Fundamental and clinical studies on imipenem/cilastatin sodium in pediatrics

Fundamental and clinical studies were carried out on imipenem/cilastatin sodium (MK-0787/MK-0791) in pediatric patients. The following results were obtained. 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. 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 10 mg/10 mg/kg, the mean serum levels of MK-0787 and MK-0791 were 29.9 micrograms/ml and 18.1 micrograms/ml at 1 hour and 3.4 micrograms/ml and 1.3 micrograms/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/20 mg/kg, the mean serum levels of MK-0787 and MK-0791 were 46.3 micrograms/ml and 45.2 micrograms/ml at 1 hour and 5.5 micrograms/ml and 3.1 micrograms/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 40 mg/40 mg/kg, the mean serum levels of MK-0787 and MK-0791 were 104.0 micrograms/ml and 80.9 micrograms/ml at 1 hour and 7.8 micrograms/ml and 5.9 micrograms/ml at 3 hours, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fundamental and clinical studies on imipenem/cilastatin sodium in the pediatric field

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 10(6) 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 less than or equal to 0.024 micrograms/ml against S. aureus, which were sensitive or resistant to CEZ, 0.10 micrograms/ml against E. coli, P. mirabilis, or K. pneumoniae, 0.39 micrograms/ml against S. marcescens and 1.56 micrograms/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 10 mg/10 mg/kg and 20 mg/20 mg/kg by a 30-minute intravenous drip infusion. Maximum serum levels of MK-0787, at dose levels of 10 mg/10 mg/kg and 20 mg/20 mg/kg were 41.6 micrograms/ml and 72.9 micrograms/ml, respectively, at the end of infusion and 0.1 micrograms/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 10 mg/10 mg/kg and 20 mg/20 mg/kg, were 49.7 micrograms/ml and 87.0 micrograms/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 10 mg/10 mg/kg and 20 mg/20 mg/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 100 mg/100 mg/kg/day with purulent meningitis and septicemia and 28.8 mg/28.8 mg-72.8 mg/72.8 mg/kg/day with other infections. The clinical response in all patients was excellent or good.(ABSTRACT TRUNCATED AT 400 WORDS)     

Studies on imipenem/cilastatin sodium in the field of pediatrics

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. 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 10 mg/10 mg/kg by intravenous drip infusion and the other 3 cases were given a single dose of 20 mg/20 mg/kg. Serum concentrations of MK-0787 reached their peaks at the end of drip infusion where the mean level was 17.5 +/- 1.0 micrograms/ml for the group given 10 mg/10 mg/kg, and 43.6 +/- 2.1 micrograms/ml for the group given 20 mg/20 mg/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 +/- 0.1 microgram/ml and 0.4 +/- 0.1 microgram/ml, respectively. Peak concentrations of MK-0791 were 22.6 +/- 4.8 micrograms/ml in the 10 mg/10 mg/kg group and 52.9 +/- 4.7 micrograms/ml in the 20 mg/20 mg/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 10 mg/10 mg/kg, and 62.0 +/- 7.4% and 65.3 +/- 9.2%, respectively, in the group of 20 mg/20 mg/kg. These results showed that pharmacokinetics of MK-0787 and MK-0791 in children were similar to that in adults. 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 11.4-22.8 mg/kg (of MK-0787). Duration of treatment ranged from 2.5 to 18 days and total doses ranged from 1.36 to 19.92 g. 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%.(ABSTRACT TRUNCATED AT 400 WORDS)     

Fundamental and clinical studies on imipenem/cilastatin sodium in the field of pediatrics

Fundamental and clinical studies on imipenem/cilastatin sodium (MK-0787/MK-0791) were performed in pediatric patients with infections. Results obtained were summarized below. The mean plasma half-life of MK-0787 was 0.84 hour with a dosage of 10 mg/kg and 0.90 hour with a dosage of 20 mg/kg. Mean plasma half-lives of MK-0791 were 0.40 hour and 0.71 hour for dosages of 10 mg/kg and 20 mg/kg, respectively. Urinary recovery of both MK-0787 and MK-0791 was high. 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. The MK-0787/MK-0791 was administered to 32 pediatric patients with various infections. The overall clinical efficacy rate was 96.9%. 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.     

