耐甲氧西林的金黄色葡萄球菌SCCmec分型及PVL基因的表达
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摘要
目的：分析我院MRSA分布特点及耐药情况，检测MRSA的杀白细胞素(Panton-ValentinePVL)基因携带率和SCCmec基因分型，比较CA-MRSA与HA-MRSA之间有无差别，初步了解我院MRSA分子生物学流行性特征，从而进一步指导临床治疗MRSA，指导临床用药，更好地控制MRSA引起的感染，并减少耐药株的出现。
方法：以我院2005年9月至2006年9月各临床科室的MRSA菌株共65株为研究对象，用琼脂平皿二倍稀释法测定其对苯唑西林、利福平、莫昔沙星、头孢硫米、阿米卡星、磺胺甲(口恶)唑、万古霉素、克林霉素8种药物对其的最低抑菌浓度(MIC)。采用碱裂解法提取细菌总DNA，应用PCR扩增技术，检测mecA及PVL基因，在使用多重PCR扩增技术检测SCCmec基因分型，PCR产物进行琼脂糖电泳凝胶检测，各选取一株阳性株进行基因测序。
结果：65株MRSA主要分布在ICU(15.1％)、神经外科(15.1％)、神经内科(12.1％)、呼吸内科(12.1％)、皮肤科(12.1％)、感染科(9.1％)。标本主要来源于痰液者47株(73.8％)，皮肤软组织分泌物11株。65株MRSA对利福平、莫昔沙星、头孢硫米、磺胺甲(口恶)唑、克林霉素的耐药率均较高，分别为：89.2％、92.3％、83.1％，96.9％、86.1％对阿米卡星耐药率相对较低，为55.3％。CA-MRSA的耐药率低于HA-MRSA。65株MRSA PVL基因阳性率为16.9％，其中3株分离自皮肤软组织分泌物(27.3％)，1株来源于腹腔引流液(7.7％)，其余9株分离自痰液(69.2％)其中CA-MRSA4株，占所有CA-MRSA的30.8％，HA-MRSA7株，占所有HA-MRSA的13.5％。65株MRSA的SCCmec基因分型均为Ⅲ型。
结论：MRSA对多种抗生素耐药率均较高，且多数菌株表现为多重耐药，尚未发现对万古霉素耐药的菌株。目前，万古霉素仍然是治疗MRSA的首选药物，阿米卡星耐药率相对较低，可作为辅助治疗药物。我院MRSA菌株PVL携带率较高，其中CA-MRSA携带率高于HA-MRSA。SCCmec基因分型单一，均为SCCmec-Ⅲ型，CA-MRSA与HA-MRSA基因型一致，有可能这些CA-MRSA事实上来自于HA-MRSA，或者二者在个别基因位点上不尽相同。
Objective: To study resistance of MRSA to antibiotics and its distribution, and detect mecA, Panton-Valentine leucocidin (PVL) and SCCmec typing of MRSA isolates. Compare the differences of PVL and SCCmec between the CA-MRSA and HA-MRSA. Get the message of the molecular epidemiologic characters of MRSA in our hospital and guide the treatment and prevention of MRSA infections.
Methods: The minimal inhibitory concentrations (MIC) of 8 kinds of antimicrolbiac agents against 65 strains of MRSA were tested by serial two-fold agar dilution method. Their DNAs were extracted by alkali splitting method. Detect mecA and PVL by polymerase chain reaction (PCR). SCCmec typing(Ⅰ-Ⅴ) of all clinical isolates of MRSA was performed by novel multiplex PCR assay.
