Context Methicillin-resistant Staphylococcus aureus (MRSA)
has traditionally been considered a health care–associated pathogen
in patients with established risk factors. However, MRSA has emerged in patients
without established risk factors (community-associated MRSA).
Objective To characterize epidemiological and microbiological characteristics
of community-associated MRSA cases compared with health care–associated
MRSA cases.
Design, Setting, and Patients Prospective cohort study of patients with MRSA infection identified
at 12 Minnesota laboratory facilities from January 1 through December 31,
2000, comparing community-associated (median age, 23 years) with health care–associated
(median age, 68 years) MRSA cases.
Main Outcome Measures Clinical infections associated with either community-associated or health
care–associated MRSA, microbiological characteristics of the MRSA isolates
including susceptibility testing, pulsed-field gel electrophoresis, and staphylococcal
exotoxin gene testing.
Results Of 1100 MRSA infections, 131 (12%) were community-associated and 937
(85%) were health care–associated; 32 (3%) could not be classified due
to lack of information. Skin and soft tissue infections were more common among
community-associated cases (75%) than among health care–associated cases
(37%) (odds ratio [OR], 4.25; 95% confidence interval [CI], 2.97-5.90). Although
community-associated MRSA isolates were more likely to be susceptible to 4
antimicrobial classes (adjusted OR, 2.44; 95% CI, 1.35-3.86), most community-associated
infections were initially treated with antimicrobials to which the isolate
was nonsusceptible. Community-associated isolates were also more likely to
belong to 1 of 2 pulsed-field gel electrophoresis clonal groups in both univariate
and multivariate analysis. Community-associated isolates typically possessed
different exotoxin gene profiles (eg, Panton Valentine leukocidin genes) compared
with health care–associated isolates.
Conclusions Community-associated and health care–associated MRSA cases differ
demographically and clinically, and their respective isolates are microbiologically
distinct. This suggests that most community-associated MRSA strains did not
originate in health care settings, and that their microbiological features
may have contributed to their emergence in the community. Clinicians should
be aware that therapy with β-lactam antimicrobials can no longer be relied
on as the sole empiric therapy for severely ill outpatients whose infections
may be staphylococcal in origin.
Methicillin-resistant Staphylococcus aureus (MRSA)
was identified as a nosocomial pathogen in the 1960s.1-4 Established
risk factors for MRSA infection include recent hospitalization or surgery,
residence in a long-term care facility, dialysis, and indwelling percutaneous
medical devices and catheters.5,6 More
recently, however, cases of MRSA have been documented among healthy community-dwelling
persons without established risk factors for MRSA acquisition. These infections
were apparently acquired in the community and have been referred to as either community-acquired or community-associated MRSA infections. Published reports of community-associated MRSA infections
in North America include Minnesota and North Dakota,7-9 Nebraska,10 Alaska,11 Chicago,
Ill,12-14 Dallas,
Tex,15,16 Winnipeg, Manitoba,17 Toronto, Ontario,18 and
Los Angeles County, California.19
The epidemiology of community-associated MRSA has not been fully described.
Furthermore, there are limited data comparing community-associated with health
care–associated MRSA cases, and no studies from multiple geographic
locations. Finally, there has been no systematic comparison of the molecular
characteristics (eg, exotoxin gene profiles) of community and health care
isolates in the United States. Such genetic information could improve understanding
of the pathogenesis of different MRSA strains, and could ultimately help shape
strategies for the prevention and treatment of MRSA infections both in the
hospital and in the community.
To better characterize MRSA in Minnesota, the Minnesota Department of
Health established a sentinel surveillance network of 12 laboratory facilities
in 1999. In 2000, the Minnesota Department of Health began a prospective study
of all MRSA infections identified at these facilities. The objectives of this
study were to characterize demographic and clinical features of patients with
community-associated and health care–associated MRSA, and to characterize
the microbiological and molecular features of community-associated and health
care–associated MRSA isolates.
