|Year : 2016 | Volume
| Issue : 3 | Page : 275-285
The changing face of community-acquired methicillin-resistant Staphylococcus aureus
P Kale, B Dhawan
Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||28-Oct-2015|
|Date of Acceptance||20-Jun-2016|
|Date of Web Publication||12-Aug-2016|
Department of Microbiology, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of infection, both in hospitalised patients with significant healthcare exposure and in patients without healthcare risk factors. Community-acquired methicillin-resistant S. aureus (CA-MRSA) are known for their rapid community transmission and propensity to cause aggressive skin and soft tissue infections and community-acquired pneumonia. The distinction between the healthcare-associated (HA)-MRSA and CA-MRSA is gradually fading owing to the acquisition of multiple virulence factors and genetic elements. The movement of CA-MRSA strains into the nosocomial setting limits the utility of using clinical risk factors alone to designate community or HA status. Identification of unique genetic characteristics and genotyping are valuable tools for MRSA epidemiological studies. Although the optimum pharmacotherapy for CA-MRSA infections has not been determined, many CA-MRSA strains remain broadly susceptible to several non-β-lactam antibacterial agents. This review aimed at illuminating the characteristic features of CA-MRSA, virulence factors, changing clinical settings and molecular epidemiology, insurgence into the hospital settings and therapy with drug resistance.
Keywords: Changing trend, community-acquired methicillin-resistant Staphylococcus aureus, molecular epidemiology, nosocomial
|How to cite this article:|
Kale P, Dhawan B. The changing face of community-acquired methicillin-resistant Staphylococcus aureus. Indian J Med Microbiol 2016;34:275-85
|How to cite this URL:|
Kale P, Dhawan B. The changing face of community-acquired methicillin-resistant Staphylococcus aureus. Indian J Med Microbiol [serial online] 2016 [cited 2020 Feb 20];34:275-85. Available from: http://www.ijmm.org/text.asp?2016/34/3/275/188313
| ~ Introduction|| |
Nosocomial infections caused by Staphylococcus aureus represent a considerable burden on healthcare system; infected patients have prolonged hospital stays, entail high hospital costs and suffer increased in-hospital mortality. With a few exceptions, methicillin-resistant S. aureus (MRSA) has been a problem in hospitalised patients for decades in many parts of the world.  Historically, patients who developed MRSA infections in the community had traditional risk factors associated with treatment in nosocomial settings. , With the recent emergence of MRSA infections in patients lacking contact with a hospital setting or with humans treated in hospitals, the term "community-acquired MRSA (CA-MRSA)" has been introduced. , CA-MRSA was first reported from infections in remote populations in Australia, and in the USA, in late 1990's, cases of fatal infections in children in Minnesota and North Dakota were the focus of attention. ,, Since then, MRSA infections have also been reported from Europe, ,,,,, from the near East and from Asia and Oceania.  Particularly in the USA, CA-MRSA strains are pervasive among S. aureus isolates from skin and soft tissue infections (SSTIs). ,,, Although much less frequent than infections of the skin, CA-MRSA strains also can cause invasive, rapidly progressive, life-threatening infections, such as necrotising pneumonia,  severe sepsis  and necrotising fasciitis.  Of particular concerns are recent reports about the introduction of highly epidemic CA-MRSA strains into hospitals, followed by severe infections in hospitalised patients. ,, Given the changing epidemiology, timely updated information on epidemic S. aureus strains in local and neighbouring countries is essential for the prevention and control of this pathogen. This information is also important for clinicians dealing with staphylococcal diseases. The aim of this article is to comprehensively review the epidemiology, molecular characteristics and management of CA-MRSA in the context of the recent literature.
