Published online June 2, 2008
PEDIATRICS Vol. 121 No. 6 June 2008, pp. 1090-1098 (doi:10.1542/peds.2007-2104)
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ARTICLE

Prevalence of and Risk Factors for Community-Acquired Methicillin-Resistant and Methicillin-Sensitive Staphylococcus aureus Colonization in Children Seen in a Practice-Based Research Network

Stephanie A. Fritz, MDa, Jane Garbutt, MB, ChBa,b, Alexis Elward, MD, MPHa, William Shannon, PhDb,c and Gregory A. Storch, MDa,b

Departments of a Pediatrics
b Medicine
c Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. We sought to define the prevalence of and risk factors for methicillin-resistant Staphylococcus aureus nasal colonization in the St Louis pediatric population.

METHODS. Children from birth to 18 years of age presenting for sick and well visits were recruited from pediatric practices affiliated with a practice-based research network. Nasal swabs were obtained, and a questionnaire was administered.

RESULTS. We enrolled 1300 participants from 11 practices. The prevalence of methicillin-resistant S aureus nasal colonization varied according to practice, from 0% to 9% (mean: 2.6%). The estimated population prevalence of methicillin-resistant S aureus nasal colonization for the 2 main counties of the St Louis metropolitan area was 2.4%. Of the 32 methicillin-resistant S aureus isolates, 9 (28%) were health care-associated types and 21 (66%) were community-acquired types. A significantly greater number of children with community-acquired methicillin-resistant S aureus were black and were enrolled in Medicaid, in comparison with children colonized with health care-associated methicillin-resistant S aureus. Children with both types of methicillin-resistant S aureus colonization had increased contact with health care, compared with children without colonization. Methicillin-sensitive S aureus nasal colonization ranged from 9% to 31% among practices (mean: 24%). The estimated population prevalence of methicillin-sensitive S aureus was 24.6%. Risk factors associated with methicillin-sensitive S aureus colonization included pet ownership, fingernail biting, and sports participation.

CONCLUSIONS. Methicillin-resistant S aureus colonization is widespread among children in our community and includes strains associated with health care-associated and community-acquired infections.

Key Words: community-acquired Staphylococcus aureus • methicillin resistance • practice-based research network

Abbreviations: MRSA—methicillin-resistant Staphylococcus aureus • CA—community-acquired • HA—health care-associated • SCCmec—staphylococcal cassette chromosome mec • PVL—Panton-Valentine leukocidin • MSSA—methicillin-sensitive Staphylococcus aureus • CI—confidence interval • OR—odds ratio • PFGE—pulsed-field gel electrophoresis

Until recently, methicillin-resistant Staphylococcus aureus (MRSA) infections occurred most often in people with contact with health care institutions. Since the late 1990s, however, community-acquired (CA)-MRSA infections have become common. These infections typically occur in immunocompetent hosts and range in severity from superficial skin and soft-tissue abscesses to invasive disease, including necrotizing pneumonia, pyomyositis, osteomyelitis, severe sepsis, and death.1–9

The strains of MRSA associated with CA infections have distinct features, in comparison with those associated with health care-associated (HA) infections. Methicillin resistance is conferred by the mecA gene, which is located in the staphylococcal cassette chromosome mec (SCCmec). The SCCmec elements are different in HA-MRSA and CA-MRSA strains. HA-MRSA strains typically contain the larger type I, II, or III elements, whereas CA-MRSA strains contain the smaller type IV or V elements.7,10–14 CA-MRSA isolates often are resistant to fewer classes of non–β-lactam antibiotics and often carry the genes encoding Panton-Valentine leukocidin (PVL), a leukocyte-destroying exotoxin associated with the pathogenesis of severe skin and soft-tissue infections and necrotizing pneumonia.5,8,14–19

