Reforms are ongoing in industry, government and medical society reflecting socioeconomic issues including aging, increasing numbers of patients, increasing medical expenditures, low economic growth, and increased disclosure of information. Standardization in Japan was not well accepted originally compared to western countries, but the establishment of new standards and acceptance are ongoing to cope with issues by maintaining consistency with other countries based on evidence. Evidence-based “Clinical Guidelines” for release to physicians and personnel in development would lead to better standards of medical practice, significantly increased knowledge of patients, and increased opportunities for patients to propose desired treatment to physicians by presenting some evidence that the physicians would not simply refuse. The need for informed-consent would be much more critical for both physicians and patients for sharing goal and risk of treatment, resulting in better outcome. “Clinical Guidelines” would eventually lead medical practices to “Regression to The Standard”.

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Therapeutic activities of several β-lactam antibiotics against murine pneumonia caused by penicillin susceptible, intermediate, and resistant strains of Streptococcus pneumoniae were examined using a murine simulation model reproducinghuman plasma concentrations. Orally active cephalosporins cefdinir (CFDN), cefcapene-pivoxil (CFPN-PI), and cefditoren-pivoxil (CDTR-PI) had potent therapeutic activity against murine pneumonia caused by penicillin-susceptible S. pneumoniae. However, these 3 orally active cephalosporins did not have enough efficacy against murine pneumonia caused by penicillin intermediate S. pneumoniae and did not have efficacy against that caused by penicillin-resistant S. pneumoniae, eventhough CFPN-PI and CDTR-PI had superior MICs against these strains compared to CFDN. Against murine pneumonia caused by penicillin-intermediate and penicillin-resistant S. pneumoniae, injectable agents panipenem/betamipron (PAPM/BP) and cefoselis (CFSL) had potent therapeutic activity with marked reduction of residualpathogen in lung tissue. Time above MIC (TAM) of the 3 orally active cephalosporins against PSSP was over 9 hours. In PISP and PRSP, CFPN-PI and CDTR-PI displayed TAM of 2 to 5 hours whilst CFDN did not show TAM. In contrast, PAPM/BP and CFSLshowed TAM of over 9 hours against all types of S. pneumoniae. These results suggest that β-lactam antibiotics with a TAM of over 9 hours have potent efficacy and a good reduction of residual pathogen in lungs, based on the relationshipbetween plasma concentration of β-lactam antibiotics and MIC, and is notdependent on the route of administration of β-lactam antibiotics. These antibiotics with enough TAM may have good potency in a clinical setting.

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We evaluated the usefulness of levofloxacin (LVFX) in respiratory tract infections. The pharmacodynamics of LVFX for Pneumococcus, one of the major causes of community-acquired pneumonia, were analyzed using a mouse model. We also studied the clinical usefulness of LVFX (200 mg twice daily) in patients with respiratoryinfections.
1) Pharmacodynamic study: Pharmacodynamics were analyzedin a mouse model of Streptococcus pneumoniae sepsis. We used penicillin-resistant S. pneumoniae and penicillin-susceptible S. pneumoniae. Agood correlation was observed between AUIC (AUC/MIC) and therapeutic effect withthe AUIC for 50% survival being about 20 in both strains. Based on these results, we estimated the usefulness of LVFX (100mg three times daily or 200 mg twicedaily) and compared the 2 doses. We found that 200mg twice daily would be clinically effective for the pathogen but that 100 mg 3 times daily did not have an adequate effect (MIC=2μg/mL).
2) Clinical study: An oral dose of 200 mgof LVFX twice daily was administered to 24 patients with respiratory infectionsfor 5-12 days. In one patient, the dose was decreased to once daily from day 2 ofadministration due to abdominal pain and 1 patient was withdrawn on day 5 dueto vomiting. Treatment withLVFX at 200 mg twice daily was considered clinicallyeffective in all 24 patients, including the above 2.

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The excellent combined effects of fosfomycin (FOM) and sulbactam/cefoperazone (SBT/CPZ) in vitro have been reported. We evaluated the clinical utility of this combined therapy for patients with moderate pneumonia with underlying disease. A comparative study was made between single drug therapy (single group) using SBT/CPZ and the combined drug therapy (combined group) using FOM+SBT/CPZ. Evaluable patients were 17 cases in the single group and 18 in the combined group. Clinical efficacy was 88.2% in the single group and 94.4% in the combined group, with no statistically significant differences between groups. In safety, an adverse reaction was observed in 1 case in the combined group, and abnormal evaluation of laboratory findings observed in 11.8% in the single group and in 27.8% in the combined group. Clinical utility was lower (83.3%) in the combined group than that (88.2%) in the single group. These results suggest that combined therapy of FOM and SBT/CPZ showed excellent clinical efficacy for moderate pneumonia in patients with underlying disease but involved problems of safety, requiring careful follow-up.

