Clinical trials are conducted to finally demonstrate the efficacy and safety of new agents in humans. The results of these trials a extremely important for evaluating new agents. Therefore, clinical trials. should be conducted based on an ethical consideration, and the results must be scientific and reliable. In October 1989, the Good Clinical Practice (GCP) was published as the standard for conducting clinical trials. GCP has been completely enforced since October 1990 (previous GCP). However, according to some investigators, the level of clinical trials in Japan has not yet reached that in the United States and Europe. To further improve the quality of clinical trials in Japan, the human rights of subjects should be protected, and safety and data reliability should be ensured. In May 1996, the final agreement among Japan, the United States, and Europe (ICH-GCP) was obtained at the International Conference on Harmonization (ICH). Enforcement of GCP in Japan at the international level was required. In March 1997, the new GCP was established. In April 1998, it was completely enforced. The new GCP was prepared to establish compliance matters with respect to planning, monitoring conducting surveillance, maintaining records, analyzing, and reporting clinical trials, which are conducted to collect materials for new drug application for manufacturing, and to ensure the scientific quality of clinical trials and data reliability, while protecting the human rights of subjects, safety and welfare. Concerning the influence of the new GCP on the development of antimicrobial agents, the interval after complete enforcement is still short, and future tendencies must be carefully examined. However, pharmaceutical companies and medical institutions are trying to make internal changes to meet the new GCP, and are developing an efficient operating method. In Japan, clinical trials of new drugs may be delayed in the near future. Furthermore, even if clinical trials are started, a prolonged period may be required for development compared to that previously needed. Such a delay in clinical trials will influence not only the development of new drugs but also promotion of clinical research on antimicrobial agents, thus preventing improvement in the national welfare. In the future, clinical trials at medical institutions should be adequately and smoothly conducted according to the new GCP, while resolving issues such as (1) internal changes for clinical trials, (2) increased responsibility and work for attending physicians, (3) difficult acquisition of informed consent (4) understanding and cooperation regarding inspection of materials, (5) education and utilization of clinical research coordinators, (6) importance of team medical practice, (7) enlightenment regarding enrollment in clinical trials, and (8) supply of advantages for subjects. In Japan, the environment surrounding clinical trials is extremely poor. Even antimicrobial agents are not exceptional. To resolve the current situation earlier, a motivation toward the development of antimicrobial agents should be improved in the Japan Society of Chemotherapy, and further efforts for the environmental arrangement should be made. In addition, we emphasize that all members of this society must aggressively promote a clinical research of antimicrobial agents according to the new GCP.

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The bactericidal activity of levofloxacin (LVFX) against major respiratory pathogens was compared by using two in-vitro pharmacodynamic (PD) models with dosing simulations of 100mg every 6h and 200mg every 10h for 24h. LVFX showed bactericidal activity against two strains of Streptococcus pneumoniae with MIC of 1 and 2μg/mL in the model of 200mg b. i. d. In contrast, LVFX showed bacteriostatic activity against S. pneumoniae with MIC 2μg/mL in the 100mg t.i.d. model. The regrown S. pneumoniae after 24 h incubation was also susceptible to LVFX. Against 2 strains of Haemophilus influenzae, LVFX showed bactericidal activity in both the PD models. The MICs of H. influenzae used were 0.008 and 0.03μg/mL. LVFX also showed bactericidal activity against LVFX-susceptible Moraxella catarrhalis (LVFX MIC: 0.03 %mu;g/mL), but bacteriostatic activity was observed against a strain of M. catarrhalis (LVFX MIC: 2μg/mL). The bacteria remaining at 24h after treatment with LVFX were also susceptible to the drug. From these PD data, it is suggested that the 20-25 SIT^-1·Eh of AUC/MIC of LVFX may be borderline for treating infections due to S. pneumoniae.

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We investigated the characteristics of 178 strains of Haemophilus influenzae clinically isolated between January 1996 and April 1998, with respect toβ-lactamase production, serotype, and antimicrobial susceptibility. Of these, 4.5% were type-b strains and 87.6% were not typeable. Overall, 13.5% of the isolates producedβ-lactamase. Of the 154β-lactamase-negative H. influenzae, 4 strains (2.6%) were resistant to ampicillin (β-lactamase-negative ampicillin-resistant; BLNAR). Two strains (8.3%) of the 24β-lactamase-positive H. influenzae were resistant to amoxicillin/clavulanate (β-lactamase-positive amoxicillin/clavulanate-resistant; BLPACR). The percentages of all tested isolates composed of BLNAR, and BLPACR strains were 2.2% and 1.1%, respectively. Overall, 3.9% of the isolates were resistant to ciprofloxacin and levofloxacin. The clinical courses of the patients infected with these resistant strains were good, and no treatment failure have been found.

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[Purpose] To determine the efficacy and toxicity of chemotherapy consisiting of cisplatin (CDDP) and protracted infusion of 5-fluorouracil (5-FU) and concurrent hyperfractionated radiation (RT) as preoperative therapy in patients strictly diagnosed as having locally advanced esophageal cancer.[Patients and Methods] Patients, who had been diagnosed with T 4 in the TNM classification with measurable lesions, were eligible for this study. CDDP was administered intravenously at a dose of 75 mg/m2/day over 2 hours on day 1, protracted intravenous infusion of 5-FU was performed at a dose of 300 mg/m2/day, followed by RT at a dose of 2 Gray/2 fractions/day for days 2-29. After four weeks of rest, total esophagectomy with three-field lymph node dissection was performed.[Results] Twenty patients were enrolled in this study. All were evaluable for response and toxicity, and operations were performed for all patients. One pathological CR (5%) and 8 PRs (40%), among the 20 patients, were obtained. The median disease-free interval and the median overall survival were 10.5 and 22.5 months, respectively. There was a statistically significant difference in the disease-free interval between the patients who had post-operative adjuvant therapy and those who did not (p=0.03). The major side effects were leukopenia, neutropenia, gastrointestinal toxicity and esophagitis. These toxicities were generally mild.[Conclusions] The response rate appears to be the same as those of other therapies reported previously for advanced esophageal cancer. Though the utility of adjuvant therapy has been questionable in the literature, our data suggest that not only pre-operative chemoradiotherapy but also the post-operative adjuvant therapy improve survival for patients with locally advanced esophageal cancer.

