Community-associated meticillin-resistant Staphylococcus aureus: the case for a genotypic definition

Transcription

1 Journal of Hospital Infection 81 (2012) 143e148 Available online at Journal of Hospital Infection journal homepage: Review Community-associated meticillin-resistant Staphylococcus aureus: the case for a genotypic definition J.A. Otter *, G.L. French Centre for Clinical Infection and Diagnostic Research (CIDR), Department of Infections Diseases, King s College London School of Medicine and Guy s and St. Thomas NHS Foundation Trust, London, UK A R T I C L E I N F O S U M M A R Y Article history: Received 29 June 2011 Accepted 3 April 2012 Available online 22 May 2012 Background: New distinct strains of community-associated meticillin-resistant Staphylococcus aureus (CA-MRSA) have emerged as a cause of infection in previously healthy individuals in community settings. It is important to identify CA-MRSA for clinical management, epidemiological analysis, infection prevention and control, and regulatory reporting, but definitions and nomenclature of these strains are confused. Aim: To review attempts to define CA-MRSA and propose a new definition. Methods: Non-systematic review. Findings: Epidemiological definitions were useful for differentiating CA-MRSA and healthcare-associated (HA)-MRSA strain types in the past. However, although HA-MRSA strain types are rarely transmitted in the community, CA-MRSA strains have started to be transmitted in healthcare facilities, so epidemiological definitions are breaking down. CA-MRSA are community strains of S. aureus that have acquired the meticillin resistance gene, meca. They are distinct from HA-MRSA and should be defined genetically. This may be done by combining genotypic typing by multi-locus sequence or spa with analysis of the staphylococcal cassette chromosome mec. Carriage of Panton-Valentine leukocidin or antimicrobial susceptibility profiles can be useful indicators of CA-MRSA but should not be used for their definition. Conclusion: For full assessment of their epidemiology, MRSA infections should be characterized as: (1) caused by HA- or CA-MRSA strain types; (2) acquired in community or healthcare settings; and (3) onset in the community or healthcare facility. Ó 2012 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved. Introduction The great majority of infections with meticillin-resistant Staphylococcus aureus (MRSA) have occurred as a result of * Corresponding author. Address: Directorate of Infection, 5th Floor, North Wing, St Thomas Hospital, Lambeth Palace Road, London SE1 7EH, UK. Tel.: þ44 (0) ; fax: þ44 (0) address: jonathan.otter@kcl.ac.uk (J.A. Otter). cross-infection in hospitals and other healthcare facilities. Only a limited number of clonal lineages of MRSA have been involved, and these healthcare-associated strains (HA-MRSA) have rarely spread or caused infections amongst healthy individuals in the community or amongst healthcare workers. 1,2 However, MRSA infections in previously healthy individuals with no history of healthcare contact were noticed in the early 1990s in Australia and New Zealand, in the late 1990s in the USA, and in the early 2000s in Europe and elsewhere. 1e /$ e see front matter Ó 2012 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved. doi: /j.jhin

2 144 Subsequent molecular analysis showed that these infections were being caused by new types of MRSA which appeared to be common community strains of meticillin-susceptible S. aureus that had acquired the mobile genetic element, the staphylococcal cassette chromosome mec (SCCmec) that encodes the meticillin resistance gene, meca. 6,7 There is considerable confusion in the literature regarding the definition and nomenclature of these new MRSA types. 8,9 For example, they have been termed community-associated, community-acquired, community-onset, community, true and de-novo types of MRSA. 8e10 The most common term used to describe these strains was initially community-acquired MRSA, 3,4 but this has been widely replaced by communityassociated MRSA (CA-MRSA), reflecting uncertainty as to whether the MRSA was acquired in hospital or in the community. 9,11e13 However, CA-MRSA is poorly defined and used in different ways by different authors. 