Imipenem (MK-0787) is a new carbapenem antibiotic, derivative of thienamycin with a broad spectrum of antibacterial activity. In vitro and in vivo antibacterial activities of imipenem against gram-positive and gram-negative bacteria were compared with those of newly developed cephalosporins.
The results are summarized as followes.
(1) Imipenem had a broad spectrum of in vitro antibacterial activity against gram-positive cocci, that is, S. aureus and S. faecalis. Its activity against gram-negative bacteria including S. marcescens, E. cloacae, C. freundii and P. aeruginosa was the highest compared with those of referenced drugs.
(2) Greater bactericidal activity of imipenem was demonstrated by determining the minimum bactericidal concentration (MBC).
(3) Imipenem was very stable against various types of β-lactamases except for P. maltophilia CXase L-1. Moreover imipenem showed strong inhibitory activity toward various types of β-lactamases, except for PCase type IV and P. maltophilia CXase L-1.
(4) Imipenem showed high affinity to both E. coli and P. aerugznosa PBPs and especially stronger affinity to PBP-2.
(5) Imipenem co-administered with DHPase-I inhibitor, cilastatin sodium (MK-0791) was the most effective in systemic infections in mice with S. aureus and P. aeruginosa than others, but slightly lower activity against S. marcescens, E. coli snd K. pneumoniae.

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The in vitro and in vivo antibacterial activities of imipenem (MK-0787, N-formimidoyl thienamycin), a new carbapenem were compared with those of ceftazidime, cefoperazone, cefmenoxime, latamoxef and cefotaxime.
Imipenem had a particularly broad antibacterial spectrum against gram-positive and gramnegative bacteria, especially showed potent antibacterial activities against S. aureus, S. faecalis and P. aeruginosa.
Imipenem was as stable as latamoxef and ceftazidime to all inactivating enzymes (penicillinase and cephalosporinase) produced by facultative anaerobes. In the experimental systemic infection in mice, gram-positive strains and various types of β-lactamase-producing strains were used as challenge organisms. The therapeutic effect of imipenem/cilastatin sodium was superior to that of imipenem and equivalent or superior to those of cefoperazone, cefmenoxime, caftazidime, latamoxef, cefotaxime, cefsulodin and piperacillin in all infections due to gram-positive strains and β-lactamase producing strains.
In addition, in the protecting effects against experimental mice mixed infections with each two strains among E. coli, P. aeruginosa and S. faecalis, the therapeutic effect of imipenem/cilastatin sodium was superior to that of imipenem and the most effective among antibiotics tested.

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Eithy percent minimum growth inhibitory concentrations (MIC₈₀) of imipenem (MK-0787) for 24-58 clinical isolates of S. aureus, S. aureus (MRSA), S. pneumoniae, β-streptococci, E. coli (R⁺), K. pneumoniae, P. mirabilis, P. vulgaris, C. freundii, E. cloacae, S. marcescens, P. aeruginosa, P. cepacia, P. maltophilia, A. calcoaceticus, and ABPC-resistant H. influenzae were 0.05, 12.5, ≥0. 006, 0.006, 0.78, 0.78, 6.25, 6.25, 1.56, 0.39, 12.5, 12.5, 100., 0.39, and 1.56μg/ml, respectively. Imipenem not only possessed small Ki values against types Ia, Ic, II, III (TEM), IV, and V β-lactamases, but also inactivated those β-lactamases with relatively low concentrations. Imipenem showed strong binding affinity to penicillin-binding proteins (PBPs), site of action of β-lactam antibiotics, fractions 2, 1 a, and 1 b, resulting in a morphological change of bacilli to spherical cells in the presence of this antibiotic. Synergy of imipenem and the serum complement for bactaricidal effect was not prominent, although this antibiotic manifested a good synergy of bactericidal effect with cultured mouse macrophages against E. coli. Since imipenem was not destroyed by the tissue homogenate of the mouse brain homogenate under the condition where the antibiotic was destructed by the kidney homogenate, the activity of dipeptidase in the brain is negligible, suggesting that the influence of cilastatin on the brain may not be strong.

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Bacteriological evaluation to anaerobic bacteria was made on imipenem (MK-0787)/cilastatin sodium (MK-0791), and the following results were obtained.
1) MK-0787 had a broad antibacterial spectrum against anaerobic bacteria and at 6.25μg/ml (10⁸cells/ml) inhibited the growth of all test species. The antibacterial activity of MK-0787 against these bacteria was more potent than that of CMX CTX, CZX, PIPC, CPZ, LMOX and CAZ.
2) Like LMOX, MK-0787 was very stable to β-lactamase produced by B. fragilis.
3) MK-0787 induced filament formations at concentrations of 0.2μg/ml, and spheroplast-like structures at concentrations of 0.78μg/ml with B. fragilis GM 7000. These morphological alterations of B. fragilis GM 7000, treated with MK-0787, were similar to those with LMOX, used as control drugs.
4) MK-0787, unlike CFX, LMOX, CAZ, CPZ and PIPC, supressed the abnormal growth of C. difficile in caecum contents of mice.

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The bacteriological evaluation of imipenem (MK-0787), a new β-lactam antibiotic, was studied. the following results were obtained.
MK-0787 showed a broad antibacterial spectrum against gram-positive, gram-negative bacteria with the exception of P. maltophilia and Bacteroides.
The antibacterial activity of MK-0787 against gram-positive bacteria was superior to that of cefinetazole, ceftizoxime and latamoxef. It inhibited gram-negative bacteria resistant to other agents. It did not show cross resistance for gentamicin or cefsulodin resistant P. aeruginosa.
There was minimal effect of inoculum size of E. coli and K. pneumoniae, and medium pH or horse serum had no effect on activity.
Time-kill curve confirmed a dose response bactericidal activity of MK-0787. In morphological observation of E. coli and P. aeruginosa by phase contrast microscope, exposure to MK-0787 resulted in the formation of spherical cells, bulge forms and spheroplast-like structures.
MK-0787 showed a high affinity for PBPs 2 of E. coli and P. aeruginosa.

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The therapeutic efficacies of the combination of imipenem and cilastatin sodium (1:1) on experimental infections in mice were compared with cefotiam, ceftizoxime, cefoperazone, piperacillin, cefsulodin and gentamicin.
Against experimental intraperitoneal infections caused by S. aureus, A. calcoaseticus and P. aeruginosa, the therapeutic efficacies of the imipenem in combination with cilastatin sodium were superior to those of cefotiam, ceftizoxime, cefoperazone, cefsulodin and gentamicin. Against E. coli and S. marcescens, the efficacies of imipenem in combination with cilastatin sodium were inferior to those of ceftizoxime. Against gentamicin-or β-lactam-resistant P. aeruginosa combined therapy with imipenem and cilastatin sodium showed good therapeutic efficacies that did not show the cross resistance.
The effect of the combination of imipenem plus cilastatin sodium on experimental urinary tract infection induced by E. coli was equivalent to that of cefoperazone and ceftizoxime. In the case of A. calcoaceticus, it was superior to that of cefoperazone, ceftizoxime and piperacillin. In the case of P. aeruginosa, it was more effective than cefoperazone and equivalent to that of cefsulodin and less effective than gentamicin.
Our studies using experimental pneumonia induced by K. pneumoniae DT-S in mice revealed that the effect of the combination of imipenem plus cilastatin sodium were superior to cefoperazone and piperacillin but inferior to ceftizoxime.

