以蛋白質體學技術研究鮑氏不動桿菌之多黏桿菌素抗藥性

Proteomic Analysis of Polymyxin-Resistance Acinetobacter baumannii

葉昱辰

鮑氏不動桿菌 ； 抗藥性 ； 多黏桿菌素 ； 親緣性分析 ； 蛋白質體學 ； Acinetobacter baumannii ； antimicrobial resistance ； colistin ； phylogenetic analysis ； proteomics

臺灣大學獸醫學研究所學位論文

2012年

碩士

張紹光

繁體中文

鮑氏不動桿菌 (Acinetobacter baumannii) 是一種分布廣泛的伺機性革蘭氏陰性菌，為人體皮膚上的常在菌叢（normal flora），目前也已在多種動物及相關的產品發現其存在。近年來，多重抗藥性鮑氏不動桿菌 (multidrug- resistant A. baumannii，MDRAB) 隨著抗菌劑的廣泛使用而出現，目前已成為醫療照護相關感染（healthcare associated infections，HAIs）中，難以控制細菌之一。由於MDRAB的出現，以及在藥理學上的重新認識，colistin再次的被用於臨床醫療，但抗藥性菌株也漸漸的開始出現。本研究自2010年9月至2011年3月間，自台灣北、中、南三區的傳統市場和超級市場進行檢體的逢機採樣，共216件。並以改良式Leeds Acinetobacter Medium（MLAM）培養基及馬康奇培養基進行初步分離。再以聚合酶鏈鎖反應增幅16S-23S核糖核酸基因內轉錄區，並搭配序列分析進行比對鑑定。結果共分離28/216（13％）株鮑氏不動桿菌，而傳統市場及超級市場的分離率分別為27/108（25%）及1/108（1％），北、中、南三區的分離率分別為6/36（17％）、10/36（28％）及12/36（33％），以及自台北地區醫院收集72株非重複之鮑氏不動桿菌。本研究亦進行抗菌劑感受性試驗及利用脈衝式電泳（pulsed-field gel electrophoresis，PFGE）調查兩來源菌株的抗藥性及親緣性。由結果得知，市售雞肉來源的菌株對cefazolin外藥品都保持一定的感受性（0∼36％），而人類臨床菌株則有較高的抗藥性（72∼100％），僅對colistin（7％）與ampicillin/sulbactam（10％）保持較佳的感受性。親緣性分析的結果發現，市售雞肉與人類臨床來源的菌株並不共有相同的基因型，故兩來源間應鮮少發生菌株及抗藥性的交流。本研究另外以蛋白質體學方法比較鮑氏不動桿菌標準菌株ATCC 19003及人工誘導抗colistin菌株19003 CR間蛋白質體的差異，結果發現誘導colistin的抗藥性產生，並不會造成菌株基因型別上的變化。藉由二維蛋白質電泳與質譜儀鑑定差異性蛋白質的身分，並以即時定量聚合酶鏈鎖反應（real-time PCR，qPCR）測定這些蛋白質的表現量，結果發現外膜蛋白Omp38在標準菌株有較高的表現量；sensor protein QseC、kdsA蛋白和aacD蛋白則是在抗colistin菌株有較高的表現量，推測colistin抗藥性的產生與細胞膜的合成相關，並受到二元訊號轉導系統調控，但還需更進一步研究其發生的機制。

Acinetobacter baumannii are widely distributed opportunistic Gram-negative bacteria, and also a part of normal bacteria flora of human skin. It can be found in a variety of animals and related product. In recent years, multidrug-resistant A. baumannii ( MDRAB) were emerged, caused by extensive use of antimicrobial agents, and become a part of difficult to control bacterial in healthcare associated infections (HAIs). Due to the emergence of MDRAB, and advances in pharmacology of colistin, colistin is used for clinical again. But colistin-resistant strains began to appear when it is used. In this study, two hundred and sixteen fresh raw chicken meat samples from the traditional markets and supermarkets of northern, medium and southern areas of Taiwan were collected during Sep. 2010 to Mar. 2011. Modified Leeds Acinetobacter medium (MLAM) and MacConkey agar was used as the isolation and selective medium. The samples were identified by amplify the 16S-23S internal transcribed spacers (ITS) region by polymerase chain reaction and sequence method. The total ratio of isolation was 13% (28/216). The ratio of isolation for traditional markets and supermarkets were 25% (27/108) and 1% (1/108), respectively. The prevalence of the northern, middle and southern regions was 17% (6/36), 28% (10/36) and 33% (12/36), respectively. A total of 72 isolates were consecutively collected from regional hospital in Taipei. In this study, antimicrobial susceptibility testing and pulsed field gel-electrophoresis (PFGE) are used to analysis antimicrobial resistance and phylogenic between two origin strains. The results indicated that strains from fresh raw chicken meat samples are sensitive to most tested antimicrobials (0-36%) except cefazolin. Most human clinical origin strains are highly resistant to all tested antimicrobials (72-100%); only colistin (7%) and ampicillin/sulbactam (10%) have good susceptibility. Phylogenetic analysis didn’t show any genetic relativity between chicken isolates and human isolates. The results showed isolates from two different sources were genetic and antimicrobial resistance independent. In this study, also use proteomic tool to compare the proteome differences between reference strain ATCC 19003 and artificial induced colistin-resistant strain 19003 CR. The results showed there was no genetic changes caused by induce reference strain to colistin-resistant strain by using PFGE analysis. Two-dimensional electrophoresis and MALDI-TOF analysis were used to identify the differentially expression proteins and real-time PCR was used to confirm the expression levels of these proteins. The results showed that the expression levels of outer membrane protein 38 (Omp38) increased in reference strain; sensor protein QseC, kdsA protein and aacD protein increased in artificial induced colistin-resistant strain, alternatively. It is speculate that A. baumannii may obtain their resistance against colistin through membrane biosynthesis, and it may be regulated by two component regulatory systems, but still needs further studies to verify its mechanism.

