Staphylococcus aureus is a Gram-positive coccus, facultative aerobic, and grows as grape-like clusters; it is an opportunistic pathogen for both humans and animals. The most common infections by S. aureus are skin and soft tissue infections, respiratory infections and food poisoning .
Carriage of Staphylococcus aureus
Naturally, S. aureus colonizes humans and can be found in the throat, perineum, groin, anterior nares and skin. Nasal carriage of S. aureus is one of the common risk factors causing infections in the community and in hospitals [2,3]. Nasal carriage of S. aureus is associated with infection in patients with underlying diseases including AIDS, insulin-dependent diabetes mellitus, continuous ambulatory peritoneal dialysis and skin diseases [4,5].
Prevalence of S. aureus nasal carriage varies from 9 to 100%, with a mean of 37% . S. aureus nasal carriage rates varied with the age of the human individual [3,6]; there is higher rate of S. aureus nasal carriage among children than among adults. It is more prevalent between the ages of 10 and 20 years . In addition, the rate of S. aureus nasal carriage was found to be higher in boys than in girls and is therefore associated with the hormonal status . Different strains of S. aureus can be found in the colonized individual potentially stimulating the horizontal transfer of antimicrobial-resistant genes .
Staphylococcus aureus infections
S. aureus causes many diseases in humans, including skin and soft tissue infections (abscesses, carbuncles, folliculitis, furuncles, impetigo, bullous impetigo and cellulitis), which in the absence of antimicrobial therapy may lead to bloodstream infections and septic shock . Other infections caused by S. aureus include endocarditis, pneumonia, bone and joint infections. S. aureus skin infections are frequent in the United States, Canada, Latin America, Europe and the Western Pacific, although it is isolated from cases of pneumonia and bloodstream infection worldwide . Wound and catheter-related infections are closely associated with S. aureus. One primary cause of nosocomial bacteraemia is associated with intravascular catheter-related infections . Toxin-mediated diseases such as toxic shock syndrome and food poisoning are associated with TSST-1 and enterotoxin-producing S. aureus.
Methicillin-resistant Staphylococcus aureus
History of methicillin-resistant Staphylococcus aureus
The 1940s saw the introduction of penicillin, the first antimicrobial agent effective against S. aureus. Subsequently, resistance to penicillin was observed  and a plasmid harbouring β-lactamase gene was found to be responsible for creation of penicillin-resistant S. aureus. Penicillin-resistant S. aureus became a worldwide concern during the next two decades. In 1959, methicillin (a semi-synthetic derivative of penicillin and resistant to the β-lactamase enzyme) was used for treatment of infections caused by penicillin-resistant S. aureus. After that, penicillin-resistant S. aureus decreased significantly . The first isolates of methicillin-resistant S. aureus (MRSA) were reported in 1961 . Until the late 1970s, the prevalence of MRSA was considered sporadic, but MRSA was soon observed worldwide . MRSA is now a major cause of morbidity and mortality , and increasingly prevalent in many regions .
Mechanism of resistance to methicillin in Staphylococcus aureus
Penicillin-binding proteins: the targets of β-lactam antibiotics
Peptidoglycan structure in Staphylococcus aureus
The S. aureus cell wall comprises a very thick layer of peptidoglycan. The structure of the cell wall is a repeat of β1–4-linked N-acetylglucosamine-N-acetylmuramic acid (NAM) with attached teichoic acids . Each NAM is cross-linked to four of five amino acid chains containing L-alanine, D-iso-glutamine, L-lysine and D-alanine with a penta-glycine bridge between L-Lysine and D-alanine (Fig. 1).
The bridge is formed in the cytoplasm by FemX, FemA and FemB proteins that bind the glycine residues to the L-lysine residue of the stem peptides. The cross-linking occurs on the external layer of the cytoplasmic membrane in a reaction catalyzed by penicillin-binding proteins (PBPs). The PBPs are divided into four types, namely PBP1, PBP2, PBP3 and PBP4.
