Download What Is Community-Associated Methicillin

MAJOR ARTICLE
What Is Community-Associated Methicillin-Resistant
Staphylococcus aureus?
Michael Z. David,1,a Daniel Glikman,1,a Susan E. Crawford,1 Jie Peng,1 Kimberly J. King,1 Mark A. Hostetler,2
Susan Boyle-Vavra,1 and Robert S. Daum1
1
Infectious Diseases Section and 2Emergency Medicine Section, Department of Pediatrics, the University of Chicago, Illinois
(See the article by Gorwitz et al., on pages 1226 –34; the article by Emonts et al., on pages 1244 –53; and the
editorial commentary by Flynn and Cohen, on pages 1217–9.)
Background. A community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infection has
been defined as an MRSA infection in a patient who lacks specific risk factors for healthcare exposure. We sought to
determine whether the absence or presence of these risk factors still predicts the phenotypic or genotypic characteristics of MRSA strains.
Methods. All clinical MRSA isolates were prospectively collected at the University of Chicago Hospitals from July
2004 through June 2005. Patients were interviewed and/or their medical records were reviewed. Isolates underwent
genotyping and susceptibility testing. Data on patients and isolates were stratified in accordance with 8 frequently
cited criteria for the identification of CA-MRSA and compared for concordance.
Results. Among 616 unique patients from whom MRSA isolates were recovered, 404 (65.6%) had risk factors for
healthcare exposure. Of the 404 isolates recovered from these patients, 166 (41.1%) were clindamycin susceptible, 190
(47.0%) carried staphylococcal cassette chromosome mec (SCCmec) type IV, 145 (35.9%) carried the PantonValentine leukocidin genes (PVL⫹), and 162 (40.1%) were identified as sequence type (ST) 8 by multilocus sequence
typing (MLST), all of which are characteristics commonly attributed to CA-MRSA strains.
Conclusions. Association with the healthcare environment now has little predictive value for distinguishing
patients with infection due to multidrug resistant MRSA isolates from those infected by CA-MRSA isolates, that is,
isolates that are clindamycin-susceptible, PVL⫹, ST8, and/or contain SCCmec type IV. Defining CA-MRSA by the
absence of risk factors for healthcare exposure greatly underestimates the burden of epidemic CA-MRSA disease.
Beginning with its first report in 1961 [1], methicillinresistant Staphylococcus aureus (MRSA) isolates have
been associated with a variety of infectious syndromes in
patients with exposure to the healthcare environment. A
Received 15 June 2007; accepted 10 October 2007; electronically published 28
March 2008.
Presented in part: Israeli Society for Clinical Pediatrics Conference, February
2007, Tel Aviv, Israel (abstract 21); and the 2007 Pediatric Academic Societies’
Annual Meeting, May 2007, Toronto, Canada (publication 8422.7).
Potential conflicts of interest: R.S.D. is supported by grants from the National
Institute of Allergy and Infectious Diseases (NIAID) (1R01AI067584-01A2) and the
Centers for Disease Control and Prevention (CDC) (1 U01 CI000384-01), and he has
received grant support from Sage Products, Pfizer, Sanofi Pasteur, and Chlorox. He
has served on paid advisory boards for Clorox, Sanofi Pasteur, GlaxoSmithKline,
Pfizer, and the MRSA National Faculty Meeting (sponsored by Astellas and
Theravance), and he has received lecture fees from Nabi Biopharmaceuticals and
Pfizer. The other authors report no relevant conflicts.
Financial support: CDC (R01 CCR523379 and R01 CI000373-01 to R.S.D and S.B.,
R01 CI000373-01 to M.Z.D.), the NIAID (R01 AI40481-01A1 to R.S.D and S.B.,
1R01AI067584-01A2 to S.E.C. and M.A.H), and the Grant Healthcare Foundation (to
R.S.D and S.B.).