Twelve laboratory facilities were selected as MRSA surveillance sites.
They were selected to be diverse in terms of their location, size, and facility
type. Six of the 12 participating facilities were located in the 7-county
Minneapolis-St Paul metropolitan area and 6 were located in nonmetropolitan
Minnesota. All laboratories served both outpatient clinic networks and hospital
inpatients. Ten facilities served both adult and pediatric patients and the
remaining 2 served pediatric patients exclusively.
Case Ascertainment and Case Definitions
In 2000, participating laboratory facilities identified all patients
with MRSA isolates from clinical cultures. Infection-control practitioners
at those facilities obtained additional information about the patients and
their infections via medical record review. For community-associated MRSA
cases, clinical information about underlying chronic conditions was obtained
(this information was not collected for health care–associated MRSA
cases). A surrogate for median household income was estimated using US Census
data. Community-associated and health care–associated MRSA cases were
assigned median household incomes based on the 2000 US Census for their respective
ZIP code of residence.
Health care–associated MRSA cases were
defined as patients with (1) an MRSA infection identified after 48 hours of
admission to a hospital; (2) a history of hospitalization, surgery, dialysis,
or residence in a long-term care facility within 1 year of the MRSA culture
date; (3) a permanent indwelling catheter or percutaneous medical device (eg,
tracheostomy tube, gastrostomy tube, or Foley catheter) present at the time
of culture; or (4) a known positive culture for MRSA prior to the study period.
Cases that had none of the above features were classified as community-associated. Because the community-associated case definition
depended on the absence of health care–related risk factors, patients
who appeared to have community-associated infections on the basis of medical
record review were also interviewed to ensure that they did not have any exclusion
criteria that were not documented in their medical records. Overall, 13% of
patients who appeared to have community-associated MRSA infections on the
basis of medical record review were reclassified as health care–associated
after being interviewed.
This study was approved by the institutional review boards of both the
Minnesota Department of Health and the Centers for Disease Control and Prevention.
Medical record reviews were conducted in accordance with Minnesota public
health law, and informed consent was obtained for all those who were interviewed.
Sentinel facility laboratories sent all MRSA isolates identified from
January 1, 2000, through December 31, 2000, to the Minnesota Department of
Health laboratory. All available community-associated isolates and a sample
of health care–associated isolates (every fourth isolate received per
facility) were evaluated using antimicrobial susceptibility testing and pulsed-field
gel electrophoresis (PFGE) subtyping. Laboratory staff were unaware of the
epidemiological case classification of the isolates.
Identification of S aureus was confirmed with
a tube coagulase test (Difco Laboratories, Detroit, Mich). Oxacillin (methicillin)
resistance was confirmed using an oxacillin agar screen test (Becton Dickinson,
Cockeysville, Md); susceptibility interpretations for other antimicrobials
were made using broth microdilution (PML Microbiologicals, Wilsonville, Ore)
according to break points established by the National Committee for Clinical
Laboratory Standards.20,21 Molecular
typing of isolates was performed by PFGE using Sma1
as a restriction endonuclease. The PFGE patterns were compared using the Dice
coefficient (Bionumerics Software, Applied Maths, Kortrijk, Belgium). Patterns
that had exact matches of all bands in the range of 70 to 700 kilobases were
considered indistinguishable. Isolates of MRSA that differed from a reference
strain (MR14, the most common community-associated strain) by 6 bands or fewer
were characterized as belonging to a single clonal group.22 Polymerase
chain reaction testing was performed to confirm the presence of the mecA gene.23
Additionally, 26 community-associated MRSA and 26 health care–associated
MRSA isolates were sent to the French Reference Centre for Staphylococci.