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Imipenem (MK-0787: N-formimidoyl thienamycin) is a new carbapenem antibiotic with an antibacterial spectrum covering most gram-positive and gram-negative aerobic and anaerobic bacterial species, including P. aeruginosa and E. faecalis. However, imipenem is metabolised by breakage of the β-lactam bond by a dipeptidase, dehydrapeptidase-I in the kidny. Cilastatin sodium (MK-0791) is a selective inhibitor of the dehydropeptidase. The in vitro and in vivo antibacterial activities of MK-0787/MK-0791 were compared with those of CPZ, CZX, LMOX, PIPC and CFS. The following results were obtained.
1) MK-0787 had a broad spectrum with potent activity against gram-positive and gram-negative bacteria including obligate anaerobes. On the other hand, MK-0791 did not have an antimicrobial activity.
2) The antibacterial activity of MK-0787 was bactericidal at the MIC, and was changed by pH 8.0 of medium.
3) MK-0787 had the same stability as LMOX against penicillinase and cephalorporinase.
4) Microorganisms such as S. aureus, E. coli and P. aeruginosa aquired resistance to MK-0787, as the same as CPZ, CZX LMOX and PIPC, in vitro.
5) The morphological change in S. aureus, E. coli and P. aeruginosa was observed by an electron microscope. MK-0787 made the mecillinam like bacteria.
6) The therapeutic effect of MK-0787 on experimental infection in mice against gram-positive and glucose non-fermentative gram-negative bacteria was remarkably superior to those of CPZ, CZX, LMOX, PIPC and CSF. However, the effect of MK-0787 against Enterobacteriaceae was the same or slightly superior to those of reference antibiotics.

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The acute toxicity of imipenem (MK-0787), a new carbapenem antibiotic, cilastatin sodium (MK-0791), a renal dehydropeptidase-I inhibitor, and the combination of the two was investigated in mice and rats.
1. The oral, subcutaneous and intravenous LD₅₀ of the combination was greater than 5/5g/kg, 2/2g/kg and 1/1g/kg, respectively, in both young adult mice and rats.
2. The main toxic signs observed after subcutaneous and intravenous administration of the combination were bradypnea, ataxia and convulsions.
3. The oral and subcutaneous LD₅₀ of MK-0787 alone was greater than 5 g/kg and the intravenous LD₅₀ was greater than 1g/kg in both young adult mice and rats. The oral and subcutaneous LD₅₀ of MK-0791 alone was greater than 10g/kg and the intravenous LD₅₀ was greater than 5 g/kg in both young adult mice and rats.
4. The acute toxicity induced by the drugs in combination was considered to be related to the acute toxicity of MK-0787, judging from the toxic signs and the lethal dose level.
5. The LD₅₀ of MK-0787, MK-0791 and their combination was lower in infant animals 4 days of age than in young adult animals, as has been reported with other modern antibiotics.

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The present studies were conducted to evaluate the potential toxicity of imipenem (MK-0787), a new carbapenem antibiotic, and cilastatin sodium (MK-0791) a renal dehydropeptidase-I inhibitor, when coadministered to rats.
Animals received MK-0787 and MK-0791 in combination intravenously at a dosage level of 60/60, 180/180 or 600/600mg/kg/day for 6 weeks, and intravenously at 20/20, 80/80mg/kg/day or subcutaneously at 320/320mg/kg/day for 14 or 27 weeks.
The results obtained are summarized as follows.
1. Deaths attributable to treatment were present in 3 male and 1 female rats in the 600/600mg/kg/day group of a 6-week toxicity study. Convulsions, salivation, cyanosis and/or tremors preceded two of these deaths and salivation was found in the other two. Similar signs were transiently noted in one surviving rat of each sex in the 600/600mg/kg/day group. No similar sings were seen at nonlethal dosage levels.
2. A slight decrease in average body weight gain as compared to controls was found in male rats in the 180/180 and 600/600mg/kg/day groups in the 6-week toxicity study.
3. Amber-tinted urine specimens were collected from male and female rats in 14-week and 27-week toxicity studies. This change was considered to represent the presence of MK-0787 and/or metabolite (s) in the urine but is not a manifestation of toxicity. A similar discoloration can be seen when MK-0787 is dissolved in saline and kept at room temperature.
4. Average weights of the spleen and cecum increased slightly with a dose-dependent relationship in the 6-week toxicity study. Cecal enlargement is a common finding in rodents treated with antibacterial agents. No histopathological alterations were seen in the cecum. The primary change observed histologically in the spleen was a slight increase in cellularity of lymphoreticular tissue in the white pulp. Slight but apparent treatment-related increases in incidence and degree of splenic lymphoreticular hyperplasia were found in male and female rats in the 180/180 and 600/600mg/kg/day groups, as compared to controls. No prominent differences in the incidence or degree of the splenic change were noted between the control and 60/60mg/kg/day groups.

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The combination of imipenem (MK-0787) and cilastatin sodium (MK-0791) was administered by dilly intravenous or subcutaneous injection (the highest dosage level could not be injected intravenously because of the solubility limit) to rhesus monkeys for 5, 14 and 27 weeks at dosage levels of 20/20, 60/60 or 180/180mg/kg/day.
There were no treatment-related changes observed in physical signs, body weights, ophthalmoscopic examination, serum chemistry, hematological parameters, urinalysis, organ weights, gross or histopathological findings in rhesus monkeys which received the combination of MK-0787 and MK-0791 at these dosage levels.
There were increases in kidney weight in the monkeys that received 180/180mg/kg/day of the drug for 27 weeks; however, no evidence of functional or morphological changes in the kidney were noted. The site of subcutaneous injection showed localized damage due to repeated injections of the drug for 27 weeks.
From the results mentioned above, the maximum non-toxic level of this combination of drug in the monkey was estimated to be 60/60mg/kg/day for 27 weeks.

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These studies were undertaken to evaluate the nephrotoxicity of imipenem (MK-0787), MK-0787 and cilastatin sodium (MK-0791) at a combination ratio of 1:1, cephaloridine and cefazolin in rats as well as the nephrotoxicity of these antibiotics when coadiminstered with furosemide and glycerol.
1. Nephrotoxicity was not observed in rats treated intravenously with MK-0787 or MK-0787/MK-0791 at the maximum administrable dose (600, 600/600mg/kg/day) for 21 days. The sequence of proximal tubular damage and repair observed during the course of cephaloridine administration was well correlated with the changes in urinalysis, urinary enzyme activity and serum biochemistry, while cefazolin as another reference antibiotic did not induce nephrotoxicity. No similar changes were seen with MK-0787 or MK-0787/MK-0791.
2. MK-0787, MK-0791, MK-0787/MK-0791, or cefazolin at dose levels of 600, 600, 600/600 or 600mg/kg did not potentiate the nephrotoxicity caused by injection of furosemide and glycerol. Enhanced nephrotoxicity of cephaloridine at dose level of 500 mg/kg was observed when it was coadministered with furosemide and glycerol.

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The study was undertaken to evaluate at various combination ratios the protective potential of cilastatin sodium (MK-0791) against the nephrotoxicity induced by imipenem (MK-0787). Animals treated with MK-0787 at a dose of 160 mg/kg showed functional and morphological changes in the kidney. The nephrotoxicity induced by MK-0787 was decreased or prevented as the dose of MK-0791 was increased. No evidence of renal damage was observed in animals treated with the two compounds at a combination ratio of 1:0.6 or greater. The combination of the two compounds at the ratio of 1:1 for clinical use was considered to offer a sufficient margin of safety in respect to nephrotoxicity.

