Cephem antibiotics possessing 1-methyl-1-H-tetrazol-5-yl-thiomethyl moiety at the 3 position of beta-lactam skeleton are known to play a significant role in the disturbance of coagulation and bleeding caused by the defficiency of vitamin K-dependent clotting factors. Among those factors, abnormal prothrombin, protein specifically induced by vitamin K absence or antagonist (PIVKA-II), is recognized to be important.
Cefotetan (CTT) is a cephem antibiotic with the above mentioned side chain at the 3 position. In the study reported here, CTT was administered to patients in the fields of obstetrics and gynecology for the treatment of infections (5 patients) and prophylaxis of surgical infections (142 patients). Changes in PIVKA-II levels, hematological and biochemical profiles, and the adverse effects are investigated during the cefotetan treatment.
1. Changes in PIVKA-II levels were observed in 1.2% (1 out of 81) of the patients prior to the CTT treatment and 7.4% (6 out of 81) of patients on the 14th day after the initiation of CTT treatment.
2. Although 6.8% (8 out of 117) of the patients showed slight diarrhoea on day-2 to day-5 after the initiation of CTT treatment, no patients showed any bleeding episodes or adverse effects such as abnormality of biochemical test values and physical signs after the completion of the CTT treatment.

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Norfloxacin (NFLX), an oral antibacterial agent of new quinolone derivative, was administered at daily doses of 300-600 mg t.i.d. to 20 aged patients with respiratory tract infections.The results obtained are summarized as follows.
1. Clinical efficacies were moderate in 6 patients with upper respiratory tract infections, and moderate in 11 patients and fair in 3 patients with lower respiratory tract infections. In the 20 patients, overall clinical efficacies were moderate in 17 patients, hence the efficacy rate was 85%.
2. Bacteriologically, causative organisms were detected in 10 of the 14 cases with lower respiratory tract infections. In these cases, bacteriological responses were “eradicated” in 9 cases, “decreased” in 1 case and “unknown” in 1 case, the rate of eradication was 90%. 3. No adverse reactions or abnormal laboratory test values were observed.

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It has been more than 4 years since third-generation cephems were introduced into clinical practice. The range of our drug selection definitely tends to increase, because we today have more antibiotics with wider spectrum, antibiotics with strong activities only against Gram-negative strains, such as monobactams, and those with tremendously high activities such as quinolone carboxylic acid derivatives, in comparison to those we had in the past.
Among isolates obtained mainly from sputa of 567 patients with lower respiratory tract infections at 16 institutions throughout Japan between September of 1985 and March of 1986,741 strains were determined to be causative organisms. MIC's of various antimicrobial agents were determined against 67 strains of Staphylococcus aureus, 100 strains of Streptococcus pneumoniae, 199 strains of Haemophilus influenzae, 92 strains of non-mucoid Pseudomonas aeruginosa, 40 strains of mucoid P. aeruginosa, 29 strains of Klebsiella pneumoniae, 10 strains of Escherichia coli and for 42 strains of Branhamella catarrhalis out of the above 741 strains to determine their drug sensitivities.
As for types of lower respiratory tract infections found in 1981-1983, 57.9-64.5% of the infections were chronic respiratory infections; i.e., chronic bronchitis, chronic bronchiolitis and bronchiectasis. These chronic infections, including diffuse panbronchiolitis (DPB), were found in 63.1% of lower respiratory tract infections in 1984. Their incidence dropped to 54.0% in 1985, even through DPB was included; i.e., the incidence of chronic bronchiolitis was 5.5%, that of DPB was 7.1%, and that of bronchial asthma associated with lower respiratory tract infections in 1985 was 8.8% which was twice as much as that found in 1981-1984.
Although bacterial pneumonia was found in 24.8% of all the cases in 1981, its incidence was reduced to 11.0% in 1983, 15.1% in 1984, and 17.6% in 1985. This reduction seemed to have resulted from gradual decreases in the occurrence of bacterial pneumonia among the young population. As with usual years, a high incidence rate in a total lower respiratory tract infections in 1985 was found among older patients; namely, 73.5% was at the age of 50 or over (417/567).
Next, we determined relationships between clinical isolates and isolates from respiratory infections, including chronic bronchitis, chronic bronchiolitis, bronchiectasis and DPB. H. influenzae was isolated from 50.5% of patients with these infections in 1981; however, the detection rate decreased by about 20% to 29.7% in 1985. P. aeruginosa was consistently isolated, between 24.1% and 30.4% every year. S. aureus and S. pneumoniae were isolated from 15.5% in 1981 and 20.3% in 1985, indicating a tendency toward increases. The detection rate for other Gram-negative bacteia also increased to 14.0% from 0%; Although B. catarrhalis was included in the groups of Gram-negative bacteria in 1981, its single detection was counted to be 5.1% in 1984 and 5.9% in 1985.
These results suggested that clinical isolates were more diversified in species year by year.
The trend was similar in bacterial pneumonia, the detection rate of Gram-positive cocci, including S. aureus and S. pneumoniae, being 32.4%.
The relation of antibiotic treatments to the number of isolates, which were then determined to species was examined. A total of 534 strains, mainly consisting of H. influenzae at 35.4% and S. pneumoniae at 17.4%, were isolated before treatment. The number of isolates decreased to 27 strains within 3 days after the start of treatment due to the presence of strong antibiotic effects, as we expected. However, when the treatment was prolonged to over 15 days, 92 strains were isolated and resistant strains increased in number, because infections might have become chronic. P. aeruginosa was isolated from as high as 51.1% of cases treated for a long period of time, proving the intractable nature of this organism.

