14 October 2010
Methicillin-resistant Staphylococcus aureus (MRSA): burden of disease and control challenges in Europe
Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of healthcare- and community-associated infections worldwide. Within the healthcare setting alone, MRSA infections are estimated to affect more than 150,000 patients annually in the European Union (EU), resulting in attributable extra in-hospital costs of EUR 380 million for EU healthcare systems. Pan-European surveillance data on bloodstream infections show marked variability among EU Member States in the proportion of S. aureus that are methicillin-resistant, ranging from less than 1% to more than 50%. In the past five years, the MRSA bacteraemia rates have decreased significantly in 10 EU countries with higher endemic rates of MRSA infections. In addition to healthcare-associated infections, new MRSA strains have recently emerged as community- and livestock-associated human pathogens in most EU Member States. The prevention and control of MRSA have therefore been identified as public health priorities in the EU. In this review, we describe the current burden of MRSA infections in healthcare and community settings across Europe and outline the main threats caused by recent changes in the epidemiology of MRSA. Thereby, we aim at identifying unmet needs of surveillance, prevention and control of MRSA in Europe.
Concern about the burden of healthcare-associated infections (HAIs) has a significant European dimension. It has been estimated that 8–12% of patients admitted to hospitals in European countries suffer from adverse events while receiving healthcare, with HAIs being the most prominent of them . The European Centre for Disease Prevention and Control (ECDC) has calculated that HAIs involve 4.1 million patients annually in the European Union (EU) Member States and that such infections directly result in approximately 37,000 deaths . This worrisome incidence of HAIs is rightly considered a major patient safety issue. Another cause for concern is the continuous emergence of various multidrug-resistant bacteria in many healthcare institutions, which narrows the spectrum of effective antibiotics to a clinically challenging extent. Against this background, the Council of the EU has recently launched a recommendation to Member States and the Commission to prevent HAIs and promote patient safety by community, national and institutional action plans .
Among the multiresistant bacteria, methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of HAIs in the EU. In 2008, over 380,000 HAIs due to selected antibiotic-resistant bacteria, including those of the bloodstream, lower respiratory tract, skin or soft tissues and urinary tract, were estimated to be acquired annually in hospitals of the EU Member States, Iceland and Norway . Overall, MRSA accounts for 44% (n=171,200) of these HAIs, 22% (n=5,400) of attributable extra deaths and 41% (n=1,050,000) of extra days of hospitalisation associated with these infections . The attributable extra in-hospital costs caused by MRSA are estimated to reach approximately EUR 380 million annually . Moreover, the vast extent of MRSA infections has both evoked fear and fuelled public distrust about healthcare. For many healthcare consumers, this has made MRSA bloodstream infection rates an indicator of both quality of care and outcome.
In addition to the healthcare settings (healthcare-associated methicillin-resistant Staphylococcus aureus, HA-MRSA) , the burden of MRSA colonisation and infection has recently expanded to further ecological niches. Since the 1990s, an increasing incidence of MRSA infections arising in the community (community-associated methicillin-resistant Staphylococcus aureus, CA-MRSA) has been reported from many countries worldwide . More recently, MRSA have been found to colonise or infect livestock and humans exposed to those animals in several countries. Such MRSA have been dubbed livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) . Interactions between these different reservoirs for MRSA have been reported, including nosocomial infections by CA-MRSA [5,6] and importation of LA-MRSA into hospitals .
MRSA is amongst the most challenging infection control issues. In this review, we delineate the burden of MRSA disease in Europe across healthcare sectors and review the economic impact of MRSA infections. Finally, we outline threats due to recent changes in the epidemiology of MRSA and identify unmet needs regarding surveillance, prevention and control of MRSA in Europe.
We searched PubMed and supplemented this with articles from our personal archives to retrieve the literature for this review. For the PubMed search, a restriction to articles published between 2001 and 2009 and written in English was applied. Our review is structured in two sections: (i). Epidemiology and burden of MRSA infections, in which we outline the main determinants of MRSA disease burden, compared to infections by methicillin-susceptible S. aureus (MSSA), and summarise recent trends in the epidemiology of MRSA in Europe in healthcare facilities, the community and livestock; and (ii). Discussion on new reservoirs and control challenges, where, against the background of data described in the first section, we identify potential threats from the current epidemiology of MRSA in Europe and discuss perspectives for the prevention and control of MRSA in European countries.
Epidemiology and burden of MRSA infections
Burden of disease
Monitoring the epidemiology and the burden of MRSA infections in European countries is crucial. This has been underlined by the finding that MRSA does not just replace MSSA as a causative agent for infections, but frequently adds to the latter’s disease burden, leading to a net increase in the incidence of S. aureus infections (Table 1) [8,9].
Table 1. Key elements in the recent epidemiology of MRSA infections in Europe
Moreover, it has been debated whether MRSA bacteraemia causes higher mortality than MSSA bacteraemia, e.g. due to vancomycin’s inferiority in the treatment of deep-seated S. aureus infections, compared with semi-synthetic penicillins, compared with semi-synthetic penicillins used for MSSA . Two meta-analyses have found an increased mortality risk of 1.93 (95% CI: 1.54 to 2.42)  and 2.03 (95% CI: 1.55 to 2.65)  associated with MRSA bacteraemia compared with MSSA. However, there is an ongoing discussion about methodological flaws of the studies included in these meta-analyses, e.g. with respect to whether they fully adjusted for appropriateness of therapy and severity of underlying diseases. Table 2 contains an update of additional (published between 2001 and 2009) regarding this issue: their results still do not clearly answer the initial question.
