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Nosocomial and community-acquired meticillin-resistant Staphylococcus aureus infections in hospitalized patients (Spain, 1993–2003)
Journal of Hospital Infection (2006) 63, 465e471
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Nosocomial and community-acquired meticillin-resistant Staphylococcus aureus infections in hospitalized patients (Spain, 1993e2003) ´n b, J. Vaque ´ c, J. Rossello ´ c, F. Calbo d, A. Asensio a,*, R. Canto ´ndez g, J. Garcı´a-Caballero e, V. Domı´nguez f, A. Herna A.Trilla h, EPINE Working Group1 a
Hospital Universitario Puerta de Hierro, Madrid, Spain Hospital Universitario Ramo´n y Cajal, Madrid, Spain c Hospital U. Vall d’Hebron, Barcelona, Spain d Hospital Carlos Haya, Ma´laga, Spain e Hospital La Paz, Madrid, Spain f Hospital Juan Canalejo, La Corun˜a, Spain g Hospital La Fe, Valencia, Spain h Hospital Clı´nic, Barcelona, Spain b
Received 24 August 2005; accepted 8 March 2006 Available online 15 June 2006
KEYWORDS MRSA; Nosocomial infection; Community infection; Infection rates; Trends
Summary A series of annual surveys on the prevalence of infections in hospitalized patients in Spain was undertaken from 1993 to 2003 to describe clinical and demographic characteristics, trends and geographical variations in the proportion of meticillin-resistant Staphylococcus aureus (MRSA). A total of 8312 S. aureus infections in patients from 296 acute care hospitals pertaining to 17 regions in Spain were observed during the study period. Overall, 23.8% of these organisms were reported as meticillin resistant. The proportion of MRSA varied widely across regions and during the study period. Patients with nosocomial infections (NIs) had a two-fold higher prevalence of MRSA (31%) than patients with community-acquired infections (CAIs) (14%; P < 0.001). Nevertheless, there was an increasing trend in the prevalence of MRSA isolates, both in patients with NI (from
* Corresponding author. Address: Servicio de Medicina Preventiva, Hospital Universitario Puerta de Hierro, San Martı´n de Porres, 4. Madrid E-28035, Spain. Tel.: þ34 913 445547; fax: þ34 913 445431. E-mail address: [email protected] 1 Presented at the 15th Annual Meeting of the Society for Healthcare Epidemiology of America, 9e12 April 2005, Los Angeles, CA, USA. 0195-6701/$ - see front matter ª 2006 Published by Elsevier Ltd on behalf of The Hospital Infection Society. doi:10.1016/j.jhin.2006.03.013
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A. Asensio et al. 22% to 41%; P < 0.001) and with CAI (from 7% to 28%; P < 0.001) throughout the 11-year period. Geographical variations over the last three years (2001e2003) show a centripetal gradient, with the lowest MRSA prevalence in south-west Spain and the highest MRSA prevalence in the central regions. Almost five-fold differences in MRSA proportions were seen between regions (range 10.3e54.5%). Compared with bloodstream infections, infections in other sites were more likely to be caused by MRSA (adjusted odds ratios for surgical site, urinary tract, skin and respiratory infections of 1.2, 1.2, 1.5 and 2.1, respectively). ª 2006 Published by Elsevier Ltd on behalf of The Hospital Infection Society.
Introduction The Study of the Prevalence of Nosocomial Infections in Spain (EPINE) is a country-wide initiative that has been operating since 1990. Data are collected on the annual prevalence of infections in hospitalized patients. EPINE provides information on clinical, patient and epidemiological characteristics and helps in the design of programmes to improve antibiotic policies and control activities.1 Staphylococcus aureus is, after Escherichia coli, the second most frequent cause of infection in hospitalized patients in Spain.2 EPINE results show a marked increase in the proportion of meticillin-resistant S. aureus (MRSA) in the last decade in both nosocomial infections (NIs) and community-acquired infections (CAIs).2e4 Although the definition of the latter condition is still somewhat controversial, a worldwide increase in the prevalence of community-acquired MRSA infections has been clearly described.5,6 Country-wide surveillance systems of resistant micro-organisms, such as MRSA, provide relevant information about ongoing epidemiological characteristics. This study reports MRSA infections identified by hospitals in Spain between 1993 and 2003. These data describe the changes in MRSA rates between different Spanish regions and trends in its occurrence, as well as variations by clinical, demographic and hospital characteristics. The rate of community-acquired MRSA infections identified in hospitalized patients is also presented.
Methods Each year, acute care hospitals in Spain are invited to join the EPINE prevalence survey. Data collected from 1993 to 2003 have been used in this study. Participating hospitals complete a standardized questionnaire for each hospitalized patient, and provide overall data for each hospital and
hospital ward. The criteria of the Centers for Disease Control and Prevention (CDC) were used to define and classify NIs.7 Other infections were classified as CAIs if the patient came from home or from a nursing home, and the infection developed before admission or presented during the first 48 h following admission. ‘Nosocomial infections from a previous hospitalization’ (NIPH) were infections developed prior to the current admission by patients who were transferred from another hospital or who were re-admitted to hospital because of infection (i.e. surgical site infection developed after discharge). The following information was collected for each patient: demographics (age and sex), clinical data (basal risk, assessed by McCabe-Jackson score), patient risk factors, site of infection, infectious agent and resistance to antibiotic markers for selected organisms. Antimicrobial resistance was evaluated on the basis of the routine microbiological laboratory reports processed using standard accepted procedures.8,9 Hospital-validated forms were sent to an independent central unit for further validation and analysis. A report was returned to each participating hospital to avoid possible disagreements before the collected data were finally integrated in a centralized database.
