Clinical studies on cefodizime (CDZM) were performed in patients of obstetrics and gynecology. CDZM was given to patients via drip infusion at a daily dose of 2-4 g, and the results obtained are summarized as follows:
1. A total of 10 cases included 5 cases of intrauterine infections (3 cases of puerperal endometritis, 1 endometritis and 1 puerperal fever), 2 intrapelvic infections (1 pelvic dead space infection and 1 parametritis), and 3 BARTHOLIN'S abscess.
Clinical efficacies were excellent in 3 cases, good in 6 and poor in 1. The efficacy rate was 90% (9/10).
2. Bacteriological efficacies were as follows: eradicated in 3 cases, replaced in 2, decreased in 1, persisted in 1 and unknown in 3.
3. Neither subjective and objective adverse reactions nor abnormal changes in laboratory test values were observed.

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Cefodizime (CDZM), a new cephem antibiotic, was studied in terms of its pharmacokinetics and clinical efficacy in the field of obstetrics and gynecology, and the results are summarized as follows:
Concentrations of CDZM in serum and genital tissues following 1g drip infusion (30 min.) were determined and good penetration of CDZM into tissues was recognized. The maximum level in uterine arterial serum was 56.25μg/ml and maximum tissue levels ranged 23.56-40.64μg/g which were above its MIC₈₀'s for main pathogenic organisms.
Peak concentrations of CDZM in pelvic dead space exudates following 1g intravenous bolus injection or drip infusion ranged 6.25-6.52μg/ml.
The clinical efficacy of CDZM in 17 cases of obstetrical and gynecological infections was investigated using a dose of 1-3g daily. The clinical efficacy rate was 88.2% (15/17 cases). Bacteriologically, the eradication rate was 83.3%. No side effects or abnormal laboratory test values were observed.

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Pharmacokinetic and clinical studies on cefodizime (THR-221, CDZM) were carried out and the following results were obtained.
Concentrations of CDZM in serum and uterine tissues were determined from 38 to 282 minutes after drip infusion of 1g CDZM. CDZM reached peak level of 25.0μg/g or higher in each tissue during a period of 38 to 83 minutes. Concentrations of CDZM in the dead space exudate after drip infusion of 2g CDZM were also studied. At 240 minutes after injection, CDZM concentration in exudate reached a peak of 46.88μg/ml. These levels far exceeded MICs of CDZM against major pathogens most often isolated in the field of obstetrics and gynecology.
CDZM was administered to 7 patients with their diseases diagnosed as pelvic peritonitis (4 cases) or acute adnexitis (3 cases) at a dose of 2-4g per day for 6-14 days. Clinical response was good in all cases. Transient elevation of liver function was noticed in 2 cases. No other adverse reactions were noted during the study.

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Clinical investigation of cefodizime (CDZM, THR-221), a newly developed cephem antibiotic, was carried out with regard to its distributions to genital organs, and the drug was evaluated clinically against infections in obstetric and gynecological fields.
1. Distributions to genital organs
One gram of CDZM was administered to each patient who received simple total hysterectomy by 1 hour intravenous drip infusion and concentrations of CDZM in genital organs such as antecubital vein, uterine artery, ovary, oviduct, endometrium, myometrium, cervix uteri and portio vaginalis were examined.
Serum concentrations were elevated to an average of 90.63 μg/ml in 15 minutes after administrations of CDZM and decreased gradually at fixed times. CDZM was distributed in concentration ranges of 45.32-10.96 μg/g in ovary, 26.58-10.20 μg/g in oviduct, 42.20-9.80 μg/g in endometrium, 31.28-11.72 μg/g in myometrium, 42.20-12.52 μg/g in cervix uteri and 45.32-9.40 μg/g in portio vaginalis, and these high concentrations lasted more than 3 hours after administrations.
2. Clinical evaluations
CDZM was given to 10 patients, including 7 cases with pelvioperitonitis and 1 case each with pyometra, BARTHOLIN'S abscess and puerperal fever, at a dose level of 1 or 2 gram 2 times daily by 30-60 minutes intravenous drip infusion.
Overall clinical efficacies were excellent in 3 cases and good in 7 and the efficacy rate was very high, at 100%.
Bacteriological efficacies were eradicated in 6 cases, and unknown in 2, and the eradication rate was 100%.
No adverse reactions and abnormalities in laboratory test values due to CDZM occurred in any patients.
From the above results, it appears that CDZM is a useful drug for infections in obstetric and gynecological fields.

