产超广谱β-内酰胺酶细菌流行病学与耐药性研究
|
摘要
超广谱β-内酰胺类抗生素，如头孢噻肟、头孢曲松、氨曲南和头孢他啶引入临床应用后不久，欧洲即首先在肠杆菌科细菌中发现了超广谱β-内酰胺酶(Extended-spectrum β-lactamases,ESBLs)，随后有关ESBLs的报告遍及世界各地。ESBLs是由革兰阴性菌，如肺炎克雷伯菌、大肠埃希菌、奇异变形杆菌、粘质沙雷氏菌、阴沟肠杆菌、不动杆菌和铜绿假单胞菌等产生，且能使氧亚氨基(anoxyimino group)β-内酰胺抗生素，如第三代头孢菌素和单环酰胺类氨曲南失活。由于其水解底物较广谱β-内酰胺酶(TEM-1、TEM-2和SHV-1)更加广泛，故称之为ESBLs。产ESBLs的肠杆菌科细菌的耐药问题是当前全球最重要的医院内感染耐药问题之一，且检测又是实验室的难点：另外，由于各地区流行的基因型不同而存在耐药性和检测底物的地区差别，因此，了解产ESBLs的肺炎克雷伯菌和大肠埃希菌的最佳检测底物及耐药性特点，有利于防止产ESBLs株的区域性流行，并指导临床治疗，以免延误病情和造成浪费。
1999年2月至2001年12月间，我们对安徽医科大学第一附属医院临床标本中分离出的201株肺炎克雷伯菌和大肠埃希菌的ESBLs产生情况、产ESBLs菌株的耐药性及其检测进行了研究，并对经ESBLs表型确认试验证实产ESBLs的肺炎克雷伯菌和大肠埃希菌，进行了耐药基因的初步分型。
目的是了解产超广谱β-内酰胺酶肺炎克雷伯菌和大肠埃希菌感染的危险因素和细菌耐药情况：产ESBLs检测的最佳底物；我院产ESBLs的肺炎克雷伯菌和大肠埃希菌的流行状况及产ESBLs的肺炎克雷伯菌和大肠埃希菌中β-内酰胺酶基因型的初步分布情况。
结果及结论为侵袭性操作、β-内酰胺类药物及第三代头孢菌素的应用、院内获得性感染致细菌产生ESBLs的风险明显高于非暴露组。OR值分别为2.314、2.276、3.433和2.665。检测ESBLs的最佳底物是头孢噻肟，其次为头孢曲松：头孢他啶不宜作为我院ESBLs的检测底物。
安徽医科大学硕士学位论文
我院肺炎克雷伯菌和大肠埃希菌中ESBLs检出率分别为50%和27.2%
检出率为34.6%。产ESBLs菌对头抱他咙、氨曲南、头抱西丁、头抱毗肪、
，总
头抱
呱酮/舒巴坦、呱拉西林/他哇巴坦、阿米卡星及环丙沙星等20种抗生素的耐药率
比不产酶株都有不同程度增加，但亚胺配能对所有产ESBLs菌株都敏感。故治疗
中碳青霉烯类药物是最可靠的。64株产ESBLs细菌中，主要基因型为花M型
p一内酞胺酶，其次为SHV型和CTX一M型，但具体分子流行病学状况，有待进
一步研究。
Soon after introducing the clinical use of extended-spectrum cephalosporins, such as cefetaxime, ceftriaxone, aztreonam and ceftazidime, extended-spectrum -lactamases (ESBLs) were firstly isolated from Enterobacleriaceae in Europe. Then, reports on ESBLs spread around the world. ESBLs were produced by Gram-negative bacteria, such as Klebsiella pneumoniae, Escherichia coli, Proteus mirabilis, Serratia marcescens, Enterohacter cloacae. Acinetobacter sp. and Pseudomonas aeruginosa, and could inactivate oxyimino- -lactams like third-generation cephalosporins and aztreonam, due to their wider substrates for hydrolysis than penicillinase like TEM-1, TEM-2 and SHV-1, were designated. The resistance of ESBLs-producing Enterobacteriaceae has currently become one of the most important nosocomial resistance problems around the world, and their detecting is harder in the laboratory, and due to diverse genotypes, exist distinction of resistance and detecting substrates between them. Therefore, we had a study of the bes
t detective substrates and drug-resistance of ESBLs-producing K. pneumoniae and E. coli isolates in the First Affiliated Hospital Anhui Medical University so that we could prevent regional prevalence of ESBLs producers and guide clinical therapy in order to avoid delaying therapy and wasting drugs.
we studied ESBLs epidemiology, detecting, resistance and resistant genotypes of 201 K. pneumoniae and E. coli strains isolated from the First Affiliated Hospital Anhui Medical University, Anhui Province China between 1999 and 2001.