Table 2. Estimates of mortality of MRSA bacteraemia compared with MSSA bacteraemia from studies published between 2001 and 2009*
Besides effects on mortality, several studies mainly from the USA have indicated that MRSA infections cause a significant additional financial burden over MSSA infections after adjustment for co-morbidities, which is largely the result of prolonged hospital stay and occupation of isolation rooms (Table 3).
Table 3. Estimates from recently published (2001–2009) studies of hospital financial burden associated with MRSA infections compared with MSSA infections
Moreover, a Dutch study has recently estimated that the implementation of a MRSA ’search and destroy’ policy was highly cost–effective in one hospital under investigation . During the study period, no MRSA bacteraemia was observed in this hospital. Assuming that 50% of all nosocomial S. aureus would be MRSA, if no search and destroy strategy had been implemented the authors estimated 36 MRSA bacteraemia cases per year were thus avoided .
Furthermore, it has been found that MRSA carriers are at risk for MRSA infection, since up to 29% of persons colonised with MRSA subsequently develop MRSA morbidity [30,31]. For example, MRSA carriers in long-term care facilities have a 1.4-fold increased risk for mortality within 36 months  and 5% of long-term carriers have been shown to die because of an MRSA infection within four years of carriage .
Epidemiology of healthcare-associated MRSA
Nosocomial infections acquired by patients receiving institutional healthcare have long been the classical presentation of MRSA infections. Risk factors for MRSA acquisition include hospital care, care in chronic care facilities and nursing homes for elderly people, presence of indwelling devices or chronic wounds and previous antibiotic treatment.
The majority of HA-MRSA strains isolated in European countries have emerged from the introduction of the staphylococcal cassette chromosome mec (SCCmec) harbouring the methicillin-resistance gene mecA, into five S. aureus clonal complexes (CC), as defined by multi–locus sequence typing (MLST): CC5, CC8, CC22, CC30 and CC45 .
Recent data on the burden of HA-MRSA disease on a European scale are available from two surveillance systems supported by ECDC (EARSS, HELICS). The European Antimicrobial Resistance Surveillance System (EARSS) is used in most European countries to record the incidence of bloodstream and cerebrospinal MRSA infections, representing severe clinical courses of (mostly HA-) MRSA morbidity. As shown recently, hospitals contributing to EARSS provide care for about 20% of the EU population, accession countries and Israel . However, EARSS coverage ranges between 5% and 100%, depending on the country, and therefore representative data from all countries are not available . In 2008, the proportion of MRSA in S. aureus blood culture isolates was less than 5% in Denmark, Estonia, Finland, Iceland, the Netherlands, Norway and Sweden. In three countries (Austria, Luxembourg, Slovenia), a proportion of less than 10% was found, while in eight countries the proportion was between 10%-24% (Belgium, Czech Republic, France, Germany, Hungary, Latvia, Poland, Switzerland) In total, 13 countries reported a proportion equal to or above 25% (Bulgaria, Croatia, Cyprus, Greece, Israel, Italy, Malta, Portugal, Republic of Ireland, Romania, Spain, Turkey, United Kingdom) including two countries (Malta, Portugal) with proportions above 50% .
The attributable fraction of HAI caused by MRSA is documented by the EU-wide surveillance network of infections in intensive care units (ICUs), which was established under the name “HELICS”. In 2007, the HELICS network (involving 13 European countries) reported that, of 54,574 patients staying in an ICU for more than two days, 6.2% acquired pneumonia. Overall, 17% of all cases of ICU-acquired pneumonia  were caused by S. aureus, 33% of which were MRSA. Moreover, ICU-acquired BSIs were caused by S. aureus in 11% of all 4,812 cases included in the report with an MRSA proportion of 42% .
According to EARSS 2008 data, a significant declining trend of invasive MRSA infections has been observed in Austria, Poland, Latvia, Romania, Italy, France, Belgium and the United Kingdom over the last four years of surveillance . Likewise, there was a significant decrease in the mean incidence of ICU-acquired MRSA infection reported via HELICS between 2004 and 2007 . These trends illustrate that many European countries have experienced successes in the prevention and control of MRSA in the healthcare setting as indicated by either continuously low incidence rates or recently decreasing rates of MRSA infections.
Epidemiology of community-associated MRSA
Until the 1990s, infections due to MRSA were rarely observed in the community. Since then, a rapid emergence of CA-MRSA was first reported from Australia and the USA, where outbreaks were described amongst underprivileged aboriginal communities, schoolchildren, prison inmates, soldiers, athletes and men who have sex with men . These communities have not been reported so far as major reservoirs for CA-MRSA in Europe. Risk factors for the development of CA-MRSA infection include close contact with other people with CA-MRSA, e.g. having a family member from a country with a high prevalence of CA-MRSA, living in crowded facilities, poor hygiene, sharing of personal items and performing contact sports [36,37]. These observations help to elucidate the spread of MRSA outside healthcare settings. So far, the most important risk factor for CA-MRSA infections in many European countries is travel to countries with a higher prevalence of CA-MRSA [38-40].