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We examined 1, 155 patients who underwent gastrointestinal surgery during 6 years, to ascertain the incidence and background factors of postoperative enterocolitis and MRSA enterocolitis. Postoperative patients who had more than 4 episodes of diarrhea per day with no evident cause for 2 or more consecutive days were diagnosed as having postoperative enterocolitis. MRSA enterocolitis was diagnosed when MRSA was isolated from the stool of the patients with postoperative enterocolitis. We experienced 57 postoperative enterocolitis cases, i.e. the incidences of postoperative enterocolitis were 4.9% of 1, 155 patients and 10.3% of 555 postoperative infections. MRSA were isolated from 28 (60.9%) out of 48 postoperative enterocolitis cases who underwent bacteriological examination. The incidence of MRSA enterocolitis was significantly higher in contaminated operations (P<0.01) and men (P<0.05). There was no significant difference in the incidence of MRSA enterocolitis according to the site of operation, age of patients, malignant versus benign of the disease, and with or without concomitant disease. Postoperative enterocolitis occurred frequently for 4-10 postoperative days, and there was no significant difference in the time of outbreak according to with or without isolation of MRSA. There was no significant difference in the incidence of postoperative enterocolitis and MRSA enterocolitis according to with or without administration of antibiotics preoperatively. The incidence of postoperative enterocolitis (P<0.05, P<0.001) and MRSA enterocolitis (P<0.01, P<0.001) in the patients who were administered oxacephems or third-generation cephems, and carbapenems after surgery were significantly higher than those in the patients who were administered first-or second-seneration cephems after surgery. The fact that the MRSA isolation rate from postoperative enterocolitis was rather high, is thought to be a serious problem not only for treatment of the disease but also for the prevention of hospital infection. It was suggested that the time of outbreak of diarrhea could not be a definitive factor for the diagnosis of MRSA enterocolitis. It was considered that preoperative administration of antibiotics did not affect the incidence of postoperative enterocolitis and MRSA enterocolitis. It was also considered that postoperative administration of oxacephems, third-generation cephems, or carbapenems might increase the incidence of postoperative enterocolitis and MRSA enterocolitis.

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Pazufloxacin (PZFX) mesilate, a newly developed injectable fluoroquinolone antibacterial agent, was clinically evaluated for the treatment of surgical infections and its tissue concentrations were measured. The following results were obtained. PZFX was intravenously administered at dose of 300mg or 500mg, 2 or 3 times daily for 3-14 days to patients with surgical infections. The clinical efficacy rates were 77.8%(21/27) for intra-abdominal infections, 88.2%(15/17) for biliary tract infections, 3/3 for liver abscesses, and 71.4%(15/21) for wound infbctions, and the overall efficacy rate was 79.4%(54/68), and therate 84.6%(11/13) for Pseudononas aeruginosa mixed infections was especially noteworthy. The clinical efficacy rates were 80.0%(40/50) for moderate infections and 77.8%(14/18) for severe infections. When severe infections or severe underlying diseases/complications were categorized in the severe disease group, the clinical efficacy rate was 76.0%(19/25) in the severe disease group, and it was 5/8 even for severe infections plus severe underlying diseases/complications. The clinical efficacy rate for infections with SIRS (systemic inflammatory response syndrome) at the start of this trial was 79.3%(23/29). The clinical efficacy rate in poor responders to other antimicrobial agents was 72.0%(18/25), and the rate of 75.0%(12/16) in poor responders to β-lactams (including carbapenems) was especially noteworthy. The bacteriological eradication rates were 64.0%(16/25) for Gram-positive bacteria, 78.9%(30/38) for Gram-negative bacteria and 79.3%(23/29) for anaerobic bacteria. The bacteriological eradication rate in P. aeruginosa infections was 72.7%(8/11). Adverse effects were observed in 3 cases: rash/itching, melena, and eruption. Abnormal laboratory data were observed in 14 cases (17.7%) and major findings were elevated serum transaminase levels, and a decreased leukocyte count was observed in 1 case. PZFX was intravenously administered at dose of 500mg to patients scheduled to undergo cholecystectomy. PZFX showed useful transfer, with tissue concentrations of 9.85-35.5 μg/g in the gallbladder tissue and 4.27-46.5μg/mL in gallbladder bile, compared to the corresponding serum concentrations of 3.69-19.0μg/mL. PZFX was intravenously administered at dose of 500mg to patients scheduled to undergo lung resection. PZFX yielded tissue concentrations of 3.49-12.7μg/g in the pulmonary tissues, 1.1-1.5 times higher than the corresponding serum concentrations of 3.20-9.40μg/mL. In postoperative patients, PZFX showed pus concentrations of 4.61, 4.84μg/mL, which was half the corresponding serum concentrations of 10.5, 8.12μg/mL. These results suggested that injectable PZFX is a useful antimicrobial agent for the treatment of surgical infections.

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