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Imipenem (MK-0787) is a new broad spectrum beta lactam antibiotic. Coadministration of cilastatin sodium (MK-0791) and MK-0787 prevents the renal metabolism of MK-0787 and promotes urinary recovery of unchanged antibiotic.
The present study was performed to evaluate the potential teratogenicity of the combination of these agents and the effects on growth, development, behavior, fertility and reproductive status of F₁ offspring. The drug combination was administered to three groups of 35 mated F₀ female CRCD albino rats at dosage levels of 20/20, 80/80, and 320/320 mg/kg/day once daily on days 6 through 17 of gestation. Drug was administered intravenously to the 20/20 and 80/80 mg/kg/day groups and subcutaneously to the 320/320 mg/kg/day group. A fourth group of 35 females (Control I) received saline intravenously and a fifth group of 12 females (Control II) received saline subcutaneously.
Twenty-four females from each of the Control I, 20/20, 80/80 and 320/320 mg/kg/day groups were selected to undergo cesarean section on day 20 of gestation. The reproductive status and corpora lutea count as well as results of external, visceral, and skeletal examinations of fetuses were recorded. All females in the Control II group and the remaining 11 females in the other groups were allowed to deliver naturally. The F1 pups were reared to sexual maturity and mated to produce an F₂ generation.
There was no evidence of teratogenicity or feto-toxicity based on the external, visceral, and skeletal examinations of F₁ fetuses and the external examination of F₁ pups except a slight but significant (P≤0.05) treatment-related decrease in live fetal weight in the 320/320 mg/kg/day group.
There were no effects of treatment on the viability of the F₁ generation. There were no treatmentrelated physical signs, preweaning or postweaning body weight changes in the F₁ generation.
There was a slight but significant (P≤O.05) increase in the age of testes descent among F₁ males in the 80/80mg/kg/day group. In addition, 2 pairs of small siblings in the 320/320mg/kg/day group were oldest in age at time of testes descent. These greater ages for time of testes descent may have been treatment-related. There was no effect of prenatal treatment on testes descent in the 20/20mg/kg/day group and no effect on the occurrence of other developmental signs at any dosage level.
There were no effects of prenatal treatment on the behavior test and fertility test in the F₁ generation. The maximum no effect level of the drug combination is considered to be 80/80mg/kg/day although the dosage level caused delayed testicular descent, the change was very slight and within normal variations.

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Immunogenicity of imipenem (MK-0787) and cilastatin sodium (MK-0791) was investigated using various assays for in vivo and in vitro immunological reactions. No systemic anaphylactic reaction was induced by injection of cilastatin sodium in animals immunized with this compound. In PCA assay using immune sera, no IgG-type antibody directed against cilastatin sodium was detected. Weak skin reactions with slight redness and induration was observed at 24 and 48 hours after the cutaneous challenge of high concentrations of this compound.
IgE-type antibody production was induced by the immunization of C3H/He mice with the intraperitoneal injection of antibiotic-BGG conjugates together with Al (OH) ₃ gel. Although BGG conjugates of various β-lactam antibiotics have induced high titers of IgE-type antibodies, no detectable antibody against imipenem was induced after the primary immunization with the compound. A low titer of IgE-type antibody against this compound was detected only after the booster immunization. Immunogenicity of imipenem and other antibiotics was further investigated by ring precipitin reaction, PCA reaction, and quantitative precipitation reaction, using sera from rabbits immunized with antibiotic-BSA conjugates in complete Freund's adjuvant. The precipitating and skin-sensitizing antibodies were produced against imipenem as well as other antibiotics, although the titers for imipenem were significantly lower than those for other antibiotics. In hapten inhibition assay, the cross reactivity of imipenem against antigen-antibody reactions with other antibiotics was very low, while significant cross reactivity was detected among several β-lactam antibiotics tested. In the in vitrodirect Coombs' test, imipenem, cilastatin sodium and imipenem/cilastatin sodium in combination have not induced any positive reaction.
It is, therefore, concluded that the immunogenicity of either imipenem or cilastatin sodium is relatively weak when compared to those of other antibiotics such as PcG, CFX, etc.

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Penetration of imipenem into the CSF after a single intravenous injection of imipenem/cilastatin sodium was determined in rabbits with experimental meningitis due to Staphylococcus aureus.After an intravenous injection of 200mg/kg of this drug (100mg/kg as imipenem), the average peak level in the CSF in 4 rabbits was 13.3±0.94 μg/ml at 45 minutes after injection. The CSF/serum ratio based on peak levels was 6.68%, the AUC CSF/serum ratio up to 2 hours was 14.1%, and that of the t_1/2 was 3.46.
After an intravenous injection of 100mg/kg of this drug (50mg/kg as imipenem), the average peak CSF level in 5 rabbits was 6.92±0.90μg/ml at 45 minutes after injection. The CSF/serum ratio at peak levels was 4.77%, that of the AUC up to 2 hours was 11.1% and that of t_1/2 was 2.60.
A statistical difference was observed between the CSF levels at the 200mg/kg dose group and those at the 100mg/kg dose. However, it was not observed in a CSF/serum AUC ratio, suggesting that the efficiency of penetration does not change when the dose is decreased by 50%.
These results indicate that this drug belongs to the group of β-lactams which have good penetration into the CSF. Based on its penetration into CSF and its antibacterial activity, it is suggested that this drug can be tested in the treatment of bacterial meningitis and in view of its broad spectrum, th e evaluation of its usefulness should be performed.

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Imipenem/Cilastatin sodium (MK-0787/MK-0791), a combination (1:1) of a new carbapenem antibiotic (MK-0787) with an inhibitor of renal dipeptidase (MK-0791), was administered to four healthy volunteers in a dose of 500mg/500mg by a 30-minute intravenous drip infusion to study the effects on the urinary peptides excretion and the pharmacokinetics of MK-0787 and MK-0791.
1. Effects on the urinary excretion of peptides
Amino acids derived from peptides were increased to some extent in urine excreted 0-2 hours after MK-0787/MK-0791 administration. However, 2 hours after administration, they were restored to pre-administration levels. Four kinds of ninhydrin-positive substances, which are suspected to be the drugs or its metabolites, were detected in the urine after drug administration. They had disappeared 6 hours after administration.
2. Pharmacokinetics of MK-0787 and MK-0791
Peak plasma levels of MK-0787 and MK-0791 at the end of the infusion were 23.4±9.6μg/ml and 32. 7±8.9μg/ml, respectively. The β-phase half life was 1.3±0.3 hour for MK-0787 and 0.7±0.2 hour for MK-0791. AUC's were 32.7±10.7 hr·μg/ml for MK-0787 and 36.3±8.6 hr·μg/ml for MK-0791.
Mean urinary levels of MK-0787 and MK-0791 were 2397.2±828.3μg/ml and 2742.5±1035.6μg/ml, during the 0-2 hour period after administration respectively. After that, the levels decreased gradually, but 4-6 hours after administration significant concentrations were still present 71.3±37.4μg/ml for MK-0787 and 52.4±40.8μg/ml for MK-0791. Cumulative urinary recovery rates within 6 hours after administration were 56.9±8.29 for MK-0787 and 59.0±4.0% for MK-0791.

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The concentration of imipenem (MK-0787), (5R, 6S)-3-[[2-(formimidoylamino) ethyl]thio]-6-[(R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3, 2, 0]hept-2-ene-2-carboxylic acid monohydrate, in plasma, serum, urine and bile was microbiologically determined by a thin layer cup, an agar well or a paper disk method, using B. subtilis ATCC 12432, as a test organism, and brain heart infusion agar (BHIA, Eiken), which included a clear inhibition zone. Approximately 0.1μg (potency)/ml of MK-0787 in biological specimens can be measured by a paper disk method. For the quantitative determination of MK-0787 in plasma, serum, urine and bile, 0.05 M MOPS buffer (pH7.0) was suitable for the use as the diluent of the standard solution of MK-0787.
The activity of MK-0787 in human body fluids mixed with a MOPS or a MES stabilizer unchanged during 28 days storage at -80°C.

