浩一 出口’s scientific contributions

第3世代セファロスポリン系抗生物質の経口剤であるT-2588を用い,淋菌感染症に対する治験を,男子尿道炎140例,女子子宮頸管炎6例の計算146例について行なった.分離淋菌の110株中23株(20.9%)はβ-lactamase産生淋菌(PPNG)であった.T-2588の分離菌に対する抗菌力(MIC)は,接種菌量106 CFU/mlで0.1～0.0125 μg/ml (peak 0.025 μg/ml)であった.PPNGでもpeakは0.025 μg/mlで,最高値はnon-PPNGより1管高い0.2 μg/mlであった.C. trachomatis感染合併例は男子20.9%,女子33.3%であった.男子症例に対する有効率は,1日2回400 mg投与法で3日目90.5%,7日目95.3%,PPNG分離例に限っては3日目73.3%,7日目80.0%であった.1日3回300 mg投与では3日目93.3%,7日目100%,1日3回600 mg投与では3日目100%,7日目100%であり,PPNGに対しても3日目,7日目共に100%であった.女子症例は例数が少ないので結論づけられなかったが,やはり600 mg(分3)投与がよい成績(100%)であった.副作用は軽度のものを3例(1.7%)に認めたが,そのまま治療を続行した.以上の成績から,淋菌感染症に対するT-2588による治療は,1日分3投与600 mg 3日間投与でPPNGと関係なく,充分な臨床効果を期待できると考えている T-2588, a new oral cephalosporin antibiotic, for gonorrheal infections, was administered to 146 patients with gonorrheal infection cases (140 urethritis cases in males, 6 cervicitis cases in females). Twenty three strains (20.9%) out of 110 clinically isolated gonococci were PPNG. The MICs of T-2588 for the clinically isolated gonococci strains showed a distribution peak at 0.025 microgram/ml and ranged between 0.0125 microgram/ml to 0.1 microgram/ml when an inoculum size of 10(6)/CFU/ml was used. The distribution of MICs of PPNG also showed a peak at 0.025 microgram/ml and the maximum MIC was 0.2 microgram/ml, which is one dilution tube higher than the maximum MIC of non-PPNG. The rate of complication by Chlamydia trachomatis was 20.9% in male and 33.3% in female. At the dose of 400 mg given 2 times a day, the efficacy rate for the males on the 3rd and 7th day was 90.5% (efficacy rate against PPNG, 73.3%) and 95.3% (80.0%), respectively. At the dose of 300 mg given 3 times a day, it was 93.3% and 100%, respectively, and at the dose of 600 mg given 3 times a day, it was 100% and 100%, respectively. Therefore, the administration of T-2588 3 times a day resulted in a higher efficacy rate than that given 2 times a day. This effect was extremely marked in the case of patients with PPNG. The best clinical results were obtained at a daily dose of 600 mg t.i.d. Although the female patients were few, in number and no conclusion can be drawn, the best results were obtained with a daily dose of 600 mg t.i.d. (100%). There were three mild side effects (1.7%), which could not be attributed to the administration of T-2588 in the present study. In conclusion, T-2588 can be to be expected sufficiently clinically effective against gonorrheal infections, including PPNG, at a daily dose of 600 mg t.i.d. for 3 days.