To study risk factors for infections caused by K. pneumoniae and E. coli producing extended-spectrum - lactamases and drug-resistance. To study the best detective substrate of ESBLs. To investigate the epidemiological data and drug-resistance of
ESBLs producers .To study resistant genotypes of ESBLs producers isolated from our hospital between 1999 and 2001.
Results and Conclusions The risks of ESBLs-producing bacteria infections was significantly higher in the exposure to invasive manipulations, P -lactams drugs, the third generation cephalosporins and nosocomial infections caused than the nonexposure.
Cefetaxime was the best detective substrates of ESBLs-producing K. pnewnoniae and E. coli isolates, and then ceftriaxone and aztreonam in our hospital. Relying on ceftazidime resistance as a single marker for presence of ESBLs may be unreliable.
The incidences of ESBLs in K. pneumoniae and E.coli were 50 percent and 27.2 percent respectively. The average incidence was 34.6 percent. Compared with the resistance rates of non-ESBLs producing strains, those of ESBLs producers to ceftazidime, aztreonam, cefepime, cefoxitin, piperacillin/tazobactam, cefoperazone/ sulbactam, amikacin and ciprofloxacin increased. But all ESBLs producers were susceptible to imipenem. Therefore carbapenems like imipenemwere most reliable therapeuticdrugs.
Of 64 ESBLs-producers, the main type of -lactamases was TEM-type, and then SHV-type and CTX-M-type. However, concrete molecular epidemiology will still wait for more research.
1999年2月至2001年12月间，我们对安徽医科大学第一附属医院临床标本中分离出的201株肺炎克雷伯菌和大肠埃希菌的ESBLs产生情况、产ESBLs菌株的耐药性及其检测进行了研究，并对经ESBLs表型确认试验证实产ESBLs的肺炎克雷伯菌和大肠埃希菌，进行了耐药基因的初步分型。
目的是了解产超广谱β-内酰胺酶肺炎克雷伯菌和大肠埃希菌感染的危险因素和细菌耐药情况：产ESBLs检测的最佳底物；我院产ESBLs的肺炎克雷伯菌和大肠埃希菌的流行状况及产ESBLs的肺炎克雷伯菌和大肠埃希菌中β-内酰胺酶基因型的初步分布情况。
结果及结论为侵袭性操作、β-内酰胺类药物及第三代头孢菌素的应用、院内获得性感染致细菌产生ESBLs的风险明显高于非暴露组。OR值分别为2.314、2.276、3.433和2.665。检测ESBLs的最佳底物是头孢噻肟，其次为头孢曲松：头孢他啶不宜作为我院ESBLs的检测底物。
安徽医科大学硕士学位论文
我院肺炎克雷伯菌和大肠埃希菌中ESBLs检出率分别为50%和27.2%
检出率为34.6%。产ESBLs菌对头抱他咙、氨曲南、头抱西丁、头抱毗肪、
，总
头抱
呱酮/舒巴坦、呱拉西林/他哇巴坦、阿米卡星及环丙沙星等20种抗生素的耐药率
比不产酶株都有不同程度增加，但亚胺配能对所有产ESBLs菌株都敏感。故治疗
中碳青霉烯类药物是最可靠的。64株产ESBLs细菌中，主要基因型为花M型
p一内酞胺酶，其次为SHV型和CTX一M型，但具体分子流行病学状况，有待进
一步研究。
Soon after introducing the clinical use of extended-spectrum cephalosporins, such as cefetaxime, ceftriaxone, aztreonam and ceftazidime, extended-spectrum -lactamases (ESBLs) were firstly isolated from Enterobacleriaceae in Europe. Then, reports on ESBLs spread around the world. ESBLs were produced by Gram-negative bacteria, such as Klebsiella pneumoniae, Escherichia coli, Proteus mirabilis, Serratia marcescens, Enterohacter cloacae. Acinetobacter sp. and Pseudomonas aeruginosa, and could inactivate oxyimino- -lactams like third-generation cephalosporins and aztreonam, due to their wider substrates for hydrolysis than penicillinase like TEM-1, TEM-2 and SHV-1, were designated. The resistance of ESBLs-producing Enterobacteriaceae has currently become one of the most important nosocomial resistance problems around the world, and their detecting is harder in the laboratory, and due to diverse genotypes, exist distinction of resistance and detecting substrates between them. Therefore, we had a study of the bes
t detective substrates and drug-resistance of ESBLs-producing K. pneumoniae and E. coli isolates in the First Affiliated Hospital Anhui Medical University so that we could prevent regional prevalence of ESBLs producers and guide clinical therapy in order to avoid delaying therapy and wasting drugs.
we studied ESBLs epidemiology, detecting, resistance and resistant genotypes of 201 K. pneumoniae and E. coli strains isolated from the First Affiliated Hospital Anhui Medical University, Anhui Province China between 1999 and 2001.