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High-performance liquid chromatographic methods using post-column derivatization with o-phthalaldehyde have been developed for the assay of cilastatin sodium (MK-0791) in body fluids and tissues. Whether MK-0791 was added alone or with MK-0787, the recovery of MK-0791 from human plasma, urine and bile was between 75 and 83% and the coefficients of variation were 6% or less. Calibration curves were linear in the concentration range 0.5-50μg/ml of MK-0791 and it was possible to detect 2.5μg/g of MK-0791 in tissues.
MK-0791 was stable in human plasma, urine and bile for at least 70, 56 and 56 days, respectively, when stored at-20°C or -80°C. MK-0791 was stable in rabbit tissues for at least 42 days when stored at-80°C.

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The disposition of imipenem (MK-0787) and cilastatin sodium (MK-0791), administered separately or in combination, has been studied in rats.
1. MK-0787
No significant difference in disposition was found when MK-0787 was administered alone or in combination with MK-0791; rats given ³⁵S-MK-0787 or ³⁵S-MK-0787/MK-0791 intravenously excreted most of the radioactivity in the urine without significant excretion in the feces or bile. Levels of radioactivity in blood decreased rapidly, with a half-life of about 15 min, and were dose-related in the range between 5 and 40mg MK-0787/kg. Radioactivity in the tissues was found to be highest in the kidney, which was 5-16 times higher than that in the plasma. Radioactivity in the liver decreased more slowly than in the other tissues, The radioactivity in the liver was higher than that in the plasma from 1 hr after dosing. Although no placental transfer was obserbed, the levels of radioactivity in milk were the same as those in the blood.
2. MK-0791
Following intravenous administration of ¹⁴C-MK-0791, radioactivity was excreted in the urine (-65%) and feces (-25%). Biliary excretion amounted to 40-50% of the dose and about 1/3 of biliary radioactivity was reabsorbed. These data show that enterohepatic circulation of MK-0791 occured. Blood levels of radioactivity decreased more rapidly than those of MK-0787, with a half-life of about 10 min. Tissue levels of radioactivity were high in the kidney, liver and small intestine, but those in the other tissues were lower than that in the plasma. As with MK-0787, no placental transfer of MK-0791 was observed, but transfer into milk was detected.

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¹⁴C-MK-0787 or ¹⁴C-MK-0787/MK-0791 was given to rats pretreated with MK-0787 or MK-0787/MK-0791 respectively, for 6 days at a daily intravenous dose of 10mg/kg, and their physiological disposition was studied.
No significant differences were observed in tissue or plasma levels of radioactivity when ¹⁴C-MK-0787 was administered alone or combined with MK-0791; however, clear differences in disposition of MK-0787 were observed between ¹⁴C-MK-0787 and ¹⁴C-MK-0787/MK-0791 dosing, after separation of unchanged MK-0787 and its metabolite I. Plasma and tissue levels of MK-0787 were increased while those of metabolite I were decreased when ¹⁴C-MK-0787 was administered concomitantly with MK-0791. No significant effects resulting from consecutive administration of MK-0787 or MK-0787/MK-0791 were observed.

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Imipenem (MK-0787) was coadministered intravenously with cilastatin sodium (MK-0791) to dogs, young puppies and rabbits at a dose of 10 mg/kg in order to determine intact MK-0787 and MK-0791 in plasma and urine. The following results were obtained:
1) Five minutes after the end of administration, the plasma levels of MK-0787 in descending order was rabbits, adult dogs and young puppies, but for MK-0791 plasma levels in descending order was adult dogs, rabbits and young puppies.
2) Adult dogs and young puppies showed a similar biological half-life in plasma for both MK-0787 and MK-0791. Rabbits, however, showed a significantly shorter biological half-life than that in dogs.
3) In dogs, the AUC value for MK-0791 was 1.4 to 1.5 times as high as that for MK-0787. On the contrary in rabbits, the AUC value for MK-0787 was 1.4 times as high as that for MK-0791.
4) The urinary excretion profiles of both MK-0787 and MK-0791 in young puppies showed a remarkable resemblance to those in adult dogs. The profile in rabbits, however, differed from that in dogs.
The protein binding and displacing effects on bilirubin bound to albumin of both compounds were examinedin vitro, in an attempt to explain some dynamic changes in blood levels of the compounds as described above. The results were as follows.
1) The extent of protein binding of MK-0787 as determined by centrifugal ultrafiltration was found to be less than 10% in the plasma of humans and animals, and was much lower than that of other antibiotics examined. MK-0791 binding to protein was found to be approximately 35% in the plasma of humans, dogs and rabbits, and less than 20% in the plasma of monkeys, rats and mice and in human serum albumin solution. The extent of binding of the two compounds was virtually the same, whether present alone or in combination.
2) Neither MK-0787 nor MK-0787/MK-0791 had any displacing effect on bilirubin bound to human serum albumin at concentrations from 10^-5M to 10^-4M. The association constant of MK-0791 to the site of bilirubin binding to human serum albumin was found to be 6.9×10 M^-1, which was significantly smaller than that of control antibiotics examined.

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Plasma levels and urinary excretion of cilastatin sodium (MK-0791) and N-acetyl MK-0791 were studied in rats following intravenous bolus injection and in rabbits, adult beagles and beagle puppies following intravenous infusion of MK-0787/MK-0791 at a dose of 10/10mg/kg and following results were obtained.
1) The half-life of intact MK-0791 was 15.6 and 12.7 min in rats and rabbits, respectively, and adult beagles and beagle puppies showed a half-life of 83.1 and 55.6 min, respectively.
2) In rats, N-acetyl MK-0791 disappeared from the plasma with a half-life of 7.5 min. A small amount of N-acetyl MK-0791 was found in the other species, but in beagle puppy plasma, no N-acetyl MK-0791 was detected.
3) Urinary excretion of intact MK-0791 was 0.6, 16.8, 42.7 and 31.2% of the dose in rats, rabbits, adult beagles and beagle puppies, respectively.
4) Urinary excretion of N-acetyl MK-0791 was 14.0, 40.1 and 12.4% of the dose in rats, rabbits and adult beagles, respectively, and in beagle puppies, no N-acetyl MK-0791 was detected.

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The general pharmacological properties of imipenem (MK-0787), cilastatin sodium (MK-0791) and the combination of these two agents were investigated after intravenous administration of large doses. The following results were obtained.
1. Central Nervous System: Intravenous administration of large doses (25/25, 100/100mg/kg) of imipenem/cilastatin sodium in combination had no significant influence on behavior or the result of various pharmacological tests in mice and rats. After intravenous administration of imipenem alone at doses of 25 and 100mg/kg in rats, there was a slight decrease in normal body temperature, after 25mg/kg there was a transient increase in locomotor activity, and after 100mg/kg there was a significant increase in discriminant avoidance responses. Cilastatin sodium at a dose of 25mg/kg produced a slight decrease in normal body temperature in rats and at a dose of 100mg/kg caused significantly increased locomotor activity. Intravenous administration of 200 mg/kg of imipenem and 200/200mg/kg of imipenem/cilastatin sodium produced seizure discharges in the spontaneous electroencephalogram in 1 of 11 and 2 of 11 rabbits, respectively.
2. Cardiovascular System: Intravenous administrastion of doses of 25 and 100mg/kg of either imipenem or cilastatin sodium caused no noticeable change in the blood pressure, heart rate, respiratory rate or electrocardiogram and had no significant influence on autonomic blood pressure responses in dogs. There was no significant effect on contractil force or cardiac output at these doses. Imipenem/Cilastatin sodium at doses of 25/25 and 100/100mg/kg slightly reduced blood pressure response to carotid occlusion and at a dose of 100/100mg/kg slightly decreased mean blood pressure.
3. Gastroenterological System: Intravenous administration of imipenem, cilastatin sodium and the combination of these agents at doses up to 100, 100 and 100/100mg/kg, respectively, had no significant effect on intestinal propulsion in mice or on basic gastric secretion in rats.
4. Peripheral Nervous System: Imipenem, cilastatin sodium and the combination of these two agents at doses up to 100, 100 and 100/100mg/kg, respectively, had no effect on the neuromuscular junction in rats and at concentrations up to 25 and 25/25mg/ml showed no local anesthetic activity in guinea pigs.
5. Renal System: Intravenous administration of doses of 25 and 100mg/kg of imipenem increased total Na⁺and Cl^-excretion and imipenem/cilastatin sodium at a dose of 100/100 mg/kg increased total Na⁺excretion in conscious dogs.
General pharmacological tests were performed after i. v. administration of imipenem, cilastatin sodium and the combination of these two agents and no marked effect was demonstrated in various pharmacological tests. Noticeable effects of imipenem and imipenem/cilastatin sodium in some tests were observed only when administered in doses much higher than doses showing an antibiotic effect.

