Community-Acquired Methicillin-Resistant Staphylococcus aureus in a Rural
American Indian Community
 JAMA. 2001;286:1201-1205


Author Information <http://jama.ama-assn.org/issues/v286n10/rfull/#aainfo>
Amy V. Groom, MPH; Darcy H. Wolsey, MPH; Timothy S. Naimi, MD, MPH; Kirk
Smith, DVM, PhD; Sue Johnson, MS; Dave Boxrud, MS; Kristine A. Moore, MD,
MPH; James E. Cheek, MD, MPH
Context  Until recently, methicillin-resistant Staphylococcus aureus (MRSA)
infections have been acquired primarily in nosocomial settings. Four recent
deaths due to MRSA infection in previously healthy children in the Midwest
suggest that serious MRSA infections can be acquired in the community in
rural as well as urban locations.
Objectives  To document the occurrence of community-acquired MRSA infections
and evaluate risk factors for community-acquired MRSA infection compared
with methicillin-susceptible S aureus (MSSA) infection.
Design  Retrospective cohort study with medical record review.
Setting  Indian Health Service facility in a rural midwestern American
Indian community.
Patients  Patients whose medical records indicated laboratory-confirmed S
aureus infection diagnosed during 1997.
Main Outcome Measures  Proportion of MRSA infections classified as community
acquired based on standardized criteria; risk factors for community-acquired
MRSA infection compared with those for community-acquired MSSA infection;
and relatedness of MRSA strains, determined by pulsed-field gel
electrophoresis (PFGE).
Results  Of 112 S aureus isolates, 62 (55%) were MRSA and 50 (45%) were
MSSA. Forty-six (74%) of the 62 MRSA infections were classified as community
acquired. Risk factors for community-acquired MRSA infections were not
significantly different from those for community-acquired MSSA. Pulsed-field
gel electrophoresis subtyping indicated that 34 (89%) of 38
community-acquired MRSA isolates were clonally related and distinct from
nosocomial MRSA isolates found in the region.
Conclusions  Community-acquired MRSA may have replaced community-acquired
MSSA as the dominant strain in this community. Antimicrobial susceptibility
patterns and PFGE subtyping support the finding that MRSA is circulating
beyond nosocomial settings in this and possibly other rural US communities.
JAMA. 2001;286:1201-1205
JOC00996
Methicillin-resistant Staphylococcus aureus (MRSA) first emerged as a
nosocomial pathogen in the early 1960s. 1
<http://jama.ama-assn.org/issues/v286n10/rfull/#r1>  Since then, data from
the Centers for Disease Control and Prevention's National Nosocomial
Infection Surveillance system indicate that the occurrence of MRSA infection
in US hospitals has been increasing steadily and that MRSA accounted for
more than 40% of S aureus isolates in 1998. 2
<http://jama.ama-assn.org/issues/v286n10/rfull/#r2>  Established risk
factors for MRSA infection include recent hospitalization, recent surgery,
residence in a long-term care facility, and injection drug use. 3
<http://jama.ama-assn.org/issues/v286n10/rfull/#r3>
Methicillin-resistant strains of S aureus are resistant to all beta-lactam
antibiotics and, frequently, to many other antibiotic classes. 1
<http://jama.ama-assn.org/issues/v286n10/rfull/#r1>  beta-Lactam resistance
is due to an alteration of the penicillin-binding protein PBP 2a, which is
encoded by the chromosomal gene mecA. 4
<http://jama.ama-assn.org/issues/v286n10/rfull/#r4> , 5
<http://jama.ama-assn.org/issues/v286n10/rfull/#r5>  Most circulating
strains of MRSA appear to be derived from only 2 or 3 clones. 6
<http://jama.ama-assn.org/issues/v286n10/rfull/#r6> , 7
