臺灣博碩士論文加值系統

根據世界衛生組織的資料顯示，每年約有6千2百萬的淋病新發生個案；我國疾病管制局的資料顯示，2005年台灣地區淋病通報個案數為1515位，盛行率約為每十萬人口分之6.67，感染這群人的淋病雙球菌中有多少比例是具有抗藥性的菌株，若不知道現行抗藥情形，誤用沒有感受性的抗微生物製劑而導致治療失敗，將可能帶來後續其他的公共衛生問題。

過去的三十年間，淋病雙球菌已被偵測出具有抗sulfonamide、penicillin、tetracycline等傳統用來治療淋病的抗生素，故這幾類抗生素已不適合用於治療淋病雙球菌的感染，改以氟喹諾酮類(FQ；fluoroquinolones；FQ)來治療淋病。由於大量使用甚至濫用氟喹諾酮類抗微生物製劑之故，以及當時未有及時且適當之淋病抗藥性監測系統，因此在90年代末期，全球包括亞洲地區、英國、美國、加拿大等地，造成抗氟喹諾酮類(fluoroquinolones)之抗藥性菌株(fluoroquinolone-resistant N. gonorrhoeae, QRNG)的浮現。而現行台灣淋病抗藥性的資料仍嫌不足。

因此本研究將透過田野調查及健保資料庫了解台南地區治療淋病之抗微生物製劑使用情形，以及操作抗生素敏感性試驗(Etest)，了解各淋病菌株經由最小抑制濃度(MIC)所得的抗藥性型態；並在無法取得部份淋病病人菌株檢體的情形下，透過分子生物技術偵測基因突變情形，以了解台南地區淋病雙球菌抗藥性的流行現況。

本研究承接郭慕蓉的研究，自2003年10月至2004年12月底止，收集來自台南市地區6家基層診所及1家地區醫院，診斷為淋病或尿道炎或子宮頸炎病患之個案共423人，經多重引子聚合酶連鎖反應偵測，淋病盛行率為19%(80/423)。其中有93.8%(75/80)的檢體發生QRDR基因突變，推測約有87.5%(70/80)可能感染高度抗藥性淋病菌株。細分gyrA與parC突變位置之胺基酸變異的分部情形，27.5％ (22/80)的個案其胺基酸變異型態為M7，其次是M9(23.8％；19/80)。在gyrA-91(M15)以及parC-87(M18)有過去未被報告過的點突變，分別是gyrA Ser91→Leu以及parC Ser87→Cys。在醫學中心部份，1999年7月至2004年12月五年半來，於成大醫院經細菌培養確診為淋病90名病人中，保存了其中83 (92.2%；83/90)株從病人身上分離之淋病雙球菌菌株，88%(73/83)發生QRDR基因突變，M9型態佔了43.4.％ (36/83)的個案為最多。
另僅67名病人之菌株可供Etest偵測MIC值，結果顯示淋病菌株對於各抗生素均產生抗藥性，抗藥性盛行率分別為，Penicillin (100%)、TMP/SMX (100%)、Tetracycline (97%)、Fluoroquinolones (85%)、Erythromycin (20.9%)。

在抗生素使用部分，90名來自某醫學中心之淋病個案中，初次就診的用藥分佈為，四環素類(43.3%)、頭孢子素類(24.4%)、氟奎諾酮類(22.2%)、盤尼西林類(1.1%)、其他(8.9%)。全民健康保險資料庫2000、2001、2002三年之第一季(1~3月)的資料顯示，在台南大都會區被診斷為淋病個案之用藥情形分布，按醫療層級區分，非基層診所(醫學中心、區域醫院、地區醫院)之用藥前三名為四環素類(54% ; 20/37)，其次為頭孢子素類(21.6% ; 8/37)、氟奎諾酮類(8.1% ; 3/37)；基層診所用藥分佈前三名為頭孢子素類為(36.8% ; 21/57)、其次為四環素類(15.8% ; 9/57)、氟奎諾酮類(10.5%; 6/57)。

現行台灣地區無治療淋病的建議用藥準則，希望本研究未來可促使有關當局制定治療淋病之官方建議用藥準則，重視本土淋病抗藥性監測設系統設立的必要性，以偵測新興抗藥性淋病菌株之浮現。

A physician-based sentinel surveillance on Neisseria gonorrhoeae (GC) infection has identified hidden epidemic of gonorrhea in a southern Taiwan city (Tainan), where there is no standard national treatment guideline and no definite patterns of antimicrobial resistance are available currently. Therefore, we conducted a study, and the goals of this study include: (1) to determine quinolone resistance in GC positive urine specimens from the surveillance by molecular techniques; and (2) to determine the antimicrobial resistance profiles in GC isolates from a medical center in the same city. In addition, we would also identify current antimicrobial prescriptions for GC infections in Tainan.

