Minimum inhibitory concentrations (MICs) of cephem antibiotics against 405 strains belonging to 17 species of clinical isolates were investigated using the standard method of the Japanese Congress of Chemotherapy. The results obtained are summarized below.
1. Cephem antibiotics showed weak antibacterial activities against Enterococcus sp., B. fragilis and S. marcescens.
2. S. pneumoniae, S. agalactiae, E. coll, K. pneumoniae and P. mirabilis were susceptible to cephem antibiotics.
3. Cephem antibiotics of the 1st and the 2nd generations showed weak antibacterial activity against Citrobacter sp. and E. cloacae, while cephem antibiotics of 3rd generation had a good antibacterial activity against these species.
4. Cephem antibiotics of the 2nd and the 3rd generations showed high antibacterial activity against H. influenzae and indole positive Proteus group.
5. Cefoperazone showed high antibacterial activity against P. aeruginosa.
6. Resistance to latamoxef, ceftizoxime and cefoxitin was observed among Staphylococcus sp., while the MICs of other antibiotics against Staphylococcus sp. were fairly low.
7. Number of strains resistant to the 3rd cephem antibiotics seems to be increasing because the 3rd generation of cephem antibiotics have been used frequently. Further investigation will be required on resistant organism to these antibiotics including β-lactamase producing strains.

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In vitro activities of several antimicrobial agents against bacterial pathogens isolated from patients with primary and postoperative infections were investigated in 1982 and 1983. Antimicrobial agents examined were as follows: sulbenicillin (SBPC), piperacillin (PIPC), cephalothin (CET), cefazolin (CEZ), cefmetazole (CMZ), cefotiam (CTM), cefoperazone (CPZ), cefotaxime (CTX), ceftizoxime (CZX), cefmenoxime (CMX), latamoxef (LMOX), lincomycin (LCM), gentamicin (GM) and amikacin (AMK). Specimens for bacterial isolation included pus, fluid drawn by centesis, or bile. Blood samples of septicemia were excluded. The antimicrobial activities of these drugs were determined by the agar plate dilution method of the Japanese Society of Chemotherapy.
There were 123 strains obtained in the 1982 survey and 252 strains in the 1983 survey. Little or no differences were seen in frequencies of isolation between the isolates of principal species in 1982 and those in 1983.
Isolation frequencies of pathogens in primary infections were, in an order of decreasing frequency, E. coli (25.6%), anaerobes (21.1%), Streptococcus sp.(14.3%), Staphylococcus sp.(11.3%); in postoperative infections, Streptococcus sp. was most frequent (28.6%), followed by Pseudomonas sp.(17.6%), anaerobes (12.6%), E. coli (10.9%), Staphylococcus (10.1%).
Against S. aureus, CEZ, CTM, LCM and GM had similar degree of activity with CET being somewhat more active. CMX was the most active drug among the third generation cephems tested against S. aureus.
No strain was CTM, CEZ, and LCM-resistant at the same time.
Over 90% of E. coli, were sensitive to CTX, CZX and CMX, inhibited by 0.10 μg/ml, while E. coli were slightly less susceptible to CPZ and LMOX.
Penicillins were not very active against K. pneumoniae, and only 60% of K. pneumoniae were inhibited by PIPC at concentrations of 12.5 μg/ml. Third generation cephems, CTX, CMX and CZX, proved highly active against K. pneumoniae; over 90% of K. pneumoniae was inhibited by CTX, CMX and CZX at a concentration of 0.10 μg/ml.
About 60% of P. aeruginosa was inhibited by 3.13 μg/ml of PIPC and GM but was resistant to SBPC.
This survey should be very useful for the selection of an appropriate drug for prophylaxis if the frequencies of incidences of pathogens in postoperative infections are taken into account in selecting the most active antibiotic agent (s) against the most frequent genus, genera and species of pathogens.