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In order to evaluate the safety and pharmacokinetics of imipenem (MK-0787), cilastatin sodium (MK-0791) and their combination, MK-0787/MK-0791, single dose and multiple dose studies and a combination ratio-finding study were performed.
A total of 107 healthy volunteers were involved in these studies. The studies were carried out in sequence:MK-0787 phase I study, MK-0791 phase I study, MK-0787/MK-0791 combination ratio finding study and MK-0787/MK-0791 phase I study.
Adverse effects were observed in 2 out of 107 volunteers. These two volunteers complained of nausea during the MK-0787 multiple dose study. In one subject, the symptom disappeared during the study. In the other subject, the symptom occurred on day 2 and administration was suspended on day 4 because the nausea became worse. In laboratory findings, transient elevation of S-GOT and S-GPT were observed in the MK-0787 multiple dose study. This elevation was considered to be due to changes produced in MK-0787 as a result of the diluent used. In the MK-0791 single dose study, a transient increase in total serum bilirubin was observed. In the other studies, no abnormal laboratory findings due to the drugs were observed.
Maximum plasma levels of MK-0787 were observed at the end of the infusion, and their levels showed dose-dependence. The half-life was about one hour. Detectable levels continued until 6 hours after administration. Concomitant administration of MK-0791 influenced the pharmacokinetics of MK-0787 slightly. In multiple dose studies, no cumulative tendency was observed. Plasma levels of MK-0791 were similar to the MK-0787 plasma levels.
Urinary excretion of MK-0787 was grossly different after administration of MK-0787 alone from that after admininistration of MK-0787 and MK-0791 concomitantly. MK-0791 an inhibitor of the dehydropeptidase which hydrolyzes MK-0787, enhances the urinary recovery of MK-0787. The urinary recovery after MK-0787 alone was only 20-30%. On the other hand, it was enhanced to approximately 70% when an equivalent dose of MK-0791 was used concomitantly. When MK-0787/MK-0791 was administered, the urinary level of MK-0787 reached a peak one hour after administration, and decreased to non-detectable levels within 12-24 hours. The urinary level of MK-0791 showed a similar tendency in each study. It showed a peak level one hour after administration, and it was detectable until 6-12 hours. Neither MK-0787 nor MK-0791 showed any cumulative tendency.

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Imipenem/Cilastatin sodium (MK-0787/MK-0791) is a combination of MK-0787, a new carbapenem antibiotic, and MK-0791, a dehydropeptidase inhibitor. The antibacterial activity of MK-0787 was tested with an inoculum size of 10⁶cells/ml using plate dilution method. The MIC of MK-0787 was≤0.4μg/ml forS. aureus, 0.2μg/ml forE. coli, 0.2-0.8μg/ml for K. pneumoniae, 0.4μg/ml forP. mirabilis, 0.4μg/ml forP. morganii, 0.2-0.8μg/ml forS. marcescensand 0.8-3.1μg/ml forP. aeruginosa.
The pharmacokinetics of MK-0787/MK-0791 was investigated in 6 healthy male volunteers. A thirty-minute intravenous drip infusion of 500mg/500mg yielded peak plasma levels of 21.6-60.0μg/ml (MK-0787) and 23.1-45.0μg/ml (MK-0791).
The β-phase biological half-life of the drug was estimated to be 0.79 hour (MK-0787) and 0.84 hour (MK-0791).
The AUC was estimated to be 40.0 hr·μg/ml (MK-0787) and 32.6 hr·μg/ml (MK-0791). The urinary excretion rate within 6 hours was 76.7%(MK-0787) and 56.8%(MK-0791).
Twenty patients, including 1 with endocarditis, 5 with respiratory tract infections and 14 with urinary tract infections were treated with MK-0787/MK-0791, mainly with 500 mg/500 mg b. i. d. drip infusion for 5-9 days. The clinical response to the treatment was excellent in 10 patients, good in 6, fair in 3 and poor in 1. The effectiveness rate was calculated as 80%. The only side effect noted was diarrhea which occurred in one patient.

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To evaluate the clinical efficacy of imipenem/cilastatin sodium (MK-0787/MK-0791), the treatment was made with the drug in 10 patients including 3 with pneumonia, 3 with chronic bronchitis, 1 with chronic cystitis, 1 with acute pyelonephritis, and 2 with acute biliary tract infection. Responses were excellent in 3 patients, good in 6, and poor in 1. The efficacy rate of MK-0787/MK-0791 was 90%.
Side effect was not observed after the treatment of the drug. Three patients showed the following abnormal laboratory findings after the treatment; temporal slight elevations of Al-P and γ-GTP and slight elevation of GOT each in one case.

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Imipenem/Cilastatin sodium (MK-0787/MK-0791) therapy was performed in 10 cases of pulmonary infections including 3 cases with acute pneumonia, 3 cases with pulmonary suppuration, 3 cases with infectious emphysematous bulla, and one with relapse into diffuse panbronchiolitis. 8 cases-had underlying disease such as diabetes mellitus, bronchial asthma, diffuse panbronchiolitis, and cholangitis. Degree of severity, in 6 cases was severe, in 3 cases, moderate and in one case, mild.
MK-0787/MK-0791 was administered at a dose of 500mg/500mg ×2-3/day for 3 to 21 days (average 12 days) except in one case of multiple pulmonary suppuration with septicemia in which 500mg/500mg×4/day combined with TOB 120 mg×2/day. was administered.
The overall clinical efficacy of each case was rated on a five-step scale (excellent, good, fair, poor and unevaluable), according primarily to the degree of improvement in chest X-ray photographs and bacteriological effect from sputum and also by reference to other laboratory findings and subjective symptoms including adverse reactions.
Clinical response was excellent: in 1 case, good in 4 cases, fair in one case, poor in one case and unevaluable in 3 cases. The cases evaluated fair and poor were emphysematous bulla and pulmonary infection. Two cases of the unevaluable cases were pneumionia due to Candida and 1 case was combined with TOB. Therefore the clinical effectiveness rate was 71%. The case combined with TOB was of severemultiple pulmonary-suppuration with septicemia due to Pseudonnonas aeruginosa. It opposed prechemotherapy by TIPC, DKB, CFS etc, but dramatically improved with combined MK-0787/MK-0791 and TOB. It was an interesting case of combined treatment.
No adverse reaction was observed. Abnormal laboratory findings were noted in 2 cases with slight elevation of GOT, GPT in one case with moderate elevation of GOT, GPT, LDH and in one case with minor eosinophilia.

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Imipenem/Cilastatin sodium (MK-0787/MK-0791), a new combination antimicrobial agent, was administered to 11 patients who were suffering from bacterial respiratory infections complicating chronic respiratory desease. Investigation of the relevant pathogens using a quantitative sputum culture revealed 8 patients withPseudomonas aeruginosa, 2 withHaemophilus influenzaeand 1 with Escherichia coli. The administration of the drug was done by drip infusion, twice a day, with doses of 250/250-500/500-1000/1000 mg of MK-0787/MK-0791 administered each time.P. aeruginosawas eradicated in 4 out of 8 patients, although 3 of them became reinfected with the same pathogen shortly after complete eradication.
MICs of the drug againstP. aeruginosarevealed that the increase in MIC value was remarkable in such patients with persistent infections.
With regard to adverse effects, gastrointestinal symptoms such as nausea and vomiting were observed in 4 patients, and these usually occurred immediately after drip infusion. Laboratory findings revealed slight elevation of transaminases in 1 patient.