Results: The 65 strains of MRSA mainly distributed in ICU (15.1%), neurosurgery department (15.1%), respiratory department(12.1%), neurology department (12.1%), dermatology department (12.1%) and infection disease ward (9.1%) .Most of them came from sputum, secretion, The resistant rate to rifampicin, moxfloxacin, cefathiamidine, SMZ, clindamycin and amikacin were 89.2%、92.3%、83.1, 96.9%、86.1% and 55.3% respectively. 100% MRSA strains were susceptible to glycopeptides such as vancomycin. The resistant rate of CA-MRSA was lower than that of HA-MRSA. PVL had been found in 11 strains of these MRSA, 3 of them came from secretion, 1 strain came from ascite while 7 strains came from sputum. There were 4 CA-MRSA strains and 7 HA-MRSA strains. All of the isolates genotypied into SCCmec typeⅢ. Conclusions: This study has demonstrated that MRSA isolates in our hospital are resistant to multidrug, but sensitive to glycopeptides, therefore glycopeptides is recommended as the first line candidate medicine to treat the MRSA infections, amkacin can be used as auxiliary medicine. The positive rate of PVL in CA-MRSA is higher than in HA-MRSA. The SCCmec type of MRSA in our hospital is unity. Maybe these "CA-MRSA" isolates are indeed "HA-MRSA", or there have some difference at special gene site between them.
方法：以我院2005年9月至2006年9月各临床科室的MRSA菌株共65株为研究对象，用琼脂平皿二倍稀释法测定其对苯唑西林、利福平、莫昔沙星、头孢硫米、阿米卡星、磺胺甲(口恶)唑、万古霉素、克林霉素8种药物对其的最低抑菌浓度(MIC)。采用碱裂解法提取细菌总DNA，应用PCR扩增技术，检测mecA及PVL基因，在使用多重PCR扩增技术检测SCCmec基因分型，PCR产物进行琼脂糖电泳凝胶检测，各选取一株阳性株进行基因测序。
结果：65株MRSA主要分布在ICU(15.1％)、神经外科(15.1％)、神经内科(12.1％)、呼吸内科(12.1％)、皮肤科(12.1％)、感染科(9.1％)。标本主要来源于痰液者47株(73.8％)，皮肤软组织分泌物11株。65株MRSA对利福平、莫昔沙星、头孢硫米、磺胺甲(口恶)唑、克林霉素的耐药率均较高，分别为：89.2％、92.3％、83.1％，96.9％、86.1％对阿米卡星耐药率相对较低，为55.3％。CA-MRSA的耐药率低于HA-MRSA。65株MRSA PVL基因阳性率为16.9％，其中3株分离自皮肤软组织分泌物(27.3％)，1株来源于腹腔引流液(7.7％)，其余9株分离自痰液(69.2％)其中CA-MRSA4株，占所有CA-MRSA的30.8％，HA-MRSA7株，占所有HA-MRSA的13.5％。65株MRSA的SCCmec基因分型均为Ⅲ型。
结论：MRSA对多种抗生素耐药率均较高，且多数菌株表现为多重耐药，尚未发现对万古霉素耐药的菌株。目前，万古霉素仍然是治疗MRSA的首选药物，阿米卡星耐药率相对较低，可作为辅助治疗药物。我院MRSA菌株PVL携带率较高，其中CA-MRSA携带率高于HA-MRSA。SCCmec基因分型单一，均为SCCmec-Ⅲ型，CA-MRSA与HA-MRSA基因型一致，有可能这些CA-MRSA事实上来自于HA-MRSA，或者二者在个别基因位点上不尽相同。
Objective: To study resistance of MRSA to antibiotics and its distribution, and detect mecA, Panton-Valentine leucocidin (PVL) and SCCmec typing of MRSA isolates. Compare the differences of PVL and SCCmec between the CA-MRSA and HA-MRSA. Get the message of the molecular epidemiologic characters of MRSA in our hospital and guide the treatment and prevention of MRSA infections.
Methods: The minimal inhibitory concentrations (MIC) of 8 kinds of antimicrolbiac agents against 65 strains of MRSA were tested by serial two-fold agar dilution method. Their DNAs were extracted by alkali splitting method. Detect mecA and PVL by polymerase chain reaction (PCR). SCCmec typing(Ⅰ-Ⅴ) of all clinical isolates of MRSA was performed by novel multiplex PCR assay.