Statistical analysis Data collected in annual surveys from 1993 to 2003 were used for the current analysis. MRSA proportions were calculated as the number of MRSA infections divided by the total number of S. aureus infections recorded. To test national and regional trends in the occurrence of MRSA, a logistic regression model was created, by region and for the whole country, which included the year of the enquiry as an independent variable and MRSA as a dependent variable to test the hypothesis that there
Nosocomial and community-acquired MRSA in Spain was a linear trend throughout the 11-year period. Geographical variation was evaluated by displaying the prevalence of MRSA by region for the last three-year period. The effect of factors potentially associated with MRSA infection was evaluated by univariate analysis-Chi-square test, by Chi-square test for trend, or by t-test if appropriate. A multiple logistic regression model was created to adjust the effect of factors associated with MRSA prevalence. The association of potentially associated factors was determined by odds ratios with 95% confidence intervals. A significant difference was defined as P < 0.05. Statistical analyses were performed using Epi-Info 6 and Stata 8 SE statistical software.
Results Between 1993 and 2003, EPINE collected data on a total of 160 699 infections from 580 386 patients hospitalized in 296 centres distributed throughout all 17 regions of Spain. The number of patients included annually in the prevalence surveys ranged from 46 983 in 1993 to 54 864 in 2003. The hospitals included in the study provide healthcare services for an estimated population of approximately 17.5e20.4 million people/year. This represents about 50% of the Spanish population. By hospital size, 58% of the hospitals had more than 500 beds, 30% hospitals had between 200 and 500 beds, and 12% of the hospitals had less than 200 beds. In total, 8302 S. aureus infections were recorded over the 11 annual prevalence surveys. Fifty percent of all S. aureus infections fulfilled CDC criteria for NIs, whereas 39% were classified as CAIs and 11% were classified as NIPHs. Overall, 23.8% of infections due to S. aureus in hospitalized patients were reported to be MRSA. Table I shows the number of hospitals, the total number of S. aureus and MRSA infections, and the proportion of MRSA infections by region. Patients infected with MRSA were older than patients with a meticillin-susceptible S. aureus infection [mean age 63.0 years, standard deviation (SD) 19.3 vs 55.5 years, SD 22.8; P < 0.001]. The prevalence of MRSA infections increased linearly with age, from 10% at less than 10 years to 32% at greater than 80 years (P < 0.001). There was no difference in the prevalence of MRSA infection by sex (P ¼ 0.65). The proportion of MRSA was higher among patients admitted to intensive care units (ICUs) (34%) than among patients in medical (25%), surgical (22%), obstetric (11%) or paediatric wards (9%; P < 0.001) (Figure 1). Patients with an NI had a two-fold higher prevalence of MRSA (31%) than
467 Table I Overall proportion of meticillin-resistant Staphylococcus aureus (MRSA) infections in hospitalized patients, and number of hospitals participating in EPINE from 1993 to 2003, by Spanish region Region
Andalucia Arago ´n Asturias Baleares Canarias Cantabria Castilla-La Mancha CastillaLeo ´n Catalonia Extremadura La Rioja Galicia Madrid Murcia Navarra Valencia Pais Vasco Total
Number of hospitals participating
Number of Total MRSA number of S. infections (%) aureus infections
41 10 14 7 8 3 14
825 299 331 159 253 251 280
122 142 44 50 70 45 81
20
812
218 (27.0)
64 7 2 22 25 9 5 28 17 296
1416 143 62 862 1038 152 123 659 637 8302
346 28 17 172 343 19 17 168 93 1976
(14.8) (47.5) (13.3) (31.4) (27.7) (17.9) (28.9)
(24.4) (19.6) (27.4) (20.0) (33.0) (12.5) (13.8) (25.5) (14.6) (23.8)
patients with a CAI (14%; P < 0.001). Nevertheless, there was an increasing trend in the prevalence of MRSA isolates for both NI (from 22% to 41%; P < 0.001) and CAI (from 7% to 28%; P < 0.001) throughout the 11-year period (Figure 2). No glycopeptide resistance was detected during the study period.
Figure 1 Proportion of meticillin-resistant Staphylococcus aureus (MRSA) infections in hospitalized patients by type of ward. ICU, intensive care unit.
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Figure 2 Yearly proportions of meticillin-resistant Staphylococcus aureus (MRSA) in hospitalized patients (nosocomial or community-acquired), Spain, 1993e2003 (Chi-square for linear trend, P < 0.0001).
Basal risk, assessed by McCabe-Jackson score, was linked to MRSA prevalence, with MRSA prevalence rates of 17%, 24% and 32% in patients with low, moderate and severe basal risk, respectively (P < 0.001). The prevalence of MRSA increased with the number of intrinsic risk factors in a relatively linear trend, from 15% in patients with no intrinsic risk factors to 48% in patients with more than five risk factors (P < 0.001) (Figure 3). Hospital size was also associated with the rate of MRSA, from 22% in hospitals with less than 200 beds to 26% in hospitals with more than 500 beds (P < 0.001). However, it should be noted that the prevalence of community-acquired MRSA infection
Figure 3 Proportion of meticillin-resistant Staphylococcus aureus (MRSA) infections in hospitalized patients by number of intrinsic risk factors (Chi-square for linear trend: 224.6; P < 0.0001).
was inversely associated with hospital size; 14% in hospitals with more than 500 beds and 17% in hospitals with less than 200 beds (P < 0.025). For both CAI and NI, the lowest prevalence of MRSA was found when the primary site of infection was bacteraemia (11% and 25%, respectively) and the highest prevalence was found for respiratory tract infections (23% and 40%, respectively) (Figure 4). Table II shows the proportion of MRSA, nationally and by region, for the first and last threeyear periods of the study, and also the annual rate of change estimated by logistic regression analysis. It can be seen that increases in MRSA proportions were significant in all regions except for Asturias, Extremadura, La Rioja, Murcia and
Figure 4 Proportion of meticillin-resistant Staphylococcus aureus (MRSA) infections in hospitalized patients by site of infection (nosocomial or communityacquired). SSI, surgical site infection; UTI, urinary tract infection.
