Experimental chemotherapy using high-dose methotrexate (MTX) with citrovorum factor (CF) was performed on ddN strain mice bearing ⁸⁹Sr-induced osteosarcoma and the antitumor efficacy was analyzed through autoradiography ([³H]thymidine). The administration was done using sustained infusion via the tail vein using our own device to maintain certain elevated blood levels of the drugs. As the first experiment, MTX was administered to 4 different groups of mice with dose levels of 250, 500, 1,000, 2,000 mg/kg for 6 hours followed by CF 200 mg/kg for 24 hours. It was found that the blood levels of MTX were maintained at 10^-4M by the dosage of 500 mg/kg, but no higher levels were achieved by increasing dosage. Tissue such as the small intestine and the bone marrow recovered from the toxicity of MTX in about 1 week after the dosage of 500 mg/kg. In tumors, on the other hand, the tissue showed a gradual recovery with time, but the uptake of [³H]thymidine by the tissue was not restored to the pretreatment level. When the antitumor efficacy of a single dosage of 1,000 mg/kg and 2 dosages of 500 mg/kg each with 1 week interval were compared, the latter was definitely more effective. It was, therefore, concluded that the administration of the drugs should be done repeatedly with optimum doses of MTX and CF rather than with ultrahigh doses of MTX and CF all at once.

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Human tumor colony-forming assay for the efficacy of antitumor agents, established by SALMON and HAMBURGER, has become the subject of vigorous investigations because of its close correlation to the clinical course in cancer patients. However there are yet no reports of this assay being applied to sarcoma of bone which is difficult to cultivate. To find out if this assay is useful or not for malignant bone tumors, especially osteosarcoma, 10 specimens obtained through biopsy, resection or thoracotomy were employed in the colony-forming assay. While 7 samples showed colony forming ability, the sensitivity tests were possible only in 3 specimens because of low rates of colony formation. The results of the 3 sensitivity tests corresponded appreciably to clinical courses of the patients; hence this assay seemed useful in planning a chemotherapeutic schedule for the treatment of osteosarcoma.

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The concentration of antibiotics in cerebrospinal fluid is of great interest in therapeutics, especially for the treatment of the central nervous system. We studied the penetration of mezlocillin (MZPC) in 3 cases with V-P shunt and 7 cases after neurosurgical operation. After intravenous injection of 4 g MZPC in the 3 cases with V-P shunt, a peak concentration (0.26-3.6 μg/ml) of MZPC in the cerebrospinal fluid was reached in 2-4 hours. In the 7 cases after neurosurgical operation, cerebrospinal fluid was sampled at 4 hours after the intravenous injection of 4 g MZPC by spinal tap. Concentrations of MZPC in cerebrospinal fluid ranged from 1.1 to 17.5 μg/ml. The mean maximum concentration of MZPC was 5.85 μg/ml, which exceeded 90% MIC (minimal inhibitory concentration) against S. epidermidis, E. faecalis, H. influenzae. It is concluded MZPC can be useful for the prophylaxis of meningitis.

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Incidences of methicillin-resistant strains of Staphylococcus (MRS) have been increasing because of the extensive uses of cephalosporins and semisynthetic, 9-lactamase-resistant penicillins. Most of these strains are known to be resistant to lactam antibiotics due to their production of penicillinases and mutated penicillin-binding proteins. Our recent clinical isolates of MRS were also suspected to be this type because of their temperature sensitive resistance to methicillin.
We studied in vitro antibiotic activity of cefuzoname (CZON) a cephalosporin developed against Staphylococcus, against these MRS in comparison with those of the representative cephalosporins, cefazolin (CEZ), cefamandole (CMD), cefotiam (CTM), cefoperazone (CPZ) and cefpiramide (CPM). It was found that CZON was the most active against MRS among these cephalosporins under normal body temperatures as well as at lower temperatures.