<http://jama.ama-assn.org/issues/v286n10/rfull/#r7>  Once introduced into a
microbial population, mecA may be transferred horizontally and recombined
among methicillin-susceptible S aureus (MSSA) cells. 7
<http://jama.ama-assn.org/issues/v286n10/rfull/#r7>  This has led to the
global spread of MRSA in association with increasing geographic mobility of
infected patients and carriers of the organism. 8-10
<http://jama.ama-assn.org/issues/v286n10/rfull/#r8>
Despite the increased incidence of MRSA infection in nosocomial settings,
reports of infection acquired in the community have been relatively rare
until recently. In the 1990s, studies of MRSA in Western Australia, 11
<http://jama.ama-assn.org/issues/v286n10/rfull/#r11> , 12
<http://jama.ama-assn.org/issues/v286n10/rfull/#r12>  the Canadian prairies,
13 <http://jama.ama-assn.org/issues/v286n10/rfull/#r13>  Illinois, 3
<http://jama.ama-assn.org/issues/v286n10/rfull/#r3> , 14
<http://jama.ama-assn.org/issues/v286n10/rfull/#r14> , 15
<http://jama.ama-assn.org/issues/v286n10/rfull/#r15>  southern Texas, 16
<http://jama.ama-assn.org/issues/v286n10/rfull/#r16>  Hawaii, 17
<http://jama.ama-assn.org/issues/v286n10/rfull/#r17>  and California 18
<http://jama.ama-assn.org/issues/v286n10/rfull/#r18>  suggested the
emergence of MRSA as a community-acquired pathogen. Medical record reviews
documented that most patients had no established risk factor for MRSA
infection. 3 <http://jama.ama-assn.org/issues/v286n10/rfull/#r3> , 11
<http://jama.ama-assn.org/issues/v286n10/rfull/#r11> , 14-18
<http://jama.ama-assn.org/issues/v286n10/rfull/#r14>  Furthermore,
antimicrobial susceptibility patterns showed that, unlike many nosocomial
strains of MRSA, community-acquired MRSA isolates tended to remain
susceptible to most non–beta-lactam antibiotics. 3
<http://jama.ama-assn.org/issues/v286n10/rfull/#r3> , 11
<http://jama.ama-assn.org/issues/v286n10/rfull/#r11> , 12
<http://jama.ama-assn.org/issues/v286n10/rfull/#r12> , 14
<http://jama.ama-assn.org/issues/v286n10/rfull/#r14> , 15
<http://jama.ama-assn.org/issues/v286n10/rfull/#r15> , 17
<http://jama.ama-assn.org/issues/v286n10/rfull/#r17> , 18
<http://jama.ama-assn.org/issues/v286n10/rfull/#r18>  All studies from the
United States and Canada, however, were conducted in large hospitals in
urban areas, where patients are more likely to have exposure to tertiary
care facilities. 3 <http://jama.ama-assn.org/issues/v286n10/rfull/#r3> ,
13-18 <http://jama.ama-assn.org/issues/v286n10/rfull/#r13>  The only studies
that examined community-acquired MRSA among patients from nonurban areas
were those conducted in Australia. 11
<http://jama.ama-assn.org/issues/v286n10/rfull/#r11> , 12
<http://jama.ama-assn.org/issues/v286n10/rfull/#r12>
A 1996 national survey of Indian Health Service (IHS) facilities, many of
which provide few or no inpatient services, found that, overall, 40%
(600/1490) of S aureus isolates tested from the Midwest and Northern Plains
were MRSA (IHS, unpublished data, 1996). Subsequently in 1999, 4 deaths
among children in Minnesota and North Dakota, 1 of which occurred in an
American Indian, were attributed to community-acquired MRSA infection. 19
<http://jama.ama-assn.org/issues/v286n10/rfull/#r19>  These findings
suggested that MRSA was being acquired outside nosocomial settings. We
therefore sought to examine the prevalence of community-acquired MRSA and to
evaluate risk factors for community-acquired MRSA infection compared with
those for community-acquired MSSA infection in a rural American Indian
community.