Nosocomial and community-acquired MRSA in Spain
469
Table II Proportion of meticillin-resistant Staphylococcus aureus (MRSA) resistance for the 1993e1995 and 2001e 2003 three-year periods, and relative annual changes in MRSA proportion, estimated by logistic regression, by Spanish regions Region
Proportion of MRSA 1993e1995
Proportion of MRSA 2001e2003
Relative change per year, odds ratio
95% CI of estimated change
P value
4.0 34.0 24.3 0.0 10.3 4.8 19.7 4.3 23.2 21.1 36.8 7.9 18.4 8.0 11.9 19.5 3.6 14.0
20.8 54.5 14.8 50.0 33.3 39.1 35.2 44.2 27.8 14.0 23.3 34.7 44.1 16.7 10.3 35.1 26.1 32.5
1.20 1.10 1.01 1.59 1.19 1.41 1.11 1.35 1.04 0.94 0.94 1.27 1.15 0.99 0.97 1.12 1.42 1.15
1.12e1.28 1.02e1.19 0.89e1.13 1.32e1.91 1.07e1.33 1.23e1.61 1.02e1.21 1.27e1.44 0.96e1.08 0.80e1.09 0.81e1.09 1.20e1.35 1.10e1.20 0.86e1.15 0.82e1.13 1.06e1.18 1.29e1.57 1.13e1.17
<0.001 0.014 0.993 <0.001 0.002 <0.001 0.022 <0.001 0.083 0.406 0.399 <0.001 <0.001 0.917 0.654 <0.001 <0.001 <0.001
Andalucia Aragon Asturias Baleares Canarias Cantabria Castilla-La Mancha Castilla-Leo ´n Catalonia Extremadura La Rioja Galicia Madrid Murcia Navarra Valencia Pais Vasco Total CI, confidence intervals.
Navarra, which remained below 24% during the last three-year period. The highest relative variation was found in Baleares, Cantabria, Castilla-Leo ´n and Pais Vasco, with average annual increases ranging from 1.35 to 1.59. In Catalonia, resistance rates did not increase significantly and remained at intermediate levels (28%) during the last threeyear period. It is notable that none of the Spanish regions experienced a significant decreasing trend. Geographical distribution over the 1993e1995 and 2001e2003 periods showed wide variation (Table II). During the last three-year period, the lowest MRSA prevalence (<25%) was recorded in southern Spain (Andalucia, Murcia and Extremadura) and some small regions in northern-central Spain (Navarra and Asturias, La Rioja), with the highest prevalence (>35%) seen in Madrid, the two Castillas, Arago ´n, Cantabria, Baleares and Valencia (Figure 5). Almost five-fold differences in MRSA proportion by regions were observed during the last three-year period, with the lowest in Navarra (10.3%) and the highest in Arago ´n (54.5%) (Table II). The multi-variate analysis, after controlling for age, nosocomial origin, number of intrinsic risk factors and basal risk, and infections localized to the respiratory tract, skin and surgical site, showed an increased risk of being caused by MRSA when compared with bacteraemia (adjusted odds ratios 2.1, 1.5 and 1.2, respectively) (Table III).
Discussion MRSA is responsible for a large number of infections and its increased prevalence is a matter of public concern. The potential acquisition of vancomycin resistance and the emergence and
Figure 5 Geographical distribution of proportions of meticillin-resistant Staphylococcus aureus infections in hospitalized patients by Spanish regions. Average proportion for the period 2001e2003. A, Andalucia; AR, Arago ´n; AS, Asturias; B, Baleares; C, Canarias; CA, Cantabria; CL, Castilla-Leo ´n; CM, Castilla-La Mancha; CT, Catalonia; E, Extremadura; G, Galicia; LR, La Rioja; M, Madrid; N, Navarra; PV, Pais Vasco; V, Valencia; MU, Murcia.
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Table III Factors associated with meticillin-resistant Staphylococcus aureus (MRSA) infections in hospitalized patients. Odds ratios unadjusted and adjusted by multiple logistic regression MRSA N ¼ 1975 Age, mean (SD) for every 10 years Onset of infection (nosocomial/community)a Median number of intrinsic risk factors Basal risk Low Moderate Severe Site of infection Bloodstream Other Skin and soft tissue Surgical site Urinary tract Respiratory tract
MSSA N ¼ 6326
Unadjusted odds ratio (95% CI)
Adjusted odds ratio (95% CI)
1.2 (1.1e1.2) 2.8 (2.5e3.2)
1.1 (1.1e1.2) 2.7 (2.3e3.1)
1
1.4 (1.3e1.4)
1.2 (1.1e1.3)
497 (15) 545 (24) 451 (32)
2713 (85) 1713 (76) 939 (68)
1 1.7 (1.5e2.0) 2.6 (2.3e3.0)
1 1.1 (0.9e1.3) 1.4 (1.1e1.6)
255 262 380 445 98 535
1019 1372 1277 1411 269 978
1 0.8 1.2 1.3 1.5 2.2
1 1.2 1.5 1.2 1.2 2.1
63.0 (22.8) 1283 (31) 2
(20) (16) (23) (24) (27) (35)
55.5 (19.3) 2822 (69)
(80) (84) (77) (76) (73) (65)
(0.6e0.9) (1.0e1.4) (1.1e1.5) (1.1e1.9) (1.8e2.6)
(0.9e1.5) (1.2e1.9) (1.0e1.5) (0.9e1.7) (1.7e2.6)
MSSA, meticillin-susceptible S. aureus; SD, standard deviation; CI, confidence intervals. a Of 7370 infections (excluded infections from a previous hospitalization).