8 This review will discuss the limitations of an epidemiological definition of CA-MRSA, and propose practical ways to define CA-MRSA by genotype. Definitions of CA-MRSA J.A. Otter, G.L. French / Journal of Hospital Infection 81 (2012) 143e148 CA-MRSA were traditionally regarded as MRSA strains causing infection in previously healthy young patients without prior healthcare contact, susceptible to most non-b-lactam antimicrobial agents, and carrying Panton-Valentine leukocidin (PVL) genes and SCCmec types IV or V (Table I). 2,4,14 However, as the microbiology and epidemiology of CA-MRSA have evolved, traditional definitions has broken down. 8 Table I Clinical, microbiological and genetic features of communityassociated meticillin-resistant Staphylococcus aureus (MRSA) Clinical features Affected patients are less likely to have had healthcare contact 14,63 Can affect healthy individuals of all ages 14,36 Characterized by primary SSTIs occurring in patients with no initial skin wound, especially abscesses 2 Can cause life-threatening invasive infections such as bacteraemia and necrotizing pneumonia 64 Occasionally fatal in previously healthy paediatric patients and young adults 64 Apparent association with non-nasal sites of colonization 65 Recurrent SSTIs 24,25 Transmission within family groups 66 Microbiological features Faster growth rate and competitive advantage with HA-MRSA in vitro 67 Less frequent resistance to non-b-lactam antimicrobial classes 4,14 Low-level/heterogeneous expression of meticillin resistance 67 Genetic features Usually SCCmec IV or V 2,7 Epidemiological association with PVL carriage 4,14 Distinct and diverse MLST types and clonal complexes 2,7 SSTI, skin and soft tissue infection; HA-MRSA, healthcare-associated MRSA; SCCmec, staphylococcal cassette chromosome mec; PVL, Panton-Valentine leukocidin; MLST, multi-locus sequence type. Epidemiological definitions Epidemiological definitions of CA-MRSA are based on the timing of the first MRSA isolate relative to hospital admission, and were originally developed to determine whether an infection was likely to have been acquired during a hospital stay. 15 Typically, these definitions regard MRSA colonization or infection presenting in community settings or at hospital re-admission as community-acquired or community-associated, regardless of whether or not the patient has a history of healthcare contact. 16e18 MRSA causing such infections may then be misclassified as CA-MRSA. For example, several studies have found that most MRSA bacteraemias diagnosed at hospital admission, and therefore designated by some as community-acquired infections, are caused by nosocomial strains of MRSA (HA-MRSA) from a previous healthcare contact. 16,17 Similarly, several reports in the era before the emergence of true or de-novo CA-MRSA described HA-MRSA strains causing infection in community settings as community MRSA. 19,20 The limitations of epidemiological definitions of CA-MRSA are illustrated by a study comparing two different epidemiological definitions of CA-MRSA: one identified 49% of 100 isolates as CA-MRSA, whereas the other only identified 5% as CA-MRSA. 21 The US Centers for Disease Control and Prevention (CDC) proposed an epidemiological definition of CA-MRSA that has been widely adopted. 21e24 In order to fulfil the current CDC definition of CA-MRSA, MRSA must be identified in the outpatient setting or less than 48 h after hospital admission in an individual with no medical history of MRSA infection or colonization, admission to a healthcare facility, dialysis, surgery or insertion of indwelling devices in the past year. 8,23 In the CDC definition, the inclusion of an assessment of previous healthcare contact means that MRSA linked to a hospitalization but presenting in the community or at hospital re-admission are classified correctly as HA-MRSA. Indeed, in a recent study from Oxford, none of the MRSA bacteraemias identified on hospital admission met the CDC definition of CA-MRSA. 16 However, as more patients in the community are affected by CA-MRSA, repeat MRSA episodes are increasingly likely to be misclassified as HA-MRSA by epidemiological definitions. 25,26 A particular challenge to epidemiological definitions is the transmission of CA-MRSA among the injecting drug user/ homeless group. 27,28 These patients often have a history of previous hospital admission for other reasons, but their infections may be caused by CA-MRSA strains originally acquired in the community. Epidemiological definitions are further limited by the emergence of CA-MRSA clones as an increasingly common cause of healthcare-associated infection. 9,11e13 Purely epidemiological definitions of CA-MRSA do not consider the genetic background of the MRSA involved and will misclassify CA-MRSA acquired in hospital. Need for a genotypic definition Millar et al. proposed guidelines for developing a definition of CA-MRSA combining epidemiological factors, antimicrobial susceptibility (AMS) pattern, clinical presentation and SCCmec type. 8 However, although this is an improvement on the CDC definition, these guidelines are confounded by CA-MRSA acquired in healthcare settings which only meet

