**9. Other virulence factors of MRSA**

The pathogenicity of *S. aureus* depends on several determinants, among them, the production of toxins and extracellular membrane components (Jarraud et al., 2002; Gandhinagar & Silva, 2004). The molecular basis of pathogenicity of *S. aureus* depends on the expression of broad classes of accessory genes producing components of the cell wall and extracellular proteins. The expression of these virulence factors is regulated by genes in the operon *agr* (accessory gene regulator), which regulates the expression of genes for toxins and adhesins (Purcell & Fergie, 2005). Enzymes such as coagulase and catalase are responsible for its evasion of the immune system (Gandhinagar & Silva, 2004).

The toxins are related to staphylococcal toxic shock syndrome (TSS), staphylococcal scarlet fever (both due to the toxin of toxic shock syndrome 1 [TSST-1] and staphylococcal enterotoxins), scalded skin syndrome (SSS due to exfoliatins) and food poisoning (SE's, staphylococcal enterotoxins) (Santos et al., 2007; Jarraud et al., 2002; Johnson et al., 1991). Genetic sequencing of a strain called MW2, CA-MRSA, revealed the presence of genes responsible for specific virulence factors such as the PVL toxin, staphylococcal enterotoxin H (*seh*) and staphylococcal enterotoxin C (*sec*) (Saïd-Salim et al., 2005).

Toxic shock syndrome was related primarily to the use of a particular brand of tampons in 1980. The TSS can occur in patients of any age, with the main presenting symptoms being

CA-MRSA: Epidemiology of a Pathogen of a Great Concern 67

these strains. CA-MRSA USA 100 and 200 clones have emerged with alpha +/- and gammatoxin +/-, PVL +/- PSM+ and TSST-1+ profiles. Probably the production of several cytotoxins combined with superantigen action culminates in a devastating disease

Beta hemolysin was also related to lung injury as demonstrated by Hayashida et al. (2009). In this study, the hemolysin was attributed to the ability to increase the influx of neutrophils in the lung and alveolar spaces, causing leakage of serum proteins into the lung parenchyma and exudation of protein rich fluid into the air. The neutrophil migration is indirectly modulated by beta-hemolysin through the stimulation of other host factors. Thus, the virulence of hemolysin increases the regulation of various pro-inflammatory cytokines and

Given the great potential of CA-MRSA infections to develop into serious and/or systemic infections, there is an interest in reintroducing drugs such as trimethoprim/ sulfamethoxazole, tetracycline and clindamycin for treatment of CA-MRSA. In severe cases where there is need for hospitalization and intravenous therapy, antibiotics such as

The combination of trimethoprim/sulfamethoxazole (cotrimoxazole) has been considered a good therapeutic option for the treatment of patients affected by CA-MRSA. *In vitro* tests show that it has excellent bactericidal activity, but its activity can be reduced in the presence of rifampicin. Several antimicrobial combinations were tested, such as linezolid and cotrimoxazole, rifampicin,. Cotrimoxazole, minocycline, linezolid, clindamycin or moxifloxacin, cotrimoxazole alone proved to be more effective in *in vitro* tests (Kaka

However, in another study with patients affected by CA-MRSA treated with trimethoprim/sulfamethoxazole, clindamycin and cephalexin resulted in a treatment failure rate of 26%, 25% and 33%, respectively. In addition, patients who received the drainage of abscesses in addition to antibiotic therapy had lower rates of treatment failure (25%) than

One of the main strains in the community, the USA300 had plasmid-mediated resistance to tetracycline, clindamycin, and mupirocin (Han et al., 2007). In addition, there is the possibility of clindamycin inducible resistant strains resulting in treatment failure. In places where there is high frequency of isolation of strains with this characteristic, it is necessary to choose alternative treatments. It is estimated that this phenomenon occurs in approximately 13% of CA-MRSA strains (LaPlante et al., 2007) and from 36% to 56% of HA-MRSA (Siberry et al., 2003). The treatment of clindamycin-sensitive strains was assessed showing that the best options were daptomycin, clindamycin, doxycycline, vancomycin, linezolid and trimethoprim/sulfamethoxazole, respectively, with the latter three being equally effective. Treatment with daptomycin was better than vancomycin and linezolid, the latter two having equal effect, but all three overcame the effects of clindamycin since these strains can show induced resistance and the treatment with clindamycin also induces the emergence of

vancomycin, linezolid and daptomycin are reliable options (LaPlante et al., 2008).

patients who received only incision and drainage (60%) (Frei et al., 2010).

generates an exaggerated response in the host (Hayashida et al., 2009)

**10. Current antimicrobial drug choice** 

constitutive resistance (LaPlante et al., 2008).

