Over the past 50 years, treating bacterial infections has become more difficult because staphylococcal species have become resistant to various antimicrobial agents, including the commonly used penicillin-related antimicrobial agents.1 Staphylococcus aureus species continues to become a common problem worldwide causing a variety of infection ranging from mild skin and soft-tissue infections to severe invasive high mortality rate infections of 80%.2,3 The bacteria are normally present as normal flora on the skin and nose of a healthy individual both in hospital setting and also in the community. On the other hand, it possesses multiple virulence factors that can evade host response to be passed on person to person. Its remarkable ability to acquire resistance to various types of antibiotics in Australia will be described where the current situation and future development will also be focused. 134
History of antibiotics
Sir Alexander Fleming first discovered penicillin antibiotic in 1929 where inhibition of staphylococci on an agar plate contaminated by a Penicillium mould was observed.1 He concluded that the bacteria around the ring on the plate had been killed off by some substance that had come from the mould. In 1939, Ernst Chain and Howard Florey successfully developed a way to isolate penicillin to treat bacterial infections during the Second World War. Penicillin eventually became generally available for treating staphylococci and streptococci especially, in 1946. It was believed that penicillin had the mechanism to kill bacterial pathogens without harming the host that harboured them. During this period, Fleming predicted that the misused of this drug could lead to selection of resistant forms of bacteria. It was truly used inappropriately for non-bacterial diseases inclusive and taking less than the optimal dose would likely lead to mutant forms. Therefore, by 1946, it was reported that 28% of staphylococcal stains isolated from patients were penicillin resistant in a hospital.4 And followed by a total of 59% resistance strain to penicillin was reported from the same hospital at the end of the decade.4 In 1940s to 1950s, new antibiotics such as streptomycin, tetracycline and chloramphenicol were also come into full use and were effective against the most pathogenic causing bacteria for only 2 years.1 It was fortunate that new classes of drugs, such as vancomycin and methicillin, were already developed by 1960s that overcame the problem of antibiotic resistance. Hence, these agents remain the agents of choice for most S. aureus infections at that time. As the year passed, antibiotic resistance has moved on in increasing numbers of S. aureus infections commonly found in hospital settings that was caused by methicillin-resistant S. aureus strains (MRSA). This problem was similar to the emergence of penicillinase-mediated resistance in S. aureus decades ago. 303
Emergence of antibiotic resistance in Australia
Australia (Figure 1) is a continent with a unique small population of about 19,000,000 in a large country of 7.7 million km2, where major population is concentrated in major urban centres in eight national, state and territory capital cities and also 50 km within the coast.5 Due to its geographic and demographic features, it also significantly has impact on the spread of MRSA and its prevalence in different centres that led to the emergence of three types of MRSA over the years. 82
Figure 1: Map of Australia illustrating states, capital cities and territories.5
Hospital-acquired MRSA (HA-MRSA)
The first MRSA infection in Australia was predominantly found exclusively in a Sydney Hospital in October 1965.5,6 Where it was labelled as a major cause of hospital-acquired infection in tertiary hospitals along the eastern seaboards by the late 1970s and was known as hospital-acquired MRSA (HA-MRSA).5 The combination of invasive procedures in hospital settings such as intensive care units, orthopaedic surgery, urology and cardiothoracic surgery; and high rates of antibiotic use are the potential of increase resistance predominantly in older patients. This HA-MRSA causes a full range of deep abscesses, endocarditis, prosthetic device infections, post-operative wound infections and line sepsis of staphylococcal infections. These infections are resistant to ï¢-lactams, clindamycin, gentamicin, erythromycin and tetracycline. 110
Community-acquired MRSA (CA-MRSA)
It was then observed in Perth hospitals in 1989 that another antibiotic resistance patterns differed markedly from the earlier multi-resistant strains from a randomly screened Aboriginal patients from the Kimberley region in the far north of Western Australia with no admission history from interstate hospitals.7 These strains were of imported from the eastern states and referred to as Western Australian MRSA (WA-MRSA) or community-acquired MRSA (CA-MRSA).8 The strains were non-multiresistant and it is characterised by penicillin and methicillin resistant but susceptible to other antimicrobials. The Aboriginal population is more likely to develop life-threatening invasive disease as a result of skin and soft tissue infection can be as high as 42% than that of the non-Aboriginal population and the outcomes are worse.5 Infections in the eastern states represents a lower proportion of infection than in the west and also responsible for the frequently outbreaks in hospitals that are commonly isolated throughout the country. The WA-MRSA spread eastwards from the Kimberley region to South Australia and the Northern Territory, acquiring resistance to fusidic acid and mupirocin.5,8 The CA-MRSA infrequently carries the virulence factor genes encoding Panton-Valentine leukocidin (PVL)-negative clones. It is a necrotizing toxin that causes destruction of leukocyte and tissue necrosis and is associated with severe pneumonia and abscesses among the young otherwise healthy people. 214
