产ESBLs肠杆菌科细菌对氨基糖苷类抗生素耐药性的研究
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摘要
目的:测定与分析对第三代头孢菌素(头孢他啶、头孢噻肟、头孢曲松)MIC值≥2ug/ml的肠杆菌科细菌对临床常用抗生素的耐药情况(NCCLS推荐对第三代头孢菌素的MIC值≥2ug/ml者为产ESBLs的可疑株);研究产超广谱β—内酰胺酶(extended spectrum beta-lactamases, ESBLs)肠杆菌科细菌对氨基糖苷类抗生素的耐药性及耐药分子机制,为临床治疗产ESBLs菌株感染合理用药提供依据。
方法:对四川大学华西医院2003年7月～2004年1月从临床分离的210株对第三代头孢菌素(头孢他啶、头孢噻肟、头孢曲松)任一种MIC值≥2ug/ml的肠杆菌科细菌(主要为大肠埃希菌、肺炎克雷伯菌和阴沟肠杆菌)采用琼脂对倍稀释法测定11种抗菌药物的最低抑菌浓度(minimal inhibitory concentration, MIC)。采用PCR方法对耐氨基糖苷类抗生素的产ESBLs菌株进行氨基糖苷类耐药性及耐药机制研究,并同时对钝化酶基因DNA测序,进行网上基因相似性检索。
结果:三种肠杆菌科细菌对环丙沙星的耐药率(以中敏和耐药合并计算)均超过50%。而90%的分离株对亚胺培南敏感。在氨基糖苷类抗生素中,以阿米卡星和依替米星的抗菌活性最强,但阴沟肠杆菌对阿米卡星和依替米星耐药率较高,分别为56.77%和65.38%。所收集菌株对
Objective: To study the resistance of extended spectrum β -lactamaseproducing clinical isolates in Enterobacteriaceae to other antimicrobial agents, and investigate the molecular mechanisms of the aminoglycosides-resistance in ESBLs-producing Enterobacteriaceae strains.Methods: A totle of 210 strains include E. coli, K. pneumonia and E.cloacae.The Enterobacteriaceae clinical isolates were collected from West China Hospital of Sichuan University from July,2003 to January,2004,and the ESBLs-producing strains were screened and confirmed by double agar dilution method according to NCCLS Guidelines.The MICs of 11 antibacterial agents against the clinical isolates was detected by double agar dilution method.The nucleotide sequence of aminoglycoside modification genes in ESBLs-producing plus aminoglycoside-resistant strains that were amplified by PCR were detected by automatic sequencer,and compared with relative DNA sequencing reported by others in internet gene bank through Blastn searching.Results:The resistant rate of E. coli, K. pneumonia and E. cloacae in Enterobacteriaceae to ciprofloxacin was above 50%.Imipenem was active
against 90% of the isolates.Most of the Enterobacteriaceae were multidrug resistance.Amikacin and etilmicin were the most active against the clinical isolates in the aminoglycosides.However the resistant rates of E. cloacae to amikacin and etilmicin were 56.77% and 65.38%,respectively.The resistant rate of clinical isolates to gentamicin was above 80%.Cross-resistance to aminoglycosides exist significantly. Among 20 aminoglycoside-resistant plus ESBLs-producing strains,aminoglycoside modifying enzymes gene have been found.They were aminoglycoside acetyltransferase(3)-I gene (aac(3)-I), aminoglycoside acetyltransferase(3)-II gene (aac(3)-IT) ^ aminoglycoside acetyltransferase(6')-I gene (aac(6')-I)^ aminoglycoside acetyltransferase (6')-II gene (aac(6 ')-II) ^ aminoglycoside adenyltransferase (2")-I gene (ant(2")-I) and aminoglycoside phosphoryltransferase(3')-VI gene (aph(3')-VI).The DNA sequences of modifying enzyme gene were in concordance with other aminoglycoside modifying enzymes refer to Internet gene bank.BlarEM were detected in all 20 ESBLs-producing strains.Conclusions: The situations of multidrug resistance of ESBLs-producing strains in Enterobacteriaceae was severe and prevalent. Imipenem is still the most active antibiotic for treatment of the infections caused by these resistant strains.There were aminoglycoside modifying enzyme in ESBLs-producing strains of Enterobacteriaceae. The aminoglycosides should be prudent used empirically when combined with other antibiotics or evidence-based prescribed according to the results of in-vitro combination suscepitibility test.
