Study of Decreased Susceptibility to Vancomycin in Methicillin-Resistant Staphylococcus aureus Strains isolated from a Romanian Multidisciplinary Emergency Hospital

Open access


The clinical relevance of Staphylococcus aureus strains with heterointermediate susceptibility to vancomycin (hVISA) is still controversial, however they could be responsible for treatment failures in patients treated with vancomycin. The lack of standardization and the complexity of testing methods are the main challenge in indentifying such strains. The aim of our study was to evaluate the frequency of hVISA strains in Targu-Mures Clinical Emergency Hospital. One hundred twenty-two, non-duplicate, methicillin-resistant S. aureus (MRSA) isolates susceptible to vancomycin using standard E-test (MIC≤2 mg/L) were screened for heteroresistance with Glycopeptide Resistance Detection test (E-test GRD). Population analysis profile-area under the curve (PAP/AUC) method was used for confirmation. Twenty-four strains (19.5%) were found positive with the screening method. Two of them (1.63%) were confirmed having hVISA phenotype and no strains with intermediate vancomycin susceptibility (VISA) were detected. In conclusion, the rate of MRSA strains with reduced vancomycin susceptibility was low. However, their monitoring may be useful, taking into consideration the wide usage of glycopeptides in the treatment of serious MRSA infections.

1. 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(1):405-10. DOI: 10.1128/AAC.01133-10

2. Filleron A, Chironb R, Reverdyc ME, Jean-Pierred H, Dumitrescu O, et al. Staphylococcus aureus with decreased susceptibility to glycopeptides in cystic fibrosis patients. Journal of Cystic Fibrosis 2011;10(5):377-82. DOI: 10.1016/j.jcf.2011.05.001

3. Garnier F, Chainier D, Walsh T, Karlsson A, Bolmström A, Grelaud C, et al. A 1 year surveillance study of glycopeptide-intermediate Staphylococcus aureus strains in a French hospital. J Antimicrob Chemother. 2006;57(1):146-9. DOI: 10.1093/jac/dki413

4. Charles PG, Ward PB, Johnson DR, Howden BP, Grayson LM. Clinical features associated with bacteremia due to heterogeneous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis. 2004;38(3):448-51. DOI: 10.1086/381093

5. Rong SL, Leonard SN. Heterogeneous vancomycin resistance in Staphylococcus aureus: a review of epidemiology, diagnosis, and clinical significance. Ann Pharmacother. 2010;44(5):844-50. DOI: 10.1345/ aph.1M526

6. Wang Y, Hu YJ, Ai XM, Xu HT, Sun TY. Prevalence and clinical prognosis of heteroresistant vancomycin- intermediate Staphylococcus aureus in a tertiary care center in China. Chin Med J 2013;126(3):505-9.

7. Tenover FC, Moellering RC Jr. The rationale for revising the Clinical and Laboratory Standards Institute vancomycin minimal inhibitory concentration interpretive criteria for Staphylococcus aureus. Antimicrob Agents Chemoter. 2007;48:4926-8.

8. EUCAST. European Committee on Antimicrobial Susceptibility Testing Breakpoint tables for interpretation of MICs and zone diameters, Version 2.0. http://www. Breakpoint_tables/Breakpoint_table_v_2.0_120221. pdf.

9. EUCAST guidelines for detection of resistance mechanisms and specific resistances of clinical and/or epidemiological importance. December 2012. http://www. Consultation/EUCAST_guidelines_detection_of_resistance_ mechanisms_121222.pdf.

10. Székely E, Man A, Mare A, Vas KE, Molnár Sz, Bilca D, et al. Molecular epidemiology and virulence factors of methicillin-resistant Staphylococcus aureus strains in a Romanian university hospital. Rev Romana Med Lab. 2012;20(4):371-82.

11. Wootton M, Howe RA, Hillman R, Walsh TR, Bennett PM, MacGowan AP. A modified population analysis profile method to detect Staphylococcus aureus with decreased susceptibilities to vancomycin in a UK hospital. J Antimicrob Chemother. 2001;47(4):399-404. DOI: 10.1093/jac/47.4.399

12. Riederer K, Shemes S, Chase P, Musta A, Mar A, Khatib R. Detection of intermediately vancomycin-susceptible and heterogeneous Staphylococcus aureus isolates: comparison of Etest and Agar Screening Methods. J Clin Microbiol. 2011;49(6):2147-50. DOI: 10.1128/ JCM.01435-10

13. 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(1):456-9. DOI: 10.1128/JCM.41.1.456-459.2003

14. Howden BP, Davies JK, Johnson PDR, Stinear TP, Grayson ML. Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate dtrains: resistance mechanisms, laboratory detection, and clinical implications. Clin Microbiol Rev. 2010;23(1):99-139. DOI: 10.1128/CMR.00042-09

15. Kirby A, Graham R, Williams NJ, Wootton M, Broughton CM, Alanazi M, et al. Staphylococcus aureus with reduced glycopeptide susceptibility in Liverpool, UK. J Antimicrob Chemother. 2010(4);65:721-4. DOI: 10.1093/jac/dkq009