Results: The 65 strains of MRSA mainly distributed in ICU (15.1%), neurosurgery department (15.1%), respiratory department(12.1%), neurology department (12.1%), dermatology department (12.1%) and infection disease ward (9.1%) .Most of them came from sputum, secretion, The resistant rate to rifampicin, moxfloxacin, cefathiamidine, SMZ, clindamycin and amikacin were 89.2%、92.3%、83.1, 96.9%、86.1% and 55.3% respectively. 100% MRSA strains were susceptible to glycopeptides such as vancomycin. The resistant rate of CA-MRSA was lower than that of HA-MRSA. PVL had been found in 11 strains of these MRSA, 3 of them came from secretion, 1 strain came from ascite while 7 strains came from sputum. There were 4 CA-MRSA strains and 7 HA-MRSA strains. All of the isolates genotypied into SCCmec typeⅢ. Conclusions: This study has demonstrated that MRSA isolates in our hospital are resistant to multidrug, but sensitive to glycopeptides, therefore glycopeptides is recommended as the first line candidate medicine to treat the MRSA infections, amkacin can be used as auxiliary medicine. The positive rate of PVL in CA-MRSA is higher than in HA-MRSA. The SCCmec type of MRSA in our hospital is unity. Maybe these "CA-MRSA" isolates are indeed "HA-MRSA", or there have some difference at special gene site between them.
引文
1．李艺 杨信怡 游雪甫，耐甲氧西林金葡菌的耐药分子机制研究，国外医药抗生素分册[J]，2005，26(4)
2. Deplano, A., W. Witte, W. van Leeuwen, Y. Brun, and M. J. Struelens. 2000. Clonal dissemination of epidemic methicillin-resistant Staphylococcus aureus in Belgium and neighboring countries. Clin. Microbiol. Infect. 6:239-245.
3. De Sousa, M. A., S. Sanches, M. L. Ferro, M. J. Vaz, Z. Saraiva, et al. 1998.Intercontinental spread of a multidrug-resistant methicillin-resistant Staphylococcus aureus strain. J. Clin. Microbiol. 36:2590-2596.
4. Robert Koch Institut.. Zur MRSA-Situation in Deutschland im Jahr 2003. Epidemiol. Bull. 2004 42:358 - 359.
5. Sabine P, Klaus O, Longitudinal Study of the Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus at a University Hospita, Journal of clinical microbiology, Dec. 2006,44(12). 4297 - 4302
6．王清涛，杜小玲，曲寿山，等．金黄色葡萄球菌耐药性分析．中华医学检验杂志，1997，20(5)：2772279．
7．朱德妹．上海地区甲氧西林耐性金黄色葡萄球菌的研究．中华传染病杂志，1988，6(1)：224．
8．程绍云，闫志勇．青岛市市区耐甲氧西林金黄色葡萄球菌的临床分布与耐药谱分析．齐鲁医学杂志，2003，18(4)：3852387．
8. Berglund C ,Molling P , Sjoberg L , et al. Predominance of
9. Palazzo ICV, Araujo MLC, Darini ALC: First Report of Vancomycin-Resistant Staphylococci Isolated from Healthy Carriers in Brazil. J Clin Microbiol 2005, 43:179-185.
