[in Japanese]

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To obtain useful informations for determining the optimal dosage of drugs in patients with impaired liver function, pharmacokinetics of cefoperazone (CPZ) was studied in healthy adults (normal control group) and 35 patients with liver disease (liver disease group). CPZ is a new third generation cephalosporin which is mainly excreted into the bile and has serum half-life of about 2 hours.
After a rapid intravenous injection of CPZ, peripheral blood and urine samples were obtained at the time according to the protocol of this study. Serum and urine concentrations of CPZ were determined by the bioassay method using Micrococcus luteus ATCC 9341 as the test strain. From the concentrations of CPZ in serum and urine, pharmacokinetic parameters were calculated by means of a “ two-compartment open model ”.
After an administration of CPZ, the serum concentration declined more slowly in the liver disease group as compared to the normal control group. At 1 hour after intravenous injection of CPZ, the difference of the serum level was already observed between these 2 groups. The half-life of elimination (T 1/2) was 2 to 4 times longer in the liver disease group. The elimination rate constant (K10) and total clearance (CI,) of CPZ were much lower in the liver disease group than in the control group except for hepatocellular carcinoma.
On the other hand, urinary excretion rate (Ur) was lower in the normal control group than in the liver disease group.
There was a close correlation between disappearance rate of indocyanine green (KICG) and parameterssuch as T1/2, K10, CIt and Cler with coefficients of-0. 642, 0. 723, 0. 690 and 0. 682, respectively. Furthermore, creatinine clearance (Ccr.) and liver function tests (albumin and gammaglobulin) were also correlated closely to those pharmacokinetic parameters.
From these results, it was suggested that pharmacokinetics of CPZ was strongly affected by impaired liver function. In many liver function tests, Kiec was a valuable parameter to determine the dosage of drugs in case of liver disease, because of close correlations with pharmacokinetic parameters of CPZ. Finally, it should be remembered that in patients with liver disease associated with renal dysfunction the alteration of pharmacokinetics of CPZ may be emphasized by decreased urinary excretion.

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The metabolic fate of cefoperazone (CPZ) was studied in 19 cases which underwent percutaneous transhepatic cholangial catheterization (PTC-catheterization, PTCC) and were under various conditions of the liver function.
1. The peak of bile levels of CPZ immediately after PTCC differed greatly from one case to another at 12. 6-7, 260ug/ml with 1 g intravenous injection and 23. 0-5, 800ug/ml with 2g intravenous injection.
2. The ratio of the peak of bile level to the serum level immediately after PTCC showed the highest negative correlation with the serum total bilirubin level. It also showed a significant negative correlation with GOT, GPT, Al-P and LAP.
3. The serum CPZ level and half-life showed no significant trend except half-life showed a significant correlation with LAP.
4. The recovery rate in urine up to 12 hours was in the range of 14. 8-93. 6%, showing a significant correlation with the ratio of the peak of bile levels to the serum level and the date of liver function tests.
5. The bile level, serum level and recovery rate in urine at the time the bile outflow from the catheter has become constant after PTCC (during the course of PTCC) showed a trend almost similar to that immediately after PTCC, there being no significant difference as to each parameter during the course of PTCC and immediately after PTCC.
6. In the cases in which the sample was collected by the cross-over technique, the ratio of the peak of bile levels to the serum level from immediately after PTCC to during the course of PTCC increased in 2 cases and decreased in 6 cases. The 2 cases that showed the increase in the ratio were the case in which the serum total bilirubin level improved almost to normal.
Findings above suggest that sufficient biliary decompression can improve the movement of CPZ into bile, despite the fact that the pharmacokinetics of CPZ is affected by the liver function, particularly serum total bilirubin level, that a decrease in the movement to bile and a compensatory increase in urinary excretion are observed in jaundice and disturbance of the liver function and that the ratio of the peak of bile level to the serum level decreases during the course of PTCC rather than immediately after PTCC in some cases.

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Fosfomycin sodium (FOM-Na) was studied both fundamentally and clinically in the field of obstetrics and gynecology with following results.
It showed good transference into the uterine tissues when given intravenously. The peak concentrations achieved in the uterine tissues following intravenous administration of 2g of FOM-Na were 26. 56 to 53. 48ug/g when given as one shot injection and 20. 16 to 39. 47ug/g as drip infusion. In the serum of vein and uterine artery, peak concentrations of 163. 6 to 143. 40ug/ml and 120 to 113. 12 ug/ml were reached following one shot injection and drip infusion, respectively. In general, FOM-Na concentrations in the uterine tissues showed similar changes as those observed for serum concentrations.
Clinically, FOM-Na was used in the treatment of 17 cases of obstetrical and gynecological infections at 2g per dose twice daily as intravenous drip infusions. In all of these cases, good clinical efficacy was obtained. No side effects were observed.