1. 2. 衛生署疾病管制局. 新版醫療照護相關感染監測定義. http://www.cdc.gov.tw/downloadfile.aspx?fid=6C8DCFCC75071A7D. 2009.
   連結：
2. 3. Adams MD, Nickel GC, Bajaksouzian S, Lavender H, Murthy AR, Jacobs MR, Bonomo RA. Resistance to colistin in Acinetobacter baumannii Associated with Mutations in the Pmrab Two-Component System. Antimicrob Agents Chemother. 53: 3628-3634, 2009.
   連結：
3. 4. Anderson ME, Lefebvre SL, Weese JS. Evaluation of Prevalence and Risk Factors for Methicillin-Resistant Staphylococcus aureus Colonization in Veterinary Personnel Attending an International Equine Veterinary Conference. Vet Microbiol. 129: 410-417, 2008.
   連結：
4. 5. Baran G, Erbay A, Bodur H, Onguru P, Akinci E, Balaban N, Cevik MA. Risk Factors for Nosocomial Imipenem-Resistant Acinetobacter baumannii Infections. Int J Infect Dis. 12: 16-21, 2008.
   連結：
5. 6. Barbe V, Vallenet D, Fonknechten N, Kreimeyer A, Oztas S, Labarre L, Cruveiller S, Robert C, Duprat S, Wincker P, Ornston LN, Weissenbach J, Marliere P, Cohen GN, Medigue C. Unique Features Revealed by the Genome Sequence of Acinetobacter Sp. Adp1, a Versatile and Naturally Transformation Competent Bacterium. Nucleic Acids Res. 32: 5766-5779, 2004.
   連結：
6. 8. Beavers SF, Blossom DB, Wiemken TL, Kawaoka KY, Wong A, Goss L, McCormick MI, Thoroughman D, Srinivasan A. Comparison of Risk Factors for Recovery of Acinetobacter baumannii During Outbreaks at Two Kentucky Hospitals, 2006. Public Health Rep. 124: 868-874, 2009.
   連結：
7. 9. Becker GJ. Bioinformatics, Computational Biology, and the National Centers for Biomedical Computing. J Am Coll Radiol. 2: 398-400, 2005
   連結：
8. 12. Boerlin P, Eugster S, Gaschen F, Straub R, Schawalder P. Transmission of Opportunistic Pathogens in a Veterinary Teaching Hospital. Vet Microbiol. 82: 347-359, 2001.
   連結：
9. 13. Bou G, Cervero G, Dominguez MA, Quereda C, Martinez-Beltran J. Pcr-Based DNA Fingerprinting (Rep-Pcr, Ap-Pcr) and Pulsed-Field Gel Electrophoresis Characterization of a Nosocomial Outbreak Caused by Imipenem- and Meropenem-Resistant Acinetobacter baumannii. Clin Microbiol Infect. 6: 635-643, 2000.
   連結：
10. 14. Bouvet PJM, Jeanjean S. Delineation of New Proteolytic Genomic Species in the Genus Acinetobacter. Research in Microbiology. 140: 291-299, 1989.
    連結：
11. 15. Bukhary Z, Mahmood W, Al-Khani A, Al-Abdely HM. Treatment of Nosocomial Meningitis Due to a Multidrug Resistant Acinetobacter baumannii with Intraventricular colistin. Saudi Med J. 26: 656-658, 2005.
    連結：
12. 16. Camp C, Tatum OL. A Review of Acinetobacter baumannii as a Highly Successful Pathogen in Times of War. Labmedicine. 41: 649-657, 2010.
    連結：
13. 17. Campos MA, Vargas MA, Regueiro V, Llompart CM, Alberti S, Bengoechea JA. Capsule Polysaccharide Mediates Bacterial Resistance to Antimicrobial Peptides. Infect Immun. 72: 7107-7114, 2004.