| ~ Definitions|| |
CA-MRSA was traditionally regarded as MRSA strains causing infection in previously healthy young patients without prior healthcare contact, susceptible to most non-β-lactam antimicrobial agents, and carrying Panton-Valentine leucocidin (PVL) genes and staphylococcal cassette chromosome (SCCmec) types IV or V.  In order to fulfil the current Centers for Disease Control and Prevention (CDC) definition of CA-MRSA, MRSA must be identified in the outpatient setting or <48 h after hospital admission in an individual with no medical history of MRSA infection or colonisation, admission to a healthcare facility, dialysis, surgery or insertion of indwelling devices in the past year. In the CDC definition, the inclusion of an assessment of previous healthcare contact means that MRSA linked to a hospitalisation but presenting in the community or at hospital re-admission are classified correctly as healthcare-associated (HA)-MRSA. 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. A particular challenge to epidemiological definitions is the transmission of CA-MRSA among the injecting drug user/homeless group. Epidemiological definitions are further limited by the emergence of CA-MRSA clones as an increasingly common cause of HA infection. Consequently, as the microbiology and epidemiology of CA-MRSA have evolved, these traditional definitions have broken down, arguing in favour of a genotypic classification of strains. As a result, there is a growing consensus to define MRSA strains by combination of genotyping methods such as multi-locus sequence typing (MLST), spa gene type and/or pulsed-field gel electrophoresis (PFGE) with SCCmec analysis to infer their likely epidemiological origin. ,
| ~ Story of Emergence of Community-Acquired Methicillin-resistant Staphylococcus aureus|| |
Penicillin resistance that surfaced shortly after its discovery, results from a plasmid-encoded penicillin-degrading enzyme (β-lactamase), methicillin resistance is mediated by SCCmec, a mobile genetic element encoding for an altered penicillin binding protein (PBP2a, mecA) with a decreased affinity to β-lactams.  It is claimed that SCCmec was acquired by S. aureus through interspecies horizontal gene transfer from Staphylococcus sciuri, a penicillinase negative zoonotic coloniser. SCCmec is composed of a mecA gene complex encoding the PBP2a determinant that is responsible for the β-lactam resistance of MRSA, and a ccr gene complex encoding recombinase that mediate the integration of SCCmec into and its excision from the recipient chromosome, and so-called three junkyard regions of different sizes. Till date, at least 11 types of SCCmec elements have been identified.  The emergence of HA-MRSA was concurrent with penicillin resistant S. aureus (1960); however, it spread over to the community nearly three decades later (1990). The first genuine cases of CA-MRSA infection were reported among individuals from Kimberley, Western Australia (WA) in the early 1990s.  Notably, these patients were from remote and sparsely populated areas, and thus did not have close contact with individuals who had access to large medical centres. In addition, the MRSA isolates (later known collectively as strain WA-MRSA-1 or WA-1) from the patients were not multi-drug resistant and were distinct from other MRSA strains present in Australia.  Similarly, during 1997-99, four children in the upper Midwestern region of the USA died from sepsis or necrotising pneumonia that was caused by MRSA. Whole-genome sequencing of these strains (MW2) showed a staphylococcal chromosomal cassette mecA (SCCmec), named SCCmec IV, which contains the mecA gene that encodes resistance to methicillin. Unlike SCCmec elements I-III, which encodes molecules that provide resistance to several classes of antibiotics, SCCmec IV encodes resistance only to β-lactam antibiotics, accounting for the non-multi-drug-resistant phenotype of MW2. MW2 also contains genes encoding PVL, a prophage-encoded bicomponent toxin that targets phagocytic leucocytes. SCCmec IV and PVL are molecular markers associated with the emergence of CA-MRSA worldwide; although PVL does not seem to be present in all CA-MRSA strains (WA-MRSA-1 strains typically do not have PVL). ,,
| ~ Molecular Typing of Staphylococcus aureus|| |
An understanding of the molecular typing of S. aureus is a pre-requisite to appreciate the nomenclature for describing the global epidemiology of the disease. Among the primary methods, PFGE and MLST, have been developed for numerous bacterial and fungal species, while spa typing and SCCmec typing for MRSA are specific to staphylococci. 
PFGE is a classic 'fingerprinting' method which compares banding patterns from whole-genome macro-restriction digests, and it is considered the gold standard for outbreak investigations involving closely-related strains. , The technique is highly discriminatory and reproducible and all strains are typeable by this method. The restriction enzymes selection is important as it generates simpler patterns consisting of less number of bands, making interpretation easier. Restriction enzyme Sma I has been used for investigating MRSA strains by PFGE. The PFGE database in the USA, for example, classifies major S. aureus clones as USA100, USA200, USA300 and so on, whereas other international designations include EMRSA (United Kingdom), WA and CMRSA (Canada). ,, PFGE is the most frequently used method for identifying MRSA; however, it remains a technically demanding and effort-intensive procedure with a long turnaround time of 2-4 days, prompting a search for alternatives.  Results of PFGE are difficult to compare across laboratories and over time, so its use in long-term macro-epidemiology studies has been questioned.
MLST is a sequence-based typing method characterised by universal nomenclature, with an unambiguously curated database. The S. aureus MLST scheme is based on 7 'housekeeping' genes (arcC, aroE, glpF, gmk, pta, tpiA, yqiL) dispersed throughout the genome, fragments of which are sequenced and submitted to the S. aureus MLST database for identification (http://saureus.mlst.net).  Known variants of each gene are thereby assigned allelic numbers, which are then concatenated to form unique allelic profiles referred to as 'sequence types (STs)'. Related STs may be visualised readily using the program eBURST (http://eburst.mlst.net), which groups together STs that share at least 5/7 alleles into 'clonal complexes (CCs)' that highlight the underlying population structure of the species. ,,, MLST has also proved beneficial in identifying livestock associated MRSA strains and their transmission between humans and animal species.  The technique is expensive, labour intensive and time consuming due to the involvement of various gene targets. There is a good degree of concordance between MLST, PFGE and spa typing.
