[in Japanese]

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Sulbactam/cefoperazone (SBT/CPZ) is a preparation containing CPZ and SBT, an inhibitor of β-lactamases, at the ratio 1:1. The reliability of the SBT/CPZ disc susceptibility test in estimating approximate values of MICs and the utilization of the test in the evaluation of proper administrative doses were studied using 365 strains of clinical isolates.
The antimicrobial activity of SBT/CPZ was stronger than that of CPZ alone. This increase in the antimicrobial activity due to the addition of SBT was well observed in the disc diffusion susceptibility test and MIC values. The MIC₈₀s of SBT/CPZ against Staphylococcus aureus was 12.5μg/ml, while that of CPZ alone was 50μg/ml. MIC₈₀s of SBT/CPZ against Escherichia coli, Pseudomonas aeruginosa, Serratia marcescens and Enterobactor aerogenes were smaller than those of CPZ, and were 0.20, 12.5, 25 and 3.13μg/ml, respectively. However, MIC₈₀s of SBT/CPZ against Staphylococcus epidermidis, Klebsiella pneumoniae, Proteus mirabilis and Proteus vulgaris were not changed compared to those of CPZ alone, and MIC₈₀s were 6.25, 0.20, 0.78, and 0.78μg/ml, respectively.
The reliability of the SBT/CPZ disc diffusion susceptibility test in the quantitative estimation of antimicrobial activities was well demonstrated using commercialized 8mm diameter discs (Showa) and 6mm diameter discs prepared in this laboratory, both of which contained 30μg of CPZ and 30μg of SBT. These disc susceptibility test results were well correlated with MICs, hence the SBT/CPZ disc susceptibility test should be useful for the estimation of approximate MIC values.
To interpret results of the Showa SBT/CPZ disc test, the following 4 category classification was used: (+++) MIC≤3μg/ml,(++) 3μg/ml<MIC≤15μg/ml,(+) 15μg/ml<MIC≤60μg/ml,(-) MIC >60μg/ml. In both 6 and 8mm diameter disc tests, when uniform break points of inhibitory zone diameter were similarly applied to all strains isolated clinically, some strains of S. aureus, E. faecalis, and P. aeruginosa, brought false positive (susceptible) results showing slightly greater inhibitory zone diameters compared to MICs. However, if different break points against P. aeruginosa as indicated in this study were applied and E. faecalis was excluded from the test, excellent results were obtained in the quantitative estimation of MICs.
Antimicrobial activities of antibiotic agents have been reported to be reduced by serum prctein binding. Furthermore, antibiotics with stronger protein bindings have lower ratios of free drugs available to penetrate into tissues than antibiotics with weaker protein bindings. Therefore, to evaluate antimicrobial activities in blood and the distribution of antibiotics in the body, blood levels of free and bound forms must be considered. CPZ, which is the major component of SBT/CPZ, would tend to remain within the intravascular compartment, giving rise to high concentrations in the protein fraction (90%), but low concentrations in the umbound free fraction (10%).
Based on the antimicrobial activity of SBT/CPZ, the pharmacokinetic data for SBT/CPZ and the recommended modest dose schedule (2-4g/day), MIC break points of 3μg/ml and 15μg/ml in the 4 category system appear to be more useful than break points of 16μg/ml and 64μg/ml used in the 3 category system in estimating whether levels of free and bound forms in the blood of this drug exceed the MICs.

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Synergistic activities of isepamicin (ISP) and a β-lactam antibiotic such as piperacillin (PIPC)or cefotaxime (CTX) against Pseudomonas aeruginosa were demonstrated in vitro and in vivo.
In vitro synergistic activity was observed when ISP was used together PIPC or CTX.
The synergy observed in vitro was reproduced in vivo against experimental mouse infections, and a ISP-PIPC or a ISP-CTX combination showed significantly greater protective effects than individual antibiotics by themselves.

