in 18 patients and good in 8 patients.
6. Eradication occurred with 16 isolates; only two strains of Salmonella-B were not eradicated.
7. Anorexia in 1 patient was the only clinical adverse effect reported, and the only adverse effects found in laboratory tests were eosinophilia and thrombocytosis in 1 patient, respectively, and elevation of the S-GOT and S-GPT in 1 patient.

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Fundamental and clinical studies were performed on a newly developed carbapenem antibiotic, imipenem/cilastatin sodium (MK-0787/MK-0791), and results were summarized as follows.
The antibacterial activity of MK-0787 at an inoculum of 106 cells/ml against strains of S. aureus which were sensitive or resistant to cefazolin (CEZ), E. coli, P. mirabilis, K. pneumoniae, S. marcescens and P. aeruginosa were determined and compared with activities of ceftazidime (CAZ), CEZ, cefmetazole (CMZ), ceftizoxime (CZX), latamoxef (LMOX), cefamandole (CMD), cefoperazone (CPZ), cefsulodin (CFS) and piperacillin (PIPC).
The peak MIC of MK-0787 was ≤0.024μg/ml against S. aureus, which were sensitive or resistant to CEZ, 0.10μg/ml against E. coli, P. mirabilis, or K. pneumoniae, 0.39μg/ml against S. marcescens and 1.56μg/ml against P. aeruginosa.
The antibacterial activity of MK-0787 against these bacteria was, on the whole, superior to that of CAZ, CEZ, CMZ, CZX, LMOX, CMD, CPZ, CFS or PIPC.
The pharmacokinetics of MK-0787/MK-0791 was studied in 10 children at dose levels of 10mg/10mg/kg and 20mg/20mg/kg by a 30-minute intravenous drip infusion.
Maximum serum levels of MK-0787, at dose levels of 10mg/10mg/kg and 20mg/20mg/kg were 41.6μg/ml and 72.9μg/ml, respectively, at the end of infusion and 0.1μg/ml and 0.2μg/ml at 6 hours, respectively, after drip infusion. The half-life of both dose levels was 0.9 hour. Mean peak serum levels of MK-0791, at dose levels of 10mg/10mg/kg and 20mg/20mg/kg, were 49.7μg/ml and 87.0μg/ml, respectively, with half-life of 1.1 and 0.6 hour, respectively.
Urinary recovery rates of MK-0787 for 6 hours at dose levels of 10mg/10mg/kg and 20mg/20mg/kg, were 47.8-82.7% and 25.5-78.0%, respectively, and of MK-0791 for 6 hours were 51.7-93.4% and 40.3-94.4%, respectively.
Twenty-four patients, including 1 with purulent meningitis, 1 with septicemia, 1 with pyothorax, 10 with bronchopneumonia, 7 with pyelonephritis and 4 with infections of cutaneous soft tissue were treated with MK-0787/MK-0791 at dose levels of over 100mg/100mg/kg/day with purulent meningitis and septicemia and 28.8mg/28.8mg-72.8mg/72.8mg/kg/day with other infections. The clinical response in all patients was excellent or good.
No adverse reaction was observed. Abnormal laboratory findings were noted in 2 patients with the elevation of GOT, GPT, in one with the elevation of GOT and in another with thrombocytosis.