(Schlievert, 2009).

et al., 2006).

fever, rash, and toxicity, which often progresses to hypotension with a prior history of watery diarrhea, sore throat, nausea, vomiting and myalgia. A number of other symptoms involving dehydration and its effects are often related to the syndrome. Blood cultures may be negative for the pathogen. The strain that carries TSST-1 reacts with phage group I and is likely to produce toxins, including other enterotoxins, and exoproteins. It may also exhibit resistance to heavy metals, and proteolytic characteristics are not often haemolytic and usually tend to be pigmented. It is interesting that strains produce TSST-1 positive alphahemolysin in low quantities even if they have the gene, suggesting that certain genetic events leading to repression of some genes (e.g., hemolysin) at the same time the expression of other genes (i.e. TSST -1) is increased (Todd, 1988).

Scalded skin syndrome (SSS), better known as Ritter's disease was first described by German physician Baron Gotfried Ritter von Rittershain who observed the widespread phenomenon in 297 children calling it neonatal exfoliative dermatitis. This disease usually appears in children with clinical features ranging from localized to disseminated bullous impetigo, known for easily rupturing on the skin surface, releasing a fluid with features ranging from thin to thick, being opaque purulent yellowish, whitish or opaque. In neonates lesions are mainly located in the perineum, or both in the periumbilical region, and in older children the lesions are located near the umbilicus. This is the mildest form of the disease, in which the skin around the preserved area remains without systemic signs and symptoms. The generalized form of the disease is mainly spread across the surface of the skin and mucous membranes are usually spared. In infants, onset of symptoms begins between 3 to 16 days. Patients with systemic SSS present fever, malaise, lethargy, irritability, loss of appetite, followed by the appearance of erythematous papules that usually start in the head and neck and spread to the rest of the body in a few days (Ladhani et al., 1999).

Another mechanism of virulence that has often been identified in samples of CA-MRSA is phenol-soluble Moduline . PSM was first detected in cultures of *S. epidermidis*. Antimicrobial activity against Group A *Streptococcus* (Cogen et al., 2010) and activities that stimulate the immune system of NFkB nuclear factor kB in THP-1 cells and cytokines in THP-1 monocytes and its role in the infection still need to be clarified (Mehlin et al., 1999). In PVL-positive CA-MRSA samples, the PSM effect is to intensify the effects of the toxin in the presence of both units (LukS-and LukF-PV) (Hongo et al., 2009).

The detection of PSM in CA-MRSA strains was higher than in HA-MRSA strains showing that *S. aureus* PSM activate human neutrophils triggering an inflammatory response and thereby contributes to staphylococcal virulence. CA-MRSA PSM has an important role in leukocyte cytolysis by CA-MRSA primarily participating in evasion of the host defense system (Wang et al., 2007).

PVL, alpha-toxin and protein A, represent the virulence factors involved in pneumonia caused by *S. aureus.* Alpha-toxins and PVL form pores in the polymorphonuclear cells and thus causes an exaggerated response by the release of cytokines and reactive oxygen specimens and contributing to damage in lung tissue (Hayashida et al., 2009).