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Antibacterial activities of monobactam antibiotics (carumonam (CRMN) and aztreonam (AZT)) against Gram-negative bacilli isolated from inpatients in the latter half of 1987 were investigated using penicillin (PC: piperacillin (PIPC)), cephems (CEPs: ceftazidime (CAZ), cefotaxime (CTX), latamoxef (LMOX), cefsulodin (CFS)), carbapenem (imipenem (IPM)) and pyridonecarboxylic acids (norfloxacin (NFLX) and ofloxacin (OFLX)) as reference antibiotics.
A total of 400 strains of 13 species, i. e. Escherichia coli, Klebsiella pneumoniae, Klebsiellaoxytoca, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Pseudomonas aeruginosa and Haemophilus influenzae, were used as test strains.
1. CRMN and AZT, both monobactam antibiotics, were roughly comparable in their activities and no resistant strain to these antibiotics were found among isolates of E. coli, Klebsiella spp., Proteus spp., M. morganii, P. rettgeri or H. influenzae and few resistant strains were observed among isolates of S. marcescens. On the other hand, isolates of C. freundii, Enterobacter spp. and P. aeruginosa included rather numerous strains resistant to the monobactam antibiotics. Among these cases, whereas R strains, i. e. resistant strains showing MICs≥50 μg/ml, accounted for a large proportion of strains resistant to PC and CEPs, I strains, i. e. intermediately resistant strains showing MICs between 12.5 and 25μg/ml, accounted for a large proportion of strains resistant to the monobactam antibiotics.
2. Strains resistant to PIPC, a PC, were detected with high and more or less uniform frequencies over the entire spectrum of the isolates examined.
3. Antibacterial activities of CEPs varied against different bacterial species. While strainsresistant to CTX, CAZ and LMOX were commonly detected with high frequencies among isolates of C. freundii, Enterobacter spp. and S. marcescens, large percentages of LMOX-resistant strains of C. freundii and Enterobacter spp. were of the I type. CTX-resistant strains were also found among isolates of P. vulgaris and M. morganii. Proportions of CEP-resistant strains ofP. aeruginosa were 28% for CFS and 12% for CAZ.
4. No or few strains among the isolates of 13 species investigated were resistant to IPM, a carbapenem antibiotic, which showed the most stable antibacterial activity, but it was less active than monobactam antibiotics and CEPs against Klebsiella spp., P. mirabilis and H. influenzae.
5. While NFLX and OFLX, both pyridonecarboxylic acids, were closely comparable in their activities, high frequencies of resistant (inclusive of I resistance) strains were present among P. vulgaris, M. morganii, P. rettgeri, S. marcescens and P. aeruginosa. Moreover, resistant strains were sporadically found among isolates of K. pneumoniae, C. freundii, E. aerogenes and H. influenzae.

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In vitro antibacterial activities of aztreonam (AZT) and cephems against clinically isolated 334 strains were investigated. The results obtained in the study are summaried as follows:
1. AZT showed excellent antibacterial activities against clinically isolated 334 strains.
2. AZT showed potent activities against Escherichia coli, Klebsiella pneumoniae, Proteus spp., Enterobacter aerogenes and Citrobacter freundii.3. Antibacterial activities of AZT were superior against Enterobacter cloacae, Serratia marcescens and Pseudomonas aeruginosa to those of cephems.