3 J.A. Otter, G.L. French / Journal of Hospital Infection 81 (2012) 143e some of the proposed criteria for CA-MRSA. 8 Also, the guidelines recommend the use of SCCmec typing alone for inferring the MRSA genetic background, but this is not useful for determining the MRSA lineage because isolates with a nontypeable SCCmec cassette may be missed, and SCCmec IV carrying HA-MRSA lineages such as ST22-IV (EMRSA-15) and ST5-IV (USA800/paediatric clone) may be misclassified as CA-MRSA. 2,29 CA-MRSA are usually common community types of meticillin-susceptible S. aureus that have acquired meca de novo. 6,7 Therefore, it is proposed that combining a genotyping method [such as multi-locus sequence typing (MLST), spa or pulsed-field gel electrophoresis] with SCCmec analysis to infer the likely origin of the MRSA is the best way to define CA-MRSA strains at the current time. These isolates may be PVL-positive or PVL-negative, have any clinical presentation, have any AMS pattern, and can be classified as either healthcare- or community-associated using epidemiological criteria. Practical definition of CA-MRSA The introduction of a genotypic method into the definition of CA-MRSA adds extra cost, time and requirement for laboratory equipment, expertise and experience to define these strains. However, the costs of genotyping are decreasing, and the equipment and expertise required, particularly for spa typing, is within the capabilities of most clinical laboratories. 30 Furthermore, collaboration with reference centres can be sought to provide genotyping. If this approach becomes more widely accepted and the demands for genotyping increase, it is likely that simpler/automated methods may become commercially available. Despite these difficulties, the authors believe that future studies of MRSA should use genotypic rather than epidemiological definitions of CA-MRSA. Ideally, all isolates should be genotyped, but in many circumstances, molecular markers or AMS profiles can be used to select representative strains for more detailed genotypic analysis, as discussed below. Molecular markers There is no single, stable genetic marker for CA-MRSA strains. PVL has been proposed as a marker of CA-MRSA. 8,22,31 There is undoubtedly an epidemiological association between CA-MRSA and the carriage of PVL, 4,14 but some globally disseminated CA-MRSA clones do not carry PVL. 22,32,33 Many of the reports of CA-MRSA have come from the USA, where USA300 (ST8-IV), which is predominantly PVL-positive, 34 is the dominant clone. 1,2,12,35 In contrast to the dominance of USA300 in the USA, the common CA-MRSA clones in Europe and elsewhere are heterogeneous, including a mixture of PVL-positive and PVL-negative clones. 1,2 Successful PVL-negative CA-MRSA clones include ST1-IV (WA-MRSA-1), which is the most common CA-MRSA clone in Western Australia 33 and was the most common CA-MRSA clone at a London hospital from 2000 to 2006, 36 and the ST398-V pig-associated clone in Europe. 37 One study reported the co-existence of sibling clones of PVLpositive and PVL-negative USA400 in Canada. 32 A study from Ireland found that only two (7%) of 30 isolates that met the CDC definition of CA-MRSA carried PVL. Therefore, although MRSA producing PVL are likely to be CA-MRSA, PVL production should not be used as part of the definition of CA-MRSA. CA-MRSA usually carry SCCmec types IV or V, whereas HA- MRSA usually carry SCCmec types IeIII. 7,38 Some researchers have used the carriage of SCCmec IV as a molecular marker for CA-MRSA. 39,40 For example, a retrospective study from Chicago used an AMS-based algorithm for the presumptive detection of SCCmec IV phenotype isolates, which were used to infer changes in the prevalence of CA-MRSA. 39 Since the study was performed in the USA, this approach was valid given the dominance of SCCmec IV USA300 and the fact that SCCmec IV HA-MRSA lineages are rare in the USA. However, the SCCmec region is variable, and new types and subtypes are emerging constantly, leading to problems with nomenclature. 