Methicillin-resistant Staphylococcus aureus in the Australian community: an evolving epidemic

The emergence of new hypervirulent strains of methicillin-resistant Staphylococcus aureus (MRSA) causing moderate to severe community-acquired infections is now a worldwide phenomenon. Epidemics have been reported in Canada,1 the United States,2 and Europe.3 These reports have a number of findings in common including: lack of association with risk factors for health care-associated acquisition of MRSA; lack of resistance to non-β-lactam antibiotics; frequent association with indigenous populations; and association with subcutaneous abscess formation and necrotising pneumonia. The latter clinical conditions have been shown to correlate strongly with possession of the genes for Panton–Valentine leukocidin (PVL), an extracellular toxin that destroys leucocytes and causes tissue necrosis.3,4

In Australia, non-multiresistant MRSA associated with community infection (CA-MRSA) was first observed in Western Australia in the early 1990s, initially in Indigenous people in remote communities, and became known as WA-MRSA.5 Subsequently, other strains of CA-MRSA appeared in WA. Infection caused by CA-MRSA was first noted in the eastern states in the mid-1990s.6 Studies in Queensland7 and New South Wales8 initially reported a strong association between community-acquired infection with non-multiresistant MRSA and Polynesian background. The “south-west Pacific” (SWP) strain of CA-MRSA causing these infections was indistinguishable from that reported previously in Auckland, New Zealand,7,8 and was initially characterised by the western Samoan phage typing pattern. A second strain, the “QLD” strain, was first identified in Queensland in 2000, causing community-acquired infection in people of European background.9

Both the SWP and QLD strains, but not the WA strains, usually carry PVL genes and are associated with abscess formation, bacteraemia and necrotising pneumonia.3,10,11 However, PVL genes are carried on prophages, which are capable of generating bacteriophages (viruses that infect baceria) and consequently have the potential to spread to other strains of S. aureus.12

The epidemiology of community-onset MRSA can be confusing. Because of the differences in virulence, spectrum of infection and antibiotic sensitivity patterns, it is important to distinguish between infections caused by MRSA strains circulating in the community and not found in hospitals, and infections with onset in the community caused by health care-associated strains (HA-MRSA). The spread of the latter into the community is well documented, although these strains do not spread readily from person to person in the community.13 The distinction between these two types of acquisition is based on the patient’s risk factors for health care acquisition, such as recent hospitalisation, surgery, antibiotic medication, chronic medical conditions, long-term care and health care occupational status.14 It is also possible to discriminate between these epidemiologically distinct strains by a variety of molecular typing methods.

The Australian Group for Antimicrobial Resistance (AGAR) previously established that the predominant MRSA strains circulating in the community are WA-1, SWP and QLD, which are now widely dispersed geographically.15 This report describes changes in prevalence and geographic range of community-associated strains and the extent of PVL gene carriage in community-associated strains.

In the 2004 survey, we assessed 2652 isolates of S. aureus, compared with 2486 in the 2000 survey, and 2488 in 2002. In 2004, 14.9% of isolates (395/2652) were resistant to oxacillin (and therefore methicillin), compared with 10.3% in 2000 (257/2498), and 15.2% in 2002 (363/2386).

The proportion of S. aureus isolates which were HA-MRSA and CA-MRSA differed significantly between the three surveys (P = 0.006 and P = 0.001, respectively; Box 1). However, when analysed by city, HA-MRSA proportions differed significantly between surveys only in Darwin (P = 0.03).

Significant increases in CA-MRSA occurred over the same period in four cities: Darwin (5% to 20%, P = 0.003), Brisbane (5% to 13%, P < 0.0001), Sydney (5% to 8%, P = 0.04), and Adelaide (3% to 7%, P = 0.03). The total proportion of CA-MRSA also increased significantly, from 4.7% in 2000 to 7.3% by 2004 (P = 0.001). In 2004, CA-MRSA strains accounted for over 10% of all clinical outpatient isolates of S. aureus in Darwin, Brisbane and Perth. The proportion of CA-MRSA strains in Melbourne and Hobart remained lower than in other states and did not increase significantly.