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Latamoxef (LMOX, Siomarin® ) at a dose of 2g was intravenously administered to each of 23 patients undergoing the open heart surgery and the concentrations in serum, pericardial fluid and auricle of heart were measured. Pharmacokinetic observations are summarized below.
1. The peak serum concentration (t=0) was 227. 3 μ g/ml and the serum half-life (T1/2β ) was 1. 74 hours.
2. In pericardial fluid, LMOX reached the peak concentration of 28. 44 μ g/ml at 4. 9 hours and the half-life was 9. 99 hours.
3. In auricle of heart, LMOX reached the peak concentration of 42. 78 μ g/g at 6. 9 minutes and the half-life was 1. 74 hours.
4. It was shown that LMOX penetrates well into the pericardial fluid and the auricle of heart, and it is considered that their levels exceed the minimal inhibitory concentration against a majority of clinical isolates except Pseudomonas aeruginosa.

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Clinical evaluation of cefmenoxime (CMX, Bestcall® ) was performed against infections associated with hematological, respiratory tract and other disorders. Clinical effectiveness of CMX against severe infectionswith hematological disorders including sepsis, pneumonia, pyelitis and so on was 74. 4% for good responses and against the respiratory tract infections, 96. 2% for good responses was obtained.
Neither objective or subjective side effects nor extreme abnormalities in laboratory tests were observed in these patients.
It can be concluded, therefore, that CMX is one of the most useful drugs against infectious diseases associated with hematological disorders, respiratory tract and other disorders.

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To test the effectiveness of cefmenoxime (CMX) and cefotiam (CTM) in patients with biliary tract diseases, concentrations of either antibiotic were measured after an intravenous bolus injection of 1. 0 g of CMX or CTM, or simultaneous injection of both (1. 0 g each).
1. CMX or CTM was injected in 76 patients with biliary tract diseases (mostly cholelithiasis) prior to a cholecystectomy and concentrations of CMX or CTM were measured by the bioassay (agar well) method at 30 to 60 minutes after the injection.
(1) Average concentrations of both CMX and CTM in gallbladder bile and gallbladder tissue sufficiently exceeded the minimal inhibitory concentration (MIC) against main causative organisms of biliary tract infections.
(2) Concentrations of both antibiotics in gallbladder bile were significantly higher in patients with patent cystic ducts than with obstructed cystic ducts.
(3) Concentrations of both antibiotics in the gallbladder tissue reached at a similar high level regardless of the patency of the cystic ducts, but concentrations were lower in severely inflammed gallbladders.
2. CMX and CTM were administered alternatively (cross-over fashion), or simultaneously (combined) to 13 patients with T-tube drainage or percutaneous transhepatic cholangio-drainage, and concentrations of both antibiotics in bile from the drainage tube were measured by high performance liquid chromatography at hourly intervals after the injection.
(1) Concentrations of both antibiotics were far greater than MICs against main attributable microorganisms in biliary tract infections. The concentration of CMX slightly exceeded that of CTM.
(2) Concentrations of both antibiotics were lower in bile of patients showing abnormally high serum GTP, Al-P, and total bilirubin levels than in bile of patients with normal values of these variables.
(3) It is speculated that the secretion of both antibiotics in the bile may decrease in cases with severe hepatic failure, but effective concentrations of both antibiotics in the gallbladder tissue should be maintained as long as the blood circulation in the gallbladder was maintained.

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Concentrations of cefotaxime (CTX) in bone marrow blood and venous blood were examined with the passage of time in 21 cases which received operations of bone and joint.
1. Concentrations of CTX in bone marrow blood at 30 minutes of a single intravenous administration 2g each of CTX were found to be 85. 2± 24. 5μ g/ml.
2. Concentration ratio of CTX in bone marrow blood to that in venous blood was reached the peak at 120 minutes after administration.
3. Concentrations of CTX observed were higher than the MIC of CTX against major pathogens responsible for the postoperative infections in orthopaedic field.
The CTX, therefore, is expected to have an effective antibiotic in prophylaxis.