CA-MRSA causes mainly skin- and soft-tissue infections ranging in severity from furuncles to necrotising fasciitis . Moreover, the description of serious invasive CA-MRSA infections, such as necrotising pneumonia, is cause for concern, because these infections are associated with a lethality of up to 75% .
The epidemic rise in CA-MRSA infections in the USA was mainly due to the successful spread of an MRSA strain associated with the pulsed-field gel electrophoresis (PFGE) profile USA300 within the MLST ST8/SCCmec IV clone and harbouring the lukS-lukF genes, encoding the Panton-Valentine leukocidin (PVL) . Other clones have contributed to this epidemic to a lesser extent .
In several European countries, infections due to the predominant USA clone (USA300/ST8) have also been reported [39,42-44]. However, the spread of this clone seems hitherto limited in Europe where other PVL-positive CA-MRSA clones, especially ST80/t044/SCCmec IV, are also prevalent [3,46].
Defining the overall burden of CA-MRSA in European countries and comparing proportions of CA-MRSA among all MRSA isolates between different studies is hindered by differences in the definitions used . However, the proportion of CA-MRSA with respect to total MRSA is reported to range between 1% and 2% in Spain and Germany [42,43] and 29–56% in Denmark and Sweden, partly reflecting the low prevalence of HA-MRSA in these Scandinavian countries [47,48]. Among outpatients with S. aureus infections, MRSA accounted for 6% in the Ligurian region in Italy , 14% in Germany , 18% in France  and 30% in Greece .
Epidemiology of livestock-associated MRSA
Recently, it has been found that the burden of MRSA colonisation and infection also involves animals, particularly livestock. In Europe, a recent survey published by the European Food Safety Authority (EFSA) identified MRSA in pig holdings of 17 EU Member States . The MRSA clone, which was isolated from the vast majority of pigs, was non-typeable by PFGE after SmaI digestion – due to DNA methylation not, however, affecting the SmaI isoschizomer Cfr9I  – was tetracycline-resistant, and belonged to MLST CC398 .Besides swine, MRSA CC398 strains have also been detected in other animals such as cattle  and poultry . Although the animals are mostly colonised by MRSA, infections have been described in pigs  and horses .
The impact of a livestock reservoir for humans is currently under investigation. Whereas 23–38% of persons having contact with MRSA-positive pigs or veal calves were colonised with MRSA [7,58,59], only 4% of their family members, who had no direct exposure to the animals, were colonised in one study . In areas with a high density of MRSA CC398-positive swine, this clone can influence the MRSA epidemiology markedly in healthcare settings. For instance, it has led to a three-fold increase in MRSA incidence over a few years in a Dutch hospital located in a pig-dense area , and, in a German hospital situated in a region with intense livestock farming, 22% of MRSA patients colonised with MRSA at hospital admission carried it .
This continuous import of MRSA CC398 from an animal reservoir into hospitals can result in nosocomial spread of MRSA to patient groups susceptible to the development of MRSA infections . Nosocomial transmission of MRSA CC398 has indeed been reported . Moreover, this strain has caused severe human infections such as endocarditis, soft-tissue infections and ventilator-associated pneumonia [63-65].
Nevertheless, the burden of human infections caused by MRSA CC398 in Europe remains poorly understood. The proportion of MRSA CC398 among all MRSA ranges from 0.3% in Germany  to 41% in the Netherlands . Matters of further concern include the facts that PVL-encoding genes have been detected in a few MRSA CC398 isolates  and a cfr plasmid conferring resistance against oxazolidinones was found in an MRSA CC398 background .
Another potential human health threat is related to food contamination with MRSA, which was documented by a Dutch study in 11.9% of retail meat products from several animal species, including beef (10.6%), pork (10.7%) and chicken (16%) ; detection by use of
enrichment cultures only suggests low quantity contamination. The majority of these isolates belonged to the CC398 lineage, with only 15% to other clonal lineages . To date, two outbreaks of human disease have been related to the consumption of MRSA-contaminated meat, one as a classical food intoxication  and the other with contaminated food as the source of nosocomial transmission . Both were caused by non-CC398 MRSA strains. Thus, presently, food does not seem to be an important source for MRSA transmission or infection.
New reservoirs and control challenges
The recently decreasing or maintained low-level incidence of HA-MRSA in BSIs in many European countries  is encouraging. In a majority of countries, these successes can be linked to the implementation of multi-faceted preventive interventions (including measures focussing on screening, contact precautions, decolonisation, antibiotic stewardship, or bundles of preventive measures and care). In France, a national hospital infection control programme has been initiated and developed over 16 years, resulting in a 30% reduction of surgical site infections and a 20% decrease in MRSA rates from blood cultures . In Belgium, a sustained decrease in the incidence of HA-MRSA infections was recorded between 2004 and 2008, measureable as a decrease in the mean proportion of MRSA of S. aureus (30–25%) and a decrease in the median incidence of nosocomial MRSA (3.2 to 1.6 per 100 admissions) . This success has been achieved by a multi–faceted approach, including the update and strengthening of national MRSA guidelines, the extension of prospective surveillance and screening activities , and activities to promote the prudent use of antibiotics . In England, a governmental reduction target in MRSA bacteraemia was set in 2004, demanding halving the number of MRSA isolated from blood cultures by 2008, against the baseline of 2003–2004. In order to achieve this aim, a bundle of measures was consecutively implemented in English hospitals, including the mandatory reporting of all MRSA bacteraemia by the hospital chief executive officers, public benchmarking of MRSA incidence rates, the production of guidance on preventing HAIs, the establishment of a national hand hygiene campaign, prudent use of antibiotics, and the implementation of so called ’high impact interventions’, i.e. care bundles focussing on key clinical procedures that can increase the risk of infection if not performed appropriately (e.g. central venous catheter care) . After five years, data confirm a 62% reduction in the incidence of MRSA from blood cultures in England .