Fundamental and clinical studies with imipenem/cilastatin sodium, a new carbapenem antibiotic, in the field of pediatrics

Fundamental and clinical evaluations of imipenem/cilastatin sodium (MK-0787/MK-0791) were carried out in pediatric patients. The following results were obtained: After intravenous drip infusion of single doses of 10 mg/10 mg/kg to 20 mg/20 mg/kg of MK-0787/MK-0791 in children, peak plasma levels of MK-0787 ranged from 32.0 to 82.0 micrograms/ml at the end of the infusion. The half-life was 49.9 to 64.0 minutes. The cumulative urinary recovery at 6 to 7 hours after the 1 hour drip infusion ranged from 65.5 to 88.9%. Fecal levels of MK-0787 were 4.2 and 23.1 micrograms/g at 6 hours after a 30-minute intravenous drip infusion of 200 mg/200 mg of MK-0787/MK-0791. 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. MK-0787/MK-0791 was administered clinically in doses of 30 mg/30 mg/kg/day to 200 mg/200 mg/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. Eradication occurred with 16 isolates; only two strains of Salmonella-B were not eradicated. 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.     

Fundamental and clinical evaluation of imipenem/cilastatin sodium in the field of pediatrics

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. 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 7.4 mg/7.4 mg/kg to 11.8 mg/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/25.85 mg/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%. 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. 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 micrograms/ml occurring at the end of the infusion, and then the concentration decreased to 13.9 micrograms/ml in 0.5 hour, 8.9 micrograms/ml in 1 hour, 2.8 micrograms/ml in 2 hours, 0.63 microgram/ml in 4 hours and 0.14 microgram/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 micrograms/ml for 5 to 7 hours.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacokinetic and clinical studies of imipenem/cilastatin sodium in the field of obstetrics and gynecology

Imipenem/cilastatin sodium (MK-0787/MK-0791) was studied for its penetration into the adnexa uteri and uterine tissue, as well as for its clinical efficacy in the treatment of patients with obstetric and gynecologic infections. The following results were obtained. When 500 mg/500 mg of MK-0787/MK-0791 was administered by an intravenous drip infusion, peak levels of MK-0787 in tissues of adnexa uteri and uterus ranged from 14.6 micrograms/g to 25.8 micrograms/g, Tmax ranged from 0.55 hour to 0.98 hour, and the AUC ranged from 25.6 micrograms X hr/g to 45.2 micrograms X hr/g. Thus, the penetration of the drug into these tissues was good. Clinical efficacy of MK-0787 was evaluated in 30 patients in the field of obstetrics and gynecology. The clinical efficacy was excellent or good in all patients. Bacteriological effects of MK-0787/MK-0791 were very good, and 90% of the organisms detected before the treatment were eradicated. The antimicrobial activity of MK-0787 was tested against pathogens isolated before, during and after the treatment. Mean MIC80 values of MK-0787 were 0.39-0.78 micrograms/ml against all Gram-positive bacteria, 0.20-0.39 micrograms/ml against all Gram-negative bacteria, and less than or equal to 0.10-0.20 micrograms/ml against all anaerobic bacteria. The antimicrobial activity of MK-0787 appeared very good. No side effects or abnormal laboratory findings were observed except a slight elevation of S-GPT in 1 patient.     

Clinical study on imipenem/cilastatin sodium in the field of pediatrics

Imipenem/cilastatin sodium (MK-0787/MK-0791) was administered to pediatric patients with infections, and the following results were obtained. Pharmacokinetic study Two children, 11 years of age (38 kg body weight) and 3 years of age (15.5 kg body weight), were administered by 30 minutes intravenous drip infusion a single dose of 500 mg/500 mg (13.2 mg/13.2 mg per kg) and 250 mg/250 mg (16.1 mg/16.1 mg 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 56.33 micrograms/ml and 55.98 micrograms/ml, respectively. Concentrations of the drug decreased as the time after the administration increased, and they reached 0.14 microgram/ml and 0.12 microgram/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 0.52 microgram/ml 2 hours after the drip infusion and the serum concentration at the time was 4.02 micrograms/ml. Peak serum concentrations of MK-0791 in the 2 children were 53.73 micrograms/ml and 22.99 micrograms/ml, respectively, at the end of drip infusion. After 1 hour, the serum concentration of the drug decreased to 10.54 micrograms/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%. 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 2 2/3-4 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 54.5-66.7 mg/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.     