To study risk factors for infections caused by K. pneumoniae and E. coli producing extended-spectrum - lactamases and drug-resistance. To study the best detective substrate of ESBLs. To investigate the epidemiological data and drug-resistance of
ESBLs producers .To study resistant genotypes of ESBLs producers isolated from our hospital between 1999 and 2001.
Results and Conclusions The risks of ESBLs-producing bacteria infections was significantly higher in the exposure to invasive manipulations, P -lactams drugs, the third generation cephalosporins and nosocomial infections caused than the nonexposure.
Cefetaxime was the best detective substrates of ESBLs-producing K. pnewnoniae and E. coli isolates, and then ceftriaxone and aztreonam in our hospital. Relying on ceftazidime resistance as a single marker for presence of ESBLs may be unreliable.
The incidences of ESBLs in K. pneumoniae and E.coli were 50 percent and 27.2 percent respectively. The average incidence was 34.6 percent. Compared with the resistance rates of non-ESBLs producing strains, those of ESBLs producers to ceftazidime, aztreonam, cefepime, cefoxitin, piperacillin/tazobactam, cefoperazone/ sulbactam, amikacin and ciprofloxacin increased. But all ESBLs producers were susceptible to imipenem. Therefore carbapenems like imipenemwere most reliable therapeuticdrugs.
Of 64 ESBLs-producers, the main type of -lactamases was TEM-type, and then SHV-type and CTX-M-type. However, concrete molecular epidemiology will still wait for more research.
引文
1, Jacoby GA, Medeires AA. Moreextended-spectrom beta-lactamases. Antimicrob Agents Chemother, 1991, 35(7): 1697-1704
2，王辉，谢秀丽，徐英春，等．革兰阴性杆菌对12种抗生素的耐药监测-Etest法．中华医学检验杂志，1997，20(5)：265-269．
3，王露霞，徐德兴，刘刃，等．革兰阴性杆菌超广谱酶、诱导酶及药敏检测结果．中华医院感染学杂志，1998，8(1)：52-56．
4，朱德妹，熊自忠，等．产超广谱B-内酰胺酶和细菌耐药性．中华传染病杂志，2000，18(3)：151-154．
5，李家斌，徐元宏，俞云松，等．合肥市产ESBLs肺炎克雷伯和大肠埃细菌流行 状况及耐药性研究．中国抗生素杂志，2001，26(5)：358-360．
6，陈亚岗，俞云松，周伟琳，等．浙江省产超广谱 β-内酰胺酶大肠杆菌和肺炎克雷伯菌流行情况及耐药性．中华传染病杂志，2000．16(4)：236-238．
7, Pai H. The characteristics of extended-spectrum beta-lactamases in Korean isolates of Enterobacteriaceae. Yonsei Med J, 1998, 39(3):514-519
8，胡云建，杜迪君，张秀珍．产超广潜 β-内酰胺酶大肠埃希菌的耐药性及脉冲场电泳分型研究．中华医院感染学杂志，2000，10(2)：154-155．
9, Quinn JP.Clinical significance of extended-spectrum beta-lactamases [J].Eur J Clin Microbiol Infect Dis, 1994,Suppl 1:39
10. Pena C, Pujol M, Ricart A, et al. Risk factors for faecal carriage of Klebsiella pneumoniae producing extended-spectrum β-lactamases(ESBL-KP) in the intensive care unit [J]. Hosp Intect, 1997, 35(1):9
11，林庆安，罗文侗，修清玉等．超广谱β-内酰胺酶肺炎克雷伯菌大肠埃希菌耐药监测．中华检验医学杂志，2001，24(4)，203-204．
12, Sirot D, Recule C, Chaibi EB, et al. A complex mutant of TEM-1 β-lactamases with mutations encountered in both IRT-4 and extended-spectrum TEM-15, produced by an Escherichia Coli [J]. Antimicrob Agents Chemother, 1997, 41(6): 1322-1325.
13, Bush K, Singer SB. Biochemical characteristics of extended broad spectrumβ-lactamases [J]. Infection, 1989, 17(6):429-433.
14, French GL, Shannon KP, Simmons N. Hospital outbreak of Klebsiella pneumoniae resistant to broad-spectrum cephalosporins and β-lactam-βlactamase inhibitor combinations by hyperproduetion of SHV-5 β-lactamase [J]. J olin Microbiol, 1996, 34(2): 358-363.
