臺灣博碩士論文加值系統

抗藥菌問題已成為全球規模性的公眾議題，抗藥性的產生不僅限制了治療上的選擇，也造成致病率、死亡率和治療成本的增加。多重抗藥性鮑氏不動桿菌被認為是最難控制和治療的院內感染菌株，尤其近年來出現的多重抗藥性鮑氏不動桿菌 (Multidrug-resistant Acinetobacter baumannii, MDRAB)、碳青黴烯類抗藥性鮑氏不動桿菌(Carbapenem resistant Acinetobacter baumannii , CRAB)、超廣譜乙內醯胺酶格蘭氏陰性菌(Extended-spectrum β-lactamases producing gram-negative bacteria，ESBL producing GNB) ，高度抗藥性 (Extensively drug-resistant Acinetobacter baumannii, XDRAB)及泛抗藥性 (Pandrug-resistant Acinetobacter baumannii, PDRAB)等菌株。由於抗藥性機轉的不同，雖然許多醫療單位已著手管控抗生素的使用與關注抗藥性的議題，但唯有瞭解院內抗藥菌的傳播路徑與抗藥機制，方能有效即時掌控、制定預防之道。本研究收集自嘉義基督醫院所分離的臨床菌株，並應用統計方法進行抗藥性、特定抗藥基因組合與生物膜生成的交互作用分析。利用紙錠擴散法和最低抑菌濃度進行抗生素敏感性測試，包括11種抗生素，分別為Cephalexin, Ceftazidime, Imipenem, Gentamycin, Amikacin, Streptomycin, Piperacillin, Ticarcillin, Carbenicillin, Tetracyline, Sulfamethoxazole-Triethoprim。 基因分型探討計分析9個與抗藥性有關的基因，包括: blaOXA-51-like, blaOXA-23-like, blaOXA-58-like, blaOXA-24-like, blaOXA-143-like, tnpA, ISAba1, blaNDM和blaADC。此外，利用Carba NP test快速檢測抗藥菌所攜帶的基因，及分析碳青黴烯類抗藥性鮑氏不動桿菌其抗藥基因的關聯性。生物膜生成利用分光光度測量法及掃描式電子顯微鏡觀察，並分析生物膜生成相關的基因bap, blaPER, ompA和csuE。本研究結果顯示大部分測試菌株具有多重抗藥性，且多數的碳青黴烯類抗藥性鮑氏不動桿菌 (93%) 攜帶ISAba1基因，其中高達68%的菌株同時攜帶tnpA和ISAba1基因。在生物膜生成分析，發現具有抗藥基因的菌株其生物膜形成量明顯較高，且多數具有多重抗藥性。本研究證實測試菌株的抗藥性、生物膜的生成和攜帶的抗藥基因型具有關聯性，分析其抗藥機轉有助於臨床抗藥菌的篩選、鑑定、診斷、治療與管控，可提供預防菌株產生抗藥性的重要參考指標。

The problem of antibiotic-resistant strains has become a global public issue; antibiotic resistance not only limits the choice of treatments but also increases the morbidity, mortality and treatment costs. The multi-drug resistant Acinetobacter baumannii is occurring simultaneously in hospital and has become a major public health issue worldwide. Antimicrobial-resistant strains of Acinetobacter baumannii, including multidrug-resistant Acinetobacter baumannii (MDRAB), carbapenem resistant Acinetobacter baumannii (CRAB), extended-spectrum β-lactamases producing gram-negative bacteria (ESBL producing GNB), extensively drug-resistant Acinetobacter baumannii (XDRAB) and pandrug resistant Acinetobacter baumannii (PDRAB) strains, endanger the efficacy of antibiotics and threaten with millions of lives of the world. Although many medical units have begun to control the use of antibiotics and paid attention to the issue of drug resistance, understanding of the transmission pathways of clinical drug-resistant bacteria and drug-resistant mechanisms can be effective to real-time control and prevent the outbreak of antibiotic resistant pathogens. In this study, a total of 154 isolates of Acinetobacter baumannii obtained from Chia-Yi Christian hospital were collected for antibiotic-susceptibility assay, specific resistance genotyping and biofilm formation analysis. The statistical analysis was used to determine the interaction between antibiotic-susceptibility, specific resistance genotype combinations and biofilm formation. Antibiotic-susceptibility assays were conducted with disc diffusion method and minimum inhibitory concentration determination; a total of 11 antibiotics included cephalexin, ceftazidime, imipenem, gentamycin, amikacin, streptomycin, piperacillin, ticarcillin, carbenicillin, tetracyline and sulfamethoxazole-triethoprim were used for the assays. Nine genes related to drug resistance, including blaOXA-51-like , blaOXA-23-like, blaOXA-58-like, blaOXA-24-like, blaOXA-143-like, tnpA, ISAba1, blaNDM and blaADC were selected for genotyping analysis. In addition, Carba NP test was used to rapidly analyze the resistant genes. The analysis of biofilm formation was determined by spectrophotometry and scanning electron microscope observation, and the biofilm related genes, including bap, blaPER, ompA and csuE, were analyzed. The results showed that most of the tested strains possessed multiple drug resistance against most of the test antibiotics. Among the carbapenem resistant strains of Acinetobacter baumannii, 93% of the strains carried ISAba1 gene and 68% of the highly multidrug-resistant strains carried tnpA and ISAba1 genes. In the biofilm formation analysis, it was found that the multiple drug resistant isolates usually provided a higher biofilm formation. The experimental results indicated that the antibiotic resistance, the formation of biofilm and the resistant genotype were significantly related. The results of this study can effectively help to understand the correlation between drug resistance, biofilm formation and its resistant genotype. The analysis on the antibiotic resistant mechanism provides the valuable information to the screening, identification, diagnosis, treatment and control of clinical antibiotic-resistant pathogens, and an important reference pointer to prevent strains from producing resistance.

