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Resistance Determinants and Antimicrobial Susceptibilities of Mupirocin-Resistant Staphylococci Isolated from a Korean Hospital

국내 한 대학병원에서 수집된 Mupirocin 내성 포도알균의 내성 유전자 및 항생물질 감수성 분석

  • Min, Yu-Hong (Department of Herbal Skin Care, Daegu Haany University) ;
  • Lee, Jong-Seo (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Kwon, Ae-Ran (Department of Herbal Skin Care, Daegu Haany University) ;
  • Shim, Mi-Ja (Department of Life Science, University of Seoul) ;
  • Choi, Eung-Chil (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University)
  • 민유홍 (대구한의대학교 한방피부미용학과) ;
  • 이종서 (서울대학교 약학대학, 종합약학연구소) ;
  • 권애란 (대구한의대학교 한방피부미용학과) ;
  • 심미자 (서울시립대학교 생명과학과) ;
  • 최응칠 (서울대학교 약학대학, 종합약학연구소)
  • Received : 2011.12.15
  • Accepted : 2012.03.05
  • Published : 2012.06.30

Abstract

We analyzed mupirocin resistance rates among staphylococcal isolates collected from a Korean hospital in 2003 (100 isolates), 2005 (195 isolates), 2006 (151 isolates), and 2009 (112 isolates). In Staphylococcus aureus, rates of high-level mupirocin resistance (MIC, minimal inhibitory concentration ${\geq}512{\mu}g/ml$) decreased and did not appear since 2005. In contrast, low-level mupirocin resistance (MIC $8-256{\mu}g/ml$) was not detected in 2003 and 2005 but its rates later increased to 6.9% in 2009. Total resistance rates of coagulase-negative staphylococci (CNS) were significantly higher than those of S. aureus. The rates of high-level resistance of CNS increased from 16.0% in 2003 to 31.5% in 2009. The rate of low-level resistance of CNS was 8.0% in 2003 and around 11% later. In all high-level resistant isolates, the ileS-2 gene was detected. All low-level resistant isolates contained the known V588F mutation in ileS gene. Previously unknown mutations such as V458G in S. aureus and D172A, Y490H and I750V in CNS were identified additionally. One S. aureus isolate with high-level resistance was resistant to oxacillin and several topical antibiotics commonly used for the treatment of skin infection. Ten S. aureus isolates with low-level resistance were also resistant to all of these antibiotics except fusidic acid. CNS isolates with high-level (61 isolates) and low-level resistance (27 isolates) exhibited significantly higher resistance rates to these antibiotics than mupirocin-susceptible CNS isolates (167 isolates). In conclusion, prevention of the emergence of mupirocin resistance is necessary for the effective treatment of skin infection by staphylococci.

서울의 한 종합병원에서 포도알균 임상균주들을 2003, 2005, 2006 및 2009년에 각각 100, 195, 151 및 112주를 수집하여 mupirocin 내성율 변화 추이를 분석하였다. Staphylococcus aureus의 mupirocin에 대한 고도내성(최소억제농도 ${\geq}512{\mu}g/ml$) 빈도는 감소 추세로 2005년 이후에는 나타나지 않았다. 반면 S. aureus의 저도내성(최소억제농도 $8-256{\mu}g/ml$)은 2005년까지 나타나지 않았으나 2006년부터 나타나기 시작하여 2009년에는 6.9%에 이르렀다. Coagulase-negative staphylococci (CNS)의 전체적인 내성율은 S. aureus와 달리 상당히 높은 수준이었다. 2003년 CNS의 고도내성율은 16.0%이었으나 지속적으로 상승하여 2009년에는 31.5%에 이르렀다. CNS의 저도내성율은 2003년 8.0%이었고 이후 11% 정도의 일정 수준을 나타내었다. 모든 고도내성 균주들에서 ileS-2의 존재가 확인되었으며, 모든 저도내성 균주들에 대하여 ileS 유전자의 염기서열을 분석한 결과, 저도내성의 원인으로 알려진 V588F 변이가 공통적으로 발견되었다. 이외에도 S. aureus에서 V458G, 그리고 CNS에서 D172A, Y490H, I750V 변이들이 새로 발견되었다. Mupirocin 내성 균주들의 oxacillin 및 피부감염 치료에 사용되는 주요 외용 항생물질들에 대한 내성율을 측정한 결과, 고도내성인 S. aureus 1주는 이들 모든 항생물질에 내성이었고 저도내성인 S. aureus 10주는 fusidic acid를 제외한 모든 항생물질에 내성이었다. Mupirocin에 고도내성(61주) 및 저도내성(27주)인 CNS 균주들은 감수성인 CNS 균주들(167주)보다 이들 항생물질에 대하여 상당히 높은 내성율을 보였다. 따라서 포도알균에 의한 피부감염의 효과적인 치료를 위해선 mupirocin 내성 균주의 출현을 방지해야 한다.