Spa typing is another sequence-based technique which targets the sequence polymorphism in the variable region of the spa gene for S. aureus surface protein A (spa). The spa repeats are typically 24 bp in length, with presumptive duplications, deletions and rearrangements contributing to the identification of more than 10,000 unique patterns known as 'spa types'.  Spa typing can be used to conjecture CCs as it is in agreement with MLST, also it is cost effective. As with MLST, spa typing data is unambiguous and portable. , Misclassification of a small number of lineages is a drawback of this method.
SCCmec typing classifies distinct allotypes of the horizontally acquired SCCmec elements present in MRSA strains. Eleven SCCmec types have been described thus far (http://www.SCCmec.org), with traditional HA-MRSA clones characterised by the possession of types I, II and III, while CA-MRSA strains typically feature smaller type IV and V elements. MRSA nomenclature rely on the juxtaposition of MLST (or CC) and SCCmec type (e.g. ST5-II, ST8-IV), with additional resolution provided by other molecular methods such as spa typing. , Its disadvantages being low throughput, high cost, no standard protocol and evolving nomenclature of MRSA strains.
Multi-locus variable-number tandem repeat analysis is being used increasingly. It appears to have higher discriminatory power than spa or PFGE-based analyses, although considerable congruence has been demonstrated between all three methods. Furthermore, it is also a rapid, high-throughput method. 
| ~ Molecular Epidemiology|| |
Majority of the MRSA clones have evolved from five groups of related CCs having a distinct ancestral genotype. Currently, worldwide reports of CA-MRSA are associated with >20 distinct genetic lineages five of which are globally predominant, including ST1-IV (WA-1, USA400), ST8-IV (USA300), ST30-IV (South West Pacific [SWP] clone), ST59-V (Taiwan clone) and ST80-IV (European clone).  ST8-IV and ST30-IV may be considered pandemic, as they have been isolated repeatedly from every continent. ST8-IV is primarily associated with the global spread of USA300. ST30-IV, commonly referred to as the SWP, was previously considered a descendant of the pandemic phage-type 80/81 penicillin resistant S. aureus strain, but appears to have diverged from a common CC30 ancestor along with HA-MRSA strain EMRSA-16. The USA400, ST1-MRSA-Iva (CC1) was the predominant clone till 2001 in USA, superseded by USA300 ST8-MRSA-IVa (CC8). By contrast, ST1-IV primarily associated with native American communities in Alaska and the mid-Western regions of the U.S.(USA400) and Canada (CMRSA-7) is PVL positive and with aboriginal communities in WA-1, which is PVL negative. , It is the leading cause of community associated MRSA, on account of its enhanced virulence characterised by exclusive presence of arginine catabolic mobile element (ACME) and over-expression of α-toxin, phenol-soluble modulins (PSMs) and many proteases in North America and Canada. 
CA-MRSA is generally less prevalent in Europe than it is in the USA  and is characterised by considerable genetic heterogeneity, in contrast to the predominant spread of USA300 in North America. The so called 'European CA-MRSA' clone ST80-IV nevertheless stands out by virtue of having been isolated in nearly every European country sampled to date. It is postulated that the ST80 descended from the African immigrants. , ST 30-IVA (CC30, USA1100) and USA 400 are leading cause of infections in Australia. ST93-IV (Queensland clone), currently the primary CA-MRSA strain in Australia, but rarely isolated elsewhere, ST75-IV, an early-branching lineage considered a potential subspecies of S. aureus, and restricted to remote aboriginal communities in Australia. 
In Africa, CC5 is the predominant CC in the healthcare setting. The hospital-associated MRSA ST239/ST241-III (3A) was identified in nine African countries.  This clone was also described with SCCmec type IV (2B) in Algeria and Nigeria and type V (5C) in Niger. In Africa, the European ST80-IV (2B) clone was limited to Algeria, Egypt and Tunisia. The clonal types ST22-IV (2B), ST36-II (2A) and ST612-V (2B) were only reported in South Africa. No clear distinctions were observed between MRSA responsible for hospital and community infections. The community clones ST8-IV (2B) and ST88-IV (2B) were reported both in the hospital and community settings in Angola, Cameroon, Gabon, Ghana, Madagascar, Nigeria and SγoTomι and Prνncipe. 
