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The emergence of hospital-acquired infections presents a serious contemporary challenge in medicine. The rise of drug resistance in such pathogens complicates the treatment of patients even further. Such is the case with methicillin-resistant Staphylococcus aureus (MRSA), a versatile pathogen which has a unique drug resistance mechanism towards the penicillin derivative methicillin. This disease often presents with a broad range of symptoms and may cause fatal secondary infections in patients who are already seeking hospital care for other maladies. Since its initial discovery and rise in the 1960s, MRSA incidence has steadily increased to the point where approximately 25% of nosocomial isolates of S. aureus are methicillin resistant (Chambers 1997). This paper will look to highlight its primary clinical features, epidemiology, characteristics of its causative organism, and investigate its underlying mechanism for drug resistance, as well as the diagnostic procedures which currently exist to identify infected individuals.
Due to the ability of S.aureus to colonize skin membranes and the mucosal membranes of the upper respiratory tract, skin infections and pneumonia are typical symptoms of MRSA in unsuspecting healthy individuals(Nakamura et al, 2002). Being an "opportunist pathogen", S.aureus is most commonly associated with post-operative surgical patients, specifically those who have undergone orthopaedic or general surgical procedures. The superficial wounds, surgical incision sites, and burns that these patients often present with are high risk areas attacked by the pathogen, causing deep infections. More serious outcomes of infection can include endocarditis, osteomyelitis, bacteremia, and epidermal necrolysis (Stapleton et al, 2002). Examination of the epidemiological features of MRSA reveals a heavy environmentally-dependant rate of infection. This means that the transmission of MRSA is reliant upon the isolation procedures and sterility of the clinical surroundings. The rate of infection is found to be lower in countries with more stringent hospital cleaning protocols (Banning, 2005). The rate of methicillin resistance in isolates of S.aureus has been found to be higher in hospitals where the patient has had a prolonged-stay, coupled with intensive (often indiscriminate) antibiotic treatment, underlying illness, invasive procedures, and an extremity in age (either a senior or a child) (Banning, 2005). Conversely, countries with procedures which place guidelines on using antibiotics, and screening protocols to limit staff-patient and patient-patient exposure tend to have lower incidences of methicillin resistance in S.aureus (Kunori et al, 2002). All of these aforementioned measures demonstrate that the rate of MRSA incidence is heavily dependent upon the level and quality of care provided to individuals.
The causative organism behind MRSA is Staphylococcus aureus, a Gram-positive coccus of the Staphylococcaceae family and the staphylococci genus (Stapleton et al, 2002). The organism is spherical in shape and can present in clusters of grape-like structures (Banning, 2005). The size of the cocci range from 0.8 µm -1.0µm in diameter and are non motile (Jawetz, et al, 1998). As mentioned above, the anterior nasal passage is the most common primary environment for S.aureus to colonize. When looking at the conditions of its primary environment, it is evident that the organism thrives at 37°C and in low salt concentrations (Banning, 2005). This, coupled with its small size, allows it to effectively infiltrate the environmental barriers of the body and aids in explaining how 20% of patients are persistently colonized and 30% are intermittently colonized (Gordon et al, 2008 ).
When examining S.aureus, it is evident that the organism's complex structure and interactions with its environment play a large role in its pathogenesis of infection. Microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) are surface proteins produced by the organism which promote binding to host tissues (Gordon et al, 2008). These proteins are not isolated to just binding to the host's cell wall. The MSCRAMMs also attach to the extracellular proteins, fibrinogen, and collagen (Gordon et al, 2008). This can explain the multitude of potential secondary infections which arise as these proteins enable the organism to adhere to a variety of tissues. The MSCRAMMs could also be a contributing factor to the high rate of recurrent infection in patients. A primary example is with bacteremia, where S.aureus has been found to attach to "blood group A" antigens of buccal epithelial cells (Smith, 1999). Epithelial cells have been shown to allow S.aureus to invade and escape host defences (including antibiotics) without causing significant host damage (Gordon et al, 2008).
Using antiphagocytic mechanisms as its primary defence, S.aureus has the unique ability to resist antibody opsonisation. Normally, the pathogen would be marked for ingestion by a phagocyte (opsonisation), however MSCRAMM protein A binds to the immunoglobulin to prevent this (Gordon et al, 2008). In particular, MSCRAMM protein A found on the S.aureus cell wall attaches itself onto the immunoglobins in an unconventional orientation (Goodyear et al, 2003). This inherently prevents any phagocytic engulfment.
What enables S.aureus to induce rapid infection in the host are enzymes. These enzymes facilitate the metastasis and destruction of host tissue. For example, the actions of protease based exfoliative toxins are responsible for Staphylococcal scalded skin syndrome, SSSS (Banning, 2005). Other enzymes such as lipases and elastases have similar roles in damaging host tissue. The organism also uses the host cell's own immune system to produce toxins. A primary example of this is with pyrogenic toxin superantigens (PTSAgs). PTSAgs have superantigen activities which cause non-specific activation of host T-cells that cause for excessive amounts of cytokine to be released (Goodyear et al, 2003). Ultimately, this heightened level of toxicity can damage tissue and organ systems, displaying what is also known as Toxic Shock Syndrome (Goodyear, et al, 2003).
