In vitro interactions between aztreonam (AZT) and 8 other antibiotics were studied using the agar dilution checkerboard technique against 88 clinical isolates of Escherichia coli, Proteus vulgaris, Serratia marcescens and Pseudomonas aeruginosa. Combinations of AZT with 8 other antibiotics were generally additive or indifferent. Synergism was occasionally seen against S. marcescens or P.aeruginosa with AZT plus isepamicin (ISP). Antagonism was observed only between AZT and latamoxef against P. vulgaris. In a phase-contrast microscopic study, synergistic effects between AZT and aspoxicillin or ISP were confirmed against E. coli 177 and P. aeruginosa 15846. AZT in combination with ISP demonstrated a synergy against experimental urinary tract infection in mice caused by P. aeruginosa 15846.
We believe that combinations of several antibiotics with AZT should be considered for initial therapy of infections because synergism and additive action were observed and antagonism was rarely found in our study.

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We investigated the postoperative bile excretion and serum concentration of cefuzonam (CZON) in 6 cholecystectomized patients with postsurgical biliary drainage. CZON was administered intravenously by infusion at a dose of 1.0g immediately following the operation. Serum and bile concentrations of CZON were determined on the day of the operation and the second day after the operation. The following results were obtained.
1. Serum concentrations of CZON were at their highest levels at 30 minutes after administration of CZON. Levels were 45.8±13.8μg/ml on the day of the operation and 60.9±12.2μg/mlon the second postsurgical day.
2. Bile concentration peaked 1 hour after administration (4,083±1,427μg/ml on the day of the operation and 4,376±630μg/ml on the second postsurgical day). In paticular, bileconcentrations of CZON at 6 hours (259±140μg/ml and 154±23μg/ml) exceeded MIC80 of CZONagainst Gram-negative bacteria except for Pseudomonas aerugionsa.
3. Serum and bile concentrations were higher on the second postsurgical day than on the day of the operation, but the differences between these 2 days were not significant.
These results have indicated that CZON is a useful drug with excellent bile excretion following cholecystectomy, and that bile concentrations of CZON are maintained at high levels for 6 hours after intravenous administration.

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Flucytosine (5-FC), an oral antifungal agent, was used in the treatment of 37 patients with urinary tract infections due to fungi.Criteria for treatment included pyuria of ≥ 5 WBCs/HPF, fungal colony counts in urine greater than lO³CFU/ml and the presence of candiduria in 2 consecutive urine culture with interval of 7 days.Patients received 2-8 g/day of 5-FC for 7 to 14 days.
The clinical emcacy was evaluated in 27 patients with 14 day-treatment and overall efficacy rate was 77.8%.In patients with indwelling catheter, overall eMcacy rate was lower than that in patients without catheter.
Twenty-two of 30 strains (73.3%) were eradicated by the treatment.The MIC of 5-FC for isolates was less than0.78μg/ml except for 5 strains.The secondary resistance during 5-FC treatment was observed in early phase in 6 patients whose clinical efficacy was poor.
The loss of appetite and mild leukocytopenia were observed as adverse effects.
From the results of our study, 5-FC appears to be effective and safe in the treatment of urinary tract infection due to fungi.

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ased on the results of a study on pulmonary tissue uptake of flomoxef (FMOX), a new antibiotic agent, in 45 patients undergoing thoracotomy, the following conclusions were drawn:
1. Immediately preoperative 1 hour-drug infusion of 1g FMOX led to maximum serum concentration (averaging 42.4 μg/ml) 1 hour later, with a half-life of its β phase of 1.26 hours.
2. Normal lung (alveolar) tissue concentration was C_max 17.98μg/g with its ratios to serum peak value being 31.8, 27.1, 22.2, 9.4, 5.9 and 5.0% at 1, 2, 3, 4, 5 and 6 hours later, respectively.
3. Bronchiolar tissue concentration was C_max 31.91μg/g, with its ratios to serum peak value being 27.8, 19.3 and 10.1% at 2, 3 and 4 hours later, respectively, indicating its good bronchiolar intra-tissue transition.
The above results suggested the usefulness of FMOX for both the treatment of respiratory infections and the prevention of postoperative infections.