10. Bataineh AB: Resistance of Staphylococcus aureus to Vancomycin in Zarqa, Jordan. Pak J Med Sci 2006, 22:144-148
11. Hare Krishna Tiwari and Malay Ranjan Sen Emergence of vancomycin resistant Staphylococcus aureus (VRSA) from a tertiary care hospital from northern part of India BMC Infectious Diseases 2006, 6:156-159
12. Ko KS, Lee JY, Suh JY, et allDistribution ofmajor genotypes amongmethicillin2resistant Staphylococcus aureus clones in Asian countriesl J ClinMicrobiol, 2005 , 43: 4212-4261
13. Arakere G, Nadig S, Swedberg G, et allGenotyp ing of methicillin-resistant Staphylococcus aureus strains from two hosp itals in Bangalore, South IndialJ ClinMicrobiol, 2005, 43: 3198-32021
14. Mulligan ME, et al. Methicillin-Resistant Staphylococcus aureus:A Consensus Review of the Microbiology, Pathogenesis and Epidemiology Witn Implication for Prevention and Managenment. AmJ Med, 1993,94:313-316
15. Abdullah K, Li H. J, Charles W., et al, Antimicrobial Susceptibility Patterns and Staphylococcal CassetteChromosome mec Types of, as Well as Panton-Valentine Leukocidin Occurrence among, Methicillin-Resistant Staphylococcus aureus Isolates from Children and Adults in Middle Tennessee, journal of clinical microbiology, Dec. 2006, p. 4436-4440
16．松木庆藏，抗生素的使用方法和耐药菌感染，综合临床，1994；9(2)：53-57
17．李胜利，耐甲氧西林金黄色葡萄球菌医院感染的研究进展，中华医院感染杂志，1998，8(1)：622
18．陶传敏，陶传敏，陈慧莉，杜晓青等，金黄色葡萄球菌的耐药性监测与预防对策，华西医学，2006，21(1)．52-53
19．樊剑锋，杨永弘，马琳，耐甲氧西林金黄色葡萄球菌抗生素耐药和耐药基因的检测，首都医科大学学报，2005，26(540-544)
20. Fridkin SK, Hageman JC , Morrison M , et al . Met hicillin resistant Staphylococcus aureus disease in three communities[J]. New Engl J Med , 2005 ,352:1436-1444.
21. Martinez - Aguilar G, Avalos - Mishaan A. Community -acquired methicillin - resistant and methicillin - susceptible Staphylococcus aureus musculoskeletal infections in children [J].Pediatr Infect Dis J , 2004 , 23 (8) : 701-704
22. Michael M. Idcp snapshots [J]. Infect Dis Clin Prac, 2002,11(6) : 327-331
23. Francis J S, Carroll K. Community - acquired MRSA: a notable adversary [J]. South Med J , 2005 , 98 (11) : 1061-1068
24. Vandenesch F , Naimi T , Mark C, et al . Community-acquired Methicillin-resistant Staphylococcus aureus carrying panton-valenine leukocidin genes : worldwide emergence. Emerg Infect Dis , 2003 , 9(8) :978-984.
25. Eguia JM, Chambers HF. Community-acquried methicillin-resistant Staphylococus aureus : epidemiology and potential virulence factors. Cur Infect Dis Rep , 2003 , 5 (6) :459-466.
26. Zhang K.Y, Jo-Ann McClure, Sameer Elsayed, Novel Multiplex PCRA ssay for Characterization and Concomitant Subtyping of Staphylococcal Cassette Chromosome mec Types Ⅰ to Ⅴ in Methicillin-Resistant Staphylococcus aureus, Journal of clilical microbiology, 2005,43(lO) 5026 - 5033
27．孙光明，马筱玲，戴媛媛，耐甲氧西林金黄色葡萄球菌SCCmec基因分型的研究，中国抗生素杂志[J]，2006，31(5)：287-290
28．皮博睿，陈亚岗，俞云松等，甲氧西林耐药葡萄球菌SCCmec研究，中华微生物和免疫学杂志[J]，2006，26(12)：1108-1110
1. Chambers HF. Methicillin resistant in staphylococci: molecular and biochemical basis and clinical imp lications[ J ]. Clin M icrobiol Rev, 1997, 10 (4) : 781-785