One method of assessing the extent of dispersion of an organism such as S aureus in a community involves measuring the rate of colonization with the organism. The most consistent colonization site for S aureus is the anterior nares.20 In some populations, S aureus nasal colonization has been associated with increased rates of S aureus infections.20–22 However, this relationship has not been established in the community-based pediatric setting. To date, there have been few large-scale, community-based studies of MRSA colonization. Studies performed between 1999 and 2001 revealed prevalence rates of CA-MRSA nasal colonization in the outpatient pediatric population ranging from 0.4% to 0.8%, whereas a study performed in 2004 reported a rate of 9.2%.23–25 Among those studies, risk factors for CA-MRSA colonization varied and included employment of a household member in health care and antibiotic use within the previous 6 months.24–26

We now report the largest community-based, pediatric, MRSA nasal colonization prevalence study to date, which was performed in collaboration with pediatric practices affiliated with the Washington University Pediatric and Adolescent Ambulatory Research Consortium, a practice-based research network. The objectives of this study were to define the prevalence of MRSA nasal carriage among children in the St Louis community, to characterize the colonizing isolates, and to identify epidemiological risk factors associated with MRSA colonization.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Participant Recruitment
This study was approved by the Washington University Human Research Protection Office. Washington University Pediatric and Adolescent Ambulatory Research Consortium consists of 65 clinicians representing 28 geographically and demographically diverse community practices in the St Louis metropolitan area. Each of the Washington University Pediatric and Adolescent Ambulatory Research Consortium-affiliated practices was invited to participate in the study. The 11 practices that agreed to participate were dispersed throughout the St Louis area and represented the socioeconomic diversity of the St Louis population. Over an 8-month period (October 2005 to June 2006), we performed a cross-sectional study, enrolling children from birth to 18 years of age whose parents spoke English and who were presenting to their pediatrician for well or sick visits. Written, informed, parental consent and patient assent were obtained. Only 1 child per family was enrolled. An anterior nasal swab was obtained from both nares (BBL CultureSwab; Becton Dickinson, Sparks, MD). A questionnaire was administered to the participant or parent, to collect demographic data and to identify possible epidemiological risk factors for S aureus nasal colonization.

Laboratory Methods
Specimens were transported to the St Louis Children's Hospital bacteriology laboratory and plated within 8 to 18 hours after sampling. Nasal swabs were plated to tripticase soy agar plus 5% sheep blood (BBL; Becton Dickinson), incubated at 35°C in 5% carbon dioxide for 24 to 48 hours, and screened for the presence of S aureus isolates on the basis of appearance (colony morphologic features, β-hemolysis, and Gram staining), catalase activity, and coagulase activity (Staphaurex; Remel, Lenexa, KS). Antibiotic susceptibility profiles for 10 antibiotics were performed with the disk diffusion method on Mueller-Hinton agar (BBL; Becton Dickinson), according to procedures recommended by the Clinical and Laboratory Standards Institute.27 Isolates were classified as MRSA if they demonstrated resistance to cefoxitin.27 The D-zone test for inducible clindamycin resistance also was performed.27–29 Multiplex polymerase chain reaction assays for SCCmec typing and for assessments of the presence of the lukF-PV gene (encoding part of the PVL toxin) were performed with all MRSA isolates by using established methods.30,31 Pulsed-field gel electrophoresis (PFGE) typing was performed with selected isolates at the Centers for Disease Control and Prevention, according to the methods described by McDougal et al.32

Statistical Methods
Statistical analyses were performed by using SAS 9.1 (SAS Institute, Cary, NC) unless otherwise specified. All tests for significance were 2-tailed. P values of ≤.05 were considered significant.

In univariate analyses, the SAS statistical procedure PROC GLIMMIX was used to fit mixed models with colonization status as the categorical outcome variable and pediatric practice as the random effect. Odds ratios (ORs) and confidence intervals (CIs) were calculated with this procedure by using the link=logit option.