Amongst the Asian countries, ST59-IV and ST59-V (USA 1000), is the most common CA-MRSA strains in Taiwan, China and other Asian countries. These clones are also frequented in USA, Europe and. Australia. The former is limited to USA while the later, Taiwan clone is abundant in Asia and Australia. ,,, ST72-IV (USA700), the primary CA-MRSA strain in South Korea;  ST88-IV (or ST88-V), frequently found in Africa and Asia. ,,,
In India, MRSA is a common cause of hospital-acquired infections. Previous molecular typing of nosocomial MRSA strains recovered from our hospital revealed a similar scenario to that documented from several Indian hospitals where the Brazilian and Hungarian epidemic clone (ST239-MRSA-III) was dominant. ,,,
Recently, MRSA isolates from a population of mixed patients with hospital-associated and community-associated infection from Mumbai were investigated and showed that 25% of the isolates were SCCmec III, 34% were SCCmec IV and 41% were SCCmec V. Ninety percent of SCCmec IV and 62% of SCCmec V isolates were PVL-positive. ST22-IV and ST772-V were commonly identified. ST22-IV MRSA strain (CC22) is a variant of the UK epidemic MRSA (EMRSA)-15 strain.  ST772 was first reported in Bangladesh and has also been reported in Malaysia. , ST772-MRSA-V, known as the Bengal Bay Clone, is a multi-resistant PVL-positive CA-MRSA initially isolated in India in 2004/2005. Transmission of Bengal Bay MRSA has subsequently occurred in several countries including England, Ireland, Germany, Norway, Italy, Abu Dhabi, Saudi Arabia, Hong Kong, Malaysia, Australia and New Zealand.  Shambat et al. have reported two MRSA clones, ST1208 (CC8) and ST672 as emerging clones from Bengaluru. 
| ~ Virulence Factors|| |
The CA-MRSA strains are robust than the HA-MRSA strains, causing infections in otherwise healthy people and have the ability to cause unusually severe disease as proven in the animal models. ,, The following virulence factors contribute for the severity, persistence and increased transmission of the disease.
| ~ Panton-Valentine Leucocidin|| |
PVL is a bicomponent toxin encoded by luk S-PV and luk-F PV, located in the genomes of bacteriophages, i.e. ɸSa2958, ɸSa2MW, ɸPVL, ɸ108PVL, ɸSLT and ɸSa2USA and infrequently associated with MSSA, is a major determinant of SSTIs and severe necrotising pneumonia. This toxin is highly associated with CA-MRSA clones in that nearly all USA300, USA400 and USA1100 clinical isolates are positive for PVL as are many USA1000 strains, also epidemiological and clinical reports indicate a strong correlation between PVL production and severe/SSTIs necrotising pneumonia and fasciitis. , Neutrophils are a key component of the inflammatory response and are the most prominent cellular defence against S. aureus infections. PVL exerts its toxic effect on neutrophils. Most CA-MRSA strains have lukSF genes, while their frequency in MSSA is much lower and they are absent from predominant HA-MRSA clones. PVL is lytic to human neutrophils at concentrations between 0.3 and 2 μg/ml.  Concentrations of PVL reaching or exceeding that range was demonstrated in human skin abscesses and in some clinical specimens from different infection types.  PVL is significantly correlated with invasive CA-MRSA disease; however, recent clinical studies demonstrate that CA-MRSA strains lacking PVL can still cause disease outbreaks. An increasing number of CA-MRSA clones are found that do not contain lukSF genes, for example in Korea and the United Kingdom.  A recent study from western Australia concluded that PVL positive infections had a distinct clinical picture, predominantly associated with pyogenic SSTIs often requiring surgery, inexplicably affecting patients who are younger, indigenous or with fewer health-care risk factors. Moreover, the resistance to most antibiotics was increased with the exception of higher susceptibility to clindamycin. 
