CA-MRSA: Virulence of CA-MRSA

CA-MRSA: Virulence of CA-MRSA

CA-MRSA: Virulence is refers to the degree or intensity of pathogenicity. Where as pathogenicity is an organism capability or potential to cause disease (Willey et al., 2008). Then resistant is the inability of an organism to be killed or inhibited by clinically achievable drug concentration. Methicillin is a beta-lectamase-resistant member of the beta-lactam family of antibiotics that inhibit cell wall biosynthesis. Then methicillin –resistant is resistance to methicillin-type of antibiotics.

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Staphylococcus aureus is a Gram positive cocci bacterium. When sir Alexander Ogston discovered Staphylococcus aureus in 1880, it was one of the first bacteria pathogens to be identified (Smith G.1982). Ever since, S.aureus has remained a serious threat to human health, and S.aureus infections cause a severe financial burden for public health system (Lowy FD. 2003).

The emergency of a community –pathogen depends on its ability to survive in different environments and to interact successfully with the host. S.aureus is one of the most successful and adaptable human pathogens. The remarkable ability of the bacteria to acquire antibiotic resistance mechanisms and advantageous pathogenic determinants has contributed to its emergence in both nosocomial and community settings. However, because of difference exist selective pressures; several notable differences exist between nosocomial isolates and community –associated strain.

Methicillin resistance first appeared among nosocomial isolates of S.aureus in 1961. (Jevons Mp.1961). Since that time methicillin-resistance S.aureus (MRSA) has become widespread. In hospitals and intensive care wilts around the world. MRSA is one of the most common cause of bacterial nosocomial infections, accounting for 40- 70% of the S.aureus infections in intensive care units (Sahm et al., 1999; Diekema DJ 2001). In the past, acquisition of MRSA colonization or infection was generally considered to be restricted to the nosocomial setting. However, in the past decade new strains of MRSA have emerged in the community, causing aggressive infections in young, otherwise health people (Herold et al; 1998; MMWR 2003; Francis et al; 2005). Suppurative skin infections (including epidemics of furunculosis and severe necrotizing pneumonias are the most well known clinical syndromes cause by these new strain. The increasing prevalence of community –associated MRSA in multiple countries and the substantial morbidity and mortality associated with these infections suggest that community –associated MRSA will continue to develop into a challenging public –health problem.     What makes these new isolates of community –associated MRSA    particularly well equipped to succeed as community based pathogens is to be considered in the subsequent chapters.

Antibiotic Resistance and Virulence Of Staphylococcus Aureus

S. aureus is hospital associated (HA) infections (Klevens et al, 2007; Lowy F.D. 1998). It also causes diseases in the community, such as abscesses, endocarditis, toxic shock syndrome, sepsis and pneumonia, some of which may be severe and life threatening. In the United States, about half a million people acquire a staphylococcal infection annually and the costs related to S. aureus health care-associated infections alone exceed 14 billion dollars per year (Klein et al, 2009; Noskin et al, 2007). This abundance of S. aureus infections is due mostly to the pathogenis pronounced capacity to acquire and express antibiotic resistance (Lowy FD. 2003). In the 1940s, S. aureus fast developed resistance to the first known antibiotic, penicillin, by acquiring the gene for penicillinase (Barbar M. and Rozwaidowska – Dowezeiko M. 1948; Kirby WM. 1944) after penicillinase resistance Methicillin was introduced into use, resistant strains were found only about one year later (Barbaer M. 1961; Jevons et al, 1963). These first MRSA (Methicillin-resistant S. aureus) strains spread substainably on a global level in the next decades, leading to several epidemic outbreaks (Enright et al., 2002), including the first MRSA outbreak in the United States in the late 1960s (Barrett et al., 1968).

In the meantime, S. aureus has acquired resistance to virtually all antibiotics (Lowy FD. 2003). Additionally, multidrug-resistance to methicillin and several other antibiotics are relatively frequent in the hospital setting. Several novel antibiotics are in the drug development pipeline and there are working alternative to methicillin such as Linzolid and daptomycin (Anstead et al., 2000). However, resistance mechanisms to these antibiotics already have been discovered (Pantosti et al., 2007). Overall, the situation of antibiotic resistance in S. aureus is alarming.