Keywords

References

  1. Andrews, J.M. 2009. BSAC standardized disc susceptibility testing method (version 8). J. Antimicrob. Chemother. 64, 454-489. https://doi.org/10.1093/jac/dkp244
  2. Antonio, M., McFerran, N., and Pallen, M.J. 2002. Mutations affecting the Rossman fold of isoleucyl-tRNA synthetase are correlated with low-level mupirocin resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 46, 438-442. https://doi.org/10.1128/AAC.46.2.438-442.2002
  3. Bastos, M.C.F., Mondino, P.J.J., Azevedo, M.L.B., Santos, K.R.N., and Giambiagi-deMarval, M. 1999. Molecular characterization and transfer among Staphylococcus strains of a plasmid conferring high-level resistance to mupirocin. Eur. J. Clin. Microbiol. Infect. Dis. 18, 393-398. https://doi.org/10.1007/s100960050306
  4. Caierao, J., Berquo, L., Dias, C., and d'Azevedo, P.A. 2006. Decrease in the incidence of mupirocin resistance among methicillin-resistant Staphylococcus aureus in carriers from an intensive care unit. Am. J. Infect. Control 34, 6-9. https://doi.org/10.1016/j.ajic.2005.08.006
  5. Clinical and Laboratory Standards Institute. 2006. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. M7-A7. CLSI, Wayne, Pa, USA.
  6. Clinical and Laboratory Standards Institute. 2009. Performance standards for antimicrobial susceptibility testing. M100-S19. CLSI. Wayne, Pa, USA.
  7. Creagh, S. and Lucey, B. 2007. Interpretive criteria for mupirocin susceptibility testing of Staphylococcus spp. using CLSI guidelines. Br. J. Biomed. Sci. 64, 1-5. https://doi.org/10.1080/09674845.2007.11732746
  8. Dyke, K.G., Aubert, S., and el Solh, N. 1992. Multiple copies of IS256 in staphylococci. Plasmid 28, 235-246. https://doi.org/10.1016/0147-619X(92)90055-F
  9. Emsley, P. and Cowtan, K. 2004. Coot: model-building tools for molecular graphics. Acta Crystallogr. D. Biol. Crystallogr. 60, 2126-2132. https://doi.org/10.1107/S0907444904019158
  10. Fujimura, S., Tokue, Y., and Watanabe, A. 2003. Isoleucyl-tRNA synthetase mutations in Staphylococcus aureus clinical isolates and in vitro selection of low-level mupirocin-resistant strains. Antimicrob. Agents Chemother. 47, 3373-3374. https://doi.org/10.1128/AAC.47.10.3373-3374.2003
  11. Gilbart, J., Perry, C.R., and Slocombe, B. 1993. High-level mupirocin resistance in Staphylococcus aureus: evidence for two distinct isoleucyl-tRNA synthetases. Antimicrob. Agents Chemother. 37, 32-38. https://doi.org/10.1128/AAC.37.1.32
  12. Hodgson, J.E., Curnock, S.P., Dyke, K.G., Morris, R., Sylvester, D.R., and Gross, M.S. 1994. Molecular characterization of the gene encoding high-level mupirocin resistance in Staphylococcus aureus J2870. Antimicrob. Agents Chemother. 38, 1205-1208. https://doi.org/10.1128/AAC.38.5.1205
  13. Hurdle, J.G., O'Neill, A.J., Mody, L., Chopra, I., and Bradley, S.F. 2005. In vivo transfer of high-level mupirocin resistance from Staphylococcus epidermidis to methicillin-resistant Staphylococcus aureus associated with failure of mupirocin prophylaxis. J. Antimicrob. Chemother. 56, 1166-1168. https://doi.org/10.1093/jac/dki387
  14. Kim, S.M., Lee, D.C., Park, S.D., Kim, B.S., Kim, J.K., Choi, M.R., Park, S.Y., Hwang, S.M., Shin, N.Y., Shim, E.S., and et al. 2009. Genotype, coagulase type and antimicrobial susceptibility of methicillinresistant Staphylococcus aureus isolated from dermatology patients and healthy individuals in Korea. J. Bacteriol. Virol. 39, 307-316. https://doi.org/10.4167/jbv.2009.39.4.307