increased identification of community-acquired MRSA have raised interest in this pathogen even further.6,10 The results of this study represent the most comprehensive assessment of MRSA trends in Spain during the last decade. Information gathered at hospital level, based on resistance patterns reported by clinical microbiology laboratories, seems to be a reliable method of estimating country-wide rates of meticillin resistance. The prevalence of MRSA in hospitalized patients in Spain increased significantly at a rate of 1.15% annually during the 1993e2003 period, reaching 41% of all nosocomial S. aureus infections and 28% of all communityacquired S. aureus infections by 2003. When comparing EPINE data with data reported by the European Antimicrobial Resistance Surveillance System for bloodstream isolates in Spain during 2000e2002, no statistical differences were found (proportion of MRSA for nosocomial bacteraemia 23% vs 24%; P ¼ 0.52).3 Overall prevalence (34%) was also similar to that reported by Cuevas et al. (31%) in a single-day surveillance study performed in Spain in 2002.4 This study also shows that the increasing MRSA trend is not a homogeneous event. Differences between Spanish regions demonstrated that local factors must play an important role in the incidence and spread of MRSA. Differences in infection control measures, host susceptibility and antibiotic prescription policies may account for this variability.11
It is of note that the overall prevalence of MRSA was 2.8 times higher for NIs than for CAIs. This difference was reduced during 2002 and 2003 due to an increase in community-acquired MRSA infections. Unlike other reports, the nature of the present study precludes the identification of settings where MRSA is acquired.12,13 In addition, the genetic background of the isolates could not be determined in order to assess their relationship with known community-acquired MRSA or pathogenic clones.14,15 Nevertheless, it was possible to ascertain that S. aureus infections which were acquired in the hospital setting had a higher risk of being MRSA infections than those which were acquired in the community. As has been reported previously, age, basal risk, number of risk factors, intensive care unit and hospital size were associated with MRSA infection.16 The primary site of infection was also related to the risk of MRSA acquisition. Body regions that were most exposed to external contamination, such as the respiratory tract or the skin, were the infection sites with the highest prevalence of MRSA (35e23%), while the bloodstream showed the lowest prevalence of MRSA (20%). These observations may be true differences or the MRSA infection rate may be overestimated in some sites if isolates represent colonization rather than clinical infection. However, as EPINE methodology applies CDC criteria, microbiological isolates should correspond to diagnosed infections, even if not all identified organisms are playing the
Nosocomial and community-acquired MRSA in Spain pathogenic role. It is noteworthy that although most pathogenic community-acquired MRSA isolates have been associated with skin disease, the prevalence of skin infections in this study (14%) was much lower than that of urinary tract infections (21%) or respiratory tract infections (23%).15 This study shows that the prevalence rate of MRSA infection may be higher than suspected previously. In contrast to the findings of a previous, but smaller, study, the prevalence of MRSA is far from stabilizing in Spain.3 Clinicians and public health authorities must be aware of the role of hospital hygiene and infection control protocols, as well as antimicrobial drug policies and mechanisms for the regional spread of MRSA throughout hospitals. Increased numbers of patients admitted to hospitals with MRSA infection or colonization represent a growing clinical problem and may contribute to the endemicity of this pathogen in the hospital setting.
Acknowledgements The authors wish to thank Martin Hadley-Adams for his assistance with the English language and preparation of the manuscript. This study was supported by the Fondo de Investigacio ´n Sanitaria, Spanish Ministry of Health, grant PI20765 FIS.
