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Staphylococcus is a genus of Gram positive coccus that is a commensal of the skin and mucous membranes which can also cause a wide range of infections. Staphylococcus aureus, which colonizes the nasal mucosa of approximately 30 % of individuals,1 is among the most commonly isolated human bacterial pathogens and remains an important source of nosocomial and community-acquired infections, causing mild skin and soft tissue infections such as impetigo and furunculosis, to severe invasive infections such as necrotising pneumonia and infective endocarditis, and toxin-associated diseases such as toxic shock syndrome.2
The introduction of penicillin was an important breakthrough in the treatment of staphylococcal infections. However, S. aureus quickly developed penicillin resistance, leading to the use of methicillin and other derivatives.3 Unfortunately, methicillin-resistant S. aureus (MRSA) emerged following the clinical use of methicillin.4 Vancomycin was then extensively used as the first-line drug in the treatment of MRSA infections, leading to the development of vancomycin-intermediate S. aureus (VISA) or glycopeptides-intermediate S. aureus (GISA), which are isolates with decreased susceptibility to the glycopeptides antibiotics. The emergence of community and hospital-acquired MRSA isolates remains the main public health concern although a few cases of VISA and GISA were reported in Australia. As such, it is vital to understand the relevant advances in the emergence of the antibiotic-resistant S. aureus, particularly in the clinical diseases these resistant organisms cause, the mechanism of resistance, the current and future therapeutic options, as well as the infection control and management practices in the country.
Emergence of methicillin-resistant and vancomycin-intermediate Staphylococcus aureus (MRSA & VISA)
Worldwide, a pandemic of penicillin-resistant S. aureus following the introduction of penicillin in the mid-1940s due to Î²-lactamase production has led to the development of the semi-synthetic Î²-lactamase resistant anti-staphylococcal methicillin in 1959.4 Two years later, the first clinical isolate of S. aureus resistant to methicillin was reported in London. By the late 1970s, MRSA was reported as the major cause of nosocomial infection in tertiary hospitals worldwide. Epidemics of community-acquired infections have also been reported in Canada, the United States and Europe.5 Table 1 indicates the predominant clones of community-associated MRSA (CA-MRSA) in different regions.
Table 1: Worldwide dissemination of multiple CA-MRSA clones6
Sequence Type (ST)
ST59-V [5C2 & 5]
South West Pacific community-associated MRSA ([SWP] CA-MRSA)
Bengal Bay clone
The widespread use of vancomycin in the treatment of infections due to MRSA and as surgical prophylaxis has been a major factor contributing to the emergence of vancomycin resistance.7 Isolates of MRSA with reduced susceptibility to vancomycin (VISA) were first reported in Japan in 1997 with subsequent emergence in other countries from cases with long term MRSA infection.4,7 A heteroresistant vancomycin S. aureus (hVISA) phenotype was also detected in France.4
In Australia, the first MRSA epidemic started in 1965 in Sydney, followed by an epidemic of nosocomial infections involving multi-resistant strains in the east coast in the mid 1970s.4 The EMRSA-15 clone (initially described in the United Kingdom) is a non-multiresistant healthcare-associated MRSA (HA-MRSA) which was first reported in Perth, Western Australia in 1997, with subsequent spread to Adelaide, Brisbane and Sydney. Among the MRSA isolated between July 2010 - June 2011, 14.8 % isolates were identified as being HA-MRSA and has remained stable since 2006/07.8
In contrast, 85.2 % of MRSA isolated during the same period were CA-MRSA.8 The first non-multiresistant CA-MRSA, known as WA-MRSA, was noted in remote Western Australian communities in the early 1990s.4,5 Subsequently, the south-west Pacific (SWP) strain, which was linked to infections in Auckland, New Zealand, was associated with infections in Queensland and New South Wales. Another strain of CA-MRSA, the QLD strain, was first identified in Queensland in 2000. The Australian Group for Antimicrobial Resistance (AGAR) has established that these three CA-MRSA strains are now widely disseminated geographically.5 Table 2 and Figure 1 show the geographical distribution of CA-MRSA and HA-MRSA strains in Australia.