7,38 For example, SCCmec V, which is carried by successful CA-MRSA lineages, 1 was first reported in 2004, a decade after the first emergence of CA-MRSA. 41 A particular problem with the use of SCCmec type as a marker for CA-MRSA is the presence of successful hospital lineages carrying SCCmec IV in some parts of the world. For example, unlike most other parts of the world, the most common HA-MRSA clone in the UK, ST22 EMRSA-15, is SCCmec IV, 2,29 as is the ST5/USA800 paediatric clone which is disseminated in the USA and South America. 2 Furthermore, these SCCmec IV carrying HA-MRSA tend to be relatively susceptible to antimicrobial agents, compounding the likelihood that they will be misclassified as CA-MRSA unless their lineage is determined. 29 AMS-based markers The SCCmec IeIII cassettes, common in HA-MRSA, carry additional antimicrobial resistance genes that are not present in the smaller SCCmec IV and V cassettes associated with CA-MRSA. 8,34 Furthermore, CA-MRSA have emerged without the antimicrobial pressure that selects for multiple antimicrobial resistance in hospitals. 42 Consequently, the first CA-MRSA were susceptible to non-b-lactam antimicrobial agents, 4,14 and this susceptibility has been used as a screening marker for these strains. For example, ciprofloxacin susceptibility has been used as a phenotypic marker of CA-MRSA in the UK. 30,40,41 Several studies have attempted to assess the accuracy of AMS-based algorithms for the presumptive identification of CA- MRSA. 43e45 However, even the best AMS-based classification systems only have a sensitivity of 70e80%. 43e45 For example, in one UK study, the use of ciprofloxacin susceptibility as a marker missed approximately one-third of CA-MRSA isolates, 43 and it is likely that mutational ciprofloxacin resistance will increase in these strains in future. 42 AMS profiles tend to vary with lineage, thus algorithms for the presumptive identification of CA-MRSA will need to be developed locally. 4,35,43 The resolution of AMS-based algorithms is likely to decrease further over time as CA-MRSA develop broader antimicrobial resistance by continued exposure to antimicrobial selective pressure in hospitals. 24,46,47 In addition, a particular problem with using antimicrobial susceptibility as a phenotypic marker of CA- MRSA in the UK is that the most common cause of HA-MRSA, EMRSA-15, is typically susceptible to most non-blactam antimicrobials. 29 Furthermore, useful algorithms will need to be assessed periodically to reflect changes in resistance patterns.

4 146 Addressing variation in the molecular epidemiology of CA-MRSA Genotypic definitions of CA-MRSA will need to reflect differences in the molecular epidemiology of community and healthcare-associated MRSA, and variations in the molecular techniques adopted between countries and laboratories. 1,2 A genotypic definition is easier to derive in the USA and Latin America, where predominant HA-MRSA lineages are not SCCmec IV and USA300 is so prominent among CA-MRSA. 2,35,48 Similarly, genotypic definitions are straightforward where there is a predominant CA-MRSA clone; for example, PVL-positive ST30- IV ( SWP ) in Uruguay, 49 a novel PVL-positive ST5-IV clone in Argentina, 50 PVL-positive ST22-IV and ST772-V in India, 51 PVLpositive ST80-IV in North Africa, 52,53 and PVL-positive ST59-VII in Taiwan. 54e56 However, developing a genotypic definition is more difficult in Europe and Australia where CA-MRSA are currently characterized by genotypic heterogeneity. 1,4,33,57 The global molecular epidemiology of CA-MRSA is poorly described, so it is difficult to judge how easy it would be to derive a workable genotypic definition in many parts of the world. 1,2 The present authors recently developed a genotypic definition of CA-MRSA at their London teaching hospital, 43 which currently has a low but apparently increasing prevalence of CA- MRSA, 36 and the predominant HA-MRSA clone is ST22-IV EMRSA CA-MRSA were defined as isolates that were SCCmec IV or V that did not have a spa type in the same clonal cluster as EMRSA-15 (using Based Upon Repeat Pattern clustering). 