方法:对四川大学华西医院2003年7月～2004年1月从临床分离的210株对第三代头孢菌素(头孢他啶、头孢噻肟、头孢曲松)任一种MIC值≥2ug/ml的肠杆菌科细菌(主要为大肠埃希菌、肺炎克雷伯菌和阴沟肠杆菌)采用琼脂对倍稀释法测定11种抗菌药物的最低抑菌浓度(minimal inhibitory concentration, MIC)。采用PCR方法对耐氨基糖苷类抗生素的产ESBLs菌株进行氨基糖苷类耐药性及耐药机制研究,并同时对钝化酶基因DNA测序,进行网上基因相似性检索。
结果:三种肠杆菌科细菌对环丙沙星的耐药率(以中敏和耐药合并计算)均超过50%。而90%的分离株对亚胺培南敏感。在氨基糖苷类抗生素中,以阿米卡星和依替米星的抗菌活性最强,但阴沟肠杆菌对阿米卡星和依替米星耐药率较高,分别为56.77%和65.38%。所收集菌株对
Objective: To study the resistance of extended spectrum β -lactamaseproducing clinical isolates in Enterobacteriaceae to other antimicrobial agents, and investigate the molecular mechanisms of the aminoglycosides-resistance in ESBLs-producing Enterobacteriaceae strains.Methods: A totle of 210 strains include E. coli, K. pneumonia and E.cloacae.The Enterobacteriaceae clinical isolates were collected from West China Hospital of Sichuan University from July,2003 to January,2004,and the ESBLs-producing strains were screened and confirmed by double agar dilution method according to NCCLS Guidelines.The MICs of 11 antibacterial agents against the clinical isolates was detected by double agar dilution method.The nucleotide sequence of aminoglycoside modification genes in ESBLs-producing plus aminoglycoside-resistant strains that were amplified by PCR were detected by automatic sequencer,and compared with relative DNA sequencing reported by others in internet gene bank through Blastn searching.Results:The resistant rate of E. coli, K. pneumonia and E. cloacae in Enterobacteriaceae to ciprofloxacin was above 50%.Imipenem was active
against 90% of the isolates.Most of the Enterobacteriaceae were multidrug resistance.Amikacin and etilmicin were the most active against the clinical isolates in the aminoglycosides.However the resistant rates of E. cloacae to amikacin and etilmicin were 56.77% and 65.38%,respectively.The resistant rate of clinical isolates to gentamicin was above 80%.Cross-resistance to aminoglycosides exist significantly. Among 20 aminoglycoside-resistant plus ESBLs-producing strains,aminoglycoside modifying enzymes gene have been found.They were aminoglycoside acetyltransferase(3)-I gene (aac(3)-I), aminoglycoside acetyltransferase(3)-II gene (aac(3)-IT) ^ aminoglycoside acetyltransferase(6')-I gene (aac(6')-I)^ aminoglycoside acetyltransferase (6')-II gene (aac(6 ')-II) ^ aminoglycoside adenyltransferase (2")-I gene (ant(2")-I) and aminoglycoside phosphoryltransferase(3')-VI gene (aph(3')-VI).The DNA sequences of modifying enzyme gene were in concordance with other aminoglycoside modifying enzymes refer to Internet gene bank.BlarEM were detected in all 20 ESBLs-producing strains.Conclusions: The situations of multidrug resistance of ESBLs-producing strains in Enterobacteriaceae was severe and prevalent. Imipenem is still the most active antibiotic for treatment of the infections caused by these resistant strains.There were aminoglycoside modifying enzyme in ESBLs-producing strains of Enterobacteriaceae. The aminoglycosides should be prudent used empirically when combined with other antibiotics or evidence-based prescribed according to the results of in-vitro combination suscepitibility test.