These isolates were selected by alphabetizing the list of case isolates in
each group, then choosing every fourth community-associated MRSA isolate and
every ninth health care–associated MRSA isolate. The isolates sent for
gene testing were representative of the larger group of isolates from which
they were selected (eg, there were no statistically significant differences
in terms of case sex, age, race, or infection site). Investigators from the
Reference Centre were blinded regarding the epidemiological case classification
of the isolates. Sequences specific for a variety of staphylococcal enterotoxin
genes, the toxic shock syndrome toxin gene, exfoliative toxin genes, Panton
Valentine leukocidin genes, the leukocidin E-D gene, the leukocidin M gene, β
and γ hemolysin genes, methicillin-resistance (SCCmec) gene alleles and accessory gene regulator alleles were detected
by polymerase chain reaction as previously described.24-26 Toxin
results of a portion of the community-associated MRSA isolates have been previously
characterized27; however, a direct comparison
of community-associated MRSA and health care–associated MRSA isolates
obtained from the 12 sentinel sites in 2000 has not been reported previously
and is reported herein using similar laboratory methods.27
Bivariate analysis of data was performed using Epi Info statistical
software (Version 6.04c, Centers for Disease Control and Prevention, Atlanta,
Ga). The Yates continuity-corrected χ2 test was examined for
comparison of categorical data and the t test was
used for continuous data. Unconditional logistic regression models were used
to predict case definition (community-associated vs health care–associated).
An α = .05 significance level was required for predictors to remain
in the model. Results were computed using SAS statistical software (Version
8.0, SAS Institute Inc, Cary, NC). Because of the high incidence (>10%) of
outcome measures, odds ratios (ORs) and 95% confidence intervals (CIs) were
corrected to approximate relative risk using methods previously described.28
During 2000, 4612 unique patients with a S aureus isolate from a clinical culture were identified from 10 participating
facilities (data on total S aureus infections were
not available at 2 facilities) (Table 1). Approximately 25% of all S aureus infections
were MRSA (range among sites, 10%-49%). Among MRSA infections, 12% (131) MRSA
cases were classified as community-associated, 85% (937) were classified as
health care–associated, and 3% (32) could not be classified due to lack
of information. Among the sites, the proportion of MRSA cases that were community-associated
ranged from 4% to 50%. Of the community-associated MRSA cases, 53% (70) were
identified at Minneapolis-St Paul metropolitan sites and 47% (61) were identified
at greater Minnesota sites. However, the ratio of community-associated MRSA
cases to total MRSA cases was somewhat higher at greater Minnesota sites than
at Minneapolis-St Paul metropolitan sites (61/358 [17%] vs 70/710 [10%]; OR,
1.66 [95% CI, 1.24-2.15).
Case Characteristics and Antimicrobial Treatment
Community-associated MRSA patients were younger than health care–
associated MRSA patients (median age, 23 years vs 68 years; P<.001) (Figure 1 and Table 2). After excluding cases from the
2 pediatric hospitals, the median age of community-associated MRSA patients
was still significantly younger than health care–associated MRSA patients
(median age, 30 years vs 70 years; P<.001). Race/ethnicity
was documented for 72% of community-associated MRSA cases and 64% of health
care–associated MRSA cases. Among those whose race/ethnicity was documented,
community-associated MRSA patients were more likely than health care–associated
MRSA patients to be nonwhite (OR, 3.13; 95% CI, 2.16-4.32). Median surrogate
household income was less for patients with community-associated
($25 395) and health care–associated ($28 290)
MRSA infection. The median household incomes for both types of cases were
both considerably less than the median for state residents overall ($47 111).
Among pediatric (age <18 years) community-associated MRSA cases,
dermatological conditions (9% [5 patients]) were the most common underlying
medical condition documented in the medical record (Table 3). Among adult community-associated MRSA cases (age ≥18
years), tobacco use (19% [15 patients]) and diabetes (17% [13 patients]) were
the most common underlying conditions by medical record review, followed by
dermatological conditions (13% [10 patients]).