References 1. Tiemersma EW, Bronzwaer S, Lyytika ¨inen O, et al. Methicillinresistant Staphylococcus aureus in Europe, 1999e2002. Emerg Infect Dis 2004;10:1627e1634. 2. Asensio A, Canto ´n R, Vaque ´ J, Rossello ´ J. Arribas JL y Grupo de Trabajo EPINE. Etiology of nosocomial infections in Spain (EPINE, 1990e1999). Med Clin (Barc) 2002;118:725e730. 3. Oteo J, Baquero F, Vindel A, Campos J. Antibiotic resistance in 3113 blood isolates of Staphylococcus aureus in 40 Spanish hospitals participating in the European Antimicrobial
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Resistance Surveillance System (2000e2002). J Antimicrob Chemother 2004;53:1033e1038. Cuevas O, Cercenado E, Vindel A, et al. Evolution of the antimicrobial resistance of Staphylococcus spp. in Spain: five nationwide prevalence studies, 1986 to 2002. Antimicrob Agents Chemother 2004;48:4240e4245. de Sousa MA, de Lencastre H. Bridges from hospitals to the laboratory: genetic portraits of methicillin-resistant Staphylococcus aureus clones. FEMS Immunol Med Microbiol 2004;40:101e111. Said-Salim B, Mathema B, Kreiswirth BN. Communityacquired methicillin-resistant Staphylococcus aureus: an emerging pathogen. Infect Control Hosp Epidemiol 2003; 24:451e455. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988;16:128e140. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disk susceptibility tests. 8th edn. NCCLS document M2-A8. Approved standard. Wayne, PA: National Committee for Clinical Laboratory Standards; 2003. National Committee for Clinical Laboratory Standards. MIC methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. 6th edn. NCCLS document M7-A6. Approved standard. Wayne, PA: National Committee for Clinical Laboratory Standards; 2003. Enright MC. The evolution of a resistant pathogen e the case of MRSA. Curr Opin Pharmacol 2003;3:474e479. Boyce JM, Havill NL, Kohan C, Dumigan DG, Ligi CE. Do infection control measures work for methicillin-resistant Staphylococcus aureus? Infect Control Hosp Epidemiol 2004;25:395e401. Tambyah PA, Habib AG, Ng TM, Goh H, Kumarasinghe G. Community-acquired methicillin-resistant Staphylococcus aureus infection in Singapore is usually ‘‘healthcare associated’’. Infect Control Hosp Epidemiol 2003;24:436e438. Charlebois ED, Perdreau-Remington F, et al. Origins of community strains of methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2004;39:47e54. Vandenesch F, Naimi T, Enright MC, et al. Communityacquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: worldwide emergence. Emerg Infect Dis 2003;9:978e984. Melles DC, Gorkink RF, Boelens HA, et al. Natural population dynamics and expansion of pathogenic clones of Staphylococcus aureus. J Clin Invest 2004;114:1732e1740. Rao GG. Risk factors for the spread of antibiotic resistance bacteria. Drug 1988;55:323e330.
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Nosocomial and community-acquired meticillin-resistant Staphylococcus aureus infections in hospitalized patients (Spain, 1993e2003) ´n b, J. Vaque ´ c, J. Rossello ´ c, F. Calbo d, A. Asensio a,*, R. Canto ´ndez g, J. Garcı´a-Caballero e, V. Domı´nguez f, A. Herna A.Trilla h, EPINE Working Group1 a
Hospital Universitario Puerta de Hierro, Madrid, Spain Hospital Universitario Ramo´n y Cajal, Madrid, Spain c Hospital U. Vall d’Hebron, Barcelona, Spain d Hospital Carlos Haya, Ma´laga, Spain e Hospital La Paz, Madrid, Spain f Hospital Juan Canalejo, La Corun˜a, Spain g Hospital La Fe, Valencia, Spain h Hospital Clı´nic, Barcelona, Spain b
Received 24 August 2005; accepted 8 March 2006 Available online 15 June 2006
KEYWORDS MRSA; Nosocomial infection; Community infection; Infection rates; Trends
Summary A series of annual surveys on the prevalence of infections in hospitalized patients in Spain was undertaken from 1993 to 2003 to describe clinical and demographic characteristics, trends and geographical variations in the proportion of meticillin-resistant Staphylococcus aureus (MRSA). A total of 8312 S. aureus infections in patients from 296 acute care hospitals pertaining to 17 regions in Spain were observed during the study period. Overall, 23.8% of these organisms were reported as meticillin resistant. The proportion of MRSA varied widely across regions and during the study period. Patients with nosocomial infections (NIs) had a two-fold higher prevalence of MRSA (31%) than patients with community-acquired infections (CAIs) (14%; P < 0.001). Nevertheless, there was an increasing trend in the prevalence of MRSA isolates, both in patients with NI (from
* Corresponding author. Address: Servicio de Medicina Preventiva, Hospital Universitario Puerta de Hierro, San Martı´n de Porres, 4. Madrid E-28035, Spain. Tel.: þ34 913 445547; fax: þ34 913 445431. E-mail address: [email protected] 1 Presented at the 15th Annual Meeting of the Society for Healthcare Epidemiology of America, 9e12 April 2005, Los Angeles, CA, USA. 0195-6701/$ - see front matter ª 2006 Published by Elsevier Ltd on behalf of The Hospital Infection Society. doi:10.1016/j.jhin.2006.03.013
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A. Asensio et al. 22% to 41%; P < 0.001) and with CAI (from 7% to 28%; P < 0.001) throughout the 11-year period. Geographical variations over the last three years (2001e2003) show a centripetal gradient, with the lowest MRSA prevalence in south-west Spain and the highest MRSA prevalence in the central regions. Almost five-fold differences in MRSA proportions were seen between regions (range 10.3e54.5%). Compared with bloodstream infections, infections in other sites were more likely to be caused by MRSA (adjusted odds ratios for surgical site, urinary tract, skin and respiratory infections of 1.2, 1.2, 1.5 and 2.1, respectively). ª 2006 Published by Elsevier Ltd on behalf of The Hospital Infection Society.
Introduction The Study of the Prevalence of Nosocomial Infections in Spain (EPINE) is a country-wide initiative that has been operating since 1990. Data are collected on the annual prevalence of infections in hospitalized patients. EPINE provides information on clinical, patient and epidemiological characteristics and helps in the design of programmes to improve antibiotic policies and control activities.1 Staphylococcus aureus is, after Escherichia coli, the second most frequent cause of infection in hospitalized patients in Spain.2 EPINE results show a marked increase in the proportion of meticillin-resistant S. aureus (MRSA) in the last decade in both nosocomial infections (NIs) and community-acquired infections (CAIs).2e4 Although the definition of the latter condition is still somewhat controversial, a worldwide increase in the prevalence of community-acquired MRSA infections has been clearly described.5,6 Country-wide surveillance systems of resistant micro-organisms, such as MRSA, provide relevant information about ongoing epidemiological characteristics. This study reports MRSA infections identified by hospitals in Spain between 1993 and 2003. These data describe the changes in MRSA rates between different Spanish regions and trends in its occurrence, as well as variations by clinical, demographic and hospital characteristics. The rate of community-acquired MRSA infections identified in hospitalized patients is also presented.