For multivariate analyses, the generalized estimating equation procedure was used to estimate regression model parameters, to compare subjects according to colonization status, taking into account correlated data resulting from subjects being cared for by the same pediatric practice.33 The multivariate analysis was performed by using factors a priori thought to be associated with MRSA or methicillin-sensitive S aureus (MSSA) colonization and select factors that were significant in the univariate analyses.

Comparison of potential risk factors between participants colonized with HA-MRSA and CA-MRSA strains was performed with Fisher's exact test for categorical variables and the Mann-Whitney U test for continuous variables, by using SPSS for Windows 14.0 (SPSS, Chicago, IL). Linear trend analysis with the {chi}2 test was performed by using EpiInfo 3.3.2 (Centers for Disease Control and Prevention, Atlanta, GA).

Geographic Information System Mapping
Participants' home addresses were mapped by using geographic information system software (ArcView 3.2 and ArcGIS 9.1 Streetmap; ESRI, Redlands, CA). Census demographic information for the 2 main counties in the St Louis metropolitan area (St Louis County and St Louis City) was obtained from the Missouri Office of Social and Economic Data Analysis (www.oseda.missouri.edu). Estimated rates of MRSA and MSSA colonization for these 2 counties were calculated as the number of colonized children in our study population, weighted according to age and race within each county, divided by the number of children within the respective category in each county population, as determined in the 2000 US Census.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study Population
We enrolled 1300 children from 11 general pediatric practices. Their characteristics are presented in Table 1. Black children more frequently than white children had Medicaid or no health insurance and lived in crowded homes (defined as >2 people per bedroom) (P < .001 for both variables). The number of children enrolled from each practice ranged from 100 to 197, except for 1 practice from which only 11 children were recruited. The practice characteristics are shown in Table 2.


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  		TABLE 1 Demographic Characterization of Study Participants

 

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  		TABLE 2 Pediatric Practice Characteristics

 
Culture Results and Risk Factors for Colonization
MRSA
Overall, 32 children were colonized with MRSA. The proportion of children colonized with MRSA within each practice varied from 0% to 9% (mean: 2.6%) (Fig 1A). On the basis of the rate of colonization in groups defined according to age and race, we estimated the total number of children in the 2 main counties of the St Louis metropolitan area (St Louis City and St Louis County) colonized with MRSA to be 8455 (95% CI: 8279–8631), corresponding to 2.4% of the population <18 years of age at the time of the study (Table 3).


Figure 1
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  		FIGURE 1 MRSA and MSSA colonization according to practice (A), age (B), race (C), and proportion of Medicaid enrollment in practice (D).

 

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  		TABLE 3 Estimated Numbers of Children in the St Louis Core Metropolitan Area Colonized With MRSA and MSSA, According to Age Group and Race

 
Rates of MRSA colonization were similar in all age groups (Fig 1B). The rate of MRSA nasal colonization in black children was 4.7%, and the rate in white children was 1.2% (P = .023) (Table 1 and Fig 1C). Children with Medicaid or no health insurance were more likely to be colonized with MRSA than were children with private health insurance (P = .008) (Table 1). Higher rates of MRSA colonization were noted in practices with greater proportions of Medicaid enrollment (P < .001) (Fig 1D).

Significant epidemiological risk factors associated with MRSA colonization are presented in Table 4. Factors included in the questionnaire but not significantly associated with colonization are listed in the footnotes. Unexpectedly, day care attendance (for children ≤5 years of age) was a significant protective factor (OR: 0.10; 95% CI: 0.02–0.59), and children who bathed more frequently were more likely to be colonized with MRSA (OR: 0.42; 95% CI: 0.25–0.71). In our study population, more children with private health insurance attended day care, compared with children with Medicaid or no health insurance (P = .028). Colonization status did not differ for children presenting to the pediatrician for a sick visit or a well-child examination. In the multivariate analysis, factors that remained significant for MRSA nasal colonization were black race (P = .007) and previous systemic infection (P = .023).