To what extent the multi–faceted approaches linked to the decreasing trends in MRSA infections in these countries can serve as examples of good practice for planning and implementing national control interventions in other EU countries with different healthcare structures and resource attribution, remains to be seen.
Nevertheless, the burden of HA-MRSA extends beyond acute care hospitals to long-term care facilities (LCTFs), such as nursing homes. This has been underlined in several studies showing high prevalence rates of MRSA carriage among LTCF residents and marked rate variation between nursing homes and regions in Belgium (2–43%) , Germany (1%) , Spain (16%) , France (38%)  and the UK (5–23%) [82,83]. Despite this variation, in the majority of cases, the clonal structure of MRSA isolates from nursing home residents was closely related to that found among patients in neighbouring acute care hospitals . In addition, a recent study has shown that within six weeks after discharge from a hospital, less than 14% of LTCF residents are readmitted , which highlights that an appreciable percentage of patients circulates between hospital and LTCF several times per year. Consequently, effective MRSA containment in the healthcare setting cannot be limited to acute care hospitals, but must include LCTFs also. Otherwise, the significant MRSA reservoir that has developed in LTCFs and the transmission dynamics between LTCFs and acute care hospitals due to the transfer of patients is bound to compromise control. That this problem may be underestimated is indeed suggested by an admittedly limited number of published investigations .
A second challenge concerns CA-MRSA which has now emerged across Europe. Although its prevalence is still considerably lower than in the USA, the number of CA-MRSA infections appears to be increasing, especially in those European countries where the incidence of HA-MRSA is low and surveillance of MRSA more extensive [30,31]. The problem of CA-MRSA infections is not limited to the community but also affects nosocomial infections due to the introduction of CA-MRSA in healthcare settings [86,87]. In addition, only a limited number of European countries have developed national strategies and no common European strategy has yet been developed for the surveillance or the prevention of CA-MRSA spread.
The final challenge to tackle is the animal MRSA reservoir. Despite the EU-wide spread of MRSA in pigs, its implications for humans directly or indirectly exposed to livestock and for patients attending healthcare institutions located in farming areas remain unclear. Although epidemic spread of LA-MRSA among persons without direct contact to animals is rare, and the burden of human infections caused by LA-MRSA strains is still lower than that observed for CA-MRSA, infection control guidelines in many European countries should address the potential risk of acquiring MRSA via contact with livestock farming.
MRSA infections constitute an important and still evolving public health challenge for European countries. Successful MRSA control in some countries and facilities offers opportunities for identifying effective interventions and reassessment of best practice. In contrast, the rapid emergence of MRSA in the community and in livestock underpins the fact that MRSA transmission can occur in everyday life, in home care, during travel, leisure activities, cross-border commuting, exposure to contaminated food samples or livestock transport. For long-term success in controlling MRSA, coordinated actions between different healthcare sectors (acute, long-term, ambulatory) and veterinary care are warranted and concerted efforts at European level will be of increasing importance. These efforts should begin with an agreement upon definitions for CA- and LA-MRSA and continue with the improvement of evidence-based guidance and the implementation of preventive measures to result in better prevention and control of MRSA in Europe (Table 4).
Table 4. Controlling MRSA: public health challenges and perspectives
* Erratum: by mistake, a wrong table (Table 2) was posted with the original article. We apologise for this error and corrected it on 15 October 2010.
- Council of the European Union. Council recommendation of 9 June 2009 on patient safety, including the prevention and control of healthcare-associated infections (2009/C151/01). Official Journal of the European Union. 3 Jul 2009. Available from: http://ec.europa.eu/health/patient_safety/docs/council_2009_en.pdf
- European Centre for Disease Prevention and Control/European Medicines Agency (ECDC/EMEA). Joint technical report The bacterial challenge: time to react. Stockholm:ECDC/EMEA; 2009. Available from: http://www.ecdc.europa.eu/en/publications/Publications/0909_TER_The_Bacterial_Challenge_Time_to_React.pdf
- Deurenberg RH, Vink C, Kalenic S, Friedrich AW, Bruggeman CA, Stobberingh EE. The molecular evolution of methicillin-resistant Staphylococcus aureus. Clin Microbiol Infect. 2007;13(3):222-35.
- Nemati M, Hermans K, Lipinska U, Denis O, Deplano A, Struelens M, et al. Antimicrobial resistance of old and recent Staphylococcus aureus isolates from poultry: first detection of livestock-associated methicillin-resistant strain ST398. Antimicrob Agents Chemother. 2008;52(10):3817-9.
- Moore CL, Hingwe A, Donabedian SM, Perri MB, Davis SL, Haque NZ, et al. Comparative evaluation of epidemiology and outcomes of methicillin-resistant Staphylococcus aureus (MRSA) USA300 infections causing community- and healthcare-associated infections. Int J Antimicrob Agents. 2009;34(2):148-55.
