Staphylococcus aureus can cause a wide variety of diseases ranging from mild skin and soft-tissue infections to severe systemic infections in human and animals (Lowy, 1998). Serious S. aureus infections such as bacteremia are generally associated with high morbidity and mortality, and the acquisition of methicillin resistance further limits therapeutic options (Cosgrove et al., 2003; Wang et al., 2008; Bassetti et al., 2012). Since methicillin-resistant S aureus was first identified at a hospital in the United Kingdom in 1961, it quickly became an important pathogen globally (referred to as hospital-associated MRSA; HA-MRSA). Until the late 1980s and early 1990s, some cases of MRSA in young and otherwise healthy patients without hospital-related risk factors were reported. These isolates were called community-associated MRSA (CA-MRSA) and their emergence and spread increased the risk to public health.

Compared to traditional HA-MRSA strains, CA-MRSA isolates harbor different types of SCCmec elements encoding methicillin(mec) resistance genes. To date, 13 SCCmec types (indicated by roman numerals I to XIII) and three mec(mecA/B/C) genes have been identified among S. aureus in the world (Hiramatsu et al., 2013; Kaya et al., 2018). The majority of CA-MRSA isolates have SCCmec type IV or V, do not exhibit resistance to multiple antibiotics (except to β-lactams), and possess different exotoxin gene profiles (Dinges et al., 2000). Within the last decade, rates of CA-MRSA infection have been increasing, while HA-MRSA infection rates have generally declined (David et al., 2014). The epidemiological impact of CA-MRSA strains is believed to stem from a combination of methicillin resistance and extraordinary virulence, allowing these strains to infect otherwise healthy individuals and spread rapidly throughout the population. As a result, there is an urgent need to understand the molecular characteristics of CA-MRSA isolates to achieve more effective infection control.

Community-associated-Methicillin-resistant S. aureus strains are considered more virulent than HA-MRSA strains because they possess specific virulence factors. The increased expression of various genes has also been associated with increased virulence in CA-MRSA (Otto, 2013). For example, Panton–Valentine leukocidin (pvl), a bicomponent leukotoxin virulence factor, has been linked to severe skin and soft tissue infections and necrotizing pneumonia caused by CA-MRSA strains (Lina et al., 1999), but has also been found in HA-MRSA and CA-MSSA isolates. The superantigen exotoxin (TSST-1), exfoliatin A (ETA) and B (ETB), staphylococcal enterotoxins (SEs) found to be closely related to different types of staphylococcal infections (Hanakawa et al., 2002; Jarraud et al., 2002; Warner and Onderdonk, 2004). However, the significance of these factors in CA-SA bacteremia is not well understood.

It has been found that various CA-SA clones, and especially CA-MRSA, circulate in different countries or regions. For example, ST1-IV and ST8-IV clones are mainly found in the United States and Canada, whereas ST80-IV clones are more prevalent in Europe and ST59-IV/V are the most common CA-MRSA clones in China and several other Asian countries. The prevalence of CA-SA varies with age, geography, disease, and time, and the occurrence rate of CA-MRSA varies substantially worldwide, ranging from < 1% to > 50% in different countries (Deurenberg and Stobberingh, 2008; Chen and Huang, 2014). The incidence of CA-SA infections is higher in children (Huang and Chen, 2011). Although CA-SA infection and transmission has become a serious public health problem worldwide (David et al., 2015; McMullan et al., 2016; Pena Amaya et al., 2017; Kang et al., 2017; Roediger et al., 2017), the information regarding CA-SA associated with bloodstream infections (BSIs) in children in China is still very limited. The aim of this study was to investigate the molecular profile, antimicrobial resistance, and virulence genes associated with 78 CA-SA isolates recovered from pediatric patients with BSIs between 2012 and 2017 in a hospital in China.

Recently, the incidence of community-associated MRSA infection has been increasing. CA-MRSA typically presents as skin and soft tissue infection (SSTI), but invasive infection such as bacteremia can occur, which can lead to serious or even fatal consequences, especially in children and immunocompromised patients. Given this dangerous consequence of CA-MRSA infection in pediatric patients, there is an urgent need to understand the prevalence, molecular characteristics, and virulence profiles of CA-MRSA strains isolated from BSIs to initiate measure to control infection and transmission in local communities.

The occurrence rate of CA-MRSA varies substantially worldwide, ranging from < 1% to > 50% in different countries (Deurenberg and Stobberingh, 2008; Chen and Huang, 2014). In an ANSORP study conducted in 17 hospitals in eight Asian countries, namely Korea, Taiwan, Hong Kong, Thailand, the Philippines, Vietnam, India, and Sri Lanka, the rate of MRSA among CA-SA infections ranged from 2.5 to 39% (Chen and Huang, 2014). In addition, the rate of CA-MRSA among childhood infections in Taiwan increased significantly from 9.8% in 1999–2000 to 56% in 2004–2005. In China, based on a study performed in Beijing Children’s Hospital, 14(4%) of 351 CA-SA infections were caused by MRSA (Wu et al., 2010). These studies focused on CA-MRSA infection, mainly from SSTIs. Few data describing the rate of CA-MRSA isolated from BSI are available. As a result, we characterized 78 CA-SA isolates recovered from pediatric patients with BSIs between 2012 and 2017 in Shanghai and identified 34.6% as MRSA strains. This indicates that MRSA is an important pathogenic bacterium associated with severe, life-threatening infections in children, and suggests the urgent need for active surveillance of such infections and transmission in children.