Pharmacokinetic and clinical studies of imipenem/cilastatin sodium in the pediatric field

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 20 mg/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 30 mg/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 15.3 mg/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. In 6 children, 3 each who were given doses of 10 or 20 mg/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 micrograms/ml for MK-0787 and 44.85 and 93.32 micrograms/ml for MK-0791 after the dose of 10 and 20 mg/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 10 mg/kg group, the mean half-lives 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 20 mg/kg group. In both group, MK-0787 tended to have longer half-lives than MK-0791. In 9 children, 3 each who were administered doses of 10, 20 and 30 mg/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.(ABSTRACT TRUNCATED AT 400 WORDS)     

Experience with imipenem/cilastatin sodium in the field of obstetrics and gynecology

Fundamental and clinical studies on a new carbapenem antibiotic, imipenem/cilastatin sodium (MK-0787/MK-0791), were carried out in the field of obstetrics and gynecology. The following results were obtained. The concentration of MK-0787 in uterine tissue was 3.5 approximately 8.2 micrograms/g at about 30 minutes after an administration of 0.5 g/0.5 g of MK-0787/MK-0791 by a 30-minute intravenous drip infusion. The concentration decreased to less than 0.5 microgram/g by approximately 3 hours. The level of MK-0787 in the pelvic dead space exudate reached a peak of 24.0 +/- 4.4 micrograms/ml at 1 hour after an administration of MK-0787/MK-0791 0.5 g/0.5 g and was higher than the plasma level at 1 hour. The level in the pelvic dead space exudate was 2.0 +/- 0.8 microgram/ml at about 6 hours. The MK-0787/MK-0791 was administered to 4 patients with gynecologic infections (2 patients with pelvic peritonitis, 1 patient with salpingitis, 1 patient with a vulvar abscess). The clinical efficacy was good in all 4 patients. Neither adverse effects nor abnormal laboratory findings were observed. It appears that MK-0787/MK-0791 is a safe and useful antibiotic for the treatment of obstetrical and gynecological infections.     

Clinical and pharmacokinetic evaluation of imipenem/cilastatin sodium in children

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 25.2 kg. The MK-0787/MK-0791 was administered intravenously by a 30-60 minutes infusion, in doses ranging from 8-42 mg/8-42 mg/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 20.0 micrograms/ml at 15 minutes and 5.6 and 2.1 micrograms/ml at 2 hours after a 10 mg/10 mg/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/20 mg/kg intravenous 30-minute drip infusion into 2 other children, plasma concentrations of MK-0787 were 46.8 and 44.0 micrograms/ml at 15 minutes and 7.8 and 7.4 micrograms/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 less than 0.2, 0.2 and 1.2 micrograms/ml just before the next doses in 3 patients given 11-20 mg/11-20 mg/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 0.3 micrograms/ml just before the next dose and 8.2 micrograms/ml at 2 hours after multiple doses of 14 mg/14 mg/kg every 6 hours for 3 days and then 28 mg/28 mg/kg every 6 hours for 35 days.(ABSTRACT TRUNCATED AT 400 WORDS)     

Fundamental and clinical studies of imipenem and imipenem/cilastatin sodium in the field of obstetrics and gynecology