複雑性尿路感染症に対するDL-8280の有効性,安全性と有用性を客観的に評価するため,Pipemidic acid (PPA)を対照薬とし二重盲検法で比較検討した.DL-8280は1回200 mg, 1日3回,PPAは1回500 mg, 1日4回,を5日間連続経口投与した.総投与例数は311例で,除外,脱落を除く228例(DL-8280群115例,PPA群113例)に対し有効性を評価した.安全性の評価は306例(DL-8280群153例,PPA群153例),有効性の評価は250例(DL-8280群124例,PPA群126例)につきおこなった.両群の背景因子には差はなかった.総合臨床効果は,DL-8280群で著効39.1%,有効80.9%,PPA群それぞれ23.9, 57.5%と比較し有意に高かった.疾患病態群別には,第2群(単独感染,前立腺術後感染症)と第3群(単独感染,上部尿路感染症)を除き,DL-8280群の総合臨床効果はPPA群に比し有意に優っていた.膿尿に対する効果は,正常化率+改善率がDL-8280群で59.1%, PPA群で46.0%で,前者が,優る傾向をみた.細菌尿に対する効果では,DL-8280群の陰性化率は76.5%, PPA群は50.4%で,DL-8280群が有意に優っていた.細菌学的効果では,DL-8280群の分離菌の消失率89.0%に対し,PPA群は72.1%で,有意差であった.グラム陰性桿菌,グラム陽性球菌についてもDL-8280群の消失率は有意に優っていた.主治医による臨床効果はDL-8280群が著効46.1%,有効83.5%で,PPA群はそれぞれ26.5, 61,1%で,前者が有意に優っていた.有用性は,DL-8280群が"非常に満足","満足"合わせて71.8%, PPA群が47.6%でDL-8280群が有意に優っていた.副作用はDL-8280群で11例,PPA群で12例に認め,有意差はなく,大部分は消化器症状で,重篤なものはなかった.臨床検査値悪化もDL-8280群で10例,PPA群で9例にみ,有意差はなかった The clinical efficacy, safety and usefulness of DL-8280 for the treatment of complicated urinary tract infections were compared with those of pipemidic acid (PPA) by a double-blind method. DL-8280 and PPA were orally administered at a daily dose of 600 mg (t.i.d.) and 2.0 g (q.i.d.) for 5 days, respectively. Of the 311 patients who received DL-8280 or PPA, clinical efficacy, safety and usefulness were evaluated in 228 patients (DL-8280, 115; PPA, 113), 306 patients (DL-8280, 153; PPA, 153) and 250 patients (DL-8280, 124; PPA, 126), respectively. There was no significant difference in the background characteristics between the two groups. In the DL-8280 group the overall clinical efficacy was excellent in 39.1% and moderate in 41.7%, the effectiveness rate being 80.9%, whereas in the PPA group it was excellent in 23.9% and moderate in 33.6%, the effectiveness rate being 57.5%. The efficacy in the DL-8280 group was significantly higher than that in the PPA group (P less than 0.001). According to classification by the type of infection, the overall clinical efficacy of DL-8280 in groups except group 2 (monomicrobial infection, post prostatectomy) and group 3 (monomicrobial infection, upper urinary tract infection) was superior to that of PPA, the difference being significant. Pyuria was cleared or improved in 59.1% of the patients treated with DL-8280 and in 46.0% of the patients with PPA. The difference was not significant. Bacteriuria was eliminated in 76.5% in the DL-8280 group and in 50.4% in the PPA group. DL-8280 demonstrated a significantly higher response than PPA (P less than 0.001). Of the bacteria isolated from the DL-8280 group and PPA group 89.0% and 72.1%, respectively, were eradicated after the treatment, a significant difference being observed between the two groups (P less than 0.001). The clinical efficacy evaluated by the doctor in charge was excellent in 46.1% and good in 37.4% of the patients treated with DL-8280 and excellent in 26.5% and good in 34.5% of the patients treated with PPA, the intergroup difference in the efficacy being significant (P less than 0.001). The evaluation of usefulness of DL-8280 and PPA was "satisfactory" for 71.8% and 47.6%, respectively, the difference being significant (P less than 0.001). Side effects were observed in 11 patients (7.2%) in the DL-8280 group and in 12 patients (7.8%) in the PPA group, but none were serious.(ABSTRACT TRUNCATED AT 400 WORDS)

The efficacy of single administration of NY-198 in the treatment of gonococcal infections was studied employing male patients with gonorrheal urethritis and female patients with gonorrheal cervicitis. The clinical efficacy was evaluated on the basis of the efficacy rates which was estimated on each observation day for each patient. In the male patients, NY-198 was administered in a dose of 200 mg in 25 cases and a dose of 400 mg in 65 cases. The rate of eradication of N. gonorrhoeae (i.e. efficacy) on the 3rd day of administration was 96% in the 200 mg administration group and 100% in the 400 mg administration group. On the 7th day after administration, the eradication rate was 100% in both the 200 mg and 400 mg administration groups. When the eradication rate on the 7th day was statistically estimated for patients who returned to the hospital only on the 3rd day, it was 97.9% in the 200 mg administration group. In the female patients, NY-198 was administered in a dose of 200 mg to 4 cases and a dose of 400 mg to 5 cases. The eradication rate on each observation day was 100% in both dosage groups. In conclusion, single administration of NY-198 in a dose of 200 mg or 400 mg was highly effective, and considered to be a therapeutic method highly useful clinically.

