研究者詳細 - 安田　満

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尿路感染症の薬物治療細菌感染症のトピックス

安田満, 出口隆

MEDICAMENT NEWS 1764 1 - 3 2003年01月

外来診療のすべて改訂第3版

安田満, 出口隆

124 - 125 2003年01月

男子淋菌性尿道炎に対するセフィキシム400mg，分2，3日間投与の細菌学的効果の検討

前田真一, 久保田恵章, 玉木正義, 安田満, 出口隆

日本性感染症学会誌 14 121 - 124 2003年01月

Mycoplasma genitaliumと尿道炎

安田満, 出口隆

日本マイコプラズマ学会誌 30 52 - 55 2003年01月

Grade3表在性膀胱癌の臨床的検討

楊睦正, 土屋朋大, 亀井信吾, 山田徹, 安田満, 西野好則, 西田泰幸, 谷口光宏, 永井司, 竹内敏視, 出口隆

日本泌尿器科学会雑誌 ( 一般社団法人日本泌尿器科学会 ) 94 ( 2 ) 266 - 266 2003年

DOI CiNii

膀胱全摘除症例における術前化学療法の有用性の検討

土屋朋大, 亀井信吾, 山田徹, 安田満, 楊睦正, 西野好則, 西田泰幸, 谷口光宏, 永井司, 竹内敏視, 出口隆

日本泌尿器科学会雑誌 ( 一般社団法人日本泌尿器科学会 ) 94 ( 2 ) 213 - 213 2003年

DOI CiNii

Treatment of uncomplicated gonococcal urethritis by double-dosing of 200mg cefixime at a 6-h interval

Takashi Deguchi, Mitsuru Yasuda, Shigeaki Yokoi, Ken-Ichiro Ishida, Masayasu Ito, Satoshi Ishihara, Ken Minamidate, Yoshimasa Harada, Kanhin Tei, Kentaro Kojima, Masayoshi Tamaki, Shin-Ichi Maeda

Journal of Infection and Chemotherapy ( Springer Japan ) 9 ( 1 ) 35 - 39 2003年

The efficacy of antimicrobial regimens for the treatment of uncomplicated gonococcal urethritis depends partially upon the period of time (therapeutic time) during which the drug concentration in the blood after the concentration peak is greater than four times the minimum inhibitory concentration for 90% of clinical isolates of Neisseria gonorrhoeae (MIC90). A therapeutic time of at least 10h is suggested as an important determinant for elimination of 95% or more of the infection. In this study, therapeutic times for a single 400-mg dose of cefixime at various MIC90s were calculated, and pharmacokinetic profiles of double-dosing of 200mg cefixime at various intervals were simulated. Subsequently, a dosing interval of 6h was tested in 6 healthy Japanese men, and then 93 Japanese men with gonococcal urethritis were treated with a regimen of two 200-mg doses of cefixime given at a 6-h interval. For a single dose of 400mg cefixime, therapeutic times were calculated to be 12.8, 9.1, 5.4, and 1.7h for MIC90s of 0.06, 0.125, 0.25, and 0.5 μg/ml, respectively. In the simulation study of double-dosing of 200mg cefixime at a 6-h interval, the therapeutic times for the MIC90s of ≤0.125 μg/ml were longer than 10h. Of the 93 patients, 68 were evaluated for microbiological outcome, and N. gonorrhoeae was eradicated in 60 (88.2%). The MIC90 of cefixime for the 61 isolates tested was 0.125 μg/ml. All strains with MICs of ≤0.06 μg/ml were eradicated, whereas 8 of 16 strains with MICs of ≥0.125 μg/ml persisted after treatment. This regimen would not be effective against infection by strains exhibiting cefixime MIC90s of ≥0.125 μg/ml. For such strains, a different regimen with a higher dose of cefixime would be required.