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We studied the optimal clinical dose of pazufloxacin mesilate, a new quinolone antibiotic for injection, in respiratory tract infection and complicated urinary tract infection based on clinical results in open and dose-finding studies.
1) Respiratory tract infection
In an open study, clinical efficacy was 75.4%(172/228). Efficacy in the 600mg a day group was 75.4 %(49/65) and 74.4%(116/156) in the 1, 000mg a day group. In a dose-finding study on bacterial pneumonia, clinical efficacy was 100%(32/32) in the 600mg a day group and 92.6%(25/27) in the 1, 000 mg a day group, with no significant difference between groups. The incidence of adverse effects was 2.6%(2/77) in the 600mg group and 5.1%(9/175) in the 1, 000mg group in an open study and 0%(0/35) in the 600mg group and 3.0%(1/33) in the 1, 000mg group in a dose-finding study. The incidence of abnormal change in laboratory findings was 17.4%(12/69) in the 600mg group and 12.4%(20/161) in the 1, 000mg group in an open study and 14.7%(5/34) in the 600mg group and 24.1%(7/29) in the 1, 000 mg group in a dose-finding study. The major abnormalities were transaminase elevation and eosinophilia. In the 1, 000mg a day group, moderate to severe cases with underlying disease or complications were treated effectively, with no severe adverse effects observed. From these results, we concluded that a daily dose of 1, 000mg was the optimal clinical dose for pazufloxacin mesilate in respiratory tract infection.
2) Complicated urinary tract infection
In an open study, overall clinical efficacy was 78.7%(118/150). Efficacy in the 600mg a day group was 81.6%(40/49) and 77.0%(77/100) in the 1, 000mg a day group. In a dose-finding study on complicated urinary tract infection, overall clinical efficacy was 86.7%(26/30) in the 600mg group and 78.8%(26/33) in the 1, 000mg group, with no significant difference between groups. The incidence of adverse effects was 1/1 in the 300mg a day group and 0.8%(1/123) in the 1, 000mg group in an open study and 2.8%(1/36) in the 600mg group and 0%(0/38) in the 1, 000mg group in a dose-finding study. The incidence of abnormal change in laboratory findings was 6.3%(3/48) in the 600mg group and 8.8%(10/113) in the 1, 000mg group in an open study and 14.3%(5/35) in the 600mg group and 16.2%(6/37) in the 1, 000 mg group in a dose-finding study. The major abnormalities were transaminase elevation and eosinophilia. The bacteriological response, especially eradication against resistant strains, was better in the 1, 000mg group than in the 600mg group in a dose-finding study, and no severe adverse effects were observed in the 1, 000mg group. From these results, we concluded that a daily dose of 1, 000mg was the optimal clinical dose for pazufloxacin mesilate in complicated urinary tract infection.

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Quinolones have potent convulsant activity and that the activity is enhanced by the concurrent administration of anti-inflammatory drugs. We studied the effect of antiinflammatory drugs on the convulsant activity of norfloxacin (NFLX) and gatifloxacin (GFLX) to classify antiinflammatory drugs based on drug interaction with quinolones. Intraventricular injection of NFLX induced convulsions dosedependently in mice. The convulsant activity of NFLX was markedly enhanced by coadministration with biphenylacetic acid and flurbiprofen. Indomethacin and ketoprofen had intermediate enhancing activity, and loxiprofen and (-)-naproxen had weak activity. Mefenamic acid, sodium diclofenac, ibuprofen, tenoxicam, naproxen, aspirin and acetaminophen did not affect the activity. Intraventricular injection of GFLX induced convulsions dose-dependently in mice with weaker convulsant activity than NFLX. The convulsant activity of GFLX was weakly enhanced by coadministration of biphenylacetic acid. Other antiinflammatory drugs examined in this study did not affect the activity of GFLX. These results suggest that individual antiinflammatory drugs have different effects on drug interaction with quinolones.

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