| ~ Phenol-soluble Modulins|| |
PSMs are a family of amphipathic, α-helical peptide produced by staphylococci having pronounced cytolytic activity against variety of human cells, including neutrophils and erythrocytes. ,, PSMs are produced in high amounts in CA-MRSA strains, whereas production is lower in typical HA-MRSA strains such as USA100 and USA200 strains. This is postulated due to the facts that (i) the accessory gene regulator (agr) virulence regulator exerts an exceptionally strict control over PSM expression and (ii) HA-MRSA strains often show low, while CAMRSA strains commonly have high agr activity.  PSMα peptides, above all PSMα3, mediate quorum sensing-induced neutrophil killing after S. aureus ingestion are responsible for the increased neutrophil killing capacity that distinguishes CA-from HA-MRSA strains. ,,,
| ~ Alpha-toxin|| |
Alpha-toxin is a cytolysin that is produced by most S. aureus strains that lyses macrophages, erythrocytes and others cells but not neutrophils. The cytolytic activity of alpha-toxin is dependent on the interaction with the ADAM10 receptor.  It also leads to neutrophil chemotaxis and has pro-inflammatory effects, including induction of the inflammation and generation of highly pro-inflammatory cytokines such as interleukin (IL)-1 β and IL-18 and penetration of the epithelial barrier during skin infection with USA300. ,,,
| ~ Arginine Catabolic Mobile Element|| |
Of all the genetic elements acquired by CA-MRSA isolates, only the ACME is completely unique to USA300, acquired from S. epidermidis through horizontal gene transfer via a mechanism likely involving the SCCmec-related ccrAB recombinases. ,,, The ACME of USA300 contains a complete arginine deaminase (arc) system that converts L-arginine to L-ornithine for both ATP and ammonia production. The island also encodes a putative oligopeptide permease, a zinc-containing alcohol dehydrogenase, and a spermine/spermidine acetlytransferase (SpeG). , ACME aids primarily in USA300 colonisation, in part, through the Arc mediated ammonification of the acidic skin environment.
| ~ Protein A|| |
The S. aureus specific gene spa encodes protein A, which is expressed on the surface of nearly all S. aureus strains. Protein A contributes to the prevention of opsonisation and subsequent phagocytosis by ineffectually binding the Fc region of IgG. ,,, It also initiates a proinflammatory cascade in the airway by activating tumour necrosis factor receptor 1 and B-cells in concert with other ligands. Protein A was also shown to enhance the activity of alpha-toxin in a murine model of skin infection. MRSA strains with certain spa types have a decreased ability to invade human cells in vitro, suggesting an association with certain spa types and virulence. ,,,, This observation has not been confirmed by experiments using isogenic bacterial mutants with different spa types, and further research is needed to assess the importance of protein A as a virulence factor in CA-MRSA strains.
Induction of the staphylococcal proteolytic cascade by unsaturated fatty acids is another feature that should now be evaluated as a potential contributing factor in the aggressive nature of SSTIs caused by USA300 and as a general virulence mechanism of S. aureus.
| ~ Clinical Spectrum|| |
Though S. aureus is considered as a normal human flora with about one in three people harbouring it in the nostrils, throat, axilla, groin and perirectal area, but CA-MRSA strains can cause infection in the absence of nasal colonisation. , There is regional variation in the colonisation of S. aureus and thereby burden of CA-MRSA. Various reports from world over claim high S. aureus carriage rates, with varying prevalence of CA-MRSA.  Carriers of S. aureus have a higher risk of infection than do non-carriers, and they are an important source of spread of infection. The rapid dissemination of CA-MRSA strains and the high attack rate in outbreak settings suggest that they are more easily transmitted than are other S. aureus strains. ,
CA-MRSA, like all strains of S. aureus, is transmitted by direct contact with the organism, usually by skin-to-skin contact with a colonised or infected individual.  However, fomites contaminated with CA-MRSA might have a role in transmission in some settings. The Centers for Disease Control and Prevention in Atlanta, USA, have proposed five factors or five Cs of MRSA transmissions such as crowding, frequent skin-to-skin contact, compromised skin integrity, contaminated items and surfaces and lack of cleanliness. Thus, the subgroups of population, especially military recruits, children in day care centres are at high risk of infection. ,,,,,
CA-MRSA is mainly associated with SSTIs, especially presenting with abscesses or cellulitis and purulent discharge and the disease spectrum similar to MSSA. , Few strains are associated with severe and invasive disease, claiming their robust virulence causing pyomyositis, myositis, purpura fulminans with or without Waterhouse-Friderichsen's syndrome, necrotising fasciitis, osteomyelitis and pneumonia. ,,,,,
The risk factors for acquisition of CA-MRSA infection and the high risk groups involved are enlisted in [Table 1].
|Table 1: High - risk groups for community - acquired methicillin-resistant Staphylococcus aureus |
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| ~ Detection of Community-Acquired Methicillin-resistant Staphylococcus aureus|| |
CA-MRSA clones can be distinguished from traditional HA-MRSA strains by genotyping by PFGE, spa, MLST or SCCmec and presence of PVL genes. The use of SCCmec IV as a marker for CA-MRSA has substantial limitations, as SCCmec IV elements are also present in a number of HA-MRSA lineages, such as ST5, ST254, ST22 and ST45. Regarding molecular typing characteristics, there are CA-MRSA isolates attributed to clonal lineages for which HA-MRSA isolates have not been reported so far, such as ST59 and ST152; there are, however, also clonal lineages from which both HA-MRSA and CA-MRSA isolates have evolved, such as ST1, ST5, , ST8  and ST22.  Whole genome sequencing has provided insights into the origins of antibiotic-resistant strains, the genetic basis of virulence, the emergence and spread of lineages and the population structure of S. aureus. 