引文
1.文细毛,任南,徐秀华,等.全国医院感染监控网医院感染病原菌分布及耐药性分析.中华医院感染杂志,2002,12(4):43-45
2.许锦民,苏丹红.大肠埃希和克雷伯属产ESBLs检测[J].中华医学检验杂志,1998,21:373
3. Ni Y. The drug-resistance of plasmid-mediated extended spectrum β-lactamases. [J].Chin J Med Lab Sci, 1999,22(5):316
4. Shen D X, Bai L Y, Luo Y P, et al. Detection of extended spectrum β-lactamases and AmpC β-lactamases from Escheria coli and Klebsiella pneumoniae. [J].Chin J Microbiol Immunol,2001,21(Suppl):67
5.戴自英,刘裕昆,汪复.氨基糖苷类抗生素.实用抗菌药物学,168—177
6.李杰,李霞,张银旺,等.2000年武汉地区产超广谱β-内酰胺酶菌种的分布及药敏分析[J].临床内科杂志,2003,20(8):405—407
7. MIC Interpretive Standards(ug/ml) for Enterobacteriaceae. National Committee for Clinical Laboratory Standard. MIC testing Supplemental Tables. January 2003:20-24
8.糜祖煌,陆亚华.氨基糖苷修饰酶及其基因检测,现代实用医学,2004,16(1):13—14
9. Chosen S P, McMurry L M, Levy S B. MarA locus cause decreased expression of OmoF porin in multiple antibiotic resistance (Mar) mutants of Escherichia coli. [J].J Bacteriol,1988;170 (12): 5416—22
10. Okusu H, Ma D, Nikaido H. AcrAB efflux pump plays a maijor role in the antibiotic resistance phenotype of Escherichia coli multiple-antibiotic-resistance (Mar) mutants. [J].J Bacteriol, 1996,178:306-8
11.吴艳,黄茂,赵旺胜.下呼吸道感染的病原菌变迁及产超广谱—内酰胺酶菌株的耐药分析.南京医科大学学报(自然科学版),2003,23(4):390—392
12. Linder H J, Notka F, Irtenkauf C, et al. Increase in MICs of ciprofloxacin in vivo in two close related clinical isolates of Enterobacter cloacae.[J].J Antimicrob Chemother,2002,49:625-632
13.韩善桥,陆晓白,李杰,等。肠杆菌科细菌产超广谱β—内酰胺酶检测及耐药性分析,中国抗生素杂志,2003,28(8):475-7
14. Kohn T H, Sng I H, Babini G S, et al. Carbapenem-Resistant Klebsiella pneumonia in Singapore Producing IMP-1 β-lactamase and Lacking an Outer Membrane Protein.[J].Antimicrob Agents Chemother, 2001; 45: 1939-1940
15. Martinez-Martinez L, Pascual A, Hernandez-Ales S, et al. Roles of beta-lactamases and porins in activities of cabapenems and cepholosporins against Klebsiella pneumoniae[J].Antimicrob Agents Chemother, 1999;43(7):1669
16. Jeong S H, Lee K, Chong Y, et al. Characterization of a new integron containing VIM-2,a metallo-β-lactamase gene cassette,in a clinical isolate of Enterobacter cloacae.[J].J Antimicrob Chemother, 2003, 51:397-400
17.朱德妹,熊自忠,汪复,等.超广谱β—内酰胺酶和细菌耐药性.中华传染病杂志,2000,18(3),151～154
18.曹彬,王辉,陈民钧,等.产超广谱β—内酰胺酶菌院内感染分析.中华内科杂志,2001,40:581—584
19. Meyer K S, Urban C, Eagan J A, et al. Nosocomial outbreak of Klebsiella infections resistant to late-generation cephalosporins.[J]. Ann Intern Med. 1993;119:353-358.
20. Pena C, Pujol M, Ardanuy C, et al. Epidemiology and successful control of a large outbreak due to Klebsiella pneumoniae producing extended spectrum [beta]-lactamases.[J].Antimicrob Agents Chemother. 1998;42: 53-58.
21. Quale J M, Landman D, Bradford P, et al. Molecular epidemiology of a citywide outbreak of extended spectrum [beta]-lactamase-producing Klebsiella pneumoniae infection.[J]. Clin Infect Dis. 2002;35:834-841.
