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Methicillin-resistant Staphylococcus aureus: risk factors associated with community-onset infections in Denmark
ORIGINAL ARTICLE
10.1111/j.1469-0691.2008.02055.x
Methicillin-resistant Staphylococcus aureus: risk factors associated with community-onset infections in Denmark S. Bo¨cher1, A. Gervelmeyer2,*, D. L. Monnet1,†, K. Mølbak3, R. L. Skov1 and The Danish CA-MRSA Study Group‡ 1
National Centre for Antimicrobials and Infection Control, 2European Programme for Intervention Epidemiology Training, Department of Epidemiology and 3Department of Epidemiology, Statens Serum Institut, Copenhagen, Denmark
ABSTRACT The proportion of methicillin-resistant Staphylococcus aureus (MRSA) in Denmark has been below 1% for more than 30 years. However, a marked increase in community-onset MRSA (CO-MRSA) started in 2002. To identify possible risk factors for CO-MRSA infections, a nationwide case–control study was conducted in 2004. Cases (34) were patients with CO-MRSA infections; controls (87) were patients with community-onset methicillin-sensitive S. aureus infections (CO-MSSA). Demographic and clinical data and exposures to possible risk factors during the last 24 months were collected with a structured telephone-administered questionnaire. Skin and soft tissue were the predominant sites of infection, both for cases (68%) and for controls (60%). A large proportion of cases (26%) and controls (38%) had an underlying skin disease. The majority of cases (76%) and controls (61%) had received antibiotics within the last 6 months, and 51% and 31%, respectively, had been hospitalized within the previous year. In a multivariate analysis, non-Danish origin, defined as being from or having parents from outside Denmark, was the only independent risk factor for CO-MRSA infection (OR 30.5, 95% CI 3.6–257.3). Prior hospitalization for >7 days within the previous 6 months tended to be associated with CO-MRSA infection (OR 5.7, 95% CI 0.9–36.4). The predominant MRSA clones found in this study were CC80 (26%), CC8 (24%) and CC5 (18%). Resistance to three or more antimicrobial drug classes was seen in 47% of CO-MRSA isolates. Panton–Valentine leukocidin was found in 47% of CO-MRSA isolates. Apart from a non-Danish origin, CO-MRSA shared the same risk factors as CO-MSSA, which makes control a challenge. Keywords
Case–control, community onset, MRSA, risk factors, skin infections
Original Submission: 19 December 2007;
Revised Submission: 25 March 2008;
Accepted: 18 April 2008
Edited by J.-C. Desenclos
Clin Microbiol Infect 2008; 14: 942–948 INTRODUCTION The burden of infections due to methicillin-resistant Staphylococcus aureus (MRSA) continues to increase worldwide [1,2]. This can be ascribed Corresponding author and reprint requests: Sidsel Bo¨cher, National Centre for Antimicrobials and Infection Control, Statens Serum Institut, Copenhagen, Denmark E-mail: [email protected] *Present address: Outbreak Investigation Unit, Bundesinstitut fu¨r Risikobewertung, Germany. †
Present address: Scientific Advice Unit, European Centre for Disease Prevention and Control, Stockholm, Sweden.‡The CAMRSA study group members are listed in the Acknowledgement section.
partly to a recent change in the epidemiology of MRSA infections; MRSA is no longer confined to the healthcare environment, but is increasingly seen in outpatients [3,4]. The change in epidemiology has been concomitant with a change in the characteristics of the circulating MRSA strains [5,6]. Strains responsible for community-onset infections (CO-MRSA) often contain the smaller staphylococcal cassette chromosome mec (SCCmec) elements IV and V, which seem to be introduced more easily into methicillin-susceptible strains and entail a lower cost of fitness for the bacteria [7]. This has led to the emergence of new MRSA strains, which are now spreading in the community.
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For more than 30 years, Denmark has had a low prevalence (<1%) of MRSA (http://www. ssi.dk/sw3425.asp). This has been achieved by a rigorous practice of isolation of all hospitalized patients suspected or confirmed to be MRSApositive, and a relatively low antibiotic selection pressure due to a restricted use of broad-spectrum antimicrobials. However, the low prevalence of MRSA probably also reflects the fact that MRSA has, until recently, been confined to the healthcare sector. The number of MRSA cases in Denmark has increased by a factor of 10 during the last decade, primarily due to emerging clones responsible for CO-MRSA infections (http:// www.ssi.dk/sw45633.asp). Cases of MRSA detected outside the hospital setting consist of two groups: (i) patients with community onset and healthcare-related risk factors (Healthcare Associated Community Onset [HACO]), e.g. previous hospitalization, residence in a nursing home or employment in a health care setting; and (ii) patients without healthcarerelated risk factors, but rather community risk factors, e.g. sports activity, day-care institution, or prison residence, and those with no known risk factor (Community Associated [CA]). Several risk factors have been reported for CA infections, including poor hygiene combined with a crowded environment [8–12]. Most of these studies have been carried out in countries with a high prevalence of MRSA, and often in highly selected populations such as prison inmates and military personnel [9,13]. Little is known about the risk factors for MRSA in the general population in low-prevalence countries such as Denmark. However, two recent Danish studies have described CO-MRSA related to local outbreaks, and found kindergarden attendance, nursing home residence, previous hospitalization and travel abroad to be important risk factors for acquisition and spread of MRSA [14,15]. The objective of the present study was to identify the risk factors for MRSA infection among persons infected with S. aureus in the Danish community. Identification of such risk factors would facilitate the development of guidelines to identify, at the time of consultation with a general practitioner or upon hospital admission, which type of patient with suspected S. aureus infection would be more likely to require empirical treatment covering MRSA and which measures would prevent further transmission.