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In vitro susceptibilities of 2,133 strains of various pathogens isolated from clinical materials in 1985 to various cephem antibiotics were studied using the Shows disk diffusion test. The following antibiotics were evaluated: cephalexin (CEX), cephalothin (CET), cefazolin (CEZ), cefotiam (CTM), cefoxitin (CFX), cefmetazole (CMZ), cefotaxime (CTX), cefoperazone (CPZ), ceftizoxime (CZX), cefmenoxime (CMX), latamoxef (LMOX) and cefsulodin (CFS).
S. aureus: Susceptible strains to CET, CEZ, CTM, CFX and CMZ with MICs less than 15 μg/ml accounted for 93, 73, 94, 80 and 96% of the strains tested respectively, while those susceptible to CTX, CPZ, CZX, CMX, LMOX and CFS accounted for 91, 65, 53, 96, 65 and 95%, respectively. Susceptible strains to CEX at MICs≤20 μg/ml were 52%. Prevalence of bacterial resistance to CEX and CEZ, which have been used extensively, was greater than that to CET, CTM or CMZ, showing a bimodal distribution of MICs. The third generation cephems studied, in general, also showed bimodal distributions of MICs.
S. epidermidis: Susceptible strains to CET, CEZ, CTM, CMZ, CTX, CPZ and CMX with MICs less than 15 μg/ml were more than 82% of the strains tested.
S. pyogenes: All strains studied were susceptible to CET, CEZ, CTM, CFX, CMZ, CTX, CPZ, CZX and CMX at MICs≤15 μg/ml. However, susceptible strains to either LMOX or CFS accounted for 95%, while those to CEX at MICs≤20 μg/ml accounted for 95%.
S. pneumoniae: At MICs less than 3 μg/ml, all strains were susceptible to all cephem antibiotics tested except CEZ, CFX, CMZ, CFS and CEX at MICs≤5 μg/ml.
E. faecalis: Only very few strains were susceptible to these antibiotics.
E. coli, K. pneumoniae and Proteus spp.: Susceptible strains of E. coli and K. pneumoniae to CEX at MICs≤20 μg/ml accounted for 83 and 87% of the strains tested, while those of indole negative and positive Proteus accounted for 74 and 8%, respectively. Strains of E. coli susceptible to CET, CEZ, CTM, CFX and CMZ at MICs≤15 μg/ml were 80 to 98%, while those susceptible to CTX, CPZ, CZX, CMX and LMOX were 96 to 100%. Strains of K. pneumoniae susceptible to the first and the second generations of antibiotics were 84 to 98%, while those to CTX, CPZ, CZX, CMX and LMOX were 100%. Susceptible strains of indole negative Proteus to the first and the second generations were 81 to 100% and those to the latter were 99-100%. Indole positive Proteus susceptible to CET and CEZ were only 5 to 8%, whereas those susceptible to CFX, CTM and CMZ were 65 to 95%, and strains susceptible to CTX, CPZ, CZX, CMX and LMOX were 96 to 100%. Susceptible strains of these clinical isolates to CFS were only 3 to 6%.
H. influenzae: Susceptible strains to CET, CEZ, CTM, CFX and CMZ at MICs 515 μg/ml were 95, 86, 94, 88 and 96%, respectively. On the other hand, all strains were susceptible to CTX, CPZ, CZX, CMX and LMOX at the same MICs.
P. aeruginosa: No susceptible strains to CET, CEZ, CTM, CFX and CMZ were observed at MICs≤15 μg/ml and to CEX at MICs 20 μg/ml, but susceptible strains to CTX, CPZ, CZX, CMX, LMOX and CFS at MICs≤15 μg/ml were 58, 62, 34, 60, 23 and 75%, respectively.
S. marcescens: 66 to 87% of the tested strains were susceptible to CTX, CZX, CMX and LMOX at MICs≤15 μg/ml, but no significant susceptibility to other antibiotics studied was observed
E. aerogenes, Citrobacter spp. and Acinetobacter spp.: The third generation cephems showed significant activity against these pathogens except CPZ and LMOX against Acinetobacter spp., whereas the first and the second generation cephems were ineffective (susceptible strains 69 to 100% vs. 1 to 75%).

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Susceptibility of 203 strains of 34 bacterial species or subspecies to cephapirin (CEPR) was determined by the 2-fold agar dilution method in parallel with the determination of inhibition zone diameter in the singledisc method.
These experiments demonstrated a significant correlation between the MIC by the dilution method and the diameter of inhibition zone determined by the conventional assay using an over-night (about 16 hours) incubation, the delayed assay (about 24 hours incubation), or the rapid assay (after 3-4 or 5-6 hours incubation), hence applicability of the single-disc assay for CEPR was confirmed.
An analysis of the data obtained using CEPR discs (each containing 30 μg) revealed that primary regression equations were as follows: D (diameter, mm)=25.8-9.7 log MIC (μg/ml) in the conventional assay; D=31.2-12.3 log MIC in the delayed assay; D=21.7-7.1 log MIC in the 5-6-hour rapid assay and D=17.9-5.0 log MIC in the 3-4-hour rapid assay, and especially for β-lactamase producing Staphylococci, they were: D=24.9-9.2 log MIC in the conventional assay, D=20.4-7.4 log MIC in the 5-6-hour rapid assay and D=17.5-5.8 log MIC in the 3-4-hour rapid assay.
The range of variations in MICs of CEPR estimated from diameters of inhibition zones in the disc test was then calculated and compared with the range in MICs determined by the 2-fold dilution assay as the reference to estimate the experimental error which may have been resulted from the error in the estimation of MICs by the single-disc assay.