The Journal of Infectious Diseases 2008; 197:1235– 43
© 2008 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2008/19708-0005$15.00
DOI: 10.1086/533502
defined group of risk factors for exposure to MRSA was
established, including hospitalization, surgery, receipt
of hemodialysis, a stay in a long-term care facility, or
undergoing surgery during the previous year, as well
as the presence of an indwelling device or vascular catheter [2,3]. MRSA strains recovered from patients who
frequent healthcare facilities, so-called healthcareassociated MRSA (HA-MRSA), were typically resistant
to clindamycin and other non–␤-lactam antimicrobials.
This multidrug-resistant MRSA phenotype was due in
part to the presence of relatively large DNA elements, the
staphylococcal cassette chromosome mec (SCCmec), integrated into the bacterial genome. An SCCmec element
carries the mecA gene, which mediates resistance to
methicillin and, by inference, resistance to all other
available ␤-lactam drugs and is the molecular hallmark
a
M.Z.D. and D.G. contributed equally to this work.
Reprints or correspondence: Dr. Michael Z. David, Section of Infectious Diseases and Department of Pediatrics, the University of Chicago, 5841 S. Maryland
Ave., MC 6054, Chicago, IL 60637 ([email protected]).
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of MRSA strains. The relatively large type II–III SCCmec elements associated with HA-MRSA strains also carry genes responsible for resistance to other antibiotic classes [4].
Beginning in the late 1990s, there appeared many reports of
MRSA colonization and infection in the community that involved patients who had no recent contact with healthcare facilities [5–10]. It was initially suspected that these cases represented
the spread of HA-MRSA strains into the community. Although
HA-MRSA strains do sometimes circulate in the community,
distinct community-associated MRSA (CA-MRSA) strains were
identified that carry 1 of 2 novel, smaller SCCmec types, IV and
V, and share genetic backgrounds with S. aureus strains not previously known to carry SCCmec elements [11–13]. These novel
CA-MRSA strains differ from their HA-MRSA counterparts by
usually being susceptible to clindamycin and other non–␤lactam antibiotics [10]. They also typically carry the 2 genes encoding Panton-Valentine leukocidin (PVL), a pore-forming
toxin that was rarely found among clinical isolates of S. aureus
[10, 14]. Certain S. aureus genotypes have been identified, distinct from HA-MRSA genotypes, that commonly cause CAMRSA infections in the community. The predominant strain in
the United States is designated USA300, which usually corresponds to sequence type 8 (ST8) as identified by multilocus sequence typing (MLST) [15, 16]. Several new clinical staphylococcal syndromes have been described that are associated with
CA-MRSA strains [17–19], ranging from skin and soft tissue
infections (SSTIs) that initially resemble the bite of an arachnid
[5, 6, 10] to severe, life-threatening infections [18].
Many investigators have identified the isolates that cause CAMRSA infection by using a definition based on the patient’s lack
of healthcare risk factors, a definition advocated by the Centers
for Disease Control and Prevention (CDC) in 2000 [2, 3]. This
definition states that a case of MRSA infection is communityacquired when it is diagnosed in an outpatient or within 48
hours of hospitalization if the patient lacks the following traditional risk factors for MRSA infection: receipt of hemodialysis,
surgery, residence in a long-term care facility, or hospitalization
during the previous year; the presence of an indwelling catheter
or a percutaneous device at the time culture samples were obtained; or previous isolation of MRSA.
There are several problems with the use of an approach based
on the lack of these healthcare risk factors. First, both CA-MRSA
and HA-MRSA strains now circulate in the community. Second,
so-called CA-MRSA strains are gradually becoming entrenched
as nosocomial pathogens [20 –25]. This complex, changing epidemiology raises doubts about the distinction between CAMRSA and HA-MRSA strains based on healthcare exposure in
both clinical practice and epidemiologic research. Third, new
high-risk groups for MRSA infection and colonization in the
community have been identified, including children [5, 6], athletes [26 –28], incarcerated populations [29, 30], military recruits [31], Native Americans [7], Pacific Islanders [8], men who
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David et al.
have sex with men [9], impoverished adults in the inner city
[32], and adult emergency department patients [33].