- Skov RL, Jensen KS. Community-associated meticillin-resistant Staphylococcus aureus as a cause of hospital-acquired infections. J Hosp Infect. 2009;73(4):364-70.
- van Rijen MM, Van Keulen PH, Kluytmans JA. Increase in a Dutch hospital of methicillin-resistant Staphylococcus aureus related to animal farming. Clin Infect Dis. 2008;46(2):261-3.
- Wyllie DH, Crook DW, Peto TE. Mortality after Staphylococcus aureus bacteremia in two hospitals in Oxfordshire, 1997-2003: cohort study. BMJ. 2006;333(7562):281.
- Stamm AM, Long MN, Belcher B. Higher overall nosocomial infection rate because of increased attack rate of methicillin-resistant Staphylococcus aureus. Am J Infect Control. 1993;21(2):70-4.
- Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, Carmeli Y. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis. 2003;36(1):53-9.
- Whitby M, McLaws ML, Berry G. Risk of death from methicillin-resistant Staphylococcus aureus bacteremia: a meta-analysis. Med J Aust. 2001;175(5):264-7.
- Wang F, Chen YY, Chen TL, Liu CY. Risk factors and mortality in patients with nosocomial Staphylococcus aureus bacteremia. Am J Infect Control. 2008;36(2):118-22.
- Blot SI, Vandewoude KH, Hoste EA, Colardyn FA. Outcome and attributable mortality in critically Ill patients with bacteremia involving methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Arch Intern Med. 2002;162(19):2229-35.
- Melzer M, Eykyn SJ, Gransden WR, Chinn S. Is methicillin-resistant Staphylococcus aureus more virulent than methicillin-susceptible S. aureus? A comparative cohort study of British patients with nosocomial infection and bacteremia. Clin Infect Dis. 2003;37(11):1453-60.
- Shurland S, Zhan M, Bradham DD, Roghmann M. Comparison of mortality risk associated with bacteremia due to methicillin-resistant and methicillin-susceptible Staphylococcus aureus. Infect Control Hosp Epidemiol. 2007;28(3):273-9.
- Reed SD, Friedman JY, Engemann JJ, Griffiths RI, Anstrom KJ, Kaye KS, et al. Costs and outcomes among hemodialysis-dependent patients with methicillin-resistant or methicillin-susceptible Staphylococcus aureus bacteremia. Infect Control Hosp Epidemiol. 2005;26(2):175-83.
- Talon D, Woronoff-Lemsi MC, Limat S, Bertrand X, Chatillon M, Gil H, et al. The impact of resistance to methicillin in Staphylococcus aureus bacteremia on mortality. Eur J Intern Med. 2002;13(1):31-36.
- Cosgrove SE, Qi Y, Kaye KS, Harbarth S, Karchmer AW, Carmeli Y. The impact of methicillin resistance in Staphylococcus aureus bacteremia on patient outcomes: mortality, length of stay, and hospital charges. Infect Control Hosp Epidemiol. 2005;26(2):166-74.
- Gastmeier P, Sohr D, Geffers C, Behnke M, Daschner F, Ruden H. Mortality risk factors with nosocomial Staphylococcus aureus infections in intensive care units: results from the German Nosocomial Infection Surveillance System (KISS). Infection. 2005;33(2):50-5.
- Lodise TP, McKinnon PS. Clinical and economic impact of methicillin resistance in patients with Staphylococcus aureus bacteremia. Diagn Microbiol Infect Dis. 2005;52(2):113-22.
- Guilarde AO, Turchi MD, Martelli CMT, Primo MG. Staphylococcus aureus bacteremia: incidence, risk factors and predictors for death in a Brazilian teaching hospital. J Hosp Infect. 2006;63(3):330-6.
- Wang JL, Chen SY, Wang JT, Wu GH, Chiang WC, Hsueh PR, et al. Comparison of both clinical features and mortality risk associated with bacteremia due to community-acquired methicillin-resistant Staphylococcus aureus and methicillin-susceptible S. aureus. Clin Infect Dis. 2008;46(6):799-806.
- Libert M, Elkholti M, Massaut J, Karmali R, Mascart G, Cherifi S. Risk factors for meticillin resistance and outcome of Staphylococcus aureus bloodstream infection in a Belgian university hospital. J Hosp Infect. 2008;68(1):17-24.
- Rieg S, Peyerl-Hoffmann G, de With K, Theilacker C, Wagner D, Hubner J, et al. Mortality of S. aureus bacteremia and infectious diseases specialist consultation--a study of 521 patients in Germany. J Infect. 2009;59(4):232-9.
- Malani PN, Rana MM, Banerjee M, Bradley SF. Staphylococcus aureus bloodstream infections: the association between age and mortality and functional status. J Am Geriatr Soc. 2008;56(8):1485-9.
- Engemann JJ, Carmeli Y, Cosgrove SE, Fowler VG, Bronstein MZ, Trivette SL, et al. Adverse clinical and economic outcomes attributable to methicillin resistance among patients with Staphylococcus aureus surgical site infection. Clin Infect Dis. 2003;36(5):592-8.
- Ben-David D, Novikov I, Mermel LA. Are there differences in hospital cost between patients with nosocomial methicillin-resistant Staphylococcus aureus bloodstream infection and those with methicillin-susceptible S. aureus bloodstream infection? Infect Control Hosp Epidemiol. 2009;30(5):453-60.