16. Campanile F, Borbone S, Perez M, Bongiorno D, Cafiso V, Bertuccio T, et al. Heteroresistance to glycopeptides in Italian meticillin-resistant Staphylococcus aureus (MRSA) isolates. International Journal of Antimicrobial Agents 2010;36(5):415-34. DOI: 10.1016/j. ijantimicag.2010.06.044

17. Reverdy ME, Jarraud S, Bobin-Dubreux S, Burel E, Girado P, Lina G, et al. Incidence of Staphylococcus aureus with reduced susceptibility to glycopeptides in two French hospitals. Clin Microbiol Inf. 2001;7(5):267-72. DOI: 10.1046/j.1198-743x.2001.00256.x

18. Nonhoff C, Denis O, Struelens MJ. Low prevalence of methicillin-resistant Staphylococcus aureus with reduced susceptibility to glycopeptides in Belgian hospitals. Clinical Microbiology and Infection, 2005;11(3):214-20. DOI: 10.1111/j.1469-0691.2004.01060.x

19. Denis O, Nonhoff C, Byl B, Knoop C, Bobin-Dubreux S, Struelens MJ. Emergence of vancomycin-intermediate Staphylococcus aureus in a Belgian hospital: microbiological and clinical features. J Antimicrob Chemother. 2002;50(3):383-91. DOI: 10.1093/jac/dkf142

20. Rybak MJ, Leonard SN, Rossi KL, Cheung CM, Sadar HS, Jones RN. Characterization of vancomycin-heteroresistant Staphylococcus aureus from the metropolitan area of Detroit, Michigan, over a 22-year period (1986 to 2007). J Clin Microbiol. 2008;46(9):2950-4. DOI: 10.1128/JCM.00582-08

21. Horne KC, Howden BP, Grabsch EA, Graham M, Ward PD, Xie S, et al. Prospective comparison of the clinical impact of heterogeneous vancomycin-intermediate methicillin-resistant Staphylococcus aureus (MRSA) and vancomycinsusceptible MRSA. Antimicrob Agents Chemother. 2009;53(8):3447-52. DOI: 10.1128/ AAC.01365-08

22. Tóth A, Kispál G, Ungvári E, Violka M, Szeberin Z, Pászti J. First report of heterogeneously vancomycin-intermediate Staphylococcus aureus (hVISA) causing fatal infection in Hungary. J Chemother. 2008;20(5):655-6. DOI: 10.1179/joc.2008.20.5.655

23. Dorneanu OS, Vremeră T, Năstase EV, Logigan C, Bădescu AC, Miftode EG. Detection of mecA gene in clinical Staphylococcus aureus isolates from Infectious Diseases Hospital, Iasi, Romania. Rev Romana Med Lab. 2011;19(3):259-65.

24. Ionescu R, Mediavilla JR, Chen L, Grigorescu DO, Idomir M, Kreiswirth BN, et al. Molecular characterization and antibiotic susceptibility of Staphylococcus aureus from a multidisciplinary hospital in Romania. Microb Drug Resist. 2010;16(4):263-72. DOI: 10.1089/ mdr.2010.0059

25. Sader HS, Jones RN, Rossi KL, Rybak MJ. Occurrence of vancomycin-tolerant and heterogeneous vancomycin- intermediate strains (hVISA) among Staphylococcus aureus causing bloodstream infections in nine USA hospitals. J Antimicrob Chemother. 2009;64(5):1024-8. DOI: 10.1093/jac/dkp319

26. Yusof A, Engelhardt A, Karlsson A, Bylund L, Vidh P, Mills K, et al. Evaluation of a new Etest vancomycin-teicoplanin strip for detection of glycopeptide-intermediate Staphylococcus aureus (GISA) in particular, heterogeneous GISA. J Clin Microbiol. 2008;46(9):3042-7. DOI: 10.1128/JCM.00265-08

27. Filleron A, Chiron R, Reverdy ME, Jean-Pierre H, Du mitrescu O, Aleyrangues L, et al. Utility of the Etest GRD for detecting Staphylococcus aureus with reduced susceptibility to glycopeptides in cystic fibrosis patients. Eur J Clin Microbiol Infect Dis. 2012;31(4):599-604. DOI: 10.1007/s10096-011-1353-4

28. Leonard SN, Rossi KL, Newton KL, Rybak MJ. Evaluation of the Etest GRD for the detection of Staphylococcus aureus with reduced susceptibility to glycopeptides. J Antimicrob Chemother. 2009;63(3):489-92. DOI: 10.1093/jac/dkn520

29. Walsh TR, Bolmstrom A, Qwarnstrom A, Ho P, Wootton M, Howe RA, et al. Evaluation of current methods for detection of staphylococci with reduced susceptibility to glycopeptides. J Clin Microbiol. 2001;39(7):2439-44. DOI: 10.1128/JCM.39.7.2439-2444.2001

