Using direct parenchymal infection and the ascending infection model of rat, prophylaxis of renal scar formation following bacterial pyelonephritis was investigated. Mannose-sensitive (MS) piliated bacteria strongly stimulated renal scarring, but not afimbriated or mannoseresistant (MR) piliated bacteria. In neutropenic rats injected with cyclophosphamide 2 days before bacterial inoculation, renal scarring was significantly reduced. Treatment with prednisolone and ulinastatin significantly suppressed renal scarring at doses of 1 to 2mg/kg and 1, 000 to 4, 000 unit/kg, respectively. At 6 hours after the bacterial inoculation, administration of ciprofloxacin (CPFX) completely suppressed renal scarring, but not at 72 hours. When CPFX was administered at 72 hours after the bacterial inoculation, combined treatment with prednisolone significantly suppressed renal scarring. These results suggested that MS-piliated bacteria promoted renal scar formation by the stimulation of the inflammatory process and that the early initiation of treatment by antimicrobial agents was important to prevent scarring. When the initiation of antimicrobials was delayed, combined treatment with optimal doses of anti-inflammatory agents was effective in preventing renal scar formation.

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The production of reactive oxygen species by whole blood and polymorphonuclear leukocytes (PMNs) in the peripheral blood of 20 patients with gram-negative septicemia was studied by using the method of luminol-dependent chemiluminescence (CL) stimulated with non-opsonized zymosan or phorbol myristate acetate (PMA). The CL responses of 10-fold diluted whole blood and PMNs in these patients were significantly increased when compared with those of healthy persons. The number of granulocytes in the blood of patients was increased in many cases. To clarify the reason why the CL response of phagocytes in septic patients is augumented, I studied the priming effect of inflammatory cytokines including tumor necrosis factor -α, (TNF-α), interleukin-1β(IL-1β), IL-6 and lipopolysaccharide (LPS: endotoxin) on the CL response of normal human phagocytes. These cytokines and LPS are often detectable in the serum of patients with severe gram-negative sepsis. Whole blood and PMNs were incubated for 10 or 60 min at 37°C with various concentrations of each cytokine or LPS, and the integrated CL response induced by zymosan or PMA was measured for 20 min, permitting comparisons of the effects of cytokines or LPS. Preincubation with TNF-α or LPS resulted in an increase in the CL response of PMNs at concentrations of more than 1 U/ml and 100 ng/ml, respectively. Similar results were obtained in diluted whole blood samples. However, no significant priming effect was observed when PMNs were incubated for 10 and 60 min with various concentrations (1-100 ng/ml) of IL-1β or IL-6. The priming effect of TNF-α was significantly prevented when TNF-α was preincubated with a murine anti-TNF-α monoclonal antibody (TNF-α MAb) or a TNF-binding protein-II (TNF-BPII) for 10 min at 37°C prior to the exposure to whole blood sample. These inhibitory effects were dose-dependent. The present study showed that TNF-α MAb and TNF-BP II have the ability to prevent the enhanced CL response in human whole blood samples primed with TNF-α. These findings may be useful for supportive therapy in patients with gram-negative septicemia and septic shock, especially in cases involving serious PMN-mediated organ damage caused by excessive release of toxic products such as reactive oxygen species.

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We investigated the sensitivity of 40 strains of Streptococcus pneumoniae, which were isolated from clinical materials in Japan from 1982 to 1990, to various oral antimicrobial agents. There were 5 benzylpenicillin (PCG)-insensitive strains and no PCG-resistant strains. The MIC₈₀s of cefteram and amoxicillin against the PCG-sensitive strains (35 strains) were the best and were followed by cefroxime, cefpodoxime>cefdinir>cefotiam>tosufloxacin, cefixime>sparfloxacin>levofloxacin, cefaclor>ciprofloxacin, ofloxacin, cephalexin>ceftibuten, minocycline>josamycin, erythromycin and clarithromycin. The MICs of amoxicillin, cefteram, cefroxime, cefpodoxime, cefdinir, cefotiam and tosufloxacin against PCG-insensitive strains (5 strains) were superior to those of other agents. Correlations between MICs of various β-lactams revealed that some strains became insensitive especially to cephems having an oxyimino or a 2-carboxyethylidene group on the 7-acyl side-chain.

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The bactericidal activity of fleroxacin against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa was determined using an in vitro pharmacokinetic model. Viable cell counts of S. aureus, E. coli and P. aeruginosa decreased to undetectable levels in the model of a 300 mg once-daily oral dose, and regrowth was not observed until 24 h except for P. aeruginosa. The activity against P. aeruginosa in the model of a twice-daily dose (at a 12 h interval) was equal to that of the once-daily dose. The effect of pharmacokinetic parameters such as peak level and elimination half-life on bacterial kill kinetics was also studied in this model. The extent of bactericidal activity and length of the bacteriostatic period was dependent on peak level and time above MIC, respectively.

