We experimentally investigated an effective method of antimicrobial chemotherapy utilizing a new form of oral fluoroquinolone, DU-6859a, for the treatment of moderately cases of complicated urinary tract infection (UTI) without an indwelling a catheter. Prior to the clinical investigation, an in vitro investigation was performed using an experimental model of moderately complicated UTI. This computer-controlled model can simulate fluctuations in the urinary concentration of antimicrobials. As a result of the in vitro investigation, we decided upon a regimen of DU-6859a. Afterwards, a clinical investigation utilizing this regimen was performed, and the results were then compared. The following results were obtained.
1) We examined the MIC₇₀ of DU-6859a with bacteria isolated from non-catheterized complicated UTI patients. The MIC₇₀ was 0.5 μg/ml. According to our previous reports, this regimen, in which the breakpoint MIC is higher than the MIC₇₀ of causative bacteria, is effective for clinical treatment.
2) The breakpoint MIC of the regimen, 50 mg DU-6859a twice per day, was measured using our experimental model. Pseudomonas aeruginosa strains, whose MICs were lower than 2 μg/ml, and Enterococcus faecalis strains, whose MICs were lower than 2 μg/ml, were eradicated utilizing this regimen. Thus, the breakpoint MIC of this regimen was 2 μg/ml, having a higher value than the MIC₇₀ described above. These results suggest that this regimen is effective for clinical treatment.
3) A clinical investigation was also performed utilizing a regimen of 50 mg DU-6859a twice per day. The eradication rate was 85.4%(41/48), and the efficacy rate was 85.4%(41/48). These results suggest that this regimen of DU-6859a, as determined by our experimental model, is effective for clinical treatment.
Utilizing our experimental model makes it possible to determine the most effective regimen for the treatment of moderately complicated UTI prior to clinical treatment.

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We examined the bactericidal activity of arbekacin (ABK) against methicillin resistant Staphylococcus aureus (MRSA) in conparison with that of vancomycin (VCM). Against MRSA JM 1010 and JM 1011, isolated clinical materials, ABK showed good bactericidal activity in a does dependent manner, while VCM showed time dependent activity. Over 6 hours, however we observed a marked tendency for re-growth of MRSA after ABK treatment. We also examined synergistic activities of a combination of ABK and imipenem (IPM) against MRSA, With treatment utilizing both drugs, we observed good synergistic effects producing strong bactericidal activity and inhibition of there-growth phenomenon as compared with ABK alone. We therefore recomended combination therapy with ABK and IPM for patients with MRSA infections.

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Basal levels of cytosolic calcium ([Ca²⁺] i), phagocytic activity and chemotaxis in erythromycin (EM) or clarithromycin (CAM) pretreated human polymorphonuclear leukocytes (PMNLs) were investigated in vitro. EM and CAM both lowered the basal levels of [Ca²⁺] i, enhanced the phagocytosis of Escherichia coli and fMLP-stimulated chemotaxis of PMNLs at therapeutically achievable concentrations (0.04-0.2μg/ml). At the relatively higher concentration, however, EM and CAM only slightly reduced the [Ca²⁺] i levels of PMNLs. At this concentration (1.0μg/ml), CAM had less enhanced effects on phagocytosis and chemotaxis of PMNLs while EM activated phagocytosis and chemotaxis in a concentration-dependent manner. These findings suggest that EM and CAM can reduce [Ca²⁺] i and enhance PMNL functions by activating calcium pumps and controlling intracellular Ca²⁺ stores. They also imply that macrolides may improve the impaired PMNL functions of patients with elevated [Ca²⁺] i levels in PMNLs due to calcium-exchanging abnormalities.

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In the early 1980's, methicillin-resistant Staphylococcus aureus (MRSA) was reported as a major pathogenic organism of geriatric hospital infection in Japan. At that time on our geriatric wards, including 190 beds, MRSA infection was prevalent. In the early 1980's minocycline was one of the antibiotics to which MRSA isolated from our wards were most sensitive and was thus frequently used against MRSA pneumonias and bacteremia. This was necessary because vancomycin was not allowed for the treatment of MRSA before 1991 in Japan. In the late 1980's MRSA strains resistant to minocycline increased rapidly. To decrease minocycline-resistant strains of MRSA, since 1987, the use of minocycline has been limited. Moreover, since Oct. 1991, to decrease nosocomial infections some active preventive measures instituted, including limited use of 2nd and 3rd cephems, have been. In this study, 22 antimicrobial agents' MICs for 313 strains of Staphylococcus aureus isolated between March 1992 and June 1993 were determined and compared with the MIC data before the introduction of preventive measures. Patterns of susceptibility remained largely unchanged, including susceptibility to vancomycin. Most strains were susceptible to rifampicin, arbekacin and sulfamethoxazole-trimethoprim, during the study period, the only exception being the MIC for minocycline. The MICs for strains sensitive to minocycline were observed again on our geriatric wards. Indeed, the restoration of sensitivity took approximately 5 years after the limitation on the use of minocycline was imposed in 1987.

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Several recent reports on the decreased susceptibility of Streptococcus pneumoniae and Haemophilus influenzae to some antibiotics have called attention to clinical failures caused by resistant organisms in patients with meningitis. Though it is necessary to obtain high concentrations of antibiotics in cerebrospinal fluid (CSF) to kill causative bacteria, the determinations of both MIC and antibiotic levels in CSF are not always possible in many hospitals in Japan. This study was designed to clarify the clinical significance of CSF back-titrations determined in patients with bacterial meningitis, instead of measuring the MIC of causative bacteria and antibiotic levels in CSF. Bacteriostatic back-titers in CSF against each strain causing meningitis were determined by a microtiter technique, in which serial two-fold dilutions of CSF in supplemented Mueller-Hinton broth were used. A bacteriostatic back-titer in CSF of ≥1: 8 was necessary to achieve a clinical effect. The combination in clinical cases utilizing either ampicillin and cefotaxime or ampicillin and latamoxef did not reveal higher CSF back-titers than cefotaxime alone. Determination of CSF back-titers is a useful examination method for evaluating the efficacy of antibiotics in the treatment of bacterial meningitis.

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