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There have been no report on concentrations in human lung tissue of aminoglycoside antibiotics which are frequently used in combination with cephem antibiotics in the treatment of severe respiratory infections. The authors examined lung tissue concentration of astromicin (ASTM) during clinical trials in thoracotomized patients using intravenous drip infusion just before operation. And the following conclusions have been obtained:
1. The average peak serum level obtained upon intravenous drip infusion of ASTM 200 mg for 1 hour just before operation was 11.2 μg/ml at 1 hour after starting the administration and half-life of ASTM in β phase was 2.90 hours.
2. ASTM concentrations in the lung tissue upon 1 hour intravenous drip infusion just before operation at a dose level of 200 mg reached a maximum at 2 hours after the start of the administration averaging 7.7μg/ml and were 27.7-68.8% of serum peak level.
3. Bronchiolar concentrations of ASTM 200 mg upon 1 hour intravenous drip infusion just before operation were 33.0-72.3% of peak serum level. These concentrations appear to be sufficient for the treatment of target infections.
4. The 1 hour intravenous drip infusion of ASTM 200mg appeared to be clinically safety and useful as was the intramuscular injection of ASTM 200mg.

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Twenty three neonates and young infants were treated with imipenem/cilastatin sodium (IPM/CS) and its clinical efficacy and side effects were evaluated. Ages of the patients ranged from 0 to 83 days, and their body weights ranged from 750 to 4,760g. Doses of IPM/CS ranged from 17.4 to 21.5mg/kg as IPM every 6 to 12 hours for 3 to 12 days. Sixteen patients with infections including sepsis, meningitis and pneumonia, appeared to have responded to the IPM/CS treatment. Among them, clinical results were excellent in 2, good in 12 and fair in 2 patients. The drug was well tolerated, but 1 patient had diarrhea, 1 had redness of body during infusion, 1 had elevated GOT and GPT, and 2 patients showed only elevated values of GOT only among the 23 patients.
The pharmacokinetics of IPM/CS were studied in 7 patients. Their ages ranged from 0 to 9 days, and body weights ranged from 2.5 to 4.0kg. Serum concentrations of IPM were between 18.0 and 96.9μg/ml and those of CS ranged 31.7 and 144.5μg/ml in 6 patients at the end of intravenous drip infusion 20mg/20mg/kg during 30 or 60 minutes. Elimination half-lives of IPM ranged from 1.2 to 2.0 hours, and those of CS ranged from 1.4 to 2.7 hours. Serum concentrations of IPM was 14.7μg/ml and that of CS was 32.4μg/ml in 1 patient at the end of 30 minute-drip infusion 10mg/10mg/kg. Theelimination half-lives of IPM was 1.5 hours, and that of CS was 2.9 hours. The urinary recovery of IPM/CS in 6 hours during and after drip infusion in 5 patients,IPM ranged from 12.5 to 26.3% and CS ranged from 14.9 to 57.6%.
In 1 patient with bacterial meningitis given 20mg/kg of the drug every 6 hours, the cerebrospinal fluid/serum concentration ratio of IPM at 2.75 hours after a dose on the third day of treatment was 23.8%, and that at 3.5 hours after a dose on theseventh day was 19.1%.

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Pharmacokinetic and clinical evaluations of imipenem/cilastatin sodium (IPM/CS) were carried out in neonates.
The following results were obtained:
1. The plasma concentrations of IPM/CS were determined upon doses of 10mg/10mg/kg and 20mg/20mg/kg administered using 30-and 60-minute drip infusion, respectively. Peak concentrations of IPM/CS were 19.0-34.7μg/ml/32.6-73.4μg/ml, respectively, at the end of the drip infusion. Plasma half-lives of IPM and CS were 1.4-1.6 hours and 1.7-2.1 hours, respectively.
2. Over a period of 6-8.5 hours, urinary excretions of IPM and CS totaled 19.8-42.7% and 46.9-89.3% of the dose administered, respectively.
3. Clinical responses to IPM/CS were excellent in 4 patients, good in 8 patients and unknown in 1 patient.
4. No side effect was observed except for a platelet increase in 2 patients.
From the above results, it has been concluded that IPM/CS is an effective and safe drug in the treatment of neonatal infections.