METHODS A prospective case–control study was conducted from January to December 2004. A case of CO-MRSA was defined as a patient infected with MRSA and seeking outpatient care, i.e. from a general practitioner or at a hospital emergency room. A control was defined as patient with a community-onset methicillin-sensitive S. aureus (MSSA) infection (CO-MSSA), seeking outpatient care. The local clinical microbiology laboratories identified eligible MRSA cases and MSSA controls. MSSA controls were randomly selected among persons with CO-MSSA identified on the same day as the case from five of the participating laboratories. Following written consent, patients were interviewed using a structured, telephone-administered questionnaire that captured demographic and clinical data, i.e. socio-economic status, household composition, non-Danish origin (defined as being from or having parents with a country of origin other than Denmark), and exposure to possible risk factors during the last 24 months. The questionnaire also included information about hospitalization, emergency room visits or outpatient visits to clinics, surgical procedures, underlying medical conditions, antibiotic use, intravenous drug use, dermatological conditions, household contact with MRSA-infected persons, household contact with persons with known risk factors for MRSA, occupation as a healthcare worker in a hospital or a long-term care facility, close contact with a healthcare worker, close contact with nursing home residents, foreign travel, and day-care attendance. Patients who, for physical or mental reasons, could not participate in the interview were excluded from the study. For each case and each control, the general practitioner in charge of the patient was contacted by mail. They were informed about the study and asked to provide information on the clinical picture of the patient’s S. aureus infection, as well as on relevant comorbidity factors. A standard questionnaire and a pre-stamped return envelope were provided. MRSA and MSSA isolates were identified using the standard methods of the local laboratory. All MRSA isolates were sent to Statens Serum Institut for confirmation and further characterization, including creation of an antimicrobial susceptibility profile. The MRSA isolates were typed by pulsedfield gel electrophoresis (PFGE) according to the HARMONY protocol [16]. Restriction patterns were analyzed with BIONUMERICS version 4.61 (Applied Maths, St. Martenlatem, Belgium) using Dice coefficients and the unweighted pair group method with arithmetic mean (UPGMA). A similarity coefficient of ‡80% was used to define major clusters or PFGE types [17]. The PFGE types were annotated to clonal complexes (CCs), on the basis of sequence typing of spa [18] and ⁄ or multilocus sequence typing [19] of representatives from each PFGE cluster. The presence of the lukF ⁄ lukS gene for production of Panton–Valentine leukocidin (PVL) was determined as previously described [20]. Susceptibility testing of the MRSA isolates was performed using Neo-Sensitabs (Rosco, Taastrup, Denmark) on Danish Blood agar (Statens Serum Institut, Copenhagen, Denmark) with semiconfluent (106 CFU ⁄ mL) inoculum and overnight incubation in ambient air at 35–36C. Susceptibility to glycopeptides was tested using the Etest (AB BIODISK, Solna, Sweden) macromethod for screening and Population Analysis
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Profile-Area Under the Curve (PAP-AUC) as confirmation [21,22]. Antimicrobial multiresistance was defined as resistance against three or more different classes of antimicrobial drugs (other than methicillin). Statistical analysis was performed using STATA STATISTICAL SOFTWARE 8 (Stata Corporation, College Station, TX, USA). Univariate analysis was performed with a Pearson chi-squared test for the different exposures. For the multivariate analysis, a backward stepwise logistic regression model for variables with p <0.25 was built. The Danish Scientific Ethical Committee approved the study protocol and all relevant documents used during the study.
RESULTS Between January and December 2004, 13 participating clinical microbiology laboratories in Denmark identified 99 eligible MRSA patients and 330 eligible MSSA patients. Fifteen MRSA and 14 MSSA patients did not meet the inclusion criteria. Among the eligible patients meeting the inclusion criteria, 46 MRSA patients and 87 MSSA patients agreed to participate in the study and were interviewed. For 34 MRSA patients and 87 MSSA patients, additional clinical information was received from their respective general practitioners. Analyses were performed on these 121 patients (34 cases and 87 controls). The average delay between diagnosis of infection and interview was 140 days for the cases and 205 days for the controls. No significant differences in the male ⁄ female ratio or age ranges were found (Table 1). Most people in both groups attended school for 9– 11 years, and the three most populated categories reflecting current occupation in both groups were retired people, schoolchildren and skilled workmen. Approximately 25% of the cases had a country of origin other than Denmark, whereas only one control had such a background (Table 1). In both groups, a high proportion of patients had been hospitalized within the last 2 years Table 1. Demographic characteristics of methicillin-resistant Staphylococcus aureus (MRSA) cases and methicillinsusceptible S. aureus (MSSA) controls Characteristic
MRSA (n = 34)
MSSA (n = 87)
Sex (male ⁄ female ratio) Median age, years (range) Country of origin (n)
1.0 38 (1–88) Denmark (26) USA (2) Jordan (2) Spain (1) Switzerland (1) Finland (1) Iran (1)
0.7 43 (0–83) Denmark (86) Swedish (1, one parent)
(cases 52%, controls 66%) and a high percentage had received antibiotics within the last 2 years (cases 76%, controls 69%). Within the last 12 months, 66% of cases and 49% of controls had received antibiotics. The use of steroids was high in both groups (cases 24%, controls 37%), and included both topical steroids for skin diseases and systemic or inhalation steroids for pulmonary diseases. In the univariate analysis, two risk factors were found to be significant (p <0.05): previous hospitalization for more than 7 days within 6 months before infection (p 0.03) and non-Danish origin (defined as being from or having parents with a country of origin other than Denmark) (p <0.001) (Table 2). In the multivariate analysis, the only significant risk factor for CO-MRSA infection was nonDanish origin (Table 3). In addition, prior hospitalization for more than 7 days within the last 6 months tended to be associated with CO-MRSA infection. None of the cases or the controls reported using intravenous drugs. The predominant type of infection was skin and soft tissue infection, among both cases (68%) and controls (60%). The sites of infection were Table 2. Univariate analysis of risk factors ⁄ exposures for community-onset methicillin-resistant Staphylococcus aureus (MRSA) infections in Denmark
Risk factor
No. of MRSA (%) n = 34
No. of MSSA (%) n = 87
OR (95% CI)
p-Value
Contact with day care Contact with healthcare Steroids Underlying skin disease Prior antibioticsa Sports Travel abroad Prior hospitalizationb Non-Danish originc
6 9 8 9 26 20 25 4 8
18 19 32 33 60 40 49 2 1
0.92 1.29 0.57 0.58 1.8 1.68 2.15 5.67 27.52
0.87 0.59 0.22 0.22 0.21 0.20 0.08 0.03 <0.001
(18) (26) (24) (26) (76) (59) (73) (12) (24)
(21) (21) (37) (38) (69) (46) (56) (2) (1)
(0.29–2.84) (0.45–3.51) (0.20–1.53) (0.22–1.50) (0.6–6.2) (0.70–4.05) (0.84–5.84) (0.75–64.52) (3.21–615.11)
MSSA, methicillin-susceptible S. aureus. a For 2 years before MRSA infection. b For more than 7 days, within 6 months before MRSA infection. c Including one MRSA case and one MSSA control from other low-incidence countries.
Table 3. Multivariate analysis of independent risk factors for community-onset methicillin-resistant Staphylococcus aureus (MRSA) infections in Denmark Risk factor a
Non-Danish origin Prior hospitalizationb a
OR
95% CI
p-Value
30.5 5.7
3.6–257.3 0.9–36.4
0.002 0.064
OR increases to infinity if persons from low-endemicity countries are excluded. For more than 7 days, within 6 months before MRSA infection.
b
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primarily the face, the legs and the hands. Approximately one-third of the participants had an underlying skin disease. Besides skin and soft tissue infections, only urinary tract infections, ear infections and sinusitis were observed. None of the participants had an invasive infection. Chronic obstructive lung disease and diabetes were the most prevalent underlying diseases in both groups. Microbiological investigation (Table 4) showed that 68% of the isolates belonged to one of the three following types: CC80 (26%), CC8 (24%) and CC5 (18%). Four of the eight CC8 isolates belonged to the USA 500 clone. Twenty-eight (82%) of the 34 isolates carried SSCmecIV, two CC398 isolates carried SSCmecV, and four isolates were non-typeable. In total, 47% of MRSA isolates were PVL-positive. All CC80 and CC30 isolates were PVL-positive. CC8 was the predominant clone among patients with a history of hospitalization, whereas CC80 was the predominant clone among patients with no obvious risk factor or a history of acquisition in the community, e.g. within the household. Among the 34 MRSA isolates, 47% were resistant to three or more antibiotic classes. All isolates were susceptible to rifampicin and linezolid. Eighty-five percent were susceptible to ciprofloxacin, 68% to clindamycin, 65% to fusidic acid, and 62% to erythromycin. Glycopeptide resistance was tested for 30 of the 34 MRSA isolates, and all were susceptible. DISCUSSION In the present study, the aim was to identify risk factors for MRSA infections with community Table 4. Expression of SSCmec types, Panton–Valentine leukocidin (PVL) and multiresistance in the 34 isolates from methicillin-resistant Staphylococcus aureus (MRSA) cases CC group
No. of isolates
SSCmec type (no. of isolates)
CC80 CC8 CC5 CC30 CC398 CC1 CC22 CC45 CC59 CC72 CC97
9 8 6 3 2 1 1 1 1 1 1
IV IV (6), NT IV (5), NT IV
(9) (2) (1) (3) V IVA IV NT IV IV IV
No. of PVL-positive isolates
No. of multiresistant isolatesa
9 3 1 3 0 0 0 0 0 0 0
7 5 1 0 2 0 0 0 0 1 0
CC, clonal complex; NT, non-typeable. a Resistant to three or more antimicrobial drugs other than methicillin.