METHODS



The study was conducted at a small IHS hospital with a busy outpatient
clinic located in a rural midwestern community. The annual catchment
population was 8311. All laboratory-confirmed S aureus infections among
patients treated at this facility between January 1 and December 31, 1997,
were evaluated using a retrospective cohort study design and medical record
review. Cases of laboratory-confirmed MRSA infection were compared with
those of laboratory-confirmed MSSA infection. The research proposal for this
study was approved by the IHS National Institutional Review Board and the
local tribal council.
Laboratory Methods

Initial antimicrobial susceptibilities were determined locally using
MicroScan panels (Dade Behring MicroScan Inc, West Sacramento, Calif).
Confirmatory antimicrobial susceptibility testing of 50 MRSA isolates (81%)
was conducted at the Minnesota Department of Health using Etest (AB Biodisk,
Solna, Sweden). 20-22 <http://jama.ama-assn.org/issues/v286n10/rfull/#r20>
Oxacillin agar screen testing and pulsed-field gel electrophoresis (PFGE)
23-25 <http://jama.ama-assn.org/issues/v286n10/rfull/#r23>  were performed
on a sample of MRSA isolates. Pulsed-field gel electrophoresis was performed
using a previously published method 26
<http://jama.ama-assn.org/issues/v286n10/rfull/#r26>  with slight
modifications (100 U of mutanolysin were added to the lysis solution; run
conditions were 2.2 seconds for the initial switch time and 37.3 seconds for
the final switch time, with linear ramping for 18 hours; and SeaKem Gold
agarose [BioWhittaker Molecular Applications, Rockland, Me] was used in
place of PFGE-certified agarose). The control strain, NCTC 8325, was run 3
times on a 10-well gel and 4 times on a 15-well gel. Restriction-fragment
patterns derived using the enzyme SmaI (ProMega, Madison, Wis) were compared
using Molecular Analyst Fingerprinting Data Sharing Tools, version 1.6
(Bio-Rad, Hercules, Calif) set to a 1% molecular weight position tolerance.
Pulsed-field gel electrophoresis types were defined as having
indistinguishable band patterns in the 30- to 600-kilobase range and were
considered clonally related when patterns differed from a reference strain
by 3 or fewer bands. 27 <http://jama.ama-assn.org/issues/v286n10/rfull/#r27>
Five MRSA isolates representing different PFGE subtypes underwent polymerase
chain reaction amplification for detection of the mecA gene. 28
<http://jama.ama-assn.org/issues/v286n10/rfull/#r28>
Data Collection

Laboratory records from the on-site laboratory for 1989-1997 were reviewed.
We gathered information from patients' medical records using a standardized
data abstraction instrument. Abstracted data included basic demographic
information, anatomical site of infection, clinical symptoms, and treatment
of S aureus infection. Information on exposure to established risk factors
for MRSA infection in the year before infection was also obtained. No
patients were contacted directly.
Infections were classified as community acquired if isolates were obtained
in an outpatient setting or less than 48 hours after hospital admission and
if patients had no history of hospitalization, renal dialysis, or residence
in a long-term care facility during the year before infection and no
documented history of injection drug use. Risk factor analyses were limited
to cohort members who met the criteria for a community-acquired infection.
Statistical Analysis

Adjusted chi2 or 2-tailed Fisher exact tests were performed for comparisons
of categorical data using Epi Info, version 6.04c, 29
<http://jama.ama-assn.org/issues/v286n10/rfull/#r29>  and StatXact 3. 30
<http://jama.ama-assn.org/issues/v286n10/rfull/#r30>  Risk ratios (RRs) and
exact 95% confidence intervals (CIs) were also calculated for all
categorical data in evaluating exposures among cohort members.
Kruskal-Wallis tests were used to evaluate non–normally distributed
continuous data.