DOI PubMed

Association of mycoplasma genitalium persistence in the urethra with recurrence of nongonococcal urethritis

S Maeda, M Tamaki, K Kojima, T Yoshida, H Ishiko, M Yasuda, T Deguchi

SEXUALLY TRANSMITTED DISEASES ( LIPPINCOTT WILLIAMS & WILKINS ) 28 ( 8 ) 472 - 476 2001年08月 [査読有り]

Background. Most patients with recurrent symptomatic nongonococcal urethritis receive negative test results for Chlamydia trachomatis and Ureaplasma urealyticum, and the cause of such recurrence usually is unknown. Goal: To assess the association of Mycoplasma genitalium with recurrent nongonococcal urethritis. Study Design: In this study, 72 men with nongonococcal urethritis were treated with levofloxacin. Before and after treatment. symptoms and signs were assessed and first-pass urine was examined for C trachomatis, M genitalium, U urealyticum, and Mycoplasma hominis by polymerase chain reaction- based assays. Results: In 6 of 45 men who had no symptoms and no evidence of inflammation after treatment, nongonococcal urethritis recurred. Of these 6 men, 5 had positive test results for M genitalium before levofloxacin treatment, which remained positive afterward. After the second treatment for recurrent nongonococcal urethritis, one man was still had a positive test result for the mycoplasma and experienced a subsequent recurrence. Conclusions: This study suggests that the persistence of M genitalium in the urethra may be associated with recurrence of nongonococcal urethritis.

腎細胞癌におけるcentrosomal kinase AIK1およびAIK3発現の免疫組織化学的検討

江原英俊, 横井繁明, 山田徹, 玉木正義, 安田満, 西野好則, 山本直樹, 高橋義人, 石原哲, 出口隆, 木村正志, 岡野幸雄

日本泌尿器科学会雑誌 ( 一般社団法人日本泌尿器科学会 ) 91 ( 3 ) 395 - 395 2000年

DOI CiNii

1998年に当科で分離された尿路由来緑膿菌の抗菌剤耐性関連遺伝子の状況について

石原哲, 安田満, 横井繁明, 西野好則, 江原英俊, 山本直樹, 高橋義人, 出口隆

日本泌尿器科学会雑誌 ( 一般社団法人日本泌尿器科学会 ) 91 ( 3 ) 198 - 198 2000年

DOI CiNii

上部尿路上皮内癌におけるBCG灌流療法の検討

西野好則, 安田満, 横井繁明, 江原英俊, 山本直樹, 原田吉將, 米田尚生, 高橋義人, 石原哲, 竹内敏視, 酒井俊助, 鄭漢彬, 出口隆

日本泌尿器科学会雑誌 ( 一般社団法人日本泌尿器科学会 ) 91 ( 3 ) 400 - 400 2000年

DOI CiNii

Improved antimicrobial activity of DU-6859a, a new fluoroquinolone, against quinolone-resistant Klebsiella pneumoniae and Enterobacter cloacae isolates with alterations in GyrA and ParC proteins

T Deguchi, M Yasuda, T Kawamura, M Nakano, S Ozeki, E Kanematsu, Y Nishino, Y Kawada

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY ( AMER SOC MICROBIOLOGY ) 41 ( 11 ) 2544 - 2546 1997年11月 [査読有り]

Detection of mutations in the gyrA and parC genes in quinolone-resistant clinical isolates of Enterobacter cloacae

T Deguchi, M Yasuda, M Nakano, S Ozeki, E Kanematsu, Y Nishino, S Ishihara, Y Kawada

JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY ( OXFORD UNIV PRESS ) 40 ( 4 ) 543 - 549 1997年10月 [査読有り]