- Shorr AF, Tabak YP, Gupta V, Johannes RS, Liu LZ, Kollef MH. Morbidity and cost burden of methicillin-resistant Staphylococcus aureus in early onset ventilator-associated pneumonia. Crit Care. 2006;10(3):R97.
- van Rijen MM, Kluytmans JA. Costs and benefits of the MRSA Search and Destroy policy in a Dutch hospital. Eur J Clin Microbiol Infect Dis. 2009;28(10):1245-52.
- Datta R, Huang SS. Risk of infection and death due to methicillin-resistant Staphylococcus aureus in long-term carriers. Clin Infect Dis. 2008;47(2):176-81.
- Huang SS, Platt R. Risk of methicillin-resistant Staphylococcus aureus infection after previous infection or colonization. Clin Infect Dis. 2003;36(3):281-5.
- Suetens C, Niclaes L, Jans B, Verhaegen J, Schuermans A, Van Eldere J, et al. Methicillin-resistant Staphylococcus aureus colonization is associated with higher mortality in nursing home residents with impaired cognitive status. J Am Geriatr Soc. 2006;54(12):1854-60.
- European Antimicrobial Resistance Surveillance System (EARSS). EARSS Annual Report 2008. Bilthoven:EARSS; 2009. [Accessed 14 Jun 2010]. Available from: http://www.rivm.nl/earss/Images/EARSS%202008_final_tcm61-65020.pdf
- European Centre for Disease Prevention and Control (ECDC). Annual epidemiological report on communicable diseases in Europe 2009. Stockholm:ECDC; 2010. [Accessed 14 Jun 2010]. Available from: http://www.ecdc.europa.eu/en/publications/Publications/ 0910_SUR_Annual_Epidemiological_Report_on_Communicable_Diseases_in_Europe.pdf
- Tenover FC, Goering RV. Methicillin-resistant Staphylococcus aureus strain USA300: origin and epidemiology. J Antimicrob Chemother. 2009;64(3):441-6.
- Ellington MJ, Perry C, Ganner M, Warner M, McCormick S, Hill RL, et al. Clinical and molecular epidemiology of ciprofloxacin-susceptible MRSA encoding PVL in England and Wales. Eur J Clin Microbiol Infect Dis. 2009; 28(9):1113-21.
- Diederen BM, Kluytmans JA. The emergence of infections with community-associated methicillin resistant Staphylococcus aureus. J Infect. 2006;52(3):157-68.
- Denis O, Deplano A, De Beenhouwer H, Hallin M, Huysmans G, Garrino MG, et al. Polyclonal emergence and importation of community-acquired methicillin-resistant Staphylococcus aureus strains harbouring Panton-Valentine leucocidin genes in Belgium. J Antimicrob Chemother. 2005;56(6):1103-6.
- Larsen AR, Stegger M, Goering R, Sørum M, Skov R. Emergence and dissemination of the methicillin resistant Staphylococcus aureus USA300 clone in Denmark (2000-2005). Euro Surveill. 2007;12(2):pii=682. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=682
- Bocher S, Gervelmeyer A, Monnet DL, Molbak K, Skov RL, Danish CA-MRSA Study Group. Methicillin-resistant Staphylococcus aureus: risk factors associated with community-onset infections in Denmark. Clin Microbiol Infect. 2008;14(10):942-8.
- Gillet Y, Issartel B, Vanhems P, Fournet JC, Lina G, Bes M, et al. Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet. 2002;359(9308):753-9.
- Witte W, Strommenger B, Cuny C, Heuck D, Nuebel U. Methicillin-resistant Staphylococcus aureus containing the Panton-Valentine leucocidin gene in Germany in 2005 and 2006. J Antimicrob Chemother. 2007;60(6):1258-63.
- Manzur A, Dominguez AM, Pujol M, Gonzalez MP, Limon E, Hornero A, et al. Community-acquired methicillin-resistant Staphylococcus aureus infections: an emerging threat in Spain. Clin Microbiol Infect. 2008;14(4):377-80.
- Bartels MD, Boye K, Rhod Larsen A, Skov R, Westh H. Rapid increase of genetically diverse methicillin-resistant Staphylococcus aureus, Copenhagen, Denmark. Emerg Infect Dis. 2007;13(10):1533-40.
- Ruppitsch W, Stoger A, Schmid D, Fretz R, Indra A, Allerberger F, et al. Occurrence of the USA300 community-acquired Staphylococcus aureus clone in Austria. Euro Surveill. 2007;12(10):E071025.1.
- Goering RV, Larsen AR, Skov R, Tenover FC, Anderson KL, Dunman PM. Comparative genomic analysis of European and Middle Eastern community-associated methicillin-resistant Staphylococcus aureus (CC80:ST80-IV) isolates by high-density microarray. Clin Microbiol Infect. 2009; 15(8):748-55.
- Larsen AR, Stegger M, Bocher S, Sorum M, Monnet DL, Skov RL. Emergence and characterization of community-associated methicillin-resistant Staphyloccocus aureus infections in Denmark, 1999 to 2006. J Clin Microbiol. 2009;47(1):73-8.
- Fang H, Hedin G, Li G, Nord CE. Genetic diversity of community-associated methicillin-resistant Staphylococcus aureus in southern Stockholm, 2000-2005. Clin Microbiol Infect. 2008;14(4):370-6.
- Marchese A, Gualco L, Maioli E, Debbia E. Molecular analysis and susceptibility patterns of meticillin-resistant Staphylococcus aureus (MRSA) strains circulating in the community in the Ligurian area, a northern region of Italy: emergence of USA300 and EMRSA-15 clones. Int J Antimicrob Agents. 2009;34(5):424-8.
- Jappe U, Heuck D, Strommenger B, Wendt C, Werner G, Altmann D, et al. Staphylococcus aureus in dermatology outpatients with special emphasis on community-associated methicillin-resistant strains. J Invest Dermatol. 2008;128(11):2655-64.
- Thibaut S, Caillon J, Huart C, Grandjean G, Lombrail P, Potel G, et al. Susceptibility to the main antibiotics of Escherichia coli and Staphylococcus aureus strains identified in community acquired infections in France (MedQual, 2004-2007). Med Mal Infect. 2010;40(2):74-80.
- Vourli S, Vagiakou H, Ganteris G, Orfanidou M, Polemis M, Vatopoulos A, et al. High rates of community-acquired, Panton-Valentine leukocidin (PVL)- positive methicillin-resistant S. aureus (MRSA) infections in adult outpatients in Greece. Euro Surveill. 2009;14(2):pii=19089. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19089
- European Food Safety Authority (EFSA). Analysis of the baseline survey on the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in holdings with breeding pigs, in the EU, 2008 - Part A: MRSA prevalence estimates. EFSA Journal 2009;7(11):1376.
- Bosch T, de Neeling AJ, Schouls LM, van der Zwaluw KW, Kluytmans JA, Grundmann H, et al. PFGE diversity within the methicillin-resistant Staphylococcus aureus clonal lineage ST398. BMC Microbiol. 2010;10:40.
- Monecke S, Kuhnert P, Hotzel H, Slickers P, Ehricht R. Microarray based study on virulence-associated genes and resistance determinants of Staphylococcus aureus isolates from cattle. Vet Microbiol. 2007;125(1-2):128-40.
- Schwarz S, Kadlec K, Strommenger B. Methicillin-resistant Staphylococcus aureus and Staphylococcus pseudintermedius detected in the BfT-GermVet monitoring programme 2004-2006 in Germany. J Antimicrob Chemother. 2008;61(2):282-5.
- Cuny C, Strommenger B, Witte W, Stanek C. Clusters of infections in horses with MRSA ST1, ST254, and ST398 in a veterinary hospital. Microb Drug Resist. 2008;14(4):307-10.
- Voss A, Loeffen F, Bakker J, Klaassen C, Wulf M. Methicillin-resistant Staphylococcus aureus in pig farming. Emerg Infect Dis. 2005;11(12):1965-6.
- Denis O, Suetens C, Hallin M, Catry B, Ramboer I, Dispas M, et al. Methicillin-resistant Staphylococcus aureus ST398 in swine farm personnel, Belgium. Emerg Infect Dis. 2009;15(7):1098-101.
- Cuny C, Nathaus R, Layer F, Strommenger B, Altmann D, Witte W. Nasal colonization of humans with methicillin-resistant Staphylococcus aureus (MRSA) CC398 with and without exposure to pigs. PLoS One. 2009;4(8):e6800.
- Köck R, Harlizius J, Bressan N, Laerberg R, Wieler LH, Witte W, et al. Prevalence and molecular characteristics of methicillin-resistant Staphylococcus aureus (MRSA) among pigs on German farms and import of livestock-related MRSA into hospitals. Eur J Clin Microbiol Infect Dis. 2009;28(11):1375-82.
- Wulf MW, Markestein A, van der Linden FT, Voss A, Klaassen C, Verduin CM. First outbreak of methicillin-resistant Staphylococcus aureus ST398 in a Dutch hospital, June 2007. Euro Surveill. 2008;13(9):pii=8051. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=8051
- Ekkelenkamp MB, Sekkat M, Carpaij N, Troelstra A, Bonten MJM. [[Endocarditis due to meticillin-resistant Staphylococcus aureus originating from pigs]. Ned Tijdschr Geneeskd. 2006;150(44):2442-7. Dutch.
- Pan A, Battisti A, Zoncada A, Bernieri F, Boldini M, Franco A, et al. Community-acquired methicillin-resistant Staphylococcus aureus ST398 infection, Italy. Emerg Infect Dis. 2009;15(5):845-7.
- Witte W, Strommenger B, Stanek C, Cuny C. Methicillin-resistant Staphylococcus aureus ST398 in humans and animals, Central Europe. Emerg Infect Dis. 2007;13(2):255-8.
- Dutch Working Party on Antibiotic Policy (SWAB). NethMap 2008, Consumption of antimicrobial agents and antimicrobial resistance among medically important bacteria in the Netherlands, 2009. Amsterdam:SWAB. [Accessed 14 Jun 2010]. Available from: http://www.swab.nl/swab/cms3.nsf/uploads/6E11368E7BB72739C12575940049664D/$FILE/NethMap_2008.pdf
- Welinder-Olsson C, Floren-Johansson K, Larsson L, Oberg S, Karlsson L, Ahren C. Infection with Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus t034. Emerg Infect Dis. 2008;14(8):1271-2.
- Kehrenberg C, Cuny C, Strommenger B, Schwarz S, Witte W. Methicillin-resistant and -susceptible Staphylococcus aureus strains of clonal lineages ST398 and ST9 from swine carry the multidrug resistance gene cfr. Antimicrob Agents Chemother. 2009;53(2):779-81.