The PBPs have two protein domains, one of the domains is in cross-linking and another in transglycosylation. β-lactam antibiotics such as methicillin and oxacillin bind to the terminal D-alanyl-D-alanine of the stem peptide, thereby inhibiting the first domain of PBPs (transpeptidation) and the initiation of cross-linking. Therefore, the peptidoglycan is unable to crosslink, allowing leakage of cytoplasm outside the cell, resulting in the death of the bacterial cells . MRSA has developed a different foreign PBP called PBP2a (resistant to methicillin).
Penicillin-binding protein 2a
The difference between methicillin-sensitive S. aureus and MRSA is the presence of mecA gene, which encodes a different 78-kDa PBP (PBP2a). The mecA gene is originally from Staphylococcus sciuri. CcrA and B, located in mec element, code a recombinase protein that is responsible for unifying and fission of the mec element into the chromosome . The mec element is highly conserved between different isolates. PBP2a is a motif from the other PBP, which has a low affinity to bind with β-lactam antibiotics. Notably, resistance to methicillin and other β-lactam antibiotics in S. aureus is associated with mobile staphylococcal chromosomal cassettes that harbour the mecA gene and is known as Staphylococcal chromosomal cassettes mecA (SCCmecA) .
The ccr gene complex
The ccr gene complex includes the ccr genes and ORFs. S. aureus has three different ccr genes, which are ccrA, B and C. CcrA and B are divided into four different allotypes. Ccr genes, which have more than 85% similarity in their sequences, are classified as the same allotype. The ccrC gene has more than one different allele, ccrC1 allele 2, ccrC1 allele 3. Different ccr have different allotypes; for example, S. aureus type 1 harboured ccrA1B1 and type 2 possesses ccrA2B2 .
As mentioned, mecA is associated with resistance to the β-lactam antibiotics. mecA encodes PBP2a, which is different from the other PBPs . MecI and mecR1 are the regulator genes that control mecA. MecI is the repressor for mecA, while mecR1 plays a different role as a signal for transduction cascade . In addition, mecA is also under control of two corepressors (blaI and blaR1). BlaI is homologous of mecI and blaR1 is similar to mecR1. These two corepressors are responsible for controlling blaZ that is responsible for penicillin resistance . Also, blaI is able to bind to mecA operator and suppress the transcription of mecA.
Staphylococcal cassette chromosome mec
Staphylococcal cassette chromosome mec (SCCmec) is known as a genomic island of unknown origin, as it has the antimicrobial resistance gene mecA. SCCmec also has other genes including ccrA and ccrB, which code the recombinase proteins for incorporation and fission of the SCCmec elements from S. aureus chromosome . SCCmec elements are divided into different types with various mec and ccr genes. These different SCCmec elements cause variation of antimicrobial resistance and different kinds of infections . Types I–III SCCmec are large elements, which possess other antimicrobial resistance genes and are found in community-associated MRSA and hospital-associated MRSA (CDC, 2007). On the contrary, types IV and V are found more in community-associated MRSA .
In all types, the integration occurs in the attBscc site near to the origin of the replication of S. aureus. There are three classes of mec as follows: class A mec contains two mecI (transcriptional repressor protein) and mecR1 (signal transduction protein) genes , while class B mec includes mecA (with deletion of mecI and some parts of mecR1) and insertion sequence 1272 that are incorporated into the deletion site of mecA. Class C2 contains two copies of insertion sequence 431, mecA (short mecR1) . Thus, type I SCCmec harbours class B mec and ccrA; type II SCCmec has class A mec and ccrB; type III SCCmec contains class A mec and type ccrC; type IV carries class B mec and type ccrB; and type V possess class C mec and type 5 ccr. Therefore, naming of a new SCCmec type is based on ccr complex and class of mec gene.
Public health importance
MRSA is one of the most important antibiotic-resistant pathogens. There is an increasing prevalence of MRSA worldwide. ICUs in the United States showed an increase in MRSA from 36% in 1992 to 64.5% in 2003 . In Europe, the prevalence ranges from 1 to 50%. The morbidity and mortality caused by MRSA infections in the UK increased during the period 1993–2005 (National Statistics, 2007). In 2012, a meta-analysis study in Iran showed that the prevalence of MRSA ranged from 20.4% in Isfahan to 90% in Tehran. Infections by MRSA lead to longer term hospitalization and higher care costs .
