Tatiana Baranovich Tatsuo YAMAMOTO Tomomi TAKANO Wataru HIGUCHI Akihito NISHIYAMA

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1 Tatiana Baranovich Tatsuo YAMAMOTO Tomomi TAKANO Wataru HIGUCHI Akihito NISHIYAMA MRSA1961 MRSA hospital-acquired MRSA HA-MRSA MRSA MRSA MRSA The prevalence of MRSA ranges from 0.6 in The Netherlands to 66.6 in JapanDeurenberg 2007 MRSA MRSA MRSA 1 3 MRSA MRSA MRSA community-acquired MRSA CA -MRSA 2 MRSA ST CC spa agr SCC mec SE MIC ST multilocus sequence type 7 housekeeping MRSA website ST CC ST founder MRSA ST30 MRSA MRSA PFGE SCCmec meca DNA DNA methicillin-susceptible S. aureus MSSA SCCmec MRSA SCCmec I V I 39.3 kbii 58.2 kbiii kb MSSA MRSA MRSA IV kb V 28.6 kbmssa MRSA MRSA IV V MSSA SCCmec MRSA Division of Bacteriology, Department of Infectious Disease Control and International Medicine, Niigata University Graduate School of Medical and Dental Sciences (1-757 Asahimachidori, Chuo-ku, Niigata-shi)

2 MSSA MRSA ST CC eburst MRSA 4 MRSA pandemic MRSA 7 New York Japan ST5 SCCmecII Pediatric ST5 SCCmecIVBerlin ST45 SCCmecIV Iberian ST247 SCCmecIABrazilian ST239 SCCmecIII EMRSA-15 ST22 SCCmecIV EMRSA-16 ST36 SCCmecII MRSA New York Japan ST5 SCCmecII TSST-1 SEC SEL SaPI1 SEG SEI SEM SEN SEO egc MRSA 48 MRSA 50 MRSA MRSA MRSA 1 MRSA 48 MRSA MSM MRSA 2 ST1 ST8 ST ST ST8 ST1 ST8 ST80 ST59 ST30 Panton-Valentine PVL

3 EMRSA-16 clone Berlin clone ST 36 sea +, tst +, egc + ST 45 sea -, tst -, egc + EMRSA-15 clone ST 22 sea -, tst -, egc + Pediatric clone ST 5 sea -, tst -, egc + Iberian clone ST 247 sea +, tst -, egc - Hungarian clone ST 239 sea +, tst -, egc - NY/ Japan clone ST 5 sea -/+, tst +, egc + NY/ Japan clone ST 5 sea -, tst -, egc + Brazilian clone S. aureus MSSA Insertion of SCCmec MRSA MRSA ST 239 sea -, tst -, egc - Europe Africa ST : 1, 5, 8, 22, 30, 36, 37, 59, 80, 377, 766 SCCmec : IV, V Europe Resistance : FA, KM, TC, EM or others Drug resistance : EM, CLDM Oceania ST : 30, 93 SCCmec : IVa Western Samoa New Zealand ST : 1, 8 Canada SCCmec : IV, IVa Russia Alaska Resistance : Norway EM, CLDM, MU or others Scotland Finland ST : 30 The Netherlands DenmarkLatvia ST : 30 North America United Kingdom SCCmec : IVc Canada France Belgium Germany Resistance : None Switzerland North Dakota Portugal Minnesota Italy Greece Vladivostok Russia Turkey Japan California USA Algeria ST : 80 China Japan USA Egypt Asia Texas ST : 30 ST : 1, 8, 30, 59, 72 Egypt ST : 30 Taiwan Taiwan SCCmec : IVa ST : 30 ST : 59 ST : 59 SCCmec : IV Resistance : SCCmec : V EM, CLDM, TC, MU, KM, SCCmec: IV, V T Resistance : None or GM Resistance : None LVFX or others Oceania Australia Queens land South America ST : 30 Brazil SCCmec : IV Brazil Resistance : None Resistance : None, TC or others Deaths due to necrotizing or fatal pneumonia Resistance to non-ß-lactam antimicrobial agents MU : mupirocin MRSA

