Methicillin-Resistant Staphylococcus Aureus in Community Settings: Spread of Drug Resistance and Uncontrollable Infections

T. Yamamoto 1 , 2 , T.W. Wan 1 , 3 , O. Khokhlova 1 , 2 , W.C. Hung 4 , Y.T. Lin 5 , O. Peryanova 2  and L.J. Teng 3
  • 1 Department of Epidemiology, Genomics, and Evolution, International Medical Education and Research Center, Niigata, Japan
  • 2 Russia-Japan Center of Microbiology, Metagenomics and Infectious Diseases, Krasnoyarsk
  • 3 Department of Clinical Laboratory Sciences and Medical Biotechnology, Taipei
  • 4 Department of Microbiology and Immunology, Kaohsiung
  • 5 Department of Medical Laboratory Science and Biotechnology, Taichung


Methicillin-resistant Staphylococcus aureus (MRSA) is a major multidrug-resistant bacterial pathogen. The evolution of MRSA is dynamic posing an ongoing threat to humans. The evolution of MRSA includes horizontal gene transfer, which is mediated by mobile genetic elements, plasmids, and bacteriophages, and also mutations. In this review, we clarify the recent trends in MRSA from the perspectives of drug-resistance transfer and uncontrollable infections, particularly those occurring in community settings. We first address the role of MRSA as a disseminator of multidrug resistance. We have studied the cell-to-cell transfer of drug resistance, in which transfer frequencies range from 10-3 to 10-8. The mechanisms of drug-resistance transfers include the self-transmission of large plasmids, the mobilization of small nonconjugative plasmids, the generalized transduction of phages, and the transfer of transposons with circular intermediates. We then discuss uncontrollable infections. Although several anti-MRSA agents have been developed, uncontrollable cases of MRSA infections are still reported. Examples include a case of uncontrollable sepsis arising from a community-associated MRSA (CA-MRSA) with the ST8/SCCmecIVl genotype, and a relapsing severe invasive infection of ST30/SCCmecIVc CA-MRSA in a student athlete. Some of these cases may be attributable to unique adhesins, superantigens, or cytolytic activities. The delayed diagnosis of highly adhesive and toxic infections in community settings may result in CA-MRSA diseases that are difficult to treat. Repeated relapse, persistent bacteremia, and infections of small-colony variants may occur. To treat MRSA infections in community settings, these unique features of MRSA must be considered to ensure that diagnostic delay is avoided.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. World Health Organization [site]. Antimicrobial resistance: global report on surveillance. Geneva: World Health Organization; 2014 [cited 2019 Oct 12]. 257 p. Available from:

  • 2. International Working Group on the Classification of Staphylococcal Cassette Chromosome Elements (IWG-SCC). Classification of staphylococcal cassette chromosome mec (SCCmec): guidelines for reporting novel SCCmec elements. Antimicrob Agents Che-mother. 2009;53:4961–7.

  • 3. David MZ, Daum RS. Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev. 2010;23:616–87.

  • 4. Otto M. Community-associated MRSA: what makes them special? Int J Med Microbiol. 2013;303:324–30.

  • 5. Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA. 2007;298:1763–71.

  • 6. Naimi TS, LeDell KH, Como-Sabetti K, Borchardt SM, Boxrud DJ Etienne J, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA. 2003;290:2976–84.

  • 7. Harinstein L, Schafer J, D’Amico F. Risk factors associated with the conversion of meticillin-resistant Staphylococcus aureus colonisation to healthcare-associated infection. J Hosp Infect. 2011;79:194–7.

  • 8. Lyon BR, Skurray R. Antimicrobial resistance of Staphylococcus aureus: Genetic basis. Microbiol Rev. 1987;51:88–134.

  • 9. Oliveira DC, Tomasz A, de Lencastre H. The evolution of pandemic clones of methicillin-resistant Staphylococcus aureus: identification of two ancestral genetic backgrounds and the associated mec elements. Microb Drug Resist. 2001;7:349–61.

  • 10. Enright MC, Robinson DA, Randle G, Feil EJ, Grundmann H, Spratt BG. The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA). Proc Natl Acad Sci U S A. 2002; 99:7687–92.

  • 11. Aires de Sousa M, Conceição T, Simas C, de Lencastre H. Comparison of genetic backgrounds of methicillin-resistant and -susceptible Staphylococcus aureus isolates from Portuguese hospitals and the community. J Clin Microbiol. 2005;43:5150–7.