Queensland clone CA-MRSA
The 'south-west Pacific' (SWP) strain or Queensland clone of CA-MRSA from Samoa and Tonga was a wider community-acquired non-multiresistant MRSA epidemic that was also reported causing infections in New Zealand during the early 1990s with similar characteristics and were associated with patients of Polynesian extraction.9 This was initially characterised by the Western Samoan phage pattern (WSPP) from patients with no recent contact with healthcare facilities. This strain also became the predominant CA-MRSA clone in Southern Queensland and New South Wales notably causing necrotising pneumonia, bacteraemia, septic arthritis and osteomyelitis among the Caucasians population.9 The clone spread widely to the rest of the country showing consistent community-acquired strains of phage groups WSPP1 and WSPP2 of PVL-positive that belonged to the New Zealand strain. In conclusion, the presence of PVL determines the possible emergence in the community and rarely in HA-MRSA isolates. 121
Monitoring antimicrobial resistance in Australia
The establishment of MRSA systemic surveillance in Australia started in 1986. The surveillance study by the Australian Group for Antimicrobial Resistance (AGAR) first initiated when there was a rapid spread of MRSA infections throughout major Australian hospitals.10 It was coincidently occurred around the same time that the first strain of a new community strain began to appear in Western Australia.5,10 It has been more than 15 years that AGAR targeted and conducted annual surveys of the prevalence and susceptibilities of S. aureus in tertiary care institutions in major capital cities (Canberra, Sydney, Melbourne, Darwin, Perth, Adelaide Brisbane and Hobart) (Figure 1). This trend has important implications for empirical antibiotic prescribing and infection control measures in hospitals, urban settings and remote communities. Surveillance in S. aureus also supports the detection of the resistance mechanisms and their genetic basis of antibiotic susceptibility. The group surveyed the WA-MRSA-1 clone essentially spread throughout Australia in both 2000 and 2002.10 The AGAR group demonstrated that the southwestern Pacific clone both patterns of WSPP1 and WSPP2 phages were present in all eastern state capitals by 2000 and a national spread from Adelaide, Darwin and Perth by 2002.10 191
Between 1989-1999 period, AGAR studied that ciprofloxacin increased resistant to oral antibiotics for nosocomial MRSA in each centres of the state. Both rifampicin and fusidic acid developed resistance to MRSA that led to the elimination of oral treatment options. Vancomycin was then put into great use in treating the infections as it demonstrated a decrease in glycopeptides susceptibility.5 Other than the surveillance program, additional precautionary measures should be implemented in the management of MRSA, which includes:
Regular hand-washing habits.
Screening of both patients and health-care workers to avoid further transmission in the community.
A mask must be worn if there are colonised respiratory secretions.
Healthcare staff must use clean, non-sterile gowns and gloves when entering a patient's room at the hospital.
Health care worker must thoroughly follow infection control procedure.
Avoid the overuse of antibiotics will help bacteria from adapting and mutating. 142
Mechanisms of antibiotic resistance
Methicillin resistance is due to the production of an additional penicillin-binding protein (PBP2a). It involves altered and low affinity for penicillin and ï¢-lactams. The four native staphylococcal PBPs are inactivated in the presence of ï¢-lactam antibiotics and the reactions directed by these enzymes for the synthesis of the peptidoglycan chains constituting the bacterial cell wall are blocked. However, PBP2a is not inhibited in the presence of ï¢-lactams and is able to take over the peptidoglycan biosynthesis from the native PBPs. Staphylococcal cassette chromosome mec Staphylococcal cassette chromosome mec (SCCmec) (Figure 2) is a large mobile genetic element that is introduced in MRSA strain. This confers a broad resistance against all members of the ï¢-lactam antibiotics, including penicillins, cephalosporins, penems and carbapenems. PBP2a is a transpeptidase that takes over the function of biosynthesis of cell-walls, which is otherwise blocked in the presence of b-lactam antibiotics. SCCmec is inserted into the chromosome at a specific site (attBscc) at the 3 prime end of an open reading frame of unknown function (orfX) located near the origin of replication of S. aureus and therefore replicated at an earlier stage. This has strategic importance for immediate transcription of imported antibiotic resistance genes. SCCmec type determines the genetically distinction between HA-MRSA and CA-MRSA strains. Although some epidemic HA-MRSA clones contain SCCmec IV, most HA-MRSA strains carry one of three of SCCmec (type I, II or III). MRSA arises by the introduction of SCCmec into distinct successful methicillin-susceptible S. aureus lineages.11 Typically, multiresistant nosocomial strains of MRSA harbor SCCmecII (Figure 1) and SCCmecIII, which are larger and include multiple resistance determinants. On the other hand, the more recent community-associated MRSA strains harbor the smaller SCCmecIV, which carry fewer resistance elements and thus often retain susceptibility to macrolides, quinolones, tetracyclines, trimethoprim-sulfamethoxazole, and lincosamides. Moreover, the smaller size of SCCmecIV has been postulated to allow it to be more mobile and supportive evidence of this is the fact that SCCmecIV has been inserted into multiple lineages of S. aureus whereas SCCmecII and SCCmecIII have only been found in three and two lineages, respectively.