onset. By choosing CO-MSSA patients as the control group, risk factors for CO-MRSA among patients with staphylococcal infections were investigated. This choice of design was motivated by the objective of identifying risk factors specific to MRSA in the community, in order to enable general practitioners or hospital physicians to decide upon empirical treatment for MRSA in patients with signs and symptoms compatible with staphylococcal infections. The study was based on a representative sample of patients with staphylococcal infection from the general population in Denmark. To our knowledge, this is the first national study comparing risk factors for CO-MRSA and CO-MSSA infection in a low-prevalence country. Demographic and clinical differences and various exposures were sought. The only significant risk factor for CO-MRSA infections in Denmark was non-Danish origin. An increased frequency of close contact with relatives and friends still living in countries where MRSA is highly prevalent is a probable explanation for this finding. In several studies, lower socio-economic status was found to be a risk factor for CO-MRSA infection [12,20,23], but no differences related to educational background and socio-economic status were observed in this study. Two cases were presumably related to pig farming; one individual worked at a pig farm and the other had a farm in the same area in Denmark. Both were infected with type CC398, which in The Netherlands has been related to pig farming and to veterinarians in contact with pig farms [24,25]. MRSA type CC398 has now been reported from pig farms in Denmark [26]. In The Netherlands, this clone is now responsible for a number of MRSA infections, which, in most cases, have a community onset [25]. In this case–control study, we did not systematically collect data on animal exposure, which, retrospectively, is seen as an increasingly important risk factor. The present study highlighted some general characteristics of patients with staphylococcal infections, although it was not possible to quantify these characteristics, as an appropriate group of community controls without staphylococcal infections was not included. In both cases and controls, a high prevalence of underlying disease, i.e. skin disease, diabetes and chronic lung disease, was noted. An underlying skin disease was reported by 26% of cases and 38% of controls, as
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compared to an estimated prevalence of skin disease in 7–10% of the general population. This corresponds to what has been reported in previous studies regarding skin disease and carriage rate for staphylococci [27–29]. Use of antibiotics during the previous 6 months was high, among both cases (66%) and controls (49%). In comparison, the percentage of individuals in Denmark who receive an antibiotic each year is c. 30% (http://www.dkma.dk). The use of steroids was also high in both groups, and is probably higher than in the general population, due to the high prevalence of skin disease and chronic lung disease in these patients. Both groups had a high rate of prior hospitalization, and hospitalization of more than 7 days within the last 6 months tended to be a risk factor for MRSA infection. This, however, could be a coincidental observation, as the MRSA clones isolated from these patients were not classical hospital clones, but rather clones that are seen in both the community and hospitals, i.e. CC5, CC8 and CC59. The present study has some limitations. The number of cases was small, which reduces the study’s statistical power and prevented the use of matching criteria, e.g. age, which would have been relevant, as risk factors for MRSA infection vary between children and the elderly. The findings should therefore be interpreted with caution. On the other hand, the cases and controls were consecutively chosen from 13 of the 15 departments of clinical microbiology in Denmark, and can therefore be considered to be representative of the country. This is corroborated by the clonal distribution, which corresponds to national surveillance data concerning all MRSA cases in Denmark that were categorized as community onset in 2004 (CC80 25%, CC8 23%, CC5 17%). Bias in relation to socio-economic status might have occurred, even though the cases and controls were randomly selected at the local departments of clinical microbiology. Only c. 46% of cases agreed to participate, and this could have introduced selection bias. In addition, selection bias might also have occurred for non-Danish cases and controls, as non-Danish individuals may have had difficulties in understanding and answering the questionnaire. Finally, the long delay from diagnosis to interview may have introduced recall bias, and thus detailed information concerning antibiotics used prior to the MRSA ⁄ MSSA infection was not
used, as many patients did not recall the name, the dose or the exact reason for antibiotic prescription. The increasing number of MRSA cases within a healthy population without obvious risk factors is worrisome. In Denmark, antistaphylococcal penicillins, e.g. dicloxacillin, are the drugs of choice for the treatment of suspected staphylococcal infections. For outpatients, treatment is often initiated without taking a clinical sample. In the case of MRSA infections, this would lead to delayed initiation of adequate therapy, with a risk of a poorer outcome. Furthermore, delayed initiation of adequate therapy increases the period during which transmission is possible, which contributes not only to the increase of MRSA in the community, but also to repeated introduction of community MRSA into hospitals, with the risk of causing serious nosocomial infections. Nevertheless, and considering the present low prevalence of MRSA in Denmark, changing the national recommendation for suspected staphylococcal infections from an antistaphylococcal penicillin to a drug including MRSA in its spectrum of activity, e.g. linezolid, would be a threat to the Danish antibiotic policy, which gives preference to penicillins and, in general, narrow-spectrum antibiotics. It would also result in increasing costs for the healthcare system and possibly increase the number of patients with adverse side effects from these drugs. Denmark remains a low-prevalence country despite the alarming increase in the number of MRSA cases, especially with community onset. This study was designed with the purpose of identifying risk factors for MRSA infection in a low-prevalence country, in order to allow development of a prediction rule to identify which patients require empirical treatment for MRSA at the time of consulting a general practitioner or at hospital admission. On the basis of the findings in this study, we advise physicians to be aware that among patients with a presumed staphylococcal infection, those patients with social contacts, i.e. relatives and possibly close friends, in countries with a high prevalence of MRSA, as well as patients who have frequently been hospitalized for longer periods, should be considered at risk for MRSA. The study further indicates that many of the risk factors for CO-MRSA infection are also risk factors for staphylococcal infections in general. Because MRSA shares these characteristics
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Bo¨cher et al. Risk Factors for CO-MRSA 947
with MSSA, it is at present impossible to establish a clinical epidemiological algorithm that would give precise decision support for the management of staphylococcal infections besides the two aforementioned risk factors. This makes control of CO-MRSA a particular challenge. In November 2006, the Danish National Board of Health made MRSA a reportable disease and launched national MRSA control guidelines (http://www.sst.dk/publ/Publ2006/CFF/MRSA/ Vejl_MRSA.pdf). These guidelines include recommendations regarding hygienic precautions, as well as household cleaning and disinfection, for MRSA patients identified at outpatient clinics or by a general practitioner.