The efficiency of the pathogenic processes of S.aureus has been greatly investigated. It has been discovered that the metabolic activities of the organism occur in a two tier fashion regulated by the accessory gene regulator, agr (Yarwood et al, 2003). First, expression of MSCRAMM occurs during the replication stages to facilitate the initial colonization of the tissue. During this stage, S. aureus degrades glucose to pyruvate (Gordon et al, 2008). The S.aureus clusters then exit from this exponential phase of growth as soon as the store of glucose has been depleted (Gordon et al, 2008). The second stage classified as the "stationary phase", is marked by secretions of various virulence factors such as exotoxins to spread the infection (Gordon et al, 2008). This coordination may explain the relative formulation of secondary infections (listed above) only after the initial skin infections and pneumonia have appeared in most patients.
Prior to the existence of methicillin, Benzylpenicillin, a Î²-lactam antibiotic, was originally used to treat S.aureus. Resistance to this antibiotic was seen within a decade of its arrival in the clinical environment in the form of an inactivation enzyme produced by S.aureus (Stapleton et al, 2002). Subsequently, the penicillin derivative methicillin was introduced in 1959 to treat Staphylococcus aureus (Stapleton et al, 2002). This Î²-lactam antibiotic was different from its precursor in that it had methoxy groups producing steric hinderance around an amide bond (Chambers, 1997). This ultimately reduced the drugs ability to be inactivated by S.aureus enzymes (Chambers, 1997). The first recorded isolate of methicillin resistant Staphylococcus aureus appeared a year later in 1960 (Stapleton et al, 2002).
Normally in a staphylococcal cell, the peptidoglycan layer covering the cell is composed of 20 alternating N-acetylmuramic acid and [beta]-1-4-N-acetyglucosamine residues (Giesbrecht et al, 1998). Each N-acetylmuramic residue is attached to a stem peptide which is interconnected through the formation of pentaglycine crosslinkages (Giesbrecht et al, 1998). These stem peptides play a large role in the structural stability of the staphylococcal cell. Combinations of 4 penicillin-binding proteins (PBP) catalyze these cross linkages on the external cytoplasmic membrane. Methicillin, a Î²-lactam antibiotic, normally functions in non-resistant strains by inhibiting these crosslink formations (Giesbrecht et al, 1998). This causes the cell wall to become structurally weak, thereby increasing the likelihood for the cell to rupture and die (Giesbrecht et al, 1998). However, in MRSA, the presence of an additional PBP, known as PBP2a, takes over the catalyzation of cross linking which was inhibited by methicillin in the original 4 PBPs (reference). This PBP2a presents with a lower affinity for interactions with any type of Î²-lactam, thereby inducing resistance (Stapleton et al, 2002). PBP2a is coded for by the mecA gene, located on the mec element of the MRSA genome (Stapleton et al, 2002). The presence of the mec element, which is exclusive to MRSA, extends the S.aureus genome by 45-61Kb (Stapleton et al, 2002). On either side of the mecA gene are one of two complementary regulatory sequences, mecR1 and mecI. These 2 sequences aid in transcriptional activities during the formation of PBP2a and contain repressor and initiation sequences (Sharma et al, 1998). During early years of methicillin resistance, it was found that PBP2a expression was slowly induced in S.aureus cells in comparison to other mechanisms of resistance against other Î²-lactams (Kobayashi et al, 1998). This caused for isolates of MRSA which carried the mecA gene to still express a certain amount of susceptibility to methicillin. However, through the overuse of antibiotics and increased exposure to ideal environments for cell proliferation, MRSA isolates with deletions in the mecI regulatory sequence were selected for (Kobayashi et al, 1998). This caused for an inactive repressor to be translated from mec1 which subsequently increased the rate of PBP2a induction in cells (Kobayashi et al, 1998).
Upon analysis of the mechanism for methicillin resistance in MRSA, it is possible to state that any intervention that effects the expression of the mecA or mecI gene and the proper functioning of PBP2a will cause MRSA to have increased susceptibility to methicillin. As such, a primary focus in the establishment of new antibiotics would be to investigate and target limitations of PBP2a. For example, it has been found that stem peptides, which are a crucial component of crosslinks inside peptidoglycan, must have an unhampered peptide conformation for PBP2a to correctly catalyze these linkages (Stapleton et al, 2002). The addition of an extra amino acid may prevent the peptide sequence from having the two terminal alanine residues which are required. Similarly, it has been found that the pentaglycine cross-bridge must also be in original conformation for PBP2a to function (Stapleton et al, 2002). The precursor genes for Fem- proteins which attach lysine to glycine residues for the formation of the pentaglycine cross-bridges are potential weak areas (Stapleton et al, 2002). Inactivation of any of these genes would result in structurally weak cell walls being formed.
There exist few types of susceptibility tests for detection of methicillin resistance in Staphylococcus aureus. Most tests involve using a modified culture to visually increase the expression of resistance if found (Chambers 1997,). Examples of these tests include dilution tests and Agar screen tests. Other tests such as those based on PCR and DNA hybridization are used to detect the presence of the mecA gene in both heterogeneous and homogeneous phenotypes (Chambers, 1997). Heterogeneous phenotypes are defined as cell populations with only a small minority showing high-level methicillin resistance (Stapleton et al, 2002). Homogeneous phenotypes consist of cell populations with the majority being highly resistant to methicillin (Stapleton et al, 2002).
Overall, Methicillin-Resistant Staphylococcus aureus is a complex, and highly efficient pathogen which renders the host highly susceptible to numerous secondary infections. The coordination of biosynthetic and degradative pathways facilitated by the accumulation of toxins allows for infiltrative infection.