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Fosfomycin (FOM) is a synthetic antibiotic having a unique structural formula and bactericidal mechanism and a broad spectrum of antimicrobial activity against various bacterial species. It has higher activity in vivo than in vitro.
As therapy, FOM-Na in a daily dose of 4 g (2gx2) was given by intravenous drip infusion for 5 to 10 days to 6 cases with infectious diseases (2 cases of acute cholecystitis, 3 cases of acute localized peritonitis due to phlegmonous appendicitis and 1 case of acute diffuse peritonitis due to perforative appendicitis). The clinical response was rated as “ excellent ” in 1 case, “ good ” in 4 cases, “ fair ” in 1 case and “ poor ” in none. No adverse effects were observed in any of the patients.
Six clinical isolates were obtained, and these consisted of 4 strains of Escherichia coli and 1 strain each of Klebsiella pneumoniae and Bacteroides fragilis. The MICs of FOM were from 6. 25 to 12. 5ug/ml for E. coli, 50ug/ml for K. pneumoniae, and 100ug/ml for B. fragilis.
FOM-Na was administered to the 6 cases intravenously in a dose of 2 g before surgery, and tissue specimens and body fluid samples were taken during the operation. The FOM concentration was determined by bioassay with a Proteus sp.(MB 838) as the test organism.
The mean FOM concentration in bile from the common bile duct was 61. 85 ± 17. 13ug/ml (n=5) at 95 to 108 minutes after FOM-Na intravenous bolus injection. The mean FOM concentration in the gall bladder bile was 80. 06 ± 92. 36ug/ml, while that in the gall bladder wall was 146. 65 ± 39. 10ug/g. The mean FOM concentration in purulent ascites was 58. 20 ± 13. 9ug/ml, 36. 22 ± 14. 63ug/g in the appendix wall and 12. 64 ± 11. 34ug/ml in pus in the appendix. The FOM concentrations in the infected tissues and body fluids thus exceeded the MICs of FOM for the pathogenic bacteria. Therefore, FOM-Na appears to be a very useful drug when used for chemotherapy of infections encountered in the surgical field.

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Dibekacin (DKB), an antibiotic of aminoglycoside group, was administered at 4 different dosages of 0. 5, 1. 0, 1. 5 and 2. 0 mg/kg as intravenous drip infusion taking 30 minutes or 1 hour. For each dose level, 3 cases each were used out of 24 boys from 1 year and 1 month to 14 years and 7 months of age, and serum concentrations as well as urinary concentrations and recovery rate were determined. After removed of 4 cases unassessable of therapeutic efficacy, 7 cases consisting of 1 case of chronic bronchitis, 1 case of lung abscess and 5 cases of urinary tract infections were treated with DKB at a mean daily dosage of 3. 3 mg/kg in 2 or 3 divided doses as intravenous drip infusion taking 30 minutes or 1 hour. The mean treatment period was 7 days. The clinical and bacteriological results were analyzed in these cases and for analysis of side effects drop out cases were also included. The following results were obtained.
1. Following 30 minutes intravenous drip infusion of DKB at 0. 5, 1. 0, 1. 5 and 2. 0 mg/kg, the serum concentration peaked at the end of infusion for all dose levels. The highest peak concentration of 9. 17mcg/ml was obtained for the dose level of 2. 0mg/kg. The highest dosage with which serum concentration does not exceed concentrations of 10 to 12mcg/ml was found to be 2. 0mg/kg. The mean highest serum concentrations obtained were 1. 65, 3. 49, 5. 40 and 8. 67mcg/ml for the dosages of 0. 5, 1. 0, 1.5 and 2.0 mg/kg, respectively, and the mean AUCs determined by the two-compartment model were 2. 99, 6. 04, 10 5 and 14.2mcg·hr/ml, respectively, showing dose response relation in terms of peak concentration and AUC among groups. The mean T1/2 values for each dosage were 1. 55, 1. 54, 1. 77 and 2. 03 hours, respectively, with a longer tendency in T1/2 for the dose level of 2. 0mg/kg with unknown cause.
When 0. 5, 1. 0, 1. 5 and 2. 0 mg/kg of DKB were infused taking 1 hour, the peak of serum concentration appeared also at the end of the infusion. The highest concentration was obtained with 2. 0mg/kg and it was 7. 02mcg/ml. Considering from the concentrations obtained for 0. 5mg/kg and 1. 0mg/kg groups the highest dosage at which the serum concentration does not exceed 10 to 12mcg/ml was estimated to be 2. 5mg/kg. The mean highest serum concentrations for dose levels of 0. 5, 1. 0, 1. 5 and 2. 0mg/kg were 1. 61, 3. 75, 4. 80 and 5. 68mcg/ml, respectively. Except for 1. 0 mg/kg group the serum concentrations obtained with 1 hour intravenous drip infusions were slightly lower than those with 30 minutes intravenous drip infusions. A dose response relation was observed among each group. While were some cases in which AUC could not be determined by the two-compartment model, the analysis of results by the one-compartment model revealed dose response relation among groups. As to T1/2 no comparison could be made by mean values. However, from the results of the analysis by the one-compartment model no remarkable difference was shown in T1/2 between 30 minutes drip infusions and 1 hour drip infusions.
2. Following both 30 minutes and 1 hour intravenous drip infusions the urinary concentration reached its highest value at 1 to 2 hours period most frequently, followed by 2 to 3 hours period. The urinary recovery rate within the first 7 hours following 30 minutes infusion was 42. 3, 49. 7, 59. 3 and 55. 1% for 0. 5, 1. 0, 1. 5 and 2. 0mg/kg, respectively, with corresponding figures being 58. 9, 65. 2, 55. 6 and 46. 9%, respectively, for 1 hour drip infusion.
3. Clinical efficacy was rated as good or excellent in 5 cases of urinary tract infections out of 7 cases.
4. Out of these 7 cases, disappearance of organisms could be obtained in all of 5 cases which could be assessed of bacteriological efficacy. In 1 of these cases of urinary tract infections, the change pattern of organisms from P. aeruginosa to E. faecalis was observed.