Studies in the United States report that the USA400 strain responsible for lethal pneumonia in three children, had cytotoxins, such as virulence factors alpha and gamma, PVL, phenolsoluble Moduline (PSMs), staphylococcal enterotoxin (SE) B or C. The profile of toxigenic strains of USA300 is similar, except for staphylococcal-like enterotoxin (SE-l) Q present in

fever, rash, and toxicity, which often progresses to hypotension with a prior history of watery diarrhea, sore throat, nausea, vomiting and myalgia. A number of other symptoms involving dehydration and its effects are often related to the syndrome. Blood cultures may be negative for the pathogen. The strain that carries TSST-1 reacts with phage group I and is likely to produce toxins, including other enterotoxins, and exoproteins. It may also exhibit resistance to heavy metals, and proteolytic characteristics are not often haemolytic and usually tend to be pigmented. It is interesting that strains produce TSST-1 positive alphahemolysin in low quantities even if they have the gene, suggesting that certain genetic events leading to repression of some genes (e.g., hemolysin) at the same time the expression

Scalded skin syndrome (SSS), better known as Ritter's disease was first described by German physician Baron Gotfried Ritter von Rittershain who observed the widespread phenomenon in 297 children calling it neonatal exfoliative dermatitis. This disease usually appears in children with clinical features ranging from localized to disseminated bullous impetigo, known for easily rupturing on the skin surface, releasing a fluid with features ranging from thin to thick, being opaque purulent yellowish, whitish or opaque. In neonates lesions are mainly located in the perineum, or both in the periumbilical region, and in older children the lesions are located near the umbilicus. This is the mildest form of the disease, in which the skin around the preserved area remains without systemic signs and symptoms. The generalized form of the disease is mainly spread across the surface of the skin and mucous membranes are usually spared. In infants, onset of symptoms begins between 3 to 16 days. Patients with systemic SSS present fever, malaise, lethargy, irritability, loss of appetite, followed by the appearance of erythematous papules that usually start in the head

and neck and spread to the rest of the body in a few days (Ladhani et al., 1999).

Another mechanism of virulence that has often been identified in samples of CA-MRSA is phenol-soluble Moduline . PSM was first detected in cultures of *S. epidermidis*. Antimicrobial activity against Group A *Streptococcus* (Cogen et al., 2010) and activities that stimulate the immune system of NFkB nuclear factor kB in THP-1 cells and cytokines in THP-1 monocytes and its role in the infection still need to be clarified (Mehlin et al., 1999). In PVL-positive CA-MRSA samples, the PSM effect is to intensify the effects of the toxin in the presence of both

The detection of PSM in CA-MRSA strains was higher than in HA-MRSA strains showing that *S. aureus* PSM activate human neutrophils triggering an inflammatory response and thereby contributes to staphylococcal virulence. CA-MRSA PSM has an important role in leukocyte cytolysis by CA-MRSA primarily participating in evasion of the host defense

PVL, alpha-toxin and protein A, represent the virulence factors involved in pneumonia caused by *S. aureus.* Alpha-toxins and PVL form pores in the polymorphonuclear cells and thus causes an exaggerated response by the release of cytokines and reactive oxygen

Studies in the United States report that the USA400 strain responsible for lethal pneumonia in three children, had cytotoxins, such as virulence factors alpha and gamma, PVL, phenolsoluble Moduline (PSMs), staphylococcal enterotoxin (SE) B or C. The profile of toxigenic strains of USA300 is similar, except for staphylococcal-like enterotoxin (SE-l) Q present in

specimens and contributing to damage in lung tissue (Hayashida et al., 2009).

of other genes (i.e. TSST -1) is increased (Todd, 1988).

units (LukS-and LukF-PV) (Hongo et al., 2009).

system (Wang et al., 2007).

these strains. CA-MRSA USA 100 and 200 clones have emerged with alpha +/- and gammatoxin +/-, PVL +/- PSM+ and TSST-1+ profiles. Probably the production of several cytotoxins combined with superantigen action culminates in a devastating disease (Schlievert, 2009).

Beta hemolysin was also related to lung injury as demonstrated by Hayashida et al. (2009). In this study, the hemolysin was attributed to the ability to increase the influx of neutrophils in the lung and alveolar spaces, causing leakage of serum proteins into the lung parenchyma and exudation of protein rich fluid into the air. The neutrophil migration is indirectly modulated by beta-hemolysin through the stimulation of other host factors. Thus, the virulence of hemolysin increases the regulation of various pro-inflammatory cytokines and generates an exaggerated response in the host (Hayashida et al., 2009)