From January through March of 1985, the Sapporo Clinical Research Group for STD treated 69 cases of gonococcal infections (61 cases of male gonococcal urethritis and 8 cases of female gonococcal cervicitis) at its facilities in Sapporo City. The therapeutic efficacy of one shot therapy of Spectinomycin (SPCM) was investigated, and an epidemiological study on the cases and bacteriological studies on the isolated strains of Neisseria gonorrhoeae were made. The male patients were between 19 and 55 years old, with a peak age distribution in the younger half of the twenties. The female patients were between 18 and 40 years old. The major source of infections was a so-called special massage parlor which accounted for 36.1% of male cases. The isolation rate of PPNG were 16.7% (11/66). The MIC (inoculum size; 10(6) CFU/ml) of SPCM ranged from 3.13 to 25 micrograms/ml regardless of beta-lactamase production. In male patients, the eradication rate (efficacy rate) of N. gonorrhoeae by SPCM was 94.7% on the first day, 93.6% on the third day and 100% on the seventh day after 2 g one shot therapy. In female patients, the rate was 100% on the third and seventh day after 2 g one shot therapy, and 75% on the first day, 66.7% on third day and 100% on seventh day after 4 g one shot therapy. We considered that one shot therapy of SPCM was effective for gonococcal infection also in the present time. Especially SPCM was effective for infections by PPNG, since it was not resolved by beta-lactamase of N. gonorrhoeae. Positive rate of Chlamydia trachomatis was 16.3% in male gonococcal urethritis, and the serous discharge tended to remain longer in the positive patients than in the negative patients. There was only one side effect (1.4%), therefore SPCM was recognized to be a safely administrated antimicrobial agent.

MK-0787/MK-0791をUTIを主とした感染症や,感染防止目的で35例36回,原則として1日0.5 g×2を10日間以上にわたり投与した.1)評価可能26例で有効以上は,治療初期で88.5%,終了時で92.3%であった.有用性についても全く同様の成績を得た.P. aeruginasa等を含む分離菌35株の全てが治療後除菌された.投与後出現菌は,真菌類が多かった.2)長期投与の方が短期投与に比べて,有用性が高い傾向を認めた.3)副作用として,嘔吐による中止例が1例あった.臨床検査値異常では,血小板減少1件,好酸球増多1件,GOT上昇2件,GPT上昇3件,γ-GTP上昇1件をみたが,変動幅は小さく,中止により可逆的であった MK-0787 (Imipenem)/MK-0791 (Cilastatin sodium), a new compound of Thienamycin, was administered in treatment of 35 patients (36 cases) with chronic complicated UTI or for prevention of serious infections with much complicated factors. The patients were principally treated at a daily dose of 1 g for over 10 days. The efficacy rate of 26 patients who were evaluable in the early phase (4-7 days) was 88.5%, while it became up to 92.3% in the final phase judgment. As for clinical usefulness, the result was obtained to be as high as that of the clinical efficacy. In bacteriological study, 35 strains were clinically isolated including 7 strains of P. aeruginosa from UTI. All the strains disappeared with an eradication rate of 100% after treatment. Strains appearing after Imipenem/Cilastatin sodium treatment mainly consisted of fungi. Usefulness judgements tended to be greater in the final phase than in the early phase. As for side effects, vomiting was recorded in one case, in which the administration was discontinued. In laboratory findings there were 3 cases with elevated GPT, 2 cases with elevated GOT, one case with elevated gamma-GTP, one with thrombocytopenia, and one with eosinophilia each, but these abnormal values were slight and transient. In summary our clinical study showed that Imipenem/Cilastatin sodium was a very effective antibiotic in treatment on moderate or serious UTI or preventive use for infections in compromised hosts. Considering the features of this agent, it might be more effective and useful for clinical use in treatment on polymicrobial infections including stubborn organisms than any other antimicrobial compounds. Furthermore, it was safe and well tolerable in a long term treatment.