What makes S. aureus a dangerous pathogen is the contribution of antibiotic resistance and high virulence. The virulence potential of S. aureus is defined by a series of virulence determinants that are often redundant in their function. For example, S. aureus has multiple surface-located binding proteins to facilitate adhesion to host tissue and many mechanisms to evade attacks by human host defenses (Foster T.J. 2005; Foster T.J. and Hook M. 1998). The composition of virulence determinants may vary significantly from strain to strain, which is mainly a consequence of acquisition and loss of virulence determinants that are encoded on mobile genetic elements (MGEs) (Novick et al., 2002). This redundancy and variation pose a severe problem for target-Oriented drug development aimed to interface with S. aureus virulence (Alkene LE. 2000). Transfer of antibiotic resistance and virulence genes visually occurs separately (Novick et al., 2001). However, a toxin gene was discovered that hitchlikes on an MGE primarily in charge of transferring resistance to methicillin (Queek et al., 2009), a combination that may allow an even faster exchange of both of these major determinants of S. aureus pathogenicity.

The relative ease with which S. aureus exchanges genetic material encoding antibiotic resistance and virulence determinants within the species, but also with other sources, such as staphillococcus epidemitis (Otto M. 2009), suggests that the rise of a hypervirulent, multidrug-resistant superbug was only a matter of time. Until recently, MRSA strains were found to mainly infect predisposed patients in the hospital setting and had not achieved a virulence potential high enough to cause disease in otherwise healthy individuals. The recent occurrence of community-associated (CA-) MRSA infections and their fast epidemic spread shows that some MRSA strains have now overcome this limitation, representing an even more severe danger for public health. The CA-MRSA epidemic led to an overall increase of MRSA infections in the United states (Kaplan et al, 2005; Kleven et al, 2007), and the aimed death rate due to MRSA in the United State was estimated the highest among all those caused by an infections agent, higher for example than the annual death rate due to HIV/AIDs (Klevens et al., 2007).

Genetic Basis of Methicilin Resistance

Resistance to penicillin is now wide-spread in S. aureus and may be conferred by the production of a beta-lactamese coded by the bla Z gene. Methicillin resistance results from the production of an altered penicillin binding protein known as PBP2a, which has decreased affinity for most beta-lactam antibiotics (Chambers HF. 1997; Kateyama antibiotics Sabath L.D. 1982; Asheshov E.H. 1968)

PBP2a is encoded by the gene mec A, which is carried on a mobile genetic element known as the staphylococcal cassette chromosome (SCC) mec. (Chamber H.F. 2003; Ito et al, 2001). Besides the mec A gene itself, the SCCmec element contains regulatory genes, an insertion sequence element (IS431 mec), and a unique cassette of recombinese genes (ccr) responsible for the integration and excision of sccmec (Ito et al., 2001). Based on the class of mec A gene complex and the type of ccr gene complex, at least five types of Sccmec elements have been identified and are numbered I to v (Ito et al, 2003; Ito et al., 2004). A second Scc mec typing system has also been described (Oliveira DC. 2002) that uses a multiplex PCR assey to accurately identify types i-iv. This assey identifies SCC mec types based on loci located up-stream and down stream of the Mec A gene and does not take into account the specific ccr gene complex.

Type 1 Sccmec contains the mec A gene as the sole resistance determinant, where as sccmec types II and III contain multiple determinates for resistance to non-beta-lactam antibiotics and are responsible for the multidrug resistance commonly found in nosocomial MRSA isolates. However, most probably due to their larger size, the horizontal transfer of. Sccmec types II and III occurs with less ease compared with types IV (I to et al., 2003; Feg et al., 2003; Oliveira et al., 2002; Charlebois et al., 2004) and spread of MRSA strains harboring these elements mainly occurs as a result of the selective pressure of antibiotic exposure over time (Vertical spread). (Ito et al., 2003).

Several subtypes of types IV sccmec are now recognized based on the polymorophism of the region upstream of the ccr genes, a location know as L-C (Ito et al., 2003; Ma et al., 2002; Hiramatsm et al., 2002).

Strains of community- associated NRSE that have emerged over the past decade have mostly harboured the sccmec type IV element (Ito et al., 2004; Ma et al., 2002;   Feg et al., 2003) to multiple antibiotics with nonbeta-lactam susceptibility patterns resembling those of methicillin- susceptible S. aureus (MSSA) strains prevalent in the community. Therefore, most authorities feel that it is the acquisition of the sccmec IV element by MSSA strains in the community that has given rie to the emerging, community- associated MRSA strains (Hiramatsu et al., 2002; Payne et al., 1966).