Methods Each year, acute care hospitals in Spain are invited to join the EPINE prevalence survey. Data collected from 1993 to 2003 have been used in this study. Participating hospitals complete a standardized questionnaire for each hospitalized patient, and provide overall data for each hospital and
hospital ward. The criteria of the Centers for Disease Control and Prevention (CDC) were used to define and classify NIs.7 Other infections were classified as CAIs if the patient came from home or from a nursing home, and the infection developed before admission or presented during the first 48 h following admission. ‘Nosocomial infections from a previous hospitalization’ (NIPH) were infections developed prior to the current admission by patients who were transferred from another hospital or who were re-admitted to hospital because of infection (i.e. surgical site infection developed after discharge). The following information was collected for each patient: demographics (age and sex), clinical data (basal risk, assessed by McCabe-Jackson score), patient risk factors, site of infection, infectious agent and resistance to antibiotic markers for selected organisms. Antimicrobial resistance was evaluated on the basis of the routine microbiological laboratory reports processed using standard accepted procedures.8,9 Hospital-validated forms were sent to an independent central unit for further validation and analysis. A report was returned to each participating hospital to avoid possible disagreements before the collected data were finally integrated in a centralized database.
Statistical analysis Data collected in annual surveys from 1993 to 2003 were used for the current analysis. MRSA proportions were calculated as the number of MRSA infections divided by the total number of S. aureus infections recorded. To test national and regional trends in the occurrence of MRSA, a logistic regression model was created, by region and for the whole country, which included the year of the enquiry as an independent variable and MRSA as a dependent variable to test the hypothesis that there
Nosocomial and community-acquired MRSA in Spain was a linear trend throughout the 11-year period. Geographical variation was evaluated by displaying the prevalence of MRSA by region for the last three-year period. The effect of factors potentially associated with MRSA infection was evaluated by univariate analysis-Chi-square test, by Chi-square test for trend, or by t-test if appropriate. A multiple logistic regression model was created to adjust the effect of factors associated with MRSA prevalence. The association of potentially associated factors was determined by odds ratios with 95% confidence intervals. A significant difference was defined as P < 0.05. Statistical analyses were performed using Epi-Info 6 and Stata 8 SE statistical software.
Results Between 1993 and 2003, EPINE collected data on a total of 160 699 infections from 580 386 patients hospitalized in 296 centres distributed throughout all 17 regions of Spain. The number of patients included annually in the prevalence surveys ranged from 46 983 in 1993 to 54 864 in 2003. The hospitals included in the study provide healthcare services for an estimated population of approximately 17.5e20.4 million people/year. This represents about 50% of the Spanish population. By hospital size, 58% of the hospitals had more than 500 beds, 30% hospitals had between 200 and 500 beds, and 12% of the hospitals had less than 200 beds. In total, 8302 S. aureus infections were recorded over the 11 annual prevalence surveys. Fifty percent of all S. aureus infections fulfilled CDC criteria for NIs, whereas 39% were classified as CAIs and 11% were classified as NIPHs. Overall, 23.8% of infections due to S. aureus in hospitalized patients were reported to be MRSA. Table I shows the number of hospitals, the total number of S. aureus and MRSA infections, and the proportion of MRSA infections by region. Patients infected with MRSA were older than patients with a meticillin-susceptible S. aureus infection [mean age 63.0 years, standard deviation (SD) 19.3 vs 55.5 years, SD 22.8; P < 0.001]. The prevalence of MRSA infections increased linearly with age, from 10% at less than 10 years to 32% at greater than 80 years (P < 0.001). There was no difference in the prevalence of MRSA infection by sex (P ¼ 0.65). The proportion of MRSA was higher among patients admitted to intensive care units (ICUs) (34%) than among patients in medical (25%), surgical (22%), obstetric (11%) or paediatric wards (9%; P < 0.001) (Figure 1). Patients with an NI had a two-fold higher prevalence of MRSA (31%) than
467 Table I Overall proportion of meticillin-resistant Staphylococcus aureus (MRSA) infections in hospitalized patients, and number of hospitals participating in EPINE from 1993 to 2003, by Spanish region Region
Andalucia Arago ´n Asturias Baleares Canarias Cantabria Castilla-La Mancha CastillaLeo ´n Catalonia Extremadura La Rioja Galicia Madrid Murcia Navarra Valencia Pais Vasco Total
Number of hospitals participating
Number of Total MRSA number of S. infections (%) aureus infections
41 10 14 7 8 3 14
825 299 331 159 253 251 280
122 142 44 50 70 45 81
20
812
218 (27.0)
64 7 2 22 25 9 5 28 17 296
1416 143 62 862 1038 152 123 659 637 8302
346 28 17 172 343 19 17 168 93 1976
(14.8) (47.5) (13.3) (31.4) (27.7) (17.9) (28.9)
(24.4) (19.6) (27.4) (20.0) (33.0) (12.5) (13.8) (25.5) (14.6) (23.8)
patients with a CAI (14%; P < 0.001). Nevertheless, there was an increasing trend in the prevalence of MRSA isolates for both NI (from 22% to 41%; P < 0.001) and CAI (from 7% to 28%; P < 0.001) throughout the 11-year period (Figure 2). No glycopeptide resistance was detected during the study period.
