Dịch tễ học phân tử nhiễm MRSA

Practices of Molecular Epidemiology Lecture 9: Molecular epidemiology of Methicillin-resistant Staphylococcus aureus (MRSA) infections National Institute of Infectious Disease January 18, 2017 Healthhype.com Staphylococcus aureus (SA): pathovar vs non-pathovar  Why some strains of SA cause disease while others not?  Why some strains of SA cause epidemics while others not?  Because of drug resistance?  Because of biological factors unrelated to drug resistance?  Because of epidemiological factors not related to any biological factors?  Does colonization with SA predispose to subsequent invasive disease? Healthhype.com Staphylococcus aureus overview     ~30% are carriers of SA (nares, intestine) In the US, more people die of S aureus infections than from HIV/AIDS Prevalence of MRSA varies from 0.6% in The Netherlands to >60% in Japan Community-associated-methicillin-resistant (CA-MRSA) or community-onset SA emerged in the 1990’s  Responsible for the increasing incidence of all MRSA infections in the US and other regions of the world  Gaining resistance to multiple drugs  Associated with severe clinical manifestations:  Necrotizing faciitis  Severe or necrotizing pneumonia  bone and joint infections with septic thromboembolic disease  purpura fulminans with or without Waterhouse-Friderichsen syndrome  orbital cellulitis and endophthalmitis  central nervous system infection  bacteremia  endocarditis Story of drug-resistant S aureus  1940-60’s: First wave: Plasmid-encoded penicillinase; became pandemic by the mid     1950s to 1960s; mostly caused by phage-type 80/81 S aureus 1960s: Second wave: Methicillin resistance reported in 1961 from UK; resistance encoded by mecA (encodes penicillin binding protein, PBP 2a—low affinity to PCN); mostly caused by COL, mostly limited to Europe 1970s-80s: Third wave: Iberian and other clones—spread to the US and the globe in hospitals and health care settings; epidemic evolving with emergence of VISA and VRSA 1990s: Fourth wave: CA-MRSA earliest cases reported from Australia among the indigenous populations; US: 1997-99—severe disease in children with no underlying medical problems 2010s: Fifth wave: CA-MRSA emerging in healthcare settings Genotyping methods for SA  MLST: based on housekeeping genes (arcC, aroE,glpF, gmk, pta, tpiA, yqiL)(http://saureus.mlst.net/)  Sequence type (ST): identical sequences in all genes  Clonal complex (CC): identical sequences in or more of the genes  PFGE:  Based on SmaI-digested S aureus genomic DNA  Used to examine more recent evolutionary changes  SCCmec  spa typing:  Based on 24-bp tandem repeats of the spa gene—diversity results from deletions, duplications, and mutations  Rapid but not as discriminatory as PFGE  Useful in an outbreak situation Common globally-spread MRSA lineages Clonal complex MLST designation PFGE and other designations CC1 ST1 USA400; Native Americans in Alaska, Canada ST59 USA1000; most common CA-MRSA in Asia ST80 Most common CA-MRSA in Europe ST5 USA100 and NewYork/Japan clone (N315) ST5 EMRSA-3 ST5 USA800/Pediatric clone ST5 HDE288/Pediatric clone (Portugal) ST250 Archaic (includes COL): Europe, UK in the 70’s; never entered the US; now gone ST247 Iberian clone and EMRSA-5 ST239 Brazilian/Hungarian clone ST239 EMRSA-1: most common in Asia (except Japan, Korea, Australia) ST8 AUS-2 and AUS-3 ST8 Irish-1 ST8 USA500 and EMRSA-2,-6 ST8 CA-MRSA USA300 CC5 CC8 Common globally-spread MRSA lineages—cont Clonal complex MLST designation PFGE and other designations CC22 ST22 EMRSA-15 CC30 ST30 USA200 and EMRSA-16; phagetype 80/81 CC45 ST45 USA600 Otto M, Cell Microbiol 2012 