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  		TABLE 4 Univariate Risk Factors for MRSA and MSSA Colonization

 
MSSA
A total of 331 participants were colonized with MSSA. The rate varied among practices, ranging from 9% to 32% (mean: 24.2%) (Fig 1A). The estimated total number of children with MSSA colonization in the 2 main St Louis metropolitan counties was 84552 (95% CI: 84122–84982), corresponding to a prevalence rate of 24.6% (Table 3).

Rates of MSSA colonization were higher in older children (P < .001) (Fig 1B). The rate of nasal colonization with MSSA was 21.1% in black children, compared with 28.0% in white children (P = .065) (Fig 1C). The rate of MSSA colonization was greater among participants cared for in practices with an intermediate proportion of Medicaid recipients, compared with the rates of colonization in practices with smaller or larger proportions of Medicaid recipients (P = .025) (Fig 1D). Insurance status of the study participants was not significantly related to the risk of MSSA colonization (Table 1).

Epidemiological risk factors associated significantly with MSSA colonization in the univariate analyses are listed in Table 4. The multivariate model revealed nail biting (P < .001) and sports participation (P = .057) as risk factors for MSSA colonization.

Microbiologic Findings
Molecular analysis identified a heterogeneous population of MRSA isolates (Fig 2). Nine (28%) of the isolates contained the type II SCCmec element (HA-MRSA), 21 (66%) contained the type IV cassette (CA-MRSA), and 2 contained the mecA gene but the SCCmec type could not be determined. Four of the 9 isolates carrying the type II SCCmec cassette were characterized through PFGE, and all were USA100. Thirteen of the 21 isolates containing type IV SCCmec also were characterized through PFGE. Of these, 7 were USA300 (all were positive for a PVL gene), 3 were USA800 (none carried a PVL gene), and 3 were USA1000 (none carried a PVL gene). The PVL gene was present in 16 of the CA-MRSA isolates (76%) but in none of the HA-MRSA isolates (P < .001). Resistance to clindamycin was present in 8 (89%) of the 9 HA-MRSA isolates (6 with constitutive resistance and 2 with inducible resistance) and 2 (9.5%) of the 21 CA-MRSA isolates (both with inducible clindamycin resistance). Of the 331 MSSA isolates, clindamycin resistance was present in 62 (18.7%; 7 with constitutive resistance and 55 with inducible resistance). All S aureus isolates were susceptible to trimethoprim/sulfamethoxazole, rifampin, and vancomycin.


Figure 2
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  		FIGURE 2 Characterization of MRSA isolates. Resistance to clindamycin (Clinda) was classified as either constitutive or inducible (positive D-test). R indicates resistant; S, sensitive. a Two MRSA isolates were neither SCCmec type II nor type IV.

 
Comparison of HA-MRSA and CA-MRSA
MRSA isolates containing the type II SCCmec cassette (HA-MRSA) were compared with MRSA isolates containing the type IV cassette (CA-MRSA) (Table 5). Children colonized with HA-MRSA were more likely to be white (P = .002), to have private health insurance (P = .042), and to live in a household with a pet (P = .046). Although the finding was not statistically significant, children colonized with CA-MRSA strains were younger than those colonized with HA-MRSA strains (median ages of 2.65 and 9.43 years, respectively). Although there were no significant differences in individual health-related factors (eg, hospitalization or emergency department visits) between groups colonized with HA-MRSA and CA-MRSA, 77.8% of children colonized with HA-MRSA either had a household member working in health care or had visited someone in the hospital or a nursing home ("indirect" exposure to health care), compared with 33.3% of children with CA-MRSA (P = .046).