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In vitroantimicrobial activity of MK-0787, a new β-lactam antibiotic, was examined by the broth dilution method with the MIC 2000 system. The minimum inhibitory concentrations (MICs) of MK-0787 against 120 clinical isolates were compared with those of ceftazidime (CAZ), cefoperazone (CPZ), latamoxef (LMOX) and gentamicin (GM) against 20 isolated each ofS. aureus, E.coli, K. pneumoniae, S. marcescens, Enterobacterspp. andP. aeruginosa. AgainstS. aureus, MK-0787 was shown to be most active among the five drugs and significantly more active than CPZ against all other isolates tested.
The therapeutic efficacy of MK-0787/MK-0791 was evaluated in patients with respiratory tract infections. Eighteen patients were treated with intravenous drip infusions of this drug at the dose of 0.5 gram of MK-0787 twice to four times a day. The response to treatment was excellent in one patient, good in eleven, fair in two and poor in four. Slight epigastralgia was observed in one patient during administration of this drug, and laboratory test revealed eosinophilia in two patients, elevation of serum transaminase in four and elevation of blood urea nitrogen in one. All of these abnormalities in laboratory tests were of slight, transient and returned to normal after cessation of the administration of the drug.

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Imipenem/Cilastatin sodium (MK-0787/MK-0791), a new antibiotic, was used in 9 patients with respiratory tract infections.
MK-0787/MK-0791 was administered to 5 patients with pneumonia, 2 with pulmonary suppuration and 2 with secondary infection complicating bronchiectasis. A dose of 500mg/500mg dissolved in 100ml of solution was given twice or three times a day by intravenous drip infusion. Clinical response was good in 7 patients, fair in 1 patient and poor in 1 patient.
Exanthema was found in one patient with pneumonia, and it disappearred after discontinuing the drug. A transient elevation of S-GPT in one patient was also restored to normal after discontinuing the drug.
MK-0787/MK-0791 appears to be useful antibiotic in the treatment of respiratory tract infections.

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MK-0787/MK-0791, a new antimicrobial agent imipenem/cilastatin sodium, was studied in 15 cases of respiratory tract infection including six cases of pneumonia, six cases of lung abscess, one case of acute exacerbation of chronic bronchitis, one case of diffuse panbronchiolitis and one case of pyothorax.
The drug was administered intravenously at d daily dose of one gram/one gram for 14 days (13 cases), 11 days (one case) and six days (one case).
The following six potential pathogens were recovered from the sputum at a start of the treatment with MK-0787/MK-0791 and four pathogens (S. pneumoniae, Peptococcus, S. aureus, S. epidermidis) were eradicated.
The clinical response to the treatment with MK-0787/MK-0791 was excellent in 11. cases, good in two cases, fair in one case and poor in one case (efficacy rate=86.7%).
No side effects were observed but the slightly elevation of transaminase was observed in four cases.
From the above results, it is concluded that MK-0787/MK-0791 is effective, useful and safe antimicrobial agent.

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Clinical application of imipenem/cilastatin sodium (MK-0787/MK-0791), a new carbapenem antibiotic, was employed in ten patients: three with respiratory tract infections, three with urinary tract infections, one with bacteremia and three with fever of unknown origin.
The drug was administered at a dose of 0.25/0.25-0.5/0.5 g intravenously every 12 hours except in one patient with chronic renal failure.
The clinical results were evaluated as excellent in two patients, good in six, and poor in two.
Side effects were noted in three patients: exanthema in two and elevation of GOT and GPT in one.

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Imipenem/Cilastatin sodium (MK-0787/MK-0791) was administered intravenously, at a dose of 1.0g (0.5g as MK-0787) by drip infusion for 30 minutes, into 2 patients with renal insufficiency, and its concentration in the plasma was determined. In one case, the plasma concentration showed relatively lower levels and reached the peak immediately after the drip infusion and slowly declined. In another case, its concentration reached the peak 30 minutes after the end of administration and the high plasma levels continued over ti long time period.
MK-0787/MK-0791 was administered to 21 patients: 15 respiratory tract infection, 2 sepsis, 2 liver abscess and 2 other infection. It was given intravenously 2 or 3 times a day at a dose of 0.5 to 1.0g to the patients with normal renal function and once a day at a dose from 0.25 to 1.0g to the patients with renal insufficiency. Clinical response was excellent in 2 cases, good in 16, fair in 1, poor in 1 and undetermined in 1.
As an adverse reaction, an eruption was observed in one patient, and laboratory tests revealed an eosinophilia in another patient. No severe side effects caused by MK-0787/MK-0791 were observed.

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Imipenem/Cilastatin sodium (MK-0787/MK-0791) was administered to 11 patients with various infectious diseases. In each case of acute epiglottitis, bilateral tonsillitis with left peritonsillitis and bilateral peritonsillar abscess one excellent and two good effects were observed. In one case of secondary infection of pulmonary emphysema and one case of pneumonia not responded by LMOX and MINO, good clinical effects were observed. No response was observed in one case of abscess of liver and abdominal wall caused by E. coli associated with cancer of gallbladder. In two cases of acute exacerbation of chronic pyelonephritis, good in one which did not isolate causative organisms because of pretreatment of CEZ, and excellent in the other one which isolated E. coli.
In one case of right perinephric abscess associated with appendicitis diagnosed by abdominal CT, clinical symptoms and signs were improved and good effect was obtained. In two cases of septicemia of S. aureus and S. aureus mixed by A. anitratus excellent and good effects were observed. No side effect nor abnormality of laboratory findings was observed in any cases.
MICs of MK-0787 against two strains of S. aureus isolated from these patients were 0.013-0.025 μg/ml, 0.05-0.1 μg/ml against 4 strains of E. coli and 0.2 μg/ml against one strain of A. anitratus.

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Imipenem/Cilastatin sodium (MK-0787/MK-0791) was administered by intravenous drip infusion to 5 patients with respiratory tract infections, 2 with sepsis and 1 with urinary tract infection, and the clinical response was excellent in 6 patients and good in 2 patients.
Mild nausea and vomiting were observed in 1 patient who received a high dose.
No severe laboratory adverse findings were observed.

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Efficacy of imipenem/cilastatin sodium (MK-0787/MK-0791) was evaluated by measuring MICs of the drugs for clinically isolated strains, and by administering the drug to the patients with various infectious diseases.
For most of the strains studied in vitro, MICs of the MK-0787/MK-0791 were lowest compared withthose of other antibiotics, i. e. CMX, CPZ, CZX and PIPC. Even the strains resistant to other antibiotics such as S. epidernzidis, were also sensitive to MK-0787/MK-0791.
MK-0787/MK-0791 were administered to thirty patients with infectious diseases (15 with RTI, 3 with cholecystitis, 2 with UTI) by intravenous drip infusion to total doses ranging 2 to 71g.
The overall efficacy rate was 72% while efficacy rate for RTI, cholecystitis, and UTI were 61. 5%, 100%, and 100% respectively.
Bacteriological efficacy rate was 85. 7%. No significant adverse effect nor abnormalities in laboratory fi ndings were observed without slight stools loose in two cases, eruption in one case and slight elevation of γ-GTP and Al-P in one case.