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To investigate the clinical and bacteriological usefulness of orally administered midecamycin acetate (MOM), the susceptibility of clinical isolates to MOM, Mb-12 (the main metabolite of MOM), josamycin (JM), ampicillin (ABPC) and cephalexin (CEX) was determined.
The results are summarized as follows.
1. Antibacterial activities of MOM against aerobic Gram-positive cocci, B. catarrhalis, and anaerobic bacteria were inferior to those of JM by 2-fold, but superior to those of CEX. Activities of MOM against S. aureus, Bacteroides spp., Fusobacterium spp., Veillonella spp. were superior to those of ABPC and CEX.
2. Since serum and tissue concentrations of Mb-12 after 200mg administration in humans have been reported to be 1-2 μg/ml, it can be presumed that the causative bacteria would be eradicated by a usual dosage of MOM used in the present study.
From these considerations, it is speculated that MOM may be successfully used in the treatment of dental and oral surgical infections.

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A multi-center open study was conducted to investigate cefuzonam (L-105, CZON), a newly developed cephalosporin from pharmacokinetic, bacteriological and clinical aspects, in the pediatric field with the participation of 17 institutions and their related facilities. The results are summarized as follows.
1. Serum concentrations and urinary excretion
The pharmacokinetics in pediatric patients was investigated with a dose of 20mg/kg, via one shot intravenous injection or intravenous drip infusion over 1 hour. The results were nearly the same as those in adult patients. Mean serum concentrations 5 minutes after one shot intravenous injections were: 52.8μg/ml with the dosage of 10mg/kg, 135μg/ml with 20mg/kg, and 317μg/ml with 40mg/kg, and T 1/2 β's for the 3 dosages were 1.07 hours, 0.91 hour, and 1.01 hours, respectively. With 1-hour intravenous drip infusion, mean serum concentrations at the end of infusion were: 22.4μg/ml with 10mg/kg, 46.3μg/ml with 20mg/kg, 72.5μg/ml with 40mg/kg, and 69.2μg/ml with 50mg/kg, and T1/2β's for these dosages were 1.31 hours, 1.45 hours, 0.84 hour, and 0.66 hour, respectively. In 6 hours after administration of CZON, urinary excretion rates were 43.5-51.4% for one shot intravenous injections of 10-40mg/kg, and 42.7-58.6% for 10-50mg/kg drip infusions.
2. Concentrations in cerebrospinal fluid
Penetrations into cerebrospinal fluids in patients with purulent meningitis achieved levels of 2.80-6.40μg/ml with the administration of CZON at 100mg/kg in acute cases of within 6 days after onset. When the administration of the drug was done at the earlier stage, the greater penetration occurred. However, rates of penetration were 3.10% to 5.03% within 4 days after a drug administration, thus, the penetration was not thought to be as good as other β-lactam agents which achieve higher penetration rates.
3. Clinical results
Of 407 cases treated with CZON, 18 cases were excluded from the statistical analysis. The remaining 389 cases plus 8 cases each of which had 2 complicated diseases, with a total of 397, were statistically analyzed for the clinical effectiveness of this drug against various infections.
The efficacy was evaluated as “good” or “excellent” in 248 out of 266 cases from which pathogens were isolated, for an efficacy rate of 93.2%. The efficacy rate was 88.5% for 131 cases for which pathogens were unidentified, thus no statistically significant difference was noted between the 2 groups. The overall efficacy was evaluated as “good” or “excellent” in 364 cases out of total 397 cases, for an efficacy rate was 91.7%.
With regard to microbiological effect on pathogens, 240 out of 268 strains isolated as pathogens were eliminated, for an elimination rate of 89.6%.
Among Gram-positive bacteria, 45 out of 53 strains of Staphylococcus aureus were successfully eliminated, for an elimination rate of 84.9%. An excellent elimination activity of CZON was also noted against Streptococcus pneumoniae and Streptococcus pyogenes. On the whole, 90 out of 101 strains of Grampositive bacteria were eliminated, for an elimination rate of 89.1%.
For Gram-negative bacteria, the following causative microbes were eliminated including all the strains of Escherichia coli (49) and Klebsiella pneumoniae (5), 2 out of 3 strains of Proteus mirabilis, and 88 strains, or 90.7%, of 97 Haemophilus spp. strains. Out of a total of 154 strains of the 4 genera, 144 were eliminated, the elimination rate being as good as 93.5%. In total, 150 out of 164 strains of Gram-negative bacteria were eradicated, and the eradication rate was 91.5%.
The clinical effects of the drug on pathogens were evaluated as “good” or “excellent” in 266 out of 248 cases, for an efficacy rate of 93.2%.

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A new member of injectable cephem antibiotics, cefuzonam (L-105, CZON) was administered in the treatment of 11 chronic complicated urinary tract infections (CC-UTI) which were considered to be for indications of long-term chemotherapy. The results obtained are summarized as follows.
Responses in 6 cases out of 9, 66.7%, were evaluated as excellent or moderate by the criteria of the Japan UTI committee at fifth day's judgement. At the end of the treatment, however, only 3 out of 8, 37.5% were determined to be effective. The apparent decrease in the efficacy of the drug after the longer treatment period was caused by replacements of susceptible bacteria with resistant strains.
Side reactions were observed in 2 cases, one was diarrhea and the other was chill and fever. In these cases, the administration of the drug was discontinued, and the conditions returned to normal within a few days. In laboratory tests, a slight decrease of thrombocyte was observed in 1 case.
The CZON was very effective against infections caused by susceptible bacteria. No differences between CZON and other related compounds were found with regard to safety, hence it was estimated that the drug was highly useful for a long-term treatment on infections caused by susceptible strains to CZON.