  15. Kim, S.M., Park, S.Y., and Park, S.D. 2011. Isolation and antimicrobial susceptibility of mupirocin-resistant and methicillin-resistant Staphylococcus aureus from clinical samples. J. Bacteriol. Virol. 41, 279-286. https://doi.org/10.4167/jbv.2011.41.4.279
  16. Kresken, M., Hafner, D., Schmitz, F.J., and Wichelhaus, T.A. 2004. Prevalence of mupirocin resistance in clinical isolates of Staphylococcus aureus and Staphylococcus epidermidis: results of the Antimicrobial Resistance Surveillance Study of the Paul-Ehrlich-Society for Chemotherapy, 2001. Int. J. Antimicrob. Agents 23, 577-581. https://doi.org/10.1016/j.ijantimicag.2003.11.007
  17. Lee, A.S., Macedo-Vinas, M., Francois, P., Renzi, G., Vernaz, N., Schrenzel, J., Pittet, D., and Harbarth, S. 2011a. Trends in mupirocin resistance in meticillin-resistant Staphylococcus aureus and mupirocin consumption at a tertiary care hospital. J. Hosp. Infect. 77, 360-362. https://doi.org/10.1016/j.jhin.2010.11.002
  18. Lee, A.J., Suh, H.S., Jeon, C.H., and Kim, S.G. 2011b. Prevalence and clinical characteristics of mupirocin-resistant Staphylococcus aureus. Korean J. Clin. Microbiol. 14, 18-23. https://doi.org/10.5145/KJCM.2011.14.1.18
  19. Lee, H.J., Suh, J.T., Kim, Y.S., Lenz, W., Bierbaum, G., and Schaal, K.P. 2001. Typing and antimicrobial susceptibilities of methicillin resistant Staphylococcus aureus (MRSA) strains isolated in a hospital in Korea. J. Kor. Med. Sci. 16, 381-385. https://doi.org/10.3346/jkms.2001.16.4.381
  20. Leyden, J.J. 1990. Mupirocin: a new topical antibiotic. J. Am. Acad. Dermatol. 22, 879-883. https://doi.org/10.1016/0190-9622(90)70117-Z
  21. Lim, K.T., Hanifah, Y.A., Yusof, M.Y.M., and Thong, K.L. 2010. Prevalence of mupirocin resistance in methicillin-resistant Staphylococcus aureus strains isolated from a Malaysian hospital. Jpn. J. Infect. Dis. 63, 286-289.
  22. Long, B.H. 2008. Fusidic acid in skin and soft-tissue infections. Acta Derm. Venereol. 88, Supplement 216, 14-20. https://doi.org/10.2340/00015555-0387
  23. Morton, T.M., Johnston, J.L., Patterson, J., and Archer, G.L. 1995. Characterization of a conjugative staphylococcal mupirocin resistance plasmid. Antimicrob. Agents Chemother. 39, 1272-1280. https://doi.org/10.1128/AAC.39.6.1272
  24. Oommen, S.K., Appalaraju, B., and Jinsha, K. 2010. Mupirocin resistance in clinical isolates of staphylococci in a tertiary care centre in south India. Indian. J. Med. Microbiol. 28, 372-375.
  25. O'Shea, S., Cotter, L., Creagh, S., Lydon, S., and Lucey, B. 2009. Mupirocin resistance among staphylococci: trends in the southern region of Ireland. J. Antimicrob. Chemother. 64, 649-669. https://doi.org/10.1093/jac/dkp227
  26. Park, S.Y., Kim, S.M., and Park, S.D. 2012. The prevalence, genotype and antimicrobial susceptibility of high- and low-level mupirocin resistant methicillin-resistant Staphylococcus aureus. Ann. Dermatol. 24, 32-38. https://doi.org/10.5021/ad.2012.24.1.32
  27. Petinaki, E., Spiliopoulou, I., Kontos, F., Maniati, M., Bersos, Z., Stakias, N., Malamou-Lada, H., Koutsia-Carouzou, C., and Maniatis, A.N. 2004. Clonal dissemination of mupirocin-resistant staphylococci in Greek hospitals. J. Antimicrob. Chemother. 53, 105-108.
  28. Schmitz, F.J., Lindenlauf, E., Hofmann, B., Fluit, A.C., Verhoef, J., Heinz, H.P., and Jones, M.E. 1998. The prevalence of low- and high-level mupirocin resistance in staphylococci from 19 European hospitals. J. Antimicrob. Chemother. 42, 489-495. https://doi.org/10.1093/jac/42.4.489
