To evaluate the pharmacokinetic and clinical effects of the newly developed combination antibiotic tazobactam/piperacillin (TAZ/PIPC, YP-14) on various infections in pediatric field, a study group was organized, and a joint research by 17 institutions and their related hospitals was conducted. Informed consents of subjects were obtained prior to the study. The results obtained in this study are as follows:
1. Blood concentration and urinary excretion
Pharmacokinetics of TAZ/PIPC was studied in children at doses of 25 and 50 mg/kg through intravenous injection or intravenous drip infusion. With intravenous injection, maximum blood concentrations (C_max's) of TAZ and PIPC were achieved 5 minutes after the administration. C_max's of TAZ were 26.9μg/ml with 25mg/kg and 45.1μg/ml with 50 mg/kg, and those of PIPC were 131.0 and 199.6μg/ml, respectively. Values of the total area under the blood concentration curve (AUC's) of TAZ were 14.2μg·hr/ml with 25 mg/kg and 26.1μg·hr/ml with 50 mg/kg, and those of PIPC were 64.0 and 112.8μg·hr/ml, respectively; thus dose dependency was observed with both TAZ and PIPC.
The C_max's of desethyl piperacillin (DEt-PIPC), the active metabolite of PIPC, achieved at 60 minutes after administration, were 1.2 and 2.0μg/ml, respectively. The AUC's of DEt-PIPC were 2.6 and 4.2μg·hr/ml, respectively.
The half-lives (T 1/2's) of TAZ were 0.60 and 0.54 hour, respectively, and those of PIPC were 0.62 and 0.65 hour, respectively.
In the first 6 hours after the initiation of administration, the cumulative recovery rates of TAZ in the urine were 46.7 and 56.0% respectively, those of PIPC were 46.1 and 57.2%, respectively, and those of DEt-PIPC were 5.9 and 3.0%, respectively.
With intravenous drip infusion, the C_max's of both TAZ and PIPC were achieved at the completion of drip; the C_max's of TAZ were 12.1μg/ml with 25 mg/kg and 28.9μg/ml with 50 mg/kg, and those of PIPC were 54.6 and 137.9μg/ml, respectively. The AUC's of TAZ were 11.6μg·hr/ml with 25 mg/kg and 25.6μg·hr/ml with 50mg/kg, and those of PIPC were 49.0 and 117.2μg·hr/ml, respectively; thus dose dependency was observed with both TAZ and PIPC. C_max's of DEt-PIPC, achieved at 60 minutes after completion of drip, were 0.9 and 1.7μg/ml, respectively. The AUC's of DEt-PIPC were 2.0 and 3.8μg·hr/ml, respectively.
The half-lives (T1/2's) of TAZ were 0.59 and 0.62 hour, respectively, and those of PIPC were 0.58 and 0.57 hour, respectively.
In the first 6 hours after the initiation of drip, the cumulative recovery rates of TAZ in the urine were 43.3 and 56.9%, respectively, those of PIPC were 39.9 and 56.4%, respectively, and those of DEt-PIPC were 2.1 and 2.3%, respectively.
Cerebrospinal fluid concentrations of TAZ, administrated at a dose of 70 to 108 mg/kg, to patients with purulent meningitis were 0.26 to 3.88μg/ml in 2 to 4 hours after administration, and those of PIPC were 0.29 to 3.89μg/ml.
2. Clinical results
Three-hundred cases were assessable for analysis of clinical effects after 32 cases of exclusion and drop-out were deduced from a total of 332 cases; however, the cumulative number of cases assessable for analysis was considered to be 302, because two cases that had two different diseases at the same time were counted twice in each category of disease.
In the cases where causative organisms were identified (group A), 177 of 178 cases were rated as good or excellent, hence the efficacy rate was 99.4%. In the cases where causative organisms were not identified (group B), 117 of 124 cases were rated as good or excellent, thus the efficacy rate was 94.4%.