30. Vaudaux P, Huggler E, Bernard L, Ferry T, Renzoni A, Lew DP. Underestimation of Vancomycin and Teicoplanin MICs by Broth Microdilution Leads to Underdetection of Glycopeptide-Intermediate Isolates of Staphylococcus aureus. Antimicrob Agents Chemother. 2010;54(9):3861-70. DOI: 10.1128/AAC.00269-10

31. CDC. Algorithm for testing S. aureus with vancomycin. html. [Online]

32. Wootton M, MacGowan AP, Walsh TR, Howe RA. A multicenter study evaluating the current strategies for isolating Staphylococcus aureus strains with reduced susceptibility to glycopeptides. J. Clin. Microbiol. 2007;45(2):329-32. DOI: 10.1128/JCM.01508-06

33. Voss A, Mouton JW, van Elzakker EP, Hendrix RG, Goessens W, Kluytmans AJ, et al. A multi-center blinded study on the efficiency of phenotypic screening methods to detect glycopeptide intermediately susceptible Staphylococcus aureus (GISA) and heterogeneous GISA (h-GISA). Ann Clin Microbiol Antimicrob. 2007;6:9. DOI: 10.1186/1476-0711-6-9

34. ECDC. EARSS Manual 2005. http://www.ecdc.europa. eu/en/activities/surveillance/ears-net/documents/ ears-net-microbiological-manual.pdf. [Online]

35. Fitzgibbon MM, Rossney AS, O’Connell B. Investigation of reduced susceptibility to glycopeptides among methicillin-resistant Staphylococcus aureus isolates from patients in Ireland and evaluation of agar screening methods for detection of heterogeneously glycopeptide-intermediate S. aureus. J Clin Microbiol. 2007;45(10):3263-9. DOI: 10.1128/JCM.00836-07

36. 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(5):1492-502. DOI: 10.1128/AAC.46.5.1492-1502.2002

37. Sakoulas G, Eliopoulos GM, Moellering RC Jr., Novick RP, Venkataraman L, Wennersten C, et al. Staphylococcus aureus accessory gene regulator (agr) group II: is there a relationship to the development of intermediate- level glycopeptide resistance? J Infect Dis. 2003;187(6):929-38. DOI: 10.1086/368128

38. Tsuji BT, Rybak MJ, Lau KL, Sakoulas G. Evaluation of accessory gene regulator (agr) group and function in the proclivity towards vancomycin intermediate resistance in Staphylococcus aureus. Antimicrob Agents Chemother. 2007;51(3):1089-91. DOI: 10.1128/ AAC.00671-06

39. Casapao AM, Leonard SN, Davis SL, Lodise TP, Patel N, Goff DA, et al. Clinical outcomes in patients with heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) bloodstream infection. Antimicrob Agents Chemother. 2013[Epub ahead of print]. DOI: 10.1128/AAC.00380-13

40. Fong RK, Low J, Koh TH, Kurup A. Clinical features and treatment outcomes of vancomycin-intermediate Staphylococcus aureus (VISA) and heteroresistant vancomycin- intermediate Staphylococcus aureus (hVISA) in a tertiary care institution in Singapore. Eur J Clin Microbiol Infect Dis. 2009;28(8):983-7. DOI: 10.1007/ s10096-009-0741-5

41. Maor Y, Hagin M, Belausov N, Keller N, Ben-David D, Rahav G. Clinical features of heteroresistant vancomycin- intermediate Staphylococcus aureus bacteremia versus those of methicillin-resistant S. aureus bacteremia. J Infect Dis. 2009;199(5):619-24. DOI: 10.1086/596629

42. Park KH, Kim ES, Kim HS, Park SJ, Bang KM, Park HJ, et al. Comparison of the clinical features, bacterial genotypes and outcomes of patients with bacteraemia due to heteroresistant vancomycin-intermediate Staphylococcus aureus and vancomycin-susceptible S. aureus. J Antimicrob Chemother. 2012;67(8):1843-9. DOI: 10.1093/jac/dks131

43. Khatib R, Jose J, Musta A, 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(7):1594-9. DOI: 10.1093/jac/ dkr169

44. Soriano A, Marco F, Martínez JA, Pisos E Almela M, Dimova VP, et al. Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin- resistant Staphylococcus aureus bacteremia. Clin Infect Dis. 2008;46(2):193-200. DOI: 10.1086/524667

45. Sakoulas G, Moellering RC Jr., Eliopoulos GM. Ad aptation of methicillin-resistant Staphylococcus aureus in the face of vancomycin therapy. Clin Infect Dis 2006;42(Suppl 1):40-50. DOI: 10.1086/491713

46. 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(6):1640-4. DOI: 10.1128/JCM.02135-08

Revista Romana de Medicina de Laborator

Romanian Journal of Laboratory Medicine

Journal Information

IMPACT FACTOR 2017: 0.400
5-year IMPACT FACTOR: 0.320

CiteScore 2017: 0.31

SCImago Journal Rank (SJR) 2017: 0.144
Source Normalized Impact per Paper (SNIP) 2017: 0.195


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 137 137 9
PDF Downloads 44 44 8