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6. Ko KS, Lee JY, Suh JY, et allDistribution ofmajor genotypes among methicillin2resistant Staphylococcus aureus clones in Asian countries [J ]ClinMicrobiol, 2005 , 43: 421-426
7. Arakere G, Nadig S, Swedberg G, et allGenotyp ing of methicillin-resistant Staphylococcus aureus strains from two hosp itals in Bangalore, South IndialJ ClinMicrobiol, 2005, 43: 3198-32021
8. Michael M. Idcp snapshots [J ] . Infect Dis Clin Prac , 2002 , 11(6) : 327-335
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10. Francis J S , Carroll K. Community - acquired MRSA: a notable adversary [J ] . South Med J , 2005 , 98 (11) : 1061-1068
11. Holmes A , Ganner M, Guane M S , et al. Staphylococcus aureusisolates carrying panton - valentine leucocidin genes in England and wales : frequency , characterization , and association with clinical disease [J ] . J Clin Microbiol , 2005 , 43 (5) : 2384
13. Vandenesch F , Naimi T , Enright MC , et al . Community-acquired met hicillin2resistant staphylococcus aureus carrying panton-valentine leukocidin genes : worldwide emergence. Emerg Infect
15. Martinez - Aguilar G, Avalos - Mishaan A. Community -acquired , methicillin - resistant and methicillin - susceptible Staphylococcus aureus musculoskeletal infections in children [J ] . Pediatr Infect Dis J , 2004 , 23 (8) : 701-705
16. Drew RH , Perfect K, Srinath L , et al . Treatment ofme2 Thicillin-resistant Staphylococcus aureus infections with quinupristin/ dalfopritin in patients intolerant of or failing prior therapy [J ] . J A ntimicrob Chemother , 2000 ,46 (3) : 775-784
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22. Noskin GA. Methicillin-resistant Staphylococcus aureus and Vancomycin-resistant Enterococci:Emerging problem and new prospects for management. Annals Academy of Medicine. 2001,30(3):320-331
23. Miyata A, Araake M, Ogawa H, et al. Effect of arbekacin on the production of toxic shock syndrome toxin 1 by methicillin-resistant Staphylococcus aureus. Jpn J Antibiot, 2001 Jul, 54(7):372-381
2. Deplano, A., W. Witte, W. van Leeuwen, Y. Brun, and M. J. Struelens. 2000. Clonal dissemination of epidemic methicillin-resistant Staphylococcus aureus in Belgium and neighboring countries. Clin. Microbiol. Infect. 6:239-245.
3. De Sousa, M. A., S. Sanches, M. L. Ferro, M. J. Vaz, Z. Saraiva, et al. 1998.Intercontinental spread of a multidrug-resistant methicillin-resistant Staphylococcus aureus strain. J. Clin. Microbiol. 36:2590-2596.
4. Robert Koch Institut.. Zur MRSA-Situation in Deutschland im Jahr 2003. Epidemiol. Bull. 2004 42:358 - 359.
5. Sabine P, Klaus O, Longitudinal Study of the Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus at a University Hospita, Journal of clinical microbiology, Dec. 2006,44(12). 4297 - 4302
6．王清涛，杜小玲，曲寿山，等．金黄色葡萄球菌耐药性分析．中华医学检验杂志，1997，20(5)：2772279．
7．朱德妹．上海地区甲氧西林耐性金黄色葡萄球菌的研究．中华传染病杂志，1988，6(1)：224．
8．程绍云，闫志勇．青岛市市区耐甲氧西林金黄色葡萄球菌的临床分布与耐药谱分析．齐鲁医学杂志，2003，18(4)：3852387．
8. Berglund C ,Molling P , Sjoberg L , et al. Predominance of
9. Palazzo ICV, Araujo MLC, Darini ALC: First Report of Vancomycin-Resistant Staphylococci Isolated from Healthy Carriers in Brazil. J Clin Microbiol 2005, 43:179-185.