HA-MRSA  Dominant type: ST239  Other names: Brazilian, British epidemic (EMRSA-1, -4, -7, -9 and -11),Canadian epidemic (CMRSA-3), Hungarian, Portuguese, Nanjing/Taipei, Vienna, and Eastern Australian epidemic (EMRSA Aus-2 and -Aus-3) clones Baines, SL et al, mBio, 2015 Emergence of Major CA-MRSA Clonal Lineages Diep and Otto, Trends in Microbiol 2008 Community-acquired MRSA (CA-MRSA)  Five major STs: ST1, ST8, ST30, ST59, ST80  ST8 (USA300): most common in the US  Panton-Valentine Leukocidin (PVL)-positive, SCCmecIV  ST59: most common in Taiwan  Taiwan clone: PVL-positive ST59/SCCmec V  Asian-Pacific clone: PVL-negative ST59/SCCmec IV  Could be MRSA and MSSA Severe HA-MRSA epidemic in China (Li et al, Nature Medicine, 2012)  sasX, sasG genes (encoding surface proteins) associated with enhanced colonization and increased virulence  Found in sublineages of ST239 strains  Located at the 3’ end of a 127.2-kb ΦSPβ‐like prophage (mobile element)  In China,the frequency of sasX+ MRSA isolates increased from 21% to 39% between 2003-2011, mostly in hospital isolates Phenotypes of sasX, G MRSA strains (Roche et al 2003; Li et al, Nat Med, 2012)  Associated with:  attachment to human nasal epithelial cells in vitro  better colonization in nasal colonization mouse model  promotes biofilm production  decreased phagocytosis by neutrophils  Increased abscess formation in skin and lungs in mouse models Staphylococcus aureus (SA): pathovar vs non-pathovar  Why some strains of SA cause disease while others not?  Why some strains of SA cause epidemics while others not?  Because of drug resistance?  Because of biological factors unrelated to drug resistance?  Because of epidemiological factors not related to any biological factors?  Does colonization with SA predispose to subsequent invasive disease? Healthhype.com Methicillin-susceptible SA (MSSA) vs MRSA (Chambers & DeLeo, Nat Rev Med, 2009):  88% of those causing infections from1961 through 2004 from continents: CC1, CC5, CC8, CC9, CC12,CC15, CC22, CC25, CC30, CC45, and CC51/121 SCCmec gene of HA- and CA-MRSA macrolide-lincosomide-streptogramin B antibiotics, spectinomycin 2013: 11 SCCmec types (http://www.sccmec.org/Pages/SCC_TypesEN.html) Factors associated with increased transmissibility  Arginine catabolic mobile element (ACME) (Diep BA et al JID, 2008)  SasX protein (Li et al, Nat Med, 2012)  Lower human transmissibility of ST398 (LA-MRSA) compared to other MRSA (Hetem DJ et al, EID, 2013) Staphylococcus aureus (SA): pathovar vs non-pathovar  Why some strains of SA cause disease while others not?  Why some strains of SA cause epidemics while others not?  Because of drug resistance?  Because of biological factors unrelated to drug resistance?  Because of epidemiological factors not related to any biological factors?  Does colonization with SA predispose to subsequent invasive disease? Healthhype.com Are there nonhuman reservoirs of MRSA? Livestock as a source? Companion animals? Livestock associated MRSA (LA-MRSA): MRSA prevalence in veterinary personnel  Australia: CC8, (ST8-IV [2B], spa t064; and ST612-IV [2B], spa variable) and ST22 associated with equine practice veterinarians (Groves MD et al PLoS One, 2016)  Europe: ST398 prevalence among livestock veterinarians: ~40% (Verkade E et al Clin Infect Dis, 2013; Cuny C et al, PLoS One, 2009)  North America: CC8 prevalence 10-18% among equine veterinarians (Weese JS et al, Emerg ID, 2005)  United Kingdom: ST22 prevalence ~18% among companion animal veterinarians  Japan (Hokkaido): ST5, ST30 from companion animal (dog) veterinarians (Ishihara K Microbiol Immunol 2014)  Contrast to human healthcare workers: 