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					                                            BEYOND MRSA: THE GROWING MENANCE OF H-VISA AND VISA

                                                                       Deepti Bulchandani, MD, Jagdish Nachnani, MD, Curtis Fitzsimmons, MD, Paul Jost, MD, Joseph Brewer,
                                                                                                                      MD

                       Introduction                                                                                                                                                                                Treatment Options
                                                                                                                     Discussion                                                   The detection of h-VISA and VISA infections should lead to
•   Vancomycin resistance in Staphylococcus aureus has emerged                  The National Committee for Clinical Laboratory Standards (also called Clinical and               discontinuation of the glycopeptide therapy and consideration of
    as an important clinical problem                                            Laboratory Standard Institute )has break points for susceptibility of Staphylococcus aureus       alternate regimens. Antibiotic options for hVISA( 1)
•   Heterogeneous resistance to vancomycin of Staphylococcus                    to vancomycin as follows :                                                                                 Agent               Usual Dosage(                                      Comments
    aureus (hVISA) is thought to be a precursor of patients with                - Susceptible-MIC less than or equal to 2mcg/ml                                                                                   Adults)
    VISA (vancomycin intermediate staphylococcus aureus) which                  - Intermediate - MIC of 4mcg/ml                                                                  Rifampicin plus            600 mg daily (PO)               Always use in combination to prevent
    is not responsive to glycopeptide therapy . (1)                             - Resistant - MIC of 8 mcg/ml or greater                                                         Fusidic acid               500 mg tid (PO)                 development of resistance.
                                                                        •        The first documented case of infection with VISA was reported from Japan with the MIC                                                                      Useful for long term oral therapy
•   VISA and hVISA is being reported more frequently from                       of that isolate being 8ug/ml.
    countries across the globe and this been linked with the failure                                                                                                             Linezolid                  600 mg bid ( PO or              Good oral bioavailability is a major
                                                                        •       Later in around the year 2000, a new strain of Staph aureus called the h-VISA was defined                                   IV)                             advantage.
    of glycopeptide antimicrobial therapy . (1-3)                               as the precursor of VISA and Vancomycin resistant Staph aureus . These are strains of S.                                                                    Hematological abnormalities and
•   We present the case of a person with MRSA diskitis with                     aureus containing subpopulations of vancomycin-intermediate daughter cells; the MICs for                                                                    neuropathies ( optic or peripheral)
    suspected hVISA infection and who was treated successfully                  the parent strains of these daughter cells fall within the susceptible range of 1 to 4 µg/ml .   Quinopristin-              7.5 mg/kg bid-tid               Phlebitis is common, arthralgias(9%) and
    with surgery and Daptomycin.                                        •       By population analysis ,subpopulations of h-VISA can be detected as these represent only         dalfopristin                                               myalgias(6%) are common
                                                                                1in 100,000 daughter cells . However population analysis profiling is very difficult to do                                                                  Dose reduction in patients with liver
   We also review the literature associated with hVISA and VISA                                                                                                                                                                            dysfunction
    and about the importance of recognizing these infections and                and is not available in commercial labs currently.
                                                                                                                                                                                 Daptomycin                 6 mg/kg daily ( IV              Myopathy and increased creatine kinase
    the treatment options for the same .                                •       Methods used to detect h-VISA : Routine susceptibility will not detect this resistance .                                    only)                           are major side effects
    Case Presentation and Methodology                                   •       CDC criterion: Innoculum of 106 CFU/ml on BHI containing 4 mcg/ml Vancomycin.                                                                  Conclusion   Dose reduction in renal impairment
                                                                                            TABLE 1. Prevalence of hVISA in 5 epidemiologic studies                                    •        hVISA and VISA may represent the beginning of the
                                                                                                                                                                                                era of vancomycin resistance in staphylococcal
   50 year old African American patient was admitted in March                    STUDY                                         MRSA strains
    2005 with a foot infection and MRSA was isolated from the                                                                                                                                   species. Identifying isolates with subpopulations
    wound. The strain showed susceptibility to Vancomycin .He was                                         Number of isolates               Number of hVISA         % hVISA                      demonstrating heterogeneous resistance to
    treated with 6 weeks of IV Vancomycin and the foot healed up            1) Bierbaum et al.                 367                                2                  0.54                       vancomycin is difficult.
    well.                                                                   (8)
                                                                                                                                                                                       •        The emergence of hVISA and VISA present a real and
   He was readmitted with back pain in July 2005 and was                   2) Hiramatsu et                         1,149                           35               3.05
                                                                            al.(2)                                                                                                              present danger. They highlight the importance of
    diagnosed with MRSA diskitis after a disc biopsy was obtained.
                                                                            3) Song et al (6)                       1,357                            58              4.30
                                                                                                                                                                                                antibiotic resistance and about the reducing options in
   Patient had MRSA bacteremia and the strain was sensitive to                                                                                                                                 treatment of these “super bugs” .They reemphasize the
    Vancomycin with a MIC of 2 .                                            4) Kim et al. ( 7)                      3,371                            59              1.75
                                                                                                                                                                                                importance of the prudent use of antibiotics.
   Patient was treated with Vancomycin for 3 months and his blood          Total                                   6,244                           154              2.46
    cultures cleared.                                                                                                                                                                  •        It is important for clinicians and laboratories to be
                                                                                 Foot infection          MRSA diskitis          MRSA diskitis              MRSA abscess                         aware of this growing threat and clinical problem so
   Patient was readmitted in November 2005 with severe back pain
                                                                                 MRSA MIC 2              MIC 2                  MIC 2                      MIC 2                 1)             that early treatment options caused by vancomycin-intermediate Staphylococcus
                                                                                                                                                                                           Howden BP. Recognition and management of infections can be considered and
    .This time also patient had MRSA diskitis and the patient was                                                                                                                                                           References
                                                                                                                                                                                           aureus (VISA) and heterogeneous VISA (hVISA). Intern Med J. 2005 Dec;35 Suppl 2:S136-40.
    given around 2 months of vancomycin.                                                                                                                                         2)             instituted.
                                                                                                                                                                                           Hiramatsu K, Hanaki H, Ino T, Yabuta K, Oguri T, Tenover FC. Methicillin-resistant Staphylococcus aureus
                                                                                                                                                                                           clinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother. 1997 Jul;40(1):135-6.
   During the admission in February 2006, the patient’s disc                                                                                                                    3)        Tenover FC, Biddle JW, Lancaster MV. Increasing resistance to vancomycin and other glycopeptides in
                                                                                                                                                                                           Staphylococcus aureus. Emerg Infect Dis. 2001 Mar-Apr;7(2):327-32.
    cultures grew out MRSA with sensitivity to Vancomycin with a                                                                                                                 4)        http://www.nccls.org.
                                                                                       March 2005                 July 2005    November 2005              February 2006          5)        Charles PG, Ward PB, Johnson PD et al Clinical features associated with bacteremia due to heterogeneous
    MIC of 2.                                                                                                                                                                              vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis. 2004 Feb 1;38(3):448-51.
   The patient did not improve with Vancomycin and was                                                                                                                          6)        Song et al Emergence in Asian Countries of Staphylococcus aureus with Reduced Susceptibility to
                                                                                                                                                                                           Vancomycin Antimicrobial Agents and Chemotherapy, December 2004, p. 4926-4928, Vol. 48, No. 12
    suspected to have hVISA. The patient had to undergo surgical                        IV                   IV   Vancomycin      IV   Vancomycin           IV                   7)        Kim, M.-N., C. H. Pai, J. H. Woo, J. S. Ryu, and K. Hiramatsu. 2000. Vancomycin-intermediate
                                                                                                                                                                                           Staphylococcus aureus in Korea. J. Clin. Microbiol. 38:3879-3881.
    debridement. Patient was also started on Daptomycin. The                            Vancomycin                                                          Daptomycin           8)        Bierbaum, G., K. Fuchs, W. Lenz, C. Szekat, and H. G. Sahl. 1999. Presence of Staphylococcus aureus with
    patient rapidly improved and his blood cultures cleared in one                                                                                                                         reduced susceptibility to vancomycin in Germany. Eur. J. Clin. Microbiol. Infect. Dis. 18:691-696
                                                                                                                                                                                 9)        Ward PB, Johnson PD, Grabsch EA, Mayall BC, Grayson ML. Treatment failure due to methicillin-resistant
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                                                                             Hetero resistant VISA produces greater quantities of penicillin binding proteins 2 and 2’ and of             5;175(9):480-3.
   The patient has been seen in follow up recently and is doing                                                                                                                 10)       Howden BP, Ward PB, Charles PG, Korman TM, Fuller A, du Cros P, et al Treatment outcomes for serious
                                                                            cell – wall precursors presumably trapping vancomycin extracellularly .(10)                                    infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin
    very well, with minimal pain and free of infection at 6 month
                                                                            A complex reorganisation of cell wall metabolism leading to grossly thickened cell wall with                  Infect Dis. 2004 Feb 15;38(4):521-8
    follow up.                                                                                                                                                                   11)       Hanaki H et al. Activated cell-wall synthesis is associated with vancomycin resistance in methicillin-resistant
                                                                            reduced peptidoglycan cross linking .(11-13)                                                                   Staphylococcus aureus clinical strains Mu3 and Mu50. J Antimicrob Chemother 1998;42:199-209.
                                                                                                                                                                                 12)       Hanaki H et al Increase in glutamine-non-amidated muropeptides in the peptidoglycan of vancomycin-resistant
                                                                                                                                                                                           Staphylococcus aureus strain Mu50. J Antimicrob Chemother 1998;42:315-20.