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We have investigated relationships between patients´ backgrounds and isolates from urinary tract infections in reference to various conditions, such as sexes, age distribution by sex, species of causative organisms by sex, age distribution according to species and types of infections, species and infections before and after treatment with antibacterial agents, and species and detected places. As for the relationship between sexes and types of infections, although simple urinary tract infections were consistently found at about 20% in men and at about 80% in women between 1981 and 1983, these infections were seen at 24.4% in men and at 75.6% in women in 1984, and at 26.6% and at 73.4% in 1985, indicating slight decreases in the ratio of women.By contrast, complex urinary tract infections were found in men at about 60-70% from 1981 up to 1985, regardless of the presence or absence of indwelling catheter. There were no noticeable changes according to age during this 5-year period in incidences of infections including simple urinary tract infection and complex urinary tract infection with or without indwelling catheter. Thus, backgrounds of patients with urinary tract infections, including sex, age and simple or complex infections, were fairly consistent throughout this period, while there were relatively large changes in species of isolates. Enterococcus faecalis was isolated at about 8% of both men and women in 1982 and 1983, but its isolation rates were increased to 22.5% of men and 17.9% of women in 1984. In 1985 this species was isolated in 14.9% of men and 7.6% of women, and in 11.2% of all patients. Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus spp. and Enterococcus spp. were detected at rates of 3.2%, 8.1%, 0.7% and 1.0%, respectively, and 24.2% of isolated strains were Gram-positive organisms. When species of isolates before treatment with antibacterial agents and their isolation rates were analyzed, it was found that the isolation rate of E. faecalis increased dramatically in 1983, and that this tendency was still seen in 1984. The isolation rate of Gram-positive organisms was 25% in 1984 and 24.3% in 1985. Escherichia coli was consistently isolated at about 40%, but, as far as simple urinary tract infections are concerned, its isolation rate decreased by about 10% in 1985, compared to 1982 and 1983. These results suggested that causative organisms for simple urinary tract infections became similar to those for complex urinary tract infections. In other words, isolates obtained from complex urinary tract infections before treatment were similar to those of simple infections. When antibacterial agents were administered for more than 8 days, most of urinary tract infections from which bacteria were isolated were of complex types. Pseudomonas aeruginosa and Serratia spp. were found slightly more in cases without indwelling catheter than those cases having indwelling catheter. In cases with indwelling catheter, S. aureus was isolated at 4.8% in 1984, and its isolation rate increased to 10.0% in 1985. Although about 90% of causative organisms for simple urinary tract infections had been thought to be E. coli, the isolation rate of E. coli among our cases with simple urinary tract infections was below 50% and has been gradually decreasing year by year. E. coli, as a causative organism for simple urinary tract infections, has been replaced by other species which had been considered as causative organisms for complex urinary tract infections, resulting in more complication of urinary tract infections. Increases in detection rate of Gram-positive organisms, especially S. aureus and E. faecalis, seemed to indicate the presence of causal relation to drug treatment. Therefore, it was thought that unbalanced uses of limited types of drugs should be avoided, although this point requires a further study.