慢性前立腺炎症例に対し新pyridone carboxylic acid系薬剤AT-2266の治療検討および慢性前立腺炎の病態分析を行なった.前立腺液中に白血球30以上/400倍視野以上の97例を対象とし,その71%に淋菌性又は非淋菌性尿道炎の既往があった.前立腺液の細菌培養で44.1%にGPCを分離した.直前治療のない症例中56.0%に尿道又は排尿関連刺激症状を認め,他は不定愁訴のみであった.AT-2266 600 mg(分3) 14日間投与の治療効果は,直前治療のなかった未治療群と治療のあるもので,7日間治療の有効率はそれぞれ有効以上32.7%,36.0%であり,14日間治療ではそれぞれ54.3%,56.5%であった.尿道及び排尿関連刺激症状の改善はかなり見られるが,更に7日間の治療により改善度は増加した.関連不定愁訴の改善は良好でなく,前立腺内白血球の改善率も著しくはなかった.副作用は軽度のものが投与例の1.8%に見られた AT-2266 is a new antibiotic of the pyridone carboxylic acid class which possesses a broad, low-MIC antibacterial spectrum. Therapeutic studies were carried out on the use of this drug in the treatment of chronic prostatitis, and at the same time a pathological analysis was performed on chronic prostatitis. The subjects were 97 chronic prostatitis patients for whom the prostate fluid had been confirmed to contain at least 30 leukocytes per 400-power magnification field. An analysis of the background factors revealed that 71% of these patients had a past history of gonorrheal or non-gonorrheal urethritis. Culture of the prostate fluid yielded gram-positive cocci (S. epidermidis in most cases) in 44.1% of the patients. E. coli was detected in 3.2% of the patients, while the remaining cases gave negative cultures. In 53.9% of the patients who had not been receiving therapy prior to inclusion in this study, the subjective symptoms consisted of urethral irritation or irritation upon urination. In the other patients, the relationship of the complaints to the disease could not be clearly established. In the patients who had been receiving therapy, the majority did not complain of subjective symptoms. AT-2266 was administered in a daily dosage of 600 mg (in 3 divided doses) for 14 days. The therapeutic efficacy was evaluated. At the end of 7 days of AT-2266 therapy, 15.5% of the previously-untreated group and 8% of the previously-treated group were "excellent" cases, and the efficacy rate was 32.8% and 36%, respectively, when the "good" cases were also included. At the end of the full 14 days of therapy, the corresponding efficacy rates were 21.7% and 17.4%, and 54.3% and 56.5%. Considerable improvement was achieved in the subjective symptoms of urethral irritation and irritation upon urination at the end of 7 days of therapy, and the improvement was even greater following the next 7 days of treatment. With regard to the complaints for which the relationship to the disease could not be clearly established, however, the improvement was not very good: there was not much difference between the results on the 7th and 14th days, and the elimination rate even after 14 days was slightly below 30%. In the previously-untreated patients, improvement in leukocyte count in the prostate fluid to 10 or fewer cells per microscopic field was achieved in 15.6% at 7 days and 21.7% at 14 days. As side effects of AT-2266, mild symptoms were observed to occur in only 1.8% of the patients.