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  		TABLE 5 Comparison of Demographic and Health-Related Risk Factors According to SCCmec Type

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The dramatic increase in the number of children in our community presenting with CA-MRSA infections prompted us to initiate an investigation to define the prevalence of CA-MRSA nasal colonization in the metropolitan St Louis pediatric population and to identify risk factors for MRSA colonization, with the goal of developing control strategies. The results of our survey revealed evidence of dissemination of MRSA in our community, with 32 children from 9 different practices colonized with MRSA, as well as 331 colonized with MSSA. The MRSA colonization rates within individual practices ranged from 0% to 9% for MRSA and from 9% to 32% for MSSA. We estimated, on the basis of the survey, that 2.4% of children in the core St Louis metropolitan area were colonized with MRSA, corresponding to >8000 colonized children.

Molecular typing revealed heterogeneity among our isolates, with the majority classified as CA-MRSA strains and a smaller proportion of strains classified as those typically associated with HA infections. The prevalence of MRSA colonization among children in other studies ranged from 0.6% in the National Health and Nutrition Examination Survey,34 performed in 2001–2002, to 9.2% in a study performed in 2004 by Creech et al,26 which sampled children from 2 practices in Nashville, Tennessee. Few colonization prevalence studies reported SCCmec typing of their isolates. However, those 2 studies found both HA-MRSA and CA-MRSA strains in their populations, with proportions similar to those in the present study (C. B. Creech, MD, personal communication, 2007).35

It is possible that the true prevalence in our community is even higher than demonstrated by our survey, because participants were sampled only once and from only 1 body site. Enrolling 1 child per household also might have underestimated the prevalence of MRSA in the community, although we think this effect, if present, would be very small. In addition, our nasal specimens were plated directly onto nutritive blood agar plates, whereas samples collected by Creech et al26 were incubated overnight in MRSA enrichment broth before being plated onto mannitol salt agar, which yielded a higher rate of MRSA recovery than direct plating (C. B. Creech, MD, personal communication, 2007). The lower rate of colonization in the National Health and Nutrition Examination Survey, compared with the present study and the Nashville study, probably reflects the increased dissemination of MRSA into the community that occurred during the interval between the studies, although geographic variation could account for some of the difference.

Our survey identified several important new risk factors for MRSA colonization. This is the first report in the pediatric population showing that MRSA colonization is associated with low socioeconomic status, represented by enrollment in the Medicaid insurance program and household crowding. In contrast, the study by Creech et al26 found that children of different socioeconomic levels did not differ significantly in their colonization status. A possible explanation for this discrepancy is the broader population base of the present study. In addition, this study found a significantly greater number of black children colonized with MRSA than white children. Although other studies demonstrated higher rates of MRSA infections in black subjects than in white subjects,35,36 this association was not demonstrated previously in other MRSA colonization studies.26,37 Possible explanations for this racial disparity include environmental factors leading to greater exposure or a genetic predisposition to colonization, such as a difference in receptors for MRSA.

Although all samples were obtained from children in an outpatient setting, we found that past health care-related exposures were significant risk factors for MRSA colonization. In contrast to multiple studies that did not show a relationship between CA-MRSA infections and contact with the health care system, we found that children colonized with both CA-MRSA and HA-MRSA were more likely to have had personal contact with the health care system than were children not colonized with MRSA. However, children with HA-MRSA were more likely than children with CA-MRSA to have had indirect exposure to health care. These relationships may suggest an evolution of the epidemic, with blurring of the distinction between HA-MRSA and CA-MRSA. This has been reflected in reports of "nosocomial" outbreaks with CA-MRSA, suggesting that CA-MRSA strains are being introduced and spread through health care facilities.38,39

Several other risk factors associated previously with MRSA infections were not associated with colonization in this study population. Suggestions for limiting transmission of MRSA between family members and teammates include not sharing personal hygiene items such as towels and washcloths.40 In this study, however, children sharing bath towels or face cloths were not at increased risk for MRSA colonization. Although outbreaks of MRSA infections have been reported among athletes41–44 and within prisons,45,46 sports participation, contact with a recent inmate, and a household member working in the corrections system were not significant risk factors for MRSA colonization in this study. These findings highlight the concept that factors associated with colonization may differ from factors associated with transmission of the organism or with clinical infection.