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ACKNOWLEDGEMENTS Preliminary results from this study were presented at the 16th ECCMID in Nice, France, as an oral presentation (O313) in the session ‘Epidemiology of MRSA in Europe’. We thank the Danish CA-MRSA study group: J. O. Jarløv, H. Westh, K. Kristoffersen, J. J. Christensen, L. P. Andersen, B. Bruun, D. S. Hansen, O. Heltberg, B. G. Hansen, C. Reese, S. Strøbæk, B. Christensen, J. K. Møller, J. Prag, H. Schumarcher and T. Urth.
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TRANSPARENCY DECLARATION The authors state that there are no dual or conflicting interests regarding this paper.
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REFERENCES 1. Voss A, Doebbling BN. The worldwide prevalence of methicillin-resistant Staphylococcus aureus. Int J Antimicrob Agents 1994; 5: 101–106. 2. Grundmann H, Aires-de-Sousa M, Boyce J, Tiemersma E. Emergence and resurgence of meticillin-resistant Staphylococcus aureus as a public-health threat. Lancet 2006; 368: 874–885. 3. Boyce JM. Are the epidemiology and microbiology of methicillin-resistant Staphylococcus aureus changing? JAMA 1998; 279: 623–624. 4. Chambers HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis 2001; 7: 178–182. 5. Enright MC, Robinson DA, Randle G, Feil EJ, Grundmann H, Spratt BG. The evolutionary history of methicillinresistant Staphylococcus aureus (MRSA). Proc Natl Acad Sci USA 2002; 99: 7687–7692. 6. Eady EA, Cove JH. Staphylococcal resistance revisited: community-acquired methicillin resistant Staphylococcus aureus—an emerging problem for the management of skin and soft tissue infections. Curr Opin Infect Dis 2003; 16: 103–124. 7. Lee SM, Ender M, Adhikari R, Smith JM, Berger-Bachi B, Cook GM. Fitness cost of staphylococcal cassette chromosome mec in methicillin-resistant Staphylococcus aureus by
17.
18.
19.
20.
21.
way of continuous culture. Antimicrob Agents Chemother 2007; 51: 1497–1499. Leman R, Alvarado-Ramy F, Pocock S et al. Nasal carriage of methicillin-resistant Staphylococcus aureus in an American Indian population. Infect Control Hosp Epidemiol 2004; 25: 121–125. Aiello AE, Lowy FD, Wright LN, Larson EL. Meticillinresistant Staphylococcus aureus among US prisoners and military personnel: review and recommendations for future studies. Lancet Infect Dis 2006; 6: 335–341. Begier EM, Frenette K, Barrett NL et al. A high-morbidity outbreak of methicillin-resistant Staphylococcus aureus among players on a college football team, facilitated by cosmetic body shaving and turf burns. Clin Infect Dis 2004; 39: 1446–1453. Nguyen DM, Mascola L, Brancoft E. Recurring methicillinresistant Staphylococcus aureus infections in a football team. Emerg Infect Dis 2005; 11: 526–532. Bratu S, Landman D, Gupta J, Trehan M, Panwar M, Quale J. A population-based study examining the emergence of community-associated methicillin-resistant Staphylococcus aureus USA300 in New York City. Ann Clin Microbiol Antimicrob 2006; 5: 29–35. Crum NF, Lee RU, Thornton SA et al. Fifteen-year study of the changing epidemiology of methicillin-resistant Staphylococcus aureus. Am J Med 2006; 119: 943–951. Urth T, Juul G, Skov R, Schonheyder HC. Spread of a methicillin-resistant Staphylococcus aureus ST80-IV clone in a Danish community. Infect Control Hosp Epidemiol 2005; 26: 144–149. Bartels MD, Boye K, Larsen AR, Skov RL, Westh H. Rapid increase of genetically diverse methicillin-resistant Staphylococcus aureus, Copenhagen, Denmark. Emerg Infect Dis 2007; 13: 1533–1540. Murchan S, Kaufmann ME, Deplano A et al. Harmonization of pulsed-field gel electrophoresis protocols for epidemiological typing of strains of methicillin-resistant Staphylococcus aureus: a single approach developed by consensus in 10 European laboratories and its application for tracing the spread of related strains. J Clin Microbiol 2003; 41: 1574–1585. McDougal LK, Steward CD, Killgore GE, Chaitram JM, McAllister SK, Tenover FC. Pulsed-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: establishing a national database. J Clin Microbiol 2003; 41: 5113–5120. Harmsen D, Claus H, Witte W et al. Typing of methicillinresistant Staphylococcus aureus in a university hospital setting by using novel software for spa repeat determination and database management. J Clin Microbiol 2003; 41: 5442– 5448. Strommenger B, Kettlitz C, Weniger T, Harmsen D, Friedrich AW, Witte W. Assignment of Staphylococcus isolates to groups by spa typing, SmaI macrorestriction analysis, and multilocus sequence typing. J Clin Microbiol 2006; 44: 2533–2540. Dufour P, Gillet Y, Bes M et al. Community-acquired methicillin-resistant Staphylococcus aureus infections in France: emergence of a single clone that produces Panton– Valentine leukocidin. Clin Infect Dis 2002; 35: 819–824. Wootton M, Howe RA, Hillman R, Walsh TR, Bennett PM, MacGowan AP. A modified population analysis profile (PAP) method to detect hetero-resistance to vancomycin in
2008 The Authors Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14, 942–948
948 Clinical Microbiology and Infection, Volume 14 Number 10, October 2008
22.
23.
24.
25.
26.
Staphylococcus aureus in a UK hospital. J Antimicrob Chemother 2001; 47: 399–403. Walsh TR, Bolmstrom A, Qwarnstrom A et al. Evaluation of current methods for detection of staphylococci with reduced susceptibility to glycopeptides. J Clin Microbiol 2001; 39: 2439–2444. Bagger JP, Zindrou D, Taylor KM. Postoperative infection with meticillin-resistant Staphylococcus aureus and socioeconomic background. Lancet 2004; 363: 706–708. de Neeling AJ, van den Broek MJ, Spalburg EC et al. High prevalence of methicillin resistant Staphylococcus aureus in pigs. Vet Microbiol 2007; 122: 366–372. Huijsdens XW, van Dijke BJ, Spalburg E et al. Communityacquired MRSA and pig-farming. Ann Clin Microbiol Antimicrob 2006; 5: 26–30. Guardabassi L, Stegger M, Skov R. Retrospective detection of methicillin resistant and susceptible Staphylococcus
aureus ST398 in Danish slaughter pigs. Vet Microbiol 2007; 122: 384–386. 27. Williams JV, Vowels BR, Honig PJ, Leyden JJ. S. aureus isolation from the lesions, the hands, and the anterior nares of patients with atopic dermatitis. Pediatr Dermatol 1998; 15: 194–198. 28. Goh CL, Wong JS, Giam YC. Skin colonization of Staphylococcus aureus in atopic dermatitis patients seen at the National Skin Centre, Singapore. Int J Dermatol 1997; 36: 653–657. 29. Gong JQ, Lin L, Lin T et al. Skin colonization by Staphylococcus aureus in patients with eczema and atopic dermatitis and relevant combined topical therapy: a double-blind multicentre randomized controlled trial. Br J Dermatol 2006; 155: 680–687.