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Transfer of antibiotic (cefmetazole, CMZ) into the liver tissues of the infant with hepatic dysfunction, 6 cases of congenital biliary atresia, 4 cases of congenital bile duct dilatation, 1 case of congenital biliary hypoplasia, hepatic hemangioma and umbilical hernia with congenital heart disease is reported here.
CMZ level in the liver tissues with hepatic dysfunction shows extremely low.
Our study revealed that poor transfer of CMZ into the liver tissues might be a main cause of the poor excretion of CMZ into the bile in case of jaundiced infant.

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The third part of our 3-years' continuous investigation on the clinical effect of cefaclor (CCL) against urinary tract infections was reported herein. CCL, a daily dose of 0.75g t. i. d., has been applied for the treatment of (I) 69 cases with the uncomplicated acute cystitis in the women, and (II) 44 cases with the complicated. Rates of effectiveness obtained were 94.2% in (I), which was a little lower than the first or the second part of our report, and 70.5% in (II), which equaled the mean value of our first and second reports. Any definite difference was not obtained between the effectiveness rates in those who had ever been treated with CCL and those who not, in both (I) and (II) groups.

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Amikacin (AMK) by intravenous drip infusion was given to patients with infections in the field of internal medicine and the results were followings:
1. AMK was administered to 19 patients. Diagnosis included sepsis or suspected sepsis (11 cases), pneumonia (2 cases), chronic respiratory tract infections (3 cases) and urinary tract infections (3 cases).
2. Underlying disease included hematologic disease (13 cases), lung fibrosis (1 case), chronic respiratory insufficiency (1 case), diabetes mellitus (1 case), hepatic coma and bronchial asthma (1 case) and prostatic hypertrophy (1 case).
3. Nineteen episodes responded to single therapy (2 cases) or combined therapy with other antibiotics (17 cases).
4. AMK by intravenous drip infusion (dissolved in not less than 100ml of saline or glucose) was administered at the dose of 200mg/day to 600mg/day divided into 2 or 3 times, over 1 hour to 2 hours. The mean duration of therapy was 10 days and the mean total dose was 4.3g.
5. Clinical effects: Excellent in 7 cases, good in 7 cases, fair in 3 cases and poor in 2 cases, and efficacy rate was 74%.
6. Bacteriological effects: Disappeared in 3 cases, partly disappeared and unchanged in 3 cases, superinfection in 1 case and newly appeared in 1 case. Four strains out of 7 cases of which were detected the causative bacteria were disappeared.
7. GM resistant bacteria (S. marcescens in 2 strains and C. diversus in 1 strain) were disappeared by the administration of AMK, also some clinical symptoms and signs were improved.
8. No side effects and no abnormalities in laboratory findings were noted in any cases attributed to AMK.
9. In conclusion, high efficacy rate was obtained without any side effects, intravenous drip infusion of AMK seemed to be useful for infections in patients with bleeding tendency (e. g. leukemia) or malignant disease.