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Fundamental and clinical studies were carried out on imipenem/cilastatin sodium (MK-0787/MK-0791) in pediatric patients. The following results were obtained.
1. A total of 238 clinical isolates stocked by our department was employed to determine the minimum inhibitory concentrations (MICs) of MK-0787 against various species of bacteria. The MK-0787 showed strong antibacterial activities against E. coli, Salmonella, Klebsiella, Proteus, Serratia, E. faecalis and S. epidermidis. Somewhat weaker activities were observed against P. aeruginosa and S. aureus.
2. The MK-0787/MK-0791 was drip-infused intravenously into patients over a period of 1 hour, and serum levels of MK-0787 and MK-0791 were determined. At the dose level of 10mg/10mg/kg, the mean serum levels of MK-0787 and MK-0791 were 29.9μg/ml and 18.1μg/ml at 1 hour and 3.4μg/ml and 1.3μg/ml at 3 hours, respectively. The half-lives were 0.89 hour for MK-0787 and 0.99 hour for MK-0791.
At the dose level of 20 mg/20mg/kg, the mean serum levels of MK-0787 and MK-0791 were 46.3μg/ml and 45.2μg/ml at 1 hour and 5.5μg/ml and 3.1μg/ml at 3 hours, respectively. The half-lives were 0.97 hour for MK-0787 and 0.83 hour for MK-0791.
At the dose level of 40mg/40mg/kg, the mean serum levels of MK-0787 and MK-0791 were 104.0μg/ml and 80.9μg/ml at 1 hour and 7.8μg/ml and 5.9μg/ml at 3 hours, respectively. The half-lives were 0.92 hour for MK-0787 and 0.53 hour for MK-0791.
3. The total urinary recovery was determined for the first 6 hours after administration of MK-0787/MK-0791. The recovery was 9.5-105.9% for MK-0787 and 4.6-113.0% for MK-0791.
4. The penetration of MK-0787 and MK-0791 into the cerebrospinal fluid ranged from 3.0-8.3% of serum levels for MK-0787 and 1.1-10.8% for MK-0791.
5. The MK-0787/MK-0791 was administered to 13 patients with bacterial infections. Good or excellent clinical effects were observed in 12 patients (92.3%).
6. Eradication of bacteria was observed in all of 8 patients who were evaluated bacteriologically.
7. As a side effect, diarrhea was observed in 1 patient. Abnormalities in laboratory findings observed were thrombocytosis in 2 patients, elevation of GOT and direct bilirubin in 1, and elevation of GOT and GPT in 1 patient.

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Basic and clinical studies have been performed on imipenem/cilastatin sodium (MK-0787/MK-0791) in the pediatric field.
1. Antibacterial activities of MK-0787 against 14 clinical isolates of S. aureus and 67 isolates of E. coli were determined. The MIC of MK-0787 was 0.10μg/ml or less against all 14 strains of S. aureus. The MIC of MK-0787 was 0.39μg/ml or less against all 67 strains of E. coli.
2. The pharmacokinetics of MK-0787/MK-0791 was studied at dose levels of 10mg/10mg/kg and 20mg/20mg/kg. The peak serum levels of MK-0787 achieved approximately 1 hour after the administration of 10mg/10mg/kg and 20 mg/20mg/kg doses were 38.6μg/ml and 36.2μg/ml, respectively. The serum half-lives were 0.8 hour and 0.9 hour, respectively. The total 6-hour urinary excretions were 82.1% and 66.7%, respectively.
3. The MK-0787/MK-0791 was administered to 13 children with bacterial infections. The clinical results were excellent or good in all cases. The overall efficacy rate was 100%.
4. As a side effect, diarrhea was observed in 1 patient. Abnormalities in laboratory findings observed were elevation of direct bilirubin in 1 patient, thrombocytosis in 2, and a prolonged prothrombin time in 1 patient.
Based on the above results, it can be concluded that MK-0787/MK-0791 is a safe and effective drug to use for the treatment of pediatric infections.