36 Isolates with non-typeable SCCmec regions were defined as CA-MRSA because they were considered to be unlikely to represent epidemic hospital lineages, and all other isolates were classified as HA-MRSA. 43 In common with previous reports (Table I), isolates defined as CA-MRSA were more likely to be associated with younger patients, abscess formation and PVL production; classified as community acquired by epidemiological criteria; and resistant to fewer classes of antimicrobial agents than isolates defined as HA-MRSA. 43 Until the emergence of CA-MRSA as a cause of healthcare-associated infection, both genotypic and epidemiological definitions would have identified a broadly similar set of isolates. This is now not the case, as illustrated by the fact that 70% of these CA-MRSA isolates were classified as HA-MRSA by epidemiological criteria. This highlights the limitations of epidemiological classifications if used for presumptive identification of CA- MRSA types, and thus supports the use of a genotypic definition. Although the authors suspect that many of these patients, such as intravenous drug users, probably had community acquisition followed by repeated hospital contacts, genuine nosocomial transmission of CA-MRSA strains appears to be occurring with increasing frequency in other parts of the world. 9,11e13 Acquisition and onset of clinical infection J.A. Otter, G.L. French / Journal of Hospital Infection 81 (2012) 143e148 Although it is essential to have clear definitions to distinguish between HA- and CA-MRSA strain types, the time and place of onset of colonization and/or infection are also important for epidemiological analysis, and infection prevention and control. Thus, CA-MRSA can be acquired in either community (common) or healthcare (uncommon but increasing) settings. HA-MRSA strains are nearly always acquired during healthcare contact, but with both strain types, the onset of infection may be in either the community or in hospital. Where the information is available, MRSA infections should therefore be characterized as: (1) caused by HA- or CA-MRSA strain type; (2) acquired in community or healthcare settings; and (3) onset in the community or healthcare facility. These data are important for epidemiological analysis, risk assessment, regulatory reporting, and the development of appropriate infection prevention and control in the community, healthcare facility and community/hospital interface. Recommendations and conclusion At the current time, MRSA strains involved in outbreaks should either be typed by individual hospital laboratories or referred to reference laboratories in order to determine whether they are CA-MRSA or HA-MRSA strain types, because a wider group of patients and staff may be at risk and novel control strategies may be required for CA-MRSA. 11,13,59 Novel strategies may include hospital staff screening, increased follow-up of cases with hospital and community onset to reduce household transmission, enhanced infection prevention and control measures in community settings, and a focus on preventing transmission of MRSA from livestock to humans in affected areas. 1,13,60 Periodic investigation of AMS patterns among MRSA infections, perhaps combined with typing of local sets of isolates, would also be useful to ensure that empiric therapy is appropriate, given that the emergence of CA-MRSA in some parts of the world has forced a change of empiric therapy of staphylococcal skin infections to cover MRSA. 61,62 Reference laboratories should continue to type representative sets of isolates periodically to ensure that MRSA trends and emerging strain types are monitored adequately. 31,58 For full assessment of their epidemiology, MRSA infections should be characterized as: (1) caused by HA- or CA-MRSA strain types; (2) acquired in community or healthcare settings; and (3) onset in the community or healthcare facility. Conflict of interest statements JAO is employed part-time by Bioquell UK Ltd. GLF declares no potential conflict of interest. Funding sources None. References 1. Otter JA, French GL. Molecular epidemiology of communityassociated meticillin-resistant Staphylococcus aureus in Europe. Lancet Infect Dis 2010;10:227e Chambers HF, Deleo FR. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol 2009;7:629e Centers for Disease Control and Prevention. Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus e Minnesota and North Dakota, 1997e1999. JAMA 1999;282:1123e Vandenesch F, Naimi T, Enright MC, et al. Community-acquired methicillin-resistant Staphylococcus aureus carrying Panton- Valentine leukocidin genes: worldwide emergence. Emerg Infect Dis 2003;9:978e984.