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The pharmacokinetics of cefmenoxime (CMX) were studied in 13 patients with cholecystolithiasis, 6 male and 7 female, ranging from 27 to 69 years of age. All patients received a single intravenous dose of CMX 2g given in a drip infusion over 30 minutes.
The level of CMX in gallbladder tissues fell from 350±101μg/g (mean concentrations, 2.7 hours after administration) to 68±13μg/g by 7.2 hours. In bile, the mean concentrations of CMX, 2,595±624μg/ml were reached at 2.7 hours after administration, and at 7.2 hours the mean concentrations were 103±60μg/ml.
In the study reported here, a single 2g dose of CMX was administered intravenously, and high concentrations of CMX in gallbladder tissue and bile were reached at 2.7 hours after administration.
These results suggested that the administration of CMX at about 2.5 hours before surgery might be most effective for prophylaxis.

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In order to assess clinical utility of cefminox (CMNX, MT-141), its transference into internal genital organtissues and pelvic dead space was determined. In addition, transference of CMNX from maternal blood into fetal umbilical cord blood as well as into amniotic fluid was evaluated.
In the clinical study, CMNX was administered in 4 cases. The following results were obtained.
1. Transference into internal genital organ tissues
The concentration ratio of each tissue against serum concentration ranged from 25.3 to 42.7%, showing favourable transference as compared to other cephems.
2. Transference into pelvic dead space At 6 hours after intravenous injection of 1g CMNX, its concentration in the pelvic dead space reached its peak of 38.8μg/ml of the serum concentration, followed by gradual descrease.
3. Transference into umbilical cord blood and amniotic fluid
Following intravenous injection of 1g CMNX, its concentration in umbilical cord blood became almost similar to that of maternal blood at about 3 hours later, being 20μg/ml. After that, it tended to decrease in accordance with the concentration in maternal blood. It appears that the drug persists for a more prolonged period in amniotic fluid.
4. Clinical results
Clinically, CMNX was used in the treatment of 4 cases including 2 cases of lymphocystitis, 1 case of intrapelvic cellulitis and 1 case of postoperative wound abscess, and the results obtained were rated as excellent in 1 case, good in 2 cases and poor in 1 case with an efficacy rate of 75%.
None of the cases treated experienced adverse reactions nor any laboratory abnormalities were observed.

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Micronomicin (MCR) at a daily dose of 120 to 360mg was administered to patients with severe infections who had hematopoietic disorders as underlying diseases. Efficacy and safety of the drug were evaluated.
The underlying diseases in the 56 patients included in the evaluation of efficacy were acute myelocytic leukemia (24 cases), acute lymphocytic leukemia (8), acute promyelocytic leukemia (6), acute monomyelocytic leukemia (4), acute monocytic leukemia (1), erythroleukemia (1), chronic myelocytic leukemiablastic crisis (4), malignant lymphoma (3), aplastic anemia (2), and others (3). The infections were septicemia in 9 patients, suspected septicemia in 48, respiratory tract infection in 7, and perianal abscess in 2. The clinical efficacy of MCR was ‘excellent’ in 12 patients, ‘good’ in 17, ‘fair’ in 7, ‘poor’ in 30 for an efficacy rate of 43.9%. The efficacy rate classified according to infections was 22.2% in septicemia, 56.3% in suspected septicemia. The organisms isolated from the patients with septicemia were Escherichia coli in 2, Klebsiella pneumoniae in 2, Pseudomonas aeruginosa in 1, α-Streptococcus in 1, Serratia marcescens in 1, and Acinetobacter sp. in 1. The efficacy rate was 15.4% in the 13 patients whose causative organisms were identified. The efficacy rate for patients who had failed to respond to prior antibiotic therapy was 43.9%. The efficacy rate in patients (34 cases) with an initial neutrophil count less than 100/μl was 44.1%. Side effect which might have been caused by MCR was skin eruption in only one episode among 83 episodes those were evaluated for safety.

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The treatment of the patients with ruptured cerebral aneurysm in acute stage is performed by direct neck clipping and cisternal drainages for preventing vasospasm. The cisternal drainage is carried out for 1 to 2 weeks' duration. The cisternal drainage has higher risk for bacterial infections in the cerebrospinal fluid (CSF). In this paper, penetration characteristics of cefotiam (CTM) in CSF were studied. CTM concentrations in CSF were measured at 1, 3 and 6 hours after intravenous drip infusion of CTM (2g). CTM concentration in cisternal CSF was higher than that of ventricular CSF. The peak concentration in CSF was higher than 0.78μg/ml and obtained at 3 hours after intravenous drip infusion. Our data suggest that CTM is a useful cephalospolin for treatment of meningitis (Staphylococcus aureus, Streptococcus pneumomae et al.).
Apart from meningitis, the higher concentration of CTM in CSF was obtained in the cases with the vasospasm. The result may support that the breakdown of blood brain barrier is induced by the peroxidative substance from the cisternal subarachnoid clots which has the vasospastic activity.