| ~ Spread of Community-Acquired Methicillin-resistant Staphylococcus aureus into Hospitals|| |
CA-MRSA strain types have begun to emerge as a cause of hospital outbreaks. ,,,,,,,,, It has known since 2003 to cause hospital outbreaks in North America, Israel, Germany, Greece, UK and Switzerland.  The healthcare associated outbreaks have been caused by a single cross-infecting strain, although six heterogeneous bloodstream infections in patients in a Houston neonatal Intensive Care Unit (NICU) may have been due to repeated introduction of different local CAMRSA strains.  In a NICU in New York, 93 neonates were infected and 167 were colonised with MRSA. Surveillance cultures were performed for 1336 neonates during outbreak investigations, and 115 (8.6%) neonates had MRSA-positive culture results. , During 2001-2004, HA MRSA clones, carrying SCCmec type II, pre-dominated. From 2005, onward, most MRSA clones were CA-MRSA with SCCmec type IV, and in 2007, USA300 emerged as the principal clone in this region.  A study conducted in 2009 in Argentina among 591 clinical isolates from 66 hospitals in a prospective cross-sectional, multi-center study, revealed a significantly higher MRSA proportion among community onset-than hospital onset S. aureus infections (58% vs. 49%); mainly in children (62% vs. 43%). Most CA-MRSA belonged to two major clones: PFGE-type N-ST30-SCCmecIVc-t019-PVL+ and PFGE-type I-ST5-IV-SCCmecIVa-t311-PVL+ (45% each).  There have been outbreaks in health care workers (HCWs), including their household contacts. ,, Most of the reported healthcare outbreak strains have been caused by PVL-positive CA-MRSA strains, one outbreak in Israel and two in the UK were caused by PVL-negative strains, demonstrating that CA-MRSA do not need PVL to cause nosocomial infections. , USA300 a common community pathogen in the USA has a parallel tendency to cause nosocomial infections, including outbreaks in newborns and post-operative prosthetic joint infections. , Subsequently, USA300 has been reported as causing a significant proportion of HA bacteraemias.  In Greece, PVL-positive CA-MRSA accounted for 45% of HA-MRSA infections at several hospitals during 2001-2003.  In Denmark, the incidence of CA-MRSA isolates increased tenfold from 1999 to 2006 and exceeded that of HA-MRSA isolates in 2006 (2.81 vs. 1.34 per 100,000 inhabitants).  The SWP clone (ST30-IV) is replacing traditional nosocomial strains in one hospital in Uruguay.  In Korea, 24% of HA bacteraemias in 2007 were caused by the pre-dominant ST72-IV CA-MRSA clone.  Although reports from Africa are rare, the European clone (ST80-IV) appears to account for the majority of HA-MRSA in Tunisia and Algeria. ,,
A prospective cohort study of inpatients in Orange County, California, systematically collected clinical MRSA isolates from thirty hospitals, to assess MRSA diversity and distribution.  USA300 (t008/ST8), USA100 (t002/ST5) and a previously reported USA100 variant (t242/ST5) were the dominant clones.  A new strain of CA-MRSA, ST772-MRSA-V, which is widespread in India was recovered from seven colonised neonates in a NICU in a maternity hospital in Ireland during 2010 and 2011, two colonised NICU staff, one of their colonised children, and a NICU environmental site. The isolates exhibited multi-drug resistance, spa type t657 and were assigned to ST772-MRSA-V by DNA microarray profiling. All isolates encoded resistance to macrolides (msr [A] and mpb [BM]) and aminoglycosides (aacA-aphD and aphA3) and harboured the PVL toxin genes (lukF-PV and lukS-PV), enterotoxin genes (sea, sec, sel and egc) and one of the immune evasion complex genes (scn).  Another study from Japan in 2013 analysed microbiological and molecular epidemiological features of CA-MRSA strains at a Japanese tertiary care hospital using polymerase chain reaction based-open reading frame typing (POT). Of 219 isolates (76 clonal groups), 64 (29.3%) were clinical-HA/POT-CA isolates (22 clonal groups). The most frequent genotype of molecular CA-MRSA was multi-locus ST 5-SCCmecIV, previously not detected in Japan.  A Korean study reported that CA-MRSA ST72-SCCmecIV was associated with bloodstream infections (22.4%) along with ST5-SCCmecII and ST239-SCCmecIII. 