2008 The Authors Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14, 942–948
10.1111/j.1469-0691.2008.02055.x
Methicillin-resistant Staphylococcus aureus: risk factors associated with community-onset infections in Denmark S. Bo¨cher1, A. Gervelmeyer2,*, D. L. Monnet1,†, K. Mølbak3, R. L. Skov1 and The Danish CA-MRSA Study Group‡ 1
National Centre for Antimicrobials and Infection Control, 2European Programme for Intervention Epidemiology Training, Department of Epidemiology and 3Department of Epidemiology, Statens Serum Institut, Copenhagen, Denmark
ABSTRACT The proportion of methicillin-resistant Staphylococcus aureus (MRSA) in Denmark has been below 1% for more than 30 years. However, a marked increase in community-onset MRSA (CO-MRSA) started in 2002. To identify possible risk factors for CO-MRSA infections, a nationwide case–control study was conducted in 2004. Cases (34) were patients with CO-MRSA infections; controls (87) were patients with community-onset methicillin-sensitive S. aureus infections (CO-MSSA). Demographic and clinical data and exposures to possible risk factors during the last 24 months were collected with a structured telephone-administered questionnaire. Skin and soft tissue were the predominant sites of infection, both for cases (68%) and for controls (60%). A large proportion of cases (26%) and controls (38%) had an underlying skin disease. The majority of cases (76%) and controls (61%) had received antibiotics within the last 6 months, and 51% and 31%, respectively, had been hospitalized within the previous year. In a multivariate analysis, non-Danish origin, defined as being from or having parents from outside Denmark, was the only independent risk factor for CO-MRSA infection (OR 30.5, 95% CI 3.6–257.3). Prior hospitalization for >7 days within the previous 6 months tended to be associated with CO-MRSA infection (OR 5.7, 95% CI 0.9–36.4). The predominant MRSA clones found in this study were CC80 (26%), CC8 (24%) and CC5 (18%). Resistance to three or more antimicrobial drug classes was seen in 47% of CO-MRSA isolates. Panton–Valentine leukocidin was found in 47% of CO-MRSA isolates. Apart from a non-Danish origin, CO-MRSA shared the same risk factors as CO-MSSA, which makes control a challenge. Keywords
Case–control, community onset, MRSA, risk factors, skin infections
Original Submission: 19 December 2007;
Revised Submission: 25 March 2008;
Accepted: 18 April 2008
Edited by J.-C. Desenclos
Clin Microbiol Infect 2008; 14: 942–948 INTRODUCTION The burden of infections due to methicillin-resistant Staphylococcus aureus (MRSA) continues to increase worldwide [1,2]. This can be ascribed Corresponding author and reprint requests: Sidsel Bo¨cher, National Centre for Antimicrobials and Infection Control, Statens Serum Institut, Copenhagen, Denmark E-mail: [email protected] *Present address: Outbreak Investigation Unit, Bundesinstitut fu¨r Risikobewertung, Germany. †
Present address: Scientific Advice Unit, European Centre for Disease Prevention and Control, Stockholm, Sweden.‡The CAMRSA study group members are listed in the Acknowledgement section.
partly to a recent change in the epidemiology of MRSA infections; MRSA is no longer confined to the healthcare environment, but is increasingly seen in outpatients [3,4]. The change in epidemiology has been concomitant with a change in the characteristics of the circulating MRSA strains [5,6]. Strains responsible for community-onset infections (CO-MRSA) often contain the smaller staphylococcal cassette chromosome mec (SCCmec) elements IV and V, which seem to be introduced more easily into methicillin-susceptible strains and entail a lower cost of fitness for the bacteria [7]. This has led to the emergence of new MRSA strains, which are now spreading in the community.
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For more than 30 years, Denmark has had a low prevalence (<1%) of MRSA (http://www. ssi.dk/sw3425.asp). This has been achieved by a rigorous practice of isolation of all hospitalized patients suspected or confirmed to be MRSApositive, and a relatively low antibiotic selection pressure due to a restricted use of broad-spectrum antimicrobials. However, the low prevalence of MRSA probably also reflects the fact that MRSA has, until recently, been confined to the healthcare sector. The number of MRSA cases in Denmark has increased by a factor of 10 during the last decade, primarily due to emerging clones responsible for CO-MRSA infections (http:// www.ssi.dk/sw45633.asp). Cases of MRSA detected outside the hospital setting consist of two groups: (i) patients with community onset and healthcare-related risk factors (Healthcare Associated Community Onset [HACO]), e.g. previous hospitalization, residence in a nursing home or employment in a health care setting; and (ii) patients without healthcarerelated risk factors, but rather community risk factors, e.g. sports activity, day-care institution, or prison residence, and those with no known risk factor (Community Associated [CA]). Several risk factors have been reported for CA infections, including poor hygiene combined with a crowded environment [8–12]. Most of these studies have been carried out in countries with a high prevalence of MRSA, and often in highly selected populations such as prison inmates and military personnel [9,13]. Little is known about the risk factors for MRSA in the general population in low-prevalence countries such as Denmark. However, two recent Danish studies have described CO-MRSA related to local outbreaks, and found kindergarden attendance, nursing home residence, previous hospitalization and travel abroad to be important risk factors for acquisition and spread of MRSA [14,15]. The objective of the present study was to identify the risk factors for MRSA infection among persons infected with S. aureus in the Danish community. Identification of such risk factors would facilitate the development of guidelines to identify, at the time of consultation with a general practitioner or upon hospital admission, which type of patient with suspected S. aureus infection would be more likely to require empirical treatment covering MRSA and which measures would prevent further transmission.