4 ST1 20ST8 33 PVL SSTI UTI 2 7 Waterhouse- Friderichsen PVL 75 MRSA CDC community-acquired pneumonia CAP 6 MRSA CAP CDC MRSA CAP IDSA ATS 2007 SARS H5N1 MRSA moderate recommendation level III evidence 5 PVL MRSA USA400 USA400 USA400 ST80 ST80 ST377 ST30 ST59 : SCCmecIV MRSA USA400 MW2 : ST1 : spa227 SCCmecIVa USA300T8 : SCCmecIV USA300 ST8 : spa008 SCCmecIVa USA300 ST8 : SCCmecIVa ST30 : agr3 SCCmecV USA300 ST8 : spa8 SCCmecIVa CDC 1999 CDC 1999 CDC 1999 CDC 1999 Dufour2002 Dufour2002 Garnier2006 Wannet2005 Francis2005 Peleg2004 Gilbert2006 Tseng2005 CDC 2007 Martin2006 Enany2007 Sifiri2007

5 PVL S 32 kda F 34 kda S F PVL 5 nm Bcl-2 c caspase-9 caspase nm PVL PVL -S PVL 2 1 Labandeira-Rey 2007 PVL PVL protein A Spa Spa PVL Spa TNF PVL IL -8 B 4 Voyich 8 PVL MRSA ST765, spa43, SCCmecIVx ST30, spa19, SCCmecIVc SCCmecIV ST30, spa19, SCCmecIVc ST30, spa19, SCCmecIVc ST30 ST30, spa19, SCCmecIVa ST30 GM GM GM Yamamoto2006 Yamamoto2006 Hisata2005 Takizawa2004 Takizawa2004 Okubo2007 6, 7 PVL

6 2006 PVL MRSA PVL PVL Voyich PVL MRSA ST8 USA300 9 SCCmecIVa-ACME ACME arca δ-hemolysin hld ΦSA3usa Fibrin-specific blood-colt dissolving enzyme sak Chemotaxis inhibitory Protein chs Truncated β-hemolysin hlb mec orfx 2.16 Mbp Leukocidin ED luke-lukd γ-hemolysin hlga,c,b SCCmec a 24 kb A (S) Agr regulon agrb, D, C, A SCCmec IVa ACME SCCmec IVa MecA (PBP2 ) meca 2.9/0 Mbp ACME type I B (F) C (S) aroe arcc Arginine deiminase arca ΦSA2usa CA-MRSA USA300 (ST8) 2,872,769bp S F Protein A spa Coagulase (III) coa ACME31kb α-hemolysin hla mec complex ccr complex arc cluster opp-3 cluster glpf gmk yqil Oligopeptide permease operon opp Mbp Panton-Valentine leukocidin (PVL) luks-pv-lukf-pv pta tpi Arginine deiminase pathway (arc cluster) Oligopeptide permease system (opp-3 cluster) SET set Mbp Staphylococcal accessory regulator A sara Clumping factor clfa SEK sek SEQ seq SAPI5 IS431 meca mecr1 IS1272 ccrb2 ccra2 arcc arcb arcd arca arcr arca : arginin deiminase opp-3a opp-3b opp-3c opp-3d opp-3f DR SCCmec DR ACME DR ACME AGAAGCTTATCATAAATGATGCGGTTTTT AAAAACCGCATCATTAACTGATAAGCAGAAGCGTATCACAA AAAAACCGCATCATTAACCGATACGCAGAGGCGTATCATAA IR SCCmec IR SCCmec IR ACME MRSA ST8 USA300 9 SCCmecIVa ACME DNA GenBank accession no. CP000255

