Many antiarrhythmic drugs are known to prolong the QT interval and provoke torsades de pointes. Recently, an increasing number of non-cardiac drugs have also been reported to have the same effects. Torsades de pointes is a particular form of polymorphic ventricular tachycardia and can lead to sudden death. The development of torsades de pointes is associated with QT prolongation. Some drugs used to treat non-cardiac diseases (psychotropic agents, antihypertensives, antihistaminics, antifungals, antimicrobial agents, et al.) have electrophysiological effects. Recent attention has been directed to the quinolones. Despite the excellent safety of early quinolones (ciprofloxacin, ofloxacin, et al.) newer quinolones (sparfloxacin, moxifloxacin, grepafloxacin, et al.) can prolong the QT interval, potentially increasing the risk of torsades de pointes and sudden death. Consequently the following studies are essential to the investigation of new drugs:
(1) Structure-activity studies to associate a definite pharmacophore with an action on a specific ion channel.
(2) Standardization of procedures in preclinical in vitro and in vivo studies to screen for those molecules with the potential ability to prolong the QT interval.
(3) Carefully designed phase I-III studies for drugs that appear to have an effect on the QT interval in preclinical tests.

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The resistance of Helicobacter pylori to clarithromycin (CAM) is mainly due to adenine (A)-to-guanine (G) point mutations at the A 2142 or A 2143 of the 23S rRNA gene. In this study, CAM MICs for 302 clinical isolates of H.pylori were determined by agar dilution based on the guideline (M 100-S 10) established by the National Committee for Clinical Laboratory Standards (NCCLS). The relationship between the CAM breakpoint for H.pylori and the point mutation in the 23S rRNA gene was studied. When H.pylori strains isolated in advance from patients in whom strains were eradicated with CAM therapy were tested, CAM MICs for 258 (98.5%) of the 262 isolates ranged from ≤0.015 to 0.5μg/mL. CAM MICs for 23 (57.5%) and 17 (42.5%) of 40 strains isolated from patients in whom strains were not eradicated with CAM therapy were ≤0.25μg/mL and ≥4μg/mL. The 4 H.pylori strains (MIC;≥8μg/mL) isolated from patients in whom strains were eradicated had A 2143 G mutation and 17 strains (≥4μg/mL) from patients in whom strains were not eradicated had A 2143 G and A 2142 G mutations. H.pylori isolates belonging to the S (MIC;≤0.25μg/mL) or I (0.5μg/mL) category in the NCCLS guideline did not possess any type of mutation in the 23S rRNA gene, but all isolates belonging to the R category (≥1μg/mL) had point mutations. It is thus noteworthy that CAM breakpoint MICs for H. pylori based on the NCCLS guideline agreed with point mutations in the 23S rRNA gene of test isolates.

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The susceptibility of 2, 197 clinical isolates in Japan to trovafloxacin and other antimicrobial agents was determined by broth microdilution. Test strains were isolated from 1997 to 1999 from patients with bacterial infections other than urinary tract infections at 14 hospitals in Japan. The activity of trovafloxacin against gram-positive organisms was greater than that of ciprofloxacin, tosufloxacin, sparfloxacin, levofloxacin or cephems. MIC₉₀ of trovafloxacin against methicillin-susceptible Staphylococcus aureus was 0.03μg/mL, of Streptococcus pyogenes 0.25μg/mL, of Streptococcus pneumoniae 0.25μg/mL and Streptococcus agalactiae 0.5μg/mL. Trovafloxacin exhibited great activity against S.pneumoniae, regardless of penicillin resistance. Although trovafloxacin and other fluoroquinolones exhibited low activity against Enterococcus faecalis and Enterococcus faecium, trovafloxacin (MIC₉₀, 2μg/mL) was more active against Enterococcus avium than other agents. The activity of trovafloxacin (MIC₉₀s, 0.12 to 1μg/mL) against Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter aerogenes, Proteus vulgaris, and Morganella morganii was comparable to or greater than that of cephems and imipenem. Trovafloxacin and other fluoroquinolones (MIC₉₀s, ≤0.015 to 0.06μg/mL) exhibited great activity against Moraxella catarrhalis and Haemophilus influenzae. Fluoroquinolones (MIC₉₀s, 4 to 8μg/mL) including trovafloxacin were more active against Pseudomonas aeruginosa than other agents. Trovafloxacin was the most active against Bacteroides fragilis with an MIC₉₀ of 2μg/mL.