The distribution of clinical infections differed between community-associated
and health care–associated MRSA cases (Table 4). Compared with health care–associated cases, community-associated
case infections were more likely to involve skin and soft tissue (OR, 4.25;
95% CI, 2.97-5.90) and less likely to be respiratory tract infections (OR,
0.22; 95% CI, 0.09-0.49) or urinary tract infections (OR, 0.04; 95% CI, 0-0.24)
(P<.001 for all comparisons). Bloodstream infections
were more common among health care–associated cases (9% [83 patients]
vs 4% [5 patients]), although this was not statistically significant. Of the
131 community-associated cases, 24% (31) were hospitalized due to their MRSA
infection and 5% (7) required intensive care treatment.
Among community-associated cases, oral or parenteral antimicrobial treatment
was documented in 70% (92/131) of cases. Of these cases, 77% (71/92) were
skin and soft tissue infection, similar to the skin and soft tissue infection
rate of 72% (28/39) for infections without documented antibiotics. Sixty-one
percent (80) of community-associated MRSA infections were initially treated
exclusively with β-lactam antimicrobials to which these isolates are
not susceptible. Other antimicrobial treatment included 13% who received quinolones;
7%, clindamycin; 5%, trimethoprim-sulfamethoxazole; 5%, tetracycline; 3%,
vancomycin; 3%, aminoglycosides; and 2%, macrolides.
Microbiological Characterization of MRSA Isolates
Susceptibility and PFGE testing were performed on 106 community-associated
isolates (25 isolates were unavailable from participating facilities) and
a representative sample of 211 health care–associated isolates (see
"Methods" section). Oxacillin resistance (a surrogate for methicillin resistance)
was confirmed in all MRSA isolates. Community-associated MRSA isolates were
generally susceptible to antimicrobials other than β-lactams and were
more likely than health care–associated isolates to be susceptible to
multiple agents (Table 5). Among
community-associated isolates, susceptibilities did not differ between pediatric
and adult isolates. Community-associated isolates from skin sites were more
likely to be susceptible to ciprofloxacin (OR, 1.90; 95% CI, 1.44-2.11) and
clindamycin (OR, 1.46; 95% CI, 1.04-1.68) compared with community-associated
isolates from other sites. Community-associated MRSA isolates were also more
likely than health care–associated MRSA isolates to be susceptible to
all 4 of the following antimicrobial agents: ciprofloxacin, clindamycin, gentamicin,
and trimethoprim-sulfamethoxazole (OR, 5.88; 95% CI, 4.86-6.64). In a logistic
regression model adjusted for age, sex, surrogate income, laboratory location
(Minneapolis-St Paul metropolitan vs greater Minnesota), and culture site
(skin vs other), susceptibility to all 4 antimicrobials was an independent
predictor of having a community-associated case definition (adjusted OR, 2.44;
95% CI, 1.35-3.86).
Overall, 119 distinct PFGE subtype patterns were identified. Five clonal
groups containing 3 or more isolates were identified; these clonal groups
accounted for 96% of all isolates. One PFGE clonal group, designated clonal
group A, accounted for 62% (66) of community-associated isolates compared
with 9% (18) health care–associated isolates (OR, 4.61; 95% CI, 3.82-5.16)
(Figure 2 and Figure 3). Clonal group A isolates comprised the majority of the
community-associated isolates from various age groups (31 [63%] of 49 isolates
from patients <18 years and 35 [61%] of 57 isolates from patients aged
18 years or older), racial groups (19 [95%] of 20 from American Indians, 8
[80%] of 10 from blacks, and 23 [52%] of 44 from whites), and geographic regions
(31 [57%] of 54 from Minneapolis-St Paul metropolitan–area hospitals
and 35 [67%] of 52 from greater Minnesota hospitals). Clonal group B also
was associated with community-associated MRSA infection, with 15 (14%) of
the community-associated MRSA isolates being in group B compared with 5 (2%)
of the health care–associated isolates (OR, 2.43; 95% CI, 1.61-2.93).