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Imipenem/cilastatin sodium (MK-0787/MK-0791) was administered to pediatric patients with infections, and the following results were obtained.
1. Pharmacokinetic study
Two children, 11 years of age (38kg body weight) and 3 years of age (15.5kg body weight), were administered by 30 minutes intravenous drip infusion a single dose of 500mg/500mg (13.2mg/13.2mg per kg) and 250mg/250mg (16.1mg/16.1mg per kg) of MK-0787/MK-0791, respectively. Serum concentrations of MK-0787 reached their peaks at the end of drip infusion at a value of 56.33μg/ml and 55.98μg/ml, respectively. Concentrations of the drug decreased as the time after the administration increased, and they reached 0.14μg/ml and 0.12μg/ml, respectively in the older and the younger children at 6 hours after the administration.
Half-lives (T 1/2) of the drug in serum were calculated to be 1.21 hours and 1.04 hours, respectively. The concentration of the drug in cerebrospinal fluid for the 11 years old was 0.52μg/ml 2 hours after the drip infusion and the serum concentration at the time was 4.02μg/ml. Peak serum concentrations of MK-0791 in the 2 children were 53.73μg/ml and 22.99μg/ml, respectively, at the end of drip infusion. After 1 hour, the serum concentration of the drug decreased to 10.54μg/ml in 1 case and not detectable in the other case.
Urinary recovery rates of MK-0787 in 6 hours after the drip infusion was 82.9% and 63.6% in the 2 children and those of MK-0791 were 57.9% and 74.6%.
2. Clinical study
Clinical studies on MK-0787/MK-0791 were carried out in 6 pediatric patients; 1 each with femoral cellulitis, sepsis suspected, salmonellosis, acute tonsillitis, bronchopneumonia and streptococcosis.
Lengths of treatment were 22/3-4 days for 5 cases and 6 days for 1 case. The patients were treated by 30-60 minutes intravenous drip infusions twice a day for 1 case, and 3 times a day for 5 cases at daily doses of 54.5-66.7mg/kg. The treatment was effective in all cases, with 3 cases judged excellent and 3 cases good.
The safety of the drug was studied in 7 patients. No side effects nor clinically abnormal values were observed in any cases.

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Fundamental and clinical studies on imipenem/cilastatin sodium (MK-0787/MK-0791) were performed in pediatric patients with infections. Results obtained were summarized below.
1. The mean plasma half-life of MK-0787 was 0.84 hour with a dosage of 10mg/kg and 0.90 hour with a dosage of 20mg/kg. Mean plasma half-lives of MK-0791 were 0.40 hour and 0.71 hour for dosages of 10mg/kg and 20mg/kg, respectively.
Urinary recovery of both MK-0787 and MK-0791 was high.
2. The antibacterial activity of MK-0787 against clinically isolated organisms was determined. The MK-0787 was bactericidal against a broad spectrum of both Gram-positive and Gram-negative pathogens.
3. The MK-0787/MK-0791 was administered to 32 pediatric patients with various infections. The overall clinical efficacy rate was 96.9%.
4. Side effects observed were loose stools in one patient, diarrhea in another and slight elevations of platelet and direct bilirubin, and eosinophilia were observed in 3 patients, respectively.

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Pharmacokinetic and clinical studies on imipenem (MK-0787)/cilastatin sodium (MK-0791), a combined drug of carbapenem antibiotics (MK-0787) and renal depeptidase inhibitor (MK-0791) in a 1: 1 ratio, were performed in the field of pediatrics.
1. Absorption and excretion
Serum levels and urinary excretion of MK-0787/MK-0791 were determined in 7 children aged 4 to 11 years. Four cases were administered with a single dose of MK-0787/MK-0791 at 10mg/10mg/kg by intravenous drip infusion and the other 3 cases were given a single dose of 20mg/20mg/kg.
Serum concentrations of MK-0787 reached their peaks at the end of drip infusion where the mean level was 17.5±1.0μg/ml for the group given 10mg/10mg/kg, and 43.6±2.1μg/ml for the group given 20mg/20mg/kg. Concentrations decreased with half-lives of 0.82±0.10 hour and 0.74±0.04 hour for the low and high doses, respectively, and serum levels at 6 hours after administration were 0.3±0.1μg/ml and 0.4±0.1μg/ml, respectively. Peak concentrations of MK-0791 were 22.6±4.8μg/ml in the 10mg/10mg/kg group and 52.9±4.7μg/ml in the 20mg/20mg/kg group at the end of the drip infusion. Half-lives were 0.56±0.17 hour and 0.46±0.11 hour for the 2 doses, respectively while MK-0791 levels were below detection limit at 6 hours after administration.
Mean urinary recovery rates in 6 hours after administration were 54.0±15.3% and 49.3±7.8% for MK-0787 and MK-0791, respectively, in the group of 10mg/10mg/kg, and 62.0±7.4% and 65.3±9.2%, respectively, in the group of 20mg/20mg/kg. These results showed that pharmacokinetics of MK-0787 and MK-0791 in children were similar to that in adults.
2. Clinical study
MK-0787/MK-0791 was used for treatment in a total of 22 pediatric patients to evaluate clinical effectiveness, bacteriological efficacy and adverse reactions. Each of patients was treated 3 or 4 times per day at a single dose of 11.4-22.8mg/kg (of MK-0787). Duration of treatment ranged from 2.5 to 18 days and total doses ranged from 1.36 to 19.92g.
Clinical efficacy in cases including 2 with acute purulent tonsillitis, 1 with acute purulent otitis media, 9 with acute pneumonia, 1 with pythorax, 3 with acute purulent lymphadenitis, and 6 with acute pyelonephritis were judged excellent in 20 cases and good in 2 cases; an efficacy rate of 100%.
Causative organisms isolated from these patients included 4 strains of E. coli, 3 strains of H. influenzae, and 1 strain each of S. aureus, S. pneumoniae, H. parainfluenzae, K. pneumoniae and P. aeruginosa. All the organisms were eliminated by the treatment, thus the bacteriological eradication rate was 100%.
No adverse reactions were observed. Among clinical laboratory findings, there was 1 case with elevated Bilirubin, GOT and GPT, another case with elevated GOT and GPT, 2 cases with only elevated GOT, and 3 cases with increased platelet. But these abnormalities were transient, and returned to normal after discontinuation of the drug in all the cases except one (elevation of only GOT) which was not tested any further.
From the above results, it has been concluded that MK-0787/MK-0791 is a very useful and safe drug for use in the field of pediatrics.