RESULTS



Demographics

From 1989 to 1997, MRSA infections increased dramatically in this community
( Figure 1
<http://jama.ama-assn.org/issues/v286n10/fig_tab/joc00996_f1.html> ). Our
cohort contained 112 patients with S aureus infections during 1997, of whom
62 (55%) had an MRSA infection and 50 (45%) had an MSSA infection. All study
patients were American Indians. Infections occurred year-round, and there
were no significant differences between patients with MRSA and patients with
MSSA with regard to sex or age (median age for MRSA patients, 20.5 [range,
0.1-91.4] years and for MSSA patients, 19 [range, 0.03-79.4] years).
Community-Acquired vs Non–Community-Acquired Infections

Most MRSA infections (46 [74%]) were classified as community acquired. A
similar proportion of MSSA infections (32 [64%]) could also be classified as
community acquired.
Antimicrobial susceptibility patterns of MRSA isolates demonstrated uniform
resistance to beta-lactam antibiotics. Most community-acquired MRSA
isolates, however, were susceptible to many other non–beta-lactam
antibiotics ( Table 1
<http://jama.ama-assn.org/issues/v286n10/fig_tab/joc00996_t1.html> ).
Community-acquired MRSA isolates were significantly more likely than
non–community-acquired MRSA isolates to be susceptible to ciprofloxacin (P =
.01), although other differences were not significant. All 5 tested MRSA
isolates demonstrated presence of the mecA gene.
Fifty (81%) of 62 MRSA isolates were available for PFGE subtyping.
Thirty-eight isolates (76%) were from community-acquired MRSA infections and
12 isolates (24%) were from non–community-acquired infections. One clonal
group, designated as group A, accounted for 80% of all isolates tested.
Group A subtypes were significantly more likely among community-acquired
isolates (34/38 [89%]) than non–community-acquired isolates (6/12 [50%]) (P
= .007). The 3 most commonly identified PFGE group A subtype patterns, which
accounted for 32 of the 34 community-acquired group A isolates, were
distinct from non–group A subtypes from residents of a long-term care
facility in that community ( Figure 2
<http://jama.ama-assn.org/issues/v286n10/fig_tab/joc00996_f2.html> ).
Among community-acquired infections, a similar proportion of patients with
community-acquired MRSA (89%) and community-acquired MSSA (94%) presented
with skin infection (P = .76). Six patients with community-acquired MRSA
(13%) and 1 patient with community-acquired MSSA (3%) were hospitalized
because of their infection (P = .31). No deaths were attributed to S aureus
infection in either group.
Prior Health Care Exposures and Underlying Medical Conditions

Among patients treated at either the outpatient clinic or the emergency
department during the year before their infection, 45 (60%) of 75 developed
a community-acquired MRSA infection compared with 1 (33%) of 3 patients who
were not treated at the clinic/emergency department (RR, 1.80; 95% CI,
0.56-59.76). The median of 7 clinic/emergency department visits (range, 1-22
visits) among patients with community-acquired MRSA was not significantly
different from the median of 6 visits (range, 1-34 visits) among patients
with community-acquired MSSA (P = .19). Among patients with underlying
chronic health conditions, 12 (50%) of 24 developed a community-acquired
MRSA infection compared with 34 (63%) of 54 patients with no underlying
chronic condition (RR, 0.79; 95% CI, 0.34-1.36).
In regard to exposure to antibiotics, we found no significant difference
between patients with community-acquired MRSA and community-acquired MSSA.
Among patients prescribed at least 1 course of antibiotics during the year
before infection, 31 (61%) of 51 developed community-acquired MRSA compared
with 15 (56%) of 27 who were not prescribed antibiotics (RR, 1.09; 95% CI,
0.65-2.11). Of those who received an antibiotic course, the median number of
antibiotic courses for patients with community-acquired MRSA was 3.0 vs 2.0
for those with community-acquired MSSA; the difference was not significant
(P = .32).



