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

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 on imipenem/cilastatin sodium in the field of obstetrics and gynecology

Fundamental and clinical studies on imipenem/cilastatin sodium (MK-0787/MK-0791) in the field of obstetrics and gynecology were carried out. The concentration of MK-0787 in uterine tissue was 5.9-12.2 micrograms/g at 30 minutes after an administration of 500 mg/500 mg of MK-0787/MK-0791 by a 30-minute intravenous drip infusion and 0.9-1.1 micrograms/g at 185 minutes. The clinical application of the drug to 9 patients with gynecological infections produced "good" results with all the patients clearly showing clinical or bacteriological improvement. Neither side effects nor abnormal laboratory findings were observed. Based on these findings, MK-0787/MK-0791 appeared to be a useful antibiotic for the treatment obstetrical and gynecological infections.     

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

Fundamental and clinical studies on imipenem/cilastatin sodium (MK-0787/MK-0791) were carried out and the following results were obtained. Concentrations of MK-0787 in plasma and uterine tissues were determined at 30 minutes to 390 minutes after the completion of an intravenous drip infusion of 500 mg/500 mg of MK-0787/MK-0791 sodium. Levels of MK-0787 in oviduct, ovary, endometrium, myometrium, uterine cervix and portio vaginalis were 5.1, 5.3, 4.2, 6.6, 5.2 micrograms/g and 6.0 micrograms/g, respectively, at 30 minutes after the completion of the infusion. These levels far exceeded the MICs of MK-0787 against major pathogens (Gram-negative rods and anaerobic bacilli) most often isolated in the field of obstetrics and gynecology. MK-0787/MK-0791 was administered by intravenous drip infusion to 11 patients, including 4 with pelvic peritonitis, 4 with adnexitis and one each with peritonitis, tubo-ovarian abscess, and endometritis, at a dose of 1 g/1 g-1.5 g/1.5 g per day for a period of 4 to 9 days. Clinical response was excellent in 2 and good in 9. No adverse reactions or abnormal laboratory findings were observed in any of the patients.     

Fundamental study of imipenem/cilastatin sodium in obstetrics and gynecology

Following results were obtained from drip intravenous administration of imipenem/cilastatin sodium (MK-0787/MK-0791) (500 mg/500 mg) by measuring concentration of MK-0787 in uterine arterial plasma, cubital venous plasma, oviduct, ovary and several sites in uterine tissue in cases of simple hysterectomy, and pelvic cavity fluid in cases of radical operation. Cervix uteri, portio vaginalis, myometrium showed higher concentration among various uterine tissues in any time after the end of administration. In cases of radical operation, the pelvic cavity fluid showed 6.6 approximately 7.8 micrograms/ml at 5 hours after the end of administration. In the field of obstetrics and gynecology, it was considered that MK-0787/MK-0791 has good efficacy in infections especially caused by Gram-positive aerobic bacteria.     

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

The penetration of imipenem/cilastatin sodium (MK-0787/MK-0791) into tissues of 6 patients and clinical efficacy in 21 patients with infectious diseases were studied in the field of obstetrics and gynecology. The results are summarized below. The transfer of MK-0787/MK-0791 into genital organ tissues was very good. The clinical efficacy was evaluated for 11 patients with intrauterine infections, 5 patients with intrapelvic infections and 5 patients with other infections. Clinical responses were excellent in 7 (33.3%), good in 13 (61.9%) and poor in 1 patient (4.8%), and the efficacy rate was 95.2 percent. Infective bacteria were eradicated in 4, diminished in 2, unchanged in 1 and replaced by other bacteria in 2 patients. No side effect was observed.     

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.     

Clinical studies on imipenem/cilastatin sodium in the field of obstetrics and gynecology]

The efficacy and safety of imipenem/cilastatin sodium (IPM/CS) were studied in patients with obstetric and gynecologic infections and in those given the drug as prophylaxis against postoperative infections. The following results were obtained: 1. Efficacy rates were 96.0% (48/50) in patients with obstetric and gynecologic infections and 100% (28/28) in those with urinary tract or other infections. The overall efficacy rate was 97.4% (76/78). Bacteriologically, 30 organisms were isolated from 28 patients. The eradication rate was 95.2% (20/21) and the efficacy rate was 96.4% (27/28). 2. Changes in blood elastase before and after treatment were compared with those in CRP, WBC, and ESR in the patients with obstetric and gynecologic infections. The changes in elastase were similar to those in CRP. 3. The efficacy rate was 98.0% (48/49) in the patients given prophylaxis against postoperative obstetric and gynecologic infections. 4. An adverse reaction was observed in only one patient (diarrhea), and abnormal laboratory findings were noted in 2 patients (elevation of GOT and GPT). These results indicate that IPM/CS is very useful for the treatment of obstetric and gynecologic infections.     

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.     