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Twenty cases intravenously received 1g of cefotetan before the transurethral prostatectomy. High serum and prostatic concentrations were obtained and half-lives were 298 minutes for serum and 250 minutes for the prostate. The mean value of their creatinine clearance was as low as 46.6ml/min and it was found to be the reason why the serum half-life time was longer than that reported for normal volunteers.

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Forty-three cases were studied to determine the most optimal timing to discontinue an oral antibacterial agent for preventing urinary tract infection after transurethral prostatectomy. On the 5th postoperative day intravenous antibiotic treatment was replaced by oral medication of 1.5g talampicillin hydrochloride (TAPC, Yamacillin®), which was tapered and discontinued depending on the urinary findings.
Nine out of 15 cases who discontinued the medication within 2 weeks failed to keep the urine sterile. It may be advisable to continue the medication at least 3 weeks and to discontinue thereafter when pyuria has vanished. All 24 cases who followed this principle became sterile within 8 weeks. Medication continued over 8 weeks seemed to have no additional benefit. Four cases dropped out from this treatment mainly because of gastrointestinal symptoms.

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The pharmacokinetics and bacteriological efficacy of nafcillin (NFPC), vancomycin (VCM), amikacin (AMK) and rifampicin (RFP) alone and in VCM combinations were evaluated in the experimental rabbit meningitis caused by methicillin-susceptible Staphylococcus aureus (MSSA) or methicillin-resistant Staphylococcus aureus (MRSA). The mean concentrations of NFPC, VCM, AMK and RFP in cerebrospinal fluid (CSF) with MSSA meningitis exceeded the minimal bactericidal concentrations of MSSA during 8 hours therapy period. The mean CSF penetration rates of the 4 drugs during therapy were from 1% to 26% which are comparable to those observed in humans with meningitis. The median CSF bactericidal titers of RFP, VCM plus RFP, AMK, VCM plus AMK regimens were larger than 1: 8 during therapy of MSSA meningitis study. In experimental MRSA meningitis, RFP and VCM plus RFP achieved titers greater than 1: 16 during therapy and at 24 hours. No statistically significant reduction in the CSF bacterial colony count was obtained with any of the antibiotic regimens in MSSA meningitis. By contrast, in 8 hours MRSA meningitis model, significant reductions in the number of MRSA were observed in animals treated for 8 hours with VCM plus RFP (P & lt;0.01), RFP (P & lt;0.05), and NFPC plus RFP (P & lt;0.01).

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Of clinically isolated Staphylococcus aureus showing resistance to multiple drugs among penicillins (PCs), cephem antibiotics (CEPs), aminoglycosides (AGs), minocycline (MINO) and fosfomycin (FOM), 64 strains were selected for the determination of MIC. Twenty-one drugs were used for the determination of MIC, with ampicillin (ABPC), cloxacillin (MCIPC), cephalothin (CET), cefazolin (CEZ), cefotiam (CTM), cefuroxime(CXM), cefamandole (CMD), cefotaxime (CTX), ceftizoxime (CZX), cefmenoxime (CMX), cefmetazole (CMZ), cefoxitin (CFX), latamoxef (LMOX), cefotetan (CTT), cefoperazone (CPZ), gentamicin (GM), dibekacin (DKB), tobramycin (TOB), amikacin (AMK), MINO, and FOM.
1. MIC₈₀ of each drug at 10⁶ CFU/ml were: ABPC, MCIPC, CEZ, CTM, CXM, CTX, CZX, CMX, CFX, LMOX, CTT, CPZ, GM, DKB and TOB 100 μg/ml; CET 50 μg/ml; CMD and AMK 25 μg/ml; CMZ 12.5 μg/ml; FOM 6.25 μg/ml; and MINO 0.78 μg/ml.
2. The ratio of highly resistant strains with MIC 100 μg/ml at 10 CFU/ml varied according to drug, and a difference tended to be seen in the degree of influence by resistant factors reflected upon MIC, e. g. drugs for which a high resistance of more than 50% was confirmed were ABPC, CXM, CZX, LMOX and TOB, and 20-30% MCIPC, CTM, CTX, CMX and CFX.
3. MIC on MCIPC which has a correlation of structural activity with methicillin correlated with cephems (CEPs) resistance to a high degree, but many of the so-called new CEPs showed resistance even to the strains with a low MIC on MCIPC.
4. It was assumed that CEPs resistant strains have multiple drug resistant factors based on the fact that such strains showed multiple drug resistance.
5. Among CEPs, CMZ and CMD were found to have comparatively stabilized antibacterial potency, and it is expected that this mechanisms, will be elucidated.
6. Strains which show a high resistance of 10.9% to FOM and strains whose sensitivity decreased somewhat with MIC of 3.13-6.25 μg/ml to MINO in 4.7% were confirmed.