We have determined partial sequences of the gyrA and parC genes of Enterobacter cloacae type strain including the regions analogous to the quinolone resistance-determining region of the Escherichia coli gyrA gene. The deduced 65- and 49-amino acid sequences of the determined regions of the E. cloacae gyrA and parC genes were identical to the corresponding regions of the E. coli GyrA and ParC proteins, respectively. We examined 40 clinical strains of E. cloacae isolated from patients with urinary tract infection for susceptibilities to nalidixic acid and ciprofloxacin. Based on the nalidixic acid and ciprofloxacin MICs, these isolates were divided into 19 quinolone-susceptible strains (MICs of nalidixic acid, 3.13-25 mg/L; MICs of ciprofloxacin, less than or equal to 0.025 mg/L) and 21 quinolone-resistant strains (MICs of nalidixic acid, 400 to >800 mg/L; MICs of ciprofloxacin, 0.39-100 mg/L). We analysed five quinolone-susceptible and 21 quinolone-resistant strains for alterations in GyrA and ParC. The five quinolone-susceptible strains had amino acid sequences in GyrA and ParC identical to those of type strain. Of the 21 quinolone-resistant isolates, three (MICs of nalidixic acid, 400 to >800 mg/L; MICs of ciprofloxacin, 0.39-3.13 mg/L) had a single amino acid change at the position equivalent to Ser-83 in the E. coli GyrA protein and no alterations in ParC; one (MIG of nalidixic acid, >800 mg/L; MIC of ciprofloxacin, 3.13 mg/L) had a single amino acid change at Ser-83 in GyrA and a single amino acid change at the position equivalent to Glu-84 in the E. coli ParC protein; two (MIG of nalidixic acid, >800 mg/L; MIC of ciprofloxacin, 25 mg/L) had double amino acid changes at Ser-83 and Asp-87 in GyrA and no alterations in ParC; and 15 (MICs of nalidixic acid, >800 mg/L; MICs of ciprofloxacin, 25-100 mg/L) had double amino acid changes at Ser-83 and Asp-87 in GyrA and a single amino acid change at Ser-80 or Glu-84 in ParC. This study suggests, that in clinical isolates of E. cloacae, DNA gyrase is a primary target of quinolones, that only a single amino acid change at Ser-83 in GyrA is sufficient to generate high-level resistance to nalidixic acid and to decrease susceptibility to ciprofloxacin, and that the accumulation of amino acid changes in GyrA and the simultaneous presence of the ParC alterations play a central role in developing high-level resistance to ciprofloxacin.

In-vitro antimicrobial activity of HSR-903, a new fluoroquinolone, against clinical isolates of Neisseria gonorrhoeae with quinolone resistance-associated alterations in GyrA and ParC

T Deguchi, M Yasuda, S Ishihara, Y Takahashi, E Okezaki, O Nagata, Saito, I, Y Kawada

JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY ( OXFORD UNIV PRESS ) 40 ( 3 ) 437 - 439 1997年09月 [査読有り]

The in-vitro antimicrobial activity of HSR-903, a new fluoroquinolone, was tested against 51 clinical Neisseria gonorrhoeae isolates in comparison with ciprofloxacin, levofloxacin and sparfloxacin. The MICs of HSR-903 for 11 isolates with alterations in both GyrA and ParC, for 19 isolates with alterations only in GyrA and for 21 isolates without alterations in either GyrA or ParC ranged from 0.03 mg/L to 1.0 mg/L (MIC90 = 0.25 mg/L), from 0.03 mg/L to 0.5 mg/L (MIC90 = 0.125 mg/L) and from less than or equal to 0.001 mg/L to 0.008 mg/L (MIC90 = 0.004 mg/L), respectively. Levofloxacin and ciprofloxacin were the least active of the four quinolones tested, particularly against the mutant strains. Sparfloxacin was more active, but HSR-903 exhibited the most potent in-vitro activity against the clinical N. gonorrhoeae isolates, including those harbouring quinolone-resistance-associated alterations in GyrA and ParC.

Mutations in the gyrA and parC genes associated with fluoroquinolone resistance in clinical isolates of Citrobacter freundii

Y Nishino, T Deguchi, M Yasuda, T Kawamura, M Nakano, E Kanematsu, S Ozeki, Y Kawada

FEMS MICROBIOLOGY LETTERS ( ELSEVIER SCIENCE BV ) 154 ( 2 ) 409 - 414 1997年09月 [査読有り]

We determined partial sequences of the gyrA and parC genes of Citrobacter freundii type strain, and then examined 38 C. freundii clinical strains isolated from patients with urinary tract infections for the association of alterations in GyrA and ParC with susceptibility to fluoroquinolones. Our results suggest that in C. freundii DNA gyrase may be a primary target of quinolones, that an amino acid change at Thr-83 or Asp-87 in GyrA is sufficient to decrease susceptibility to fluoroquinolones, and that accumulation of changes in GyrA with the simultaneous presence of an alteration at Ser-80 or Glu-84 in ParC may be associated with the development of high-level fluoroquinolone resistance in C. freundii clinical isolates.