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The transplacental passage of single intravenous doses of aztreonam (AZT), 1g or 2g, was examined in 7 sheep and 14 women in late pregnancy, respectively and the obtained data were analyzed by a two-compartment model. The obtained results were summarized as follows.
1. After single 2g intravenous doses were given to pregnant sheep, the mean peak level of AZT in maternal blood was 83.79μg/ml and the half-life of the β-phase was 1.525 hours.
2. After single 1g intravenous doses were administered to pregnant women, the mean peak level of AZT in blood was 102.62μg/ml and the half-life of β-phase was 2.128 hours. The peak levels in umbilical venous blood and amniotic fluid were 14.43μg/ml and 11.86μg/ml, respectively.

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The materno-fetal transfer of aztreonam by a single intravenous dose of 1g was examined in 7 volunteer women undergoing induced abortion in early pregnancy and the following results were obtained.
1. After administration of the drug, maternal blood levels at 15, 30, 60 and 120 minutes were 77.24±6.09μg/ml (Mean±S. E.), 37.84±5.85μg/ml, 25.62±3.15μg/ml and 18.10±2.22μg/ml, respectively.
2. Amniotic fluid level of the drug was low in 3 cases, of which amniotic fluid levels were determined; 0.74μg/ml after 229 minutes, 0.83μg/ml after 280 minutes and 0.74μg/ml after 328 minutes. Fetal tissue concentration of the drug was below our detection limit at 120 minutes. Tissue levels of villus and decidua in 6 cases were also too low to be detectable between 89 and 328 minutes after injection.

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The pharmacokinetics of norfloxacin (NFLX) was studied in 5 patients with chronic renal failure and rats with renal obstruction. The drug was orally given to patients on on-and off-dialysis days in a crossover fashion. Serum levels of NFLX showed a similar profile during both on-and off-dialysis days, and the hemodialysis treatment did not affect the elimination of the drug from the serum. The mean serum elimination half-life was 8.8±1.2 hours (standard error) for on-dialysis day and it was 7.0±0.8 hours for off-dialysis day. The urinary recovery of NFLX for 24 hours was less than 0.1% of administered doses in these patients. Rats with renal obstruction exhibited higher drug levels in serum for longer periods of time and elevated biliary excretion ratios in comparison to sham-operated rats, and no significant change in the fraction of biliary metabolites was observed. The biliary excretion of NFLX was likely to be enhanced in patients with renal failure.

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Ninety nine patients with leukemia and/or related disorders were treated with cefmenoxime (CMX). Among them, 77 patients had severe infections, while other 22 patients did not suffer from infection, but it was expected that they would fall into serious conditions if they were infected.
Sixty of the 77 patients who had severe infection were used in the evaluation of effectiveness. The remaining 17 patients were not evaluated because they were subjected to combined treatments of CMX and other therapeutic agents such as other antibiotics, rglobulin or interferon. Excellent responses were found in 26 (43. 3%) patients and good responses in 12 (20. 0%) patients. In total, the rate of effectiveness was 63. 3%.
Nineteen of the 22 patients who were treated prophylactically with CMX were used in the evaluation of effectiveness, while 3 patients were excluded from the evaluation because peripheral neutrophils were counted to be more than 1, 000/mm³ before CMX was administrated, although these 3 patients were used in the final evaluation to examine side effects. In the prophylactic treatment, the rate of effectiveness was 89. 5%.
The side effects were seen in 4 patients (4/82: 4. 9%). A different symptom was identified in each patient. These symptoms were skin rash, mild nausea, mild diarrhea and slight elevation of serum bilirubin. Prompt improvements of these symptoms occurred as soon as CMX administration was stopped.
These results show that CMX is a therapeutically effective and safe antibiotics for the treatment of severe infections or for the prophylaxis of infections in patients associated with leukemia and/or related disorders.

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To patients with chronic complicated urinary tract infections (UTI) which were in compliance to the UTI standard, cefmenoxime (CMX) was given singly or in combination with cefsulodin (CFS) and efficacies of the respective preparations were examined.
Of 53 patients examined, 40 were given CMX alone while 13 were given a combined preparation of CMX and CFS.
Results are summerized as follows.
1. With respect to the general clinical effects, 7 patients given CMX alone were markedly improved, 21 improved and 12 unchanged indicating an efficacy rate of 70%. In case of the CMX-CFS combined administration, 2 patients were markedly improved, 7 improved and 4 unchanged giving an efficacy rate of 69%.
2. As for the bacteriological effects, 38 of 54 strains isolated from the patients given CMX alone were eliminated, 4 decreased, 12 unchanged and 15 substituted. Of 16 strains isolated from the patients given the CMX-CFS combined preparation, 14 were eliminated, 2 unchanged and 3 substituted. Thus, incidence of bacterial substitution was low in the combination treatment.
3. The combination of CMX and CFS was more inhibitory to P. aeruginosa than CMX alone.
4. Regarding side-effects, drug eruption was observed in one of the 53 patients and slight elevation of GOT and GPT was recognized in another.