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We have attempted to clinically define the therapeutic usefulness of ceftizoxime suppository (CZX-S) in children with bacterial pneumonia, in a randomized trial. Intravenous injection of ceftizoxime (CZX) was used as the control. The results are summarized below.
1. Subjects were inpatients with bacterial pneumonia, ranging in age from 9 months to 7 years and 10 months. As a rule, the daily dose was either four 250mg (in potency) suppositories given at 6-hour intervals or 60mg/kg body weight intravenous CZX (control) given in 4 injections at 6-hour intervals over a period of 7 days.
2. The number of children in the study was 67. These children were divided into 2 dosage groups (suppository, 35; injection, 32) with matching pretreatment background factors.
3. The severity of the target disease in the majority of the children was “moderate”. The rate of therapeutic effectiveness was 97.1% for the suppository and 93.8% for the injection, and did not differ significantly between the 2 groups. Rates of efficacy by severity, presence or absence of underlying diseases, daily dose and/or complicitions were high without exception, and did not differ significantly between the 2 groups.
4. Eradication rates for causative microorganisms, as studied in 16 children of each group, were both 93.8%. The 2 most frequently isolated causative organisms were Haemophilus influenzae and Streptococcus pneumoniae.
5. Side effects were examined for 36 children of each group. The frequency of side effects did not differ significantly between the suppository group (2 with diarrhea and 1 with abdominal pain) and the injection group (1 with urticaria), and 8.3% and 2.8%, respectively. The frequency of abnormal laboratory test findings differed significantly (P<0.01) with respect to eosinophilia which occurred in 7 (20.6%) of the injected subjects but was not encountered in the subjects treated with suppositories. Other abnormal laboratory findings included thrombocytosis in 3 (14.3%) of the injection group and increased GOT in 1 (3.2%) of the suppository group.
The suppository formulation of CZX appears to be a highly useful substitute for the injectable form, and should find a special use in children whose treatment with injections experiences some difficulty.

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Transfer of cefotetan (CTT) into exudates from excoriated skin wounds was studied in 9 adult patients. Each subject was given an intravenous bolus injection of 50mg/kg of body weight. Concentrations of CTT in serum and in exudate fluid were determined by bioassay using Escherichia coli NIHJ as the test organism.
The mean (±S. D.) CTT concentration in serum reached 274.3±78.3μg/ml at 30 minutes after the injection and decreased to 30.0±12.0μg/ml at 8 hours after the injection. The peak value of CTT in exudate fluid was 143.1±22.3μg/ml at 1 hour. Eight hours after the injection, the mean concentration in the exudate was 25.7±21.1μg/ml.
The data obtained were analysed pharmacokinetically: CTT concentrations in serum were analysed by two-compartment model, and those in exudate fluid rom excoriated skin wounds were analysed by the model in which skin was considered as a small part of the peripheral compartment. Thus T1/2(β) of CTT levels in serum was calculated as 2.38 hours, AUC_0→∞ was 1,000.2μg·hr/ml and Vd was 164.5 ml/kg. T_max and C_max of CTT levels in exudates were calculated as 1.05 hours and 131.2μg/ml, respectively.

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Seven hundred and thirteen cases of proved bacteremia experienced at 48 pediatric institutions throughout Japan during 1980-1984 were analyzed with respect to their chemotherapeutic treatment and prognosis.
Case fatality rate was the lowest in cases of monotherapy and the highest in those treated with 3 different antibiotics. Those treated with 2 different antibiotics showed significantly higher fatality rate than in cases treated with single antibiotic.
Cephalosporins showed a trend to be administered singly more often than penicillins.
Of all penicillin prescriptions ampicillin (ABPC) was chosen in 61.1% and in 62.3% of any combination therapies of penicillins.
Among combination therapies gentamicin (GM) was most frequently combined with ABPC, i. e., in 58.9%.
In 135 cases treated with combination of ABPC and GM or similar combination like ABPC and antipseudomonas aminoglycosides, deaths resulted in 42 cases compared with 108 deaths out of 578 cases treated with other chemotherapy revealing a statistically significant difference (P<0.005). The utilization of new cephem antibiotics found in this study clearly paralleled to the trend of the consumption of new injectable cephalosporins in Japan since the appearance of new cephem antibiotics in 1980.
The clinical effect of new cephem antibiotics in pediatric bacteremia seems fairly good but will need further observations, particularly when combined with aminoglycosides.
A very large difference exists in the choice of chemotherapy for bacteremia in children among different hospitals. In general, those institutions that prefer monotherapy with some combination therapies of other antibiotics than penicillins and aminoglycoside demonstrated better therapeutic results than those that prefer therapies with the orthodox ABPC and GM combination.
Further analysis is necessary concerning backgrounds of these cases examined in our study.