The concurrent emergence and expansion of multiple PVL-positive CA-MRSA clones on different continents has been rapid and striking. This epidemic has been very well documented in Australia by AGAR: annual studies conducted exclusively in teaching hospitals from 1989 to 1999 showed that non-multiresistant MRSA, a surrogate marker for CA-MRSA, began to increase in Perth in the early 1990s and in more easterly cities in the late 1990s.10

The biennial studies reported here and previously have established the major strains causing community-onset MRSA infection in Australia.15 Clearly, CA-MRSA now represents a major clinical and public health problem. The large distances between Australian cities have been no barrier to the rapid spread of the major epidemic strains, WA-1, SWP and QLD. The first two of these are pandemic strains which have appeared on multiple continents.3,18,19 Demonstration of the presence of the relatively small SCCmec type IV element (one of a range of elements responsible for methicillin resistance) in increasing numbers of lineages of S. aureus is of great concern: this element is of a size (about 28 kilobases) to allow spread by bacteriophage transduction.

The increase in prevalence of CA-MRSA is due to two mechanisms: first, clonal expansion of successful lineages, such as the QLD strain; and second, the transmission of SCCmec to an increasing number of lineages of S. aureus. This raises the prospect of widespread acquisition of methicillin resistance in S. aureus, similar to the spread of penicillin resistance seen in the latter half of the 20th century, which led to penicillin resistance levels greater than 80%.10,20 Furthermore, the ability of CA-MRSA strains to acquire resistance to other antimicrobials will almost certainly pose a longer term challenge. While only 2% of CA-MRSA isolates were resistant to more than three non-β-lactam antimicrobials in the 2004 survey, no CA-MRSA isolates had that level of resistance in the previous two surveys.

The spread of virulence genes is also a potential problem. PVL genes are carried on a prophage and so can be transmitted to receptive strains by transduction.12 We demonstrated the presence of PVL in five CA-MRSA strains, three of which (WA-1, QLD and SWP) are major epidemic strains. PVL has been described in WA-1 only recently,21,22 and clinical data on the association of this strain with severe infections are lacking. Nonetheless, it has recently been suggested that drugs that shut down ribosomal translation of proteins in S. aureus, such as clindamycin and linezolid, might decrease production of toxins such as PVL. Therefore, these drugs may be specifically indicated in the treatment of serious CA-MRSA infections.23 This hypothesis remains to be tested in vivo.

As CA-MRSA strains are now common in many parts of Australia, it is important that doctors consider that any staphylococcal infection — acquired in the community or in hospital — may be caused by MRSA. It is important to collect appropriate microbiological specimens, such as swabs for localised infections and blood cultures for systemic infections, for culture and susceptibility testing. Delay in recognition that these infections are caused by MRSA can in turn delay definitive treatment, and this may lead to increased mortality or prolonged morbidity.11,24 Laboratories need to expedite detection of MRSA, report sensitivity to an appropriate range of non-β-lactam antibiotics, and provide advice on suitable antimicrobials.

The choice of empirical treatment should be guided by the severity of infection, the presence of risk factors for HA-MRSA infection, and the local prevalence of CA-MRSA. Where MRSA is likely, vancomycin is suggested for cases of severe or life-threatening infection, while linezolid may be considered as a second-line agent.25

If infection is mild, it is still reasonable to prescribe flu(di)cloxacillin (or alternative β-lactams in cases of intolerance or allergy), given that most strains of S. aureus are still sensitive to β-lactams. However, should MRSA be isolated, therapy should be changed to an appropriate agent. A number of readily available oral agents can be used in mild to moderate infections. Clindamycin has been suggested, but may not always be appropriate because of the presence of inducible resistance in some CA-MRSA strains.25 Erythromycin is the best indicator of this type of resistance in Australia, and we found that 14% of PVL-positive CA-MRSA isolates in this survey were resistant to erythromycin. The use of tetracyclines such as doxycycline is supported by a retrospective case series and case reports.26 Trimethoprim–sulfamethoxazole was found to be equivalent to vancomycin in serious MRSA infections in injecting drug users,27 and there is also evidence of its success in less serious community MRSA infections.28

Therefore, clindamycin, doxycycline or trimethoprim–sulfamethoxazole may be used for mild to moderate CA-MRSA infections, depending on susceptibility results. However, tetracyclines should not be used in children aged under 8 years, and trimethoprim–sulfamethoxazole should not be used in infants under 8 weeks. Ongoing surveillance is essential to assess progress of the epidemic of MRSA in the community in Australia and changes in susceptibility of the epidemic strains.