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A newly synthesized antibiotic of quinoline carboxylic acid group, ciprofloxacin (BAY o 9867, CPFX) for oral administration, has a broad spectrum and high antibacterial activity against various bacterial species including aerobic and anaerobic bacteria such as P. aeruginosa and B. fragilis. The CPFX was administered orally in a dose of 200mg 3 times daily for 5 to 8 days (6. 3± 1. 0 days) to 12 patients with biliary tract infection consisting of 2 males and 10 females. Two of them were outpatients and 10 were hospitalized. Ages ranged from 27 to 72 years (mean 51. 8± 14. 8 years), weights from 48. 5 to 73. 5 kg (mean 60. 5± 7. 7kg). All cases were complicated with cholecystolithiasis, with 4 acute and 8 subacute cases. Organisms isolated before the initiation of the CPFX treatment included 3 strains of E. colt from ERCP bile of 3 cases. Infected bacteria were eradicated in 3 cases but results were unknown in the other 9 cases. Clinical responses were excellent in 2 cases, good in 8 cases, fair in 1 case and poor in 1 case. No adverse effect was recognized.
Therefore, CPFX appears to be a very useful drug when used for chemotherapy of biliary tract infectious diseases.

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The purpose of this study was to determine the susceptibility of Neisseria gonorrhoeae to ciprofloxacin (CPFX).
The MIC's of CPFX against 50 clinical isolates of N. gonorrhoeae was examined and they were between 50. 003μg/ml and 0. 006μ g/ml including 8β-lactamase producing strains. The CPFX was administered orally to 3 groups of 10 cases with gonococcal urethritis, groups being determined by 3 dose levels: a group with 200mg b. i. d. for 3 days (a total of 1, 200 mg), another with 400 mg b. i. d.(a total of 800 mg) and the final group with single administration of 400 mg.
The effect of CPFX in the 1,200 mg-administered group was excellent in 3 and good in 7. The effect of the drug in the 800 mg-administered group was excellent in 2 and good in 8. The effect in the 400 mgadministered group was all good. Therefore, the overall cure rate was 100% including 5 patients with β-lactamase producing gonococcic infection. Side effects were not observed in the 30 cases.

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In 5 patients with respiratory tract infections, concentrations of cefotetan (CTT) in serum and sputum after 1 hour intravenous administration of 2 g of CTT to each patient were investigated, and following results were obtained.
1. Serum levels of CTT
The mean peak level of CTT was 232. 0± 16. 2μ g/ml immediately after the 1 hour drip infusion, then declined gradually and was 48. 0± 8. 8μ g/ml after 6 hours.
2. Sputum levels of CTT
Mean sputum levels of CTT were 2. 15± 0. 19μ g/ml from 2 to 4 hours after the administration and 2. 19± 0. 18μ g/ml from 4 to 6 hours.
3. Clinical evaluation of CTT
Clinical effects were excellent in 1 case, good in 3 cases and poor in 1 case. No side effects were observed.

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This paper deals with results obtained from the cefotetan (CTT, Yamatetan®) study group of department of obstetrics and gynecology in Yamagata prefecture.
Efficacy of CTT, a new cephamycin antibiotic, was studied in 50 cases (39 cases of prophylactic use for postoperative infections and 11 cases of several different infections). CTT was administered to each of the patients at a daily dose of 2 grams.
No other drugs such as antimicrobial agents, steroids and antiinflammatory drugs which might affect the efficacy of CTT were permitted during the study except for the drug therapy or surgical procedures required for treating underlying diseases.
Fever index, one of the examination items to assess the prophylactic effect for postoperative infections as well as daily changes in maximum body temperature, was examined in the prophylactic group. Daily changes in febrile pattern were examined in the infection group.
The fever indice were 3.4±4.0 degree hours in cases subjected to cesarean sections in the prophylactic group, 3.7±3.0 degree hours in cases subjected to gynecological operations in the prophylactic group and 4.5±5.5 degree hours in the infection group.
The clinical efficacy rate in the 11 cases of the infection group was 100%; excellent in 3 cases and good in 8 cases.
Bacteriological examination was conducted in 3 of the 11 cases and bacteria were eliminated in all 3 cases.
The overall clinical efficacy rate was also 100%; excellent in 5 cases and good in 6 cases.
No abnormal laboratory findings nor side effects were observed in any of the cases.