We studied the epidemiology of 109 cases of gonococcal infections (105 males with urethritis and 4 females with cervicitis), together with the basic and clinical effects of cefetamet pivoxil in the cases. The peak of age distribution of the male patients was in the younger half of their twenties, and all of the 4 female cases were between 20 and 39 years old. The major source of infections in the males younger than 25 years old was their girl friends or so-called pick-up friends, and that of the males older than 25 years old workers serving at an amusement center, for example, bars and so-called special massage parlor, which accounted for about three fourths of the male cases between 35 and 44 years old. The distribution of the MIC (inoculum size; 10(6) CFU/ml) of Cefetamet against beta-lactamase non penicillinase producing Neisseria gonorrhoeae (non-PPNG) ranged from 0.025 to 0.1 microgram/ml and that against beta-lactamase producing Neisseria gonorrhoeae ranged from 0.025 to 0.05 microgram/ml. The isolation rate of PPNG was 10.2% (9/88). In male patients with gonococcal urethritis, the efficacy rate was 100% on days 3 and 7 for 1,000 mg single dose and 7-day treatment and 500 mg single dose treatment. One of the cases treated with 250 mg single dose therapy was unchanged at 3, but the efficacy rate of the remaining cases was 100% at day 7. Complicated urethritis with C. trachomatis was noticed in 25.7% (5/105) of the male urethritis and in 25.0% (1/4) of the female cervicitis cases. The only side effect was diarrhea observed in 1 of the 124 case (0.8%).

Clinical efficacy of combination therapy with fosfomycin (FOM) and dibekacin (DKB) was studied in patients with complicated urinary tract infection (UTI). Of the 55 patients accumulated from 7 urology institutes, 39 patients who had pyuria of 5 or more white blood cells per high power field, bacteriuria of 10[4] or more• bacteria per ml of urine and underlying urinary diseases were evaluated for clinical efficacy. Patients received 4g of intravenous FOM and 100 or 200mg of intramuscular DKB a day for 5 to 7 days. The overall clinical efficacy of treatment was evaluated by the criteria proposed by the UTI Committee in Japan as excellent, moderate or poor. Of the 39 patients evaluated for clinical efficacy, 13 patients (33.3%) were infected with multiple organisms and 30 patients (76.9%) had indwelling catheters. The overall results of treatment were excellent in 17.9%, moderate in 64.1% and poor in 17.9%, overall effectiveness rate being 82. 1 %. Of the 52 strains isolated from 39 patients, 48 strains (92.3%) were eradicated and only 4 strains (7.7%) persisted. Side effects were recorded in all 55 patients including those excluded from the evaluation of clinical efficacy. Subjective side effects were not observed in any of the 55 patients. Drugrelated aggravations in laboratory test results were observed in 6 patients (10.9%) but most of them were slight and transient changes; the combination of FOM and DKB appeared to be well tolerated. From the results obtained in this study, combination therapy of FOM and DKB seemed useful in the treatment of complicated UTI, especially those due to multiple orgenisms and those associated with indwelling catheters.

札幌STD研究グループにおいて1982年6月より1年間に男子淋菌性尿道炎131例を対象としてAT-2266 1日600 mgを7日間投与し,治療効果,その他を検討した.1日1回投与,2分割投与,3分割投与の3日間治療成績は著効率がそれぞれ7.7%,50%,57%となった.3分割投与群の成績は3日間治療で著効57.0%,有効39.8%,やゝ有効3.2%であり,7日間治療では著効74.6%,有効23.9%,やゝ有効1.5%であったが,7日間治療でも分泌物や尿中白血球は残存しChlamydiaなど混合感染によると思われた.77株中8株(10.4%)にβ-lactamase産生を認めた.MICは接種菌量でほとんど変化なく,106 CFU/mlで0.05～0.2 μg/mlと3.16～12.5 μg/mlに二峰性分布を示した.AT-2266の副作用は128例中2例(1.6%)に軽度のものが認められた From August of 1982 through February of 1983, the Sapporo Clinical Research Group for STD treated 131 cases of male gonorrheal urethritis at its affiliated clinical facilities in Sapporo City. The therapeutic efficacy of AT-2266 was investigated, together with an epidemiological study on the cases and bacteriological studies on the isolated