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Pharmacokinetic and clinical studies on a new cephalosporin antibiotic, cefodizime (THR-221, CDZM), were performed and the results obtained are summarized as follows:
1. At about 84 minutes after a bolus injection of 1g dose of CDZM, the drug was tranferred well into tissues of internal genital organs and remained there at therapeutic levels for 285 minutes. The drug was also transferred quickly and sufficiently into exudate from pelvic dead space and its levels were still kept at high levels at 6 hours after administration.
2. CDZM was given to 8 women affected with gynecologic infections. The outcome of CDZM therapies showed that the drug was effective in all 8 of patients (100%) clinically and bacteriologically.
3. Notable adverse effects or abnormal laboratory test results were not observed except for 2 patients with transient and slight elevation of transaminase levels.
Based on these results, it may be concluded that CDZM is a highly effective and a very safe antibiotic for the treatment on infectious diseases in gynecologic field.

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Cefodizime (CDZM, THR-221), a newly developed injectable cephem antibiotic agent, was evaluated for its distribution in intrapelvic genital organ tissues, penetration into exudate of retroperitoneal space and breast milk and therapeutical effects on some infections in obstetrics and gynecology. The results obtained are summarized as follows.
1. When 1g of CDZM was administered by drip infusion over a 60 minutes period, its serum concentration reached 53.51μg/ml at the completion of drip infusion, then declined rapidly. Peak concentrations of CDZM in intrapelvic genital organ tissues were higher than 20μg/g at different times.
CDZM was transferred to the exudate of retroperitoneal space and its concentration reached a peak of 7.01μg/ml at 2.67 hours after initiation of 60 minutes drip infusion at a dose of 1g, then declined slowly but stood at 4.93μg/ml even at 8 hours.
The transfer of CDZM to breast milk was similar to other cephem antibiotic agents and peak levels of CDZM in milk were 0.13-0.36μg/ml at 2 or 3 hours after administration of a dose of 1g.
2. In the clinical study, CDZM was administered by drip infusion over 60 minutes to 6 patients with obstetrical and gynecological infections at a daily dose of 2-6g. Clinical results were good in 5, poor in 1, and the efficacy rate was 83.3%. No side effects nor abnormal laboratory test results were observed.

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Clinical studies on cefodizime (THR-221, CDZM), a new injectable cephem antibiotic, were performed and the following results were obtained.
Ten patients with obstetrical and gynecological infections such as intrauterine infections, pyometra, adnexitis, parametritis and lymphocystitis.
The clinical results were evaluated as excellent in 1 case, good in 4 cases and poor in 5 cases.
The efficacy rate was 50.0%.
Bacteriologically, 10 organisms were isolated from 8 patients and the eradication rate was 44.4%.
No side effects were observed in any of the cases treated with CDZM.
In laboratory examinations, transient elevations of serum GOT, GPT and Al-P were noted in 1 case.