7 Opp-3 MRSA SCCmecIVa SCCmecIVa SCCmecIVa-ACME S. pyogenes streptococcal acid glycoprotein ph ph L- L- ACME L- ATP ATP arc ACME USA300 Opp-3 opp-1 opp-2 MRSA PVL MRSA PVL MRSA, MRSA bica-mrsa ST89 ST91 MRSA ST8 bica-mrsa MRSA 88 MRSA SSTI hemodynamic instability 5cm SSTI

8 PVL MRSA pusa02 pusa03 PVL MRSA ST30 ST59 ST8 USA300 ST80 B inducible tetk aph3 -IIIa aade ermb cat blaz gyra tetk erm iles iles iles iles msra, ermc tetk mupa ermc tetk aph3 -III far Takizawa2005 Takano2008 Diep2006 Tenover2006 Han2007 Tristan2007 MRSA - ST empiric therapy MRSA MRSA D-zone test MRSA 20 FDA MRSA SSTI ST MRSA Cruciani

9 Conte, 2002 ; Wunderink, 2003 MRSA Wunderink, 2003 ; Kollef, 2004 in vitro PVL PVL Dumitrescu, 2007 MRSA MRSA MRSA Daum, 2007 MRSA MRSA 1 Centers for Disease Control and Prevention.: Four pediatric deaths from community-acquired meticillin-resistant Staphylococcus aureus-minnesota and North Dakota, , Morb. Mortal. Wkly. Rep. : , Vandenesch, F., Naimi, T., Enright, M. C., Lina, G., Nimmo, G. R., Heffernan, H., Liassine, N., Bes, M., Greenland, T., Reverdy, M. E., and Etienne, J.: Community-acquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes : worldwide emergence, Emerg. Infect. Dis. : , Zetola, N., Francis, J. S., Nuermberger, E. L., and Bishai, W. R.: Community-acquired meticillin-resistant Staphylococcus aureus : an emerging threat, Lancet Infect. Dis. : , Brumfitt, W. and Hamilton-Miller, J.: Methicillin-resistant Staphylococcus aureus. N. Engl. J. Med. : , Daum, R. S.: Clinical practice. Skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus. N. Engl. J. Med. : , Genestier, A. L., Michallet, M. C., Préost, G., Bellot, G., Chalabreysse, L., Peyrol, S., Thivolet, F., Etienne, J., Lina, G., Vallette, F. M., Vandenesch, F., and Genestier, L.: Staphylococcus aureus Panton-Valentine leukocidin directly targets mitochondria and induces Bax-independent apoptosis of human neutrophils. J. Clin. Invest. : , Labandeira-Rey, M., Couzon, F., Boisset, S., Brown, E. L., Bes, M., Benito, Y., Barbu, E. M., Vazquez, V., Höök, M., Etienne, J., Vandenesch, F., and Bowden, M. G.: Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia. Science. : , Voyich, J. M., Otto, M., Mathema, B., Braughton, K. R., Whitney, A. R., Welty, D., Long, R. D., Dorward, D. W., Gardner, D. J., Lina, G., Kreiswirth, B. N., and DeLeo, F. R.: Is Panton-Valentine leukocidin the major virulence determinant in community-associated methicillin-resistant Staphylococcus aureus disease? J. Infect. Dis. : , Diep, B. A., Gill, S. R., Chang, R. F., Phan, T. H., Chen, J. H., Davidson, M. G., Lin, F., Lin, J., Carleton, H. A., Mongodin, E. F., Sensabaugh, G. F., and Perdreau-Remington, F.: Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus. Lancet. : , 2006.

Significant human pathogen. SSTI Biomaterial related infections Osteomyelitis Endocarditis Toxin mediated diseases TSST Staphylococcal enterotoxins

Staphylococcus aureus Significant human pathogen. SSTI Biomaterial related infections Osteomyelitis Endocarditis Toxin mediated diseases TSST Staphylococcal enterotoxins Quintessential Pathogen? Nizet