Development of a rapid assay for detecting gyrA mutations in Escherichia coli and determination of incidence of gyrA mutations in clinical strains isolated from patients with complicated urinary tract infections

S Ozeki, T Deguchi, M Yasuda, M Nakano, T Kawamura, Y Nishino, Y Kawada

JOURNAL OF CLINICAL MICROBIOLOGY ( AMER SOC MICROBIOLOGY ) 35 ( 9 ) 2315 - 2319 1997年09月 [査読有り]

The MICs of ofloxacin for 743 strains of Escherichia coli isolated from 1988 to 1994 were determined by testing, The strains were from patients with urinary tract infections complicated by functional or anatomical disorders of the urinary tract, Those determined to be ofloxacin resistant (MIG, greater than or equal to 12.5 mu g/ml) comprised 3 of 395 strains (1.3%) from the 1988 to 1990 group, 2 of 166 strains (1.2%) from the 1991 to 1992 group, and 7 of 182 strains (3.8%) from the 1993 to 1994 group, The incidence of resistant strains increased significantly during this period, The percentage of isolates with moderately decreased susceptibilities to ofloxacin (MIG, 0.39 to 3.13 mu g/ml) also rose during the same period, To determine the incidence of gyrA mutations in urinary-tract-derived strains of E, coli, we developed a simple and rapid assay based on PCR amplification of the region of the gyrA gene containing the mutation sites followed by digestion of the PCR product with a restriction enzyme, Using this assay, we examined all 182 strains isolated in 1993 and 1994 for the presence of mutations at Ser-83 and Asp-87 in the gyrA gene, Of these strains, 33 (18.1%) had mutations in the gyrA gene, The incidences of mutations at Ser-83, at Asp-87, and at both codons were 10.4 (19 strains), 4.4 (8 strains), and 3.3% (6 strains), respectively, To determine the correlation of the mutations in the gyrA gene with susceptibilities to quinolones (nalidixic acid, ofloxacin, norfloxacin, and ciprofloxacin), we further examined 116 strains for which the MICs of ofloxacin were greater than or equal to 0.2 mu g/ml that were chosen from the isolates in the 1988 to 1992 group, The MICs of nalidixic acid for the strains without mutations at either Ser-83 or Asp-87 were less than or equal to 25 mu g/ml, whereas those for the strains with single mutations or double mutations were from 50 to >800 mu g/ml. For the fluoroquinolones, significant differences in the distributions of the MICs were observed among the strains without mutations, with single mutations, and with double mutations, The accumulation of mutations in the gvrA gene was associated with an increase in fluoroquinolone resistance, Ofloxacin MICs for the majority of the strains with single and double mutations were 0.39 to 3.13 and 6.25 to 100 mu g/ml, respectively, This study demonstrates a chronological increase in the percentage of not only highly fluoroquinolone-resistant strains, corresponding to those with double mutations in the gyrA gene, but also strains with moderately decreased susceptibilities to fluoroquinolones, corresponding to those with single mutations, This increase in the incidence of strains with a single mutation in the gyrA gene portends a further increase in the incidence of strains with clinically significant resistance to fluoroquinolones.