It is useful to attempt to distinguish HA-MRSA isolates from
CA-MRSA isolates and to distinguish patients with HA-MRSA
infection from patients with CA-MRSA infection. Isolate characteristics help investigators to understand and monitor the rapidly changing epidemiology of MRSA. Patient characteristics
may also be of help when a clinician is faced with a patient who
has a potential MRSA infection. The distinction between HAMRSA and CA-MRSA has been used to guide decisions about
empirical therapy, because CA-MRSA isolates are more likely to
be clindamycin susceptible.
Accordingly, for all patients at an urban tertiary care medical
center that had been experiencing epidemic CA-MRSA infections during the previous decade [5] who had MRSA isolates
recovered during a 1-year period, we analyzed the clinical and
demographic characteristics of the patients from whom the isolates were recovered, as well as the isolates’ genetic characteristics and antimicrobial resistance profiles. We also analyzed the
temporal characteristics of recovery (e.g., date of patient admission and date of specimen procurement). We evaluated several
criteria that have been associated with CA-MRSA strains or with
the patients they infect in order to understand the relative importance of these various criteria in the arenas of clinical medicine, epidemiologic studies, and basic science.
PATIENTS, MATERIALS, AND METHODS
Setting. The University of Chicago Medical Center (UCMC) is
a tertiary care medical center in Chicago, Illinois, with 577 beds
for inpatients and 26,200 annual admissions. It includes an outpatient care facility that has 389,000 annual visits and an emergency department that has more than 71,000 annual visits.
UCMC serves an inner-city population and draws tertiary referrals from the surrounding region. The study was approved by the
Institutional review board of the Biological Sciences Division of
the University of Chicago.
Microbiological studies. The UCMC Clinical Microbiology
Laboratories prospectively identified all MRSA isolates collected
between July 1, 2004 and June 30, 2005, from patients in all
clinical settings as reported elsewhere [34]. We used an automated system (Vitek 2; bioMérieux) to determine the antimicrobial susceptibility profile of each isolate for oxacillin, erythromycin, clindamycin, ciprofloxacin, rifampin, gentamicin, linezolid,
and vancomycin. All isolates identified by automated testing as
susceptible to oxacillin underwent confirmatory disk diffusion
testing for cefoxitin susceptibility. For isolates that were identified as resistant to erythromycin but susceptible to clindamycin, a D-test was performed to detect inducible clindamycin
resistance, as was a disk diffusion test for susceptibility to
trimethoprim-sulfamethoxazole. All assays were performed in
accordance with Clinical and Laboratory Standards Institute
guidelines [35].
Molecular studies. MLST was performed on all MRSA isolates, as described elsewhere [15]. Clonal complexes were assigned using the eBURST algorithm, as described elsewhere [36].
The presence of mecA was assessed, and the SCCmec type of each
strain was determined by the molecular architecture of the ccr
and mec complexes by use of criteria described elsewhere [37].
The presence of lukF-PV and lukS-PV encoding the PVL toxin
was performed by polymerase chain reaction (PCR), as described elsewhere [16].
Patient information. At least 5 attempts were made to contact each unique patient from whom an MRSA isolate was recovered to administer a standardized questionnaire that asked
about any history of previous MRSA infection, surgery in the
previous 6 months, hospitalization in the previous year, the
presence of an indwelling catheter or any prosthetic device,
and/or a history of hemodialysis. For patients who could not be
contacted, the paper medical record was reviewed and abstracted by one of us (D.G.) using the same questionnaire. Additionally, for all patients, the electronic medical record, including hospital discharge summaries and radiographic, laboratory,
pathology, operative, and outpatient clinic reports, was reviewed
(by D.G. or S.E.C.) to determine the location of care in the medical center, date of admission, demographic characteristics, date
of specimen procurement, the isolate’s antibiotic susceptibility
profile, anatomic source of the culture sample, clinical indication for the culture, radiographic results and results of other
tests, and any history of previous MRSA isolation at UCH since
1994. A clinical syndrome was assigned to each patient from
whom MRSA was recovered on the basis of all available data. For
isolates from inpatients, the number of days from admission to
specimen procurement was calculated.