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Seven hundred and thirteen cases of septicemia whose causative organisms were detected from peripheral blood at 48 pediatric institutions throughout Japan during 1980-4984 were analyzed with respect to their chemotherapeutic outcome relative to causative microorganisms.
Against Gram-positive cocci including S. pyogenes, S. agalactiae, S. viridans, S. pneumoniae, E. faecalis, penicillins (PCs) demonstrated excellent results, and cephalosporin antibiotics (CEPs) also showed good results except against E. faecalis.
Combinations of PCs and aminoglycosides (AGs) resulted in a significantly high fatality rate in streptococcal infections, and very significantly high fatality rate of 38.7% in infections due to S. aureus. Combinations of CEPs and AGs showed a little lower rate than the above combinations, but monotherapy gave the best result.
Infections due to S. epidermidis revealed better prognosis than those due to S. aureus.
We recommend that PC II (PCase resistant) and CEP I or II should be combined with fosfomycin (FOM), if necessary, for the treatment of staphylococcal septicemia.
For the treatment of septicemia due to H. influenzae, ampicillin (ABPC) is the best drug against sensitive strains and CEP IV or V may also be the drug of choice even against ABPC resistant strains.
Against septicemia due to E. coli, although its prognosis is not good in general, monotherapy gave the lowest mortality.
Among combined therapies,“CEPs+AGs” resulted in a significantly lower death rate of 13.3% than “PCs+AGs” which showed a death rate of 38.3%.
Pseudomonas septicemia is very difficult to treat with by a monotherapy using even PC IV, CEP V or AGs any of which is effective against P. aerugmosa.
However, even then, the combination of “β-lactam+AGs” gave higher mortality than monotherapies.
Enterobacter septicemia also results in a high mortality rate. The treatment of septicemia due to these causative agents needs further improvement using a combined therapy of antibiotics or other supplementary therapies.
In this paper, we reported current states of different treatment and outcomes in Japan of septicemia due to different causative agents including other agents than ones mentioned above like Gram-negative rods, Gram-positive rods, anaerobes and fungi.
Some consideration was given about high mortality rates among septicemia in children treated with orthodox combinations of “ABPC+gentamicin”.

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The following paragraphs summarize the properties of ADR, THP and ACR in terms of their pharmacokinetics.
1. The blood level of anthracyclines shows a three-phase function of decline: α, β and γ phases. Compared with other classes of anticancer agents, the anthracyclines are characterized by an extremely short T1/2 (α) and an extremely long T1/2(γ). These characteristics reflect the facts that anthracyclines are rapidly transferred to the tissues and that they are retained for a long time in the body. In comparison with ADR, the T1/2 (α) of THP is relatively short and T1/2(α, β and γ) of ACR are also short.
2. Anthracyclines show large values for K₁₂ and K₁₈, transfer rate constants of the drug from the blood to the tissues, and small values for K₂₁ and K₃₁ transfer rate constants of the drug from the tissues to the blood. This means that these drugs are rapidly transferred to the tissues, from which they are then slowly released. The order of magnitude of K₁₂ and K₁₃ was THP>ACR>ADR. The order for K₂₁ and K₃₁ was ACR>THP>ADR.
3. Anthracyclines are also characterized by small distribution volumes (V₁) in the blood circulation, and very large distribution volumes (V₂ and V₃) in the tissue compartments. The order of magnitude for V₂ and V₃ was THP>ADR>ACR.
4. Anthracyclines achieved high concentrations in such thoracic and abdominal organs such as lung, heart, thymus, liver, kidney, spleen and digestive tract. ADR showed the highest levels in liver and kidney, while THP and ACR showed their highest concentrations in lung and spleen. A decrease in the drug concentration in various organs is slow in the case of ADR, while rapid in the cases of THP and ACR. Most of the distributed drug is the unchanged form with ADR, whereas metabolites are common with ACR. THP is partially converted to ADR in liver.
5. Anthracyclines were usually excreted over a long period of time at a high rate in the bile and at a low rate in the urine.
6. Orally-administered ACR showed considerably good absorption from the digestive tract.
7. The metabolism of anthracyclines was carried out in vivo and resulted in the formation of bioactive glycoside metabolites and inactive aglycone metabolites.
8. In vitro studies employing liver tissue homogenates, revealed that the degradation of ADR and THP was small, whereas the degradation of ACR was rapid and extensive. The metabolism of ACR occurred most strongly in the liver homogenate, followed in order of intensity by the kidney, heart and testis homogenates.