    連結：
14. 18. Chang HC, Wei YF, Dijkshoorn L, Vaneechoutte M, Tang CT, Chang TC. Species-Level Identification of Isolates of the Acinetobacter Calcoaceticus-Acinetobacter baumannii Complex by Sequence Analysis of the 16s-23s rRNA Gene Spacer Region. J Clin Microbiol. 43: 1632-1639, 2005.
    連結：
15. 20. Chastre J, Trouillet JL. Problem Pathogens (Pseudomonas aeruginosa and Acinetobacter). Semin Respir Infect. 15: 287-298, 2000.
    連結：
16. 21. Chen CC, Feingold DS. Locus of Divalent Cation Inhibition of the Bactericidal Action of Polymyxin B. Antimicrob Agents Chemother. 2: 331-335, 1972.
    連結：
17. 22. Chen TL, Siu LK, Wu RC, Shaio MF, Huang LY, Fung CP, Lee CM, Cho WL. Comparison of One-Tube Multiplex Pcr, Automated Ribotyping and Intergenic Spacer (Its) Sequencing for Rapid Identification of Acinetobacter baumannii. Clin Microbiol Infect. 13: 801-806, 2007.
    連結：
18. 23. CLSI. Clinical and Laboratory Standards Institute: Performance Standards for Antimicrobial Susceptibility Testing. M100-S19. Clinical and Laboratory Standards Institute. Wayne, PA, 2009.
    連結：
19. 24. Cross RL, Muller V. The Evolution of A-, F-, and V-type ATP Synthases and ATPases: Reversals in Function and Changes in the H+/ATP Coupling Ratio. FEBS Lett. 8: 576 (1-2):1-4, 2004.
    連結：
20. 25. Delcour AH. Outer Membrane Permeability and Antibiotic Resistance. Biochim Biophys Acta. 1794: 808-816, 2009.
    連結：
21. 26. Delsol AA, Sunderland J, Woodward MJ, Pumbwe L, Piddock LJ, Roe JM. Emergence of Fluoroquinolone Resistance in the Native Campylobacter coli Population of Pigs Exposed to Enrofloxacin. J Antimicrob Chemother. 53: 872-874, 2004.
    連結：
22. 27. Deshpande L, Sader H, Gur D, Korten V, Soyletir G, Jones R. Molecular Characterisation of Carbapenem-Resistant Acinetobacter baumannii Isolated in Two Turkish Medical Centres in 2006: Report from the Sentry Antimicrobial Surveillance Program. Int J Antimicrob Agents. 29: S370-S371, 2007.
    連結：
23. 28. Dijkshoorn L, Nemec A, Seifert H. An Increasing Threat in Hospitals: Multidrug-Resistant Acinetobacter baumannii. Nat Rev Microbiol. 5: 939-951, 2007.
    連結：
24. 29. Dizbay M, Altuncekic A, Sezer BE, Ozdemir K, Arman D. colistin and Tigecycline Susceptibility among Multidrug-Resistant Acinetobacter baumannii Isolated from Ventilator-Associated Pneumonia. Int J Antimicrob Agents. 32: 29-32, 2008.
    連結：
25. 30. Eugster S, Schawalder P, Gaschen F, Boerlin P. A Prospective Study of Postoperative Surgical Site Infections in Dogs and Cats. Vet Surg. 33: 542-550, 2004.
    連結：
26. 31. Evans ME, Feola DJ, Rapp RP. Polymyxin B Sulfate and colistin: Old Antibiotics for Emerging Multiresistant Gram-Negative Bacteria. Ann Pharmacother. 33: 960-967, 1999.
    連結：
27. 32. Falagas ME, Bliziotis IA, Kasiakou SK, Samonis G, Athanassopoulou P, Michalopoulos A. Outcome of Infections Due to Pandrug-Resistant (Pdr) Gram-Negative Bacteria. BMC Infect Dis. 5: 24, 2005.
    連結：
28. 33. Falagas ME, Kasiakou SK, Michalopoulos A. Treatment of Multidrug-Resistant Pseudomonas aeruginosa and Acinetobacter baumannii Pneumonia. J Cyst Fibros. 4: 149-150, 2005.
    連結：
29. 34. Falagas ME, Siempos, II, Rafailidis PI, Korbila IP, Ioannidou E, Michalopoulos A. Inhaled colistin as Monotherapy for Multidrug-Resistant Gram (-) Nosocomial Pneumonia: A Case Series. Respir Med. 103: 707-713, 2009.
    連結：
30. 35. Fishbain J, Peleg AY. Treatment of Acinetobacter Infections. Clin Infect Dis. 51: 79-84, 2010.
    連結：
31. 36. Francey T, Gaschen F, Nicolet J, Burnens AP. The Role of Acinetobacter baumannii as a Nosocomial Pathogen for Dogs and Cats in an Intensive Care Unit. J Vet Intern Med. 14: 177-183, 2000.