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We have conducted pharmacokinetic and clinical trials of a new cephem derivative, cefodizime (THR-221, CDZM), and obtained the following results.
1. We administered CDZM to 4 cases with abdominal simple hysterectomy due to myoma uteri at a dose level of 1g by drip intravenous injection and studied average levels of transfer measured at various locations in the uterine tissues and adnexa at an average of 2 hours after administration.
CDZM level was highest in the oviduct, 13.7μg/g (ratio with respect to the uterine arterial blood: 91.3%), followed by the ovary, portio vaginalis, cervix uteri and endometrium, and was lowest in the myometrium, 8.3μg/g (55.3%).
CDZM concentrations were higher than 6.04μg/g in any tissues.
2. To study CDZM transfer to pelvic cavity fluid, we administered CDZM to 5 cases with total hysterectomy due to cervical cancer of uteri at a dose level of 2g using drip intravenous injection. The drug was transfered at high levels to the pelvic cavity fluid. A level of 11.7μg/ml was observed at 3 hours after injection. The drug levels in the pelvic cavity fluid were maintained continuously higher levels than those of venous blood.
These concentrations in the uterine tissues and pelvic cavity fluid were higher than the MIC against many strains of Gram-positive and Gram-negative bacteria, hence we considered them to be therapeutically effective concentrations.
3. Eleven cases of gynecological infections receiving in totals of 8 to 48g of CDZM demonstrated “excellent” results in 3 cases, “good” in 8 cases. Eight strains of organisms were isolated from 10 cases.
4. Neither side effects nor abnormalities in laboratory test results were observed in the 11 cases during the clinical trial and in 9 cases during the pharmacological evaluations.
Based on the results of these studies described above, this drug was considered to have excellent efficacy and safety.

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We report a rare case of Klebsiella pneumoniae meningitis associated with liver abscess, which was successfully treated with cefotaxime (CTX), one of the third-generation cephalosporins.
A 53-year-old man was admitted to Keio University Hospital on June 13, 1988, because of a fever and a headache. On June 3, he suddenly started shivering and his temperature rose to 39°C. He then began to complain of polydipsia, polyuria, and a weight loss of 4kg a week. On June 11, he developed a severe headache. Four years prior to this incident, he had been diagonosed as having diabetes after a routine medical examination, but had neglected to undergo medical treatment.
On admission, laboratory data showed leukocytosis, hyperglycemia (394mg/dl) and ketonuria (4+). A lumbar puncture yielded cloudy cerebrospinal fluid (CSF) containing 500/3 cells/mm³, of which about 70% were neutrophils. A diagnosis of diabetic ketoacidosis and purulent meningitis was made. A treatment with ampicillin (ABPC) and CTX,(12g/day, each) was begun. On the third day, cultures of a blood specimen and CSF yielded both K. pneumoniae. The MICs of CTX to K. pneumoniae isolated from blood and CSF were both 0.05μg/ml. ABPC was discontinued, gentamicin was administered for 2 days, CTX was continued at the same dosage level and an administration of prednisolone 40mg daily was begun. While we examined foci of the meningitis, a solitary hepatic abscess was found with an ultrasonography, but it later disappeared completely.
In our case, CTX was effective in the treatment of both meningitis and liver abscess. It is postulated that the meningitis was a complication of the bacteremia initiated by the liver abscess.