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Imipenem/cilastatin sodium (IPM/CS) was administered in a dose of 10mg/10mg/kg or 20mg/20mg/kg by a 1-hour intravenous drip infusion to 19 mature and premature neonates with ages from 1 to 12 days with various bacterial infections, and plasma concentrations and urinary recovery rates in these subjects were measured. Because of the small number of patients recruited, neonates were not divided into mature and premature groups, but into 3 groups based on their day-ages: 0-3 days, 4-7 days and 8 days or older.
A clinical evaluation of IPM/CS was carried out in 10 male and 3 female neonates with ages 0-28 days. These patients included 6 with pneumonia, 4 with urinary tract infection and 1 each with septicemia, suspected septicemia and maxillary sinusitis.
1. Plasma concentrations and urinary recovery rates
(1) The 1-hour intravenous drip infusion at 10mg/10mg/kg of IPM/CS
IPM: Its peak plasma concentrations were obtained at the end of drip infusion of the test drug in all 3 groups, their values ranged from 18.18 to 19.90μg/ml with no statistically significant variations. The plasma concentrations rapidly decreased to 0.32-0.98μg/ml at 8 hours after administration of IPM/CS. The half-lives tended to be shorter in older neonates, with mean half-lives being 1.87, 1.55 and 1.40 hours, respectively.
CS: Its peak plasma concentrations were obtained for all 3 groups at the end of drip infusion and were ranging from 28.23 to 30.00μg/ml with no significant variations. Plasma concentrations in the 0-3 day-age group and the4-7 day-age group slowly decreased to 6.30μg/ml and 4.58μg/ml at 8 hours after administration of IPM/CS, respectively. Half-lives were 4.10 hours and 3.08 hours, respectively. On the other hand, those of the 8-day or older group rapidly decreased to below the detection limit in 8 hours after administration with a half-life of 1.6 hours.
(2) The 1-hour intravenous drip infusion at 20 mg/20mg/kg of IPM/CS
IPM: Peak plasma concentrations were obtained in all 3 groups at the end of drip infusion and were ranging from 31.1 to 38.24 μg/ml. Plasma concentrations rapidly decreased, and were 0.95-2.08μg/ml at 8 hours after administration with half-lives of 1.5-1.88 hours.
CS: Peak plasma concentrations were obtained in all 3 groups at the end of drip infusion and were ranging from 47.0 to 55.82μg/ml. Plasma concentrations at 8 hours after administration were higher in younger neonates, i. e., 14.75μg/ml in the 0-3 day-age group, 9.40μg/ml in the 4-7 day-age group and 4.0μg/ml in the 8-day or older group. Differences in half-lives in different age groups were large, i. e., 4.48 hours in the 0-3 day-age group, 3.30 hours in the 4-7 day-age group and 2.1 hours in the 8-day or older group.
(3) Urinary recovery
The urinary recovery of IPM and CS in 8 hours after administration ranged from 21.6 to 57.3% and from 47.5 to 96.0%, respectively. In the IPM/CS 10mg/10mg/kg group, the urinary excretion rates of CS tended to increase in the older neonates.
2. Clinical results
Thirteen patients with various bacterial infections were treated with IPM/CS from 24.7/24.7 to 65.2/65.2mg/kg/day b. i. d. or t. i. d. by intravenous drip infusion.
The clinical efficacy was either excellent or good in all patients. Causative organisms were isolated from 12 out of 13 patients (Staphylococcus aureus from 4 patients, Escherichia coli from 4, Klebsiella pneumoniae from 2, group B Streptococcus from 1 and Haemophilus influenzae+Enterobacter cloacae from 1). All organisms were eradicated after IPM/CS treatment.
No adverse reaction was observed. Abnormal laboratory test values were noted in 1 patient with elevated GOT and GPT.