Virulence of CA-MRSA

While epidemiology and comparative genomic analysis led to the preliminary identification of determinants with putative roles in CA-MRSA virulence, most notably PVL (Panton- Valentine Leukocidin), it was not until recently that experimental validation of those roles was initiated. The best evidence for a virulence factor’s role in pathogenesis is provided by the analysis of isogenic gene deletion mutants in animal infection models. Models of sin and soft tissue infection, by for the most fragment types of disease caused by CA-MRSA, and pnermous, one of the most important serious complication, were performed predominantly as shown in the table below.

Table 1: Animal models used to evaluate the contribution of virulence determinants to CA-MRSA virulence

Investigated factor and effect observed
Species  Model  CA-MRSA Strain PVL Aplha-toxin PSMS ACME Reference
Mouse Pneumonia USA 300 + (Bubeck et al., 2007)
USA 400 (Bubeck et al., 2007)
USA 300 (Bubeck et al., 2008)
USA + (Brown et al., 2008)
Skin infection USA 300 (Voyich et al., 2006)
USA 400 (Voyich et al., 2006)
USA 300 (Bubeck et al., 2008)
USA 300 + (Brown et al., 2008)
USA 300 + (Wang et al., 2007)
  Bacteremia USA 300 (Voyich et al., 2006)
  USA 400 (Voyich et al., 2006)
  USA 400 + (Wang et al., 2007)
Rat Pneumonia USA 300 (Montgomery et al., 2009)
USA 300 (Montgomery et al., 2009)
Skin infection USA 300 (Montgomery cp. 2009)
Monkey Pneumonia USA 300 (Olsen et al., 2010)
Rabbit Pneumonia USA 300 + (Diep et al., 2010)
Bacterenia USA + (Diep et al., 2008)
USA 300 + (Diep et al., 2008)
Osteomyelities USA 300 + (Cremieux et al., 2009)

 

Abbreviations

ACME- Arginine catabolic mobile element

CA-MRSA- Community- Associated Methicillin- Resistance Staphylococcus

Aureus

PVL- Panton-Valentine leukocidin

PSM-Pherol- Soluble  Modulin

Although initially focused on mice, experimental investigation of CA-MRSA Virulence has now been expanded to rats, rabbits and non human privates. Owing to the recently confirmed relative insensitivity of neutrophils to          PVL in all those test animals (with the exception of rabbits) (Hongo et al., 2009; Loffler et al., 2010), rabbits are now increasing used to specifically address the role of PVL.

Nevertheless, the hypersensitivity of rabbits to other toxins such as alpha-toxin( Cassidy P, Harshman S. 1976) cells for the continued use of  other animals to achieve an integrated and balanced view of the relative contribution of virulence factor to CA-MRSA pathogenesis.

The success of an S. aureus infection depends mostly on efficient evasion of attacks by human host defenses, for which S. aureus has developed many different strategies (foster TJ. 2005; Rooijakkers et al., (2005) the most crucial is likely the production of toxins that kill human leukocytes szmigielski et al., (1999). Neutrophils represented the main leukocyte types responsible for the elimination of bacterial pathogens. Thus, in vitro analyses of CA-MRSA virulence determinants are mainly analysis of toxin-neutrophil interaction using S. aureus culture filtrates, cells or purified toxins. An important earlier finding was that CA-MRSA strains have significantly increased capacity to destroy neutrophile after uptake a likely major reason for the increased virulence of CA-MRSA (voyich et al., 2005). Therefore, leukocytic toxins, collectively called leukocidins, have been the focus of attempts to explain the exceptional virulence potential of CA-MSRA. Most work has been performed on PVL, owing to the initially strong epidemiological correlation with CA-MRSA infections (Vandenesch et al., 2003). Furthermore, alpha-toxin and phenol-soluble modulins (PSMS) were identified more recently as key factors determining CA-MRSA virulence (Bubeck et al., 2007; Wang et al., 2007). Although the controversial disease often led to the misinterpretation that CA-MRSA virulence was to be explained either by PVL or alpha –toxin and PSMS, all these toxins may play an important role in CA-MRSA pathogenesis.