COMMENT



The proportion of MRSA isolates in this community increased substantially
from 1989 to 1997, suggesting that community-acquired MRSA has emerged only
recently. Low socioeconomic status, crowded housing conditions, and limited
access to health care, which contribute to the high background rate of skin
infections in this population, 31-34
<http://jama.ama-assn.org/issues/v286n10/rfull/#r31>  may have enhanced our
ability to detect the emergence of community-acquired MRSA. These
characteristics, however, are not unique to this rural American Indian
population, and our findings suggest that over time, community-acquired MRSA
may be found in ever-increasing numbers in other communities of low
socioeconomic status.
There are multiple lines of evidence suggesting that most MRSA infections in
our study were acquired in the community rather than nosocomially. Although
recent studies suggest that exposure to hospitals is a risk factor for many
putative community-acquired MRSA infections, 35
<http://jama.ama-assn.org/issues/v286n10/rfull/#r35> , 36
<http://jama.ama-assn.org/issues/v286n10/rfull/#r36>  we found no evidence
of such exposures. Although the term community acquired is not clearly or
consistently defined in current MRSA literature, 37
<http://jama.ama-assn.org/issues/v286n10/rfull/#r37>  our criteria for
community acquisition were among the most conservative, requiring a full
year with no exposure to established nosocomial risk factors. 38
<http://jama.ama-assn.org/issues/v286n10/rfull/#r38>  Furthermore,
antimicrobial susceptibility patterns found among community-acquired MRSA
isolates in this community showed susceptibility to most classes of
antimicrobial agents other than beta-lactam antibiotics, consistent with
other studies of community-acquired MRSA. 3
<http://jama.ama-assn.org/issues/v286n10/rfull/#r3> , 11
<http://jama.ama-assn.org/issues/v286n10/rfull/#r11> , 12
<http://jama.ama-assn.org/issues/v286n10/rfull/#r12> , 14
<http://jama.ama-assn.org/issues/v286n10/rfull/#r14> , 15
<http://jama.ama-assn.org/issues/v286n10/rfull/#r15> , 17
<http://jama.ama-assn.org/issues/v286n10/rfull/#r17>  Additional evidence
supporting community acquisition is found in the PFGE patterns of these
community-acquired MRSA isolates, which were distinct from the PFGE patterns
of circulating nosocomial MRSA strains. Subtyping by PFGE revealed that most
community-acquired MRSA infections were caused by clonally related MRSA
subtypes 27 <http://jama.ama-assn.org/issues/v286n10/rfull/#r27>  that were
either indistinguishable from or clonally related to the community-acquired
MRSA subtypes associated with the previously reported pediatric fatalities
in the Midwest. 19 <http://jama.ama-assn.org/issues/v286n10/rfull/#r19>  We
found no epidemiologic links between patients in this community and any of
the 4 fatal cases of community-acquired MRSA. The lack of any connections
other than geographic proximity in the Midwest suggests that
community-acquired MRSA may be emerging throughout this region and that this
American Indian community can be regarded as a sentinel for emerging
community-acquired MRSA.
Community-acquired MRSA may be replacing community-acquired MSSA in our
study community. Although we would expect exposure to established risk
factors for MRSA to have resulted in more MRSA infections than MSSA
infections, this did not occur. Because there is apparently no significant
evolutionary "cost" in fitness for strains of MRSA relative to MSSA, even
slight selective pressure from antimicrobial drug use may cause MRSA to
overtake MSSA strains in a microbial population. This has been a common
pattern for the establishment of MRSA in nosocomial settings. 39
<http://jama.ama-assn.org/issues/v286n10/rfull/#r39> , 40
<http://jama.ama-assn.org/issues/v286n10/rfull/#r40>  A similar pattern may
be observed in community settings.
Misclassification bias is a potential limitation of this study. Our
stringent definition of community-acquired infection could have caused us to
underestimate the true proportion of these infections. In addition,
undocumented nosocomial exposures and antibiotic use could have occurred,
such as when study participants sought health care at other facilities.
Because the IHS is essentially a form of managed care, however, care
received outside the system is usually documented, decreasing the likelihood
that there were unidentified nosocomial exposures. Finally, patients with
MRSA could have had a close contact who was exposed to a nosocomial setting,
thereby providing an indirect nosocomial source of infection.
Based on our findings, health care practitioners in rural communities in the
Midwest should consider the possibility of MRSA infection among young,
healthy patients without a history of nosocomial exposure. Culturing
suspected S aureus infections and conducting antibiotic susceptibility
testing, particularly in communities with known high rates of MRSA
infection, is important to ensure that appropriate antibiotic therapy is
provided. The report describing 4 deaths in previously healthy young persons
in the Midwest highlights the potentially deadly consequences of
community-acquired MRSA infection. 19
<http://jama.ama-assn.org/issues/v286n10/rfull/#r19>  Fortunately, most
community-acquired MRSA isolates in this study were susceptible to a variety
of antimicrobial agents in addition to vancomycin. Health care practitioners
should be particularly attentive to judicious use of antibiotics in
outpatient settings to avoid an expanding spectrum of antibiotic resistance
among strains of community-acquired MRSA.
Socioeconomic factors that may have facilitated our recognition of the
emergence of community-acquired MRSA in this rural community are not unique
to American Indian populations, and it is likely that MRSA is becoming
prevalent in other populations and locations. Patients who are at risk of
MSSA infection may also soon be at risk of MRSA infection. The deaths
attributed to strains of MRSA related to those found in our study occurred
in mostly rural, non–American Indian communities in Minnesota and North
Dakota. 19 <http://jama.ama-assn.org/issues/v286n10/rfull/#r19>  This
finding as well as those of previous studies documenting community-acquired
MRSA infection in diverse populations 3
<http://jama.ama-assn.org/issues/v286n10/rfull/#r3> , 11-18
<http://jama.ama-assn.org/issues/v286n10/rfull/#r11>  suggest that the
problem of MRSA is growing and that even rural communities are not
sheltered.