中文摘要….............................................I
Abstract.............................................III
Acknowledgements......................................V
Table of Contents.....................................VI
List of Tables........................................IX
List of Figures........................................X
Chapter 1.Introduction.................................1
1.1 Introduction.......................................1
1.2. Objectives........................................3
Chapter 2. Literature review...........................4
2.1 Acinetobacter......................................4
2.1.1 Clinical manifestations of A. baumannii infections...8
2.1.2 Multidrug resistance in MDRAB....................8
2.2 β-Lactamase activity...............................9
2.2.1 β-Lactamase classification......................10
2.3 Antimicrobial and antibiotic resistance mechanisms...13
2.4 Antibiotics introduction.........................16
2.4.1 β-Lactam antibiotics............................16
2.4.2 Penicillins.....................................17
2.4.3 Ampicillin......................................18
2.4.4 Cephalosporins..................................18
2.4.5 Carbapenems.....................................20
2.4.6 Tetracyclines...................................21
2.4.7 Tigecycline.....................................21
2.4.8 Aminoglycosides.................................22
2.4.9 Sulfamethoxazole – Trimethoprim................23
2.5 Biofilm Development...............................24
2.5.1 Environmental factors affecting biofilm formation 24
2.5.2 Relationship of A. baumannii resistance with biofilm formation..............................................24
2.5.3 Biofilm formation in A. baumannii................25
Chapter 3. Materials and methods.......................27
3.1 Bacterial Strains..................................27
3.2 Antibiotic susceptibility test.....................27
3.3 Molecular characterization of antimicrobial resistance determinants...........................................28
3.4 Repetitive element PCR-mediated DNA fingerprinting (Rep-PCR)...................................................30
3.5 Carba NP test......................................30
3.6 Detection of biofilm related genes..................30
3.7 Quantitative assay of biofilm formation............31
3.8 Microscopic analysis of biofilm formation..........31
3.9 Statistical Analyses...............................32
Chapter 4. Results.....................................34
4.1 Antibiotic susceptibility test by the disk diffusion method.................................................34
4.2 Minimum inhibitory concentrations..................35
4.3 Relationship between antibiotic susceptibility and biofilm formation......................................37
4.4 Various virulence determinants are involved in the biofilm formation of A baumannii……………………………………………………………………….38
4.5 Biofilm formation quantification...................42
4.6 Microscopic analysis of biofilm formation ability..43
4.7 Molecular characterization of the antimicrobial resistance determinants................................45
4.8 Detection of OXA Carbapenemases expression.........47
4.9 Repetitive element PCR-mediated DNA fingerprinting (Rep-PCR)...................................................50
4.10 Carba NP test.....................................51
4.11 Correlation between resistant gene, DISK, MIC and biofilm determinants...................................52
Chapter 5. Discussion and conclusion...................61
5.1 Future Work........................................68
Publications...........................................69
List of papers.........................................69
List of conference papers..............................69
Supplementary Table....................................71
Supplementary Table 1. Distribution of gene, DISK and MIC results in different biofilm stress classification (n=154)71
Supplementary Table 2. Distribution of gene, DISK and MIC results in high and low biofilm producer category...... 74
Supplementary Table 3. Logistic regression analysis for association between biofilm stress category and gene, DISK and MIC results........................................75
Supplementary Table 4. Forest plot showing associations of higher odds to obtain high biofilm formation in clustering results with five clustering inclusion criteria........ 76
References…………………………………………………………………………77

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