Panton-Valentine Leukocidin (PVL)

PVL is a bicomponent toxin of the staphylococcal beta-barrel pore- forming toxin family, which also comprise alpha-toxin, gamma toxin, and similar toxin. It is encoded by the LUKS-PV genes, which are located on a prophage. Similarly to other leukocidins, PVL forms pores in the membranes of leukocytes, ultimately leading to their lysis  (Kaneko J. and Kamio Y. 2004; Kaneko et al., 1998; Panton PN and Valentine FCO. 1932).

Panton and Valentine noted a correlation between PVL production and the formation of abscesses, an observation that was confirmed more recently (Cribier et al., 1992), including for PVL – positive CA-MRSA( Lina et al., 1999). In addition, a correlation with severe necrotizing pneumonia was noted (Gillet et al., 2002). Until recently, the lukSF-PV genes were detected in the overwhelming majority of CA-MRSA STs ( Vandenesch et al., 2003). Thus, epidemiological data suggested that PVL may be a main factor defining CA-MRSA virulence and driving the CA-MRSA epidemic. However, experimental data as was discussed by some authors, did not substantiate a role for PVL in CA-MRSA pathogenesis, which initiated a more detailed and wide – ranging investigation of CA-MRSA virulence in recent years.

Alpha-Toxin

Alpha-toxin is a pore-forming toxin and a well – established major virulence determinant of S. aureus  (Bhakdis S and Tranum – Jensen J. 1991). It is produced by many S. aureus strains. Although not lytic to human neutrophils (Valeva et al., 1997), it lyses other immune cells such as macrophages, erythrocytes, and lymphocytes; promotes influx of neutrophils to infected lungs and neutrophils to endothelial cells, and has a multitude of other proinflammatory effects (Bartlett et al., 2008; Bhakdi S. 1991; Krull et al., 1996; Laang X. 2006).

Alpha toxin’s contribution to CA-MRSA virulence has so far been investigated only in experiential murine prunmonia. In that model, alpha-toxin had a significant impact on the outcome of disease caused by USA 300 and USA 400 strains (Bubeck et al., 2007), underlining the notion that it is a critical virulence determinant of CA-MRSA infection.

Phenol-Soluble Modulins (PSM)

PSMS are a class of surfactant like amphipathic, alpha- helical peptides, members of which are produced by several staphylococcal species (Donvito et al., 1997; Mcllin et al., 1999; Wang et al., 2007). PSMS of the alpha are about 20-25 amino acids in length and often have significant catalytic activity (Wang et al., 2007). Most alpha-type PSMS encoded in the PSM x operon of S. aueus (PSMx1, PSMx2, PSMx3); especially PMSx1 showed strong lysis of human neutrophils also lysed erythrocytes and monocyctes (Wang et al., 2007). Alpha-type PSMs also include delta-toxin, which has moderate leukolytic activity (Wang et al., 2007). Beta-type PSMs are longer (-45 aminoacids) and lack cytolytic activity (Wang et al., 2007). All PSMS have proinflammatory effects that include activation and induction of chemotaxis and cytokine release in human neutrophils (Wang et al., 2007) effects that mediated by specific receptor (Kretschmer et al., 2010).

Prevalence of CA-MRSA

The first case of MRSA infections that were not associated with hospitals occurred in Australia in the early 1990s (O Brien et al., 2004; Udo et al., 1993) and afterward in Chicago (Herold et al., 19998). In the late 1990s, the centers for disease control and prevention documented deaths in children to CA-MRSA infection in North Dakota and Minnesota ( CDC. 1999). Ever since, CA-MRSA infection have been reported from all over the world and reached pandemic character. Many and detected worldwide (CDC. 1999;Chheng et al., 2009; Collins et al., 2010; Coomb et al., 2008; Huang et al., 2008) and cover a wide spectrum of S. aureus gentic diversity (Diep BA and Oho M. 2008). The first CA-MRSA strains were of STI (USA 400); a characteristic representative of this lineage is the so-called Midwest clone (NW2) which caused the pediatric deaths in the Midwest of the United States (CDC. 1999).