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Laboratory and clinical studies on imipenem/cilastatin sodium were carried out and the obtained results were summarized below.
The antibacterial activity of imipenem against clinical isolates of S. aureus, E. coli, K. pneumoniae, Salmonella sp., S. marcescens and P. aeruginosa was measured by the plate dilution method with an inoculum size of 10⁶ cells/ml.
The growth of S. aureus was inhibited at an imipenem concentration of 0.025 μg/ml or lower.
The susceptibility distribution of E. colt to imipenem ranged from 0.1 to 1.56 μg/ml, and the peak of the distribution was at 0.1μg/ml.
The peak of the susceptibility distribution of
K. pneumoniae
was 0.2 μg/ml, and those of
S. marcescens
and Salmonella ranged from 0.2 to 1.56 μg/ml and from 0.1 to 0.39 μg/ml, respectively.
The growth of P. aeruginosa was inhibited at a concentration of imipenem at 6.25 μg/ml.
For a pharmacokinetic study, imipenem/cilastatin sodium was given to 1 patient in a single dose of 10mg/kg or 20mg/kg by drip infusion over 1 hour. With drip infusion of imipenem/cilastatin sodium, the peak plasma levels obtained with the two doses (10 and 20mg/kg) were 20.6/26.4 μg/ml and 19.4/36.5 μg/ml, respectively on completion of the infusion.
Clinical responses to imipenem/cilastatin sodium were excellent in 6 patients and fairly good in 1 patient, and the clinical effectiveness ratio was 85.7%.
No side effect was observed except for elevations of GOT and GPT in 1 patient.