  • 12. Centers for Disease Control and Prevention (CDC). Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus - Minnesota and North Dakota, 1997-1999. MMWR Morb Mortal Wkly Rep. 1999;48:707–10.

  • 13. Diep BA, Gill SR, Chang RF, Phan TH, Chen JH, Davidson MG, et al. Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus. Lancet. 2006;367:731–9.

  • 14. Diep BA, Otto M. The role of virulence determinants in community-associated MRSA pathogenesis. Trends Microbiol. 2008; 16:361–9.

  • 15. Tenover FC, Goering RV. Methicillin-resistant Staphylococcus aureus strain USA300: origin and epidemiology. J Antimicrob Chemother. 2009;64:441–6.

  • 16. Shallcross LJ, Fragaszy E, Johnson AM, Hayward AC. The role of the Panton-Valentine leucocidin toxin in staphylococcal disease: A systematic review and meta-analysis. Lancet Infect Dis. Lancet Infect Dis. 2013;13:43–54.

  • 17. Isobe H, Takano T, Nishiyama A, Hung WC, Kuniyuki S, Shibuya Y, et al. Evolution and virulence of Panton-Valentine leukocidin-positive ST30 methicillin-resistant Staphylococcus aureus in the past 30 years in Japan. Biomed Res. 2012;33:97–109.

  • 18. Hung WC, Takano T, Higuchi W, Iwao Y, Khokhlova O, Teng LJ, et al. Comparative genomics of community-acquired ST59 methicillin-resistant Staphylococcus aureus in Taiwan: novel mobile resistance structures with IS1216V. PLoS One. 2012;7:e46987.

  • 19. Fluit AC, Carpaij N, Majoor EA, Weinstein RA, Aroutcheva A, Rice TW, et al. Comparison of an ST80 MRSA strain from the USA with European ST80 strains. J Antimicrob Chemother. 2015;70:664–9.

  • 20. Wang R, Braughton KR, Kretschmer D, Bach TH, Queck SY, Li M, et al. Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA. Nat Med. 2007;13:1510–4.

  • 21. Uhlemann AC, Otto M, Lowy FD, DeLeo FR. Evolution of community- and healthcare-associated methicillin-resistant Staphylococcus aureus. Infect Genet Evol. 2014;21:563–74.

  • 22. Thurlow LR, Joshi GS, Richardson AR. Virulence strategies of the dominant USA300 lineage of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). FEMS Immunol Med Microbiol. 2012;65:5–22.

  • 23. Yamamoto T, Takano T, Higuchi W, Iwao Y, Singur O, Reva I, et al. Comparative genomics and drug resistance of a geographic variant of ST239 methicillin-resistant Staphylococcus aureus emerged in Russia. PLoS One. 2012;7:e29187.

  • 24. Khokhlova OE, Hung WC, Wan TW, Iwao Y, Takano T, Higuchi W, et al. Healthcare- and community-associated methicillin-resistant Staphylococcus aureus (MRSA) and fatal pneumonia with pediatric deaths in Krasnoyarsk, Siberian Russia: unique MRSA’s multiple virulence factors, genome, and stepwise evolution. PLoS One. 2015;10:e0128017.

  • 25. Wan TW, Khokhlova OE, Iwao Y, Higuchi W, Hung WC, Reva IV, et al. Complete circular genome sequence of successful ST8/SCCmecIV community-associated methicillin-resistant Staphylococcus aureus (OC8) in Russia: one-megabase genomic inversion, IS256’s spread, and evolution of Russia ST8-IV. PLoS One. 2016;11(10):e0164168.

  • 26. Firth N, Jensen SO, Kwong SM, Skurray RA, Ramsay JP. Staphylococcal plasmids, transposable and integrative elements. Micro-biol Spectr. 2018;6:GPP3-0030-2018.

  • 27. Takizawa Y, Taneike I, Nakagawa S, Oishi T, Nitahara Y, Iwakura N, et al. A Panton-Valentine leucocidin (PVL)-positive community-acquired methicillin-resistant Staphylococcus aureus (MRSA) strain, another such strain carrying a multiple-drug resistance plasmid, and other more-typical PVL-negative MRSA strains found in Japan. J Clin Microbiol. 2005;43:3356–63.

  • 28. Iwao Y, Ishii R, Tomita Y, Shibuya Y, Takano T, Hung WC, et al. The emerging ST8 methicillin-resistant Staphylococcus aureus clone in the community in Japan: associated infections, genetic diversity, and comparative genomics. J Infect Chemother. 2012;18:228–40.