5 J.A. Otter, G.L. French / Journal of Hospital Infection 81 (2012) 143e Udo EE, Pearman JW, Grubb WB. Genetic analysis of community isolates of methicillin-resistant Staphylococcus aureus in Western Australia. J Hosp Infect 1993;25:97e Enright MC, Robinson DA, Randle G, Feil EJ, Grundmann H, Spratt BG. The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA). Proc Natl Acad Sci USA 2002;99:7687e Deurenberg RH, Stobberingh EE. The molecular evolution of hospital- and community-associated methicillin-resistant Staphylococcus aureus. Curr Mol Med 2009;9:100e Millar BC, Loughrey A, Elborn JS, Moore JE. Proposed definitions of community-associated meticillin-resistant Staphylococcus aureus (CA-MRSA). J Hosp Infect 2007;67:109e Popovich KJ, Weinstein RA. Commentary: the graying of methicillin-resistant Staphylococcus aureus. Infect Control Hosp Epidemiol 2009;30:9e Witte W, Braulke C, Cuny C, et al. Emergence of methicillinresistant Staphylococcus aureus with Panton-Valentine leukocidin genes in central Europe. Eur J Clin Microbiol Infect Dis 2005;24:1e Otter JA, French GL. Nosocomial transmission of communityassociated methicillin-resistant Staphylococcus aureus: an emerging threat. Lancet Infect Dis 2006;6:753e Popovich KJ, Weinstein RA, Hota B. Are community-associated methicillin-resistant Staphylococcus aureus (MRSA) strains replacing traditional nosocomial MRSA strains? Clin Infect Dis 2008;46:787e Otter JA, French GL. Community-associated meticillin-resistant Staphylococcus aureus strains as a cause of healthcareassociated infection. J Hosp Infect 2011;79:189e Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003;290:2976e Coia JE, Duckworth GJ, Edwards DI, et al. Guidelines for the control and prevention of meticillin-resistant Staphylococcus aureus (MRSA) in healthcare facilities. J Hosp Infect 2006;63:1e Miller R, Esmail H, Peto T, Walker S, Crook D, Wyllie D. Is MRSA admission bacteraemia community-acquired? A case control study. J Infect 2008;56:163e Tacconelli E, Venkataraman L, De Girolami PC, D Agata EM. Methicillin-resistant Staphylococcus aureus bacteraemia diagnosed at hospital admission: distinguishing between communityacquired versus healthcare-associated strains. J Antimicrob Chemother 2004;53:474e Pearson A. Historical and changing epidemiology of healthcareassociated infections. J Hosp Infect 2009;73:296e Rosenberg J. Methicillin-resistant Staphylococcus aureus (MRSA) in the community: who s watching? Lancet 1995;346:132e Johnston BL. Methicillin-resistant Staphylococcus aureus as a cause of community-acquired pneumonia e a critical review. Semin Respir Infect 1994;9:199e Folden DV, Machayya JA, Sahmoun AE, et al. Estimating the proportion of community-associated methicillin-resistant Staphylococcus aureus: two definitions used in the USA yield dramatically different estimates. J Hosp Infect 2005;60:329e Rossney AS, Shore AC, Morgan PM, Fitzgibbon MM, O Connell B, Coleman DC. The emergence and importation of diverse genotypes of MRSA harboring the Panton-Valentine leukocidin gene pvl reveals that pvl is a poor marker for community-acquired MRSA in Ireland. J Clin Microbiol 2007;45:2554e Buck JM, Como-Sabetti K, Harriman KH, et al. Community-associated methicillin-resistant Staphylococcus aureus, Minnesota, 2000e2003. Emerg Infect Dis 2005;11:1532e Huang H, Flynn NM, King JH, Monchaud C, Morita M, Cohen SH. Comparisons of community-associated methicillin-resistant Staphylococcus aureus (MRSA) and hospital-associated MRSA infections in Sacramento, California. J Clin Microbiol 2006;44:2423e Fritz SA, Epplin EK, Garbutt J, Storch GA. Skin infection in children colonized with community-associated methicillin-resistant Staphylococcus aureus. J Infect 2009;59:394e Crum-Cianflone N, Weekes J, Bavaro M. Recurrent communityassociated methicillin-resistant Staphylococcus aureus infections among HIV-infected persons: incidence and risk factors. AIDS Patient Care STDs 2009;23:499e Cooke FJ, Gkrania-Klotsas E, Howard JC, et al. Clinical, molecular and epidemiological description of a cluster of communityassociated methicillin-resistant Staphylococcus aureus isolates from injecting drug users with bacteraemia. Clin