    Review of literature                                                                  WHEN SHOULD A CLINICIAN SUSPECT H-VISA??                                               13)       Geisel R, Schmitz F-J, Thomas L, Berns G, Zetsche O, Ulrich B, et al. Emergence of heterogeneous
                                                                                                                                                                                           intermediate vancomycin resistance in Staphylococcus aureus isolates in the Düsseldorf area. J Antimicrob
                                                                                                                      (15,16)                                                              Chemother 1999;43:846-8.
•   Databases searched :Pubmed and Ovid                                 1) Persistent fever > 7 days after initiation of    4) Low serum trough levels of Vancomycin in          14)       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
•   Search terms used : heterogeneous vancomycin intermediate              treatment                                        1st week                                                       vancomycin therapy. Clin Infect Dis. 2004 Jun 15;38(12):1700-5. Epub 2004 May 21.
                                                                                                                                                                                 15)       Charles PG, Ward PB, Johnson PD, Howden BP, Grayson ML. Clinical features associated with bacteremia
    staphylococcus aureus ,Vancomycin intermediate                      2) Persistent bacteremia > 7 days after                5) High bacterial load infections                           due to heterogeneous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis. 2004 Feb 1;38(3):448-
    staphylococcus aureus , Vancomycin resistant staphylococcus            treatment
                                                                                                                                                                                           51. Epub 2004 Jan 12.
                                                                                                                                                                                 16)       Khosrovaneh A et al Frequency of reduced vancomycin susceptibility and heterogeneous subpopulation in
    aureus. Limited to English literature                                                                                      6) Recurrent bacteremia in 30 days                          persistent or recurrent methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis. 2004 May