Ann Lab Med.  2015 Jul;35(4):399-403. 10.3343/alm.2015.35.4.399.

Accessory Gene Regulator Polymorphism and Vancomycin Minimum Inhibitory Concentration in Methicillin-Resistant Staphylococcus aureus

• Park MJ
• Kim HS
• Kim HS
• Kim JS
• Song W
• Kim MY
• Lee YK
• Kang HJ

• KMID: 2045861
• DOI: http://doi.org/10.3343/alm.2015.35.4.399

Abstract

BACKGROUND
Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia with a vancomycin minimum inhibitory concentration (MIC) of 2 microg/mL presents a high rate of therapeutic failure in response to vancomycin. In addition, polymorphism in accessory gene regulator (agr) is associated with vancomycin therapeutic effects. The association between agr polymorphism and vancomycin MICs was investigated in MRSA isolates.
METHODS
Agr group-specific PCR was conducted on 118 MRSA bloodstream isolates. Vancomycin susceptibility tests were conducted, while E-test GRD (bioMerieux SA, France) was used to detect heterogeneous vancomycin-intermediate S. aureus (hVISA).
RESULTS
Of the 118 MRSA isolates, 59 (50.0%), 43 (36.4%), and 10 (8.5%) isolates belonged to agr group I, II, and III, respectively. Six isolates could not be classified. Twenty-six, 73, and 19 isolates presented a vancomycin MIC of 2, 1, and 0.5 microg/mL, respectively. Nine (34.6%), 14 (53.8%), and 2 (7.7%) isolates with MICs of 2 microg/mL belonged to agr group I, II, and III, respectively. Thirty-seven (50.6%), 26 (35.6%), and 6 (8.2%) isolates with MICs of 1 microg/mL belonged to agr group I, II, and III, respectively. Thirteen (68.4%), 3 (15.8%), and 2 (10.5%) isolates with MICs of 0.5 microg/mL belonged to agr group I, II, and III, respectively. The agr group II presented more isolates with MIC of 2 microg/mL (32.6%) than the agr non-group II (16%). Four isolates tested positive for hVISA. Three of them belonged to agr group II.
CONCLUSIONS
MRSA isolates with vancomycin MIC of 2 microg/mL were more common in agr group II than in agr non-group II.

Keyword

Agr polymorphism; Staphylococcus aureus; Vancomycin

MeSH Terms

Bacteremia
Methicillin-Resistant Staphylococcus aureus*
Microbial Sensitivity Tests*
Polymerase Chain Reaction
Staphylococcus aureus
Vancomycin*
Vancomycin

Figure

• 

  Fig. 1 Distribution of vancomycin MICs by methods.Abbreviations: MIC, minimum inhibitory concentration; BMD, broth microdilution.

Reference

1. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. Twenty third Informational supplement, M100-S23. Wayne, PA: Clinical and Laboratory Standards Institute;2013.

2. Appelbaum PC. Reduced glycopeptide susceptibility in methicillin-resistant Staphylococcus aureus (MRSA). Int J Antimicrob Agents. 2007; 30:398–408. PMID: 17888634.

3. Zhuo C, Xu YC, Xiao SN, Zhang GY, Zhong NS. Glycopeptide minimum inhibitory concentration creep among meticillin-resistant Staphylococcus aureus from 2006-2011 in China. Int J Antimicrob Agents. 2013; 41:578–581. PMID: 23562222.

4. Moise PA, Sakoulas G, Forrest A, Schentag JJ. Vancomycin in vitro bactericidal activity and its relationship to efficacy in clearance ofmethicillin-resistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2007; 51:2582–2586. PMID: 17452488.

5. Lodise TP, Graves J, Evans A, Graffunder E, Helmecke M, Lomaestro BM, et al. Relationship between vancomycin MIC and failure among patientswith methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin. Antimicrob Agents Chemother. 2008; 52:3315–3320. PMID: 18591266.

6. Swenson JM, Anderson KF, Lonsway DR, Thompson A, McAllister SK, Limbago BM, et al. Accuracy of commercial and reference susceptibility testing methods for detecting vancomycin-intermediate Staphylococcus aureus. J Clin Microbiol. 2009; 47:2013–2017. PMID: 19420170.

7. Shopsin B, Mathema B, Alcabes P, Said-Salim B, Lina G, Matsuka A, et al. Prevalence of agr specificity groups among Staphylococcus aureus strains colonizing children and their guardians. J Clin Microbiol. 2003; 41:456–459. PMID: 12517893.

8. Moise-Broder PA, Sakoulas G, Eliopoulos GM, Schentag JJ, Forrest A, Moellering RC Jr. Accessory gene regulator group II polymorphism in methicillin-resistant Staphylococcus aureus is predictive of failure of vancomycin therapy. Clin Infect Dis. 2004; 38:1700–1705. PMID: 15227615.

9. Sakoulas G, Eliopoulos GM, Moellering RC Jr, Wennersten C, Venkataraman L, Novick RP, et al. Accessory gene regulator (agr) locus in geographically diverse Staphylococcus aureus isolates with reduced susceptibility to vancomycin. Antimicrob Agents Chemother. 2002; 46:1492–1502. PMID: 11959587.