    連結：
32. 37. Gales AC, Jones RN, Sader HS. Global Assessment of the Antimicrobial Activity of Polymyxin B against 54 731 Clinical Isolates of Gram-Negative Bacilli: Report from the Sentry Antimicrobial Surveillance Programme (2001-2004). Clin Microbiol Infect. 12: 315-321, 2006.
    連結：
33. 38. Gallay A, Prouzet-Mauleon V, Kempf I, Lehours P, Labadi L, Camou C, Denis M, de Valk H, Desenclos JC, Megraud F. Campylobacter Antimicrobial Drug Resistance among Humans, Broiler Chickens, and Pigs, France. Emerg Infect Dis. 13: 259-266, 2007.
    連結：
34. 39. Garnacho-Montero J, Ortiz-Leyba C, Jimenez-Jimenez FJ, Barrero-Almodovar AE, Garcia-Garmendia JL, Bernabeu-Wittel IM, Gallego-Lara SL, Madrazo-Osuna J. Treatment of Multidrug-Resistant Acinetobacter baumannii Ventilator-Associated Pneumonia (Vap) with Intravenous colistin: A Comparison with Imipenem-Susceptible Vap. Clin Infect Dis. 36: 1111-1118, 2003.
    連結：
35. 40. Georges H, Chiche A, Alfandari S, Devos P, Boussekey N, Leroy O. Adult Community-Acquired Bacterial Meningitis Requiring Icu Admission: Epidemiological Data, Prognosis Factors and Adherence to Idsa Guidelines. Eur J Clin Microbiol Infect Dis. 28: 1317-1325, 2009.
    連結：
36. 41. Gerlach RG, Hensel M. Protein Secretion Systems and Adhesins: The Molecular Armory of Gram-Negative Pathogens. Int J Med Microbiol. 297: 401-415, 2007.
    連結：
37. 42. Giamarellou H, Poulakou G. Multidrug-Resistant Gram-Negative Infections: What Are the Treatment Options? Drugs. 69: 1879-1901, 2009.
    連結：
38. 43. Gilad J, Carmeli Y. Treatment Options for Multidrug-Resistant Acinetobacter Species. Drugs. 68: 165-189, 2008.
    連結：
39. 44. Gooderham WJ, Hancock RE. Regulation of Virulence and Antibiotic Resistance by Two-Component Regulatory Systems in Pseudomonas aeruginosa. FEMS Microbiol Rev. 33: 279-294, 2009.
    連結：
40. 45. Gosbell I. Methicillin-Resistant Staphylococcus aureus in Veterinary Practice. Aust Vet J. 89: 148-151, 2011.
    連結：
41. 46. Gunn JS. The Salmonella Pmrab Regulon: Lipopolysaccharide Modifications, Antimicrobial Peptide Resistance and More. Trends Microbiol. 16: 284-290, 2008.
    連結：
42. 47. Gunn JS, Ryan SS, Van Velkinburgh JC, Ernst RK, Miller SI. Genetic and Functional Analysis of a Pmra-Pmrb-Regulated Locus Necessary for Lipopolysaccharide Modification, Antimicrobial Peptide Resistance, and Oral Virulence of Salmonella enterica Serovar Typhimurium. Infect Immun. 68: 6139-6146, 2000.
    連結：
43. 48. Hakeam HA, Almohaizeie AM. Hypotension Following Treatment with Aerosolized colistin in a Patient with Multidrug-Resistant Pseudomonas aeruginosa. Ann Pharmacother. 40: 1677-1680, 2006.
    連結：
44. 49. Hamer DH. Treatment of Nosocomial Pneumonia and Tracheobronchitis Caused by Multidrug-Resistant Pseudomonas aeruginosa with Aerosolized colistin. Am J Respir Crit Care Med. 162: 328-330, 2000.
    連結：
45. 50. Hamouda A, Vali L, Walker D, Mateus A, Dave J, Gibb A, S. D. Comparison of Acinetobacter baumannii from Human and Animal Isolates by Pulsed-Field Gel Electrophoresis in Scotland. Int J Antimicrob Ag. 29: 267-268, 2007.
    連結：
46. 51. Hamouda A, Vali L, Amyes SG. Gram-Negative Non-Fermenting Bacteria from Food-Producing Animals Are Low Risk for Hospital-Acquired Infections. J Chemother. 20: 702-708, 2008.
    連結：
47. 52. Han F, Lestari SI, Pu S, Ge B. Prevalence and Antimicrobial Resistance among Campylobacter spp. In Louisiana Retail Chickens after the Enrofloxacin Ban. Foodborne Pathog Dis. 6: 163-171, 2009.
    連結：
48. 53. Hanberger H, Diekema D, Fluit A, Jones R, Struelens M, Spencer R, Wolff M. Surveillance of Antibiotic Resistance in European Icus. J Hosp Infect. 48: 161-176, 2001.
    連結：
49. 54. Hawley JS, Murray CK, Jorgensen JH. colistin Heteroresistance in Acinetobacter and Its Association with Previous colistin Therapy. Antimicrob Agents Chemother. 52: 351-352, 2008.
