[in Japanese]

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Sultamicillin (SBTPC) is a mutual prodrug in which ampicillin (ABPC) and a potent β-lactamase inhibitor sulbactam (SBT) are ester-bound in an equimolar ratio. SBTPC is hydrolyzed during absorption after oral administration to provide ABPC and SBT for systemic circulation.
In the present study, the antimicrobial activities of SBTPC against 50 isolates each of 6 species (Staphylococcus aureus, Klebsiella pneumoniae subsp. pneumoniae, Branhamella catarrhalis, Haemophilus influenzae, Streptococcus pneumoniae and Streptococcus pyogenes) of bacteria freshly obtained from upper respiratory tract infections were examined in relation to their bacterial β-lactamase producing abilities. β-Lactamase producing strains were identified using the acidometry disc method with benzylpenicillin (PCG) of cefazolin (CEZ) as a substrate, and their frequencies of appearance were calculated as follows: S. aureus86%; K. pneumoniae subsp. pneumoniae 100%; B. catarrhalis 68%; H. influenzae 24%. Fourteen per cent of S. aureus strains examined were β-lactamase positive using both PCG and CEZ acidometry discs. SBTPC, however, demonstrated excellent antimicrobial activities even against these β-lactamase producing strains. Good activities were observed especially against those bacterial strains producing penicillinase (PCase). Average MIC₈₀, values of SBTPC were 3.13μg/ml for S. aureus and K. pneumoniae subsp. pneumoniae, 0.39μg/ml for B. catarrhalis and H. influenzae, 0.05μg/ml for S. pneumoniae and 0.025μg/ml for S. pyogenes.
As SBTPC was shown to possess excellent antimicrobial activities against PCase producing strains, the enhancement in activities of SBTPC compared to ABPC alone can be attributed to the inhibition of β-lactamase by SBT which, as noted above, is a component of SBTPC in an equimolar ratio to ABPC.

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In vitro susceptibilities of 350 strains of Staphylococcus aureus to ampicillin (ABPC), methicillin (DMPPC), cloxacillin (MCIPC), cefazolin (CEZ), cefmetazole (CMZ), cefmenoxime (CMX), latamoxef (LMOX) and 5 non-β-lactam antimicrobial agents were determined according to the standard method of Japan Society of Chemotherapy.
Frequencies of the appearance of resistant organisms (MIC≥12.5μg/ml) to β-lactam antibiotics were 45% for ABPC, 27% for DMPPC, 11% for MCIPC, 24% for CEZ, 15% for CMZ, 36% for CMX and 51% for LMOX. To non-β-lactam antimicrobial agents, resistant s trains appeared at 31% to gentamicin, 15% to amikacin, 0.6% to minocycline (MINO), 1% to norfloxacin (NFLX) and 65% to fosfomycin (FOM).
More than 80% of DMPPC-resistant strains were also resistant to LMOX, CMX, ABPC, FOM, and CEZ, but most of those were susceptible to MINO and NFLX.
Incidence of DMPPC-CEZ resistant S. aureus was 23% of the 350 strains tested.
As stated above, multiply resistant strains of S. aureus are present throughout different hospitals in Okinawa.

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Based on a quantitative analysis of sputum cultures, pathogenic bacteria in respiratory ailments isolated in our laboratory during 1984 to 1986 were classified and analyzed. During the study period, the most frequently isolated agent was Haemophilus influenzae followed by Pseudomonas aeruginosa, Branhamella catarrhalis and Streptococcus pneumoniae. They together consisted of 70-74% of all the respiratory pathogenic bacteria isolated in our study. Susceptibilities of above pathogens to antimicrobial agents were investigated using the agar dilution method. Results are summarized as follows.
1. Ratio of proportion of β-lactamase producing strains among non β-lactamase producing strains of H. influenzae markedly decreased in 1986 (6/70, 8.6%) as compared to previous years (11/73, 15.1% in 1984 and 8/49, 16.3% in 1985). In consequence, MIC₉₀ values for penicillins reduced considerably in 1986. Among the antibiotics examined cefmenoxime (CMX) and cefotaxime (CTX) were the most active agents against H. influenzae. A development of resistance to other cephems and new quinolones (norfloxacin, ofloxacin, ciprofloxacin) was not evident during the 3-year survey.
2. Against S. pneumoniae, benzylpenicillin was still the most active agent despite gradual increase of frequency of isolation. Ampicillin (ABPC), piperacillin (PIPC), CMX and CTX were also potent against S. pneumoniae. S. pneumoniae were frequently isolated from patients treated with new quinolones or minocycline (MINO). This phenomenon may be explained by higher MIC values of these agents against S. pneumoniae.
3.Of B. catarrhalis strains isolated, more than 80% were β-lactamase positive, although MIC₉₀ were not so high (1.56 μg/ml for ABPC and 0.20μg/ml for PIPC). Among the antibiotics tested, latamoxef was the most active agent against B. catarrhalis and inhibited all the strains at a concentration of 0.05μg/ml or less. No resistant strains were observed against cephems, new quinolones, erythromycin or MINO.
4. P. aeruginosa appeared to be rapidly developing resistance against new quinolones in patients with chronic P. aeruginosa respiratory infections who had been treated with these agents. In treating chronic respiratory infection due to P. aeruginosa, one must be watchful of rapid development of resistance by the organism or its replacement with S. pneumoniae.