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)     

Clinical trials of imipenem/cilastatin sodium in the field of obstetrics and gynecology

Many different infections including urinary tract infections occur in the field of obstetrics and gynecology. Furthermore, in most cases, it is practically impossible to clearly identify causative organisms as in cases of pelvic peritonitis and parametritis. In many incidents, causative organisms consist mainly of Escherichia coli, and recently, Enterococcus faecalis, Bacteroides fragilis, Klebsiella pneumoniae, Pseudomonas aeruginosa, etc. have also been identified. Because the new antibiotic, imipenem/cilastatin sodium (MK-0787/MK-0791), is very effective against these bacteria, and because of its wide spectrum, we believe it is especially effective against infections of obstetrics and gynecology. The distribution of this antibiotic into various organs and tissues was similar to other drugs, and it reaches a high level in internal genital organs, hence it should be effective for the treatment of obstetric/gynecological infections. Its toxicity is low also, and no side effects nor abnormal laboratory findings were observed in our trials. Results of our trials are summarized below: Of 9 cases of obstetric/gynecological infections, the antibiotic showed excellent effectiveness against 2, good against 6, for the efficacy ratio of 89%. No side effects nor abnormal laboratory findings were observed.     

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.     

Clinical studies on imipenem/cilastatin sodium in the field of obstetrics and gynecology in the perinatal period

Clinical studies were performed on the perinatal use of imipenem (IPM)/cilastatin sodium (CS). The obtained results are summarized as follows. 1. IPM/CS was administered to 11 perinatal infection cases which included mainly intrauterine infections and 3 mastitis cases in addition. IPM/CS showed excellent effectiveness against 1, good against 11, and the efficacy rates were 85.7%. 2. No side effects nor abnormal laboratory test values were observed.     

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)     

Clinical study of intramuscular imipenem/cilastatin sodium in the field of obstetrics and gynecology]

We evaluated the clinical efficacy and safety of intramuscular (as a new route of administration) imipenem/cilastatin sodium (IPM/CS) in patients with intrauterine infections which are typical in the field of obstetrics and gynecology. The obtained results are summarized as follows. 1. Twenty-seven patients were treated with IPM/CS, 250 mg/250 mg b.i.d. (3 patients), 500 mg/500 mg b.i.d. (22) and other dosages (a change in dosing regimen, 2). The duration of treatment ranged from 3 to 11 days and the total dosage during an entire course of treatment varied from 1.5 to 9.0 g. The drug was suspended in a lidocaine solution and administered in the gluteal muscle of the patients. 2. Clinical efficacies were excellent in 7 patients (26%), good in 19 (70%) and poor in 1 (4%) and the overall efficacy rate was 96.3%. All of the 8 patients who had not previously showed improvements with treatment by other antibiotics responded well to this drug. 3. Bacteriologically, the clinical efficacy rate was 95.8% (23/24) and the eradication rate was 76.2% (16/21). 4. No adverse effects due to the drug were observed. As abnormal laboratory test results, transient elevations of GOT and GPT were noted in one 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 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)     

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

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 10(6) cells/ml. The growth of S. aureus was inhibited at an imipenem concentration of 0.025 microgram/ml or lower. The susceptibility distribution of E. coli to imipenem ranged from 0.1 to 1.56 micrograms/ml, and the peak of the distribution was at 0.1 microgram/ml. The peak of the susceptibility distribution of K. pneumoniae was 0.2 microgram/ml, and those of S. marcescens and Salmonella ranged from 0.2 to 1.56 micrograms/ml and from 0.1 to 0.39 microgram/ml, respectively. The growth of P. aeruginosa was inhibited at a concentration of imipenem at 6.25 micrograms/ml. For a pharmacokinetic study, imipenem/cilastatin sodium was given to 1 patient in a single dose of 10 mg/kg or 20 mg/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 20 mg/kg) were 20.6/26.4 micrograms/ml and 19.4/36.5 micrograms/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.     

Fundamental and clinical studies on fosfomycin sodium in the field of obstetrics and gynecology

Fosfomycin sodium (FOM-Na) was studied both fundamentally and clinically in the field of obstetrics and gynecology with following results. It showed good transference into the uterine tissues when given intravenously. The peak concentrations achieved in the uterine tissues following intravenous administration of 2 g of FOM-Na were 26.56 to 53.48 micrograms/g when given as one shot injection and 20.16 to 39.47 micrograms/g as drip infusion. In the serum of vein and uterine artery, peak concentrations of 163.6 to 143.40 micrograms/ml and 120 to 113.12 micrograms/ml were reached following one shot injection and drip infusion, respectively. In general, FOM-Na concentrations in the uterine tissues showed similar changes as those observed for serum concentrations. Clinically, FOM-Na was used in the treatment of 17 cases of obstetrical and gynecological infections at 2 g per dose twice daily as intravenous drip infusions. In all of these cases, good clinical efficacy was obtained. No side effects were observed.