22. Asensio A, Oliver A, Gonzalez-Diego P, et al. Outbreak of a multiresistant Klebsiella pneumoniae strain in an intensive care unit: antibiotic use as a risk factor for colonization and infection.[J].Clin Infect Dis. 2000;30:55-60.
23. Lucet JC, Chevret S, Decre D, et al. Outbreak of multiply resistant Enterobacteriaceae in an intensive care unit: epidemiology and risk factors for acquisition.[J].Clin Infect Dis. 1996;22:430-436.
24.佘丹阳,刘又宁.AmpC酶和超广谱β—内酰胺酶在阴沟肠杆菌中的表达及其对耐药性的影响.中华医学杂志,2002,82(19):1355—1358
25. Tzelepi E, Giakkoupi P, Sofianou D, et al. Detection of extended spectrum β-lactamases in clinical isolates of Enterobacter cloacae and Enterobacter aerogenes. [J].J Clin Microbial,2000,38:542-546
26. Handson N D, Thomson K S, Moland E S, et al. Molecular characterization of a multiply resistant K. pneumoniae encoding ESBLs and a plasmid medicated AmpC.[J].J Antimicrob Chemother, 1999, 44: 377-380
27.杨立军,朱立华,徐国宾,等.产ESBLs肠杆菌科细菌中整合子参与多重耐药机制研究.中国抗生素杂志,2002,27(12):722—725
28. Lautenbach E, Patel J B, Bilker W B, et al. Extended spectrum [beta] lactamase-producing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on outcomes.[J].Clin Infect Dis. 2001;32:1162-1171.
29. Gniadkouwski M. Evolution and epidemiology of extended spectrum [beta]-lactamases (ESBLs) and ESBL-producing microorganisms.[J], Clin Microbiol Infect. 2001;7:597-608.
30. Paterson D L, Ko W, Von Gottberg, et al. Outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing extended spectrum [beta]-lactamases: implications for the clinical microbiology laboratory. [J].J Clin Microbiol. 2001;39: 2206-2212.
31. Wong-Beringer A, Hindler J, Loeloff M, et al. Molecular correlation for the treatment outcomes in bloodstream infections caused by Escherichia coli and Klebsiella pneumoniae with reduced susceptibility to ceftazidime. Clin Infect Dis. 2002;34:135-146.
32. Kaye K S, Cosgrove S, Harris A, et al. Risk factors for emergence of resistance to broad-spectrum cephalosporins among Enterobacter spp.[J]. Antimicrob Agents Chemother. 2001;45:2628-2630.
33. Ariza, Javier, Pujol, Miquel. Nosocomial Antibiotic Resistance in GNB at the ICUs.[J]. Clinical Pulmonary Medicine,2004,11(2):71-83
34.卓超,肖永虹,蒋玉富,等.E试验监测重症监护病房中400株革兰阴性菌的耐药性.中国抗生素杂志,2003,28(5):276—280
35.沈依群,赵敏。氨基糖苷类抗生素的耐药机制及控制耐药性的策略,国外医药抗生素分册,2002,23(3):118—120
36.顾觉奋,杨晓兵。细菌对氨基糖苷类抗生素耐药机制研究进展,药 物生物技术,2001,8(3):174—177
37.胡仪吉。氨基糖苷类抗生素耐药产生的机制及对策,中国实用儿科杂志,2003,17(3):142—144
38.张永龙,李家泰。北京地区临床分离菌对氨基糖苷类抗生素耐药情况调查研究及其耐药机理分析,中国抗生素杂志,1998,23(5):371
39.陈代杰,李燕。细菌对氨基糖苷类抗生素的耐药性与抗生素产生菌的推理选育.中国医药工业杂志,2001,32(2):85—89
40. Neonakis I, Gikas A, Scoulica E, et al. Evolution of aminoglycoside resistance phenotypes of four Gram-negative bacteria: an 8-year survey in a University Hospital in Greece.[J].Int-J-Antimicrob-Agents,2003, 22(5): 548-50
41. Over U, Gur D, Unal S, Miller G H. The changing nature of aminoglycoside resistance mechanisms and prevalence of newly recognized resistance mechanisms in Turkey.[J].Clin-Microbiol-Infect, 2001, 7(9): 470-8