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The antimicrobial activity of imipenem against group B streptococci was investigated. The clinical efficacy of imipenem/cilastatin sodium (IPM/CS) was determined in neonates and premature infants.
The results are summarized below.
1. The distribution of MIC values ofIPM against 55 clinical isolates of group B streptococci isolated from the vagina of pregnant women peaked at 0.024μg/ml. MIC values of IPM against all clinical isolates tested were 0.05μg/ml or less.
2. IPM/CS was used for treatment of bacterial infections in 9 neonates and premature infants. Among these patients, clinical responses were excellent in 5 patients and good in 4 patients. No adverse reaction was observed. Abnormal laboratory test values were observed in 4 patients, eosinophilia in 2 patients and increased platelets in 2.
3. In 7 neonates and premature infants, quantitative cultures for aerobic and anaerobic fecal flora were performed. Fecal flora change was not significantly different than those observed during treatment with latamoxef orcefmenoxime.
4. Ten neonates and premature infants were investigated for effects of IPM/CS on the blood coagulation system. Prolongations of prothrombin time (PT) and activated partial throm boplastin time (APTT) were observed in 1 patient. Abnormal prothrombin (PIVKA II) was detected in the same patient. There was no tendency for inhibition of platelet function.

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Clinical pharmacology and clinical efficacy and safety of imipenem/cilastatin sodium (IPM/CS), a beta-lactam antibiotic with a carbapenem nucleus and a dehydropeptidase-I inhibitor, were investigated in newborns.
1. Peak serum concentrations of IPM/CS at a dose of 20mg/20 mg/kg were achieved at the end of 60-minute infusion. Maximum serum levels of IPM and CS were 44.2μg/ml and 70.0μg/ml, respectively, in neonates with ages 0-3 days. IPM and CS peak levels in premature infants with ages 0-3 days were 47.2μg/ml and 56.1μg/ml, respectively. IPM and CS peak levels in neonates 4 day-old or older were 35.0μg/ml and 41.5μg/ml, respectively, and in premature infants of similar ages were 45.7μg/ml and 65.3μg/ml, respectively.
2. Mean serum half-lives of IPM and CS in 0-3 day-old neonates were 1.6 hours and 3.1 hours, respectively, and the mean serum half-lives in premature infants were 2.1 hours and 4.6 hours, respectively.
In neonates 4 day-old or older, the mean serum half-lives of IPM and CS were 1.6 hours and 2.6 hours, respectively, and in premature infants they were 1.5 hours and 1.9 hours, respectively.
3. A dose response was evident between doses of 10mg/10mg/kg and 20mg/20mg/kg of IPM and CS.
4. Urinary recovery rates of IPM for the 0-to 6-hour post IPM/CS infusion period ranged between 27.2 and 46.6%. For CS, urinary recovery rates for the 0-to 6-hour post IPM/CS infusion period ranged between 25.3 and 100.8%.
5. Clinical efficacy was evaluated in 9 patients and 7 patients showed excellent or good responses.
6. Of 14 patients who received IPM/CS treatment, 1 patient showed hematuria, leukopenia and thrombocytopenia, and 3 patients showed eosinophilia. However, these adverse reactions improved after the completion of therapy.
7. IPM has excellent antimicrobial activity against aerobic and anaerobic Gram-positive and Gram-negative bacteria. In this study, coadministration of IPM and CS produced good clinical responses and no serious adverse reactions. It is hence concluded that IPM/CS sodium is very useful for the treatment of severe bacterial infections in neonates, especially in the presence of beta-lactamase resistant strains and in polymicrobial infections.