Quinolone resistance-determining region (QRDR) of gyrA and parC were amplified by PCR on 80 GC-positive urine specimens from the surveillance during November of 2003 and December of 2004 and 67 isolates were obtained from the medical center during 1999 and 2004. Then, the amplicons were sequenced directly. Sequences of QRDR were compared to published mutations associated with decreased susceptibility or resistance to fluoroquinolones in GC. Novel mutations were identified by comparing sequences in published literature and GenBank. Antimicrobial resistance profiles (penicillin, tetracycline, ofloxacin, norfloxacin, erythromycin, azithromycin, ceftriaxone, cefixime, and trimethoprim/sulphamethoxazole) of GC isolates were performed by Etest. The antimicrobial prescription for GC infections were obtained medical records of GC patients from a medical center in Tainan and from National health insurance ambulatory claim data of Feb. to Mar. 2000, Feb. to Mar. 2001 and Feb. to Mar. 2002 respectively in the same city.

Overall, 90.8% (148/163) specimens had known mutations in QRDR with decreased susceptibility or resistance to fluoroquinolones. Majority (84/148) of them possessed mutations in both genes. Noticeably, two amino acid mutations were identified for the first time from two patients (gyrA:Ser91→Leu, parC:Ser87→Cys). The antimicrobial resistance profiles were available on 67 isolates, all were resistant to trimethoprim/sulphamethoxazole and Penicillin, followed by Tetracycline (97%), Fluoroquinolones (85%), and Erythromycin (20.9%). All isolates were susceptible to third-generation of Cephalosporins, Azithromycin and Spectinomycin. According to the medical records documented in the prescriptions, the top three antimicrobials for GC infection in order were Tetracycline (43.3%), Cephalosporins (24.4%), Fluoroquinolones (22.2%). We can also found a similar result if we combined the antimicrobial prescriptions from medical center, regional & district hospitals in the NHI database. Differently, the most use of antimicrobial for GC was Cephalosporins (36.8%) in clinics from the database of National Health Insurance.

High mutation rates in QRDR coupling with low susceptibility rates to commonly used prescribed antimicrobials for treatment of gonorrhea in this southern Taiwan city indicate that an urgent need for a national treatment guideline and an effective molecular epidemiologic surveillance on GC infection and resistance patterns is warranty before the hidden epidemic becomes out of control.

第一章 前言 1
第二章 文獻回顧 3
第一節 淋病雙球菌與淋病 3
一、淋病雙球菌 3
二、淋病 4
第二節 淋病流行病學 5
第三節 抗藥性淋病流行病學 9
一、抗盤尼西林 (Penicillin Resistance) 9
二、抗氟喹諾酮類 (Fluoroquinolones Resistance) 11
三、抗頭孢子素類 (Cephalosporins Resistance) 15
四、抗四環黴素類 (Tetracycline Resistance) 16
五、抗巨環類(Macrolides Resistance) 18
六、抗其他抗微生物製劑 (Other Antimicrobials Resistance) 20
第四節 抗藥性淋病偵測 22
一、藥物敏感性試驗偵測 22
二、質體抗藥性偵測 24
三、分子生物技術偵測 24
四、臨床診斷偵測 26
第五節 抗微生物製劑使用概況 27
一、台灣 27
二、國外地區 28
第三章 研究問題與方法 31
第一節 研究問題 31
第二節 研究對象 32
第三節 研究設計與架構 34
一、實驗室檢測 34
二、全民健康保險資料庫 48
第四節 資料分析 49
第四章 研究結果 50
第一節 診所與區域級醫院之感染淋病雙球菌個案 50
第二節 醫學中心之感染淋病雙球菌個案 52
第三節 抗微生物製劑使用情形分布 55
第五章 討論 58
第一節 研究結果討論 58
第二節 研究限制與建議 63
研究限制 63
建議 64
第六章 參考文獻 65

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