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We carried out bacteriological and clinical studies on tazobactam/piperacillin (TAZ/PIPC), a combination drug of piperacillin with the new β-lactamase inhibitor tazobactam, in various infectious diseases in surgical field such as intra-abdominal infections (peritonitis and intra-abdominal abscess), hepatobiliary infections (cholecystitis, cholangitis and hepatic abscess) and secondary infections in wound, etc. The total number of cases treated with the combination drug was 164. Of these cases, 141 cases were assessable for clinical responses including 60 cases with intra-abdominal infections, 38 cases with hepatobiliary infections, and 43 cases with secondary infections. Clinical efficacy rates of the drug were 83.3% in cases with intra-abdominal infections, 86.8% in cases with hepatobiliary infections, and 95.3% in those with secondary infections, hence the overall efficacy rate was 87.9%. In the cases from which β-lactamase producing strains were isolated, clinical efficacy rates were 84.8% in cases with intra-abdominal infections, 84.6% in those with hepatobiliary infections, and 96.2% in those with secondary infections, hence the overall efficacy rate was 88.9%. Bacteriological efficacy rates were 92.9% in cases with Gram-positive bacterial infections, 64.3% in those with Gram-negative bacterial infections, and 100% in those with anaerobic bacterial infections. Bacteriological efficacy rates were 84.2% in cases with single bacterial infections and 56.5% in those with multi-bacterial infections, and the overall bacteriological efficacy rate was 69.0%. In the cases of infections with β-lactamase producing strains, bacteriological efficacy rates were 80.0% in cases with Gram-positive bacterial infections, 75.0% in those with Gram-negative bacterial infections, and 100% in those with anaerobic bacterial infections. They were 82.6% in cases with single bacterial infections and 57.9% in those with multi-bacterial infections; the overall bacteriological efficacy rate was 67.2%. The bacterial eradication rate was 79.9% against all the isolates, and it was 79.2% against β-lactamase producing isolates. In addition, we compared the sensitivity distribution of the isolates to TAZ/PIPC with those to control drugs piperacillin (PIPC), cefotiam (CTM), ceftazidime (CAZ), sulbactam/cefoperazone (SBT/CPZ). The MIC₅₀ and MIC₉₀ values of TAZ/PIPC against all strains were 3.13 aug/ml and 50μg/ml, respectively. MIC₅₀ values show that TAZ/PIPC was two times less effective than CAZ and SBT/CPZ but four times more effective than CTM; furthermore, from the MIC₉₀ values, TAZ/PIPC was four times more effective than PIPC, CTM and CAZ. The MIC₅₀ and MIC₉₀ values of TAZ/PIPC against β-lactamase producing strains were 3.13 tig/ml and 50μg/ml, respectively. MIC₅₀ values show that TAZ/PIPC was two times more effective than PIPC and four times than CTM, whereas the combination drug was two times less effective than SBT/CPZ and four times less effective than CAZ; from the MIC₉₀ values, TAZ/PIPC was two times less effective than SBT/CPZ but four times more effective than PIPC, CTM and CAZ. The adverse effects observed in this study was diarrhea in 1 (0.6%) of 162 cases. Abnormal laboratory test values, mainly due to the increased transaminase value, were also observed in 14 (9.2%) of 152 patients. These results suggest that this combination drug is effective and safe for treatment of infectious diseases in surgical field, including infection with β-lactamase producing strains.

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Following the oral administration of DU-6859a to six healthy male volunteers at 100 mg per dose three times a day for seven consecutive days, the degree of disturbances of fecal microflora and fecal drug concentrations were examined.
The total viable count decreased transiently during the administration due to changes in the number of members of the family Bacteroidaceae, the most predominant organisms. The other obligate anaerobes and most aerobes including facultative anaerobes were suppressed markedly by DU-6859a, with an exception of yeasts. Members of the family Enterobacteriaceae and most of anaerobic bacteria were reduced to below the detection limit in all subjects from the 3rd day of administration period to one day after the discontinuation of the drug. Clostridium thjficile was detected in one of the volunteers at the end of administration. Side effects, such as mild transient soft stool and mild transient diarrhoea, were observed in five and one volunteers, respectively. During the administration, DU-6859a was detected in feces at high concentrations which correlated well with the decrease of susceptible members of fecal flora as well as their detection rate.