CA-MRSA clone of the USA 400 lineage have been predominant in Canada and  Aleska  (David  et al., 2008; Mulvey et al., 2005), while in the lower united state they are now almost entirely replaced by USA300 (STS) strains( Moran et al., 2009; Gillet et al.,, 2002). USA 300 strains show high genetic coherence with only few single nucleotide polymorphins distinguishing different isolates (Kennedy et al., 2008). Among all global outbreaks of CA-MRSA, the out break caused by USA300 in the United State is by for the most severe in terms of both frequency and severity of infection (Francis et al., 2002; Miller et al., 2005; Moran et al., 2006). In a astounding short period of time, USA300 has become the most frequent cause of skin infections in patients reporting to emergency rooms in the united state, causing 97% of MRSA and 58% of total skin infection reported (Moran et al., 2006). Remarkably USA300 is now also found to cause disease in hospital on an increasing level (Patel et al., 2008; Poporich et al., 2008).

In other parts of the world, CA-MRSA infections have not reached the scale as in the united state. In Europe, most CA-MRSA cases are caused by ST80. In Asia and Australia, CA-MRSA colonies are diverse. In Taiwan, vetnam, and China, ST59 dorminates. (Haung et al., 2008 ; Tang et at., 2007), while ST78 is prevalent in Korea (Kim et al., 2007; Lee et al., 2010) and ST30 in the south Pacific, Australia and Eaern Russia (Baranich et al., 2009; Coombs et al., 2004; Hsu et al., 2006). In cambodia, ST121 and ST 834 were found (Chheng et al., 2009). Although some CA-MRSA types other than USA 300 may severe invasive infection (Lee et al., 2010), many may be less virulent or transmissible than US300. However, it has not been proved experientially.  The first cases of USA300 have been detected in Europe (Ruppitsch et al., 2007; Witte et al., 2007) and Asia (Shibuya et al., 2008) and a variant of USA300 is spreading in South America (Reyes et al., 2009). Because of different definition of community-associated infections used in the literature, and the limited number of population-based studies that include molecular typing techniques, the reported prevalence of MRSA in the community varies widely. However, regardless of the definition, prevalence of MRSA in the community seems to be increasing. In a meta- analysis, Salgado and colleagues (Salgado et al., 2003) summarized many, studies reporting the prevalence of community –onset MRSA both with and without health- care associated risk factors in the community the authors divided the repots into two group: studies of the prevalence of community- onset MRSA infection among hospitalised patients, and studies of the prevalence of MRSA colonization in the community.

In the second group, that is the studies of prevalence of MRSA colorization in the community, ten studies reporting the prevalence of MRSA in the community with surveillance cultures were analyzed. The pooled data (8350 patients) showed a prevalence of 1.3 % for MRSA colorization (2.1% after stratification based on methodological difference). (Salgado et al., 2003). Again, most people coonised with MRSA had health- care associated risk factors. After excluding those patients, the prevalence of MRSA colorization was only 0.2%. Leman and colleague have found a similar prevalence in selected population (Leman et al., 2004). Patients with intravenous drug abuse or HIV infection have a higher prevalence of MRSA infection and colorization (Chung et al., 2004; Charlebois et al., 2002; Fleisch et al., Daly et al., 2002). Thus, further global dissemination of USA300 may only be a matter of time.

Disease Associated with Ca-Mrsa Its Transmissibility and Fitness

By far, most ca-MRSA infection presents as skin and soft tissue infection. However, CA-MRSA may cause many types of infections ranging from mild skin infections to serve abscesses, sepsis, and necrotizing pneumonia (Fridkin et al., 2005; Kapten et al., 2005; Liu et al., 2008). The more severe manifestation of disease may be fatal, such as pneumonia, which occurs 1-2% of CA-MRSA infection. Notably, CA-MRSA infection were implicated in severe fatal diseases that are only rarely reported for s. auerus, such as the water house- friderichsen syndrome in children and necrotizing fasciitis (Adem et al., 2005; Miller et al., 2005). This epidemiology indicates a virulence potential of CA-MRSA that exceeds that of traditional hospital-associated strains.

CA-MRSA outbreaks occur in many divergent groups, including high school. College, and professional athletes (Barrett et al., 1968; Kazakova et al., 2005); religious group (Coronado et al., 2007); men who have sex with men (Diep et al., 2008); prison inmates (CDC. 2003); and soliders  (Campbell et al., 2004; Elis et al., 2009). The combination of close body contact and low personal hygiene is likely what caused outbreak of CA-MRSA among these groups, illustrating that just about everyone can acquire a CA-MRSA infection when exposed to such conditions. At least, this appears to be rue for moderate skin and soft tissue infection as indicated by the outbreak among professional football player in which virtually all players around the first infected individual were diagnosed with skin infection, (Kazakova et al., 2005). On the other hand, host factors may play a significant role in determining the development of CA-MRSA disease, a hypothesis that remains to be investigated.