Table 2: Geographical distribution of CA-MRSA and HA-MRSA strains in Australia5
Throughout Australia, except Canberra
Brisbane, Sydney; not found in Melbourne and Hobart
Perth, Brisbane, Sydney, Darwin
South Australia (SA) and Western Australia (WA)
SA and WA
Sydney and Brisbane
Perth and Brisbane
Melbourne and Brisbane
AUS-2 (subtype of ST239)
Not found in Perth and Hobart
AUS-3 (subtype of ST239)
Not found in Perth, Newcastle and Canberra
Not found in Darwin, Canberra and Hobart
Not found in Darwin, Canberra and Hobart
Figure 1: Number and proportion of CA-MRSA isolates9
The geographical isolation of WA contributed to the difference in epidemiology of MRSA as compared to that in the rest of Australia.9 All strains of CA-MRSA isolated in WA are non-multidrug resistant and harbour a plasmid that encodes determinants for the production of Î²-lactamase and cadmium resistance. In the Northern Territory (NT), CA-MRSA was first isolated at Royal Darwin Hospital in 1991 and was defined as being susceptible to gentamicin and to tetracycline and/or erythromycin.9 ST75 (also designated WA MRSA-8), is a unique strain identified in the NT, and was thought to have arisen in the remote Aboriginal communities. Meanwhile in eastern Australia, non-multiresistant MRSA infections arose from the endemic HA-MRSA due to the multi-resistant ST 239 clone.9 The SWP strain (ST30) was found to be strongly associated with Polynesian ethnicity and infections were initially noted in Brisbane, Sydney, Canberra and Melbourne.
Treatment failure due to reduced vancomycin susceptibility in a patient with MRSA infection was first reported in Melbourne in 2001.4 On the other hand, the first case of hVISA was reported in Sydney in 2003, isolated from a patient with persistent septicaemia due to MRSA post-vancomycin therapy.
3. Mechanisms of antibiotic resistance in S. aureus
Mobile genetic elements (MGEs) are fragments of DNA that encode virulence factors and molecules that confer resistance to antibiotics in bacterial species.10 MGEs consist of plasmids, transposons, insertion sequences, phages, pathogenicity islands, and chromosome cassettes. Staphylococcal plasmid is responsible for penicillin and vancomycin resistance while the chromosome cassette confers resistance to methicillin.
Plasmids are auto-replicating DNA molecules. Intracellular transfer of staphylococcal plasmids occurs by transduction or conjugation due to the limited ability of S. aureus to acquire DNA from the environment.10 The production of Î²-lactamase in S. aureus confers resistance to penicillin. Î²-lactamase, encoded by the blaZ gene and the closely linked regulatory blaI and blaR genes, hydrolyzes the Î²-lactam ring of penicillin, resulting in the inactivation of the antibiotic. The production of Î²-lactamase may also lead to the production of a low affinity penicillin-binding protein (PBP2a) encoded by mecA gene. As a result, penicillin is unable to interfere with the PBPs to cross-link peptidoglycan polymers of the bacterial cell wall.
VISA has an MIC of 8 - 16 mg/L while hVISA is defined by the presence of resistant subpopulation at a rate of 1 in 105 organisms that express an intermediate level MIC.4 VISA appeared to have developed from MRSA and is characterized by cell wall thickness which is responsible for the reduced susceptibility.1,7 The thickened cell wall tends to trap vancomycin extracellularly leading to poor penetration of the drug, a factor in the expression of vancomycin resistance.4 However, the mechanism of resistance is yet to be elucidated. In contrast, vancomycin resistance in vancomycin-resistant S. aureus (VRSA) was well characterized. The emergence of VRSA is due to the acquisition of vancomycin resistance elements from enterococci during co-infection.10 The vancomycin resistance gene cluster, which is only expressed in the presence of vancomycin, is encoded by Tn1546 within a conjugative plasmid, and is transferred to MRSA from vancomycin-resistant enterococci (VRE).