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Susceptibilities of 179 strains of 30 bacterial species or subspecies to clavulanic acid/amoxicillin (CVA/AMPC) combination were determined by the 2-fold agar dilution method as well as by diameters of inhibition zones in the single-disc method, under the experimental conditions established by KANAZAWA.
The experiments demonstrated significant correlation between MICs by the dilution method and diameters of inhibition zones in each of conventional assays of the over-night (about 16 hours) incubation, the delayed assay (about 24 hours incubation), and the rapid assay (after 3-4 or 5-6 hours incubation), thus confirming applicability of the single-disc assay for activities of CVA/AMPC combination.
From an analysis of the data obtained using CVA/AMPC (1: 2) combination of disc containing 45 pg, the primary regression equations were obtained as follows: D (diameter, mm) = 27.4-10.1 log MIC (μg/ml) in the conventional assay; D=33.7-13.4 log MIC (μg/ml) in the delayed assay; D=20.7-6.6 log MIC (μg/ml) in the 5-6 hours rapid assay, and D=14.5-3.6 log MIC (μg/ml) in the 3-4 hours rapid assay.
The range of variations in MICs of CVA/AMPC combination estimated from diameters of inhibition zones by the disc test was then calculated in comparison with that in MICs determined by the 2-fold agar dilution method to estimate experimental errors involved in assaying MICs of CVA/AMPC combination by the single-disc assay.

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We studied the clinical usefulness of ofloxacin (OFLX) in 13 patients with chronic respiratory tract diseases aggravated by acute infections with identified causative bacteria.
1. Overall clinical efficacies were: highly effective 5, effective 6, slightly effective 2, and ineffective none, showing an efficacy rate of 84.6%.
2. In 6 patients with fever of over 37°C, time lengths in days for symptoms to have been alleviated due to OFLX treatment were; 1 day: 4 cases, 3 days: 1 case and 5 days: 1 case (2.0 days on average).
3. As to bacterial transitions, in 9 of 10 patients Haemophilus influenzae was eliminated and in 1 patient it was substituted by Pseudomonas aeruginosa. In 3 patients Branhamella catarrhalis was eliminated and in 1 patient, the number of P. aeruginosa was reduced. OFLX is expected to have a potent bacteriological effect on H. influenzae and B. catarrhalis.
4. As to side effects, 1 of the 13 patients (7.7%) complained of discomfort in the epigastrium. This discomfort disappeared when a gastric mucosa protective agent was administered. There was no abnormality in laboratory test values.
Judging from the above results, we consider OFLX a useful drug for the treatment of patients with chronic respiratory tract diseases aggravated by acute infections.