Management of CA-MRSA Infection Antibiotic Selection

The emergence of MRSA in the community heralds a need for new approaches to the management of both suspected and the confirmed staphylococcal infections particularly regarding the selection of empirical antibiotic regimes can be guided by the prevalence of MRSA in a given community, the presence or absence of health-care associated risk factors, and the severity and types of clinical presentation.

Vancomycin should be considered as empirical therapy for people with severe and life-threatening infections while cultures are pending in area where community, associated MRSA has been documented. Empirical therapy with vanconycin should also be considered for serious infection in patients with a history of MRSA colonization, intravenous drug use, and health- care associated risk factors.

In geographic locations with low prevalence of community-associated MRSA, individuals with less severe infection and people without health associated risk factors may be treated with a penicillinase-resistant penicillin (e. g, oxacillin or nafcillin) or a first generation cephalosporin (e. g, cefazolin ) while cultures are priding.

Community- acquired MRSA isolates form people without health care-associated risk factors are usually susceptible to a variety of non-beta lactam antibiotics, (Naimi et al., 2003). Chindamycin,  co-trmoxazole, linezolid and minocyline should be given serious consideration as alternative treatments for skin and soft tissue infections and for skin and soft tissue infection and for selected patients with necrotizing pneumonias. Daptomycin also has activity against S.aureus strains.

However, it was found inferior to comparators in a large unpublished community- associated pneumonia trial presumably of poor penetration into alveolar secretions (Anon .2004). There are contraindications for the use of co-trimoxazole in children less than 8 weeks old and tetracyclines in children under 8 years of age, thus these agents should be avoided in pediatric community-associated MRSA infection in the respective age group.

Given that community- onset MRSA from patients with health-care –associated risk factors have higher rates of resistance, (Naimi et al., 2003), clinicians may consider avoiding clindamycin, co-trimoxazole, and tetracyclines until the results of susceptibility testing are available clinicians should be aware that inducible resistance to clindemycin may not be apparent from the results of routine susceptibility testing (    Rao, 2009; Siberry et al., 2003; Drinkoric et al., 2001).

Siberry and colleagues (Siberry et al., 2003) demonstrated inducible resistance to clindamycin that could be clinically important in 56% of isolated that were resistant to erythromycin but susceptible to clindamycin on the basis of initial testing. Isolates with this resistance phenotypes should be testes to exclude inducible clindamycin resistance before this antibiotic is used for pathogen-directed therapy. Rafampicin is another option when isolates prove to be susceptible, but it should not be used alone due to the rapid selection of resistant organism.

The emergence of MRSA infections in the community place renewed emphasis on the importance of non-antibiotic management of non localized infections. Although sometimes neglected, appropriate drainage is the definitive management of many skin and soft tissue infections and is always an important adjunct to antibiotic therapy in deeper, closed space infections. Cutaneous abscesses typically resolve with proper drainage and debridement alone, and collections left without drainage in the sitting of antibiotic treatment promote the emergence of resistance, (Lee et al., 2004).

Because of the therapeutic implications every effort should be made to obtain appropriate clinical specimens for culture and susceptibility testing, particularly in area with high MRSA prevalence and in people with health- care associated risk factors, severe infection, or treatment failure. For people with mild or chronic infection, withholding antibiotics until adequate, specimens are obtained and drainage is performed will further improve the culture yield.

Renewed emphasis on the prevention of MRSA infection is also necessary, control of MRSA in the health- care setting remains on important means of limiting its spread in the community. High-risk populations (e. g, people with history of lorry-term care facilities, patients on dialysis or residing in intensive care unit) can be considered for nasal surveillance culture for MRSA on admission (Farrington  et  al; 1998; Taccnelli et al; 2003). Patient with recognized MRSA colorization or infections should be isolated and contact pretention implemented.

The eradication of MRSA colorization is controversial. Topical mupirocin applied to the nares or systemic cotrimoxazole have been used with different rates of success (Laypland, 2003; Taccnelli et al; 2003). Because of the rapid development of resistance that occurs almost invariably with time, treatment of MRSA colorization is currently not recommended for most population, (Drinkoric et al., 2001). However, given the high morbidity and mortality carrying the PVL genes, screening and declorrisation with mupirocin of selected people (e.g, individuals with recurrent skin abscesses despite antimicrobial treatment)  and heir contacts (if nasal cultures are positive may be appropriate).