Comparison of in vitro antimicrobial activity of AM-1155 with those of tosufloxacin and fleroxacin against clinical isolates of Neisseria gonorrhoeae harboring quinolone resistance alterations in GyrA and ParC

T Deguchi, M Yasuda, M Nakano, S Ozeki, E Kanematsu, H Fukuda, S Maeda, Saito, I, Y Kawada

CHEMOTHERAPY ( KARGER ) 43 ( 4 ) 239 - 244 1997年07月 [査読有り]

The in vitro antimicrobial activities of AM-1155, a new fluoroquinolone, tosufloxacin and fleroxacin were tested against 55 clinical isolates of Neisseria gonorrhoeae using the agar dilution method. In our previous study, all the strains had been examined for mutations in the region corresponding to the quinolone-resistance determining region of the Escherichia cell gyrA gene and the analogous region of the parC gene, and tested for susceptibility to ciprofloxacin. In this study, the 55 isolates of N. gonorrhoeae were assigned to one of three categories based on the presence or absence of alterations in GyrA and ParC. In each category, the antimicrobial activity of AM-1155 against the isolates was compared with those of tosufloxacin and fleroxacin. The MICs of AM-1155 for 11 highly fluoroquinolone-resistant isolates with alterations in both GyrA and ParC ranged from 0.06 to 1.0 mu g/ml. The MICs inhibiting 50% (MIC50) and 90% (MIC90) of these isolates were 0.125 and 1.0 mu g/ml, respectively. The MICs of AM-1155 for 20 moderately fluoroquinolone-resistant isolates with alterations only in GyrA ranged from 0.03 to 0.25 mu g/ ml (MIC50, 0.06 mu g/ml; MIC90, 0.125 mu g/ml). The MICs of AM-1155 for 24 of the quinolone-susceptible isolates without alterations in either GyrA or ParC ranged from 0.004 to 0.03 mu g/ml (MIC50, 0.008 mu g/ml; MIC50, 0.015 mu g/ml). There were significant differences between the MIC distribution of AM-1155 and each corresponding MIC distribution of tosufloxacin and fleroxacin in these three categories to which the 55 isolates were assigned (p < 0.05). Based on the MIC(90)s of the tested fluoroquinolones, AM-1155 was two- and eightfold more active against the highly fluoroquinolone-resistant isolates than tosufloxacin and fleroxacin, respectively. Against the moderately fluoroquinolone-resistant isolates, AM-1155 was four- and sixteenfold more active than tosufloxacin and fleroxacin, respectively. Against the quinolone-susceptible strains, AM-1155 was also two- to fourfold more active than the other fluoroquinolones. Overall, AM-1155 exhibited more potent in vitro activity against both quinolone-resistant and quinolone-susceptible isolates of N. gonorhoeae than tosufloxacin and fleroxacin. In ciprofloxacin treatment failures of gonorrhea at single doses of 500 mg. MICs for the causative organisms have ranged from 1.0 to 16.0 mu g/ml. The MICs of AM-1155 for the isolates harboring quinolone resistance-associated genetic alterations, including strains exhibiting ciprofloxacin MICs of 2.0 and 8.0 mu g/ml, still ranged from 0.03 to 1.0 mu g/ml. A single-dose study in humans has demonstrated higher peak serum concentrations and longer half-lives of AM-1155, resulting in the AUC(O-infinity) values of AM-1155, which are threefold greater than those of ciprofloxacin at the single doses of 400 and 600 mg. Because of its potent in vitro antimicrobial activity and advantageous pharmacokinetic behavior, AM-1155 may be a clinically useful agent for treating gonorrhea including that caused by quinolone-resistant strains.

In vivo selection of Klebsiella pneumoniae strains with enhanced quinolone resistance during fluoroquinolone treatment of urinary tract infections

T Deguchi, T Kawamura, M Yasuda, M Nakano, H Fukuda, H Kato, N Kato, Y Okano, Y Kawada

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY ( AMER SOC MICROBIOLOGY ) 41 ( 7 ) 1609 - 1611 1997年07月 [査読有り]

We report two cases of failure of fluoroquinolone treatment of urinary tract infections with Klebsiella pneumoniae strains harboring quinolone resistance-associated alterations in GyrA and ParC and in vivo selection of posttreatment isolates with enhanced fluoroquinolone resistance. Active efflux leading to decreased accumulation of a drug enhanced fluoroquinolone resistance in one posttreatment isolate, and an additional mutation in parC resulting in an additional amino acid change in ParC was associated with increased resistance in the other.