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We compared the in vitro antibacterial activities of ceftizoxime (CZX), cefotaxime (CTX), cefmenoxime (CMX), cefoperazone (CPZ), ceftazidime (CAZ), latamoxef (LMOX) and cefotetan (CTT) against 2,729 strains of 11 organisms freshly isolated from 10 medical institutions in Japan between June 1983 and January 1984 and obtained the following results:
Against S. pyogenes, LMOX and CTT, which have the methoxy group at the 7 position, were less active than the other drugs. LMOX inhibited 80% of S. pyogenes at 0.78 μg/ml; CTT, at 1.56 μg/ml; but CZX and CTX inhibited 100% at 0.025 μg/ml or lower; CMX, at 0.05 μg/ml; and CPZ and CAZ, at 0.20 μg/ml.
Against H. influenzae, E. coil, K. pneumoniae, P. mirabilis and indole-positive Proteus, these test antibiotics, especially CZX, CTX and CMX, which have the aminothiazolyl methoxyimino group, were potently active. Against S. marcescens CZX and CAZ were more active than the other drugs and against P. aeruginosa CAZ was more active than the other drugs.
The test organisms did not tend to acquire resistance to these cephems when our results were compared with the results obtained at the development period.

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During 1979-1983 in vitro activities of antimicrobial agents against causative bacteria isolated from patients with urinary tract infections (UTI) were investigated by Microbiological Research Group of UTI including the 8 institutions in Japan.
Of all strains (219) isolated from patients with simple UTI, 65.3% were E. coli, and 9.6% Klebsiella spp.; these species accounted for about 75% of all isolates in 1983. MPC and CCL among the oral antimicrobial agents have showed potent activities against E. coli, MPC at 1.56 μg/ml and CCL at 3.13 μg/ml inhibited 80% of E. coli from simple and complicated UTI. CTM, CTX, CZX, CMX and LMOX among the parenteral antimicrobial agents, at concentrations of 0.20μg/ml or less inhibited 90% of E. coli isolated from simple and complicated UTI.
The frequency of isolates from patients with complicated UTI, without catheter, was as follows; E. coli 27.6%, P. aeruginosa 20.1%, Streptococcus spp. 12.6%, Serratia spp. 8.8% and Klebsiella spp. 8.0%. The frequency of isolates from patients with complicated UTI, indwelling catheter, was as follows; P. aeruginosa 22.6%, Streptococcus spp. 18.0%, Serratia spp. 15.0%, Proteus spp. 12.4%, and Enterobacter spp. and Klebsiella spp. are 6.0%, respectively, in 1983.
The antibacterial activity (MIC₈₀) against E. coli, Klebsiella spp., P. mirabilis, Citrobacter spp. and Serratia marcescens from simple and complicated UTI was compared, for example, among third generation cephem antibiotics. Four drugs such as CMX, CZX, CTX and LMOX showed virtually comparable activities while CPZ was slightly less active against the strains tested.
There have been many studies reported concerning the antibacterial activity of various drugs against clinical isolates from patients with infections, but it seems that, to our knowledge, no article has dealt with yearly surveys on antimicrobial susceptibility of bacterial isolates from defined clinical specimens with the same period of each year at the same series of institutions.

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We have been collected the causative isolates from patients with urinary tract infections (UTI) from the 8 institutions in Japan during 1980-1983. All strains isolated from UTI and recognized as etiologically responsible in each institution were sent to Bacteriology Laboratory of Juntendo University Hospital, Tokyo and the species of these strains were reidentified. We classified the UTI into 3 categories, simple, complicated without catheter and complicated with catheter.
Of all strains isolated as etiologically responsible from cases of simple UTI, 65.3% were E. coli and 9.6%, Klebsiella spp. in 1983: these species accounted for about 75% of all isolates.
Most frequently isolated from patients without catheter were E. coli 27.6% in 1983, followed in order by Pseudomonas spp.(20.9%), Gram-positive bacteria (16.7%), Serratia spp.(8.8%), Klebsiella spp.(8.0%) and Proteus spp.(7.1%). In complicated UTI with catheter, Pseudomonas spp. were most frequently isolated (25.6%), followed in order by Gram-positive bacteria (22.9%), Serratia spp.(15.0%), Proteus spp.(12.4%), Enterobacter spp.(6.0%) and Klebsiella spp.(6.0%).
A remarkable difference, that is, Gram-positive bacteria, especially S. aureus, showed conspicuous increase of isolation between 1982 and 1983.
Furthermore, we discussed the detailed analysis of patient background to clinical bacterial isolates from UTI in respect of patient distribution by sex, types of infections, distributions by age in male and female, interrelations between the species of bacterial isolates and types of infection and antimicrobial chemotherapy.