    連結：
50. 55. Hermsen ED, Sullivan CJ, Rotschafer JC. Polymyxins: Pharmacology, Pharmacokinetics, Pharmacodynamics, and Clinical Applications. Infect Dis Clin North Am. 17: 545-562, 2003.
    連結：
51. 56. Ho M, Hsiung CA, Yu HT, Chi CL, Chang HJ. Changes before and after a Policy to Restrict Antimicrobial Usage in Upper Respiratory Infections in Taiwan. Int J Antimicrob Agents. 23: 438-445, 2004.
    連結：
52. 57. Hoban DJ, Bouchillon SK, Dowzicky MJ. Antimicrobial Susceptibility of Extended-Spectrum Beta-Lactamase Producers and Multidrug-Resistant Acinetobacter baumannii Throughout the United States and Comparative in Vitro Activity of Tigecycline, a New Glycylcycline Antimicrobial. Diagn Microbiol Infect Dis. 57: 423-428, 2007.
    連結：
53. 58. Hsueh PR, Teng LJ, Chen CY, Chen WH, Yu CJ, Ho SW, Luh KT. Pandrug-Resistant Acinetobacter baumannii Causing Nosocomial Infections in a University Hospital, Taiwan. Emerg Infect Dis. 8: 827-832, 2002.
    連結：
54. 59. Huang J, Tang YQ, Sun JY. Intravenous colistin Sulfate: A Rarely Used Form of Polymyxin E for the Treatment of Severe Multidrug-Resistant Gram-Negative Bacterial Infections. Scand J Infect Dis. 42: 260-265, 2010.
    連結：
55. 60. Hurwitz J. The Discovery of RNA Polymerase. J Biol Chem. 52: 42477-85, 2005 .
    連結：
56. 61. Jain R, Danziger LH. Multidrug-Resistant Acinetobacter Infections: An Emerging Challenge to Clinicians. Ann Pharmacother. 38: 1449-1459, 2004.
    連結：
57. 62. Jang TN, Lee SH, Huang CH, Lee CL, Chen WY. Risk Factors and Impact of Nosocomial Acinetobacter baumannii Bloodstream Infections in the Adult Intensive Care Unit: A Case-Control Study. J Hosp Infect. 73: 143-150, 2009.
    連結：
58. 63. Jawad A, Hawkey PM, Heritage J, Snelling AM. Description of Leeds Acinetobacter Medium, a New Selective and Differential Medium for Isolation of Clinically Important Acinetobacter spp., and Comparison with Herellea Agar and Holton's Agar. J Clin Microbiol. 32: 2353-2358, 1994.
    連結：
59. 64. Juni E. Genetics and Physiology of Acinetobacter. Annu Rev Microbiol. 32: 349-371, 1978.
    連結：
60. 65. Karlowsky JA, Draghi DC, Jones ME, Thornsberry C, Friedland IR, Sahm DF. Surveillance for Antimicrobial Susceptibility among Clinical Isolates of Pseudomonas aeruginosa and Acinetobacter baumannii from Hospitalized Patients in the United States, 1998 to 2001. Antimicrob Agents Chemother. 47: 1681-1688, 2003.
    連結：
61. 66. Katowsky M, Sabisch A, Gutberlet T, Bradaczek H. Molecular Modelling of Bacterial Deep Rough Mutant Lipopolysaccharide of Escherichia coli. Eur J Biochem. 197: 707-716, 1991.
    連結：
62. 67. Kim BN, Peleg AY, Lodise TP, Lipman J, Li J, Nation R, Paterson DL. Management of Meningitis Due to Antibiotic-Resistant Acinetobacter Species. Lancet Infect Dis. 9: 245-255, 2009.
    連結：
63. 68. Klare I, Heier H, Claus H, Reissbrodt R, Witte W. Vana-Mediated High-Level Glycopeptide Resistance in Enterococcus faecium from Animal Husbandry. FEMS Microbiol Lett. 125: 165-171, 1995.
    連結：
64. 69. Klevens RM, Edwards JR, Richards CL, Jr., Horan TC, Gaynes RP, Pollock DA, Cardo DM. Estimating Health Care-Associated Infections and Deaths in U.S. Hospitals, 2002. Public Health Rep. 122: 160-166, 2007.
    連結：
65. 70. Lee CM, Lim HK, Liu CP, Tseng HK. Treatment of Pan-Drug Resistant Acinetobacter baumannii. Scand J Infect Dis. 37: 195-199, 2005.
    連結：
66. 71. Li J, Nation RL, Turnidge JD, Milne RW, Coulthard K, Rayner CR, Paterson DL. colistin: The Re-Emerging Antibiotic for Multidrug-Resistant Gram-Negative Bacterial Infections. Lancet Infect Dis. 6: 589-601, 2006.
    連結：
67. 72. Li J, Rayner CR, Nation RL, Owen RJ, Spelman D, Tan KE, Liolios L. Heteroresistance to colistin in Multidrug-Resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 50: 2946-2950, 2006.