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A combination drug of imipenem (MK-0787), a new carbapenem antibiotic, and cilastatin sodium (MK-0791) at a ratio of 1:1 was used to treat infections in 8 children, and the concentrations of MK-0787 were determined in plasma, urine and pus of 1 patient and in cerebrospinal fluid of another patient.
1. Eight patients, aged 2 months to 12 years (males: 3, females: 5), were treated with MK-0787/MK-0791. They consisted of 3 with urinary tract infections (causative organisms: E. coli, K. oxytoca plus E. faecalis, and unknown), and 1 patient each with pneumonia (H. influenzae), enteritis (Salmonella C₁), cellulitis (S. aureus), purulent lymphadenitis (unknown) and purulent meningitis (E. coli). The dose, ranging from 7.4mg/7.4mg/kg to 11.8mg/11.8 mg/kg, 3 or 4 times daily, was administered by a 30-minute or 60-minute intravenous drip infusion for 5 to 11 days. To the patient with purulent meningitis, however, 25.85 mg/25.85mg/kg on the 1st day and 12.9 mg/12.9 mg/kg from the 2nd day were administered 4 times daily. Clinical responses in urinary tract infections were excellent in 2 and good in 1, and responses in pneumonia, enteritis, cellulitis, purulent lymphadenitis and purulent meningitis were excellent, good, good, excellent and poor, respectively. The efficacy rate in a total of 8 patients was 87.5%.
2. As adverse reactions, a rash was observed in one patient and a convulsion in another. The rash disappeared after discontinuation of the administration of the drug and the convulsion stopped after a reduction of the dosage. As abnormal laboratory findings, slight prolongation of the prothrombin time was observed in 1 patient, but no bleeding tendency was noted.
3. When MK-0787/MK-0791 (500 mg/500 mg, or 8.7 mg/8.7 mg/kg) was given by a 60-minute intravenous drip infusion to a 12-year-old boy with cellulitis, the peak plasma concentration of MK-0787 was 31.4 μg/ml occurring at the end of the infusion, and then the concentration decreased to 13.9 μg/ml in 0.5 hour, 8.9 μg/ml in 1 hour, 2.8 μg/ml in 2 hours, 0.63 μg/ml in 4 hours and 0.14 μg/ml in 6 hours. The half-life was 0.83 hour. These plasma levels provided concentrations exceeding MIC₉₀'s against major infective bacteria for 2 hours. The urinary recovery in the first 7 hours was 75.0%, and the urinary concentration was greater than 100 μg/ml for 5 to 7 hours. The concentration of MK-0787 in the pus of this patient was 3.8 μg/ml at the end of the infusion on the 3rd day. Concentrations of MK-0787 in cerebrospinal fluid in 1 patient with purulent meningitis, at 30 minutes after a 30-minute intravenous drip infusion of 25.85 mg/25.85 mg/kg, were 14.4 μg/ml on the 1st day, 8.0 μg/ml on the 2nd day, and 5.4 μg/ml after a reduction of the dosage to 12.9 mg/12.9 mg/kg on the 2nd day. The MBC of MK-0787 against E. coli isolated from this patient was 0.39 μg/ml with an inoculum of 10⁶ colonyforming units/ml.
4. The above results suggest that MK-0787/MK-0791 at a dosage of about 10 mg/10 mg/kg 3 or 4 times daily given by a 30-60-minute drip infusion will be effective in the treatment of infections other than purulent meningitis, and that it will be a very useful new antibiotic, with an extremely broad and strong antibacterial activity for the treatment infections in children having acute and progressing clinical courses. As far as purulent meningitis is concerned, however, further investigation will be required to evaluate the usefulness of MK-0787/MK-0791.