Author/Article Information


Author Affiliations: National Epidemiology Program, Indian Health Service
Headquarters, Albuquerque, NM (Mss Groom and Wolsey and Dr Cheek);
Epidemiology Program Office, Centers for Disease Control and Prevention,
Atlanta, Ga (Dr Naimi); Acute Disease Epidemiology Section (Drs Naimi and
Smith) and Division of Public Health Laboratories (Ms Johnson and Mr
Boxrud), Minnesota Department of Health, Minneapolis; and ICAN Inc, Eden
Prairie, Minn (Dr Moore).

Corresponding Author and Reprints: James E. Cheek, MD, MPH, Indian Health
Service National Epidemiology Program, 5300 Homestead Rd NE, Albuquerque, NM
87110 (e-mail: [log in to unmask] <mailto:[log in to unmask]> ).
Author Contributions: Study concept and design: Wolsey, Smith, Moore, Cheek.
Acquisition of data: Groom, Wolsey, Naimi, Smith, Johnson, Boxrud.
Analysis and interpretation of data: Groom, Naimi, Smith, Boxrud, Moore,
Cheek.
Drafting of the manuscript: Groom, Naimi, Smith, Moore, Cheek.
Critical revision of the manuscript for important intellectual content:
Groom, Wolsey, Naimi, Smith, Johnson, Boxrud, Moore, Cheek.
Statistical expertise: Groom, Naimi, Boxrud, Cheek.
Obtained funding: Smith, Cheek.
Administrative, technical, or material support: Groom, Wolsey, Naimi,
Johnson, Moore, Cheek.
Study supervision: Wolsey, Smith, Moore, Cheek.
Funding/Support: This work was supported in part by cooperative agreement
U50/CCU511190 from the Centers for Disease Control and Prevention as part of
the Emerging Infections Program.
Acknowledgment: We thank Luella Brown, Linda Frizzell, PhD, Doris Jones, and
Steve Rith-Najarian, MD, for their support of this project; Robyn Anderson,
Teresa Chasteen, Jennifer Giroux, MD, Tammy Goodwin, and Greg Rozycki for
their assistance in data collection; Terri Carter for her work in the
laboratory; Douglas Thoroughman, PhD, for his assistance with the analysis;
and Ralph Bryan, MD, and Nathaniel Cobb, MD, for their critical review of an
early version of the manuscript.




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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.