10. Bataineh AB: Resistance of Staphylococcus aureus to Vancomycin in Zarqa, Jordan. Pak J Med Sci 2006, 22:144-148
11. Hare Krishna Tiwari and Malay Ranjan Sen Emergence of vancomycin resistant Staphylococcus aureus (VRSA) from a tertiary care hospital from northern part of India BMC Infectious Diseases 2006, 6:156-159
12. Ko KS, Lee JY, Suh JY, et allDistribution ofmajor genotypes amongmethicillin2resistant Staphylococcus aureus clones in Asian countriesl J ClinMicrobiol, 2005 , 43: 4212-4261
13. Arakere G, Nadig S, Swedberg G, et allGenotyp ing of methicillin-resistant Staphylococcus aureus strains from two hosp itals in Bangalore, South IndialJ ClinMicrobiol, 2005, 43: 3198-32021
14. Mulligan ME, et al. Methicillin-Resistant Staphylococcus aureus:A Consensus Review of the Microbiology, Pathogenesis and Epidemiology Witn Implication for Prevention and Managenment. AmJ Med, 1993,94:313-316
15. Abdullah K, Li H. J, Charles W., et al, Antimicrobial Susceptibility Patterns and Staphylococcal CassetteChromosome mec Types of, as Well as Panton-Valentine Leukocidin Occurrence among, Methicillin-Resistant Staphylococcus aureus Isolates from Children and Adults in Middle Tennessee, journal of clinical microbiology, Dec. 2006, p. 4436-4440
16．松木庆藏，抗生素的使用方法和耐药菌感染，综合临床，1994；9(2)：53-57
17．李胜利，耐甲氧西林金黄色葡萄球菌医院感染的研究进展，中华医院感染杂志，1998，8(1)：622
18．陶传敏，陶传敏，陈慧莉，杜晓青等，金黄色葡萄球菌的耐药性监测与预防对策，华西医学，2006，21(1)．52-53
19．樊剑锋，杨永弘，马琳，耐甲氧西林金黄色葡萄球菌抗生素耐药和耐药基因的检测，首都医科大学学报，2005，26(540-544)
20. Fridkin SK, Hageman JC , Morrison M , et al . Met hicillin resistant Staphylococcus aureus disease in three communities[J]. New Engl J Med , 2005 ,352:1436-1444.
21. Martinez - Aguilar G, Avalos - Mishaan A. Community -acquired methicillin - resistant and methicillin - susceptible Staphylococcus aureus musculoskeletal infections in children [J].Pediatr Infect Dis J , 2004 , 23 (8) : 701-704
22. Michael M. Idcp snapshots [J]. Infect Dis Clin Prac, 2002,11(6) : 327-331
23. Francis J S, Carroll K. Community - acquired MRSA: a notable adversary [J]. South Med J , 2005 , 98 (11) : 1061-1068
24. Vandenesch F , Naimi T , Mark C, et al . Community-acquired Methicillin-resistant Staphylococcus aureus carrying panton-valenine leukocidin genes : worldwide emergence. Emerg Infect Dis , 2003 , 9(8) :978-984.
25. Eguia JM, Chambers HF. Community-acquried methicillin-resistant Staphylococus aureus : epidemiology and potential virulence factors. Cur Infect Dis Rep , 2003 , 5 (6) :459-466.
26. Zhang K.Y, Jo-Ann McClure, Sameer Elsayed, Novel Multiplex PCRA ssay for Characterization and Concomitant Subtyping of Staphylococcal Cassette Chromosome mec Types Ⅰ to Ⅴ in Methicillin-Resistant Staphylococcus aureus, Journal of clilical microbiology, 2005,43(lO) 5026 - 5033
27．孙光明，马筱玲，戴媛媛，耐甲氧西林金黄色葡萄球菌SCCmec基因分型的研究，中国抗生素杂志[J]，2006，31(5)：287-290
28．皮博睿，陈亚岗，俞云松等，甲氧西林耐药葡萄球菌SCCmec研究，中华微生物和免疫学杂志[J]，2006，26(12)：1108-1110
1. Chambers HF. Methicillin resistant in staphylococci: molecular and biochemical basis and clinical imp lications[ J ]. Clin M icrobiol Rev, 1997, 10 (4) : 781-785
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