Pseudomonas aeruginosa-infected septic mice were experimentally treated with imipenem (IPM) and ceftazidime (CAZ), and differences in the pattern of antibiotic-induced endotoxemia. The inhibition of PBP 2 in the gram-negative bachilli results in the formation of spherical cells, whereas that of PBP 3 leads to the formation of filaments. Based on these findings, many in vitro investigations on antibiotic-induced endotoxin release using IPM and other beta-lactams have been reported In those studies it was reported that the amount of endotoxin released from IPM-treated bacteria was less than that from bacteria treated with other beta-lactams, because of an increase in cell volume in the former cause. However in vivo results were in contrast to those predicted by the previous in vitro studies, as after treatment, significant elevation of peripheral blood endotoxin was noted in IPM-treated mice (p<0.05). Our succeeding in vitro study clarified that at a small inoculum size, there was no difference between the two agents in endotoxin released. Nor was there any significant difference in morphological change or bactericidal activity. Whereas IPM had strong bactericidal effects even at a large inoculum size (10⁷CFU/ml), but CAZ failed to show increased bacterial killing with increases in inoculum size. The rapid killing activity of IPM caused a high velocity release of endotoxin (p<0.05). And in vivo, endotoxin is continuously scavenged and removed from peripheral blood. Therfore this strong bactericidal activity of IPM, independent of inoculum size, was responsible for the transient elevation of endotoxin level in the peripheral blood of septic mice infected with a large inoculum size and treated with IPM. This study suggests that to evaluate antibiotic-induced endotoxemia, the velocity of endotoxin released should be considered an essential index.

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The relative phototoxicity of ten antibacterial drugs in the quinolone group was determined by an in vitro assay, in which reduction of neutral red uptake was used as a marker of cell injury. Human embryonal lung fibroblasts or Vero cells derived from a green monkey kidney were incubated with potential phototoxins. The cell cultures were irradiated with long wave-length UV, and the capacity for neutral red uptake was determined. The phototoxicity of ten quinolones was much lower than that of doxycycline, a known photosensitizer. Among them, enoxacin, lomefloxacin, ciprofloxacin, ofloxacin, and nalidixic acid demonstrated higher phototoxicity, suggesting a good correlation with the clinical occurrence of photosensitivity. Norfloxacin, balofloxacin (Q-35), AM-1155, and T-3761 had less potent phototoxicity. This methodology may provide a useful rapid method to quantitate the phototoxic potential of newly developed drugs.

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To carify the bronchoalveolar transfer of ciprofloxacin (CPFX), bronchoalveolarlavage (BAL) was carried out in 26 patients with various respiratory diseases 120minutes after asingle oral administration of 200mg of CPFX in group I and with 200mg of onoxacin (OFLX) ingroup II. Findings were compared with our previous results on cefmenoxime (CMX), astromicin (ASTM), aztreonam (AZT) and aspoxicillin (ASPC).
1. The concentration of CPFX was O.03±0.02μg/ml in BALF and 0.84±0.54μg/ml in serum in group I, while the corresponding concentrations in group II were 0.03±0.02μg/ml and 0.80±0.63μg/ml.No significant difference was found in the concentration of CPFX between groups I and II, and there were no druginteractions with OFLX, either.
2.No statistically significant differences in the concentration of CPFX were observed among diseases.
3.Considering the dose and route of administration of CPFX, bronchoalveolar transfer of CPFX was inferior to that of CMX, ASTM, OFLX, AZT and ASPC.

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We investigated the in vivo kinetics of cefteram pivoxil, an oral prodrug cephem antibiotic preparation, in elderly subject. Five elderly subjects (65-87years of age, average age of 78.2, two males and three females) with no apparent hepatic or renal dysfunction were administered 100mg oral doses of cefteram under fasting conditions, and changes in cefteram concentration in blood and urine were determined by bioassay. Peak values were obtained 1-3hours after the administration, with concentrations ranging from 0.72 to 1.9μg/ml. In one subject, cefteram first appeared in the blood two hours after administration, but we believe this was due to a delay in transport within the gastro-intestinal tract. The recovery rate from urine up to 24hours after administration was 13.7%. The drug's half-life in blood was 1.4hours, and its AUC was 5.18μg·h/ml. The blood concentration values in the elderly subjects were the same as the reported values from a group of young volunteers for up to two hours after administration, but higher concentrations were observed in the elderly subjects thereafter. We believe that delays in absorption and excretion after administration of the drug work to cancel each other out, resulting in similar changes in blood concentration until the peak value is attained, but thereafter the effects of delayed excretion become evident. We also believe that the effect in the elderly is smaller than in younger volunteers because activation of the prodrug by esterases in the intestine is delayed. Based on these results, we believe that patients as old as 80 years old may be administered the drug twice a day, as long as normal doses are used.

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Fundamental and clinical studies were performed by the YP-14 study group to evaluate the efficacy of the combination (1: 4) of tazobactam (TAZ), an inhibitor of β-lactamase, and piperacillin (PIPC), in the treatment of patients with obstetric and gynecologicinfections. The present studies were carried out at 36 medical institutes from 1992 to 1994, and the following results were obtained.
1. Clinical efficacy was evaluated in 129 patients out of a total of 151 patients with obstetric and gynecologic infections. The efficacy rate was 91.5%. Efficacy rate classified by type of infection was 94.9% for intrauterine infections, 82.1% for adnexitis, 90.0% for intrapelvic infections, and 100% for infection of the external genital organs and other infections.
2. The efficacy rate for patients who suffered from infections resistant to other drugs or from reinfections was 93.8%.
3. Of 149 organisms isolated from patients with obstetric and gynecologic infections, 40.9% were β-lactamase producing organisms. The isolated rate of β-lactamase producing organisms in aerobic gram-negative bacteria was 94.9%. The antibacterial efficacy of (TAZ/PIPC) was equal or superior to that of PIPC against clinical isolates.
4. The efficacy rate was 91.7% for monomicrobial infections and 97.8% for polymicrobial infections. The efficacy rate for infections caused by β-lactamase producingorganisms was equal to that for infections by, β-lactamase non-producing organisms.
5. The eradicated rate of clinical isolates was 92.6%. This rate was equal tothat of plactamase producing organisms.
6. Side effects were observed in 8 of the 151 patients, mainly diarrhea and eruption.
7. Abnormal laboratory findings, mainly being noted as transient elevation ofserum transaminase and increase in eosinophils, were observed in 9 of the 136 patients.
From these results, TAZ/PIPC was considered to be efficacious for the treatment of infections in the fields of obstetrics and gynecology.

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