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According to the result of the pharmacokinetic examination of T-2588 (esterified prodrug of T-2525) administered to adult male volunteers who have undergone gastrectomy, it appears that the absorption of T-2588 is delayed in the hypoacidity or the anacidity and also the excretion ratio of T-2525A (an inactive metabolite of T-2525) showed a tendency to become higher in these subjects.
Again, according to the result of the pharmacokinetic examination of T-2588 when it was administered together with probenecid to normal healthy volunteers, it appears that the T-2525 is excreted from the kidneys not only into the glomerular filtration but also partly through renal tubules.

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From clinical studies on T-2588, an oral ester type cephem, the following results were obtained.
1. Ten patients with acute tonsillitis, 3 with acute pharyngolaryngitis, 2 with acute sinusitis, 1 with acute exacerbation of chronic sinusitis and 2 with acute exacerbation of chronic otitis media were treated with T-2588 at a daily dose of 300 or 600mg. Clinical responses were excellent in 12, good in 4, fair in 1 and poor in 1. Clinical efficacy was 88.9%.
2. Bacteriologically, all isolates except one strain of S. aureus were eliminated. Clinical efficacies classified by clinical isolates correlated well with bacteriological efficacies. The MICs of T-2525 against clinical isolates were determined and compared with those of cephalexin, cefaclor and amoxicillin. The T-2525 showed potent antibacterial activity against Gram-positive and Gram-negative bacteria including S. pneumoniae, H. influenzae and β-Streptococcus, but the activity of T-2525 against S. aureus was similar to that of the other antibiotics examined.
3. Neither side effect nor abnormal laboratory finding was observed.

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Cefixime (CFIX) was given orally in a single dose of 100mg to 7 patients with varying degrees of impaired renal function (Ccr 12.0-56.7ml/min) and serum concentrations and urinary excretion rates were measured with time for the first 24 hours by the bioassay method to investigate in vivo pharmacokinetics of the drug.
The results obtained are summarized as follows.
1. The mean peak serum concentration of CFIX in 3 patients with moderately impaired renal function (group I: Ccr≥30-<60 ml/min) was 2.04μg/ml at 6 hours after dosing and gradually declined to 0.10μg/ml at 24 hours after dosing.
The half-life was 4.15 hours.
2. The mean peak serum concentration of CFIX achieved was 2.27μg/ml at 8 hours after dosing in 4 patients with severely impaired renal function (group II: Ccr≥10-<30 ml/min) and the concentration of CFIX was 0.99μg/ml even after 24 hours. The half-life was prolonged to 11.05 hours.
3. There was no great difference between groups I and II in the first 24-hour urinary excretion rates. However, the first 4-hour urinary excretion accounted for 2.14% of the administered dose of CFIX in group I but only 0.47% in group II.
Urinary concentrations of CFIX peaked at 4-6 hours after dosing in both groups, and thereafter gradually decreased in group I. Whereas, they did not decline much in group II until 24 hours after dosing.
It is concluded from these study results that CFIX should be given in once-or twice-a-day dosage to patients in group I but at the intervals of 1 day or longer in group II.

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Cefotiam (CTM) was administered to 37 cases of cesarean section and 29 cases of total abdominal hysterectomy for prophylactic purposes. Group I was given the agent at a total dose of 14g (postoperatively 4, 4, 2, 2 and 2g), group II at a total dose of 10g (postoperatively 2, 2, 2, 2 and 2g) and group III at a total dose of 10g (2g during operation and postoperatively 2, 2, 2 and 2g).
1. When fever indices between the groups were compared, group III showed the lowest level of fever index regardless the type of operation.
2. When the results of laboratory test (WBC, CRP, ESR) between the groups were compared, no significant differences were observed, but group III tended to show lower values than others.
3. No side effects due to CTM were noted.
The above results indicate that the administration of CTM during operation was the most effective for protection against postoperative infections in terms of changes in fever index and laboratory test values.

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Clinical efficacy and safety of S 6472 (long active cefaclor (CCL)) and CCL were compared by a double-blind study using 248 patients with bacterial bronchitis. Patients were orally administered with either 375mg of S 6472 2 times or 250mg of CCL 3 times daily for 7 days, and the following results were obtained.
1. Clinical efficacy judged by a committee: The efficacy rates on acute bronchitis were 87.2% for S 6472 and 82.6% for CCL, and the efficacy rates on chronic bronchitis were 70.3% for S 6472 and 64.7% for CCL. There was no significant difference between the 2 drugs in clinical efficacy.
2. Clinical efficacy judged by doctors in charge: Results of the clinical efficacy judged by doctors in charge were similar to the efficacy judged by the committee.
3. Bacteriological efficacy judged by the committee: Eradication rate for the S 6472 group was 71.1% (32 of 45 patients) and that for the CCL group was 67.4% (29 of 43 patients).
There was no significant difference between the 2 drugs in the bacteriological efficacy.
4. Side effects and abnormal laboratory findings: Side effects were observed in 5 cases (4.2%) in the S 6472 group and in 5 cases (4.0%) in the CCL group. These side effects, however, were not serious, and no remarkable abnomal laboratory values were observed. There was no significant difference between the 2 drugs in the incidence of side effects or abnormal laboratory findings.
5. Clinical utility: When the clinical utility was expressed by the utility rate (very useful and useful), it was 79.5% in the S 6472 group (117 patients) and 76.2% in the CCL group (122 patients)(judged by the committee). When the utility was judged by doctors in charge, it was 73.3% in S 6472 group (120 patients) and 71.4% in CCL group (126 patients).
From the above results, it has been concluded that S 6472 taken twice daily is equivalent to CCL in effectiveness on bacterial bronchitis.