Fundamental and clinical studies of imipenem (MK-0787), a new type of carbapenem antibiotic, and MK-0787 combined with cilastatin sodium (MK-0791), a renal dipeptidase inhibitor, were carried out. The results obtained were as follows: MK-0787 500 mg alone or MK-0787 500 mg with MK-0791 500 mg was administered by intravenous drip infusion over 30 minutes. Plasma levels of the drug were similar either following the administration of 500 mg of MK-0787 alone or 500 mg of MK-0787 with 500 mg of MK-0791. When MK-0787 was administered with MK-0791, MK-0787 and MK-0791 levels at 2 hours after the end of infusion in uterine arterial plasma were 6.8 micrograms/ml and 3.2 micrograms/ml, respectively, and in venous plasma were 8.4 micrograms/ml and 4.7 micrograms/ml, respectively. MK-0787 tissue levels ranged from 0.8 microgram/g to 3.8 micrograms/g at 205 minutes after the end of infusion. Based on these results, the plasma and tissue levels of MK-0787 and MK-0791 with b.i.d. dosage exceeded the MICs of the drug against clinical isolates in the field of obstetrics and gynecology such as E. faecalis, E. coli Klebsiella sp., Peptococcus sp., Peptostreptococcus sp. and B. fragilis immediately after the administration. However, it seemed that the b.i.d. dosage was insufficient to maintain the in vivo concentration of these agents high enough to inhibit the growth of the above bacteria. Eighteen patients with obstetric and gynecologic infection (12 with intrauterine infections, 2 with pelvic dead space inflammation, 2 with pelvic peritonitis, 1 with a vaginal cuff abscess and 1 with a vulvar abscess) and 1 patient with other infection (abdominal wall abscess) were evaluated, but 1 patient with pelvic peritonitis was later excluded from the efficacy evaluation because of a serious illness. MK-0787/MK-0791 was administered twice daily in a 30-minute intravenous drip infusion. Clinical results were excellent in 1 patient, good in 16 and poor in 1, for an efficacy ratio of 94.4%. No side effects were observed. Only abnormal laboratory findings observed were elevation of S-GOT and S-GPT in 1 patient which normalized 2 weeks after the treatment was discontinued. These results suggest that MK-0787/MK-0791 will be useful for the treatment of obstetric and gynecologic infections.     

Fundamental and clinical studies of imipenem/cilastatin sodium in the field of obstetrics and gynecology

Fundamental and clinical studies of a new carbapenem antibiotic, imipenem/cilastatin sodium (MK-0787/MK-0791), were carried out to evaluate the drug in treating infections of the female genital organs. The following results were obtained: In 4 patients undergoing hysterectomy, the penetration of MK-0787 and MK-0791 into female genital organ tissues was studied following a 30-minute intravenous drip infusion of MK-0787/MK-0791 500 mg/500 mg. Plasma levels of MK-0787 and MK-0791 in cubital venous blood following the drip infusion peaked at 0 minute with values of 51.2 micrograms/ml and 61.9 micrograms/ml, respectively, then decreased to 1.9 micrograms/ml and 0.7 microgram/ml, respectively, at 201 minutes. MK-0787 penetrated readily to female genital organ tissues and levels of the drug exceeded 0.5 approximately 1.9 micrograms/g in various organ tissues at 201 minutes following an intravenous drip infusion of 500 mg/500 mg of MK-0787/MK-0791. Clinically, MK-0787/MK-0791 was used for the treatment of obstetrical and gynecological infections at a dosage of 500 mg/500 mg twice daily by intravenous drip infusion. Clinical effects of MK-0787/MK-0791 were analyzed in 22 patients, including 9 patients with intrauterine infections, 7 with intrapelvic infections, 5 with adnexitis, and 1 with an external genital infection. Excellent responses were seen in 5 patients (22.7%), good responses in 15 (68.2%), and poor responses in 2 (9.1%). The efficacy ratio was 90.9%. After the treatment, 15 out of 18 isolates were eradicated for an 83.3% eradication rate. All strains of S. epidermidis (2 strains), Eubacterium lentum (1 strain), Peptococcus sp. (1 strain), beta-Streptococcus (1 strain), Gram-positive rods (2 strains), Enterobacter cloacae (1 strain), Bacteroides bivius (1 strain), Pseudomonas sp. (1 strain), Pseudomonas cepacia (1 strain) and Gram-negative rods (1 strain) were eradicated by the MK-0787/MK-0791 treatment. The safety of the drug was analyzed in 22 patients, effects occurred in 3 (13.6%). Among those 3 patients, diarrhea occurred in 1 patient, rash in another and nausea and vomiting in yet another. One patient had an increased BUN after the MK-0787/MK-0791 treatment. In the other 21 patients, no abnormalities in creatinine, GOT, GPT, or T. Bil. values were observed. It may be concluded that MK-0787/MK-0791 is useful for the treatment of obstetrical and gynecological infections.     