    連結：
68. 73. Linden PK, Kusne S, Coley K, Fontes P, Kramer DJ, Paterson D. Use of Parenteral colistin for the Treatment of Serious Infection Due to Antimicrobial-Resistant Pseudomonas aeruginosa. Clin Infect Dis. 37: e154-160, 2003.
    連結：
69. 74. Markou N, Markantonis SL, Dimitrakis E, Panidis D, Boutzouka E, Karatzas S, Rafailidis P, Apostolakos H, Baltopoulos G. colistin Serum Concentrations after Intravenous Administration in Critically Ill Patients with Serious Multidrug-Resistant, Gram-Negative Bacilli Infections: A Prospective, Open-Label, Uncontrolled Study. Clin Ther. 30: 143-151, 2008.
    連結：
70. 75. Matthaiou DK, Michalopoulos A, Rafailidis PI, Karageorgopoulos DE, Papaioannou V, Ntani G, Samonis G, Falagas ME. Risk Factors Associated with the Isolation of colistin-Resistant Gram-Negative Bacteria: A Matched Case-Control Study. Crit Care Med. 36: 807-811, 2008.
    連結：
71. 76. McGowan JE, Jr. Resistance in Nonfermenting Gram-Negative Bacteria: Multidrug Resistance to the Maximum. Am J Infect Control. 34: S29-37; discussion S64-73, 2006.
    連結：
72. 77. Michalopoulos A, Falagas ME. colistin and Polymyxin B in Critical Care. Crit Care Clin. 24: 377-391, x, 2008.
    連結：
73. 78. Michalopoulos AS, Karatza DC. Multidrug-Resistant Gram-Negative Infections: The Use of colistin. Expert Rev Anti Infect Ther. 8: 1009-1017, 2010.
    連結：
74. 79. Montero A, Ariza J, Corbella X, Domenech A, Cabellos C, Ayats J, Tubau F, Ardanuy C, Gudiol F. Efficacy of colistin Versus Beta-Lactams, Aminoglycosides, and Rifampin as Monotherapy in a Mouse Model of Pneumonia Caused by Multiresistant Acinetobacter baumannii. Antimicrob Agents Chemother. 46: 1946-1952, 2002.
    連結：
75. 80. Mubareka S, Rubinstein E. Aerosolized colistin for the Treatment of Nosocomial Pneumonia Due to Multidrug-Resistant Gram-Negative Bacteria in Patients without Cystic Fibrosis. Crit Care. 9: 29-30, 2005.
    連結：
76. 82. Olsson C, Ahrne S, Pettersson B, Molin G. The Bacterial Flora of Fresh and Chill-Stored Pork: Analysis by Cloning and Sequencing of 16s rRNA Genes. Int J Food Microbiol. 83: 245-252, 2003.
    連結：
77. 83. Or E, Navon A, Rapoport T. Dissociation of the Dimeric Seca Atpase During Protein Translocation across the Bacterial Membrane. EMBO J. 21: 4470-4479, 2002.
    連結：
78. 84. Orwa JA, Govaerts C, Busson R, Roets E, Van Schepdael A, Hoogmartens J. Isolation and Structural Characterization of colistin Components. J Antibiot (Tokyo). 54: 595-599, 2001.
    連結：
79. 85. Pachon-Ibanez ME, Jimenez-Mejias ME, Pichardo C, Llanos AC, Pachon J. Activity of Tigecycline (Gar-936) against Acinetobacter baumannii Strains, Including Those Resistant to Imipenem. Antimicrob Agents Chemother. 48: 4479-4481, 2004.
    連結：
80. 87. Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii: Emergence of a Successful Pathogen. Clin Microbiol Rev. 21: 538-582, 2008.
    連結：
81. 89. Reina R, Estenssoro E, Saenz G, Canales HS, Gonzalvo R, Vidal G, Martins G, Das Neves A, Santander O, Ramos C. Safety and Efficacy of colistin in Acinetobacter and Pseudomonas Infections: A Prospective Cohort Study. Intensive Care Med. 31: 1058-1065, 2005.
    連結：
82. 90. Rodriguez CH, Bombicino K, Granados G, Nastro M, Vay C, Famiglietti A. Selection of colistin-Resistant Acinetobacter baumannii Isolates in Postneurosurgical Meningitis in an Intensive Care Unit with High Presence of Heteroresistance to colistin. Diagn Microbiol Infect Dis. 65: 188-191, 2009.
    連結：
83. 91. Roseman S. The Bacterial Phosphoenolpyruvate: Sugar Phosphotransferase System. Ciba Found Symp. 225-241, 1975.
    連結：
84. 92. Rossau R, Vanlandschoot A, Gillis M, Deley J. Taxonomy of Moraxellaceae Fam-Nov, a New Bacterial Family to Accommodate the Genera Moraxella, Acinetobacter, and Psychrobacter and Related Organisms. International Journal of Systematic Bacteriology. 41: 310-319, 1991.