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A 500mg dose of cefaclor (CCL) was administered orally before surgery to each of patients with respiratory diseases and in fasting.
Average concentrations of CCL in sera were 4.04μg/ml at 1.5 hours, 3.03μg/ml at 2 hours, 1.68μg/ml at 3 hours and 0.45μg/ml at 5 hours after administration.
Average concentrations in lung tissues during operation were 0.120μg/g at 3 hours, 0.272μg/g at 4 hours and 0.297μg/g at 5 hours after administration.
Ratios of concentrations of CCL in lung tissues to that in sera were from 7.1 to 66.0 percent.
The CCL was considered to be a useful antibiotic for the treatment of patients with respiratory diseases.

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Cefazolin (CEZ) and ceftizoxime (CZX) were administered prophylactically to prevent postoperative infections after cesarean section and abdominal simple panhysterectomy, common obstetrical/gynecological procedures.
The results were summarized as follows.
1. Total fever indices in cesarean sections for the 2 drug groups were examined and CEZ (n=8) and CZX (n=10) indices were found to be 6.0±3.67 degree hours and 3.6±1.16 degree hours, respectively. In abdominal simple panhysterectomies, CEZ (n=11) and CZX (n=11) indices were 8.15±5.17 degree hours and 4.26±2.24 degree hours, respectively. Further, there was a lower daily fever index with CZX than with CEZ in both operation groups.
2. Counts of WBC in both procedure groups were lowest on the 5th postoperative day in the CZX group, so was for the CRP. As for the ESR, the CEZ group was much higher than the CZX group especially in abdominal simple panhysterectomies.
3. Neither subjective/objective side effects nor abnormal laboratory findings were observed in either CEZ or CZX group of patients.

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Two grams of cefotaxime (CTX) were administrated by drip infusion to 10 patients (11 material) with acute or chronic stage of intracranial diseases. Concentrations of CTX in the serum and the cerebrospinal fluid (CSF) were determined at 15, 30, 60, 120, 240 and 300 minutes after injection.
The results obtained were summarized as follows:
1. Serum levels: Peak levels of CTX in sera were 66.2±10.23 (S. E.)μg/ml in the acute stage group (ASG), and 75.7±31.39 (S. E.)μg/ml at 15 minutes after injection in the chronic stage group (CSG).
There were no significant difference between the 2 groups.
2. CSF levels: Peak levels of the drug in CSF were 1.35-4.32μg/ml in ASG and 0.18-0.7μg/ml in CSG.
Average concentration at 60 minutes after injection was 1.11±0.09 (S. E.)μg/ml in ASG and 0.30±0.08 (S. E.)μg/ml in CSG. The value in ASG was significantly higher than the value in CSG by t-test.
3. The ratio between CSF and serum levels: The levels increased as time passed in both groups and the values in ASG were higher than those in CSG at all time points. Average ratios at 60 minutes after injection were 3.85±0.29 (S. E.)% in ASG and 1.12±0.50 (S. E.)% in CSG.
The value in ASG was significantly higher than that in CSG by t-test.
From the above results, it is considered that CTX is useful for the prophylaxis of postoperative infections in intracranial diseases.

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Pharmacokinetics of cefoperazone (CPZ) was examined in 5 patients with end-stage renal failure on main-tenance intermittent peritoneal dialysis. Blood levels of CPZ given as a 1g intravenous bolus injection were not different whether a patient was on or off peritoneal dialysis. Peritoneal clearance of CPZ was 1.6-1.9ml/min. Blood CPZ levels reached the therapeutic level within 30-120 minutes after an intraperitoneal administration of 1g CPZ, and remained at the level at least for 3-5 hours. Side effects of CPZ were not observed in any patient. These data indicate that the peritoneal dialysis does not affect blood CPZ levels given intravenously and that effective blood levels of CPZ can be maintained for several hours after an intraperitoneal injection of the drug. Thus, CPZ is considered useful in renal failure patients on peritoneal dialysis.

