評估南臺灣fosfomycin對廣效性乙內醯胺酶腸內菌的殺菌效果以及抗藥機轉分析

抗生素的發展在近年來日漸趨緩，短期內能上市的新抗生素寥寥無幾；然而細菌的抗藥性卻逐年攀升使得臨床醫師在治療多重抗藥性(multi-drug) 細菌感染時能夠治療的手段有限；特別是廣效性乙內醯胺酶(Extended-spectrum β-lactamases ;ESBL) 腸內菌在台灣日益增加造成治療的困難。在此青黃不接的時期，國外開始回頭嘗試老藥新用將早期研發而少用的抗生素磷黴素 (fosfomycin)合併其他抗生素用來治療多重抗藥性細菌的感染，甚至於對目前現存後線抗生素完全無效的全抗藥型(pan-drugresistant)細菌。為了評估南台灣地區磷黴素對難以治療廣效性乙內醯胺酶腸內菌是否有效以及人與動物之間的盛行率，本研究收集了180株腸道桿菌包含高雄醫學大學附設中和醫院 (120株)、衛生福利部屏東醫院(38株)以及數間家畜飼養場(22株)。藥物敏感性試驗發現磷黴素對於廣效性乙內醯胺酶腸內菌多具有感受性 (大腸桿菌91%；肺炎克雷伯氏菌62%)。廣效性乙內醯胺酶調查發現肺炎克雷伯氏菌以SHV 71%(25/35)、CTX-M1 22%(8/35)及DHA 22%(8/35)基因出現機率較高而大腸桿菌以TEM 31%(45/145)、CTX-M1 23%(34/145)、CTX-M9 39%(57/145) 及CMY 24%(35/145)基因出現機率較高。磷黴素抗藥機轉分析發現四株大腸桿菌帶有fosA3抗藥基因 (三株來自動物，一株來自人類)，脈衝式電泳配合南方墨點法確認fosA3基因在質體上並在動物分離株中同時帶有CTX-M抗藥基因。基因上下游分析發現具有IS26基因可能是此基因傳遞的主因。此外14株磷黴素抗藥性大腸桿菌中發現3株MurA胺基酸發生突變、6株具有GlpT胺基酸突變與9株具有UhpT胺基酸突變影響磷黴素的藥物感受性。12株磷黴素抗藥性肺炎克雷伯氏菌中發現9株MurA胺基酸發生突變、9株具有GlpT胺基酸突變與6株具有UhpT胺基酸突變影響磷黴素的藥物感受性。這些調查及分析的實驗數據希望對未來臨床上治療ESBL腸道桿菌以及感染防治能有貢獻。

關鍵字

磷黴素

並列摘要

According to medical evolution, different antibiotics have been discovered and are used to treat serious infections. However, antibiotic resistant strains are increasingly prevalent and become a global health problem. Due to development of new antibiotic can take years and millions of dollars, the rational use of old antibiotics, like polymyxins, fusidic acid and fosfomycin may be a short-term solution. Fosfomycin has been used successfullyfor the treatment of urinary tract infections for a long time; fosfomycin could be a suitable candidate for the treatment of multidrug-resistant pathogens or extended-spectrumβ-lactamases Enterobacteriaceae. In order to evaluate the efficacy of fosfomycin against extended-spectrumβ-lactamases Enterobacteriaceae in southern Taiwan,this study collected different specimens from human and livestock.The susceptible rates of fosfomycin were 94% (115/123), and 77% (17/22)for ESBL-producing E. coli isolates from human and livestock. PFGE analysis revealed 79 pulsotypes. Transmissivepulsotypes (XXIX, XXXIV, and XLIV) found between two medical centers whereas no intersectional puslotype found in human and animal isolates. ESBLs and linkage of transposable elements found that Tn2 carrying blaTEM and ISEcp1 carrying blaCTX-M9 was predominant type in two medical hospitals and animal isolates. Among 13 (9%) fosfomycin resistant isolates, 3 and 4 isolates contained novel amino acid substitutions in MurA and plasmid-mediated fosfomycin modified enzyme (fosA3), respectively. Functionless transporters via different chromosomal mutations were identified in 11 isolates. The susceptible rates of fosfomycin were 62% (22/35),and 100%(2/2) from human and livestock ESBL-producing Klebsiella pneumoniae isolates. PFGE analysis revealed 25 pulsotypes. Transmissivepulsotypes (VI, XI, and XIV) found between two medical centers whereas no intersectional puslotype found in human and animal isolates. ESBLs and linkage of transposable elements found that Tn2 carrying blaSHV and ISEcp1 carrying blaCTX-M1 was predominant type in two medical hospitals and animal isolates. Among 12 (34%) fosfomycin resistant isolates, 9 isolates contained novel amino acid substitutions in MurA. Functionless transporters via different chromosomal mutations were identified in 3 isolates. Disable transporters were major cause offosfomycin resistant ESBLs-producing isolates and the horizontal fosA3-transferring between human and animal should be monitored in Taiwan.

並列關鍵字

fosfomycin

參考文獻

參考文獻:

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