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Vancomycin (VCM) was intravenously administered to rats for 14 days at doses of 150 mg/kg/day and 250 mg/kg/day alone or in combination with 1,000 mg/kg/day of latamoxef (LMOX), flomoxef (FMOX) or cefpirome (CPR) or 250 mg/kg/day of fosfomycin (FOM), and the influences of combined antibiotics on the VCM-induced renal damage were studied.
The renal impairment caused by VCM alone was, morphologically, demonstrated mainly as regeneration of tubular epithelium: slight regeneration was observed in a half of rats administered 150 mg/kg/day and slight to extensive regeneration in all the rats administered 250 mg/kg/day. Clinical examinations found apparent increases in urinary LDH and MDH activities in rats administered 250 mg/kg/day, thus showing a good correlation with renal pathological changes. In addition, increase in kidney weight and increase in urinary NAG activity were noted, while changes in plasma urea-N and creatinine were mild, and γ-GTP activity and protein in urine could not be used as a parameter of the renal impairment.
The slight renal impairment as noted in rats administered VCM 150 mg/kg/day alone was not observed at all when LMOX or FMOX was administered concomitantly, and less pronounced even when FOM was administered concomitantly. When CPR was administered concomitantly, the changes were the same as those observed with VCM alone. The renal impairment in rats administered VCM 250 mg/kg/day was apparently less severe when combined with LMOX, FMOX and FOM than that in rats administered VCM alone, and this was supported by apparent reduction of clinical examination values as the parameter of VCM-induced nephrotoxicity. In rats administered VCM with CPR, urinary LDH and MDH activities tended to decrease as compared with rats administered VCM alone, but modification of other parameters including renal morphological changes was not observed with concomitant use.
The above results suggest that the concomitant use of LMOX, FMOX or FOM with VCM could reduce the nephrotoxic effect of VCM. Also the concomitant use of CPR did not potentiate the nephrotoxicity of VCM.

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Minimum inhibitory concentrations (MIC) of new quinolones against both Gram-positive and Gram-negative bacteria obtained using agar-dilution and broth-microdilution procedures were compared. A primary regression curve and a correlation coefficient (r) between 2 MICs for each of ofloxacin, ciprofloxacin, tosufloxacin, sparfloxacin or balofloxacin were calculated. For the 5 quinolones, average correlation coefficients were 0.891 for the Gram-positive bacteria tested, and 0.865 for the Gram-negative bacteria. The range of, correlation coefficients for the Gram-positive bacteria for these drugs was from 0.835 to 0.919, and that for the Gram-negative bacteria was from 0.815 to 0.865. From these data, it is clear that there is a good correlation between the 2 MICs of the new quinolones obtained using the agar-dilution and the broth-microdilution procedures. It was also shown that the value of the slope of the regression curves were nearly the same for the 5 quinolones tested. However, some particular strains of Morganella morganii, Pseudomonas cepacia, Xanthomonas maltophilia, Pseudomonas aeruginosa and Streptococcus pneumoniae exhibited different correlation coefficients from other strains.

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[in Japanese]

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Synergistic enhancement of the in vitro antimicrobial activity of imipenem combined with cephalosporins against methicillin-resistant Staphylococcus aureus (MRSA) has been reported. In order to investigate which cephalosporin is more effective in enhancing the activity of imipenem against MRSA, the in vitroantimicrobial activities of imipenem, cefazolin, cephalothin, cefotiam, cefamandole and cefoperazone, alone and in combination, against methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA were assessed. Using the checkerboard Mueller-Hinton agar dilution method, strong synergy was found in 97% to 100% of MRSA strains for imipenem and all tested cephalosporins except cefoperazone; fractional inhibitory concentration (FIC) indices were ≤0.5. Among the cephalosporins studied, cefamandole most markedly in creased the activity of imipenem against MRSA, followed, in order of decreasing effect, by cefotiam, cephalothin, cefazolin, and cefoperazone. The synergistic effect of imipenem combined with cefamandole or cefotiam was confirmed using the broth dilution method with 2% of NaCl.