    連結：
85. 93. Saballs M, Pujol M, Tubau F, Pena C, Montero A, Dominguez MA, Gudiol F, Ariza J. Rifampicin/Imipenem Combination in the Treatment of Carbapenem-Resistant Acinetobacter baumannii Infections. J Antimicrob Chemother. 58: 697-700, 2006.
    連結：
86. 94. Sabuda DM, Laupland K, Pitout J, Dalton B, Rabin H, Louie T, Conly J. Utilization of colistin for Treatment of Multidrug-Resistant Pseudomonas aeruginosa. Can J Infect Dis Med Microbiol. 19: 413-418, 2008.
    連結：
87. 95. Schlegelova J, Rysanek D, Sediva I, Babak V. Comparison of Methods for the Determination of Antimicrobial Resistance in Staphylococcus aureus from Bovine Mastitis. J Vet Med B Infect Dis Vet Public Health. 48: 21-29, 2001.
    連結：
88. 96. Seifert H, Dolzani L, Bressan R, van der Reijden T, van Strijen B, Stefanik D, Heersma H, Dijkshoorn L. Standardization and Interlaboratory Reproducibility Assessment of Pulsed-Field Gel Electrophoresis-Generated Fingerprints of Acinetobacter baumannii. J Clin Microbiol. 43: 4328-4335, 2005.
    連結：
89. 97. Silbert S, Pfaller MA, Hollis RJ, Barth AL, Sader HS. Evaluation of Three Molecular Typing Techniques for Nonfermentative Gram-Negative Bacilli. Infect Control Hosp Epidemiol. 25: 847-851, 2004.
    連結：
90. 99. Smoot JC, Barbian KD, Van Gompel JJ, Smoot LM, Chaussee MS, Sylva GL, Sturdevant DE, Ricklefs SM, Porcella SF, Parkins LD, Beres SB, Campbell DS, Smith TM, Zhang Q, Kapur V, Daly JA, Veasy LG, Musser JM. Genome Sequence and Comparative Microarray Analysis of Serotype M18 Group a Streptococcus Strains Associated with Acute Rheumatic Fever Outbreaks. Proc Natl Acad Sci U S A. 99: 4668-4673, 2002.
    連結：
91. 100. Sparo M, Urbizu L, Solana MV, Pourcel G, Delpech G, Confalonieri A, Ceci M, Sanchez Bruni SF. High-Level Resistance to Gentamicin: Genetic Transfer between Enterococcus faecalis Isolated from Food of Animal Origin and Human Microbiota. Lett Appl Microbiol. 54: 119-125, 2012.
    連結：
92. 101. Sperandio V, Torres AG, Kaper JB. Quorum Sensing Escherichia coli Regulators B and C (QseBC): a Novel Two-component Regulatory System Involved in the Regulation of Flagella and Motility by Quorum Sensing in E. coli. Mol Microbiol. 43: 809-21, 2002.
    連結：
93. 102. Teale CJ. Antimicrobial Resistance and the Food Chain. Symp Ser Soc Appl Microbiol. 85S-89S, 2002.
    連結：
94. 104. Theaker C, Azadian B, Soni N. The Impact of Acinetobacter baumannii in the Intensive Care Unit. Anaesthesia. 58: 271-274, 2003.
    連結：
95. 105. Tjernberg I, Ursing J. Clinical Strains of Acinetobacter Classified by DNA-DNA Hybridization. Apmis. 97: 595-605, 1989.
    連結：
96. 107. Traub WH. Serotyping of Clinical Isolates of Acinetobacter baumannii and Genospecies 3: Detection of Additional Serovars. Zentralbl Bakteriol. 275: 487-494, 1991.
    連結：
97. 108. Tyers M, Mann M. From Genomics to Proteomics. Nature. 422: 193-197, 2003.
    連結：
98. 109. Urban C, Segal-Maurer S, Rahal JJ. Considerations in Control and Treatment of Nosocomial Infections Due to Multidrug-Resistant Acinetobacter baumannii. Clin Infect Dis. 36: 1268-1274, 2003.
    連結：
99. 110. Uzunovic-Kamberovic S, Zorman T, Heyndrickx M, Smole Mozina S. Role of Poultry Meat in Sporadic Campylobacter Infections in Bosnia and Herzegovina: Laboratory-Based Study. Croat Med J. 48: 842-851, 2007.
    連結：
100. 112. Wasinger VC, Cordwell SJ, Cerpa-Poljak A, Yan JX, Gooley AA, Wilkins MR, Duncan MW, Harris R, Williams KL, Humphery-Smith I. Progress with Gene-Product Mapping of the Mollicutes: Mycoplasma genitalium. Electrophoresis. 16: 1090-1094, 1995.
     連結：
101. 113. Wilkins M. Proteomics Data Mining. Expert Rev Proteomics. 6: 599-603, 2009.