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A patient with pleurisy caused by a methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa infection was hospitalized after the administration of vancomycin was unable to produce a cure. The combined administration of rifampicin (dose: 450mg 3×1/day), sulfamethoxazole-trimethoprin (3g 3×1/day) and levofloxacin (300mg 3×1/day) was continuedfor 2 weeks and resulted in the successfhl elimination of the two organisms from the infected tissue.

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We organized a group of physicians in private primary medical care practice (private-practice group) to take part in an antimicrobial agent clinical trial with higher-level medical institutions to determine their ability to recruit trial subjects and conduct clinical trials effectively. With timely TV and newspaper advertising recruiting trial subjects, the private-practice group of 2 hospitals and 3 clinics near Kawasaki Medical School took part from mid-April until early May in an ongoing multicenter, double-blind, dosefinding clinical trial of telithromycin in patients with pneumonia at 58 trial sites nationwide. Investigators and institutions of the private-practice group were selected by qualification criteria including sufficient clinical trial experience at Kawasaki Medical School Hospital or its affiliate, Kawasaki Hospital, and suitability to requirements of Good Clinical Practice (GCP). For effective, safe conducting of the clinical trial, Clinical Research Coordinators (CRCs) were allocated and trial sponsor monitors visited these institutions frequently. The private-practice group recruited 2 subjects who completed trial treatment with reliable, evaluable data. Because their participation was very short, the private-practice group recruited only 2 subjects, we confirmed that qualified private practitioners may participate effectively in an antimicrobial agent clinical trial and recruit subjects not previously treated with another antimicrobial agent and therefore suitable for such a trial.

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For the first time in Japan, we used combined TV and newspaper advertising -a first in Japan- to advertising to recruit clinical trial subjects, for an antimicrobial agent in patients with communityacquired pneumonia. We recruited subjects in the Okayama and Kagawa for 10 days April 17-26, 2000, during which TV ads were aired daily except Saturdays and Sundays on 3 channels 223 times and newspaper ads appeared 4 times in 2 papers 8 times.The TV ad was estimated to have been by 88.7% of people in the target regions an average of 5.8 times. The newspaper ad was estimated to have been read by 53.1% of people in Okayama and 42.5% in Kagawa. Of the 151 directly responding to our ads, 29 were referred to medical institutions participating in the clinical trial (trial sites) though none were diagnosed with pneumonia. Of those not referred to any trial site, 21 had no symptoms of pneumonia, 8 were excluded based on subject exclusion criteria, 13 could not be allocated to appropriate trial sites, and 8 did not have the time to visit any trial site. After the start of TV and newspaper ads, subject entry in target regions increased rapidly in marked contrast to nonadvertised regions regarded as a favorable ad effect in helping investigator recruit subjects. Given the number of potential trial subjects reached in the target regions, we found the TV and newspapers combination effective in encouraging people's understanding of the need for clinical trials and subject recruitment.

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Because of excessive time involved in the development of antimicrobial drugs in Japan, bridging studies are gaining currency lately, which takes in foreign clinical study data. The Japanese Society of Chemotherapy (JSC)has set up the Bridging Study Committee to discuss the issue. The following is my report. Japanese classification of adaptable diseases is more comprehensive and makes fine distinctions compared with the Western one, which calls for some adjustment of disease groups and diagnoses between Japan and the West. In bridging studies foreign endpoints and evaluation periods should in Japan. Dosing method and amount are the toughest part of bridging. Provided PK and drug sensitivity of the casual bacterium are the same, the same dosing method and amount should be used. We will need a review of the standards of standard drugs used in the treatment of diseases under study or organisms and the definition of control drugs for our efficacy and safety study. As we get more experience in bridging studies, I think it will be increasingly important that we have more disucussions with JSC and regulatory authorities.

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