42. Miller G. H., Sabatelli F J, Hare R S, et al. The Most Frequent Aminoglycoside Resistance Mechanisms—Changes with Time and Geographic Area: A Reflectin of Aminoglycoside Usage Patterns? [J].Clinical Infectious Disease, 1997, 24(Suppl 1): S46-62
43.陈炫,超广谱β-内酰胺酶的序列分析及分子进化研究。(内部资料)
44. Price K E. Epidemiological studies of aminoglycoside, resistance in the USA. [J].J Antimicrobial Chemother, 1981, 8(Supple A): 89
2.许锦民,苏丹红.大肠埃希和克雷伯属产ESBLs检测[J].中华医学检验杂志,1998,21:373
3. Ni Y. The drug-resistance of plasmid-mediated extended spectrum β-lactamases. [J].Chin J Med Lab Sci, 1999,22(5):316
4. Shen D X, Bai L Y, Luo Y P, et al. Detection of extended spectrum β-lactamases and AmpC β-lactamases from Escheria coli and Klebsiella pneumoniae. [J].Chin J Microbiol Immunol,2001,21(Suppl):67
5.戴自英,刘裕昆,汪复.氨基糖苷类抗生素.实用抗菌药物学,168—177
6.李杰,李霞,张银旺,等.2000年武汉地区产超广谱β-内酰胺酶菌种的分布及药敏分析[J].临床内科杂志,2003,20(8):405—407
7. MIC Interpretive Standards(ug/ml) for Enterobacteriaceae. National Committee for Clinical Laboratory Standard. MIC testing Supplemental Tables. January 2003:20-24
8.糜祖煌,陆亚华.氨基糖苷修饰酶及其基因检测,现代实用医学,2004,16(1):13—14
9. Chosen S P, McMurry L M, Levy S B. MarA locus cause decreased expression of OmoF porin in multiple antibiotic resistance (Mar) mutants of Escherichia coli. [J].J Bacteriol,1988;170 (12): 5416—22
10. Okusu H, Ma D, Nikaido H. AcrAB efflux pump plays a maijor role in the antibiotic resistance phenotype of Escherichia coli multiple-antibiotic-resistance (Mar) mutants. [J].J Bacteriol, 1996,178:306-8
11.吴艳,黄茂,赵旺胜.下呼吸道感染的病原菌变迁及产超广谱—内酰胺酶菌株的耐药分析.南京医科大学学报(自然科学版),2003,23(4):390—392
12. Linder H J, Notka F, Irtenkauf C, et al. Increase in MICs of ciprofloxacin in vivo in two close related clinical isolates of Enterobacter cloacae.[J].J Antimicrob Chemother,2002,49:625-632
13.韩善桥,陆晓白,李杰,等。肠杆菌科细菌产超广谱β—内酰胺酶检测及耐药性分析,中国抗生素杂志,2003,28(8):475-7
14. Kohn T H, Sng I H, Babini G S, et al. Carbapenem-Resistant Klebsiella pneumonia in Singapore Producing IMP-1 β-lactamase and Lacking an Outer Membrane Protein.[J].Antimicrob Agents Chemother, 2001; 45: 1939-1940
15. Martinez-Martinez L, Pascual A, Hernandez-Ales S, et al. Roles of beta-lactamases and porins in activities of cabapenems and cepholosporins against Klebsiella pneumoniae[J].Antimicrob Agents Chemother, 1999;43(7):1669
16. Jeong S H, Lee K, Chong Y, et al. Characterization of a new integron containing VIM-2,a metallo-β-lactamase gene cassette,in a clinical isolate of Enterobacter cloacae.[J].J Antimicrob Chemother, 2003, 51:397-400
17.朱德妹,熊自忠,汪复,等.超广谱β—内酰胺酶和细菌耐药性.中华传染病杂志,2000,18(3),151～154
18.曹彬,王辉,陈民钧,等.产超广谱β—内酰胺酶菌院内感染分析.中华内科杂志,2001,40:581—584
19. Meyer K S, Urban C, Eagan J A, et al. Nosocomial outbreak of Klebsiella infections resistant to late-generation cephalosporins.[J]. Ann Intern Med. 1993;119:353-358.