Community-associated-methicillin-resistant S. aureus infections have been reported globally and the major pandemic clones are frequently related to specific geographic areas (Mediavilla et al., 2012; Li et al., 2016). clones with ST59 are mostly found in the Asia-Pacific region including Taiwan and Australia (Chen and Huang, 2014). In China, ST59-SCCmecIV/V-t437 is always identified as the major epidemic CA-MRSA clone (Geng et al., 2010). Our current data confirms previous findings with respect to the prevalence of ST59, but minor differences were noted. ST59-SCCmecIV-t172 was present with increasing prevalence and became the most common CA-MRSA clone in Shanghai. Although there is considerable genetic diversity among MSSA clones observed in China, ST188 and ST7 have been reported to be the most prevalent clones from adult BSI cases. Our result was consistent with these data, with these strains accounting for 29.5% of all isolates. Recently, ST188 and ST7 were identified as the predominant types among MSSA strains from childhood pneumonia between January 2014 and June 2015 (Song et al., 2017). Furthermore, Our previous study also found these were the common types that caused bovine mastitis from 2014 to 2015 in Shanghai and Zhejiang areas (Li et al., 2017), implying that among the species, some prevailing clones have arisen and spread throughout China.

In the current study, ST398, ST188, ST88, and ST1 were similarly identified among both MSSA and MRSA strains, which suggested that these MSSA lineages probably provide a stable genetic environment for the integration of SCCmec to facilitate MRSA infection and transmission in both healthcare facilities and communities. Of note, ST398 was originally found to be a MSSA strain in China, and increasing numbers of ST398-MRSA isolates have emerged in many regions. Historically, ST398-MRSA, first referred to as livestock-associated MRSA (LA-MRSA), has been reported among pigs and pig farmers in France and the Netherlands (Graveland et al., 2011; Fluit, 2012). After, it has become the overwhelmingly dominant lineage in Europe and North America. In the current study, we identified nine ST398 isolates (Tables 3, 4) including five MRSA and four MSSA strains. It is very difficult to speculate on the origins of these isolates because of the absence of epidemiological data linking these to animals. However, LA-SA usually harbored an intact beta-toxin gene (hlb) and no lysogenic prophages encoding the immune evasion complex genes (sea, sep, sak, scn, and chp genes) (van Wamel et al., 2006). Among ST398 isolates in our study, they all had an intact hlb gene and didn’t contain sea and sep genes. Three strains lacked all the immune evasion complex genes, and others harbored one, two or three of sak, scn and chp genes. This was important evidence that these strains were of animal origin. Therefore, it is very important to carefully monitor the animal-to-human transmissibility of LA-SA.

The pathogenicity for S. aureus mainly relies on the presence of a variety of virulence factors that mediate adhesion, invasion, persistence, tissue invasion, the evasion/destruction of host defenses, and toxin-related disease (Dinges et al., 2000; Wardenburg et al., 2007; Diep and Otto, 2008). These include microbial surface protein (Josefsson et al., 1998), hemolysin, toxic shock syndrome toxin-1, exfoliative toxins, and SEs. In this study, adhesion genes were present in most S. aureus isolates; 100% carried the icaA and clfA genes, 85.9% harbored sdrC, and 69.2% carried sdrE. The high prevalence of adhesion genes in clinical strains is consistent with the notion that the adherence of S. aureus to host cells is the first vital step for bacterial pathogenicity. The presence of pvl has previously been strongly associated with CA-MRSA infections in many studies (Lina et al., 1999). We found ten MRSA isolates and four MSSA isolates that harbored pvl. The prevalence of pvl in MRSA isolates (37.0%) was significantly higher than that in MSSA isolates (7.8%), supporting the hypothesis that pvl is a possible marker for CA-MRSA. In addition, the distribution of some virulence genes, especially SEs, was reported to be closely associated with specific molecular types (He et al., 2013; Wang et al., 2016). A similar result was observed in the current study. The seb-sek-seq genes were present in all ST59 strains, whereas the seg-sei-sem-sen-seo genes were found to be present in different clones, including ST5, ST20, ST22, ST25, ST26, ST30, ST121, and ST487 strains. In addition, ST5 and ST59 isolates harbored more enterotoxin-encoding genes than ST188 and ST398 strains, implying that different molecular types are associated with different virulence profiles.

The current work has several limitations. Most importantly, the relatively small sample size from a single center limited the representative significance of the research. Second, it is not known whether different genotypes are associated with clinical outcomes because of the absence of clinical information. In addition, as retrospective research, it is possible that patients were misclassified as CA due to incomplete data. However, this study revealed that community-associated S. aureus strains from BSIs in children demonstrated considerable genetic diversity and identified major genotypes of CA-MRSA and CA-MSSA, with a high prevalence of MRSA.

ML and XW designed the studies and obtained funding. XW, QL, HZ, WH, and QF performed the experiments and/or analyzed the data. ML, XW, and XL wrote the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.