Microbiol Infect 2010;16:921e Otter JA, French GL. Community-associated meticillin-resistant Staphylococcus aureus in injecting drug users and the homeless in south London. J Hosp Infect 2008;69:198e Otter JA, Klein JL, Watts TL, Kearns AM, French GL. Identification and control of an outbreak of ciprofloxacin-susceptible EMRSA-15 on a neonatal unit. J Hosp Infect 2007;67:232e Aires-de-Sousa M, Boye K, de Lencastre H, et al. High interlaboratory reproducibility of DNA sequence-based typing of bacteria in a multicenter study. J Clin Microbiol 2006;44:619e Ellington MJ, Perry C, Ganner M, et al. Clinical and molecular epidemiology of ciprofloxacin-susceptible MRSA encoding PVL in England and Wales. Eur J Clin Microbiol Infect Dis 2009;28:1113e Zhang K, McClure JA, Elsayed S, Tan J, Conly JM. Coexistence of Panton-Valentine leukocidin-positive and -negative communityassociated methicillin-resistant Staphylococcus aureus USA400 sibling strains in a large Canadian health-care region. J Infect Dis 2008;197:195e Nimmo GR, Coombs GW. Community-associated methicillinresistant Staphylococcus aureus (MRSA) in Australia. Int J Antimicrob Agents 2008;31:401e Larsen AR, Goering R, Stegger M, et al. Two distinct clones of methicillin-resistant Staphylococcus aureus (MRSA) with the same USA300 pulsed-field gel electrophoresis profile: a potential pitfall for identification of USA300 community-associated MRSA. J Clin Microbiol 2009;47:3765e Otter JA, Havill NL, Boyce JM, French GL. Comparison of community-associated methicillin-resistant Staphylococcus aureus from teaching hospitals in London and the USA, 2004e2006: where is USA300 in the UK? Eur J Clin Microbiol Infect Dis 2009;28:835e Otter JA, French GL. The emergence of community-associated methicillin-resistant Staphylococcus aureus at a London teaching hospital, 2000e2006. Clin Microbiol Infect 2008;14:670e Huijsdens XW, van Dijke BJ, Spalburg E, et al. Communityacquired MRSA and pig-farming. Ann Clin Microbiol Antimicrob 2006;5: International Working Group on the Classification of Staphylococcal Cassette Chromosome Elements (IWG-SCC). Classification of staphylococcal cassette chromosome mec (SCCmec): guidelines for reporting novel SCCmec elements. Antimicrob Agents Chemother 2009;53:4961e Maree CL, Daum RS, Boyle-Vavra S, Matayoshi K, Miller LG. Community-associated methicillin-resistant Staphylococcus aureus isolates causing healthcare-associated infections. Emerg Infect Dis 2007;13:236e Davis SL, Rybak MJ, Amjad M, Kaatz GW, McKinnon PS. Characteristics of patients with healthcare-associated infection due to SCCmec type IV methicillin-resistant Staphylococcus aureus. Infect Control Hosp Epidemiol 2006;27:1025e Ito T, Ma XX, Takeuchi F, Okuma K, Yuzawa H, Hiramatsu K. Novel type V staphylococcal cassette chromosome mec driven by a novel cassette chromosome recombinase, ccrc. Antimicrob Agents Chemother 2004;48:2637e Lowy FD. Antimicrobial resistance: the example of Staphylococcus aureus. J Clin Invest 2003;111:1265e1273.

6 148 J.A. Otter, G.L. French / Journal of Hospital Infection 81 (2012) 143e Otter JA, French GL. Utility of antimicrobial susceptibility-based algorithms for the presumptive identification of genotypicallydefined community-associated methicillin-resistant Staphylococcus aureus at a London teaching hospital. Eur J Clin Microbiol Infect Dis 2011;30:459e Popovich K, Hota B, Rice T, Aroutcheva A, Weinstein RA. Phenotypic prediction rule for community-associated methicillin-resistant Staphylococcus aureus. J Clin Microbiol 2007;45:2293e Gbaguidi-Haore H, Thouverez M, Couetdic G, Cholley P, Talon D, Bertrand X. Usefulness of antimicrobial resistance pattern for detecting PVL- or TSST-1-producing MRSA in a French university hospital. J Med Microbiol 2009;58:1337e Diep BA, Chambers HF, Graber CJ, et al. Emergence of multidrugresistant, community-associated, methicillin-resistant Staphylococcus aureus clone USA300 in men who have sex with men. Ann Intern Med 2008;148:249e Ellington MJ, Ganner M, Warner M, Cookson BD, Kearns AM. Polyclonal multiply antibiotic-resistant methicillin-resistant Staphylococcus aureus with Panton-Valentine leucocidin in England. J Antimicrob Chemother 