strains of gonococcus. In addition, a few cases of female gonorrheal cervicitis were treated, and the therapeutic results for 3 of these cases evaluated. AT-2266 was administered at a daily dosage of 600 mg in one dose to 14 patients, 2 doses to 10 patients and 3 doses to 98 patients. At the end of 3 days of this therapy, the gonococci had been eliminated in all of the cases, but there was variation in the status of disappearance of the secretion. The "excellent" efficacy rates for these three regimens were thus 7.7%, 50% and 57%, respectively. These results showed that administration of the total dosage in two or more divided doses maintained higher minimum concentrations of the antibiotic in the blood and the urine, and were thus more clinically beneficial than when the dosage was given as one daily dose. Of the patients who were treated with 600 mg/day of AT-2266 in 3 divided doses, 93 were evaluated for the therapeutic efficacy. At the end of 3 days 57.0% were "excellent" cases, 39.8% were "good" cases and 3.2% were "fair" cases, and at the end of 7 days of therapy, 67 patients were 74.6% "excellent" cases, 23.9% were "good" cases and 1.5% were "fair" cases. The clinical efficacy rate was thus quite high. Those cases in which the secretion and leukocytes had not disappeared from the urine even at the end of the 7 days of therapy were probably cases of mixed infection involving Chlamydia, etc. Eight of the 77 gonococcal isolates (10.4%) were beta-lactamase producers. The MIC of AT-2266 hardly differed with the size of the bacterial inoculum. With an inoculum of 10(6)CFU/ml, the MIC distribution showed two peaks, i.e., at 0.05-0.2 micrograms/ml and 3.16-12.5 micrograms/ml. Only 11.7% of the strains were found to have high MICs. The distribution of these high MICs was found to be unrelated to the ability to produce beta-lactamase. Mild side effects of AT-2266 were seen in 2 out of 128 patients. (1.6%), an extremely low incidence.

非淋菌性尿道炎症例に対し,AT-2266 1日600 mg 7日間投与し,その治療成績の検討とともにそれら症例の各種背景因子の詳細な分析も合わせて行なった.1)非淋菌性尿道炎症例106例の年齢分布は10歳代後半から30歳代前半にかけて症例が多く15歳～19歳が11.3%にもなっている.2)感染源は歓楽街女性:素人女性の比が37:53と素人女性が多く,淋菌感染症のそれと逆転していた.3)尿道分泌物培養で得られた分離菌は,ほとんどがGPCことにS. epidermidisであったが,全症例の51.6%は菌陰性であった.4)尿道分泌物の性状は膿性のものが51.9%,漿性のものが48.1%に見られた.5) AT-2266 1日600 mg(分3服用)7日間投与による有効率は膿性分泌物例群では,3日間及び7日間治療で有効率それぞれ24.3%,61.1%であり,漿性分泌物例群ではそれぞれ,36.0%,71.4%であった.6) AT-2266服用による副作用は90例中5例に軽度の胃腸障害を中心として症状発現を見たが,投与中止の必要なものはなかった AT-2266 tablets were administered orally in a daily dosage of 600 mg for 7 consecutive days as treatment of non-gonorrheal urethritis in 106 cases. The therapeutic results in 90 cases were investigated, and a detailed analysis of various background factors was also performed. Most of the patients were between 15 and 35 years old; 11.3% of the patients were between 15 and 19 years old. The source of infection was a "professional" woman such as a prostitute in 37 cases, and a non-professional woman in 53 cases. This is noteworthy because the source is more often a "professional" women in the case of gonorrhea. Bacterial isolates were obtained by culture of the urethral secretions. Most were gram-positive cocci, especially S. epidermidis, but, in 51.7% of the patients, no bacteria could be cultured. The urethral secretion was purulent in 51.9% of the patients, and serous in the remaining 48.1%. The efficacy rates obtained when AT-2266 was administered in a daily dosage of 600 mg (in 3 divided oral doses) for 7 days were as follows. In the purulent secretion group, the 3-day and 7-day therapeutic efficacy (elimination of the secretion) rates were 24.2% and 61.2%. In the serous secretion group, the corresponding efficacy rates were 36% and 71.4%. Thus the therapeutic efficacy was slightly inferior in the purulent secretion group. Oral administration of AT-2266 resulted in side effects in 5 of the patients (5.5%). These side effects consisted primarily of mild gastrointestinal disturbances, which did not require discontinued drug administration.