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Pharmacokinetic and clinical studies of imipenem/cilastatin sodium (MK-0787/MK-0791), a newly developed combined antibiotic in a 1:1 ratio, were performed in the field of pediatrics.
The MK-0787/MK-0791 was administered to 15 children. Ten and 20mg/kg doses of MK-0787 were administered by a intravenous drip infusion for 30 minutes to 3 children each. In the remaining 9 cases, MK-0787 doses of 10, 20 and 30mg/kg were administered to 3 children each by a 1 hour intravenous drip infusion. Levels of MK-0787 and MK-0791 in plasma, urine and urinary recovery rate of the drugs were also determined. In addition, MK-0787/MK-0791 was administered to a total of 29 children; 2 children with bronchitis, 16 with pneumonia, 4 with UTI, 2 with purulent lymphadenitis and 1 child each with tonsillitis, septicemia suspected disease, peritonitis, staphylococcal scalded skin syndrome and osteomyelitis/bacteremia. The average single dose was 15.3mg/kg of MK-0787 and administrations were performed by 20-60 minutes intravenous drip infusion 3-4 times daily for an average period of 6 days. The clinical and bacteriological effects of this drug were evaluated in these cases and adverse reactions and unusual laboratory findings were also studied in a total of 33 cases including 4 other drop-out cases. Results of these studies were summarized as follows.
1. In 6 children, 3 each who were given doses of 10 or 20mg/kg, the mean peak plasma concentrations of the drugs were found at the end of the 30 minutes-infusion with values of 35.20 and 74.90 μg/ml for MK-0787 and 44.85 and 93.32 μg/ml for MK-0791 after the dose of 10 and 20mg/kg, respectively. The peak plasma levels of MK-0791 were approximately 1.3 times higher than those of MK-0787 and higher peak levels were observed in the groups with larger doses of either drugs. In the 10mg/kg group, the mean halflives of MK-0787 and MK-0791 were 0.97 and 0.71 hour, respectively and those values were 0.89 and 0.63 hour, respectively in the 20mg/kg group. In both group, MK-0787 tended to have longer half-lives than MK-0791.
2. In 9 children, 3 each who were administered doses of 10, 20 and 30mg/kg by a 1 hour intravenous drip infusion had the highest plasma levels for both MK-0787 and MK-0791 at the end of the infusion. The mean peak plasma levels of MK-0787 for dose-levels of 10, 20 and 30mg/kg were 18.04, 44.89 and 82.82 μg/ml, respectively and those of MK-0791 were 30.50, 65.25 and 104.23 μg/mI, respectively. The mean peak plasma levels of MK-0791 were 1.7, 1.5 and 1.3 times higher than those of MK-0787 for respective doselevels. The dose-response was observed for both MK-0787 and MK-0791. The mean half-lives of MK-0787 and MK-0791 were 1.14 and 0.50 hour for the group of 10mg/kg, 0.99 and 0.89 hour for the group of 20mg/kg, and 1.04 and 0.95 hour for the group of 30mg/kg, respectively. In the 3 groups, the mean half-lives of MK-0787 were equal to or longer than those of MK-0791.
3. In the 2 groups of 3 cases receiving the intravenous drip infusion for 30 minutes with dose of 10 and 20mg/kg, the mean peak urinary levels of MK-0787 were 2,038.0 and 5, 656.3 μg/ml during 0-1 hour, respectively and those of MK-0791 were 2, 318.3 and 6, 378.3 μg/ml during 0-1 hour, respectively. The mean urinary recovery rates in the first 7 hours after the administration of MK-0787 and MK-0791 were 71.8 and 78.5%, respectively for the group of 10 mg/kg and 83.5 and 90.2%, respectively for the group of 20mg/kg. The mean urinary recovery rates of MK-0791 were larger than those of MK-0787 in the either group.
4. In the 3 groups of 3 cases receiving the intravenous drip infusion for 1 hour with doses of 10, 20 and 30mg/kg, the mean urinary peak levels of MK-0787 and MK-0791 were observed either during 0-1 or 1-2 hours. The mean values of MK-0787 were 1,041.3, 2,881.5 and 4,418.3 μg/ml and those of MK-0791 were 1,014.2, 2,559.2 and 5,430.9 μg/ml for each of the 3 levels, respectively.

