對碳青黴烯類抗生素具抗藥性之克雷伯氏肺炎桿菌分子流行病學調查及產生碳青黴烯類抗生素抗藥性之危險因子研究

Molecular Epidemiology Survey of Carbapenem Resistant Klebsiella pneumoniae and Risk Factors of Acquiring Carbapenem Resistance

張嘉瑋(Chia-Wei Chang)

指導教授 ： 方啟泰

國立臺灣大學/公共衛生學院/流行病學與預防醫學研究所/碩士(2011年)

https://doi.org/10.6342/NTU.2011.02390

摘要

背景 廣泛抗藥性克雷伯氏肺炎桿菌是近年來各國關注的院內感染問題。碳青黴烯類抗生素是用來治療產超廣效性乙內醯胺分解酶腸內菌的嚴重感染症之首選抗生素，碳青黴烯類抗生素抗藥性的產生與擴散對臨床治療造成莫大的衝擊。近年在台灣臨床上分離出的克雷伯氏肺炎桿菌對碳青黴烯類不具感受性的情形似有逐漸上升的趨勢。因此，站在公共衛生的角度，偵測帶有碳青黴烯類抗生素抗藥基因的克雷伯氏肺炎桿菌，並了解使克雷伯氏肺炎桿菌對碳青黴烯類抗生素呈現抗藥性之危險因子是重要的議題。
材料與方法 我們對2007-2010年台大醫院臨床分離克雷伯氏肺炎桿菌菌株進行碳青黴烯類抗生素抗藥基因分子流行病學調查，針對58株於最小抑制濃度測試對碳青黴烯類抗生素表現不具感受性(MICERTA≥ 0.5mg/L)之克雷伯氏肺炎桿菌(ertapenem-non- susceptible K. pneumoniae)以聚合脢鏈反應方法檢測其是否帶有任何潛在的碳青黴烯類抗生素抗藥基因。對於僅帶有超廣效性乙內醯胺分解酶基因，未帶有碳青黴烯類抗生素抗藥基因但卻表現碳青黴烯類抗生素不具感受性的菌株(ESBL-producing ertapenem-non- susceptible K. pneumoniae)，我們進一步以32株對碳青黴烯類抗生素具感受性之帶超廣效性乙內醯胺分解酶基因之克雷伯氏肺炎桿菌(ESBL-producing ertapenem-susceptible K. pneumoniae) 做為對照組，以病例對照研究設計探討病人特性、菌株於抗生素暴露的情形以及所帶有的乙內醯胺分解酶之基因型是否為使ESBL-producing ertapenem-susceptible菌株獲得碳青黴烯類抗生素抗藥性之危險因子。
結果 分子流行病學調查發現，在58株在最小抑制濃度測試對碳青黴烯類抗生素表現抗藥性之克雷伯氏肺炎桿菌中，偵測到8株(14%)具有碳青黴烯類抗生素抗藥基因，分別為blaIMP-8（n=1）、blaVIM-1（n=2）、blaOXA-23（n=3）、blaOXA-65（n=5）（部分菌株帶有兩種以上碳青黴烯類抗生素抗藥基因）。剩下的50株(86%)未偵測到任何碳青黴烯類抗生素抗藥基因，僅帶有多種超廣效性乙內醯胺分解酶之抗藥基因。病例對照研究結果顯示，調整干擾因子影響後，僅有一個顯著的危險因子會增加僅帶有超廣效性乙內醯胺分解酶基因型的克雷伯氏肺炎桿菌表現碳青黴烯類抗生素抗藥性之風險，為帶有blaCTX-M-14和blaDHA-1之複合基因型 (校正後的OR=21.8, p<0.001)，其族群歸因比例為70.2%。另外，帶有blaCTX-M-14和blaDHA-1之任一基因的菌株於碳青黴烯類抗生素暴露之分層分析結果顯示，碳青黴烯類抗生素的暴露對於對僅帶有blaCTX-M-14和blaDHA-1基因型且對碳青黴烯類抗生素具感受性之克雷伯氏肺炎桿菌，會增加產生碳青黴烯類抗生素抗藥性之風險，且最小抑制濃度越高，產生抗藥性之風險越高。
結論 本研究首次在台灣的碳青黴烯類抗生素抗藥性克雷伯氏肺炎桿菌發現VIM型碳青黴烯類抗生素抗藥基因，以及OXA型碳青黴烯類抗生素抗藥基因blaOXA-23和blaOXA-65（過去僅在鮑氏不動桿菌報告過）。病例對照研究結果顯示，在公共衛生上若採取適當措施針對帶複合基因之菌株的散佈進行管控，可能可以減少70.2% 僅帶有超廣效性乙內醯胺分解酶基因但卻表現出碳青黴烯類抗生素不具感受性之克雷伯氏肺炎桿菌菌株(ESBL-producing ertapenem-non-susceptible)的浮現。