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Ten patients with infections (8 neonates and 2 infants) were treated with 10.2mg/10.2mg/kg-37.7mg/37.7mg/kg of imipenem/cilastatin sodium (IPM/CS) b. i. d. or t. i. d. by a 1-hour in-travenous drip infusion. The plasma concentrations of IPM/CS were determined in 5 of the 10 patients and in the cerebrospinal fluid of 1 patient of the 5.
1. The patients studied included 5 with pneumonia and 1 each with urinary tract infection, omphalitis, suspected meningitis, periproctal abscess and suspected septicemia. Clinical efficacy was evaluated in 9 patients: the patient with suspected meningitis was excluded from the clinical evaluation because the infection was doubtfully due to bacteria. Responses were excellent in 4 and good in 5 patients. No patient with a poor response was observed. All of the 6 etiological isolates obtained from 5 patients (2 strains of Staphylococcus aureus and 1 each of Escherichia coli, Enterococcus faecalis, Streptococcus agalactiae and Bacteroides fragilis) were eradicated.
2. As for side effects, rash was observed in 1 patient and petechiae accompanied by decreases in platelets and reticulocytes and increases in GOT and GPT were observed in another. Other abnormal laboratory test values in addition to the above abnormalities consisted of an increase in GPT in 1 patient and increases in GOT and GPT in another. These side effects and abnormalities in laboratory test values were mild and normalized after discontinuation or completion of IPM/CS administration.
3. Blood concentrations of IPM/CS at the end of a 1-hour intravenous drip infusion were 41.3μg/ml (IPM), 60.9μg/ml (CS)(about 20mg/20mg/kg, mean of 3 patients), 20.3μg/ml (IPM), 32.2μg/ml (CS)(10.2mg/10.2mg/kg) and 72.7μg/ml (IPM), 127μg/ml (CS)(37.3mg/37.3mg/kg), in-dicating dose dependence. Half-lives of IPM were 1.14-1.99 hours and those of CS varied significantly according to ages of patients, being 3.27-5.02 hours in patients 0-3 days old, 0.88 hour at 10 days and 0.86 hour at 24 days. Half-lives of CS were longer in patients at 0-3 days and shorter at 10 and 24 days than those of IPM.
4. Concentrations of IPM/CS in cerebrospinal fluid in 1 patient at 1 hour after the end of a 1-hour intravenous drip infusion of 37.3mg/37.3mg/kg were 3.90μg/ml for IPM and 6.0μg/ml for CS.
5. The above results suggest that IPM/CS may be useful as a single first choice agent in the neonatal period, though further study in additional patients will be required.

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Pharmacokinetic and clinical studies on imipenem/cilastatin sodium (IPM/CS) in pediatric surgery were performed and the results obtained are summarized below.
1. Plasma and urinary levels of IPM/CS were measured in 9 neonate patients following drip-infusion for 1 hour of IPM/CS (dose of IPM 10mg/kg for 5 patients, 20mg/kg for 4 patients). In the 10mg/kg group, peak plasma levels were observed at the end of infusion or after 1 hour of it. IPM 9.95-14.2μg/ml, CS 7.7-30.1μg/ml. In the 20mg/kg group, peak levels were found at the end of the infusion, IPM 39.2-41.7μg/ml, CS 48.1-58.87mu;g/ml. In both groups, plasma levels of IPM/CS decreased rapidly, and plasma half-lives (T 1/2) in the 20mg/kg group were 0.9-1.2 hours (IPM) and 0.8-1.1 hours (CS). Urinary recovery rates were 17.7-28.7% (10mg/kg), 21.1-36.9%,(20mg/kg) for IPM and 27.1-43.8% (10mg/kg) and 21.5-76.5% (20mg/kg) for CS.
2. Bile levels of IPM/CS were measured in 3 patients with congenital biliary atresia and 1 patient with neonatal hepatitis. Peak levels of IPM/CS in bile were noted 1 hour after the end of infusion, and they were 3.01-12.3μg/ml for IPM, and 2.5-13.1μg/ml for CS. Recovery rates in bile in 7 hours after the end of infusion were 0.03-0.12% (IPM), 0.01-0.12% (CS).
3. IPM/CS was administered to 9 patients as prophylaxis against postoperative infections and to 2 patients with postoperative cholangitis. No infectious complications were observed in patients after the prophylactic use. In 1 patient with cholangitis, clinical effect was good and organisms were eradicated. No clinical or laboratory adverse reactions due to the administration of IPM/CS were noted.
It is concluded that IPM/CS is an effective and safe antibiotic in pediatric surgery.