Figure 1 Proportion of meticillin-resistant Staphylococcus aureus (MRSA) infections in hospitalized patients by type of ward. ICU, intensive care unit.
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Figure 2 Yearly proportions of meticillin-resistant Staphylococcus aureus (MRSA) in hospitalized patients (nosocomial or community-acquired), Spain, 1993e2003 (Chi-square for linear trend, P < 0.0001).
Basal risk, assessed by McCabe-Jackson score, was linked to MRSA prevalence, with MRSA prevalence rates of 17%, 24% and 32% in patients with low, moderate and severe basal risk, respectively (P < 0.001). The prevalence of MRSA increased with the number of intrinsic risk factors in a relatively linear trend, from 15% in patients with no intrinsic risk factors to 48% in patients with more than five risk factors (P < 0.001) (Figure 3). Hospital size was also associated with the rate of MRSA, from 22% in hospitals with less than 200 beds to 26% in hospitals with more than 500 beds (P < 0.001). However, it should be noted that the prevalence of community-acquired MRSA infection
Figure 3 Proportion of meticillin-resistant Staphylococcus aureus (MRSA) infections in hospitalized patients by number of intrinsic risk factors (Chi-square for linear trend: 224.6; P < 0.0001).
was inversely associated with hospital size; 14% in hospitals with more than 500 beds and 17% in hospitals with less than 200 beds (P < 0.025). For both CAI and NI, the lowest prevalence of MRSA was found when the primary site of infection was bacteraemia (11% and 25%, respectively) and the highest prevalence was found for respiratory tract infections (23% and 40%, respectively) (Figure 4). Table II shows the proportion of MRSA, nationally and by region, for the first and last threeyear periods of the study, and also the annual rate of change estimated by logistic regression analysis. It can be seen that increases in MRSA proportions were significant in all regions except for Asturias, Extremadura, La Rioja, Murcia and
Figure 4 Proportion of meticillin-resistant Staphylococcus aureus (MRSA) infections in hospitalized patients by site of infection (nosocomial or communityacquired). SSI, surgical site infection; UTI, urinary tract infection.
Nosocomial and community-acquired MRSA in Spain
469
Table II Proportion of meticillin-resistant Staphylococcus aureus (MRSA) resistance for the 1993e1995 and 2001e 2003 three-year periods, and relative annual changes in MRSA proportion, estimated by logistic regression, by Spanish regions Region
Proportion of MRSA 1993e1995
Proportion of MRSA 2001e2003
Relative change per year, odds ratio
95% CI of estimated change
P value
4.0 34.0 24.3 0.0 10.3 4.8 19.7 4.3 23.2 21.1 36.8 7.9 18.4 8.0 11.9 19.5 3.6 14.0
20.8 54.5 14.8 50.0 33.3 39.1 35.2 44.2 27.8 14.0 23.3 34.7 44.1 16.7 10.3 35.1 26.1 32.5
1.20 1.10 1.01 1.59 1.19 1.41 1.11 1.35 1.04 0.94 0.94 1.27 1.15 0.99 0.97 1.12 1.42 1.15
1.12e1.28 1.02e1.19 0.89e1.13 1.32e1.91 1.07e1.33 1.23e1.61 1.02e1.21 1.27e1.44 0.96e1.08 0.80e1.09 0.81e1.09 1.20e1.35 1.10e1.20 0.86e1.15 0.82e1.13 1.06e1.18 1.29e1.57 1.13e1.17
<0.001 0.014 0.993 <0.001 0.002 <0.001 0.022 <0.001 0.083 0.406 0.399 <0.001 <0.001 0.917 0.654 <0.001 <0.001 <0.001
Andalucia Aragon Asturias Baleares Canarias Cantabria Castilla-La Mancha Castilla-Leo ´n Catalonia Extremadura La Rioja Galicia Madrid Murcia Navarra Valencia Pais Vasco Total CI, confidence intervals.
Navarra, which remained below 24% during the last three-year period. The highest relative variation was found in Baleares, Cantabria, Castilla-Leo ´n and Pais Vasco, with average annual increases ranging from 1.35 to 1.59. In Catalonia, resistance rates did not increase significantly and remained at intermediate levels (28%) during the last threeyear period. It is notable that none of the Spanish regions experienced a significant decreasing trend. Geographical distribution over the 1993e1995 and 2001e2003 periods showed wide variation (Table II). During the last three-year period, the lowest MRSA prevalence (<25%) was recorded in southern Spain (Andalucia, Murcia and Extremadura) and some small regions in northern-central Spain (Navarra and Asturias, La Rioja), with the highest prevalence (>35%) seen in Madrid, the two Castillas, Arago ´n, Cantabria, Baleares and Valencia (Figure 5). Almost five-fold differences in MRSA proportion by regions were observed during the last three-year period, with the lowest in Navarra (10.3%) and the highest in Arago ´n (54.5%) (Table II). The multi-variate analysis, after controlling for age, nosocomial origin, number of intrinsic risk factors and basal risk, and infections localized to the respiratory tract, skin and surgical site, showed an increased risk of being caused by MRSA when compared with bacteraemia (adjusted odds ratios 2.1, 1.5 and 1.2, respectively) (Table III).
Discussion MRSA is responsible for a large number of infections and its increased prevalence is a matter of public concern. The potential acquisition of vancomycin resistance and the emergence and
Figure 5 Geographical distribution of proportions of meticillin-resistant Staphylococcus aureus infections in hospitalized patients by Spanish regions. Average proportion for the period 2001e2003. A, Andalucia; AR, Arago ´n; AS, Asturias; B, Baleares; C, Canarias; CA, Cantabria; CL, Castilla-Leo ´n; CM, Castilla-La Mancha; CT, Catalonia; E, Extremadura; G, Galicia; LR, La Rioja; M, Madrid; N, Navarra; PV, Pais Vasco; V, Valencia; MU, Murcia.