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Susceptibilities to various antibacterial and antibiotic agents of bacterial strains isolated from urinary tract infections at 8 hospitals in Japan from July to October in 1986 are summarized as follows.
1. Enterococcus faecalis was susceptible to sulfamethoxazole/trimethoprim (ST) and imipenem (IPM) with MIC₉₀S of 0.78 and 1.56 μg/ml. Minocycline had the strongest activity against Staphylococcus aureus; the MICs for all strains tested were lower than 0.39 μg/ml. The MIC₈₀S of dicloxacillin, and arbekacin (HBK) were 0.20 and 0.78 μg/ml, respectively. Among the cephems, the MIC₈₀ of flomoxef was 25 μg/ml, whereas those of cefmenoxime (CMX) and cefotiam (CTM) were 50 μg/ml.
2. Escherichia coli was most susceptible to ofloxacin (OFLX) among the oral antibacterial and antibiotic agents tested. OFLX showed the minimum inhibitory concentration against 90% (MIC₉₀) of the 274 strains of E. coli tested to be lower than 0.10 μg/ml. The antibacterial activities of the third generation cephems such as CMX and latamoxef (LMOX) were the strongest among the injectable antibiotics tested. The MIC₉₀S of CMX and LMOX were lower than 0.10 and 0.20 μg/ml, respectively. CTM and cefmetazole, the second generation cephems, were also highly active against E. coli with MIC₉₀S of 0.39 and 1.56 μg/ml, respectively.
3. Among the oral antibacterial and antibiotic agents tested, OFLX was the most active against Klebsiella pneumoniae. Its MIC₉₀ was 0.78 μg/ml. Among the injectable antibiotics tested, CMX was the strongest with an MIC₉₀ of 0.20 μg/ml; MIC₉₀ of CTM and LMOX were 0.39 μg/ml.
4. The tested antibacterial and antibiotic agents were generally less active against Citrobacter freundii than against other bacteria. The MIC₈₀ of OFLX was 0.39 μg/ml. Gentamicin (GM) and ST were slightly active against C. freundii. Among the cephems, CMX had the MIC₈₀ of 25 μg/ml.
5. Enterobacter cloacae was less susceptible to the cephems tested. OFLX, GM, and mecillinam were active against this bacteria with MIC₈₀S of 0.78, 0.78 and 1.56 μg/ml, respectively.
6. Among the oral antibacterial and antibiotic agents and penicillins examined, piperacillin (PIPC) was the most active against Proteus mirabilis. Its MIC₉₀ was 0.39 μg/ml. Those of sulbenicillin, cefaclor, ampicillin, OFLX, and ST were 0.78, 0.78, 1.56, 3.13 and 3.13 μg/ml, respectively. CMX was highly active against P. mirabilis with an MIC₉₀ of ≤0.10 μg/ml; LMOX followed with an MIC₉₀ of 0.20 μg/ml among the injectable antibiotics tested. CTM was also active against this bacterium; the MIC₉₀ was 0.39 μg/ml.
7. The antibacterial and antibiotic agents were generally only slightly active against Proteus vulgaris. The MIC₈₀S of LMOX and CMX were 0.78 and 6.25 μg/ml, respectively.
8. Morganella morganii was only weakly susceptible to antibacterial and antibiotic agents except the third generation cephalosporins. The MIC₈₀S of CMX and LMOX were 0.78 μg/ml.
9. The antibacterial and antibiotic agents were generally less active against Serratia marcescens than against other bacteria. The MIC₈₀S of OFLX and CMX were 12.5 and 25 μg/ml, respectively.
10. Pseudomonas aeruginosa was isolated frequently from urinary tract infections. Ciprofloxacin (CPFX) and norfloxacin (NFLX), new quinolones, were highly active against this bacterium with MIC₅₀S of 0.20 and 0.78 μg/ml, respectively. The MIC₅₀S of cefsulodin, IPM, ceftazidime, and tobramycin were all 1.56 μg/ml and those of PIPC, cefoperazone, carumonam and various aminoglycosides, such as micronomicin, dibekacin, sisomicin, GM and HBK, ranged from 3.13 μg/ml to 6.25 μg/ml.

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From July to October in 1986, hospital data on 717 isolates of causative microorganism from patients with urinary tract infections and background information on 562 patients were collected. The urinary tract infections were divided into 3 groups; simple infections and complicated infections with or without the use of indwelling catheter.
We investigated such factors as the patients sex, age, and drug treatments, and the isolates obtained from the infections.
From 1981 to 1986, about 25% of the patients with simple infections were males and about 60 to 70% among those with complicated infections were males each year. During these 6 years, no noticeable changes occurred in sex and age distributions of patients with any type of the infections, but the species of isolates changed remarkably. In 1982 and 1983, the isolation rates of Enterococcus faecalis (Streptococcus spp. or Streptococcus faecalis) obtained from the patients were about 8% in both of male and female patients. In 1984, the rate in females increased to 17.9%. In 1985, the rates in males and females were 14.9% and 7.6%, respectively. Similar rates were also observed in 1986: 16.1 and 7.4%. The isolation rate of Staphylococcus aureus in 1982 was 0.7%, as was in 1983. It however, increased to 1.7% in 1984 and to 3.2% in 1985. It was 2.5% in 1986. The isolation rate of Gram-positive bacteria was 11.1% in 1982; it increased to 18.9% in 1983 and to over 20% between 1984 to 1986. Among Gram-negative bacteria, the isolation rate of Pseudomonas aeruginosa form patients with complicated urinary tract infections with a catheter was high and over 20% in both 1985 and 1986.
When antibacterial agents were administrated for 3 days, changes in number of species of isolates tended to be more pronounced in complicated infections with or without the use of catheter than in simple infections. According to date obtained in 1986, when antibiotic agents were administered for 8 or more days, the changes were definitely more drastic in complicated infections than in simple ones. An upmost care in the selection of antibiotic drugs according to their antibacterial spectra and activities, therefore, appears necessary, and an attention should be paid on future changes in species of bacteria isolated from infections.