15, Pangon B, bizet C, Bure A, et al. In vivo selection of a cephamycin-resistant porin-deficient mutant of Klebsiella pneumoniae producing a TEM-3 betalactamase [J]. J Infect Dis. 1989. 159(5): 1005
16，林庆安，罗文侗，修清玉等。上海部分地区肠杆菌科细菌产超广谱β-内酰胺酶情况及药敏监测，中华结核和呼吸杂志，2000，23(7)：241-242．
17，周清德，缪竞智，张秀珍．产ESBLs肺炎克雷伯菌医院感染分子流行病学研究．中华医院感染学杂志，2000，4(1)：146-148．
18, Pena. Control of an ESBL-outbreak [J]. ACC, 1998, 42(1):53
19, Meyer KS, Urban C, Eagen JA, et al. Nosocomial outbreak of Klebsiella infection resistant to late generation cephalosporins[J]. Ann Intern Med, 1993, 119(5):353-358.
2，王辉，谢秀丽，徐英春，等．革兰阴性杆菌对12种抗生素的耐药监测-Etest法．中华医学检验杂志，1997，20(5)：265-269．
3，王露霞，徐德兴，刘刃，等．革兰阴性杆菌超广谱酶、诱导酶及药敏检测结果．中华医院感染学杂志，1998，8(1)：52-56．
4，朱德妹，熊自忠，等．产超广谱B-内酰胺酶和细菌耐药性．中华传染病杂志，2000，18(3)：151-154．
5，李家斌，徐元宏，俞云松，等．合肥市产ESBLs肺炎克雷伯和大肠埃细菌流行 状况及耐药性研究．中国抗生素杂志，2001，26(5)：358-360．
6，陈亚岗，俞云松，周伟琳，等．浙江省产超广谱 β-内酰胺酶大肠杆菌和肺炎克雷伯菌流行情况及耐药性．中华传染病杂志，2000．16(4)：236-238．
7, Pai H. The characteristics of extended-spectrum beta-lactamases in Korean isolates of Enterobacteriaceae. Yonsei Med J, 1998, 39(3):514-519
8，胡云建，杜迪君，张秀珍．产超广潜 β-内酰胺酶大肠埃希菌的耐药性及脉冲场电泳分型研究．中华医院感染学杂志，2000，10(2)：154-155．
9, Quinn JP.Clinical significance of extended-spectrum beta-lactamases [J].Eur J Clin Microbiol Infect Dis, 1994,Suppl 1:39
10. Pena C, Pujol M, Ricart A, et al. Risk factors for faecal carriage of Klebsiella pneumoniae producing extended-spectrum β-lactamases(ESBL-KP) in the intensive care unit [J]. Hosp Intect, 1997, 35(1):9
11，林庆安，罗文侗，修清玉等．超广谱β-内酰胺酶肺炎克雷伯菌大肠埃希菌耐药监测．中华检验医学杂志，2001，24(4)，203-204．
12, Sirot D, Recule C, Chaibi EB, et al. A complex mutant of TEM-1 β-lactamases with mutations encountered in both IRT-4 and extended-spectrum TEM-15, produced by an Escherichia Coli [J]. Antimicrob Agents Chemother, 1997, 41(6): 1322-1325.
13, Bush K, Singer SB. Biochemical characteristics of extended broad spectrumβ-lactamases [J]. Infection, 1989, 17(6):429-433.
14, French GL, Shannon KP, Simmons N. Hospital outbreak of Klebsiella pneumoniae resistant to broad-spectrum cephalosporins and β-lactam-βlactamase inhibitor combinations by hyperproduetion of SHV-5 β-lactamase [J]. J olin Microbiol, 1996, 34(2): 358-363.
15, Pangon B, bizet C, Bure A, et al. In vivo selection of a cephamycin-resistant porin-deficient mutant of Klebsiella pneumoniae producing a TEM-3 betalactamase [J]. J Infect Dis. 1989. 159(5): 1005
16，林庆安，罗文侗，修清玉等。上海部分地区肠杆菌科细菌产超广谱β-内酰胺酶情况及药敏监测，中华结核和呼吸杂志，2000，23(7)：241-242．
17，周清德，缪竞智，张秀珍．产ESBLs肺炎克雷伯菌医院感染分子流行病学研究．中华医院感染学杂志，2000，4(1)：146-148．
18, Pena. Control of an ESBL-outbreak [J]. ACC, 1998, 42(1):53
19, Meyer KS, Urban C, Eagen JA, et al. Nosocomial outbreak of Klebsiella infection resistant to late generation cephalosporins[J]. Ann Intern Med, 1993, 119(5):353-358.