臺灣博碩士論文加值系統

在革蘭氏陰性菌中，克雷白氏肺炎桿菌（Klebsiella pneumoniae）是一種常引起院內感染的重要病原菌。其常易引起泌尿道感染、肺炎、腦炎、敗血性休克及系統性感染等，而且在經由抗生素治療後，仍然有相當高的死亡率。近15年來，發現一種新興的克雷白氏肺炎桿菌感染症，其臨床表現為原發性肝膿瘍合併菌血症，有時更併發轉移性眼內炎或腦膜炎，此症於台灣之發生率遠高於歐美地區且逐年升高。近年來由於在感染疾病之治療及動物飼養的抗生素使用不當，造成多重抗藥性克雷白氏肺炎桿菌大幅增加，如AmpC β-lactmases菌株，又加上目前並沒有這種β-lactmases的標準偵測方法，使得AmpC β-lactmases不容易被發現，因而導致治療上的失敗。另外，integron是近年來被認為繼質體和轉位子（transposons）外，另一個與細菌獲得新抗藥性基因及抗藥性基因散佈有關的機制，因此本研究主要分析克雷白氏肺炎桿菌中的AmpC β-lactamases（AmpCs），並探討其在菌體內的存在位置及移動散佈的情形。
實驗菌株為1993年及2004年所收集自臨床檢體分離的620株克雷白氏肺炎桿菌，以紙錠瓊脂擴散法來進行藥物敏感性試驗。結果發現在620株克雷白氏肺炎桿菌中，對cefoxtin呈現非感受性的菌株有47株（約8％），進一步利用M3D、boronic acid based disk及PCR來確認AmpCs在此47株克雷白氏肺炎桿菌中的存在情形，結果分別有17株、21株及11株為AmpCs陽性，以這三種方法任一確認AmpCs呈陽性的菌株則有25株。ampC之基因型以blaACT-like、blaDHA-like及blaCMY-2-like為主。
25株確認為AmpCs陽性的菌株，其藥敏試驗結果發現這25株克雷白氏肺炎桿菌除了對cefoxitin的抗藥性較為普遍外，對β-lactam/β-lactamase inhibitor combination藥物、第三代cephalosporins、aminoglycosides、aztreonam、ciprofloxacin呈現抗藥性菌株的比例則約12%~68%間，但仍有100％、88％的菌株對meropenem、cefepime具有感受性。有22株（88％）克雷白氏肺炎桿菌帶有class 1 integron，而攜帶之基因片匣主要包括trimethoprim抗藥基因（dfr5、12、17）、streptomycin抗藥基因（aadA1、2、5）、erythromycin抗藥基因（ereA2）、aminoglycoside-6’-N-acetyltransferase酵素（aac(6’)-Il，aac(6’)IIc）與rifampin抗藥基因（arr）等藥物之抗藥基因片匣，其中以帶有dfr12-orfF-aadA2這3個片匣組合的菌株所佔比率最高。
質體分析結果發現克雷白氏肺炎桿菌體內有不同大小的質體存在。菌株攜帶的ampC基因如blaDHA-like、blaACT-like及blaCMY-2-like分別位在分子量約130、150及100 kb的質體上，而class 1 integron則多位於30∼165 kb的質體上。接合試驗結果發現攜帶blaACT-like的質體不具轉移性，而blaCMY-2-like的質體則有轉移性，可一併散佈轉移性質體所攜帶的抗藥基因。此外，有2株未知的ampC基因與class 1 integron同時位在分子量約159 kb的質體上，並可一起隨此質體轉移。
研究結果顯示，以boronic acid based disk偵測克雷白氏肺炎桿菌中質體所表現的AmpCs有較高的敏感性，擁有AmpCs之克雷白氏肺炎桿菌大多呈現多重抗藥性，同時ampC基因可藉由轉移性質體在菌株間水平式轉移來傳遞抗藥性基因，顯示ampC基因在克雷白氏肺炎桿菌抗藥性上扮演著不可忽視的角色。

Klebsiella pneumoniae is one of the common pathogens causing community-acquired and nosocomial infections. It usually causes a wide spectrum of infections, including septicemia, pneumonia, urinary tract infection, meningitis and systemic infection. The high mortality still happened even if treatment of antibiotic. In the past 15 years, a new type of invasive K. pneumoniae disease has emerged in Taiwan that typically present as community-acquired primary liver abscess with metastatic meningitis and endophthalmitis. The high mortality rate and high incidence of K. pneumoniae pyogenic liver abscess in Taiwan make further investigation necessary. Improper use of various antibiotics for the treatment of diseases resulted in an increase of K. pneumoniae resistant to multiple drug. AmpC β-lactamases are cephalosporinases that confer resistance to a wide variety of β-lactam drugs and that may thereby create serious therapeutic problems. Currently, there are no recommendations available from the Clinical and Laboratory Standards Institute (CLSI) for detection of organisms producing AmpC β-lactamases（AmpCs）and often leaving clinicians with limited therapeutic options. Apart from R-plasmids and transposons, integron are known to be another mechanism for acquisition and dissemination of resistance genes among gram-negative bacteria. Therefore, this study attempts to detect AmpCs in K. pneumoniae. Class 1 integrons and plasmids were also characterized to further ascertain their roles in dissemination of AmpCs.