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A parenteral cephem antibiotic ceftriaxone (CTRX) was studied for its pharmacokinetic features and clinical efficacy and safety in various infections in neonates including premature infants at 11 institutions associated with Japan Perinatal Infection Research Group. The following results obtained are summarized as follows.
1. Following single intravenous bolus injections with 10 and 20mg/kg of CTRX, serum levels of the drug at 30 minutes post-dose 36-42μg/ml and 46-76μg/ml, respectively, and those at 12 hours post-dose were 10-14μg/ml and 13-21μg/ml, respectively, in a total of 105 neonates. Serum levels detected were on very gentle descending curves.
2. Half-lives (T1/2) of the drug in serum were significantly prolonged in 0-3 day age groups of both mature and premature infants: it was especially long in premature infants with age of 0-3 days; i. e., 17.1 hours. There was no difference in T1/2 between the 4-7 day and 8-28 day age groups.
3. Urinary excretion rates were 20-30% in the first 6 hours post-dose and 30-40% in 12 hours post-dose, in 80 neonates examined.
4. Clinical efficacy: Clinical efficacies were evaluated in 112 of 168 enrolled excluding infants with 90 days of age or older, who were treated for prophylaxis and unevaluable cases. The safety was evaluated in 161 of the 168.
(1) Demographic background of the 112 cases:
The 112 cases were composed of 89 neonates with ages of 28 days or younger, 21 premature infants, 57 males and 55 females. The drug was given to 102 of the cases by intravenous bolus injection, with 81 cases administered twice a day and 97 cases receiving 10-50mg/kg a day.
(2) Efficacy rate in the 112 cases:
In 60 cases for whom causative pathogens were identified the efficacy rate was 90.0% in total (excellent: 31/60; good: 23/60); efficacy rates of 87.5% were obtained in 8 cases with purulent meningitis and 90.9% in 11 with septicemia. In 52 with causative pathogen not identified, the efficacy rate was 96.2% in total (excellent: 21/52; good: 29/52).
(3) Adverse reaction:
Adverse reactions were noted in 14 of the 161 cases where the safety was evaluated (8.7%). These reactions included diarrhea in 11, vomitting in 2 and exanthema in 1. Abnormalities in laboratory test values were observed in 25 of the 152 cases (16.4%). They included eosinophilia in 14, elevated GOT in 4 and thrombocytosis in 3 etc. They were reversible and not serious.
5. Bacteriological efficacy: 67 strains were isolated from the 60 cases for whom causative pathogens were identified. Of 59 strains against which bacteriological efficacies of the drug were evaluated, 55 were eradicated. CTRX was proved to have a wide antibacterial spectrum.
It is recommended that CTRX would be administered at 20mg/kg once a day for neonates and premature infants with ages of 0-3 days and twice a day for those 4 days old or older.

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Ceftriaxone (CTRX), an injectable cephem antibiotic agent, was studied for its pharmacokinetic properties and clinical usefulness in perinatal infections in obstetrics and gynecology on a multicenter basis. The study results are summarized below.
1. Following the one-shot intravenous injection of CTRX 1g to pregnant women before labor, the maternal serum level of CTRX reached a peak at 131.8μg/ml soon after the injection then it began to decrease gradually. T1/2 was 6.7 hours. The umbilical serum level reached a peak at 16.0μg/ml at 4.9 hours post-dose and decreased gradually with a half-life of 8.1 hours. The umbilical serum level was higher than the maternal serum level at about 12 hours post-dose. The amniotic fluid level reached a peak of 9.6μg/ml at 12.8 hours post-dose. T1/2 was 15.2 hours. The amniotic fluid level at about 15 hours post-dose or later exceeded the maternal serum level and was almost equal to the umbilical serum level at 24 hours post-dose.
2. Clinical usefulness was evaluated in 79 evaluable cases out of 89 treated for various infections at puerperium or for prophylaxis of infections at cesarean section or premature rupture of membranes (PROM). The efficacy rate was 100% in 7 cases of prenatal infections such as urinary tract infection and 30 cases of postnatal infections such as puerperal intrauterine infections. In 42 cases treated for prophylaxis in cases of cesarean section or PROM, the efficacy rate was 92.9%. Bacteriologically, 29 strains of pathogens were isolated from 26 cases. The disappearance rate of the pathogens was 96.0% as 23 strains were eradicated, 1 strain was substituted and no change was observed in 1 strain with unknown results in 4 strain. Skin rash and itching appeared in 1 patient as an adverse effect (1.1%). There were 10 cases of abnormal clinical laboratory test results such as elevated transaminase level were observed in 7 patients (7.9%).
From the results, CTRX was considered to be a useful drug for the perinatal infection in the obstetrics and gynecology fields.

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Subjects in a cefotaxime (CTX) single administration group and in a CTX+fosfomycin (FOM) administration group were randomly selected for a comparative study on the utility of each product against respiratory tract infections.
Overall improvement rates were 81.3% in 32 cases of the CTX single administration group, and 75.6% in 41 cases of the CTX+FOM concomitant administration group. No statistical difference was observed.
As for adverse reactions and abnormal laboratory test results, pyrexia, thrombocytopenia, increases in GOT and GPT, and increase in GPT were observed in 4 cases of the CTX single administration group, while angialgia, increases in GOT and GPT (3 cases), and increases in BUN,(totalling 5), were observed in the CTX+FOM group. However, all the symptoms were transient, and none was serious in nature.