4.6% in review of 127 outbreaks (Albrich WC, Harbarth S, Lancet ID, 2008) LA-MRSA in livestock animals  Pigs: ST398 in Europe, occasionally in Japan, China  Pigs: ST9 in East Asia  Chicken, duck: ST8 (SCCmecIV) (Ogata K et al, J UOEH, 産業医科大学雑誌, 2014）  Horses: CC8 in Australia, Europe  Bovine milk: ST97 and ST705 in Japan (Hata E et al, J Clin Microbiol 2010)  isolates of ST5 from milk identical to ST5 (New York/Japan clone) Staphylococcus aureus (SA): pathovar vs non‐pathovar • Why do some strains of SA cause disease while others do not? • Why do some strains of SA cause epidemics while others do not? • Because of drug resistance? • Because of biological factors unrelated to drug resistance? • Because of epidemiological factors not related to any biological  factors? • Does colonization with SA predispose to subsequent invasive disease? Healthhype.com Invasive disease following colonization with CA‐MRSA  strains (Wang, M et al, in prep) • 12 articles with 6,998 subjects  • Risk of disease after MRSA colonization: OR‐‐5∙48, 4∙98‐6∙03, 7  studies • Risk of disease after MSSA colonization: OR‐‐0∙95, 0∙82‐1∙10, 4  studies.   Invasive disease following colonization with CA‐MRSA  strains (Wang, M et al, in prep) N Infected and  colonized (N) Concordant  strains (N, %) Isolate pairs  typed (N, %) Molecular typing  method Nguyen et al., 1999 201 6 (86%) 7 (78%) PFGE Gordon et al., 2005 75 2 (25%) 8 (89%) PFGE 11 11 (100%) 11 (100%) PFGE Article Ellis et al., 2009 3,066 Shet et al., 2009 107 10 4 (100%) 4 (40%) PFGE Maree et al., 2010 162 21 14 (93%) 15 (71%) PFGE Peters et al., 2013 600 17 14 (100%) 14 (82%) PFGE Miko et al., 2015 328 33 22 (71%) 31 (94%) spa typing Summary of S aureus pathovar epidemiology  Does drug-resistance contribute to their spread?  Clonal distribution found in both MSSA and MRSA strains  MRSA USA300 and MSSA USA300 show no difference in virulence in the rabbit model (Diep et al, J Infect Dis 2008)  “Successful” epidemic clones have distinct genes and encoded products that may be responsible for their increased “fitness”  Panton-Valentine leukocidin? (PVL found in phagetype 80/81)  Phenol soluble modulin α‐type?  Alpha hemolysin?  sasX?  “Successful” epidemic clones disappear as other new clones replace them This “competition” drives epidemiology of pathotypes of S aureus  Are LA-MRSA potential new reservoir for human MRSA infections? References  Chambers H and DeLeo FR Waves of Resistance: Staphylococcus aureus in the Antibiotic Era Nat Rev Microbiol 2009; 7: 629–641  Mediavilla JR, Chen L, Mathema B, Kreiswirth B Global epidemiology of communityassociated methicillin resistant Staphylococcus aureus (CA-MRSA) Current Opinion in Microbiology 2012, 15:588–595  Bal AM et al Genomic insights into the emergence and spread of international clones of healthcare-, community- and livestock-associated methicillin-resistant Staphylococcus aureus: Blurring of the traditional definitions J Glob Antimicrob Resist 2016; 6:95-101  Otto M MRSA virulence and spread Cell Microbiol 2012; 14: 1513–1521 ... clone ST239 EMRSA-1: most common in Asia (except Japan, Korea, Australia) ST8 AUS-2 and AUS-3 ST8 Irish-1 ST8 USA500 and EMRSA-2,-6 ST8 CA -MRSA USA300 CC5 CC8 Common globally-spread MRSA lineages—cont... CC22 ST22 EMRSA-15 CC30 ST30 USA200 and EMRSA-16; phagetype 80/81 CC45 ST45 USA600 Otto M, Cell Microbiol 2012 HA -MRSA  Dominant type: ST239  Other names: Brazilian, British epidemic (EMRSA-1,... disease? Healthhype.com Are there nonhuman reservoirs of MRSA? Livestock as a source? Companion animals? Livestock associated MRSA (LA -MRSA) : MRSA prevalence in veterinary personnel  Australia: