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Rapid PCR diagnostics for MRSA and MSSA

In Blackpool Teaching Hospitals NHS Foundation Trust, the introduction of rapid PCR testing was associated with a reduction in the number of MRSA infections, including bacteraemias
Achyut Guleri MD FRCPath
Rashmi Sharma FRCPath MD MRCOG
Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, UK
Aidan Kehoe BSc
Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
Annie M Jones MSc MBA
MSC Ltd, Old Malton, North Yorks, UK
Staphylococcus aureus is a gram-positive bacterium that colonises the skin and is present in the anterior nares in approximately 25–30% of healthy individuals.(1) S. aureus readily acquires resistance to all classes of antibiotics by mutation of an existing bacterial gene or horizontal transfer of a resistance gene from another bacterium.
In many parts of the world, methicillin-resistant S. aureus (MRSA) is the most commonly isolated antibiotic-resistant pathogen, including Europe, the Americas, northern Africa, the Middle East and eastern Asia.1 Although international comparisons are difficult because of the difference in testing and surveillance systems, it has been estimated that, of the two billion individuals carrying S. aureus, between 2 and 53 million individuals carry MRSA globally.(1)
As with methicillin-sensitive S. aureus (MSSA), individuals can carry MRSA in their nares (which is referred to as colonised). The carriage rate of MRSA within a population will vary widely depending on the population sampled. Individuals who have had contact with healthcare institutions have an increased risk of being colonised with MRSA. Nosocomial infections caused by MRSA are frequently associated with treatment failure, remain unrecognised or result in inadequate treatment, prolonged subsequent treatment and/or hospitalisation and additional costs.(2) The severity of MRSA infections ranges from localised skin and soft tissue infections to life-threatening infections, such as bacteraemia and endocarditis. The risk of invasive MRSA infections increases with age and pre-existing co-morbidities.(3)
In the UK, healthcare-associated infections (HAIs) are associated with annual costs of approximately £2 billion, and an increased length of stay (LOS) of between three and ten days. Eighty five percent of these costs are borne by acute hospitals. Reducing HAIs by 60% could fund an extra 30 beds in the average acute hospital.(4)
The increase in MRSA has led a number of countries and organisations to recommend that patients be screened on admission to hospital, and in 2008 the Department of Health (DoH) issued guidance recommending admission screening of all elective patients by the end of March 2009 and all emergency patients by 2010.(5) In 2011, mandatory surveillance was extended to MSSA. The National Audit Office in the UK estimated that, between financial years 2003–04 and 2008–09, the reduction in the rates of MRSA bloodstream infections had saved the National Health Service (NHS) between £45 and £59 million in treatment costs alone ( A number of publications have assessed the benefits of mandatory screening and reported conflicting results and are summarised in the ‘Point Counterpoint’ discussion published in 2010,(6) but, as yet, it is still too early to assess the impact of this initiative in the UK.
Diagnostic tests
The literature on methicillin susceptibility testing is extensive, and often conflicting in recommendations regarding the most reliable method for routine use.(7) Methicillin minimum inhibitory concentrations (MICs), that is, the amount of antibiotic needed to inhibit the growth of bacteria on test medium, are affected by test conditions. Some reports of erroneous results in studies of MRSA detection methods may actually be due to failure to detect resistance with the reference MIC tests.(2) There is also variability between test methods and organisms with high versus low MICs.(8)
Solid media
The mainstay of all MRSA testing is the solid agar plate. Media based on cefoxitin are superior to those based on oxacillin for the detection of MRSA.(9) However, MRSA strains expressing heterogeneous resistance can often be mistaken for MSSA by conventional culture.(10) Chromogenic media that contain enzyme substrates targeting microbial enzymes have the advantage of high specificity.(11) The sensitivity of these media is improved when the incubation period is prolonged to 42 hours. Confirmatory testing is recommended for colonies isolated on routine media and for confirmation of suspected resistance.(7) 
Broth enrichment
The addition of a broth enrichment step before culturing on selective agar increases the sensitivity, but has the disadvantage of increasing the time to detection and the amount of labour required. Selective broths have enabled a slight reduction in the additional labour requirements.
Latex agglutination
The commercially available latex agglutination tests based on the detection of penicillin-binding protein (PBP) 2a allow the determination of whether or not a strain of S. aureus isolated during routine culture media is methicillin resistant. Although the sensitivity of latex agglutination tests is lower for MRSA than MSSA, they are a useful addition to the diagnostic armamentarium. These tests do not require specialist equipment and take approximately 30 minutes to perform. However, coagulase-negative Staphylococci (CoNS) can also carry the mecA gene, and mixed samples can produce false positive results. 
Molecular PCR testing
Real-time polymerase chain reaction (PCR) is used for the rapid detection of bacteria and other microorganisms. PCR testing is more sensitive than conventional or chromogenic agar testing (Table 1) and can provide a more rapid turnaround time.  When used routinely for screening, the workload per PCR decreases and outweighs the expenses for molecular reagents.(12) 
The Blackpool Experience of PCR Screening for MRSA
Blackpool Teaching Hospitals NHS Trust provides healthcare for a local population of approximately 440,000 and 12 million visitors. Per annum the Trust deals with 99,500 day cases and admissions, 295,000 outpatient and 91,000 Accident and Emergency (A&E) consultations. It has an annual budget of £335 million and employs 6000 staff. Between April 2007 and March 2008, 40 cases of MRSA bacteraemia were recorded against a DoH target of 26. This represented a rate of 1.33 per 10,000 bed days. At that time screening for MRSA was performed using conventional culture-based methodology. As stated earlier, this is both time consuming to perform and takes up to three days to obtain a result. This, in turn, can lead to delays in clinical decision making, unnecessary isolation precautions, antibiotic use and increased costs.
In April 2008, a decision was made to pilot the introduction of PCR testing for routine MRSA screening of all emergency patients admitted through A&E, Critical Care, the Cardiac Intensive Care Unit or the Medical and Surgical Admissions Unit over a 12-month period. 
Results of the pilot study
Over the 12 months of the pilot study, the number of MRSA bacteraemias reported in the Trust was nine versus the 40 recorded in the previous 12 months and against a DoH target of 26. The full results of this study were published in 2011.(13)
The cost savings achieved by the Trust from the reduction in the number of MRSA bacteraemias was calculated as £336,234 to £399,381. The costs associated with the use of PCR for screening was £396,285 (net saving –£60,050 to £3100). The analysis of savings from reduction in MRSA infections other than bacteraemias is being undertaken to gain an understanding of the overall savings.
Post-pilot study experience
The use of PCR screening has continued in our Trust. Until March 2012 the number of healthcare-associated MRSA infections including bacteraemias has continued to fall (Table 2). In addition, the number of MRSA wound, respiratory, urinary and other infections has also declined, with the total number of MRSA infections falling from 883 (2007–08) to 245 (2011–12).
In addition to the progressive reduction in healthcare-associated MRSA infections, the introduction of PCR screening has had a positive effect on bed management within the Trust. The Trust was also awarded an HCAI technology and innovation award in 2009 and a patient safety award in 2011. Since 2010, the Trust has embarked on extending the use of PCR testing to screen for MSSA in surgical patients. A positive result from MRSA/MSSA pre-surgical screening is followed by topical decolonisation for colonised patients. Infected patients receive appropriate antibiotic treatment guided by site and severity of infection, underlying medical conditions and known allergies.
Statistical process control (SPC)-based analysis has been introduced in collaboration with Lightfoot Solutions Ltd.  The aims of this project are to investigate the impact of MSSA/MRSA screening on LOS, readmissions to the Trust and overall mortality using local costings. Preliminary analysis of these data show a positive trend in terms of all of these parameters. It is hoped that the full results of this initiative will be available in 2013.
Screening for MRSA to detect carriage, particularly in asymptomatic individuals, facilitates the timely use of appropriate infection control measures. In Blackpool, the introduction of PCR testing was associated with a reduction in the number of MRSA infections including bacteraemias.
However, the choice of screening technology remains a challenge. PCR molecular detection combines good sensitivity, specificity and, importantly, speed. In the current study, the costs of PCR screening were offset by the dramatic reduction in treatment costs (both in terms of LOS and antibiotic acquisition costs). 
We would like to acknowledge the support of Mr Barrie Lunt, Senior BMS Microbiology, Blackpool, Fylde and Wyre Hospitals for providing the analysis of the data included in Table 1 and the corresponding text. 
  1. Grundmann H et al. Emergence and resurgence of meticillin-resistant Staphylococcus aureus as a public-health threat. Lancet 2006;368(9538):874–85.
  2. Carroll KC. Rapid diagnostics for methicillin-resistant Staphylococcus aureus: current status. Mol Diagn Ther 2008;12(1):15–24.
  3. Nathwani D et al. Guidelines for UK practice for the diagnosis and management of methicillin-resistant Staphylococcus aureus (MRSA) infections presenting in the community. J Antimicrob Chemother 2008;61(5):976–94.
  4. National Audit Office. Reducing Healthcare Associated Infections in Hospitals in England. National Audit Office;2009.
  5. Department of Health. MRSA screening – operational guidance;2008.
  6. Peterson LR, Diekema DJ. To screen or not to screen for methicillin-resistant Staphylococcus aureus. J Clin Microbiol 2010;48(3):683–9.
  7. Brown DF et al. Guidelines for the laboratory diagnosis and susceptibility testing of methicillin-resistant Staphylococcus aureus (MRSA). J Antimicrob Chemother 2005;56(6):1000–18.
  8. Hsu DI et al. Comparison of method-specific vancomycin minimum inhibitory concentration values and their predictability for treatment outcome of meticillin-resistant Staphylococcus aureus (MRSA) infections. Int J Antimicrob Agents 2008;32(5):378–85.
  9. Smyth RW, Kahlmeter G. Mannitol salt agar-cefoxitin combination as a screening medium for methicillin-resistant Staphylococcus aureus. J Clin Microbiol 2005;43(8):3797–9.
  10. Malhotra-Kumar S et al. Current trends in rapid diagnostics for methicillin-resistant Staphylococcus aureus and glycopeptide-resistant enterococcus species. J Clin Microbiol 2008;46(5):1577–87.
  11. Nonhoff C et al. Comparison of three chromogenic media and enrichment broth media for the detection of methicillin-resistant Staphylococcus aureus from mucocutaneous screening specimens: Comparison of MRSA chromogenic media. Eur J Clin Microbiol Infect Dis 2009;28(4):363–9.
  12. Wassenberg MW et al. Rapid screening of methicillin-resistant Staphylococcus aureus using PCR and chromogenic agar: a prospective study to evaluate costs and effects. Clin Microbiol Infect 2010;16(12):1754–61.
  13. Guleri A et al. The costs and benefits of hospital MRSA screening. Br J Healthcare Manage 2011;17(2):64–71.