Clinical studies on the effect of imipenem/cilastatin sodium on infections in obstetrics and gynecology. Tissue concentrations and clinical effects

Tissue transfer and clinical effects of imipenem/cilastatin sodium (MK-0787/MK-0791), a new carbapenem antibiotic, were studied and the following results were obtained. Penetrations of MK-0787 into uterine arterial blood and into pelvic dead space exudate were good. When MK-0787/MK-0791 was administered at a dose of 500 mg/500 mg by a 30-minute intravenous drip infusion, the peak level of MK-0787 in uterine arterial blood was 22.2 micrograms/ml, 30 minutes after the completion of the drip infusion. The peak level of MK-0787 in pelvic dead space exudate was 12.9 micrograms/ml at 2 hours and it dropped to 2.6 micrograms/ml at 6 hours. MK-0791 levels were similar to those of MK-0787. Penetrations of MK-0787 into tissues were also good. When MK-0787/MK-0791 was administered at a dose of 500 mg/500 mg by a 30-minute intravenous drip infusion, the level of MK-0787 was 2.2 +/- 1.1 micrograms/g in the oviduct, 2.7 +/- 2.1 micrograms/g in the ovary, 2.5 +/- 1.2 micrograms/g in the endometrium, 3.0 +/- 1.6 micrograms/g in the myometrium, 3.1 +/- 1.9 micrograms/g in the cervix uteri and 3.8 +/- 2.0 micrograms/g in the portio vaginalis at 1 hour after administration. These levels were reduced to halves, respectively, in approximately 2 hours. Four patients with intrauterine infections and 2 with vaginal stump infections were treated with MK-0787/MK-0791 at a daily dose of 1 g/1 g (500 mg/500 mg X 2). Good clinical and bacteriological responses were observed in 5 patients and causative organisms were eradicated in 2 patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical evaluation of imipenem/cilastatin sodium in children

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 24 mg/24 mg-70.2 mg/70.2 mg 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 10 mg/10 mg/kg. The mean half-life (T1/2) 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%.     

Pharmacokinetic and clinical studies with imipenem/cilastatin sodium in the pediatric field. Pediatric Study Group for Imipenem/Cilastatin Sodium

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. Pharmacokinetic studies Peak plasma concentrations of MK-0787/MK-0791 were 27.7-190.0/28.3-216.4 micrograms/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 beta-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 micrograms/ml; however, the penetration rate of the drug into the CSF was relatively poor in patients with normal meninges. Clinical study Clinical efficacy was evaluated in 283 patients. In 112 patients the daily dosage ranged from 30/30 mg/kg to 59/59 mg/kg, and in 138 patients it ranged from 60/60 mg/kg to 99/99 mg/kg. The maximum dose administered was 222/222 mg/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.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of imipenem/cilastatin sodium in thirty cases of bone and joint infection

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 inflammatory 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 less than or equal to 0.012 to 0.024 micrograms/ml to a 10(6)/ml suspension. Thus antibacterial action of MK-0787 was very strong. The MIC against E. coli was 0.20 micrograms/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.     

Fundamental and clinical studies of imipenem/cilastatin sodium in the field of obstetrics and gynecology

To evaluate the penetration of imipenem/cilastatin sodium (MK-0787/MK-0791) into the female genital organ, concentrations of MK-0787/MK-0791 in antecubital vein blood, portio vaginalis, myometrium, endometrium, ovary and oviduct of patients who underwent simple hysterectomy and in the pelvic dead space exudate of patients who underwent radical operations for cancer of the uterine cervix were determined and analyzed using a two-compartment model. Concentrations at the end of a 30 minutes drip infusion of 500 mg/500 mg of MK-0787/MK-0791 were 48.38/52.69 micrograms/ml in plasma from the antecubital vein, 9.46/14.92 micrograms/g in the portio vaginalis, 14.10/9.79 micrograms/g in the myometrium, 6.47/11.42 micrograms/g in the endometrium, 14.72/13.30 micrograms/g in the ovary and 10.59/13.62 micrograms/g in the oviduct. Maximum concentrations of MK-0787 and MK-0791 in the pelvic dead space exudated were 10.66 micrograms/ml at 1.33 hours and 12.74 micrograms/ml at 1.15 hours after the start of the drip infusion, respectively. The concentration in plasma from the antecubital vein after an infusion of 1,000 mg/1,000 mg of MK-0787/MK-0791 reached 68.37/61.57 micrograms/ml at the end of a 60 minutes drip infusion, and the maximum concentration of MK-0787 in the pelvic dead space exudate was 20.02 micrograms/ml at 1.50 hours after the start of the drip infusion and that of MK-0791 was 14.90 micrograms/ml at 2.01 hours after the start of the drip infusion. MK-0787/MK-0791 was administered to 9 patients with obstetric and gynecological infections, and clinical efficacies were found to be excellent in 1, good in 6, and poor in 2 patients.     