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A new combined preparation, imipenem/cilastatin (MK-0787/MK-0791), was evaluated its penetration into the plasma and tissues with the following results:
1. After an intravenous drip infusion of 500mg/500mg of MK-0787/MK-0791, the plasma concentration of drug achieved in the uterine artery was almost equal to that in the antecubital vein, showing good penetration of the drug.
2. After an intravenous drip infusion of 500mg/500mg of MK-0787/MK-0791, favorable concentrations were achieved in all of the adnexal and uterine tissues studied.
3. From the results obtained, it is expected that MK-0787/MK-0791 will be highly effective in the field of obstetrics and gynecology.

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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.
1. Penetrations of MK-0787 into uterine arterial bood and into pelvic dead space exudate were good. When MK-0787/MK-0791 was administered at a dose of 500mg/500mg by a 30-minute intravenous drip infusion, the peak level of MK-0787 in uterine arterial bood was 22.2 μg/ml, 30 minutes after the completion of the drip infusion. The peak level of MK-0787 in pelvic dead space exudate was 12.9 μg/ml at 2 hours and it dropped to 2.6 μg/ml at 6 hours. MK-0791 levels were similar to those of MK-0787.
2. Penetrations of MK-0787 into tissues were also good. When MK-0787/MK-0791 was administered at a dose of 500mg/500mg by a 30-minute intravenous drip infusion, the level of MK-0787 was 2.2±1.1 μg/g in the oviduct, 2.7±2.1 μg/g in the ovary, 2.5±1.2 μg/g in the endometrium, 3.0±1.6 μg/g in the myometrium, 3.1±1.9 μg/g in the cervix uteri and 3.8±2.0 μg/g in the portio vaginalis at 1 hour after administration. These levels were reduced to halves, respectively, in approximately 2 hours.
3. Four patients with intrauterine infections and 2 with vaginal stump infections were treated with MK-0787/MK-0791 at a daily dose of 1g/1g (500mg/500mg×2). Good clinical and bacteriological responses were observed in 5 patients and causative organisms were eradicated in 2 patients.
4. No adverse effects or abnormal laboratory findings were observed in any of the patients.
5. Taking MIC values of the drug against clinical isolates into account, results obtained were favorable for the treatment, and MK-0787/MK-0791 appeared to be a safe and effective antibiotic for the treatment of obstetrical and gynecological infections.

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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 μg/g at 30 minutes after an administration of 500mg/500mg of MK-0787/MK-0791 by a 30-minute intravenous drip infusion and 0.9-1.1 μg/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.

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A combination of imipenem (MK-0787), a new carbapenem antibiotic, plus cilastatin sodium (MK-0791), a dehydropeptidase inhibitor (MK-0787/MK-0791=1:1) was studied in the field of obstetrics and gynecology and the following results were obtained.
1. Absorption and penetration into genital organ tissues were good. Following a 0.5g/0.5g intravenous drip infusion, the maximum plasma concentration in uterine arterial blood was 20.8 μg/ml, and the maximum concentrations of the drug in tissues were 9.9-16.8 μg/g, and these levels of MK-0787 exceeded the MIC values against main causative organisms. Rates of elimination of the drug from the tissue and from the plasma were similar.
2. Against gynecological and obstetrical infections, a dose of 0.5g/0.5g twice daily for an average duration of 6.3 days produced a clinical efficacy ratio of 94.4% (17/18) and a bacteriological effects rating of 76.9% (10/13). As side effects, one patient showed an eruption and another had an elevated GOT and GPT.
3. Based on the above results, MK-0787/MK-0791 appears to be effective against gynecological and obstetrical infections.