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Changes in the susceptibility of various infectious microorganisms to antimicrobial agents from 1982 to 1986 were evaluated. The microorganisms investigated were Escherichia colt, Klebsiella spp.,Citrobacter spp., Enterobacter spp., Proteus spp., Serratia marcescens and Pseudomonas aeruginosa isolated from patients with urinary tract infections. We compared susceptibilities of microorganisms obtained from simple urinary tract infections with those from complicated infections with or without indwelling catheter.
Among penicillins, mecillinam (MPC) showed the strongest activity against E. coli obtained from the patients: 3.13 to 6.25 μg/ml of MPC inhibited the growth of over 90% of the isolates. Among the second and the third generation cephalosporins, cefotiam and cefmenoxime (CMX) showed the strongest activity and the growth of isolates was inhibited at concentrations of 0.39 to 0.78 μg/ml and below 0.10 to 0.20 μg/ml, respectively.
The activities of penicillins against Klebsiella spp. were weak. CMX showed strong activity against Klebsiella spp; 91.7% of the isolates from patients with simple infections were inhibited at 0.39 μg/ml of the agent; 90.7% and 91.6% of isolates from patients with complicated infections with or without indwelling catheter were inhibited at 0.78 μg/ml and 1.56 μg/ml of the agent, respectively. Gentamicin (GM) also showed strong activity against isolates from patients with simple infections and weaker activity against isolates from patients with complicated infections with the catheter; 0.78 μg/ml of ofloxacin (OFLX) inhibited the growths of 90% of the isolates from these patients.
Penicillins showed weak activity against Citrobacter spp. obtained from the patients. Among the second and the third generation cephalosporins, CMX and latamoxef (LMOX) showed strong activities against the Citrobacter isolates; about 50% of the isolates were inhibited at 0.20 μg/ml of either agent. 1.56 μg/ml of minocycline inhibited the growth of 75 to 90% of the isolates and 1.56 μg/ml of OFLX inhibited the growth of 93 to 100% of the isolates.
Against isolates of Proteus spp. penicillins also showed weak activities. Among them, however, piperacillin (PIPC) inhibited the growth of over 90% of the isolates at concentrations ranging from 0.78 to 1.56 μg/ml. Among the second and the third generation cephalosporins, CMX and LMOX showed strong activities; 0.20 μg/ml of CMX inhibited the growth of 94.4%, 90.4%, and 83.1% of isolates from the 3 types of the patients, respectively. 0.20 μg/ml of LMOX inhibited the growth of 94.4%, 91.8%, and 88.3% of the isolates, respectively.
Enterobacter spp. showed resistance to the β-lactam antibiotics. OFLX showed strong activity; 0.39 μg/ml of the agent inhibited the growth of over 80% of the isolates.
S. marcescens was also resistant to antimicrobial agents. Among the β-lactam antibiotics, CMX showed strong activity; 1.56 μg/ml of CMX inhibited the growth of 43.5% of isolates from patients with simple infections and of 38 to 43% of isolates from patients with complicated infections. GM showed strong activity; 1.56 μg/ml of the agent inhibited the growth of 58.8% of isolates from patients with simple infections and of 66 to 70% of isolates from patients with complicated infections.
Penicillins showed weak activity against P. aeruginosa; 6.25 μg/ml of PIPC inhibited the growth of 62 to 71% of the isolates. Among the second and the third generation cephalosporins, ceftazidime exhibited the strongest activity against the P. aeruginosa isolates; 1.56 μg/ml of the agent inhibited the growth of 68.4% of isolates from patients with simple infections and of 72.2 to 66.3% of isolates from patients with complicated infections.

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