METHODS A prospective case–control study was conducted from January to December 2004. A case of CO-MRSA was defined as a patient infected with MRSA and seeking outpatient care, i.e. from a general practitioner or at a hospital emergency room. A control was defined as patient with a community-onset methicillin-sensitive S. aureus (MSSA) infection (CO-MSSA), seeking outpatient care. The local clinical microbiology laboratories identified eligible MRSA cases and MSSA controls. MSSA controls were randomly selected among persons with CO-MSSA identified on the same day as the case from five of the participating laboratories. Following written consent, patients were interviewed using a structured, telephone-administered questionnaire that captured demographic and clinical data, i.e. socio-economic status, household composition, non-Danish origin (defined as being from or having parents with a country of origin other than Denmark), and exposure to possible risk factors during the last 24 months. The questionnaire also included information about hospitalization, emergency room visits or outpatient visits to clinics, surgical procedures, underlying medical conditions, antibiotic use, intravenous drug use, dermatological conditions, household contact with MRSA-infected persons, household contact with persons with known risk factors for MRSA, occupation as a healthcare worker in a hospital or a long-term care facility, close contact with a healthcare worker, close contact with nursing home residents, foreign travel, and day-care attendance. Patients who, for physical or mental reasons, could not participate in the interview were excluded from the study. For each case and each control, the general practitioner in charge of the patient was contacted by mail. They were informed about the study and asked to provide information on the clinical picture of the patient’s S. aureus infection, as well as on relevant comorbidity factors. A standard questionnaire and a pre-stamped return envelope were provided. MRSA and MSSA isolates were identified using the standard methods of the local laboratory. All MRSA isolates were sent to Statens Serum Institut for confirmation and further characterization, including creation of an antimicrobial susceptibility profile. The MRSA isolates were typed by pulsedfield gel electrophoresis (PFGE) according to the HARMONY protocol [16]. Restriction patterns were analyzed with BIONUMERICS version 4.61 (Applied Maths, St. Martenlatem, Belgium) using Dice coefficients and the unweighted pair group method with arithmetic mean (UPGMA). A similarity coefficient of ‡80% was used to define major clusters or PFGE types [17]. The PFGE types were annotated to clonal complexes (CCs), on the basis of sequence typing of spa [18] and ⁄ or multilocus sequence typing [19] of representatives from each PFGE cluster. The presence of the lukF ⁄ lukS gene for production of Panton–Valentine leukocidin (PVL) was determined as previously described [20]. Susceptibility testing of the MRSA isolates was performed using Neo-Sensitabs (Rosco, Taastrup, Denmark) on Danish Blood agar (Statens Serum Institut, Copenhagen, Denmark) with semiconfluent (106 CFU ⁄ mL) inoculum and overnight incubation in ambient air at 35–36C. Susceptibility to glycopeptides was tested using the Etest (AB BIODISK, Solna, Sweden) macromethod for screening and Population Analysis
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Profile-Area Under the Curve (PAP-AUC) as confirmation [21,22]. Antimicrobial multiresistance was defined as resistance against three or more different classes of antimicrobial drugs (other than methicillin). Statistical analysis was performed using STATA STATISTICAL SOFTWARE 8 (Stata Corporation, College Station, TX, USA). Univariate analysis was performed with a Pearson chi-squared test for the different exposures. For the multivariate analysis, a backward stepwise logistic regression model for variables with p <0.25 was built. The Danish Scientific Ethical Committee approved the study protocol and all relevant documents used during the study.
RESULTS Between January and December 2004, 13 participating clinical microbiology laboratories in Denmark identified 99 eligible MRSA patients and 330 eligible MSSA patients. Fifteen MRSA and 14 MSSA patients did not meet the inclusion criteria. Among the eligible patients meeting the inclusion criteria, 46 MRSA patients and 87 MSSA patients agreed to participate in the study and were interviewed. For 34 MRSA patients and 87 MSSA patients, additional clinical information was received from their respective general practitioners. Analyses were performed on these 121 patients (34 cases and 87 controls). The average delay between diagnosis of infection and interview was 140 days for the cases and 205 days for the controls. No significant differences in the male ⁄ female ratio or age ranges were found (Table 1). Most people in both groups attended school for 9– 11 years, and the three most populated categories reflecting current occupation in both groups were retired people, schoolchildren and skilled workmen. Approximately 25% of the cases had a country of origin other than Denmark, whereas only one control had such a background (Table 1). In both groups, a high proportion of patients had been hospitalized within the last 2 years Table 1. Demographic characteristics of methicillin-resistant Staphylococcus aureus (MRSA) cases and methicillinsusceptible S. aureus (MSSA) controls Characteristic
MRSA (n = 34)
MSSA (n = 87)
Sex (male ⁄ female ratio) Median age, years (range) Country of origin (n)
1.0 38 (1–88) Denmark (26) USA (2) Jordan (2) Spain (1) Switzerland (1) Finland (1) Iran (1)
0.7 43 (0–83) Denmark (86) Swedish (1, one parent)
(cases 52%, controls 66%) and a high percentage had received antibiotics within the last 2 years (cases 76%, controls 69%). Within the last 12 months, 66% of cases and 49% of controls had received antibiotics. The use of steroids was high in both groups (cases 24%, controls 37%), and included both topical steroids for skin diseases and systemic or inhalation steroids for pulmonary diseases. In the univariate analysis, two risk factors were found to be significant (p <0.05): previous hospitalization for more than 7 days within 6 months before infection (p 0.03) and non-Danish origin (defined as being from or having parents with a country of origin other than Denmark) (p <0.001) (Table 2). In the multivariate analysis, the only significant risk factor for CO-MRSA infection was nonDanish origin (Table 3). In addition, prior hospitalization for more than 7 days within the last 6 months tended to be associated with CO-MRSA infection. None of the cases or the controls reported using intravenous drugs. The predominant type of infection was skin and soft tissue infection, among both cases (68%) and controls (60%). The sites of infection were Table 2. Univariate analysis of risk factors ⁄ exposures for community-onset methicillin-resistant Staphylococcus aureus (MRSA) infections in Denmark
Risk factor
No. of MRSA (%) n = 34
No. of MSSA (%) n = 87
OR (95% CI)
p-Value
Contact with day care Contact with healthcare Steroids Underlying skin disease Prior antibioticsa Sports Travel abroad Prior hospitalizationb Non-Danish originc
6 9 8 9 26 20 25 4 8
18 19 32 33 60 40 49 2 1
0.92 1.29 0.57 0.58 1.8 1.68 2.15 5.67 27.52
0.87 0.59 0.22 0.22 0.21 0.20 0.08 0.03 <0.001
(18) (26) (24) (26) (76) (59) (73) (12) (24)
(21) (21) (37) (38) (69) (46) (56) (2) (1)
(0.29–2.84) (0.45–3.51) (0.20–1.53) (0.22–1.50) (0.6–6.2) (0.70–4.05) (0.84–5.84) (0.75–64.52) (3.21–615.11)
MSSA, methicillin-susceptible S. aureus. a For 2 years before MRSA infection. b For more than 7 days, within 6 months before MRSA infection. c Including one MRSA case and one MSSA control from other low-incidence countries.
Table 3. Multivariate analysis of independent risk factors for community-onset methicillin-resistant Staphylococcus aureus (MRSA) infections in Denmark Risk factor a
Non-Danish origin Prior hospitalizationb a
OR
95% CI
p-Value
30.5 5.7
3.6–257.3 0.9–36.4
0.002 0.064
OR increases to infinity if persons from low-endemicity countries are excluded. For more than 7 days, within 6 months before MRSA infection.
b
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primarily the face, the legs and the hands. Approximately one-third of the participants had an underlying skin disease. Besides skin and soft tissue infections, only urinary tract infections, ear infections and sinusitis were observed. None of the participants had an invasive infection. Chronic obstructive lung disease and diabetes were the most prevalent underlying diseases in both groups. Microbiological investigation (Table 4) showed that 68% of the isolates belonged to one of the three following types: CC80 (26%), CC8 (24%) and CC5 (18%). Four of the eight CC8 isolates belonged to the USA 500 clone. Twenty-eight (82%) of the 34 isolates carried SSCmecIV, two CC398 isolates carried SSCmecV, and four isolates were non-typeable. In total, 47% of MRSA isolates were PVL-positive. All CC80 and CC30 isolates were PVL-positive. CC8 was the predominant clone among patients with a history of hospitalization, whereas CC80 was the predominant clone among patients with no obvious risk factor or a history of acquisition in the community, e.g. within the household. Among the 34 MRSA isolates, 47% were resistant to three or more antibiotic classes. All isolates were susceptible to rifampicin and linezolid. Eighty-five percent were susceptible to ciprofloxacin, 68% to clindamycin, 65% to fusidic acid, and 62% to erythromycin. Glycopeptide resistance was tested for 30 of the 34 MRSA isolates, and all were susceptible. DISCUSSION In the present study, the aim was to identify risk factors for MRSA infections with community Table 4. Expression of SSCmec types, Panton–Valentine leukocidin (PVL) and multiresistance in the 34 isolates from methicillin-resistant Staphylococcus aureus (MRSA) cases CC group
No. of isolates
SSCmec type (no. of isolates)
CC80 CC8 CC5 CC30 CC398 CC1 CC22 CC45 CC59 CC72 CC97
9 8 6 3 2 1 1 1 1 1 1
IV IV (6), NT IV (5), NT IV
(9) (2) (1) (3) V IVA IV NT IV IV IV
No. of PVL-positive isolates
No. of multiresistant isolatesa
9 3 1 3 0 0 0 0 0 0 0
7 5 1 0 2 0 0 0 0 1 0
CC, clonal complex; NT, non-typeable. a Resistant to three or more antimicrobial drugs other than methicillin.