Fluoroquinolone treatment failure in gonorrhea - Emergence of a Neisseria gonorrhoeae strain with enhanced resistance to fluoroquinolones

T Deguchi, Saito, I, M Tanaka, K Sato, K Deguchi, M Yasuda, M Nakano, Y Nishino, E Kanematsu, S Ozeki, Y Kawada

SEXUALLY TRANSMITTED DISEASES ( LIPPINCOTT-RAVEN PUBL ) 24 ( 5 ) 247 - 250 1997年05月 [査読有り]

Background and Objectives: Although emergence of clinical isolates of Neisseria gonorrhoeae with decreased susceptibilities to fluoroquinolones and treatment failures in gonorrhea have been reported, there have been no clinical reports that fluoroquinolone treatments actually select quinolone-resistant strains, nor have isolates that exhibited clinically significant resistance been analyzed for resistance mechanisms, Goals: To report a case of fluoroquinolone treatment failure in gonorrhea and emergence of a posttreatment isolate with enhanced resistance to fluoroquinolones; and to study mechanisms of quinolone resistance in the isolates from this patient, Study Design: A patient with gonococcal urethritis treated with ofloxacin, 200 mg, three times daily for 5 days is described, Pretreatment and posttreatment isolates were tested for minimum inhibitory concentrations (MICs) of antimicrobial agents and analyzed for alterations in DNA gyrase and topoisomerase IV, They were also examined for ofloxacin uptake, Results: Treatment failure with multiple doses of ofloxacin was observed in this case of gonorrhea, The pretreatment isolate showed decreased susceptibilities to fluoroquinolones (IMC of ofloxacin, 1.0 mg/l; MIC of ciprofloxacin, 0.25 mg/l), and had amino acid changes of Ser-91 --> Phe in GyrA and Ser-87 --> Ile in ParC. The posttreatment isolate exhibited an increase in resistance to fluoroquinolones (MIC of ofloxacin, 8.0 mg/l; MIC of ciprofloxacin, 1.0 mg/l), This isolate had identical alterations in GyrA and ParC, but exhibited significantly reduced uptake of ofloxacin. This isolate also showed a small decrease in susceptibilities to cephalosporins. Conclusions: Alterations in DNA gyrase and topoisomerase IV confer clinically significant resistance to fluoroquinolones in N. gonorrhoeae strains, Treatment with multiple doses of fluoroquinolones is likely to bring about selection of more fluoroquinolone-resistant strains of N, gonorrhoeae and to influence susceptibilities to cephalosporins.

Rapid screening of point mutations of the Neisseria gonorrhoeae parC gene associated with resistance to quinolones

T Deguchi, M Yasuda, M Nakano, E Kanematsu, S Ozeki, Y Nishino, T Ezaki, S Maeda, Saito, I, W Kawada

JOURNAL OF CLINICAL MICROBIOLOGY ( AMER SOC MICROBIOLOGY ) 35 ( 4 ) 948 - 950 1997年04月 [査読有り]

To detect quinolone resistance-associated mutations within the Asp-86, Ser-87, Ser-88, and Glu-91 codons of the Neisseria gonorrhoeae parC gene, we developed a rapid and simple assay based on amplification of the regions of the parC gene containing the mutation sites by PCR and digestion of the PCR products with restriction enzymes, By using the method of primer-specified restriction site modification, artificial SalI, PstI, EcoRI, and HinfI restriction sites were created in the regions containing the Asp-86, Ser-87, Ser-88, and Glu-91 codons, respectively, The mutations generating alterations at Asp-86, Ser-87, Ser-88, and Glu-91 were detected as failures of SalI, PstI, EcoRI, and Hinfl to digest the respective PCR products, Fifty-five clinical strains of N. gonorrhoeae were examined for mutations in the parC gene by this assay, Appropriate mutations at either the Asp-86, Ser-87, Ser-88, or Glu-91 codon were detected in each of 11 strains in which a mutation had previously been observed by DNA sequencing, This rapid and simple assay could be a useful device for screening genetic alterations in the parC gene associated with resistance to quinolones in N. gonorrhoeae.

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