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Seventeen patients with various grades of kidney function were injected each with cefsulodin (CFS) 1 g dissolved in 20 ml of saline. Serum and urine concentrations of CFS were determined using high performance liquid chromatography up to 24 hours after administration. Pharmacokinetic analysis was done using a two-compartment model. The results were discussed by comparing creatinine clearance (Ccr) values divided into 4 groups: ≥70ml/min (group I), 50-≥70ml/min (group II), 30-≥50ml/min (group III), and ≥30ml/min (group IV).
A delay in the disappearance of CFS from the blood was observed with a decrease in Ccr. Half-lives of CFS in blood (T 1/28) were 1.03 hours (group I), 2.09 hours (group II), 3.44 hours (group III), and 4.52 hours (group IV). Serum clearance (Cl_s) and Ccr were found to be related with an equation: Cl_s=1.60×Ccr+7.70. The correlation coefficient (r) was 0.881.
Ccr and T 1/2β were found to be related with an equation: T 1/2β=31.27×Ccr^-0.888, and the area under the curve (AUC) was found to be related to Ccr with AUC=4,226×Ccr^-0.81
Urinary excretion rates up to 24 hours after administration were 84.4% (group I), 69.1% (group II), 67.5% (group III), and 56.5% (group IV). This means that CFS is excreted in urine with a relatively high recovery even in the case of low Ccr ≥30 ml/min.

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Transfer of sulbactam/cefoperazone (SBT/CPZ) into the burn blister fluid was studied in 10 burn patients after one shot intravenous injection of 50mg/kg SBT/CPZ (CPZ 25mg/kg, SBT 25mg/kg). CPZ and SBT concentrations in serum and burn blister fluid were determined using bioassay and high performance liquid chromatography (HPLC).
The concentration of CPZ in serum reached 109.5±9.2 μg/ml (mean±S. E.) at 0.25 hour after injection, and decreased to 6.8±2.3 μg/ml after 8 hours. The concentration of CPZ in burn blister fluid peaked at 4 hours and reached 28.2±8.0 μg/ml. The concentration of SBT in serum reached 75.7±8.3 μg/ml at 0.25 hour after injection, and decreased to 2.3±0.7 μg/ml after 8 hours. The peak concentration of SBT in burn blister fluid was 13.5±1.8 μg/ml at 3 hours. The data obtained were analysed pharmacokinetically. C_max of CPZ and SBT levels in burn blister fluid were calculated to be 30.4 μg/ml and 13.6 μg/ml, respectively. The AUC^0-8hrs.(area under the burn blister fluid concentration of drug-time curve between 0 and 8 hours after injection), absorption rate constant (ka) and therapeutic AUC (AUC where drug concentrations were above minimum effective concentration) of CPZ were calculated to be 194.0 μg·hr/ml, 1.52 hr^-1 and 97.1 μg·hr/ml (0.3-11.1 hours), respectively. The AUC^0-8hrs·and ka of SBT were also calculated as 68.3 μg·hr/ml and 0.62 hr^-1, respectively. Comparing these values with previously reported results using 50 mg/kg CPZ alone, it may be concluded that SBT/CPZ has a much longer life in burn blister fluid than CPZ alone.
In addition, the concentrations of CPZ and SBT in serum and burn blister fluid obtained using the bioassay showed a good correlation with values obtained by HPLC.

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The effectiveness and safety of cefmenoxime (CMX) in the treatment of respiratory tract infections were evaluated, mainly in relation to the appearance of hemorrhagic tendency.
Out of 80 patients treated in this study, 57 were treated with CMX alone, and an effective rate was determined to be 75.4%. As for a tendency toward hemorrhage, none of the patients clinically exhibited a hemorrhagic tendency, while the prolongation of prothrombin time (PT) and/or activated partial thromboplastin time (APTT) was seen in 3 patients (3.8%), who were all at ages over 63. The prolongation of APTT was clearly related to CMX in 1 patient. Although the causal relation between CMX and the prolongation of PT or APTT was unclear in the remaining 2 patients because they had severe primary diseases (lung cancer and respiratory failure due to chronic obstructive lung disease in addition to severe hepatic disorder and received combination treatment with anticancer agents or other antibiotics), CMX might have a role in causing these phenomena.
Even though none of the patients showed a hemorrhagic tendency clinically arousing problems, we should be careful in using CMX in the treatment of the aged and patients in poor general conditions because PT and/or APTT was observed to prolong with the use of CMX in some patients.