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Pharmacokinetic and clinical studies on imipenem/cilastatin sodium (IPM/CS) in the perinatal period were carried out, and the results obtained are summarized below.
1. IPM/CS transfers to umbilical cord plasma and amniotic fluid were effective. Passage of IPM/CS into mother's milk was as little as with other β-lactam antibiotics.
2. Among 81 patients with perinatal infections, clinical efficacies were excellent in 16 patients, good in 62, poor in 3, with an efficacy rate of 96.3%. In addition, IPM/CS was effective in 6 patients for prophylaxis.
3. Out of 82 isolates examined for bacterial responses, 69 isolates were eradicated and 8 isolates were decreased. Especially, of 13 isolates of Enterococcus faecalis, 12 were eradicated.
4. In 109 patients administered with IPM/CS, vomiting was observed in 1 patient. No abnormal laboratory test values were observed.
5. IPM/CS was an effective and safe new antibiotic in perinatal infections. We recommend a normal dose of IPM/CS of 0.5g/0.5g twice a day and a dose for severe infections of 1g/1g twice a day in the perinatal periods.

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The placental passage and therapeutic efficacy of imipenem/cilastatin sodium (IPM/CS) were studied in the perinatal period.
The results obtained are summarized as follows:
1. The mean biological half-life of IPM in maternal serum was 30 minutes.
2. The umbilical cord serum concentration of IPM was about 70% of that in maternal serum after 30 minutes.
3. A significant level of IPM was found in the amniotic fluid. The amniotic fluid con-centration of IPM was over 1μg/ml at 45 minutes after administration and equal to that in maternal serum at about 90 minutes.
4. In 4 patients, the time course of placental transfer of IPM was investigated. The level of IPM in amniotic fluid was higher than that in maternal serum at 90 minutes after administration and gradually increased afterward.
5. The level of IPM was 3.96μg/g in the fetal membranes at 17 minutes after administration.
6. In the treatment of 12 patients with perinatal infections, the preparation showed excellent efficacies in 3 patients and good efficacies in 7 patients.
7. An adverse effect (vomiting) was observed in only one patient.
In conclusion, this drug showed satisfactory placental transfer as well as sufficient safety and excellent efficacy in the treatment of perinatal infections.

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The clinical efficacy and the safety of imipenem/cilastatin sodium (IPM/CS) in perinatal infections were studied. The results are summarized below.
1. Clinical efficacy was evaluated in 12 patients with intrauterine infections (endometritis), 3 patients with amniotic fluid infections, 2 patients with puerperal fever and 3 patients with other infections. The drug was administered by intravenous drip infusion at a 0.5g to 1.0g dose as IPM and the total doses during an entire course of treatment were 1.5g to 15g.
2. Clinical efficacies were excellent in 4 (20%) and good in 16 patients (80%) and the efficacy rate was 100%. Ten patients had not improved upon treatments with other previous antibiotics.
3. Infective bacteria were eradicated in 4, decreased in 1, and replaced in 6 patients.
4. No side effects or abnormal clinical laboratory test values were observed in any patient.

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Pharmacokinetic, bacteriological and clinical studies of imipenem/cilastatin sodium (IPM/CS) were carried out in the perinatal period, and the results obtained are summarized as follows:
Effects of IPM on bacterial growth curves of Staphylococcus aureus (sensitive and resistant strains) and Escherichia coli (sensitive strains) in amniotic fluid were determined. The bactericidal effects of IPM increased in amniotic fluid and remarkable increases against resistant strains were demonstrated.
IPM and CS were detected promptly after intravenous drip infusion to pregnant women, and reached peak levels shortly after administration in maternal plasma. Placental penetration of IPM and CS to the fetus was favorable. After intravenous drip infusion of 500mg/500mg of IPM/CS, drug concentrations in the umbilical cord plasma and the amniotic fluid exceeded MICs against main pathogenic organisms.
Clinically, IPM/CS was effective in the treatment of perinatal infections without any side effect.
The above results demonstrated that IPM/CS is a clinically useful antibiotic for the prophylaxis and the treatment of perinatal infections.