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This study was conducted to investigate susceptibilities of clinical isolates to different anti bacterial agents at 123 hospital laboratories throughout Japan from September to December of 1991. In this study, identifications and susceptibility testings were carried out at each hospital laboratory. The susceptibility testing were performed using the disk dilution method recommended by NCCLS.
Staphylococcus aureus and CNS showed high or moderate resistance rates to methicillin (DMPPC). Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, Proteus mirabilis were highly suspectible to many agents including β-lactam antibiotics. Though Enterococcus faecalis was highly susceptible to ampicillin (ABPC), piperacillin (PIPC), imipenem (IPM), sulfamethoxazole-trimethoprim (ST) compounds, Enterococcus faecium was resistant to almost all antibacterial agents but to ST compounds. High susceptibility rates were observed for strains of Enterobacter cloacae to IPM, gentamicin (GM) and ofloxacin (OFLX) and for strains of Proteus vulgaris to latamoxef (LMOX), IPM, aztreonam (AZT), GM and OFLX. Serratia marcescens and Bacteroides fragilis group were highly susceptible only to IPM. Pseudomonas aeruginosa were sensitive to ceftazidime (CAZ), IPM, amikacin (AMK) and tobramycin (TOB). Pseudomonas cepacia was relatively susceptible only to CAZ. IPM showed strong antibacterial activity to many species except for S. aureus and CNS.

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We examined β-lactamase productions by clinically isolated strains of bacteria. The results were as follows;
1. It appears that β-lactamases produced by strains of five species of Staphylococcus spp. are mostly penicillinase (90%). Souce of β-lactamase producing strains of Haemophilus influenzae (23%) and all of Moraxella subgenus Branhamella catarrhalis: strins (100%) are “High & Low producer” strains.
2. A large proportion of β-lactamase producing strains of Enterobacteriaceae and Bacteroides fragilis group appeared to be “High producer”
3. β-lactamase producing abilities are different among glucose non-fermentative Gram-negative rods.
It appears that some of the strains appeared to be “High producers”.

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After an intravenous drip infusion of 1g or 2g of ceftriaxone (CTRX), its concentrations in serum and tissue were determined using the bioassay for 18 surgical patients with chronic paranasal sinusitis.
1. The serum levels observed at 75-105, 135-165, 195-225 minutes after an intravenous drip infusion of 1g, averaged 98±38, 92±13 and 73±13μg/ml, respectively.
2. The tissue levels at 75-105, 135-165, 195-225 minutes after an intravenous drip infusion of 1 g, averaged 27±13, 27±7 and 25±9μg/g.
3. CTRX appears to be a useful drug for the treatment of chronic paranasal sinusitis.

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Ecological treatment of bacterial vaginosis with a Lactobacillus (yoghurt) was studied, and the following results were obtained.
1. A total of 11 women aged 20 to 60 with bacterial vaginosis were treated with intravaginal application of 5 ml of commercial yoghurt (pH 4.3±0.2). The effect of the treatment was evaluated 3 days after administration by monitoring the vaginal discharge and bacteriological assessment.
2. The clinical improvement was evaluated and the decreases of vaginal discharge and vaginal redness were significant and vaginal pH was lowered significantly also (P<0.05).
In the vaginal discharge 29 strains of bacteria were detected, but 3 days after administration, all 14 strains of Gram-negative bacteria disappeared. As for the overall bacteriological effects, 6/11 cases (54.5%) were eradicated. 3 cases were partly eradicated, 2 cases were replaced.
These findings indicated that the Lactobacillus therapy was effective in both clinical and bacteriological responses.

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All signals of ¹H-and ¹³C NMR spectra of oleandomycin and the esterolitic cleavage compound of oleandomycin, and all signals of ¹H-NMR spectra of oleandomycin 2'-phosphate were determined using two-dimensional methods as ¹H-¹H and ¹³C-¹H-COSY NMR, and DEPT NMR in D₂0 solution. The two modified products of oleandomycin were prepared by two strains of Escherichia coli highly resistant to erythromycin. These results are basically useful in determination of the structure of novel metabolites of oleandomycin inactivated by bacterial action.

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