20. Pena C, Pujol M, Ardanuy C, et al. Epidemiology and successful control of a large outbreak due to Klebsiella pneumoniae producing extended spectrum [beta]-lactamases.[J].Antimicrob Agents Chemother. 1998;42: 53-58.
21. Quale J M, Landman D, Bradford P, et al. Molecular epidemiology of a citywide outbreak of extended spectrum [beta]-lactamase-producing Klebsiella pneumoniae infection.[J]. Clin Infect Dis. 2002;35:834-841.
22. Asensio A, Oliver A, Gonzalez-Diego P, et al. Outbreak of a multiresistant Klebsiella pneumoniae strain in an intensive care unit: antibiotic use as a risk factor for colonization and infection.[J].Clin Infect Dis. 2000;30:55-60.
23. Lucet JC, Chevret S, Decre D, et al. Outbreak of multiply resistant Enterobacteriaceae in an intensive care unit: epidemiology and risk factors for acquisition.[J].Clin Infect Dis. 1996;22:430-436.
24.佘丹阳,刘又宁.AmpC酶和超广谱β—内酰胺酶在阴沟肠杆菌中的表达及其对耐药性的影响.中华医学杂志,2002,82(19):1355—1358
25. Tzelepi E, Giakkoupi P, Sofianou D, et al. Detection of extended spectrum β-lactamases in clinical isolates of Enterobacter cloacae and Enterobacter aerogenes. [J].J Clin Microbial,2000,38:542-546
26. Handson N D, Thomson K S, Moland E S, et al. Molecular characterization of a multiply resistant K. pneumoniae encoding ESBLs and a plasmid medicated AmpC.[J].J Antimicrob Chemother, 1999, 44: 377-380
27.杨立军,朱立华,徐国宾,等.产ESBLs肠杆菌科细菌中整合子参与多重耐药机制研究.中国抗生素杂志,2002,27(12):722—725
28. Lautenbach E, Patel J B, Bilker W B, et al. Extended spectrum [beta] lactamase-producing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on outcomes.[J].Clin Infect Dis. 2001;32:1162-1171.
29. Gniadkouwski M. Evolution and epidemiology of extended spectrum [beta]-lactamases (ESBLs) and ESBL-producing microorganisms.[J], Clin Microbiol Infect. 2001;7:597-608.
30. Paterson D L, Ko W, Von Gottberg, et al. Outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing extended spectrum [beta]-lactamases: implications for the clinical microbiology laboratory. [J].J Clin Microbiol. 2001;39: 2206-2212.
31. Wong-Beringer A, Hindler J, Loeloff M, et al. Molecular correlation for the treatment outcomes in bloodstream infections caused by Escherichia coli and Klebsiella pneumoniae with reduced susceptibility to ceftazidime. Clin Infect Dis. 2002;34:135-146.
32. Kaye K S, Cosgrove S, Harris A, et al. Risk factors for emergence of resistance to broad-spectrum cephalosporins among Enterobacter spp.[J]. Antimicrob Agents Chemother. 2001;45:2628-2630.
33. Ariza, Javier, Pujol, Miquel. Nosocomial Antibiotic Resistance in GNB at the ICUs.[J]. Clinical Pulmonary Medicine,2004,11(2):71-83
34.卓超,肖永虹,蒋玉富,等.E试验监测重症监护病房中400株革兰阴性菌的耐药性.中国抗生素杂志,2003,28(5):276—280
35.沈依群,赵敏。氨基糖苷类抗生素的耐药机制及控制耐药性的策略,国外医药抗生素分册,2002,23(3):118—120
36.顾觉奋,杨晓兵。细菌对氨基糖苷类抗生素耐药机制研究进展,药 物生物技术,2001,8(3):174—177
37.胡仪吉。氨基糖苷类抗生素耐药产生的机制及对策,中国实用儿科杂志,2003,17(3):142—144
38.张永龙,李家泰。北京地区临床分离菌对氨基糖苷类抗生素耐药情况调查研究及其耐药机理分析,中国抗生素杂志,1998,23(5):371
39.陈代杰,李燕。细菌对氨基糖苷类抗生素的耐药性与抗生素产生菌的推理选育.中国医药工业杂志,2001,32(2):85—89
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