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Biliary and urinary concentrations and recoveries of 3 different antibiotics (piperacillin (PIPC), cefbuperazone (CBPZ) and cefoperazone (CPZ)), after intravenous bolus injection were studied using the crossover method with external cholecystostomies done in order to treat obstructive jaundice due to complete obstruction of the lower biliary tract; the concentrations of antibiotics in bile and urine were determined by means of an high performance liquid chromatography method.
Drug concentrations and recoveries in the bile after intravenous injection of these antibiotics were at levels in the order of CPZ>CBPZ>PIPC. Since our patients were inflicted with various malignancies which made them impaired in terms of biliary excretion of antibiotics, the concentrations of those drugs in the bile were lower than those previously reported by several investigators. However, CBPZ and CPZ showed sufficient levels of excretion into the bile and their amounts were high enough when compared to the value of MIC 80% reported recently against Escherichia coli and Klebsiella pneumoniae, which are known to be main pathogens of biliary system infections. The excretion of CPZ into the bile was invariably found to be 2 times or more as high as the other 2 drugs tested.
Concentrations and recoveries of the 3 antibiotics excreted into urine were similar to the cefotaxime excretion, of which into urine had been reported to be excellent.
Thus, CBPZ and CPZ appeared to be effective against biliary system infections, even with blockage of antibiotics excretion into the bile.

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S 6472 granule prepartion, a sustained-release cefaclor, was orally administered to 20 acutely exacerbated cases of chronic bronchitis at a daily dosage of 750 mg (titer) in 2 divided doses for a duration of 7-15 days and its clinical usefulness was evaluated.
Clinical efficacies were good in 17 cases and fair in 3 cases, with a rate of efficacy of 85.0%.
Organisms isolated from 13 patients were totalling 14 strains, i.e., 5 strains of Streptococcus pneumoniae, 3 strains of Branhamella catarrhalis, 2 strains of Streptococcus sp., 2 strains of Klebsiella oxytoca, 1 strain of Haemophilus influenzae and 1 strain of Staphylococcus aureus.
All these strains, except the strains of Streptococcus sp., disappeared upon the administration of the durg.
With regard to the safety, no side effects nor abnormal laboratory test values were encountered.

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S 6472 granule preparation (sustained-release cefaclor) was orally administered to 15 patients with chronic respiratory tract infections (2 acutely exacerbated cases of chronic bronchitis, 13 cases of secondary infections consisting of 1 case of bronchial asthma, 2 cases of bronchial asthma/pulmonary emphysema, and 10 cases of bronchiectasis) at a daily dose of 750 mg devided into 2 doses administered after breakfast and dinner, for a duration of 14 days. The drug was ineffective in 3 of the 10 cases of bronchiectasis but was effective in the other 12 cases, with a rate of efficacy of 80%. There were no side effects or abnormal laboratory findings due to administration of this drug.

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Clinical evaluation of S 6472 (sustained release preparations of cefaclor), a granule form of cefaclor, was performed in 20 patients with chronic respiratory tract infections.
The patients subjected to the study consisted of 11 males and 9 females with ages between 44 and 76 years. S 6472 was given orally to each patient in a daily dose of 750 mg in 2 divided portions. The duration of administration was 3 days in 1 case, 7 days in 11 cases, 11 days in 3 cases and 14 days in 5 cases.
A total of 5 strains including 2 strains of Staphylococcus aureus, and 1 strain each of Staphylococcus epidermidis, Streptococcus pyogenes and Streptococcus pneumoniae were identified from sputum samples before the administration of the drug. All strains were eradicated but, instead 2 strains, 1 strain each of Enterobacter cloacae and Pseudomonas aeruginosa appeared after the therapy.
The clinical efficacy rate was 95.0% (19/20): Excellent in 5 cases, good in 14 cases and fair in 1 case.
No side effects were observed, but eosinophilia was observed in 1 case.
From the above results, it appeared that S 6472 was effective, safe and useful agent for the treatment of acute exacerbation of chronic respiratory tract infections.

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The S 6472 granule preparation (sustained-release cefaclor preparation) was administered to 15 cases of chronic bronchitis for its clinical evaluation; a daily dosage of 750 mg was orally given in 2 divided doses after breakfast and dinner for a duration of 7 to 22 days.
Clinical effects were good in 11 cases, fair in 1 case and poor in 3 cases. Among the 13 cases other than 2 unadaptable Pseudomonas infections, good effectiveness was found in 11 cases (efficacy rate: 84.6%).
There appeared to be no side effects or abnormal laboratory test values due to administration of this drug.

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S 6472 granule preparation, a sustained-release preparation of cefaclor, was administered to 21 patients with chronic respiratory airway infections for its clinical study; a daily dosage between 750 and 1,500mg was orally given in 2 divided doses after breakfast and dinner for a duration of 3 to 14 days.
Clinical effects were good in 15 cases, fair in 1 case, poor in 4 cases and unknown in 1 cases. No side effects were observed except for a case of impaired appetite. There appeared to be no abnormal laboratory test valued due to the drug.

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