It was discovered that type V SCCmec containing PVL virulence genes was widely distributed and carried on the chromosome of an Australian CA-MRSA strains.12 Due to SCCmec type V structurally and genetically diversity within the elements, it is difficult to control its multiply resistant in the community that is threatening to become a substantial health problem in the community. 403
Figure 2: Structure of the five principle types of staphylococcal chromosomal cassette mec elements.13
Clinical problems of MRSA
The typical signs and symptoms of most MRSA infections are skin infections that produce cellulitis, boils, impetigo, rash and abscesses represent at early stage of the infections. One major problem with MRSA is that S. aureus bacteria have the ability to disseminate to almost any other organs in the body and develop severe symptoms. MRSA infections that spread to internal organs can become life threatening that associated with fever, joint pains, severe headache, chills, shortness of breath and low blood pressure which need especially medical attention. Some CA-MRSA and HA-MRSA infections become severe complications such as sepsis, endocarditis, osteomyelitis, pneumonia, necrotizing fasciitis that can lead death. Those who are at risk of MRSA infections in the population are as follow:
Intravenous drug users
Frequent or excessive treatment with antibiotics
At risk age group (young children, healthcare workers and the elderly)
People with weak immune systems
Insulin dependent diabetics
Indigenous populations
People living in close proximity where MRSA is present including the length of hospital stay
People spending time in particular areas known to infect vulnerable patients such as intensive care units, renal units and the operation theatre.
Patients with indwelling devices such as urinary catheters, surgical drains, peripheral intravascular lines, endotracheal tubes
Patients with ongoing skin problems. Example eczema.
Early diagnosis and treatment usually result in better outcomes and reduction or elimination of further complications. 253
Treatment of MRSA
MRSA treatment must be properly diagnosed before proper treatment can begin. A blood test, swabbing or MRSA DNA test to identify the specific strain is important to effective treatment. It is also vital for a patient to finish a course of antibiotics as directed by a clinician if MRSA infection been diagnosed even if the symptoms seem to resolve before the prescribed dose has ended. Early stoppage of antibiotics can allow MRSA to survive and develop further antibiotic resistance. If symptoms persist and do not reduce or eliminate, it is advisable to go back to the doctor for further care.
The treatment of MRSA infections may be more complicated than a simple staph infection. Methicillin is the antibiotic that MRSA are resistant to. Some antibiotics such as clindamycin, linezolid, vancomycin and others are effective in treating MRSA. Mild infections are usually treated with mupirocin (Bactroban) while other antibiotics are reserved only for MRSA to avoid resistant strains developing by the bacteria. Most serious MRSA infections are treated with two or more intravenous antibiotics that, in combination, often still are effective against MRSA (for example, vancomycin, linezolid [Zyvox], rifampin [Rifadin]).
Antibacterial soaps and antibiotic ointments are recommended to minimise bacterial growth on the skin and in the nose with specific instructions and duration by the health professional. Regardless if it is at home or in public places, it is vital to treat MRSA infections with extra care to reduce risk of spreading the infection and at the same time increase chances for healing with fewer complications whether at home or in public places. 262
Resistance to vancomycin
Vancomycin is the treatment of choice for most MRSA infections. By 1996, first case of vancomycin resistance S. aureus (VRSA) was reported in Japan followed by few cases worldwide.14 Having Australia as an exception, VRSA cases seen so far have arisen from MRSA infections. The development of mutations in vancomycin resistance is due to long-term exposure to this drug mainly on patients with renal failure and/or diabetes. Hence, Australia importantly implemented to preserve this drug as an antibiotic of 'last resort' to treat MRSA.14 Preventing resistance from emerging in the first instance through judicious use of vancomycin may prevent MRSA from becoming VRSA directly.14 104
Conclusion
MRSA strains are now commonly caused both hospital and community-acquired infections in many parts of Australia where treating both is of particular important. Delay in treatment of these infections may lead to increase mortality or prolong morbidity. Susceptibility tests on S. aureus must be done promptly in detection of MRSA to provide advice on suitable antimicrobials to prevent misuse and overuse. Ongoing surveillance by the AGAR team is essential to assess progress of the epidemic of MRSA in the Australian community and closely monitor the changes in susceptibility of the epidemic strains. 92