Compared with health care–associated MRSA isolates, community-associated
MRSA isolates were more likely to belong to either clonal group A or clonal
group B (81 [76%] of 106 vs 23 [11%] of 211; OR, 6.52; 95% CI, 5.41-7.31).
A third clonal group, designated clonal group H, was strongly associated with
health care–associated isolates. Of health care–associated isolates,
80% (168) were in clonal group H compared with 16% (17) of community-associated
isolates (OR, 2.83; 95% CI, 2.60-2.97) (Figure
3). In another multivariate model adjusted for age, sex, surrogate
income, laboratory facility (Minneapolis-St Paul metropolitan area vs greater
Minnesota), and culture site (skin vs other), PFGE clonal groups A and B (adjusted
OR, 2.75; 95% CI, 1.58-4.26) or clonal group A alone (adjusted OR, 2.37; 95%
CI, 1.36-3.54) were independently associated with community-associated case
status.
Both exotoxin genes (eg, Panton Valentine leukocidin genes), and gene
alleles (SCCmec alleles and accessory gene regulator
alleles) were disproportionately distributed between community-associated
and health care–associated isolates (Table 6). Of 25 genes tested, 8 genes were not identified in any
isolates (listed in Table 6).
Of the 16 exotoxin genes that were present in at least some MRSA isolates,
6 (Panton Valentine leukocidins, staph enterotoxins A, C, and K, accessory
gene regulator 3, and SCCmec IV) were significantly
more likely to be found among community-associated isolates, and 7 were significantly
more likely to be found among health care–associated isolates. Only
3 exotoxin genes were found in the majority of case isolates from both groups.
Panton Valentine leukocidin genes were identified in 20 community-associated
MRSA isolates tested (77%) compared with 1 health care–associated isolate
(4%) (OR, 5.01; 95% CI, 3.49-5.25). Overall, 18 community-associated isolates
with Panton Valentine leukocidin genes (90%) were associated with skin or
soft tissue infections. Even though the mecA gene,
which confers methicillin resistance, and the accessory gene regulator alleles
were present in all isolates, SCCmec IV allele and agr 3 allele were statistically more likely to be present
in community-associated isolates than in health care–associated isolates.
Conversely, SCCmec II and agr 2
were more commonly identified among health care–associated isolates.
This is the first prospective comparison of community-associated and
health care–associated MRSA cases in the United States, to our knowledge,
and it is the first study performed at multiple sites. Overall, patients with
community-associated MRSA (defined as MRSA infections identified in patients
who lack established MRSA risk factors) were significantly younger and had
different distributions of clinical infections compared with health care–associated
MRSA patients. In fact, a previous study in Minnesota showed that there were
actually strong similarities (eg, age distribution, infection characteristics)
between community-associated methicillin-sensitive S aureus infections and community-associated MRSA patients.8 Although
the origin of community-associated MRSA strains remains speculative, these
data suggest that their emergence may be due to the insertion of a mecA gene into methicillin-susceptible S aureus strains.
This speculation is further strengthened by a recent report documenting this
event in a clinical isolate, and by the fact that SCCmec IV is probably more mobile than other SCCmec alleles.29,30
Another unique feature of our investigation was our attempt to collect
MRSA isolates from all reported cases. Community-associated MRSA isolates
were more likely to be susceptible to multiple antimicrobial classes and to
have distinct molecular features (based on PFGE) compared with health care–associated
isolates. These findings further support our contention that most community-associated
MRSA infections in Minnesota are not due to casual health care exposures or
to MRSA strains that originated in health care settings, although this remains
controversial.31-33
The differences in exotoxin genes between community-associated and health
care–associated isolates also suggest that the pathogenesis of these
MRSA infections may differ. Recent evidence indicates that Panton Valentine
leukocidins and the SCCmec IV allele, which are rarely
found in health care–associated MRSA strains globally, are common among
community-associated MRSA strains from 3 different continents, even though
community-associated strains from these continents do not share a common genetic
lineage.27 The Panton Valentine leukocidin
genes code for the production of cytotoxins that cause tissue necrosis and
leukocyte destruction by forming pores in cellular membranes. In Europe, Panton
Valentine leukocidin genes are associated with community-associated staphylococcal
skin infections and necrotizing pneumonia.26,34,35 Similarly,
in our study, most community-associated MRSA isolates that had Panton Valentine
leukocidin genes were associated with skin and soft tissue infections. Furthermore,
the community-associated MRSA strains responsible for severe cases of necrotizing
pneumonia in Minnesota and North Dakota7 all
had Panton Valentine leukocidin genes.34 However,
it is important to emphasize that the association between Panton Valentine
leukocidin genes and particular clinical manifestations needs further work
to demonstrate causation because other exotoxin genes (eg, sea, sec or sek; Table 6) or combinations of genes could
also be important pathogenic factors.