Fundamental and clinical studies of imipenem/cilastatin sodium in the field of obstetrics and gynecology. Study group of imipenem/cilastatin sodium in the field of obstetric and gynecological infections

Fundamental and clinical studies were performed by our study group to evaluate the usefulness of the combination (1:1) of imipenem (MK-0787), a carbapenem antibiotic, and cilastatin sodium (MK-0791), an inhibitor of dehydropeptidase-I, in the treatment of patients with obstetric and gynecologic infections. The following results were obtained. Antimicrobial activities of MK-0787 were tested with inocula of 10(6) cells/ml of organisms isolated from patients with obstetric and gynecologic infections. Peak MIC's of MK-0787 were less than or equal to 0.20 micrograms/ml for S. aureus, less than or equal to 0.20 micrograms/ml for S. epidermidis, 1.56 micrograms/ml for E. faecalis, 0.39 micrograms/ml for E. coli, less than or equal to 0.20 micrograms/ml for K. pneumoniae and less than or equal to 0.20 micrograms/ml for B. fragilis. When 0.5 g/0.5 g of MK-0787/MK-0791 was administered by a 30-minute intravenous drip infusion, maximum concentrations of MK-0787 in all female genital tissues were obtained at the end of the infusion, and Cmax ranged from 9.4 micrograms/g to 17.0 micrograms/g. In addition, the maximum concentration of MK-0787 in pelvic dead space exudate was 13.2 micrograms/ml at 88 minutes after the start of the infusion. The penetration of MK-0787/MK-0791 into female genital tissues and dead space exudate was found to be good and sufficient to cover MIC's against organisms isolated from patients with obstetric and gynecologic infections. Clinical efficacy was evaluated in 201 evaluable patients out of a total of 253 patients with obstetric and gynecologic infections. Clinical responses were excellent in 2, good in 181 and poor in 18 patients, and the efficacy rating was 91.0 percent. Efficacy ratings classified by types of infections were 93.2% (82/88) for intrauterine infections, 83.0% (39/47) for intrapelvic infections, 100% (26/26) for adnexitis, 90.0% (18/20) for infections of the external genital organs and 90.0% (18/20) for other infections. Side effects were observed in 6 of the 253 patients; rash in 4, nausea and vomiting in 1 and diarrhea in 1 patient. Abnormal laboratory findings were observed in 10 of the 253 patients; elevation of GOT, GPT, LDH and Al-P in 1, elevation of GOT, GPT and Al-P in 1, elevation of GOT and GPT in 4, elevation of GPT in 1, elevation of BUN in 1, increase of eosinophiles in 1, decrease of segmented neutrophils in 1 patient.     

A study on the penetration of imipenem/cilastatin sodium into the female genital tissues

A new carbapenem antibiotic, imipenem/cilastatin sodium (MK-0787/MK-0791), was administered by intravenous drip infusion at a dose level of 500 mg/500 mg to 30 patients who underwent total abdominal hysterectomy for uterine myomas with or without benign ovarian tumors. The uterine arteries were clamped bilaterally at 0.25, 0.5, 1, 2, 3, 4, 6 and 8 hours after administration, and plasma samples and uterine tissues were taken for measurements of MK-0787 by bioassay and MK-0791 by HPLC. The measured values were analyzed using a two-compartment open model. Maximum concentrations of MK-0787 at 0.5 hour after the start of intravenous drip infusion were 98.5 micrograms/ml in the antecubital vein, 100.1 micrograms/ml in the uterine artery, 26.5 micrograms/g in the oviduct, 21.2 micrograms/g in the ovary, 19.1 micrograms/g in the endometrium, 19.0 micrograms/g in the myometrium, 22.1 micrograms/g in the cervix uteri and 16.4 micrograms/g in the portio vaginalis. These results suggest that the penetration of MK-0787/MK-0791 into female genital tissues is good, and sufficient concentrations are obtained enough to inhibit organisms which are frequently isolated from patients with pelvic inflammatory disease.