Similar to other colonization studies, history of a skin or soft-tissue infection was not related to nasal carriage of MRSA.21,26 Among older children, we found that shaving and waxing of body hair were associated with MRSA colonization. It is possible that MRSA may be transmitted through the depilatory wax or related equipment or that these practices create microscopic damage or other changes in the skin that favor colonization.

We also investigated risk factors for MSSA colonization. In contrast to the findings for MRSA, race and socioeconomic status were not significantly related to the risk of MSSA colonization. Interestingly, children who had sought care in an emergency department or urgent care clinic in the previous 6 months were less likely to be colonized with MSSA than were children without an emergency department or urgent care visit. We speculate that this may be related to the large number of antibiotic prescriptions given in these settings, which may subsequently eliminate MSSA nasal carriage.

There are several limitations to our study. The relatively small number of cases of colonization with MRSA might have limited the ability to detect all risk factors. In addition, the small number of cases limited our ability to perform multivariate analysis, and it is possible that some of the risk factors we identified, such as race, Medicaid insurance, and household crowding, were linked with one another. Because we did not adjust for multiple comparisons in our statistical analyses, some variables might have reached significance through chance alone. However, our large sample size and enrollment from 11 different practices, with patient populations representing diverse socioeconomic backgrounds within the St Louis region, are strengths of this study.

The health and economic impact of CA-MRSA infections has become a significant problem in many communities. This study provides new information about the dispersion of the causative organism and associated epidemiological risk factors for colonization. In addition, it provides evidence that traditional HA-MRSA is also present among children being seen in outpatient pediatric practices. The relationship between nasal colonization and the occurrence of CA infections remains unclear. Longitudinal studies monitoring children identified as having MRSA colonization and noting their progression to infection, as well as epidemiological comparisons of children with infections and colonization, are in progress.


   ACKNOWLEDGMENTS
 
This research was supported by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award 5 T32 HD007507.

We thank the Washington University Pediatric and Adolescent Ambulatory Research Consortium physicians and staff members at Blue Fish Pediatrics, Children's Clinic, Crystal City Pediatrics, Esse Health-Creve Coeur, Esse Health-Webster Groves, Grace Hill-Soulard, Healthcare for Kids, Northwest Pediatrics, St Louis Pediatric Practitioners, Southwest Pediatrics, and Tots through Teens Pediatrics for allowing us to enroll patients in their offices; the St Louis Children's Hospital bacteriology staff members for their technical support; Richard Buller, PhD, and Monique Gaudreault for performing polymerase chain reaction analyses of our isolates; Mario Schootman, PhD, and Jim Struthers from the Washington University Division of Health Behavior Research for geographic information system mapping; Christina Banister, Rachel Orscheln, MD, and David Hunstad, MD, for technical expertise; and Roberta Carey, PhD, Gregory Fosheim, MPH, and Sigrid McAllister, MS, from the Centers for Disease Control and Prevention, Division of Healthcare Quality Promotion, Clinical and Environmental Microbiology Branch, for performing PFGE analyses of our isolates.


   FOOTNOTES
 
Accepted Oct 4, 2007.

Address correspondence to Stephanie A. Fritz, MD, Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8116, St Louis, MO 63110. E-mail: lutter_s{at}kids.wustl.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


What's Known on This Subject

Previous outpatient, pediatric, community-acquired MRSA nasal colonization studies revealed prevalences ranging from 0.4% to 9.2%. In those studies, risk factors for colonization included employment of a household member in health care and antibiotic use within the previous 6 months.

 

What This Study Adds

This is the largest community-based, pediatric, MRSA nasal colonization prevalence study to date. It is unique because it was performed in collaboration with a practice-based research network. Novel risk factors for colonization include low socioeconomic status and black race.

 


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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