2010;65:46e Reyes J, Rincon S, Diaz L, et al. Dissemination of methicillinresistant Staphylococcus aureus USA300 sequence type 8 lineage in Latin America. Clin Infect Dis 2009;49:1861e Benoit SR, Estivariz C, Mogdasy C, et al. Community strains of methicillin-resistant Staphylococcus aureus as potential cause of healthcare-associated infections, Uruguay, 2002e2004. Emerg Infect Dis 2008;14:1216e Sola C, Saka HA, Vindel A, Bocco JL. Emergence and dissemination of a community-associated methicillin-resistant Panton-Valentine leucocidin-positive Staphylococcus aureus clone sharing the sequence type 5 lineage with the most prevalent nosocomial clone in the same region of Argentina. J Clin Microbiol 2008;46:1826e D Souza N, Rodrigues C, Mehta A. Molecular characterization of methicillin-resistant Staphylococcus aureus with emergence of epidemic clones of sequence type (ST) 22 and ST 772 in Mumbai, India. J Clin Microbiol 2010;48:1806e Antri K, Rouzic N, Dauwalder O, et al. High prevalence of methicillin-resistant Staphylococcus aureus clone ST80-IV in hospital and community settings in Algiers. Clin Microbiol Infect 2011;17:526e Ramdani-Bouguessa N, Bes M, Meugnier H, et al. Detection of methicillin-resistant Staphylococcus aureus strains resistant to multiple antibiotics and carrying the Panton-Valentine leukocidin genes in an Algiers hospital. Antimicrob Agents Chemother 2006;50:1083e Boyle-Vavra S, Ereshefsky B, Wang CC, Daum RS. Successful multiresistant community-associated methicillin-resistant Staphylococcus aureus lineage from Taipei, Taiwan, that carries either the novel staphylococcal chromosome cassette mec (SCCmec) type V T or SCCmec type IV. J Clin Microbiol 2005;43:4719e Takano T, Higuchi W, Otsuka T, et al. Novel characteristics of community-acquired methicillin-resistant Staphylococcus aureus strains belonging to multilocus sequence type 59 in Taiwan. Antimicrob Agents Chemother 2008;52:837e Chen CJ, Hsueh PR, Su LH, Chiu CH, Lin TY, Huang YC. Change in the molecular epidemiology of methicillin-resistant Staphylococcus aureus bloodstream infections in Taiwan. Diagn Microbiol Infect Dis 2009;65:199e Tong SY, Lilliebridge RA, Bishop EJ, et al. Clinical correlates of Panton-Valentine leukocidin (PVL), PVL isoforms, and clonal complex in the Staphylococcus aureus population of Northern Australia. J Infect Dis 2010;202:760e Ellington MJ, Hope R, Livermore DM, et al. Decline of EMRSA-16 amongst methicillin-resistant Staphylococcus aureus causing bacteraemias in the UK between 2001 and J Antimicrob Chemother 2010;65:446e Teare L, Shelley OP, Millership S, Kearns A. Outbreak of Panton- Valentine leucocidin-positive meticillin-resistant Staphylococcus aureus in a regional burns unit. J Hosp Infect 2010;76:220e Kock R, Becker K, Cookson B, et al. Methicillin-resistant Staphylococcus aureus (MRSA): burden of disease and control challenges in Europe. Euro Surveill 2010;15: Moran GJ, Amii RN, Abrahamian FM, Talan DA. Methicillin-resistant Staphylococcus aureus in community-acquired skin infections. Emerg Infect Dis 2005;11:928e Chuck EA, Frazee BW, Lambert L, McCabe R. The benefit of empiric treatment for methicillin-resistant Staphylococcus aureus. J Emerg Med 2010;38:567e Herold BC, Immergluck LC, Maranan MC, et al. Communityacquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA 1998;279:593e Hidron AI, Low CE, Honig EG, Blumberg HM. Emergence of community-acquired meticillin-resistant Staphylococcus aureus strain USA300 as a cause of necrotising community-onset pneumonia. Lancet Infect Dis 2009;9:384e Yang ES, Tan J, Eells S, Rieg G, Tagudar G, Miller LG. Body site colonization in patients with community-associated methicillinresistant Staphylococcus aureus and other types of S. aureus skin infections. Clin Microbiol Infect 2009;16:425e Huijsdens XW, van Santen-Verheuvel MG, Spalburg E, et al. Multiple cases of familial transmission of community-acquired methicillin-resistant Staphylococcus aureus. J Clin Microbiol 2006;44:2994e Laurent F, Lelievre H, Cornu M, et al. Fitness and competitive growth advantage of new gentamicin-susceptible MRSA clones spreading in French hospitals. J Antimicrob Chemother 2001;47:277e283.