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The in vitro antimicrobial activities of antibiotics against causative pathogens isolated from patients with urinary tract infections (UTI) in the 8 institutions in Japan during the period from 1980 to 1983 were compared. A number of new β-lactam antibiotics with broad spectrum of activity have become available for clinical use in recent years. Some of them, in particular so-called third generation cephems, are reported to be responsible for developing microbial-cross resistance to multiple β-lactam antibiotics.
We have been making survey in recent years to explore changes in susceptibility to various antimicrobial agents of clinical isolates. All bacterial isolates from clinical specimens were submitted to the Department of Clinical Pathology, Juntendo University School of Medicine, where they were tested for antimicrobial susceptibility with MIC 2000 apparatus.
Of all pathogens from patients with simple UTI, the majority of the isolates was E. coil and Klebsiella spp. In cases of complicated UTI, on the other hand, Pseudomonas spp. were most frequent, followed in order by Proteus spp., Klebsiella spp., Serratia spp., Citrobacter spp. and E. coli. Conspicuous changes in antimicrobial activity of antibiotics against E. coli and Klebsiella spp. from simple UTI have not been found in our survey. Against strains of Citrobacter spp., even the third generation cephems proved to be not remarkably active and there was a significant decrease in susceptibility of isolates to the drugs test-showed MIC values of 50μg/ml and the proportion increased to 50% (22/44) with isolates obtained in 1982. The antimicrobial activity of cefsulodin and gentamicin against P. aeruginosa was decreased in 1982 compared with that in 1980 and 1981. However, resistant strains were slightly more frequent with gentamicin. In 1983, the antimicrobial activity of third generation cephems against Serratia spp. was significantly reduced from that in 1982.

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Fundamental and clinical studies on a new cephalosporin antibiotic, cefpiramide (CPM), was carried out under a joint study program, in order to evaluate the usefulness of the drug in treating infection of the female genital organs. The results obtained were as follows.
1. CPM was readily transported to female genital organ tissues, and the concentrations of the drug exceeded 35μg/g in various organ tissues in about 1 hour, following intravenous injection of 1g.
A level of more than 2μg/g was maintained even 14 hours after the injection.
2. The transport of CPM to various tissues was also studied following intravenous drip infusion of 1g for 1 hour. The concentrations in tissues were slightly low but similar to those following intravenous injection.
3. The peak concentration of the drug in the dead space exudate was 3.1-20.4μg/ml, following intravenous injection and intravenous drip infusion of 1g.
4. The MIC80 of CPM were 3.13-12.5μg/ml against S. aureus, Klebsiella sp., P. mirabilis and P. aeruginosa.
5. Clinical effects of CPM were analyzed in 158 patients, including 56 cases with intrauterine infection, 37 cases with intrapelvic infection, 22 cases with external genital infection, 31 cases with adnexitis, 6 cases with postoperative wound infection and 6 cases with other infections.
Excellent response was seen in 28 cases (17.7%), good response in 120 (75.9%), poor response in 10 (6.3%). The rate of response was calculated as 93.7%.
6. Safety of the drug was analyzed in 258 patients, and side effects occurred in 4 (1.6%). Of these 4patients, rash was in 1 patient, heat sensation in 1 patient, nausea in 1 patient and rash accompanying edema in 1 patient.
Abnormal values in clinical laboratory findings were seen in 7 patients.
Elevations of transaminase were seen in 5 patients and decrease of platelet was seen in a patient, and then elevations of transaminase with decrease of platelet was seen in a patient, and no other changes of particular note appeared.

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In vivo transfer and therapeutic efficiency of a new cephalosporin derivative, cefpiramide (CPM) have studied in perinatal and gynecologic field.
The following results have been obtained.
1. The level of CPM transferred to uterus and adnexa was higher than its MIC against majority of Gram-negative bacilli, such as E. coll.
2. This drug as demonstrated its efficiency, in treating 3 infection cases refractory to cephalothin, ampicillin and cephalexin, out of which 1 had “excellent” and 2 had “good” results.
3. No side effect was evidenced in any of our patients.
In conclusion, this drug has satisfactory tissue transfer as well as sufficient safety and excellent efficiency in treatment of perinatal infection cases.