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Pharmacokinetic and clinical studies of imipenem/cilastatin sodium (MK-0787/MK-0791), a new carbapenem antibiotic and a dehydropeptidase-I inhibitor, respectively, were carried out in a joint study in the pediatric field by a study group consisting of investigators at 16 institutions.
The results were summarized below.
1. Pharmacokinetic studies
Peak plasma concentrations of MK-0787/MK-0791 were 27.7-190.0/28.3-216.4 μg/ml at doses of 10/10-50/50 mg/kg administered by a 30 or 60-minute drip infusion. The above findings proved that dose response was clearly observed.
Over a period of 6 or 7 hours, the urinary excretion of MK-0787 and MK-0791 totaled 54.2-88.0% and 53.6-89.0% of the dose administered, respectively.
Plasma half-lives of MK-0787 and MK-0791 in the β-phase were 0.87-1.05 hours and 0.59-0.95 hour, respectively.
The cerebrospinal fluid (CSF) levels of MK-0787 in patients with purulent meningitis were 2.0-14.4 μg/ml; however, the penetration rate of the drug into the CSF was relatively poor in patients with normal meninges.
2. Clinical study
Clinical efficacy was evaluated in 283 patients. In 112 patients the daily dosage ranged from 30/30mg/kg to 59/59mg/kg, and in 138 patients it ranged from 60/60mg/kg to 99/99 mg/kg. The maximum dose administered was 222/222mg/kg. The drug was administered either 3 or 4 times per day.
The clinical efficacy rate was 92.5% among 187 patients with identified etiologic pathogens. The drug was effective in 3 out of 4 patients with purulent meningitis and in 7 out of 10 patients with septicemia. The clinical efficacy rate was 96.7% in 90 patients with respiratory tract infection (pneumonia, lung abscess, etc.), 96.5% in 57 patients with urinary tract infection, 90.9% in 11 patients with SSTI. The clinical efficacy rate in those with no identified etiologic pathogen was 97.0% among 101 patients.
Bacteriologically, the eradication rate for S. aureus was 87.9% of 33 isolates. Comprehensively, the eradication rate for Gram-positive bacteria was 94.7% of 75 isolates. The eradication rate for P. aeruginosa was 87.5% of 8 isolates. Including these strains, the eradication rate for Gram-negative bacteria was 90.3% of 134 isolates. The MK-0787/MK-0791 exhibited an eradication rate of 91.9% among a total of 211 Gram-positive and Gram-negative bacteria including anaerobes.
There were 51 patients who had failed to respond to treatments with other antibiotics (the duration of treatment was more than 3 days). Among these patients the efficacy rate and eradication rate in the treat-ment with MK-0787/MK-0791 were 94.1% and 88.6%, respectively.
3. Side effects and abnormal laboratory results
Among 300 patients, side effects seen in 18 patients were considered to be drug related; diarrhea and loose stools in 9, anorexia in 3, rash in 4, convulsion in 2, headache, nausea and vomiting in 1.
Abnormal laboratory results observed among a total of 298 patients included eosinophilia in 8 patients, abnormal liver function in 29 patients and increase in direct bilirubin 3 patients.
4. Conclusion
The MK-0787/MK-0791 has a broad spectrum of activity against Gram-positive and Gram-negative bacteria. Hence, it is useful for the treatment of polymicrobial infections. It is concluded that MK-0787/MK-0791 has established its usefulness for chemotherapy in the pediatric field.
However, it will be necessary to investigate its CSF penetration in more patients.

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A solution of 0.5 g of imipenem (MK-0787) and 0.5g of cilastatin sodium (MK-0791) in 100ml of saline was administered to adult patients before the surgery by intravenous drip infusion during 30 minutes. Fifty samples of bone marrow blood were obtained from 26 clinical cases. After centrifugation, the supernatant was mixed with the same amount of a solution of stabilizer then stored at-80°C. The peripheral blood was obtained at the same time as bone marrow blood was sampled and serum was served as control.
The concentration of MK-0787 in bone marrow blood at 35 minutes after the start of the infusion was 50 μg/ml in 1 case, and decreased to 3.8 μg/ml at 260 minutes. The half-life was 1.62 hours. When the concentration of MK-0787 in bone marrow blood was compared to that in serum, the former was higher than the latter in 26 of the 50 samples (52%). In remained 24 samples, the concentration of MK-0787 in bone marrow blood showed to be lower than that in serum (48% of 50 samples). The half-life of MK-0791 in bone marrow blood was 1.10 hours and the level of the drug in bone marrow blood was similarly higher than that in serum in 18 of 40 samples (45%). In other 22 samples, the concentration of MK-0791 in bone marrow blood was lower than that in serum (55%).
It was also found that the concentration of MK-0787 in bone marrow blood decreases with time along a similar curve of decrease observed in serum. This agent appears useful for the treatment of bone and joint infections and also for prophylaxis for major surgeries of skeletal tissues.

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Thirty cases of bone and joint infections were treated by a chemotherapy with imipenem/cilastatin sodium (MK-0787/MK-0791). An overall curative rate was 87%. It was 96% in cases of acute inflam-matory state and 50% in cases of chronic state. Thirteen cases received surgical intervention with chemotherapy and showed complete healing, but curative rate of 16 cases without surgery was 76%.
Twenty strains of microorganisms were isolated and identified from these patients. The MIC of MK-0787 against S. aureus was as small as≤0.012 to 0.024 μg/ml to a 10⁸/ml suspension. Thus antibacterial action of MK-0787 was very strong. The MIC against E. coli was 0.20 μg/ml.
Incidence of adverse reactions was small as only in two cases occurred slight nausea. Laboratory examinations of blood, liver and kidney function found no influence of the drug.

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