10. Schweizer ML, Furuno JP, Sakoulas G, Johnson JK, Harris AD, Shardell MD, et al. Increased mortality with accessory gene regulator (agr) dysfunction in Staphylococcus aureus among bacteremic patients. Antimicrob Agents Chemother. 2011; 55:1082–1087. PMID: 21173172.

11. Falagas ME, Makris GC, Dimopoulos G, Matthaiou DK. Heteroresistance: a concern of increasing clinical significance? Clin Microbiol Infect. 2008; 14:101–104. PMID: 18093235.

12. Khatib R, Jose J, MustaA , Sharma M, Fakih MG, Johnson LB, et al. Relevance of vancomycin-intermediate susceptibility and heteroresistance in methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother. 2011; 66:1594–1599. PMID: 21525024.

13. Wootton M, Walsh TR, MacGowan AP. Evidence for reduction in breakpoints used to determine vancomycin susceptibility in Staphylococcus aureus. Antimicrob Agents Chemother. 2005; 49:3982–3983. PMID: 16127089.

14. Murakami K, Minamide W, Wada K, Nakamura E, Teraoka H, Watanabe S. Identification of methicillin-resistant strains of staphylococci by polymerase chain reaction. J Clin Microbiol. 1991; 29:2240–2244. PMID: 1939577.

15. Verdier I, Reverdy ME, Etienne J, Lina G, Bes M, Vandenesch F. Staphylococcus aureus isolates with reduced susceptibility to glycopeptides belong to accessory gene regulator group I or II. Antimicrob Agents Chemother. 2004; 48:1024–1027. PMID: 14982800.

16. Yusof A, Engelhardt A, Karlsson A, Bylund L, Vidh P, Mills K, et al. Evaluation of a new Etestvancomycin-teicoplanin strip for detection of glycopeptide-intermediate Staphylococcus aureus (GISA), in particular, heterogeneous GISA. J Clin Microbiol. 2008; 46:3042–3047. PMID: 18596146.

17. van Hal SJ, Barbagiannakos T, Jones M, Wehrhahn MC, Mercer J, Chen D, et al. Methicillin-resistant Staphylococcus aureus vancomycin susceptibility testing: methodology correlations, temporal trends and clonal patterns. J Antimicrob Chemother. 2011; 66:2284–2287. PMID: 21750101.

18. van Leeuwen W, van Nieuwenhuizen W, Gijzen C, Verbrugh H, van Belkum A. Population studies of methicillin-resistant and -sensitive Staphylococcus aureus strains reveal a lack of variability in the agr D gene, encoding a staphylococcal autoinducer peptide. J Bacteriol. 2000; 182:5721–5729. PMID: 11004170.

19. Strommenger B, Cuny C, Werner G, Witte W. Obvious lack of association between dynamics of epidemic methicillin-resistant Staphylococcus aureus in central Europe and agr specificity groups. Eur J Clin Microbiol Infect Dis. 2004; 23:15–19. PMID: 14652782.

20. Goerke C, Kümmel M, Dietz K, Wolz C. Evaluation of intraspecies interference due to agr polymorphism in Staphylococcus aureus during infection and colonization. J Infect Dis. 2003; 188:250–256. PMID: 12854080.

21. Yoon HJ, Choi JY, Lee K, Yong D, Kim JM, Song YG. Accessory gene regulator group polymorphisms in methicillin-resistant Staphylococcus aureus: an association with clinical significance. Yonsei Med J. 2007; 48:176–183. PMID: 17461514.

22. Maor Y, Lago L, Zlotkin A, Nitzan Y, Belausov N, Ben-David D, et al. Molecular features of heterogeneous vancomycin-intermediate Staphylococcus aureus strains isolated from bacteremic patients. BMC Microbiol. 2009; 9:189. PMID: 19732456.

23. Fowler VGJr, Sakoulas G, McIntyre LM, Meka VG, Arbeit RD, Cabell CH, et al. Persistent bacteremia due to methicillin-resistant Staphylococcus aureus infection is associated with agr dysfunction and low-level in vitro resistance to thrombin-induced platelet microbicidal protein. J Infect Dis. 2004; 190:1140–1149. PMID: 15319865.

24. Charles PG, Ward PB, Johnson PD, Howden BP, Grayson ML. Clinical features associated with bacteremia due to heterogeneous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis. 2004; 38:448–451. PMID: 14727222.

25. van Hal SJ, Paterson DL. Systematic review and meta-analysis of the significance of heterogeneous vancomycin-intermediate Staphylococcus aureus isolates. Antimicrob Agents Chemother. 2011; 55:405–410. PMID: 21078939.

26. Musta AC, Riederer K, Shemes S, Chase P, Jose J, Johnson LB, et al. Vancomycin MIC plus heteroresistance and outcome of methicillin-resistant Staphylococcus aureus bacteremia: trends over 11 years. J Clin Microbiol. 2009; 47:1640–1644. PMID: 19369444.