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Clinical evaluation and kinetics in serum of cefoperazone (CPZ) in patients with lower respiratory tract infections have been conducted as a multicenter trial participated by 20 institutions in Kyushu area during a period of 8 months from October 1984 to May 1985.
1. Mean serum CPZ levels up to 4 hours following the end of intravenous infusion of either 1 or 2 g CPZ remained higher than the MIC₈₀ of CPZ against major causative organisms of lower respiratory tract infections such as H. influenzae, P. aeruginosa, K. pneumoniae, and S. pneumoniae.
2. Serum half-lives of CPZ following intravenous infusion were prolonged in the elderly and in patients who showed moderate liver or kidney dysfunction, but did not exceed twofold of normal value.
3. Clinical efficacy rates of CPZ were 82.9% (34/41) against pneumonia, 80% (4/5) against lung abscess, 88.9% (32/36) against acute exacerbation of chronic bronchitis, 66.7% (2/3) against panbronchiolitis, 100% (1/1) against acute bronchitis, and 85.7% (12/14), 64.3% (9/14) and 70.0% (7/10) against infections concurrent to chronic respiratory diseases, pulmonary emphysema and bronchiectasis, respectively. The overall efficacy rate was 81.5% (101/124).
4. Bacteriological eradication rates against P. aeruginosa, H. influenzae and S. pneumoniae were 60% (6/10), 88.9% (8/9) and 100% (3/3), respectively. The overall eradication rate including polymicrobial infection was 67.5% (27/40).
5. The clinical efficacy rate of CPZ in patients with underlying diseases such as lung cancer, pulmonary tuberculosis, and pneumoconiosis, etc. was not significantly different from the efficacy rate in patients without these underlying diseases.
6. Of 20 patients who failed to respond to previous antibiotic treatments, 13 were effectively treated by CPZ.
7. Adverse reactions occurred in 6.7% (11/164) of the patients, and consisted primarily of rash, fever, diarrhea and loose stool. Laboratory abnormalities were seen in 5 patients during the study. These included elevations of S-GOT and S-GPT, eosinophilia and neutropenia.
8. CPZ is a very useful drug in the treatment of lower respiratory tract infections because of its excellent clinical efficacy and rare incidence of abnormal accumulations in sera following the recommended 2-4 g/day administration even in the elderly.

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In the present study, we investigated the biliary excretion of cefoperazone (CPZ) in patients with complete obstruction in the lower bile duct governing PTC drainage, i.e., patients with completely blocked enterohepatic circulation.
The blockage was observed to cause a delay in the excretion of CPZ due to hepatic dysfunction and the half-life of CPZ levels in serum was as long as 4.9 hours on the average. This is approximately the same as the half-life of 4.8 hours in hepatic dysfunction reported by BELAIEFF.
Biliary concentration of CPZ reached their peak levels within the first 2 to 6 hours. The time to peak in cases with hepatic dysfunction was similar to that reported by observed in patients without hepatic dysfunction YURA et al. In our cases, however, peak biliary concentrations of CPZ were observed to be between 28 to 954 μg/ml with a mean of 320.5 μg/ml. These peak levels were lower than those reported by several investigators, but sufficiently effective concentrations seem to have been achieved in the bile even in jaundice because MIC₈₀ values of CPZ are reported to be 6 to 10 μg/ml against E. coll, Klebsiella, and Enterobacter and 50 μg/ml against the most resistant Serratia. As mentioned above, the lowest peak biliary concentration was found to be 28 μg/ml and peak levels reached at least 50 μg/ml in 8 out of the 10 patients.
Urinary concentrations of CPZ reached their peak levels within the first 30 minutes to 2 hours and CPZ urinary recovery ratio in 24 hours was 24.2 to 93.1% with a mean of 64.1%.
Biliary passage of CPZ was determined in 3 patients before and after amelioration of jaundice by PTC drainage. In all these patients, ICG 15-minute values were observed to be improved after amelioration of jaundice with hepatic excretions elevated. All these 3 patients showed no marked changes in CPZ serum concentrations. Biliary concentrations of CPZ clearly rose after the amelioration of jaundice. On the other hand, urinary concentrations of CPZ were lowered after the amelioration of jaundice. This fact is the suggestion that biliary passage of CPZ is not only dependent upon the enterohepatic circulation of bile acid but also the hepatic excretion is strongly interfered by the blockage.

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After introduction of anesthesia to 19 patients requiring cardiac surgery, cefoperazone sodium (CPZ) 1 g was administered intravenously and its movement to serum, pericardial fluid and tissue of the right auricle was studied.
1. The serum CPZ level was 75.68 μg/ml and 59.77 μg/ml at 60 and 120 minutes after administration, respectively, and the biological half-life time was 2.54 hours.
2. Lengths of time to achieve peak concentrations of CPZ in pericardial fluid and right auricle tissue after administration were both approximately 1 hour. The drug level in myocardial tissue was 14.52 μg/g after 240 minutes.
3. Level of CPZ in myocardial tissue was maintained, even after 240 minutes, sufficiently higher than MIC₈₀ of the drug against Gram-negative bacilli which may be responsible for many infections.
4. No side effects were observed in any case examined.

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