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Table III Factors associated with meticillin-resistant Staphylococcus aureus (MRSA) infections in hospitalized patients. Odds ratios unadjusted and adjusted by multiple logistic regression MRSA N ¼ 1975 Age, mean (SD) for every 10 years Onset of infection (nosocomial/community)a Median number of intrinsic risk factors Basal risk Low Moderate Severe Site of infection Bloodstream Other Skin and soft tissue Surgical site Urinary tract Respiratory tract
MSSA N ¼ 6326
Unadjusted odds ratio (95% CI)
Adjusted odds ratio (95% CI)
1.2 (1.1e1.2) 2.8 (2.5e3.2)
1.1 (1.1e1.2) 2.7 (2.3e3.1)
1
1.4 (1.3e1.4)
1.2 (1.1e1.3)
497 (15) 545 (24) 451 (32)
2713 (85) 1713 (76) 939 (68)
1 1.7 (1.5e2.0) 2.6 (2.3e3.0)
1 1.1 (0.9e1.3) 1.4 (1.1e1.6)
255 262 380 445 98 535
1019 1372 1277 1411 269 978
1 0.8 1.2 1.3 1.5 2.2
1 1.2 1.5 1.2 1.2 2.1
63.0 (22.8) 1283 (31) 2
(20) (16) (23) (24) (27) (35)
55.5 (19.3) 2822 (69)
(80) (84) (77) (76) (73) (65)
(0.6e0.9) (1.0e1.4) (1.1e1.5) (1.1e1.9) (1.8e2.6)
(0.9e1.5) (1.2e1.9) (1.0e1.5) (0.9e1.7) (1.7e2.6)
MSSA, meticillin-susceptible S. aureus; SD, standard deviation; CI, confidence intervals. a Of 7370 infections (excluded infections from a previous hospitalization).
increased identification of community-acquired MRSA have raised interest in this pathogen even further.6,10 The results of this study represent the most comprehensive assessment of MRSA trends in Spain during the last decade. Information gathered at hospital level, based on resistance patterns reported by clinical microbiology laboratories, seems to be a reliable method of estimating country-wide rates of meticillin resistance. The prevalence of MRSA in hospitalized patients in Spain increased significantly at a rate of 1.15% annually during the 1993e2003 period, reaching 41% of all nosocomial S. aureus infections and 28% of all communityacquired S. aureus infections by 2003. When comparing EPINE data with data reported by the European Antimicrobial Resistance Surveillance System for bloodstream isolates in Spain during 2000e2002, no statistical differences were found (proportion of MRSA for nosocomial bacteraemia 23% vs 24%; P ¼ 0.52).3 Overall prevalence (34%) was also similar to that reported by Cuevas et al. (31%) in a single-day surveillance study performed in Spain in 2002.4 This study also shows that the increasing MRSA trend is not a homogeneous event. Differences between Spanish regions demonstrated that local factors must play an important role in the incidence and spread of MRSA. Differences in infection control measures, host susceptibility and antibiotic prescription policies may account for this variability.11
It is of note that the overall prevalence of MRSA was 2.8 times higher for NIs than for CAIs. This difference was reduced during 2002 and 2003 due to an increase in community-acquired MRSA infections. Unlike other reports, the nature of the present study precludes the identification of settings where MRSA is acquired.12,13 In addition, the genetic background of the isolates could not be determined in order to assess their relationship with known community-acquired MRSA or pathogenic clones.14,15 Nevertheless, it was possible to ascertain that S. aureus infections which were acquired in the hospital setting had a higher risk of being MRSA infections than those which were acquired in the community. As has been reported previously, age, basal risk, number of risk factors, intensive care unit and hospital size were associated with MRSA infection.16 The primary site of infection was also related to the risk of MRSA acquisition. Body regions that were most exposed to external contamination, such as the respiratory tract or the skin, were the infection sites with the highest prevalence of MRSA (35e23%), while the bloodstream showed the lowest prevalence of MRSA (20%). These observations may be true differences or the MRSA infection rate may be overestimated in some sites if isolates represent colonization rather than clinical infection. However, as EPINE methodology applies CDC criteria, microbiological isolates should correspond to diagnosed infections, even if not all identified organisms are playing the
Nosocomial and community-acquired MRSA in Spain pathogenic role. It is noteworthy that although most pathogenic community-acquired MRSA isolates have been associated with skin disease, the prevalence of skin infections in this study (14%) was much lower than that of urinary tract infections (21%) or respiratory tract infections (23%).15 This study shows that the prevalence rate of MRSA infection may be higher than suspected previously. In contrast to the findings of a previous, but smaller, study, the prevalence of MRSA is far from stabilizing in Spain.3 Clinicians and public health authorities must be aware of the role of hospital hygiene and infection control protocols, as well as antimicrobial drug policies and mechanisms for the regional spread of MRSA throughout hospitals. Increased numbers of patients admitted to hospitals with MRSA infection or colonization represent a growing clinical problem and may contribute to the endemicity of this pathogen in the hospital setting.
Acknowledgements The authors wish to thank Martin Hadley-Adams for his assistance with the English language and preparation of the manuscript. This study was supported by the Fondo de Investigacio ´n Sanitaria, Spanish Ministry of Health, grant PI20765 FIS.
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