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Cefixime (CFIX) was evaluated clinically in pediatric respiratory tract infections, particularly those caused by Haemophilus influenzae:
1. The total number of children in this study treated with CFIX was 232, out of which 215 cases were evaluated for clinical efficacy and 224 cases were investigated for safety. A daily dosage of 3-6 mg/kg/day was given divided into 2 to 3 times daily for 3-15 days.
2. Causative organisms were identified in 146 cases, out of which 128 cases were found to be single microbial infections and 18 cases were mixed infections. In single microbial infections, clinical efficacy was 100% for those caused by H. influenzae/Haemophilus parainfluenzae, and was 95% for Streptococcus pyogenes with an overall efficacy of 96.9%. In mixed infections, the clinical efficacy was 100% for those caused by a combination of H. influenzae and Streptococcus pneumoniae, and the overall rate was 94.4%. An involvement of H. influenzae was observed in 108 cases with a clinical efficacy rate of 99.1%, and definite involvement of β-lactamase secreting strains of H. influenzae was found in 32 cases with a clinical efficacy of 96.9%.
3. Bacteriological effect was studied for 164 strains identified in 146 cases, and eradication rates were 89.5% for H. influenzae, 100% for H. parainfluenzae and S. pyogenes, and 71.4% for S. pneumoniae. The overall eradication rate was 91.4%. Superinfection was observed in 21 cases.MICs against 78 strains of H. influenzae were in a range of ≤0.10 μg/ml regardless of β-lactamase production, and far superior to cefaclor and amoxicillin. MICs against S. pyogenes and
S. pneumoniae were in ranges of≤0.10 μ/ml and 0.39 μg/ml, respectively.
4. Clinical efficacy was 93.0% in 215 cases (excellent: 136, good: 64, fairly good: 10, poor: 5).CFIX attained a high efficacy in the range of 89.4-95.7% in acute pharyngitis, acute tonsillitis, acute bronchitis and acute pneumonia.
5. Safety was monitored in 224 cases and there were only one case of loose stool and another of diarrhea as side effects. There were no abnormal findings in 31 cases of the laboratory test.
In conclusion, it was confirmed that CFIX is excellent and safe in the treatment of the respiratory tract infections.

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One hundred and thirteen patients who were treated at the Kyushu University Hospital and other related hospitals were randomly assigned to 2 groups to compare the effect of twice daily administration of 200 mg each and that of 300 mg each of ofloxacin (OFLX). The patients included 41 cases with pneumonia, 18 with acute bronchitis, 33 with chronic bronchitis, 15 with bronchiectasis with infection, 3 with diffused panbronchiolitis, and 3 with other secondary infectious diseases.
Fifty-five cases were administered 400 mg OFLX a day and 58 cases received 600 mg. The number of severe cases in the 600 mg group was greater than that in the 400 mg group. The ratios of general amelioration of clinical symptoms were 92.6% in the 400 mg group and 82.1% in the 600 mg group. Thus, the ratio of the 400 mg group was better than that of the 600 mg group. However, the ratio of significant amelioration in the 600 mg group was 35.7% which was better than that in the 400 mg group, 27.8%. For bacteriological effects the rate of disappearance and decrease in number of bacteria was 92% in the 400 mg group and was significantly better than that of the 600 mg group, 70%. The incidence of side effects in the 600 mg group was 22.4% and this was high in contrast to that in the 400 mg group, 3.6%. Most of the side effects in the 600 mg group involved symptoms of the central nervous system such as sleeplessness. No significant differences were observed in incidences of abnormalities of laboratory tests at 1.8% and 1.7%, respectively. Safety in the 400 mg group were 96.4% which was significantly higher in number than those in the 600 mg group, 77.6%.
Efficacy rates of twice daily administrations each with 200 mg and 300 mg OFLX for lower respiratory infections were 94.4 and 79.3%, respectively. In conclusion, the daily dose of 400 mg was the most effective.

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The transferability of cefpirome (HR810, CPR) to cerebrospinal fluid (CSF) was studied employing rabbits with experimental meningitis caused byStaphylococcus aureus.
The mean serum concentration was 362±6.63μg/ml at 15 minutes after intravenous administration of the drug at adose level of 100 mg/kg. The meanconcentration in CSF was maximum at 60 minutes after administration, and the mean maximum concentration was 14.6±2.85μg/ml.
Phamacokinetic parameters calculated from these values were as follows, C_max (CSF/serum): 4.04%; AUC (CSF/serum): 5.14% between 15 and 60 minutes, 8.12% between 15 and 120 minutes and 10.4% between 15 and 180 minutes; T 1/2 for CPR in CSF: 154 minutes; T 1/2 (CSF/serum): 3.96.
In comparison to those of other β-lactam antibiotics which were obtained in the same way, the transferability of CPR was intermediate, but the peak CSF level was high, and in consideration of the antimicrobial potency against the main pathogens of meningitis, it appears worthwhile of running clinical tria1s for this drug.