In a study from Mumbai, India, a total of 412 MRSA strains isolated from mixed hospital- and community-associated patient population were evaluated.  Of these, 136 were SCCmec IV (34%) and 162 were SCCmec V (41%). The multi-drug susceptibility and absence of patient risk factors in 72% of cases with SCCmec IV and SCCmec V MRSA demonstrated the presence of CA-MRSA in hospitals. The MLST analysis in this study showed the replacement of the multi-drug-resistant ST-239-SCCmec III in hospitals with multi-drug-susceptible ST ST 22 (SCCmec IV) and ST 772 (SCCmec V), both of which feature in other Asian studies.  In a study by Dhawan et al., 200 HA-MRSA strains and 100 CA-MRSA strains were tested based on SCCmec typing.  HA-MRSA isolates were further divided into HA-SCCmec I/II/III MRSA and HA-SCCmec IV/V MRSA, and CA-MRSA isolates into CA-SCCmec I/II/III MRSA and CA-SCCmec IV/V MRSA. Seventy-five (37·5%) HA-MRSA isolates and 83/100 CA-MRSA isolates were SCCmec IV/V genotype. HA-SCCmec IV/V MRSA was associated with malignancy and bone fractures, compared to CA-SCCmec IV/V MRSA. HA-SCCmec IV/V MRSA was associated with PVL gene carriage compared to HA-SCCmec I/II/III MRSA. ST22-MRSA-IV (EMRSA-15), ST772-MRSA-V and ST36-MRSA-IV and ST239:EMRSA-I: III were the major clones identified. This study documents the emergence of SCCmec IV and SCCmec V MRSA clones in an Indian hospital. 
| ~ Implications of Dissemination of Community-Acquired Methicillin-resistant Staphylococcus aureus into Hospitals|| |
The reasons for the emergence of CA-MRSA strains as a cause of HAI are unknown. The community reservoir feeding the spread of CA-MRSA strains in hospitals may extend beyond the human population. MRSA has been reported in substantial numbers from domestic and livestock animals. , The influx of CA-MRSA carried on patients, visitors and HCWs into hospitals present several challenges. This may be attributed to the ability of CA-MRSA to cause infections in previously healthy individuals in the absence of the selective pressure of antimicrobial agents. An increased prevalence of PVL-producing CA-MRSA strains in hospitals may increase the virulence of nosocomial MRSA infections. Although PVL has a strong epidemiological association with CA-MRSA, strains not carrying PVL can cause outbreaks in healthcare settings.
Benoit et al. reported that healthcare onset infections caused by CA-MRSA strains were more likely to cause non-skin diseases and to occur in older patients than community onset infections caused by CA-MRSA strains.  The exposure of CA-MRSA to nosocomial antibiotic pressure will encourage the emergence of multiple resistance. Just as CA-MRSA strains in healthcare environments behave more like HA-MRSA clinically, they may also come to resemble HA-MRSA strains in terms of their multi-drug-resistant antimicrobial phenotype.  In the era of CA-MRSA strains as a cause of nosocomial infections, future terminology should define true CA-MRSA based on these distinct microbiological and molecular features. The control methods currently in place in hospitals for the control of HA-MRSA have not been able to prevent the emergence of CA-MRSA strains. Thus, there is an urgent need to clarify the prevalence and epidemiology of CA-MRSA and to develop systems for the identification and control of these organisms in the community, in hospitals and other healthcare facilities, and at the community hospital interface.
| ~ Therapeutic Options for Community-Acquired Methicillin-resistant Staphylococcus aureus|| |
CA-MRSA strains remain broadly susceptible to several non-β-lactam antibacterial agents. Empirical antibacterial therapy should include an MRSA-active agent, particularly in areas where CA-MRSA is endemic. Only antibiotic therapy may not suffice as abscesses need surgical incision and drainage. For SSTIs, oral antibiotics such as doxycycline, minocycline, clindamycin, trimethoprim-sulfamethoxazole, rifampicin and fusidic acid have been used with satisfactory outcome.  Clindamycin has the added advantage of activity against Group A Streptococcus. , Fusidic acid is used in combination with rifampicin for long-term treatment of skin, soft tissue or osteoarticular infections due to MRSA. , Monotherapy with either drug is not advised as may lead to resistance. Rifampicin is the first line antitubercular agent so not applicable for anti-MRSA treatment. For complicated and resistant cases second line agents such as vancomycin, linezolid and their newer counterparts, dalbavancin, oritavancin and tedizolid have been approved. ,,,,,, Glycopeptide antibiotics, such as vancomycin though highly effective; however pose the threat of resistance, requires therapeutic drug monitoring that compromise its clinical efficacy. Dalbavancin is a long-acting intravenous semisynthetic lipoglycopeptide antibiotic with bactericidal activity against S. aureus, including MRSA and MSSA and vancomycin-intermediate S. aureus, with once a week dosing schedule. , Oritavancin is approved for use in adults with skin and soft tissue caused by susceptible S. aureus (including MRSA and MSSA).  