The mechanisms of resistance to methicillin and penicillin are similar in that both involve a low affinity PBP2a encoded by the mecA gene, which is carried on the MGE staphylococcal cassette chromosome mec (SCCmec).2,4,10 SCCs are relatively large fragments of DNA that are inserted into the orfX gene on the S. aureus chromosome.10 SCCmec was acquired by S. aureus from the coagulase negative S. sciuri group.3,10 There are 11 types of SCCmec (types I to XI),2 with the first four being the most commonly described.4 Typically, HA-MRSA strains harbour the larger SCCmecI, II, III, VI or VIII which include multiple resistance determinants whereas CA-MRSA strains carry the smaller SCCmecIV, V or VII which have fewer resistance elements.2,10 The smaller size of SCCmec in CA-MRSA plays an important role in its insertion into multiple lineages of S. aureus due to its mobility; and in retaining susceptibility to macrolides, quinolones, tetracyclines, trimethoprim-sulfamethoxazole and lincosamides.2 The generation of MRSA occurs through the horizontal transfer of the mecA gene from methicillin-susceptible S. aureus (MSSA).3 For instance in Australia, the introduction of SCCmecIV into already prevalent and virulent MSSA strains in remote aboriginal communities gave rise to new clones of CA-MRSA.11
MRSA isolates are also grouped on the basis of the resistance phenotype, i.e. multi-resistant or non-multiresistant.2 The former is defined as being resistant to â‰¥ 3 non-Î²-lactam classes of antibiotics whereas the latter is defined as being resistant to < 3 non-Î²-lactam classes of antibiotics. Earlier studies reported heterogeneity of resistance in MRSA, with a subpopulation demonstrating high methicillin resistance level.4 However, in a study conducted in Sydney, it was evident that non-multiresistant MRSA strains have acquired SCCmec independently, resulting in the emergence of new strains as there were distinct differences between isolates of non-multiresistant MRSA and multi-resistant MRSA.4
Community-associated MRSA (CA-MRSA)
CA-MRSA is defined as MRSA isolated from patients with no history of hospitalization within the past 1 year1 or <48 hours after hospital admission2 without the following risk factors: surgery, dialysis, residence in a long term care facility, or the presence of indwelling catheters or percutaneous medical devices. By bacteriological definition, CA-MRSA exhibits low MIC values for oxacillin (â‰¤ 32 Î¼g/mL) or imipenem (â‰¤ 1 Î¼g/mL).1 CA-MRSA infection occurs in young otherwise healthy individuals, predominantly as severe skin infections. Figure 2 summarizes the clinical manifestations of infection with CA-MRSA. Heavy nasopharyngeal colonization due to pre-existing chronic diseases or having been in contact with a healthcare facility prior to presentation is suggested as the major risk factor for increased CA-MRSA infection.3,4
Figure 2: Clinical manifestations of CA-MRSA infection1
A majority of CA-MRSA harbours the virulence factor Panton-Valentine leukocidin (PVL), a bi-component necrotizing toxin that causes leukocyte destruction by pore formation.2,9 The extracellular cytotoxin is associated with tissue necrosis resulting in pyogenic skin infections, furunculosis, osteomyelitis, septic arthritis, bacteraemia and severe necrotizing pneumonia.2,4,9 A gradient of PVL carriage by CA-MRSA was reported in Australia, with a high prevalence in the east and north to a lower prevalence in the west and south. There is no definitive link between mecA gene and PVL, but the combination results in S. aureus strains that are highly adapted to causing infection.
CA-MRSA has also been commonly isolated from wound infection, surgical site infection, urinary tract infection (UTI), ocular infection, meningitis and sinusitis.1 For instance, MRSA strains are often detected in staphylococcal skin lesions among the Kimberley indigenous population due to scabies infestation, trachoma, chlamydia and gonorrhoea.6 Nasal carriage and skin and soft tissue infection caused by CA-MRSA is associated with higher incidence of bloodstream infections.1 Secondary infection with CA-MRSA is rare, but results in severe systemic infection with initial presentation of cutaneous abscesses progressing to bacteraemia. Recently, purpura fulminans and Waterhouse-Friderichsen syndrome caused by CA-MRSA have become more prevalent and are associated with high mortality rate.1,2
Healthcare-associated MRSA (HA-MRSA)
HA-MRSA is typically defined as the isolation of MRSA from patients who are MRSA-negative at the beginning of hospitalization or MRSA isolated from patients >48 hours after hospital admission.1,2 HA-MRSA strains are distinguished from CA-MRSA strains by molecular means. They carry the larger SCCmec and are resistant to many classes of non-Î²-lactam antibiotics. HA-MRSA in Australia were resistant to Î²-lactams, erythromycin, clindamycin, tetracycline and gentamicin by 1980s and were differentiated from overseas strains by trimethoprim-sulfamethoxazole resistance.4
However, unlike CA-MRSA, HA-MRSA strains seldom carry the genes for PVL. Therefore, the population affected by HA-MRSA is also distinct from those affected by CA-MRSA.11 HA-MRSA strains are often isolated from individuals who are exposed to the healthcare settings and are older with one or more co-morbid conditions. Nasal colonizing strains is usually the source of infection in nasal carriers and these individuals are at greater risk of developing nosocomial staphylococcal infection.2 The source of infection is usually the nasal colonizing strains. The most common clinical manifestations are bacteraemia, pneumonia and invasive infections.