  • 29. Ishitobi N, Wan TW, Khokhlova OE, Teng LJ, Yamamori Y, Yamamoto T. Fatal case of ST8/SCCmecIVl community-associated methicillin-resistant Staphylococcus aureus infection in Japan. New Microbes New Infect. 2018;26:30–6.

  • 30. Wan TW, Teng LJ, Yamamoto T. Structures of a highly variable cell-wall anchored protein-encoding the spj gene from ST8/SCCmecIVl community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA/J) isolated from 2003 onwards: An indicator of a strongly invasive pathotype. Microbiol Immunol. 2019;63:186–93.

  • 31. Haroche J, Allignet J, El Solh N. Tn5406, a new staphylococcal transposon conferring resistance to streptogramin a and related compounds including dalfopristin. Antimicrob Agents Chemother. 2002;46:2337

  • 32. Kadlec K, Schwarz S. Identification of the novel dfrK-carrying transposon Tn559 in a porcine methicillin-susceptible Staphylococcus aureus ST398 strain. Antimicrob Agents Chemother. 2010;54:3475–7.

  • 33. Archer GL, Johnston JL. Self-transmissible plasmids in staphylococci that encode resistance to aminoglycosides. Antimicrob Agents Chemother. 1983;24:70–7.

  • 34. Forbes BA, Schaberg DR. Transfer of resistance plasmids from Staphylococcus epidermidis to Staphylococcus aureus: Evidence for conjugative exchange of resistance. J Bacteriol. 1983;153:627–34.

  • 35. Morton TM1, Eaton DM, Johnston JL, Archer GL. DNA sequence and units of transcription of the conjugative transfer gene complex (trs) of Staphylococcus aureus plasmid pGO1. J Bacteriol. 1993;175:4436–47.

  • 36. Ramsay JP, Kwong SM, Murphy RJ, Yui Eto K, Price KJ, Nguyen QT, et al. An updated view of plasmid conjugation and mobilization in Staphylococcus. Mob Genet Elements. 2016;6:e1208317.

  • 37. Haaber J, Penadés JR, Ingmer H. Transfer of antibiotic resistance in Staphylococcus aureus. Trends Microbiol. 2017;25:893–905.

  • 38. Khan SA. Rolling-circle replication of bacterial plasmids. Microbiol Mol Biol Rev. 1997;61:442–55.

  • 39. Feßler A, Kadlec K, Wang Y, Zhang WJ, Wu C, Shen J, et al. Small antimicrobial resistance plasmids in livestock-associated methicillin-resistant Staphylococcus aureus CC398. Front Micro-biol. 2018;9:2063.

  • 40. Leroy S, Christieans S, Talon R. Tetracycline gene transfer in Staphylococcus xylosus in situ during sausage fermentation. Front Microbiol. 2019;10:392.

  • 41. McCarthy AJ, Lindsay JA. The distribution of plasmids that carry virulence and resistance genes in Staphylococcus aureus is lineage associated. BMC Microbiol. 2012;12:104.

  • 42. Waldron DE, Lindsay JA. Sau1: A novel lineage-specific type I restriction-modification system that blocks horizontal gene transfer into Staphylococcus aureus and between S. aureus isolates of different lineages. J Bacteriol. 2006;188:5578–85.

  • 43. Corvaglia AR, François P, Hernandez D, Perron K, Linder P, Schrenzel J. A type III-like restriction endonuclease functions as a major barrier to horizontal gene transfer in clinical Staphylococcus aureus strains. Proc Natl Acad Sci U S A. 2010;107:11954–8.

  • 44. McGuinness WA, Malachowa N, DeLeo FR. Vancomycin resistance in Staphylococcus aureus. Yale J Biol Med. 2017;90:269–81.

  • 45. Okubo T, Yabe S, Otsuka T, Takizawa Y, Takano T, Dohmae S, et al. Multifocal pelvic abscesses and osteomyelitis from community-acquired methicillin-resistant Staphylococcus aureus in a 17-year-old basketball player. Diagn Microbiol Infect Dis. 2008;60:313–8.

  • 46. Isobe H, Miyasaka D, Ito T, Takano T, Nishiyama A, Iwao Y, et al. Recurrence of pelvic abscess from Panton-Valentine leukocidin-positive community-acquired ST30 methicillin-resistant Staphylococcus aureus. Pediatr Int. 2013;55:120–3.