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To evaluate the effectiveness of antibiotics imipenem/cilastatin sodium (MK-0787/MK-0791), a derivative of carbapenem, for respiratory infection, following studies were performed: 1. Intrabroncho-alveolar concentration of drug with experimental animal. 2. Clinical study. 3 Number of microorganism in the sputum of a case of chronic bronchitis.
MK-0787/MK-0791 was intravenously injected into albino rabbits with which was broncho-alveolar lavage performed sequentially. MK-0787 was detected from 30 to 240 minutes after injection and the peak of concentration was observed at 60 minutes.
Clinical studies were tried with each two cases of bacterial pneumonitis, chronic bronchitis, each one of pulmonary suppuration and bronchiectasis combined with chronic respiratory failure. Good effectiveness were observed with all but one case of chronic bronchitis, with whom evaluation was fair.
Number of Pseudomonas aeruginosa in the sputum of a case of chronic bronchitis decreased from 5 ×10⁵ to 2 ×10⁴ per ml in four hours after intravenous injection.
As the side effect, skin eruption was observed in 1 case. Laboratory findings revealed 1 case with a slight increase in GOT and GPT.

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Imipenem/Cilastatin sodium (MK-0787/MK-0791) is a new carbapenem derivative with broad antibacterial spectrum (Gram positive bacteria, Gram negative bacteria).
MK-0787/MK-0791 was administered intravenously to 11 patients (pneumonia 10 cases, acute bronchitis one case) at daily doses of 500 or 1000 mg and good response were obtained in 8 cases.
The causative organisms were S. pneumoniae in one case, K. pneumoniae in one case and P. aeruginosa in 4 cases. Mixed infection with Serratia liquefaciens, P. maltophilia and S. faecalis was noted in one case.
MK-0787/MK-0791 was effective in one case with Pseudonzonas infection (acute bronchitis in one case).
Laboratory findings revealed one case with an increase in GPT, one case with an increase in T-Bil., one case with an increase in Al-P and in the number of eosinophil but these were slight.

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The clinical effects of imipenem/cilastatin sodium (MK-0787/MK-0791), a new carbapenem antibio tic, in respiratory tract infections were studied.
MK-0787/MK-0791 was administered to 7 patients with chronic respiratory tract infections, 2 patients with pneumonia, 1 patient with a pulmonary cyst and 1 patient with mediastinitis.
An excellent response was obtained in 2 patients, a good response in 7, fair in 1, and unknown in 1 patient, for an efficacy rate of 90%. As for side effects, general fatigue, anorexia, nausea and vertigo were observed transiently in one patient. No abnormal findings were observed in the laboratory examinations.
From the above results, MK-0787/MK-0791 is expected to be highly useful in the treatment of respiratory tract infections.

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The antibacterial activity, pharmacokinetics and clinical effects of imipenem/cilastatin sodium (MK-0787/MK-0791) a carbapenem antibiotic, were studied and the following results were obtained:
1. Antibacterial activity
MIC_s of MK-0787 against CEZ-resistant bacteria, S. aureus, E. coli, and K. pneumoniae, were 0.39μg/ml or less, and its antibacterial activity was much superior to that of comparative drugs; CMX, CTM, CPZ, CTX and LMOX. The MIC of this drug against P. mirabilis ranged from ≤0.39 to 1.56 μg/ml, with antibacterial activity a little inferior to that of LMOX, similar to that of CTX and superior to that of CMZ, CTM, CPZ.
2. Pharmacokinetics
When MK-0787/MK-0791 was administered to healthy adult male volunteers by a 30-minute intravenous drip infusion in a dose of 500 mg/500 mg, the mean maximum plasma concentration at the end of the infusion was 35. 6μg/ml for MK-0787 and 31. 7 μg/ml for MK-0791. The mean β-phase half life was 0.9 hour and 0.7 hour, respectively, and the two compounds had similar disappearance curves. The mean urinary recovery up to 8 hours was 69. 4% for MK-0787 and 60.0% for MK-0791.
When 2g of PIPC was administered by a 30-minute intravenous infusion, the maximum plasma level was 98.3μg/ml at the end of the infusion, the β-phase half life was 0.8 hour and the urinary recovery up to 8 hours was 75.1%.
The influence of probenecid on plasma and urinary levels of MK-0787/MK-0791 was examined. The following significant results were observed with MK-0791: increased plasma concentration, prolonged β-phase half life, increased AUC and decreased urinary recovery rate.
3. Clinical effects
MK-0787/MK-0791 was administered to 5 patients with respiratory tract infections, 2 with biliary tract infections and 2 with urinary tract infections. Out of 8 patients who were judged to be evaluable, clinical results were excellent in 1, good in 6 and poor in 1.
Either fever or nausea was observed in 2 patients as adverse effects, however, no abnormality in laboratory findings was observed.

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Imipenem/Cilastatin sodium (MK-0787/MK-0791), a newly developed by Merck, was studied for its clinical efficacy.
MK-0787/MK-0791 was administered to 8 patients with various infections, 1 with sepsis, 3 with sepsis suspected, 3 with pneumonia, and 1 with chronic pyelonephritis, including 7 cases with underlying disease (AML; 2 cases, non-Hodykin malignant lymphoma; 2, multiple myeloma; 1, eosinophilia; 1).
Clinical response was observed in 6 cases, good in 2 cases and poor in 4. These were excluded in 2 cases that one was taken other drugs and the other was radiation pneumonitis.
Concerning bacteriological response, 3 cases with E. coli, H. influenzae and P. aeruginosa (that was associated other drugs) were eradicated after treatment.
No side effect was observed and abnormal laboratory findings were not obtained because of MK-0787/MK-0791.

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Imipenem/Cilastatin sodium (MK-0787/MK-0791) was used for the treatment of 48 patients with respiratory diseases including 34 patients with small airway infections, 8 with airway infections, 4 with acute pneumonia and 2 with pyothorax. Two patients were excluded from the judgement of clinical effect because one received only one dose of the drug and the other proved to have a non-infectious disease.
Thus, MK-0787/MK-0791 was effective in 71% of the patients with airway infections and in 80% of the patients with pneumonia or pyothorax.
Bacteriologically, Pseudomonas aeruginosa was identified in 20 patients before therapy. In 4 of them, it was eradicated and in other 4 patients, the number of P. aeruginosa in the sputum was decreased after treatment. However, the remaining 12 patients with Pseudomonas infections, 3 patients with mixed infections including P. aeruginosa and 5 patients with GNF-GNR infection, were not improved. There was no significant difference in the clinical effects of the drug at daily doses ranging from 500 mg/500 mg (250 mg/250 mg×2)/day to 2000 mg/2000 mg (1000 mg/1000 mg×2)/day.
In terms of side effects, one patient had severe nausea which persisted for 12 hours. Another patient complained of a burning sensation during the drip infusion of the drug.
Laboratory examinations revealed mild hepatic dysfunction in 4 patients (8. 3%) after this therapy. In conclusion, this drug should be useful as a broad spectrum β-lactam, especially in respiratory infections.

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Imipelicm/Cilastatin sodium (MK-0787/MK-0791) was administered in total daily doses of 1/1g-2/2g, given 2 or 3 times a day for 14-21 days, to a total of 12 patients with respiratory tract infections Jcute pneumonia (5 patients), pulmonary suppuration (1 patient) diffuse panbronchiolitis (4 patient) and acute exacerbation of chronic bronchitis (2 patients). The following clinical responses were obtained: excellent in 1 patient, good in 9 patients, fair in 1 patient and poor in 1 patient.
No reactions related to the administration of MK-0787/MK-0791 were observed.

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The combination of imipenem (MK-0787), a new carbapenem antibiotic, and cilastatin sodium (MK-0791), a renal dipeptidase inhibitor, was administered to patients with various infections to evaluate its clinical efficacy. The infections were acute pyelonephritis in 3 patients, acute cholecystitis, acute diverticulitis of the colon, pneumonia and acute pharyngitis each in 1 patient. Clinical efficacywas excellent in 1 patient, good in 5 and no response in 1, with an efficacy rate of 85.7%. Neither adverse reactions nor abnormalities of laboratory tests were observed.