5. Therapeutic options for MRSA infection
The most important management options for invasive infection is to completely remove infected tissue and/or prosthetic device and the drainage of staphylococcal abscesses.2 Despite the development of VISA and VRSA strains, vancomycin remains the gold standard for the treatment of MRSA bacteraemia and infective endocarditis.12 Following the emergence of antibiotic resistance S. aureus, new anti-staphylococcal antibiotics have become available.
Linezolid, a bacteriostatic agent that inhibits protein synthesis, is used for the treatment of healthcare-associated pneumonia and skin and soft tissue infections (SSTIs).2,11,12 Linezolid has better tissue penetration than vancomycin.1 However, prolonged linezolid use has been associated with thrombocytopenia, neuropathy and lactic acidosis.2,12 With the effective anti-MRSA coverage, tigecycline is often indicated for complicated skin and skin structure infections (cSSSIs) and complicated intra-abdominal infections in hospitilized patients.11 An alternative indication of cSSSIs, bacteraemia and infective endocarditis is the bactericidal daptomycin. As it is inhibited by pulmonary surfactant, daptomycin is not recommended for the treatment of staphylococcal pneumonia. It is also important to monitor creatine kinase levels during therapy. The presence of a dual mechanism of action allows telavancin to be used as anti-MRSA, anti-VISA and anti-VRSA agent. It was approved for the treatment of cSSSI and nosocomial pneumonia.
Several anti-MRSA agents with bactericidal activities have progress to Phase II and Phase III clinical trials.12 The lipoglycopeptides dalbavancin and oritavancin are reported to be effective in the treatment of bloodstream infections and SSTIs respectively. In addition to efficient treatment of both community and healthcare-associated pneumonia, the cephalosporins ceftobiprole and ceftaroline have also been demonstrated to be effective in the treatment of SSTIs. The development of effective staphylococcal vaccines is in progress to reduce infection rates and to prevent emergence of antibiotic resistance strains, but to no avail to date. Nabi Biopharmaceuticals' StaphVAXÂ®, a capsular polysaccharide conjugate vaccine, and Merck's V710Â® containing a microbial surface component that recognizes the adhesive matrix molecules of S. aureus, have been demonstrated to have no protection.2 Passive immunization has also been unsuccessful in clinical trials.
6. Infection control practices: prevention of antibiotic resistance
In Western Australia, the implementation of a 'search and destroy' approach to PVL-positive MRSA strains in the community has successfully prevented the entry of these strains into Western Australian hospitals, thereby reducing the risk of nosocomial infections.9 As such, the proportion of MRSA isolated in WA (approximately 0.4 %) and in other states (varied from 10 - 30 %) is always different. With regard to this, an active identification of MRSA carriage by surveillance followed by decolonization of carriers is an important strategy in preventing antibiotic resistance. 11,13
Infection control practice in the healthcare settings plays an important role in the prevention of antibiotic resistance. The first approach would be to ensure prudent antibiotic use, which dictates that antibiotics should only be used for infection-related purposes and narrow spectrum antibiotics should be used whenever possible.13 A study conducted by Johnson et al. demonstrated that total HA-MRSA infection was reduced following the introduction of an alcohol/chlorhexidine hand hygiene solution (ACHRS) program.14
The emergence of MRSA has greatly increased the total disease burden of S. aureus infection. There is increase blurring in distinguishing CA-MRSA and HA-MRSA due to the overlapping between the genotype, epidemiology and resistance phenotype. In addition to ongoing development of antibiotics and vaccines for the management of MRSA infections, effective infection control practices are also important in reducing infection rates as well as in preventing antibiotic resistance in S. aureus.