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Clinical studies were carried out on imipenem/cilastatin sodium (IPM/CS) in the perinatal period, and the results are summarized below.
1. IPM/CS was administered to a total of 10 patients including 7 with puerperal intrauterine infections and 3 with pyelonephritis at a dose of 0.5g/0.5g twice daily through intravenous drip infusion. IPM/CS showed satisfactory results. Clinical efficacies were excellent in 1 patient, good in 9 with an efficacy rate of 100%.
2. As for bacteriological evaluation, 12 strains out of 14 detected in 8 patients before the treatment were eradicated upon IPM/CS administration, with an eradication rate of 85.7%. The remaining 2 strains persisted.
3. Neither subjective and objective side effects nor abnormal laboratory test values were observed in any of the patients or their babies.

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To evaluate the efficacy of imipenem/cilastatin sodium (IPM/CS) in the field of obstetrics and gynecology, fundamental (measurement of IPM/CS concentrations in mothers' milk) and clinical studies were performed.
Concentrations of IPM/CS in mothers' milk were measured every 1 hour up to 6 hours after a 30-minute drip infusion of 500mg/500mg of IPM/CS. IPM/CS was distributed similarly to other cephalosporins.
In the clinical study, a 500mg/500mg dose of IPM/CS was administered to 5 patients with puerperal intrauterine infections and to 3 patients with urinary tract infections by a 30-minute drip infusion b. i. d. or t. i. d. Good responses were observed in all 8 patients, though the infections were mild or moderate.
From these results, IPM/CS appeared to be a useful drug for the treatment of perinatal infections.

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

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A clinical study was carried out on imipenem/cilastatin sodium (IPM/CS) in the perinatal period, and the results obtained are summarized as follows.
IPM/CS was given to 5 cases with puerperal intrauterine infection and 2 with puerperal fever.
The clinical efficacies were evaluated as good in 6 cases and poor in 1. The clinical efficacy rate was 85.7%.
In a bacteriological examination, 9 strains were isolated from 6 cases, and 7 strains were eradicated with an eradication rate of 77.8%.
No side effects were observed in any of the cases treated with IPM/CS.

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Pharmacokinetic and clinical studies on imipenem/cilastatin sodium (IPM/CS), a parenteral carbapenem antibiotic combination drug, were carried out in patients in the perinatal period. The obtained results are summarized as follows.
1. Concentrations of IPM and CS in umbilical cord blood, amniotic fluid and maternal blood were determined in 13 patients after 500mg/500mg of IPM/CS was administered by a drip infusion over a period of 30 minutes. Peak levels of both drugs in umbilical cord blood were about 30% of those in maternal blood. Although the levels gradually declined thereafter, the decline was slower in umbilical cord blood than in maternal blood and the levels became higher in the former than in the latter after 2 hours or more. The transfer of both drugs into amniotic fluid was slower than into umbilical cord blood. Peak levels were observed 5-6 hours after administration, averaging about 30% of that in the maternal blood for IPM and 45% for CS.
2. A 500mg/500mg dose of IPM/CS was administered to 10 patients with postpartum infections by a drip infusion over a period of 30 minutes or more twice daily in the morning and in the evening. Clinical responses were excellent in 6 patients and good in 4, with an efficacy rate of 100%. Bacteriologically, all of the 19 strains identified previous to the treatment were eradicated except for 1 strain. However, one new strain of Enterococcus sp. appeared in 1 patient. No side effects or abnormal laboratory findings were observed.
These results suggest that IPM/CS will be useful for the treatment of various infections in the perinatal period.

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