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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.
1. The concentration of MK-0787 in uterine tissue was 3.5-8.2 μg/g at about 30 minutes after an administration of 0.5g/0.5g of MK-0787/MK-0791 by a 30-minute intravenous drip infusion. The concentration decreased to less than 0.5 μg/g by approximately 3 hours.
2. The level of MK-0787 in the pelvic dead space exudate reached a peak of 24.0±4.4 μg/ml at 1 hour after an administration of MK-0787/MK-0791 0.5g/0.5g and was higher than the plasma level at 1 hour. The level in the pelvic dead space exudate was 2.0±0.8 μg/ml at about 6 hours.
3. 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.

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Imipenem (MK-0787), a new carbapenem antibiotic, combined with cilastatin sodium (MK-0791), was studied clinically and microbiologically. The following results were obtained:
1. Concentrations of MK-0787 in the plasma and internal genital tissues were measured at 1 hour after an intravenous drip infusion of MK-0787/MK-0791 (500mg/500mg) for 30 minutes.
Mean plasma levels higher than 11.8μg/ml and mean tissue levels higher than 2.3 μg/g were observed.
When its MIC values are considered, MK-0787/MK-0791 appeared to be bactericidal against many Grampositive and Gram-negative bacteria except some Pseudomosas sp. and Enterococcus faecium.
2. Clinical effects of the therapy with MK-0787/MK-0791 (500mg/500mg) using a drip infusion twice daily were evaluated in 3 patients with pyometra and 3 patients with BARTHOLIN'S gland abscess. Clinical responses were good in 5 of the 6 patients.
One patient with pyometra due to E. coli didn't respond to the therapy. No side effects or abnormal laboratory findings due to the drug were noted.

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A new carbapenem antibiotic, imipenem/cilastatin sodium (MK-0787/MK-0791), was administered by intravenous drip infusion at a dose level of 500mg/500mg 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 98.5μg/ml in the antecubital vein, 100.1μg/ml in the uterine artery, 26.5 μg/g in the oviduct, 21.2 μg/g in the ovary, 19.1μg/g in the endometrium, 19.0μg/g in the myometrium, 22.1μg/g in the cervix uteri and 16.4μg/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.

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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:
1. 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 500mg/500mg.
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 μg/ml and 61.9μg/ml, respectively, then decreased to 1.9μg/ml and 0.7μg/ml, respectively, at 201 minutes.
MK-0787 penetrated readily to female genital organ tissues and levels of the drug exceeded 0.5-1.9 μg/g in various organ tissues at 201 minutes following an intravenous drip infusion of 500mg/500mg of MK-0787/MK-0791.
2. Clinically, MK-0787/MK-0791 was used for the treatment of obstetrical and gynecological infections at a dosage of 500mg/500mg 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%.
3. After the treatment, 15 out of 18 isolates were eradicated for an 83.3% eradication rate. All strains of S. epidermults (2 strains), Eubacterium lentum (1 strain), Peptococcus sp.(1 strain), β-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.
4. The safety of the drug was analyzed in 22 patients, and side 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.
5. 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.

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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
1. 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 6.8μg/ml and 3.2μg/ml, respectively, and in venous plasma were 8.4μg/ml and 4.7μg/ml, respectively. MK-0787 tissue levels ranged from 0.8μg/g to 3.8 peg 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. colt 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.
2. 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%.
3. 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.

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Imipenem/cilastatin sodium (MK-0787/MK-0791), a carbapenem antibiotic and a dehydropeptidase-I inhibitor, was administered at a dose of 500mg/500mg twice a day for 5 days for the treatment of obstetric and gynecologic infections.
A total of 10 patients was evaluated, and the clinical results were rated as excellent in 1, good in 7 and poor in 2 patients.
As a side effect, rash was observed in 1 patient but it disappeared by the third day after the treatment was discontinued.
No abnormal laboratory findings were observed in our study.

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