  29. Silvian, L.F., Wang, J., and Steitz, T.A. 1999. Insights into editing from an Ile-tRNA synthetase structure with $tRNA^{ile}$ and mupirocin. Science 285, 1074-1077. https://doi.org/10.1126/science.285.5430.1074
  30. Sutherland, R., Boon, R.J., Griffin, K.E., Masters, P.J., Slocombe, B., and White, A.R. 1985. Antibacterial activity of mupirocin (pseudomonic acid), a new antibiotic for topical use. Antimicrob. Agents Chemother. 27, 495-498. https://doi.org/10.1128/AAC.27.4.495
  31. Thomas, D.G., Wilson, J.M., Day, M.J., and Russell, A.D. 1999. Mupirocin resistance in staphylococci: development and transfer of isoleucyl tRNA synthetase-mediated resistance in vitro. J. Appl. Microbiol. 86, 715-722. https://doi.org/10.1046/j.1365-2672.1999.00718.x
  32. Udo, E.E., Jacob, L.E., and Mathew, B. 2001. Genetic analysis of methicillin-resistant Staphylococcus aureus expressing high- and low-level mupirocin reistance. J. Med. Microbiol. 50, 909-915. https://doi.org/10.1099/0022-1317-50-10-909
  33. Vaara, M. 1992. The outer membrane as the penetration barrier against mupirocin in Gram-negative enteric bacteria. J. Antimicrob. Chemother. 29, 221-222. https://doi.org/10.1093/jac/29.2.221
  34. Vasquez, J.E., Walker, E.S., Franzus, B.W., Overbay, B.K., Reagan, D.R., and Sarubbi, F.A. 2000. The epidemiology of mupirocin resistance among methicillin-resistant Staphylococcus aureus at a Veterans' Affairs hospital. Infect. Control Hosp. Epidemiol. 21, 459-464. https://doi.org/10.1086/501788
  35. Vivoni, A.M., Santos, K.R.N., de-Oliveira, M.P., Giambiagi-deMarval, M., Ferreira, A.L.P., Riley, L.W., and Moreira, B.M. 2005. Mupirocin for controlling methicillin resistant Staphylococcus aureus: lessons from a decade of use at a university hospital. Infect. Control Hosp. Epidemiol. 26, 662-667. https://doi.org/10.1086/502599
  36. Yang, J.A., Park, D.W., Sohn, J.W., Yang, I.S., Kim, K.H., and Kim, M.J. 2006. Molecular analysis of isoleucyl-tRNA synthetase mutations in clinical isolates of methicillin-resistant Staphylococcus aureus with low-level mupirocin resistance. J. Korean Med. Sci. 21, 827-832. https://doi.org/10.3346/jkms.2006.21.5.827
  37. Yanagisawa, T., Lee, J.T., Wu, H.C., and Kawakami, M. 1994. Relationship of protein structure of isoleucyl-tRNA synthetase with pseudomonic acid resistance of Escherichia coli. A proposed mode of action of pseudomonic acid as an inhibitor of isoleucyl-tRNA synthetase. J. Biol. Chem. 269, 24304-24309.
  38. Yoo, J.I., Shin, E.S., Cha, J.O., Lee, J.K., Jung, Y.H., Lee, K.M., Kim, B.S., and Lee, Y.S. 2006. Clonal dissemination and mupA gene polymorphism of mupirocin-resistant Staphylococcus aureus isolates from long-term-care facilities in South Korea. Antimicrob. Agents Chemother. 50, 365-367. https://doi.org/10.1128/AAC.50.1.365-367.2006
  39. Yoo, J.I., Shin, E.S., Chung, G.T., Lee, K.M., Yoo, J.S., and Lee, Y.S. 2010. Restriction fragment length polymorphism (RFLP) patterns and sequence analysis of high-level mupirocin-resistant methicillin-resistant staphylococci. Int. J. Antimicrob. Agents 35, 50-55. https://doi.org/10.1016/j.ijantimicag.2009.08.017
  40. Yun, H.J., Lee, S.W., Yoon, G.M., Kim, S.Y., Choi, S., Lee, Y.S., Choi, E.C., and Kim, S. 2003. Prevalence and mechanisms of low- and high-level mupirocin resistance in staphylococci isolated from a Korean hospital. J. Antimicrob. Chemother. 51, 619-623. https://doi.org/10.1093/jac/dkg140

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