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Sensitivities to antimicrobial agents of Escherichia coli, Klebsiella spp., Citrobacter spp., Enterobacter spp., Proteus spp., Pseudomonas aeruginosa and Serratia marcescens isolated from infected patients were evaluated and compared according to the types of their infections, i.e., simple and complicated urinary tract infections with or without indwelling catheter.
There were no apparent decreases in the sensitivity of E. coli isolated from patients with simple urinary tract infections. When data obtained in 1982-1985 were summarized, it was found that a new quinoline derivative, ofloxacin (OFLX), showed the strongest activity among oral antimicrobial and antibiotic agents. This agent inhibited 100% of bacterial growth at MIC of 1.56μg/ml. The next strongest activity was found with mecillinam (MPC) which showed 89.3% growth inhibition at the same concentration. Cefaclor (CCL) also showed 84.9% growth inhibition at the same concentration.
When sensitivities of E. coli isolated from patients with complicated urinary tract infections with or without indwelling catheter to first and second generation cephems were determined, cefotiam (CTM), which inhibited 88.9%: 91.4% bacterial growth at MIC of 0.39μg/ml, had the strongest activity among CTM, cefazolin (CEZ), cefoxitin (CFX) and cefmetazole (CMZ).
Among third generation cephems, including cefmenoxime (CMX), latamoxef (LMOX), ceftizoxime (CZX), cefotaxime (CTX) and cefoperazone (CPZ), the strongest activity was observed with CZX, and the agent having the next strongest activity was CMX. LMOX and CPZ showed relatively low activities. Carumonam (CRMN) and aztreonam (AZT), monobactams, showed strong activities against E. coli.
As for Klebsiella spp., activities of pencillins against these strains were low. When activities of oral cephems (cephalexin (CEX) and CCL) and of a quinoline derivative OFLX against these strains were determined, OFLX showed strong activity; i.e., the growth of Klebsiella spp. isolated from complicated urinary tract infections was inhibited at 87.2%; 82.1% at MIC of 0.20μg/ml.
Klebsiella spp. isolated from patients having urinary tract infections with or without indwelling catheter were found to show a relatively high sensitivity to a first generation cephem, CEZ, and second generation cephems, CTM, CMZ and CFX, as follows: CTM inhibited 86.4%: 76.7/growth at MIC of 0.39μg/ml; the inhibition rate of CMZ was slightly lower at the same concentration, but was 75.3%; 65.8% at MIC of 0.78μg/ml; antibiotic potencies of CTM and CMZ against Klebsiella spp. isolated from patients with indwelling catheter were relatively low, i.e., some strains showed MIC over 100μg/ml.
Activities of third generation cephems, including CMX, CZX, CTX, LMOX and CPZ, were also determined similarly. CMX and CZX inhibited 83.3%; 71.2% and 91.7%: 83.6% growths at concentrations below 0.10μg/ml, respectively. At concentrations of ≤0.10μg/ml, LMOX and CTX inhibited 58.3%; 45.2% and 81.0%. 74.0% growths, respectively. When monobactams, CRMN and AZT, were determined for their activities, CRMN inhibited 92.3%: 85.7/ growth and AZT inhibited 82.1%; 64.3% growth, both at MIC´s below 0.10μg/ml.
As for Proteus spp., penicillins, oral cephems and first generation cephems showed only poor activities.
When sensitivities of Proteus spp., to second generation cephems were determined, Proteus spp. isolated from patients with complicated urinary tract infections with indwelling catheter showed low sensitivity. CMZ inhibited 59.7% growth at 1.56μg/ml in 1982-1985. At the same concentration, CTM inhibited 35.8% growth.
CZX, CMX and CTX of the third generation cephem group showed activities against Proteus spp. at about the same levels.

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