Surveillance programmes appear to be necessary, such as the European Antibiotic Resistance Surveillance System (EARSS), which monitors the seven most invasive bacteria responsible for antimicrobial resistance (www.earss.rivm.nl). Currently, one of the most crucial issues is the presence of MRSA in the community. In 1993, Australia reported the prevalence of the first MRSA in the community . This was followed by reports of four MRSA in the community, causing paediatric deaths. Now, the prevalence of MRSA in the community is reported worldwide , representing a change in the epidemiology of community-associated and hospital-associated MRSA worldwide.
It is estimated that the range of distribution of MRSA is between 23 and 73% worldwide. MRSA is found to be an important cause of skin and respiratory infections . Malaysia showed a high prevalence of MRSA in 1996 ; MRSA were found in the surgical wards and linked to the use of invasive procedures .
It is estimated that the prevalence of MRSA in Europe is around 26% currently. In the SENTRY programme between 1997 and 1999, European countries showed variance in the frequency of prevalence of MRSA (Fig. 2). These surveys revealed greater prevalence in southern Europe . Tiemersma et al.  revealed the prevalence of MRSA during the period 1999–2002 in Belgium, Germany, Ireland, Netherlands and the UK. The prevalence of MRSA was varied from 1% in northern Europe to 40% in southern Europe.
In 1978, the first MRSA was reported in Africa. Thereafter, the occurrence has ranged from 5 to 45% [11,37]. The first isolation of MRSA in Sudan was reported in 1999 . Figure 3 shows the prevalence of MRSA in different African countries.
The prevalence of MRSA in the Asia Pacific region is greater than in other parts of Asia with a frequency of more than 60%. In Malaysia, the prevalence of MRSA was 17% in 1986 increasing to 40% in 2000 . Figure 4 shows the prevalence of MRSA in the Pacific region.
The United States
In 1974, it was 2%, in 1995, it was 22% and in 2004, it was reported to be 64%. According to the CDC report, 1.5% of the populations of the USA were carriers of MRSA between 2003 and 2004. There was a 50–70% increase in MRSA during the period 2001–2007 in bloodstream infections .
The first report of MRSA in Australia was observed in the 1960s. The first gentamicin-resistant MRSA was found in 1976. Figure 5 shows the prevalence of multiresistant MRSA and nonmultiresistant MRSA in different parts of Australia.
Latest evidence worldwide shows that the highest rate of prevalence (>50%) is in North and South America and Asia. Intermediate rates (25–50%) are observed in China, Australia, Africa and some European countries, including Portugal (49%), Greece (40%), Italy (37%) and Romania (34%). The lowest prevalence was reported in the Netherlands and Scandinavia [42–44]. Very high prevalence of MRSA was reported from Sri Lanka (86.5%), South Korea (77.6%), Vietnam (74.1%), Taiwan (65.0%), Thailand (57.0%) and Hong Kong (56.8%). A lower frequency is found in India (22.6%) . Figure 6 displays the worldwide prevalence of MRSA.
At-risk populations for MRSA include those with HIV, lupus erythematosus, cancer, diabetes and those undergoing transplantation . MRSA is a serious risk to hospitalized patients . People in contact with livestock animals are also at risk for MRSA infections. In 2011, 24.4% of meat and poultry sold in the United States was contaminated with MRSA . Athletes are another group at risk for MRSA associated particularly with fitness centres in the United States.
MRSA are resistant to β-lactam antibiotics. The resistance to antibiotics in community-acquired MRSA (CA-MRSA) and hospital-acquired MRSA (HA-MRSA) is different. CA-MRSA are more susceptible to cotrimoxazole, tetracycline and clindamycin, but the choice for treatment of CA-MRSA is vancomycin. HA-MRSA are susceptible to vancomycin  as well as some newer antibiotics such as linezolid and daptomycin; both were found to be effective against HA-MRSA and CA-MRSA. Currently, teicoplanin, vancomycin antibiotics are the preferred choices for treatment of MRSA. Unfortunately, new strains of MRSA have appeared that are resistant to vancomycin, known as vancomycin-resistant S. aureus. Linezolid, daptomycin and tigecycline are used for treatment of infections by vancomycin-resistant S. aureus.
Conflicts of interest
There is no conflict of interest.
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