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Clinical study on cefpiramide (CPM, SM-1652), a new cephalosporin antibiotic, was carried out and the following results were obtained.
1. CPM was intravenously administrated at a daily dose of 2 g to 8 cases including 2 cases with intrauterine infection, 3 cases with adnexitis, 2 cases with intrapelvic infection and 1 case with external genital infection.
All cases responded to the drug, and marked response was seen in 2 cases, moderate response in 6 cases.
2. Neither side effects nor abnormal values in clinical laboratory findings attributable to the drug were seen.

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Transfer of cefpiramide (SM-1652, CPM) to female genital organs was studied.
CPM concentration was determined in the uterine artery, portio vaginalis, myometrium, ovary and oviduct of patients undergoing hysterectomy, and in the pelvic dead space exudate of patients undergoing radical hysterectomy due to uterocervical cancer.
Data obtained were analyzed by three-compartment model.
The maximum concentration at 1 hour after intravenous drip infusion of CPM in a dose of 1g were 244.31μg/ml in both the uterine arterial serum and uterine venous serum, 31.41μg/g in the portio vaginalis, 32.99μg/g in the myometrium, 31.67μg/g in the ovary and 31.99μg/g in the oviduct.
The concentration in the pelvic dead space exudate reached to the maximum level of 5.32μg/ml at 5.84 hours and thereafter decreased slowly.
The clinical effect of CPM was examined in 6 patients with various female genital infections and found to be effective in all cases.
Side effects and abnormal laboratory finding values were not observed at all.

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Fundamental and clinical studies of cefpiramide (CPM, SM-1652) a new semisynthetic cephalosporin were carried out in the field of obstetrics and gynecology. The results were obtained as follows:
1. In vitro antibacterial activity of CPM against recent 255 clinical isolates was compared with those of cefazolin (CEZ), cefmetazole (CMZ) and cefoperazone (CPZ). CPM showed strong antibacterial activity against Staphylococcus, K. pneumoniae, Peptococcus and Peptostreptococcus. However the minimum inhibitory concentration of CPM was inferior to those of CEZ, CMZ and CPZ against E. coli.
2. The transfer of CPM to the female genital organs was found to be good. Tissue levels over than 5μg/g were maintained after 5 hours.
3. CPM was administered to 10 patients with obstetrical and gynecological infections. Good responses were obtained in all of the cases.
4. Neither adverse reactions nor abnormal laboratory findings were observed except 1 case with slight elevation of BUN.

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Cefpiramide (CPM) was evaluated for clinical effects in the treatment of obstetrical and gynecological infections.
The following results were obtained.
1. CPM was given to 11 cases. Clinical efficacy was good in 8 cases and poor in 3 cases.
2. The poor cases were parametritis and pyometra from those Serratia sp., K. pneumoniae, P. magnus, E. faecalis and B. ovatus were isolated. Other 1 case was external genital abscess with no isolated bacteria.
3. There was a slight transaminase elevation in 1 case but no other appreciable side effects or abnormal laboratory findings were observed.

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Cefpiramide (CPM, SM-1652), a new cephem antibiotic, was fundamentally and clinically studied. The following results were obtained.
1. Serum and internal genital tissue levels of CPM were measured following intravenous drip infusion of 1g.
High serum levels of 30μg/ml and tissue levels of more than 4μg/g were at least maintained for 8 hours. Favourable transfer of CPM into the pelvic dead space exudate was observed.
The exudate level was 7.25μg/ml on average even at 8 hours after intravenous drip infusion.
2. A total of 6 cases comprising 4 with BARTHOLIN'S cyst, 1 with pelvic peritonitis and 1 with lymphocyst was treated with CPM at a dose of 0.5-2g twice daily by intravenous injection or intravenous drip infusion.
The clinical response was excellent in 1 case and good in 5 cases.
Side effects and abnormal laboratory findings due to the drug were not noted.

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Cefpiramide (SM-1652, CPM), a new cephem antibiotic was studied for the transfer into intrapelvic tissues and clinical efficacy in the field of obstetrics and gynecology.
The results were obtained as follows.
1. Clinical results of 17 patients with obstetrical and gynecological infection were excellent in 10 cases, good in 6, and poor in 1 with the efficacy rate of 94.1%.
2. Following a single intravenous 30 minutes-drip infusion of 1g dose of CPM, the peak of serum level and intrapelvic tissues were obtained at 30-60 minutes after completion of the administration.
3. No adverse reaction or abnormal laboratory findings were observed.

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