A total of 620 cinical isolates of K. pneumoniae were collected from
KMUH in 1993 and 2004. 47 K. pneumoniae isolates showing non-susceptible to cefoxitin (inhibition zone less than 18 mm) were tested further to confirm the presence of AmpC β-lactamases. AmpCs were confirmed in 17, 21 and 11 of the isolates by modified three-dimensional (M3D), boronic acid based disk test and PCR, respectively. Strains of positive for any one of the three tests included 25 K. pneumoniae isolates. PCR analysis revealed that blaACT-like、blaDHA-like and blaCMY-2-like were found in 1, 9 and 1 isolates, respectively.
Among 25 AmpCs-producing K. pneumoniae isolates, antimicrobial susceptibility tests showed that susceptibility rate to cefepime and meropenem is 88 and 100%, respectively. 12-68% of the isolates were resistance to β-lactam/β-lactamase inhibitor combination, 3rd-cephalosporins, aminoglycosides, aztreonam, and ciprofloxacin. The percentage of class 1 integrons in these 25 isolates is 88%（22 islaotes）. The gene cassettes carried by integrons included those encoding resistance to trimethoprim (dfr5, 12 and 17), streptomycin (aadA1, 2, 5), erythromycin (ereA2), aminoglycoside-6’-N-acetyltransferase (aac(6’)-Il, aac(6’)IIc), rifampin (arr). Most of the class 1 integrons carried dfr12, orfF and aadA2 cassettes.
Results from Southern hybridization pointed out there existed plasmids of different sizes. ampC genes such as blaDHA-like, blaACT-like and blaCMY-2-like were located on plasmids approximately of 130, 150 and 100 kb, respectively. Class 1 integrons were located on the plasmids ranging from 30 to 165 kb. In addition, conjugation experiments suggested that blaACT-like was located on non-transferable plasmid. On the other hand, an isolate producing CMY-2-like AmpCs possessed a plasmid of 100 kb involving in the transfer of the blaCMY-2 like gene, indicating the plasmid-mediated horizontal transfer of blaCMY-2 like gene. However, the transfer of ampC genes mediated by plasmids did not accompany class 1 integron except two isolates carrying unknown ampC genes.
This study demonstrated that the boronic acid test is more sensitive to detect AmpCs in K. pneumoniae. AmpCs-producing K. pneumoniae isolates are often multidrug-resistant. Plasmid-mediated transfer of ampC genes can lead to the dissemination of antibiotic resistance to diverse bacterial populations. Thus, the ampC may play an important role in multi-resistance of K. pneumoniae.

中文摘要 1
英文摘要 4

緒論
（一）前言 7
（二）克雷白氏肺炎桿菌（Klebsiella pneumoniae） 8
（三）抗生素與細菌抗藥性之機轉 10
（四）乙內醯胺酶（β-lactamases） 15
（五）AmpC β-lactamases 18
（六）抗藥性散佈之新機制：Integron 26
（七）研究目的 29

材料與方法
（一）實驗菌株之收集 30
（二）藥物感受性試驗（藥敏試驗） 31
（三）克雷白氏肺炎桿菌AmpCβ-lactamas偵測 32
（四）Class 1 integron之偵測 37
（五）Class 1 integron基因片匣之分析 38
（六）ampC基因及class 1 integron於菌株內存在位置之分析 42
（七）ampC基因與class 1 integron轉移之分析—接合試驗 48

結果
（一）克雷白氏肺炎桿菌對cefoxitin之感受性 51
（二）克雷白氏肺炎桿菌之AmpCs表現型之偵測 51
（三）克雷白氏肺炎桿菌之ampC基因型之偵測 52
（四）攜帶AmpCs之克雷白氏肺炎桿菌中抗藥情形 52
（五）Class 1 integron於攜帶AmpCs之克雷白氏肺炎
桿菌內存在情形及所攜帶之基因片匣 53
（六）AmpCs與菌株抗藥性及class 1 integron之相關性 55
（七）ampC基因與class 1 integron於菌體內存在位置之分析 56
（八）ampC基因與class 1 integron轉移情形 57

討論
（一）克雷白氏肺炎桿菌對cefoxitin之抗藥情形 59
（二）克雷白氏肺炎桿菌之AmpCs 60
（三）攜帶AmpCs之克雷白氏肺炎桿菌抗藥情形 62
（四）AmpCs與菌株抗藥性及class 1 integron之相關性 63
（五）ampC基因與class 1 integron於菌體內存在位置及轉
移之分析 64
（六）結論 66
表 67
圖 77
參考文獻 82
附錄
附圖一：乙內醯胺酶的分子特性與功能 90
附圖二：Integron結構圖 91
附圖三：Class 1 integron結構圖 92
附圖四：Integron主導之特定位置重組作用 93

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