Tedizolid phosphate is a second-generation oxazolidinone antibiotic that offers enhanced antimicrobial potency and low rates of bacterial resistance and effective against susceptible isolates of S. aureus (including MRSA and MSSA).  Newer cephalosporins namely ceftaroline and ceftobiprole are also active against CA-MRSA and needed to be given parenterally, hence restricted to complicated and disseminated infections. Daptomycin is a cyclic lipopeptide in clinical use and approved for the treatment of complicated skin and skin structure infections and right-sided endocarditis.  Tigecycline has potent in vitro activity against a wide range of Gram-positive and Gram-negative bacteria, including MRSA and methicillin-resistant Staphylococcus epidermidis. Tigecycline is FDA-approved for the treatment of SSTI and also for the treatment of complicated intra-abdominal infections. , Iclaprim is active against Gram-positive bacteria, including Enterococcus spp. and MRSA, VISA, VRSA and macrolide-resistant, quinolone-resistant and trimethoprim-resistant strains. In addition, iclaprim and quinupristin-dalfopristin have demonstrated activity against MRSA. ,
| ~ Community-Acquired Methicillin-resistant Staphylococcus aureus and Antimicrobial Resistance|| |
Antibiotic susceptibility patterns and molecular typing have been thought to distinguish CA-MRSA from HA-MRSA. CA-MRSA isolates have typically been susceptible to most non-β-lactam antimicrobial drugs. Although CA-MRSA isolates often remain more susceptible overall to erythromycin, clindamycin and fluoroquinolones, in contrast to HA-MRSA isolates that still have a narrow spectrum of resistance.  Isolates such as CA-MRSA ST80 are resistant to oxy tetracycline and to fusidic acid, USA300 are resistant to macrolides and fluoroquinolones.  Low-level mupirocin resistance with MICs of 8-256 μg/ml is usually associated with point mutations in the chromosomally encoded ileS gene; whereas, high-level resistance is generally due to a plasmid-mediated gene, mupA. A recent study in India have demonstrated low-level mupirocin resistance in 16.67% and high-level mupirocin resistance with MICs ≥512 μg/ml in 36.11% of the MRSA isolates. Nicholson et al. from West Indies observed the higher prevalence of low- and high-level resistance to mupirocin to the tune of 30 and 24%, respectively.  Overall mupirocin resistance reported from all over the world in different frequency as Spain 11.3%, USA 13.2%, Trinidad Tobago 26.1%, China 6.6%, India 6%, Turkey 45% and Korea 5%.  Most of these studies have not given the distinction between CA-MRSA and HA-MRSA.
A recent study summarises the mupirocin resistance reported across India by Jayakumar et al. (2013) (2.17%), Rajkumari et al. (2014) (0%), Chaturvedi et al. (2014) (9.8%) and Rudresh et al. (4.5%).  Abimanyu et al. from South India showed 32% MRSA ST239 were associated with mupirocin resistance.  Chaturvedi et al. reported higher mupirocin resistance, 18.3% in MRSA. 
The studies in the West claim higher resistance for non-β-lactam antibiotics ranging from erythromycin (96%), levofloxacin (85%), clindamycin (57%) to tetracycline (30%) in Boston.  Similarly, in a study of CA-MRSA SSTIs among MSM patients in New York, 63% were resistant to clindamycin and 91% were resistant to ciprofloxacin. 
According to Indian network for surveillance of antimicrobial resistance report, 79.3%, 70.8%, 58.3%, 55.6% and 46.6% MRSA isolates showed resistance to ciprofloxacin, erythromycin, gentamicin, cotrimoxazole and clindamycin, respectively.  Thind et al. found only 12.5% isolates to be resistant to tetracycline and 37% isolates to be resistant to cotrimoxazole,  Anupurba et al. reported a higher resistance of 84.1%, 47.5%, 89.7% and 60.5% against ciprofloxacin, netilmicin, gentamicin and amikacin, respectively.  A recent study had reported linezolid resistance in 9% MRSA isolates.  Though these studies showcase overall MRSA resistance pattern, the same reflects over to CA-MRSA owing to its high prevalence.
| ~ Conclusion|| |
To conclude, the extensive dissemination of CA-MRSA clones in both the community and hospitals, coupled with their ability to carry virulence genes as well as express resistance to multiple antimicrobial agents poses a significant challenge to therapeutic management and infection control. Thus, CA-MRSA is a major public health problem and the paradigm shift in the behaviour of the organism from community to the hospitals is a new threat and therapeutic challenge.
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Conflicts of interest
There are no conflicts of interest.
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