onset. By choosing CO-MSSA patients as the control group, risk factors for CO-MRSA among patients with staphylococcal infections were investigated. This choice of design was motivated by the objective of identifying risk factors specific to MRSA in the community, in order to enable general practitioners or hospital physicians to decide upon empirical treatment for MRSA in patients with signs and symptoms compatible with staphylococcal infections. The study was based on a representative sample of patients with staphylococcal infection from the general population in Denmark. To our knowledge, this is the first national study comparing risk factors for CO-MRSA and CO-MSSA infection in a low-prevalence country. Demographic and clinical differences and various exposures were sought. The only significant risk factor for CO-MRSA infections in Denmark was non-Danish origin. An increased frequency of close contact with relatives and friends still living in countries where MRSA is highly prevalent is a probable explanation for this finding. In several studies, lower socio-economic status was found to be a risk factor for CO-MRSA infection [12,20,23], but no differences related to educational background and socio-economic status were observed in this study. Two cases were presumably related to pig farming; one individual worked at a pig farm and the other had a farm in the same area in Denmark. Both were infected with type CC398, which in The Netherlands has been related to pig farming and to veterinarians in contact with pig farms [24,25]. MRSA type CC398 has now been reported from pig farms in Denmark [26]. In The Netherlands, this clone is now responsible for a number of MRSA infections, which, in most cases, have a community onset [25]. In this case–control study, we did not systematically collect data on animal exposure, which, retrospectively, is seen as an increasingly important risk factor. The present study highlighted some general characteristics of patients with staphylococcal infections, although it was not possible to quantify these characteristics, as an appropriate group of community controls without staphylococcal infections was not included. In both cases and controls, a high prevalence of underlying disease, i.e. skin disease, diabetes and chronic lung disease, was noted. An underlying skin disease was reported by 26% of cases and 38% of controls, as
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compared to an estimated prevalence of skin disease in 7–10% of the general population. This corresponds to what has been reported in previous studies regarding skin disease and carriage rate for staphylococci [27–29]. Use of antibiotics during the previous 6 months was high, among both cases (66%) and controls (49%). In comparison, the percentage of individuals in Denmark who receive an antibiotic each year is c. 30% (http://www.dkma.dk). The use of steroids was also high in both groups, and is probably higher than in the general population, due to the high prevalence of skin disease and chronic lung disease in these patients. Both groups had a high rate of prior hospitalization, and hospitalization of more than 7 days within the last 6 months tended to be a risk factor for MRSA infection. This, however, could be a coincidental observation, as the MRSA clones isolated from these patients were not classical hospital clones, but rather clones that are seen in both the community and hospitals, i.e. CC5, CC8 and CC59. The present study has some limitations. The number of cases was small, which reduces the study’s statistical power and prevented the use of matching criteria, e.g. age, which would have been relevant, as risk factors for MRSA infection vary between children and the elderly. The findings should therefore be interpreted with caution. On the other hand, the cases and controls were consecutively chosen from 13 of the 15 departments of clinical microbiology in Denmark, and can therefore be considered to be representative of the country. This is corroborated by the clonal distribution, which corresponds to national surveillance data concerning all MRSA cases in Denmark that were categorized as community onset in 2004 (CC80 25%, CC8 23%, CC5 17%). Bias in relation to socio-economic status might have occurred, even though the cases and controls were randomly selected at the local departments of clinical microbiology. Only c. 46% of cases agreed to participate, and this could have introduced selection bias. In addition, selection bias might also have occurred for non-Danish cases and controls, as non-Danish individuals may have had difficulties in understanding and answering the questionnaire. Finally, the long delay from diagnosis to interview may have introduced recall bias, and thus detailed information concerning antibiotics used prior to the MRSA ⁄ MSSA infection was not
used, as many patients did not recall the name, the dose or the exact reason for antibiotic prescription. The increasing number of MRSA cases within a healthy population without obvious risk factors is worrisome. In Denmark, antistaphylococcal penicillins, e.g. dicloxacillin, are the drugs of choice for the treatment of suspected staphylococcal infections. For outpatients, treatment is often initiated without taking a clinical sample. In the case of MRSA infections, this would lead to delayed initiation of adequate therapy, with a risk of a poorer outcome. Furthermore, delayed initiation of adequate therapy increases the period during which transmission is possible, which contributes not only to the increase of MRSA in the community, but also to repeated introduction of community MRSA into hospitals, with the risk of causing serious nosocomial infections. Nevertheless, and considering the present low prevalence of MRSA in Denmark, changing the national recommendation for suspected staphylococcal infections from an antistaphylococcal penicillin to a drug including MRSA in its spectrum of activity, e.g. linezolid, would be a threat to the Danish antibiotic policy, which gives preference to penicillins and, in general, narrow-spectrum antibiotics. It would also result in increasing costs for the healthcare system and possibly increase the number of patients with adverse side effects from these drugs. Denmark remains a low-prevalence country despite the alarming increase in the number of MRSA cases, especially with community onset. This study was designed with the purpose of identifying risk factors for MRSA infection in a low-prevalence country, in order to allow development of a prediction rule to identify which patients require empirical treatment for MRSA at the time of consulting a general practitioner or at hospital admission. On the basis of the findings in this study, we advise physicians to be aware that among patients with a presumed staphylococcal infection, those patients with social contacts, i.e. relatives and possibly close friends, in countries with a high prevalence of MRSA, as well as patients who have frequently been hospitalized for longer periods, should be considered at risk for MRSA. The study further indicates that many of the risk factors for CO-MRSA infection are also risk factors for staphylococcal infections in general. Because MRSA shares these characteristics
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with MSSA, it is at present impossible to establish a clinical epidemiological algorithm that would give precise decision support for the management of staphylococcal infections besides the two aforementioned risk factors. This makes control of CO-MRSA a particular challenge. In November 2006, the Danish National Board of Health made MRSA a reportable disease and launched national MRSA control guidelines (http://www.sst.dk/publ/Publ2006/CFF/MRSA/ Vejl_MRSA.pdf). These guidelines include recommendations regarding hygienic precautions, as well as household cleaning and disinfection, for MRSA patients identified at outpatient clinics or by a general practitioner.