關鍵字

克雷伯氏肺炎桿菌 ； 碳青黴烯類抗生素 ； 抗藥性 ； 抗藥基因 ； 分子流行病學 ； 危險因子

並列摘要

Background Nosocomial infection caused by multi-drug resistant Klebsiella pneumoniae has become an important public health concern worldwide. Carbapenem-class antibiotics are the main therapeutic options for life-threatening infections caused by extended spectrum beta-lactamase (ESBL)-producing enteric bacteria. Emergence and dissemination of carbapenem resistance has a great impact on clinical treatment. In recent years, there has been an increasing trend of ertapenem-non-susceptible K. pneumoniae clinical isolates in Taiwan. From a public health viewpoint, it is important to detect the emergence and dissemination of carbapenemase genes in K. pneumoniae and to identify risk factors for the acquisition of carbapenem resistance.
Materials and Methods We conducted a molecular epidemiologic survey of carbapenemase genes among 2007–2010 clinical K. pneumoniae isolates at National Taiwan University Hospital. We used polymerase chain reaction to detect carbapenemase genes in 58 K. pneumoniae strains that are not susceptible to ertapenem by a minimal concentration inhibitory test (MICERTA≥ 0.5 mg/L). For ESBL gene-carrying K. pneumoniae strains that did not carry carbapenemase genes but still showed ertapenem-non-susceptible phenotype (ESBL-producing ertapenem-non-susceptible K. pneumoniae), we conducted an epidemic case-control study among 32 ESBL-producing ertapenem-susceptible K. pneumoniae strains (ESBL-producing ertapenem-susceptible) as the control to identify whether characteristics of patients, antibiotic exposure and β-lactamase genotypes of strains are risk factors for the acquisition of carbapenem resistance ESBL-producing ertapenem-susceptible K. pneumoniae.
Results In our molecular epidemiology survey, we detected carbapenemase genes, blaIMP-8 (n=1), blaVIM-1 (n=2), blaOXA-23 (n=2), and blaOXA-65 (n=5) (some strains have ≥2 genes) in 8 (14%) out of 58 ertapenem-non-susceptible K. pneumoniae stains. The remaining 50 ertapenem-non-susceptible K. pneumoniae strains (86%), which did not carry any carbapenemase genes but did carry multiple ESBL genes, are ESBL-producing ertapenem- non-susceptible strains. The results of this epidemic case-control study showed that, after adjusting for the effects of other variables, carrying blaCTX-M-14 (adjusted OR=2.2, p=0.209), carrying blaDHA-1 (adjusted OR=10.6, p=0.008), and simultaneously carrying blaCTX-M-14 and blaDHA-1 (adjusted OR=21.8, p<0.001) are independent risk factors for acquisition of carbapenem resistance by ESBL-producing ertapenem-non-susceptible K. pneumoniae. The total population attributable fraction (PAFTotal) is 70.2%. If ESBL-producing ertapenem- susceptible K. pneumoniae carrying blaCTX-M-14 and/or blaDHA-1 are exposed to carbapenem antibiotics, the risk of acquiring carbapenem-resistance may increase.
Conclusion This study is the first to describe the identification of VIM-type and OXA-type carbapenemase genes in K. pneumoniae in Taiwan (blaOXA-23 and blaOXA-65 previously reported only in Acinetobacter baumannii). The results of an epidemic case-control study suggest that, from a public health view point, appropriate control measures targeting strains simultaneously carrying blaCTX-M-14 and blaDHA-1 may reduce the incidence of ESBL-producing ertapenem-non-susceptible K. pneumoniae by 70.2%.
Keywords: Klebsiella pneumoniae; Carbapenem; Resistance; Drug-Resistant Gene; Molecular Epidemiology; Risk Factor

並列關鍵字

Klebsiella pneumoniae ； Carbapenem ； Resistance ； Drug-Resistant Gene ； Molecular Epidemiology ； Risk Factor

參考文獻

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