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.
Methicillin-resistant Staphylococcus aureus
(MRSA) first emerged as a nosocomial pathogen in the early 1960s.1 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 Established
risk factors for MRSA infection include recent hospitalization, recent surgery,
residence in a long-term care facility, and injection drug use.3
Methicillin-resistant strains of S aureus are
resistant to all β-lactam antibiotics and, frequently, to many other
antibiotic classes.1 β-Lactam resistance
is due to an alteration of the penicillin-binding protein PBP 2a, which is
encoded by the chromosomal gene mecA.4,5
Most circulating strains of MRSA appear to be derived from only 2 or 3 clones.6,7 Once introduced into a microbial population, mecA may be transferred horizontally and recombined among
methicillin-susceptible S aureus (MSSA) cells.7 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
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,11,12
the Canadian prairies,13 Illinois,3,14,15 southern Texas,16 Hawaii,17 and California18 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.3,11,14-18
Furthermore, antimicrobial susceptibility patterns showed that, unlike many
nosocomial strains of MRSA, community-acquired MRSA isolates tended to remain
susceptible to most non–β-lactam antibiotics.3,11,12,14,15,17,18
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.3,13-18
The only studies that examined community-acquired MRSA among patients from
nonurban areas were those conducted in Australia.11,12
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 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.
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.
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 Oxacillin agar screen
testing and pulsed-field gel electrophoresis (PFGE)23-25
were performed on a sample of MRSA isolates. Pulsed-field gel electrophoresis
was performed using a previously published method26
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 Five MRSA isolates representing different PFGE subtypes
underwent polymerase chain reaction amplification for detection of the mecA gene.28
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.
Adjusted χ2 or 2-tailed Fisher exact tests were performed
for comparisons of categorical data using Epi Info, version 6.04c,29 and StatXact 3.30
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.
From 1989 to 1997, MRSA infections increased dramatically in this community
(Figure 1). 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 β-lactam antibiotics. Most community-acquired MRSA
isolates, however, were susceptible to many other non–β-lactam
antibiotics (Table 1). 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).
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).
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
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,35,36
we found no evidence of such exposures. Although the term community acquired is not clearly or consistently defined in current
MRSA literature,37 our criteria for community
acquisition were among the most conservative, requiring a full year with no
exposure to established nosocomial risk factors.38
Furthermore, antimicrobial susceptibility patterns found among community-acquired
MRSA isolates in this community showed susceptibility to most classes of antimicrobial
agents other than β-lactam antibiotics, consistent with other studies
of community-acquired MRSA.3,11,12,14,15,17
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 subtypes27 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 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.39,40
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 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
This finding as well as those of previous studies documenting community-acquired
MRSA infection in diverse populations3,11-18
suggest that the problem of MRSA is growing and that even rural communities
are not sheltered.
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