- de Boer E, Zwartkruis-Nahuis JT, Wit B, Huijsdens; XW, de Neeling AJ, Bosch T, et al. Prevalence of methicillin-resistant Staphylococcus aureus in meat. Int J Food Microbiol. 2009; 134(1-2):52-6.
- Jones TF, Kellum ME, Porter SS, Bell M, Schaffner W. An outbreak of community-acquired foodborne illness caused by methicillin-resistant Staphylococcus aureus. Emerg Infect Dis. 2002;8(1):82-4.
- Kluytmans J, van Leeuwen W, Goessens W, Hollis R, Messer S, Herwaldt L, et al. Food-initiated outbreak of methicillin-resistant Staphylococcus aureus analyzed by pheno- and genotyping. J Clin Microbiol. 1995;33(5):1121-8.
- Carlet J, Astagneau P, Brun-Buisson C, Coignard B, Salomon V, Tran B, et al. French national program for prevention of healthcare-associated infections and antimicrobial resistance, 1992-2008: positive trends, but perseverance needed. Infect Control Hosp Epidemiol. 2009;30(8):737-45.
- Scientific Institute of Public Health. National Surveillance of Hospital Infections (NSIH). National Surveillance of Nosocomial Septicemia (Hospital-wide). National Analysis. Data from 1/01/2008 to 31/12/2008. Brussels: NSIH; 30 Jun 2009. Available from: http://www.iph.fgov.be/nsih/download/SEP/sBelg_2008_data.pdf.
- Conseil Supérieur d' Hygiène. Guidelines for the control and prevention of methicillin-resistant Staphylococcus aureus transmission in Belgian hospitals [Accessed 14 Jun 2010]. Available from: https://portal.health.fgov.be/pls/portal/docs/PAGE/INTERNET_PG/HOMEPAGE_MENU/ ABOUTUS1_MENU/INSTITUTIONSAPPARENTEES1_MENU/HOGEGEZONDHEIDSRAAD1_MENU/ ADVIEZENENAANBEVELINGEN1_MENU/ADVIEZENENAANBEVELINGEN1_DOCS/7725%20MRSA%20EN%202003.PDF
- Goossens H, Coenen S, Costers M, De Corte S, De Sutter A, Gordts B, et al. Achievements of the Belgian Antibiotic Policy Coordination Committee (BAPCOC). Euro Surveill. 2008;13(46):pii=19036. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19036
- Department of Health (DH) [Internet]. London:DH. [Accessed 14 Jun 2010]. Available from: http://www.dh.gov.uk
- Health Protection Agency (HPA). Healthcare-associated Infections in England: 2008-2009 Report. London:HPA; Reviewed 10 Sept 2009. [Accessed 14 Oct 2010]. Available from: http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1252326222452
- Denis O, Jans B, Deplano A, Nonhoff C, De Ryck R, Suetens C, et al. Epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) among residents of nursing homes in Belgium. J Antimicrob Chemother. 2009;64(6):1299-306.
- von Baum H, Schmidt C, Svoboda D, Bock-Hensley O, Wendt C. Risk factors for methicillin-resistant Staphylococcus aureus carriage in residents of German nursing homes. Infect Control Hosp Epidemiol. 2002;23(9):511-5.
- Manzur A, Gavalda L, Ruiz de Gopegui E, Mariscal D, Dominguez MA, Perez JL, et al. Prevalence of methicillin-resistant Staphylococcus aureus and factors associated with colonization among residents in community long-term-care facilities in Spain. Clin Microbiol Infect. 2008;14(9):867-72.
- Eveillard M, Charru P, Rufat P, Hippeaux M, Lancien E, Benselama F, et al. Methicillin-resistant Staphylococcus aureus carriage in a long-term care facility: hypothesis about selection and transmission. Age Ageing. 2008;37(3):294-9.
- Cox RA, Bowie PE. Methicillin-resistant Staphylococcus aureus colonization in nursing home residents: a prevalence study in Northamptonshire. J Hosp Infect. 1999;43(2):115-22.
- Baldwin NS, Gilpin DF, Hughes CM, Kearney MP, Gardiner DA, Cardwell C, et al. Prevalence of methicillin-resistant Staphylococcus aureus colonization in residents and staff in nursing homes in Northern Ireland. J Am Geriatr Soc. 2009;57(4):620-6.
- Ahearn DJ, Jackson TB, McIlmoyle J, Weatherburn AJ. Improving end of life care for nursing home residents: an analysis of hospital mortality and readmission rates. Postgrad Med J. 2010;86(1013):131-5.
- Manzur A, Gudiol F. Methicillin-resistant Staphylococcus aureus in long-term-care facilities. Clin Microbiol Infect. 2009;15 (Suppl 7)(26-30).
- D'Agata EM, Webb GF, Horn MA, Moellering RC Jr., Ruan S. Modeling the invasion of community-acquired methicillin-resistant Staphylococcus aureus into hospitals. Clin Infect Dis. 2009;48(3):274-84.
- Webb GF, Horn MA, D'Agata EM, Moellering RC, Ruan S. Competition of hospital-acquired and community-acquired methicillin-resistant Staphylococcus aureus strains in hospitals. J Biol Dyn. 2009;48:271.