Our study had several limitations. It is likely that some health care–associated
MRSA cases were misclassified as community-associated MRSA cases, and vice
versa. Misclassification, however, would only have minimized the observed
differences between community-associated and health care–associated
MRSA patients and isolates. Because our study was not population-based, it
is possible that MRSA cases identified through sentinel site surveillance
were not representative of all cases that occurred throughout Minnesota. However,
to date there have been no published population-based studies of MRSA patients
and isolates. We also believe that our study is more representative than previous
studies because we identified cases from multiple laboratory facilities in
both urban and rural areas from different geographic locations statewide.
Finally, because we have not studied MRSA colonization in Minnesota, we cannot
determine the prevalence of MRSA among those colonized with S aureus, and therefore we do not know whether community-associated
MRSA strains are more likely than other S aureus strains
to cause disease.
Because there are epidemiological and microbiological differences between
community-associated and health care–associated MRSA infections, strategies
to prevent and treat these infections likely differ as well. To prevent clinical
complications from community-associated MRSA infections, clinicians working
in outpatient or emergency department settings should consider practice modifications
in areas where such infections are known to be prevalent. These modifications
could include (1) more frequent culturing and susceptibility testing of S aureus isolates of clinical infections, particularly
among pediatric patients; (2) surgical drainage of infections when appropriate;
and (3) careful selection of empirical antimicrobials when such treatment
is indicated for suspected staphylococcal infections (ie, clinicians should
be aware that MRSA organisms are nonsusceptible to β-lactam antimicrobials).
Because most community-associated MRSA isolates were susceptible to several
already-available antimicrobial agents, and because most patients had noninvasive
infections, the treatment of community-associated MRSA infections should not
routinely require the use of vancomycin. However, patients with MRSA infections
should be evaluated and treated appropriately and receive follow-up evaluation
to ensure resolution of their infection.
To improve prevention strategies, more work is needed to characterize
specific risk factors for community-associated MRSA infections. However, at
least one study has implicated prior exposure to antimicrobial agents as an
independent risk factor for community-associated MRSA infection.36 This
suggests that the judicious use of antimicrobials, particularly in outpatient
settings, could help control the emergence of community-associated MRSA strains
and limit the acquisition of additional antimicrobial resistance genes in
existing strains. Currently, there are no data to suggest that decolonization
protocols for MRSA patients or their families are necessary or have long-term
effectiveness. Resistance to antimicrobial agents used for decolonization
has evolved rapidly in settings in which such strategies have been attempted.37
Because community-associated infection is frequently identified in children,
questions have arisen regarding transmission in group settings.16,18,38 Although
it is common to exclude those with uncontained S aureus infections, there is no evidence that excluding MRSA-colonized children
from normal activities such as group child care, school, or athletics is effective
in limiting the spread of community-associated MRSA strains, and we do not
recommend such steps. Future strategies such as vaccination to prevent S aureus infections in both community and health care settings
hold greater promise. However, it is likely that antimicrobial-resistant strains
of S aureus will continue to evolve and that S aureus will remain an important and adaptive human pathogen.2,39,40
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