Development of CA-MRSA Vaccines and Therapeutic Antibodies

Attempts to find a working vaccine for S. aureus infections have recently been reinforced, prompted mainly by widespread antibiotic resistance. (Schaffer and Lee, 2009). Such attempts failed several times in clinical trials, possibly because S. aureus and especially CA-MRSA have exceptional ability to lyses neutrophils after uptake (Voyich et al., 2005), widening the efficacy of vaccines that promote opsonophagolosis  (Deleo and otto, 2008). The usefulness of a PVL vaccine is controversial, as is PVL’S role in pathogenesis (Brown et al., 2008; Bubeck Wardburg and Schneewind, 2008). Bubeck Wardenburg et al., reported that a vaccine based on a non-toxic derative of alpha- toxin was protective in a CA-MRSA marine pneumonia model, but use of PVL as an antigen in the same model did not provide protection from disease. (Bubeck Wardenburg, J, Schneewind O. 2008). Protection studies using a PVL vaccine in rabbits have not yet been performed.

Passive immunization with antibodies to sequester main virulence determinants of S. aureus may present a valuable alternative to active immunization. (Otto M. 2008). However, functional redundancy of S. aureus virulence determinant – as seen have regarding the multiple toxins affecting CA-MRSA virulence- would require a combination drug consisting of antibodies against a series of such determinants.

As the number of antibody components is limited for reasons of efficacy, it is vital to determine which determinants have the strongest impact on virulence. Monoclonal alpha-toxin antibodies proved protective in CA-MRSA hung infection. (Ragle BF and Bubeck Wardenburg J. 2009). PSM antibodies have not been developed or tested. Antibodies against alpha-toxin and PSM, IF proven efficacious, would have broader applicability then those directed toward PVL, owing to the fact that PVL production is limited to a small percentage of S. aureus strain . however, PVL antibodies may be valuable to counteract progression of severe and possibly fatal disease caused by PVL-position strain such as USA300.

Comment and Conclusion

New strains of MRSA have evolved in the community, with unique combinations of virulence factors and resistance traits that confer distinct advantages for colonization and pathogenesis. Continued emergence of MRSA I the community is a public health problem that warrants increased vigilance in the diagnosis and management of suspected and confirmed staphylococcal infections.

Probably no other subject in current S. aureus pathogenesis research is debated as intensely and controversially as the basis of CA- MRSA virulence, which is due mainly to the dispute over the role of PVL. However, recent experiment and epidemiological evidence now allows drawing an integrated view of low exceptional virulence and pathogenic success of CA-MRSA may have evolved. Without any doubt, a necessary requirement was the acquisition of  SCCmec type IV, which does not impose a fitness cost to the bacteria. When SCCmec type IV was introduced in a strain with high intrinsic expression of virulence factors, such as alpha-toxin and    PSMs, evolution had created an MRSA strain with the basic prerequisites to compete with methicillin- susceptible stain and cause severe disease. For some CA-MRSA, this combination may have been enough to spread and cause infection in otherwise healthy individuals while in many other CA-MRSA, including USA300, the additional acquisition of genes encoding PVL and other determinant further significantly increased the pathogenic potential.

While the basic of virulence in USA300 is now unfolding more clearly, the basis of virulence in other CA-MRSA strain is much less completing understood. For example, it will be important to investigate whether the less pronounced success, for example, of ST80 CA-MRSA is due to gene regulatory effects that result in an overall lower expression of toxin including PVL.

Furthermore, does generally high expression of core- genome-encoded virulence factors overcome the lack of the PVL phage in CA-MRSA strain such as ST72 and other PVL negative CA-MRSA it will be of utmost important to address these key questions about CA-MRSA pathogenesis on a more global level, including the investigation of CA-MRSA strain other than usa300, to find a working drug for all CA-MRSA infection and prevent a global scenario of the severity to determine whether the main toxin player fulfill different, possibly complementary functions in CA-MRSA pathogenesis and what these function are. In addition, the molecular basis of increased transmissibility of CA-MRSA will have to be investigated using animal idolization models. Finally, elucidation the putative contribution of host factors to the development of at least the more severe manifestation of CA-MRSA diseases represents an important task for future CA-MRSA research

 

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