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Cefpirome (CPR, HR810), a new parenteral cephalosporin antibiotic, was studied for its effect on the intestinal bacterial flora in pediatric patients.
The subjects were children admitted for infections (6 males and 3 females, 1 month to 5 years 1 month old, weighed 3.94 to 21.0 kg). CPR was intravenously administered at a dose between 19.0 to 40.0 mg/kg, 3 to 4 doses daily over 6 to 12 days. The feces from these children were collected before, during, and after administration, and bacteria were identified and counted. CPR concentration, β-lactamase activity, and Clostridium difficile D-1 antigen were also assayed.
Bacterial flora changes in feces during CPR administration showed some variance, but generally 5 cases out of the 9 showed a significant decrease in Enterobacteriaceae and Enterococcus faecalis among aerobic bacteria. The other 4 cases showed some transient decrease, but no significant change was observed. No significant changes were recognized for Enterococcus avium andEnterococcus faecium, and the total aerobic bacterial count decreased in a transient manner in only one patient. Regarding anaerobic bacteria, Bifidobacterium and Eubactrium revealed a significant decrease, a transient decrease or no change from case to case. Bacteroides showed little change incount. Consequently, the total anaerobic bacteria count did not reveal a large change aside from 1 case in which Bacteroides was not detected before administration and a significant decrease of other bacteria was noted. In no case, glucose nonfermentative Gram-negative bacilli or fungi were found dominant. Although C. difficile and C. difficile D-1 antigen were detected in 3 and 4 cases, respectively, there was no exact relationship between the number of C. difficile and the characteristics of the feces. CPR was detected in fecal samples from 6 cases during administration with concentrations ranging between 1.20 to 22.4, μg/g. High values of CPR tended to be found in specimens with low β-lactamase activity in the feces. When drug sensitivities of the bacteria isolated from feces before and after administration were compared, higher levels of resistance were found in some bacteria such as Enterococci and Bacteroides during or after administration than before administration. The above results suggest that CPR is a drug with a relatively small influence on the intestinal bacterial flora in children, but a particular attention is required for diarrhea and microbial replacement during a continuous, long-term administration of the drug.

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A research group was organized with the purpose of making basic and clinical studies on cefpirome sulfate (HR810, CPR), a newly developed cephalosporin antibiotic, in the pediatric field. Through meetings a joint research was done involving 19 key institutions and their related facilities throughout Japan. The obtained results are summarized as follows.
1. Antibacterial Activities
Minimum inhibitory concentrations (MICs) were determined against 71 Gram-positive and 110 Gram-nagative bacteria in the present clinical trials. CPR showed antibacterial activities 2-16 times higher than those of ceftazidime (CAZ) against Staphylococcus aureus and other Gram-positive bacteria including MRSA. Against Gram-negative bacteria, CPR showed a somewhat broad range of distribution in MIC against Branhamella catarrhalis, while the antibiotic inhibited the growth of all the strains of Escherichia coli and Haemophilus influenzae at concentrations no more than 0.10 and 0.20 μg/ml, respectively.
2. Blood Concentrations and Urinary Excretion Rates
The pharmacokinetics in pediatric patients was investigated with a dose of 20 mg/kg in most cases via one shot intravenous injection or 30-and 60-minute intravenous drip infusion. Mean blood concentrations of CPR at 15 minutes after one shot intravenous injection of 10, 20, and 40mg/kg were 51.2, 70.5, and 123.5 μg/ml, with half-lives of 1.21, 1.39 and 1.53 hours, respectively. Urinary excretion rates in 6 hours were 63.6, 66.0 and 71.6%, respectively for the 3 dose levels.After 30-and 60-minute intravenous drip infusions at the same dose, the pharmacokinetic parameters observed were similar to those obtained with one shot injections.
3. Concentration in the Cerebrospinal Fluid
CPR penetrated well into the cerebrospinal fluid in patients with purulent meningitis and levels of 1.85-24.2 μg/ml 45-60 minutes were achieved after intravenous injection at a dose of 40-80 mg/kg, the penetration rate of CPR was at an intermediate degree compared with other cephalosporin antibiotics.
4. Clinical Results
Clinical efficacies of CPR on infectious diseases were analyzed in 454 plus 3 cases which werecomplicated with other infectious diseases, hence totaling 457 cases out of 499 cases originallychosen for clinical evaluation. The remaining 45 cases were excluded from the clinical evaluation.
As for the clinical efficacy, CPR was found to be effective (good or excellent) in 430 (94.1%) of the 457 cases. CPR was found to be effective in 243 (95.3%) of 255 cases for which causative bacteria were identified. The efficacy rate was 92.6%(187 of 202) in those cases in which caus tive bacteria were not identified. All these figures indicated a high efficacy of CPR.
As for clinical efficacies according to different causative bacteria, CPR showed a high efficacy rate of 95.0% for infections with Gram-positive bacteria including S. aureus, and this value was as high as the efficacy rate for Gram-negative bacteria, 95.7%. The efficacy rate was also equally high (94.4%) for polymicrobial infections.
As for bacteriological effects on the basis of different causative bacteria, a total number of 266 bacterial strains out of 276 strains that had been identified as causative bacteria was eliminated, thus representing an excellent eradication rate of 96.4%. As for the eradication of Gram-positive bacteria, a high eradication rate of 89.5%(34 out of 38 strains) was observed for S. aureus and forStreptococcus pneumoniae an eradication rate of 97.4%(37 out of 38 strains) was obtained. The overall eradication rate for Gram-positive bacteria was 95.1%.
Among Gram-negative bacteria, an eradication rate of 96.6%(85 out of 88 strains) was obtained for H. influenzae.

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