  • 47. Spaulding AR, Salgado-Pabón W, Kohler PL, Horswill AR, Leung DY, Schlievert PM. Staphylococcal and streptococcal superantigen exotoxins. Clin Microbiol Rev. 2013;26:422

  • 48. Kuroda M, Ohta T, Uchiyama I, Baba T, Yuzawa H, Kobayashi I, et al. Whole genome sequencing of meticillin-resistant Staphylococcus aureus. Lancet. 2001;357:1225–40.

  • 49. Krakauer T. Staphylococcal superantigens: Pyrogenic toxins induce toxic shock. Toxins (Basel). 2019;11:E178.

  • 50. Vojtov N, Ross HF, Novick RP. Global repression of exotoxin synthesis by staphylococcal superantigens. Proc Natl Acad Sci U S A. 2002;99:10102–7.

  • 51. Takano T, Hung WC, Shibuya M, Higuchi W, Iwao Y, Nishiyama A, et al. A new local variant (ST764) of the globally disseminated ST5 lineage of hospital-associated methicillin-resistant Staphylococcus aureus (MRSA) carrying the virulence determinants of community-associated MRSA. Antimicrob Agents Chemother. 2013;57:1589–95.

  • 52. Dominguez TJ. It’s not a spider bite, it’s community-acquired methicillin-resistant Staphylococcus aureus. J Am Board Fam Pract. 2004;17:220–6.

  • 53. Mine Y, Higuchi W, Taira K, Nakasone I, Tateyama M, Yamamoto T, et al. Nosocomial outbreak of multidrug-resistant USA300 methicillin-resistant Staphylococcus aureus causing severe furuncles and carbuncles in Japan. J Dermatol. 2011;38:1167.

  • 54. Ito T, Iijima M, Fukushima T, Nonoyama M, Ishii M, Baranovich T, et al. Pediatric pneumonia death caused by community-acquired methicillin-resistant Staphylococcus aureus, Japan. Emerg Infect Dis. 2008;14:1312–4.

  • 55. Robinson DA, Kearns AM, Holmes A, Morrison D, Grundmann H, Edwards G, et al. Re-emergence of early pandemic Staphylococcus aureus as a community-acquired meticillin-resistant clone. Lancet. 2005;365:1256–8.

  • 56. Otsuka T, Saito K, Dohmae S, Takano T, Higuchi W, Takizawa Y, et al. Key adhesin gene in community-acquired methicillin-resistant Staphylococcus aureus. Biochem Biophys Res Commun. 2006;346:1234–44.

  • 57. Wan TW, Tomita Y, Saita N, Konno K, Iwao Y, Hung WC, et al. Emerging ST121/agr4 community-associated methicillin-resistant Staphylococcus aureus (MRSA) with strong adhesin and cytolytic activities: trigger for MRSA pneumonia and fatal aspiration pneumonia in an influenza-infected elderly. New Microbes New Infect. 2016;13:17–21.

  • 58. Cheung GY, Kretschmer D, Duong AC, Yeh AJ, Ho TV, Chen Y, et al. Production of an attenuated phenol-soluble modulin variant unique to the MRSA clonal complex 30 increases severity of bloodstream infection. PLoS Pathog. 2014;10:e1004298.

  • 59. Kahl BC, Becker K, Löffler B. Clinical significance and pathogenesis of staphylococcal small colony variants in persistent infections. Clin Microbiol Rev. 2016;29:401–27.

  • 60. Kahl BC, Belling G, Reichelt R, Herrmann M, Proctor RA, Peters G. Thymidine-dependent small-colony variants of Staphylococcus aureus exhibit gross morphological and ultrastructural changes consistent with impaired cell separation. J Clin Microbiol. 2003;41:410–3.

  • 61. Lin YT, Tsai JC, Yamamoto T, Chen HJ, Hung WC, Hsueh PR, et al. Emergence of a small colony variant of vancomycin-intermediate Staphylococcus aureus in a patient with septic arthritis during long-term treatment with daptomycin. J Antimicrob Chemother. 2016;71:1807–14.

  • 62. Precit MR, Wolter DJ, Griffith A, Emerson J, Burns JL, Hoffman LR. Optimized in vitro antibiotic susceptibility testing method for small-colony variant Staphylococcus aureus. Antimicrob Agents Chemother. 2016;60:1725–35.

  • 63. Mikkaichi T, Yeaman MR, Hoffmann A, MRSA Systems Immunobiology Group. Identifying determinants of persistent MRSA bacteremia using mathematical modeling. PLoS Comput Biol. 2019;15:e1007087.


Journal + Issues