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The in vitro combined effect of clindamycin (CLDM) and imipenem (IPM) was studied in 15 strains resistant to both drugs among 28 clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) strains. By means of the checkerboard agar dilution method, the fractional inhibitory concentration (FIC) index of this combination was 0.5 or less in 9 of 15 strains at 37°C, and in all of 15 strains at 32°C. Further, in the time-killing curve studies, this combination showed a synergistic effect against the no.14 strain obtained a minimal FIC index (0.16). These results suggest that the combination of CLDM and IPM produced a synergistic action against highly resistant MRSA strains.

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The antibiotic sensitivity and in vitro acquired drug resistance of methicillin-resistant Staphylococcus aureus (MRSA) isolated from infected decubitus of six patients to sulfamethoxazoletrimethoprim (ST), vancomycin (VCM), arbekacin (ABK) and minocycline (MINO) were investigated. ST was as active as VCM, ABK and MINO against the MRSA isolates. The above six strains acquired a moderate degree of drug resistance against ST. The level of drug resistance against ST was almost the same as that against VCM, ABK and MINO. However, no marked resistance occurred to these four agents. We applied an ointment (Elase^® ) containing 0.024% of ST everyday to six patients who had decubitus infected with MRSA. Open decubitus of six patients healed and closed within 34 days (mean) after initiation of this therapy, and the clinical effects were good in all cases. No drug resistance to ST of the MRSA isolated from six cases occurred during or after therapy. Transient photosensitivity was observed in one patient when a 0.048% ST ointment was used, but disappeard when it was replaced with a 0.024% ST ointment. From these results, we conclude that ST ointment therapy is useful for the treatment of decubitus infected with MRSA.

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To evaluate the clinical usefulness of SY 5555, a new oral penem, in the treatment of bacterial pneumonia, a double-blind comparative study, using cefotiam hexetil (CTM-HE) as the control drug, was conducted in various clinical institutes. The drugs were given at a daily dose of 900 mg of SY 5555 or 600 mg of CTM-HE, divided three times a day, for 14 days.
1. The clinical efficacy rates were 90.2%(83/92) for the SY 5555 group and 85.1%(86/101) for the CTM-HE group. The efficacy rates of the two drugs were not significantly different.
2. Bacteriologically, the eradication rates were 77.4%(24/31) for the SY 5555 group and 89.2%(33/37) for the CTM-HE group, showing no statisticaly significant difference between them.
3. Side effects were observed 8 of 111 patients in the SY 5555 group and 7 of 111 patients in the CTM-HE group. The main side effect was gastrointestinal symptoms in both groups.
4. The incidence of abnormal changes in laboratory findings was 19.6%(21/107) in the SY 5555 group and 16.8%(18/107) in the CTM-HE group.
5. The total usefulness rates were 88.3%(83/94) in the SY 5555 group and 81.4%(83/102) in the CTM-HE group. There was no significant difference between the two groups.
The above results showed that in terms of efficacy and safety the SY 5555 group was equal to the CTM-HE group. SY 5555 was concluded to be a useful drug for the treatment of bacterial pneumonia.

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Two different oral ofloxacin (OFLX) regimens, a biweekly multidose regimen with 3×200 mg/day (regimen A) and a daily single-dose regimen with 200 mg (regimen B), were compared to evaluate the efficacy of new quinolone regimens in controlling acute exacerbations of chronic respiratory tract infections. Fifty-seven patients consisting of 19 with bronchiectasis, 18 with chronic pulmonary emphysema, 10 with chronic bronchitis, 5 with old pulmonary tuberculosis, 4 with diffuse pan-bronchiolitis and one with multiple pulmonary bullae, were evaluated in this study: 26 in regimen A and 31 in regimen B. The corrected mean incidence of exacerbations per case during six months before and during the study was reduced from 2.66 to 0.95 in regimen A, and from 2.55 to 0.59 in regimen B, both statistically significant differences. As therapy of acute exacerbations during the study, injection therapy on admission was required in most cases of regimen A. On the other hand, simply increasing the ofloxacin dose given in the outpatient clinic managed to control acute exacerbations in most cases of regimen B. The development of resistant strains was not clinically important because only one of 12 strains of Pseudomonas aeruginosa that had been isolated continuously during the study acquired a certain degree of resistance to ofloxacin when tested by the sensitivity disk. Adverse reactions were found in 4 patients in regimen A and in 2 in regimen B, these were mainly sleep disturbance and dizziness. We conclude that the longterm administration of new quinolones, especially the daily single-dose regimen with 200mg of ofloxacin, is useful in controlling acute exacerbations of chronic repiratory tract infections.

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