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ACKNOWLEDGEMENTS Preliminary results from this study were presented at the 16th ECCMID in Nice, France, as an oral presentation (O313) in the session ‘Epidemiology of MRSA in Europe’. We thank the Danish CA-MRSA study group: J. O. Jarløv, H. Westh, K. Kristoffersen, J. J. Christensen, L. P. Andersen, B. Bruun, D. S. Hansen, O. Heltberg, B. G. Hansen, C. Reese, S. Strøbæk, B. Christensen, J. K. Møller, J. Prag, H. Schumarcher and T. Urth.
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TRANSPARENCY DECLARATION The authors state that there are no dual or conflicting interests regarding this paper.
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REFERENCES 1. Voss A, Doebbling BN. The worldwide prevalence of methicillin-resistant Staphylococcus aureus. Int J Antimicrob Agents 1994; 5: 101–106. 2. Grundmann H, Aires-de-Sousa M, Boyce J, Tiemersma E. Emergence and resurgence of meticillin-resistant Staphylococcus aureus as a public-health threat. Lancet 2006; 368: 874–885. 3. Boyce JM. Are the epidemiology and microbiology of methicillin-resistant Staphylococcus aureus changing? JAMA 1998; 279: 623–624. 4. Chambers HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis 2001; 7: 178–182. 5. Enright MC, Robinson DA, Randle G, Feil EJ, Grundmann H, Spratt BG. The evolutionary history of methicillinresistant Staphylococcus aureus (MRSA). Proc Natl Acad Sci USA 2002; 99: 7687–7692. 6. Eady EA, Cove JH. Staphylococcal resistance revisited: community-acquired methicillin resistant Staphylococcus aureus—an emerging problem for the management of skin and soft tissue infections. Curr Opin Infect Dis 2003; 16: 103–124. 7. Lee SM, Ender M, Adhikari R, Smith JM, Berger-Bachi B, Cook GM. Fitness cost of staphylococcal cassette chromosome mec in methicillin-resistant Staphylococcus aureus by
17.
18.
19.
20.
21.
way of continuous culture. Antimicrob Agents Chemother 2007; 51: 1497–1499. Leman R, Alvarado-Ramy F, Pocock S et al. Nasal carriage of methicillin-resistant Staphylococcus aureus in an American Indian population. Infect Control Hosp Epidemiol 2004; 25: 121–125. Aiello AE, Lowy FD, Wright LN, Larson EL. Meticillinresistant Staphylococcus aureus among US prisoners and military personnel: review and recommendations for future studies. Lancet Infect Dis 2006; 6: 335–341. Begier EM, Frenette K, Barrett NL et al. A high-morbidity outbreak of methicillin-resistant Staphylococcus aureus among players on a college football team, facilitated by cosmetic body shaving and turf burns. Clin Infect Dis 2004; 39: 1446–1453. Nguyen DM, Mascola L, Brancoft E. Recurring methicillinresistant Staphylococcus aureus infections in a football team. Emerg Infect Dis 2005; 11: 526–532. Bratu S, Landman D, Gupta J, Trehan M, Panwar M, Quale J. A population-based study examining the emergence of community-associated methicillin-resistant Staphylococcus aureus USA300 in New York City. Ann Clin Microbiol Antimicrob 2006; 5: 29–35. Crum NF, Lee RU, Thornton SA et al. Fifteen-year study of the changing epidemiology of methicillin-resistant Staphylococcus aureus. Am J Med 2006; 119: 943–951. Urth T, Juul G, Skov R, Schonheyder HC. Spread of a methicillin-resistant Staphylococcus aureus ST80-IV clone in a Danish community. Infect Control Hosp Epidemiol 2005; 26: 144–149. Bartels MD, Boye K, Larsen AR, Skov RL, Westh H. Rapid increase of genetically diverse methicillin-resistant Staphylococcus aureus, Copenhagen, Denmark. Emerg Infect Dis 2007; 13: 1533–1540. Murchan S, Kaufmann ME, Deplano A et al. Harmonization of pulsed-field gel electrophoresis protocols for epidemiological typing of strains of methicillin-resistant Staphylococcus aureus: a single approach developed by consensus in 10 European laboratories and its application for tracing the spread of related strains. J Clin Microbiol 2003; 41: 1574–1585. McDougal LK, Steward CD, Killgore GE, Chaitram JM, McAllister SK, Tenover FC. Pulsed-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: establishing a national database. J Clin Microbiol 2003; 41: 5113–5120. Harmsen D, Claus H, Witte W et al. Typing of methicillinresistant Staphylococcus aureus in a university hospital setting by using novel software for spa repeat determination and database management. J Clin Microbiol 2003; 41: 5442– 5448. Strommenger B, Kettlitz C, Weniger T, Harmsen D, Friedrich AW, Witte W. Assignment of Staphylococcus isolates to groups by spa typing, SmaI macrorestriction analysis, and multilocus sequence typing. J Clin Microbiol 2006; 44: 2533–2540. Dufour P, Gillet Y, Bes M et al. Community-acquired methicillin-resistant Staphylococcus aureus infections in France: emergence of a single clone that produces Panton– Valentine leukocidin. Clin Infect Dis 2002; 35: 819–824. Wootton M, Howe RA, Hillman R, Walsh TR, Bennett PM, MacGowan AP. A modified population analysis profile (PAP) method to detect hetero-resistance to vancomycin in
2008 The Authors Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14, 942–948
948 Clinical Microbiology and Infection, Volume 14 Number 10, October 2008
22.
23.
24.
25.
26.
Staphylococcus aureus in a UK hospital. J Antimicrob Chemother 2001; 47: 399–403. Walsh TR, Bolmstrom A, Qwarnstrom A et al. Evaluation of current methods for detection of staphylococci with reduced susceptibility to glycopeptides. J Clin Microbiol 2001; 39: 2439–2444. Bagger JP, Zindrou D, Taylor KM. Postoperative infection with meticillin-resistant Staphylococcus aureus and socioeconomic background. Lancet 2004; 363: 706–708. de Neeling AJ, van den Broek MJ, Spalburg EC et al. High prevalence of methicillin resistant Staphylococcus aureus in pigs. Vet Microbiol 2007; 122: 366–372. Huijsdens XW, van Dijke BJ, Spalburg E et al. Communityacquired MRSA and pig-farming. Ann Clin Microbiol Antimicrob 2006; 5: 26–30. Guardabassi L, Stegger M, Skov R. Retrospective detection of methicillin resistant and susceptible Staphylococcus
aureus ST398 in Danish slaughter pigs. Vet Microbiol 2007; 122: 384–386. 27. Williams JV, Vowels BR, Honig PJ, Leyden JJ. S. aureus isolation from the lesions, the hands, and the anterior nares of patients with atopic dermatitis. Pediatr Dermatol 1998; 15: 194–198. 28. Goh CL, Wong JS, Giam YC. Skin colonization of Staphylococcus aureus in atopic dermatitis patients seen at the National Skin Centre, Singapore. Int J Dermatol 1997; 36: 653–657. 29. Gong JQ, Lin L, Lin T et al. Skin colonization by Staphylococcus aureus in patients with eczema and atopic dermatitis and relevant combined topical therapy: a double-blind multicentre randomized controlled trial. Br J Dermatol 2006; 155: 680–687.
2008 The Authors Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14, 942–948