     連結：
102. 114. Wilson SJ, Knipe CJ, Zieger MJ, Gabehart KM, Goodman JE, Volk HM, Sood R. Direct Costs of Multidrug-Resistant Acinetobacter baumannii in the Burn Unit of a Public Teaching Hospital. Am J Infect Control. 32: 342-344, 2004.
     連結：
103. 115. Wisplinghoff H, Perbix W, Seifert H. Risk Factors for Nosocomial Bloodstream Infections Due to Acinetobacter baumannii: A Case-Control Study of Adult Burn Patients. Clin Infect Dis. 28: 59-66, 1999.
     連結：
104. 116. Yang M, Hu Z, Hu F. Nosocomial Meningitis Caused by Acinetobacter baumannii: Risk Factors and Their Impact on Patient Outcomes and Treatments. Future Microbiol. 7: 787-793, 2012.
     連結：
105. 118. Zavascki AP, Goldani LZ, Li J, Nation RL. Polymyxin B for the Treatment of Multidrug-Resistant Pathogens: A Critical Review. J Antimicrob Chemother. 60: 1206-1215, 2007.
     連結：
106. 1. 楊采菱. 院內感染多重抗藥菌分子特性及流行病學. http://www.cdc.gov.tw/uploads/files/e92c6ca3-506a-4a0f-86c0-09e58628976a.pdf. 2009.
107. 7. Baumann P. Isolation of Acinetobacter from Soil and Water. J Bacteriol. 96: 39-42, 1968.
108. 10. Bell J, Turnidge J. Sentry Antimicrobial Surveillance Program Asia-Pacific Region and South Africa. Commun Dis Intell. 27 Suppl: S61-66, 2003.
109. 11. Bergogne-Berezin E, Towner KJ. Acinetobacter spp. As Nosocomial Pathogens: Microbiological, Clinical, and Epidemiological Features. Clin Microbiol Rev. 9: 148-165, 1996.
110. 19. Chaslus-Dancla E, Lafont JP, Martel JL. Spread of Resistance from Food Animals to Man: The French Experience. Acta Vet Scand Suppl. 93: 53-60; discussion 60-51, 2000.
111. 81. Nemec A, Dijkshoorn L, Jezek P. Recognition of Two Novel Phenons of the Genus Acinetobacter among Non-Glucose-Acidifying Isolates from Human Specimens. J Clin Microbiol. 38: 3937-3941, 2000.
112. 86. Pantophlet R, Brade L, Dijkshoorn L, Brade H. Specificity of Rabbit Antisera against Lipopolysaccharide of Acinetobacter. J Clin Microbiol. 36: 1245-1250, 1998.
113. 88. Poulakou G, Kontopidou FV, Paramythiotou E, Kompoti M, Katsiari M, Mainas E, Nicolaou C, Yphantis D, Antoniadou A, Trikka-Graphakos E, Roussou Z, Clouva P, Maguina N, Kanellakopoulou K, Armaganidis A, Giamarellou H. Tigecycline in the Treatment of Infections from Multi-Drug Resistant Gram-Negative Pathogens. J Infect. 58: 273-284, 2009.
114. 98. Singh AV, Mishra B, Thakur A. Multidrug-Resistant Gram-Negative Bacteria in Postoperative Infections. J Indian Med Assoc. 107: 148-150, 163, 2009.
115. 103. Tenover FC, Arbeit RD, Goering RV, Mickelsen PA, Murray BE, Persing DH, Swaminathan B. Interpreting Chromosomal DNA Restriction Patterns Produced by Pulsed-Field Gel Electrophoresis: Criteria for Bacterial Strain Typing. J Clin Microbiol. 33: 2233-2239, 1995.
116. 106. Tomb JF, White O, Kerlavage AR, Clayton RA, Sutton GG, Fleischmann RD, Ketchum KA, Klenk HP, Gill S, Dougherty BA, Nelson K, Quackenbush J, Zhou L, Kirkness EF, Peterson S, Loftus B, Richardson D, Dodson R, Khalak HG, Glodek A, McKenney K, Fitzegerald LM, Lee N, Adams MD, Hickey EK, Berg DE, Gocayne JD, Utterback TR, Peterson JD, Kelley JM, Cotton MD, Weidman JM, Fujii C, Bowman C, Watthey L, Wallin E, Hayes WS, Borodovsky M, Karp PD, Smith HO, Fraser CM, Venter JC. The Complete Genome Sequence of the Gastric Pathogen Helicobacter pylori. Nature. 388: 539-547, 1997.
117. 111. Vaara M, Nurminen M. Outer Membrane Permeability Barrier in Escherichia coli Mutants That Are Defective in the Late Acyltransferases of Lipid a Biosynthesis. Antimicrob Agents Chemother. 43: 1459-1462, 1999.
118. 117. Yang SY, Schulz H. The Large Subunit of the Fatty Acid Oxidation Complex from Escherichia coli is a Multifunctional Polypeptide. Evidence for the Existence of a Fatty Acid Oxidation Operon (fad AB) in Escherichia coli. J Biol Chem. 16: 9780-9785, 1983.