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We measured the antibacterial activity of MK-0787 against clinical isolates of S. aureus, S. faecalis, H. influenzae, E. coli, K. pneumoniae, E. cloacae, S. marcescens, P. mirabilis, P.vulgaris and P. aeruginosa.
MK-0787 showed much better antibacterial activity than cephems against Gram-positive bacteria, and antibacterial activity similar to that of cephems against Gram-negative bacteria. Especially against P. aeruginosa, the antibacterial activity of MK-0787 was much superior to that of cephems and superior to that of CFS.
Plasma levels and urinary levels of MK-0787 were determined after intravenous drip infusion of 250 mg or 500 mg. Peak plasma levels at the end of the 30-minute infusion were 39. 2 μg/ml after 250 mg and 76. 2 μg/ml after 500 mg, and the half-life was 1. 67 hr. and 2. 52 hr., respectively. Maximum urinary levels were 279 μ/ml at 2-4 hr. after 250 mg and 1866 μg/ml at 1-2 hr. after 500 mg. Urinary recovery up to 6 hr. was 20. 6% and 20. 8%, respectively.
MK-0787/MK-0791 was administered to 17 patients. An effective clinical response was observed in 5 out of 6 patients with respiratory tract infections (excluding one unevaluable patient), in all patients with urinary tract infections and in 2 out of 3 patients with sepsis. One patient with SBE was evaluated as excellent. In 16 evaluable patients out of 17, clinical efficacy was excellent in 4, good in 10, fair in 1 and poor in 1.
Mild diarrhea in one patient was the only adverse effect observed.
Slight elevations of S-GOT, S-GPT and Al-P observed in 3 patients were the only laboratory abnormalities noted.

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The foundamental and clinical investigations on imipenem/cilastatin sodium (MK-0787/MK-0791), a new broad spectrum injectable carbapenem, were carried out.
We investigated antimicrobial susceptibilities of 38 strains of methicillin-cephem resistant S. aureus isolated from blood.
The MICs of MK-0787 to highly resistant S. aureus (28 strains, their MICs to CEZ ranged ≥100 μg/ml) distributed 0.4-≥100 μg/ml, and 6 strains were≥100 μg/ml. The MICs of MK-0787 to moderately resistant S. aureus (10 strains, their MICs to CEZ ranged 25-50 μg/ml) were lower than 6.3 μg/ml.
The MICs of clinical isolated ABPC resistant S. faecium were≥100μg/ml in<43 strains, 50 μg/ml in 3 strains and 25 μg/ml in 2 strains out of 48 strains.
MK-0787/MK-0791 were administrated by drip infusion to 7 cases with severe infection. 3 cases infected by P. aeruginosa, and in those cases, one case of meningitis, one case of respiratory tract infection and one case of sepsis associated leukemia were excellent. One case of sepsis associated AML infected by P. aeruginosa and P. cepacia was excellent. Also, one case of sepsis by P. cepacia and one case of respiratory tract infection by methicillin-cephem resistant S. aureus were excellent. But one case of sepsis by methicillin-cephem resistant S. aureus was poor.
Neither side effect nor abnormal laboratory findings were observed without polyuria in one case.

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Imipenem (MK-0787) is a new carbapenem antibiotic with an expanded spectrum and potent activity against gram-positive and gram-negative bacteria including β-lactamase producing resistant strains.
Imipenem/Cilastatin sodium (MK-0787/MK-0791) was used in the treatment of 7 cases of respiratory tract infection (RTI) by Pseudomonas aeruginosa: 3 cases of bronchiectasis with infection, 2 cases of diffuse panbronchiolitis, 2 cases of RTI, one with lung cancer and interstitial pneumonitis and the other with interstitial pneumonitis and secondary pneumothorax.
MK-0787/MK-0791 was administered by intravenous drip infusion at a dose of 0.25-1.0g twice a day for 7-48 days and results were obtained good in 3 cases, fair in 3 cases and not determined in one case.
Adverse reaction such as eruption, fever, diarrhoea etc. were not observed in our study, however slight eosinophilia was noted in one case.
From the above clinical experience, MK-0787/MK-0791 would be a clinically useful antibiotic against RTI.

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Laboratory and clinical studies were performed on a new carbapenem antibiotic, imipenem/cilastatin sodium (MK-0787/MK-0791).
A sensitivity test using clinical isolates showed that the antibacterial activities of MK-0787 were similar or slightly superior to those of cefoperazone and latamoxef against E. coli, Klebsiella, Proteus, Pseudomonas; further superior against S. aureus.
MK-0787/MK-0791 was administered to one case of pulmonary suppuration, urinary tract infection, pneumonia, sepsis, subacute bacterial endocarditis, and two cases of F. U. O.
The drug was given 1 to 2 g drip infusion twice or three times d day for 3 to 23 days.
The clinical efficacy was excellent in 1 case, good in 3 cases, fair in 1 case, poor in 2 cases.
The causative organisms were eradicated in 3 cases, decreased in 1 case, replaced in 1 case, unevaluable in 2 cases.
Transient redness on the hands and a slight elevation of S-GOT and S-GPT were observed in one patient. Thrombocytopenia and anemia were observed in another patient. And a slight elevation of S-GOT, S-GPT were observed in one patient.

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A new antibiotic, imipenem/cilastatin sodium (MK-0787/MK-0791) was administered for 1-14 days at a total daily dose of 1000 mg/1000 mg to 11 patients, including 1 patient with sepsis, 2 with pneumonia, 1 with chronic bronchitis, 1 with lung abscess, 1 with acute pyelonephritis and 5 with chronic pyelonephritis.
The results obtained were excellent in 1, good in 6, fair in 1, poor in 2, and unknown in 1. The overall efficacy rate was 70.0%.
Epigastric pain was observed in 1 patient. In the patient with acute pyelonephritis, administration of MK-0787/MK-0791 was stopped because of nausea, vomiting and abdominal pain. Abnormal laboratory, findings were not observed in any of these patients.

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Antibacterial activity against clinical isolates and usefulness in the treatment of infections in the field of internal medicine of imipenem/cilastatin sodium (MK-0787/MK-0791) were investigated.
1) The antibacterial activity of MK-0787 against S. aureus, S. faecalis, E. coli, K. pneumoniae, .E. cloacae, S. marcescens and P. aeruginosa was prominent. Its antibacterial activity was similar or superior to that of CAZ, CMX and Aztreonam.
2) MK-0787/MK-0791 was administered to a total of 18 patients ; 14 with respiratory infections, 3 with sepsis and 1 with a urinary tract infection. Clinical efficacy was evaluated as excellent in 3, good in 8, fair in 2, poor in 4 and unknown in 1. Eleven of 17 patients were evaluated as excellent or good with efficacy rating of 64.7%.
3) Causative organisms were isolated from 10 patients. Organisms were eliminated in 6, decreased in 1 and unchanged in 3. Thus, the rate of bacterial eradication was 60%.
4) In 11 patients treated with a dose of 1g/1 g or more the efficacy rate was 81.8%; this was much better than in the group that received less than 1g/1g, 6 patients with a rate of 33.3%. According to the severity, a daily dose of 1g/1 g or more appears to be needed.
5) Ten out of 14 patients (71.4%) who had received other drugs and were judged to have had no response were evaluated as good.
6) No side effects were observed.
7) Abnormal laboratory findings were observed in 3 patients.
In 2 patients, S-GOT, S-GPT and Al-P or S-GOT, S-GPT and LDH were elevated. Another patient had eosinophilia.
8) If MK-0787/MK-0791 were used after selecting the patient suitable for its characteristic, it would be a more useful antibiotic.

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