Criteria for identifying CA-MRSA. We joined clinical information for each patient with molecular data on the isolate
recovered from that patient (a combination hereafter referred to
as a “patient-isolate set”). Data on patient-isolate sets were stratified on the basis of 8 commonly cited criteria for identifying
CA-MRSA [2, 5–10, 23, 26 –33]. These criteria were as follows:
(1) the clindamycin susceptibility criterion, which identified all
isolates not shown to be resistant to clindamycin either by singleagent testing or by D-test; (2) the non–multidrug resistance
(non-MDR) criterion, which identified isolates resistant to ⬍3
non–␤-lactam antibiotics; (3) the SCCmec IV criterion, which
identified all isolates that carried SCCmec type IV; (4) the SSTI
criterion, which identified all isolates recovered from patients
with SSTI (i.e., abscesses, burn infections, felons, paronychia,
cellulitis, surgical wound infections, folliculitis, carbuncles,
furuncles, myositis, and/or pyomyositis); (5) the PVL criterion
(PVL⫹), which identified all isolates that carried the PVL genes;
(6) the ST8 criterion, which identified all isolates that were
ST8 —and thus presumptively USA300, the most common
background genotype now found in many US studies of CAMRSA [15]; (7) the 48-hour criterion, which identified all isolates obtained from outpatients, emergency department patients
not admitted to the hospital, and inpatients within 48 hours of
admission; and (8) the “lack of healthcare risk factors” criterion,
which identified the patients defined by criterion 7 who also
lacked the following risk factors for exposure to HA-MRSA: hospitalization, receipt of hemodialysis, or residence in a long-term
care facility during the previous year; surgery during the previous 6 months; the presence of an indwelling catheter or a percutaneous device at the time the culture sample was obtained; or
previous isolation of MRSA. Our “lack of healthcare risk factors”
criterion differed from the CDC definition for CA-MRSA [2,3]
only in that we included surgery as a risk factor if it occurred
during the 6 months prior to the time the isolate was recovered,
rather than during the year prior to recovery of MRSA.
Data analysis. Bacteriologic and patient data were compiled in an electronic database using Access (Microsoft). Only
the first isolate collected from each patient during the surveillance period was included in the database. Each criterion was
applied individually to the entire collection of data on patientisolate sets. Isolates that fulfilled a given criterion were deemed
CA-MRSA, and the remainder were identified as HA-MRSA.
Data were analyzed with Stata SE, version 9.2 (Stata). Comparisons between groups were performed by use of the ␹2 test. The
percentage of concordance was calculated to define the subset of
isolates that would be identified as CA-MRSA, or the subset of
patients who would be identified as having a CA-MRSA infection, by simultaneous application of any pair of the 8 criteria for
CA-MRSA. Because risk-factor data related to healthcare exposure are often readily available to the clinician at the bedside, the
“lack of healthcare risk factors” criterion for CA-MRSA was applied as a screening test for the presence of SCCmec IV and for
clindamycin susceptibility. The positive predictive value (PPV),
negative predictive value (NPV), sensitivity, and specificity were
calculated for these tests. Both the pairwise concordance and the
screening tests were applied to the entire sample and repeated for
the following subgroups: children (⬍18 years), adults, inpatients, outpatients, emergency department patients, and children and adults, respectively, in the inpatient, outpatient, and
emergency department settings. All hypotheses were evaluated
by 2-tailed tests and results were considered significant if
P ⬍ .05.
RESULTS
There were 1225 MRSA isolates identified by the UCH Clinical
Microbiology Laboratories during the study period, of which
560 were not analyzed further because they were recovered from
patients who had already had MRSA isolates recovered during
the study period. Thirty-five patients declined to participate in
the study, 9 isolates were identified as methicillin-susceptible
What is CA-MRSA?
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Table 1. Demographic and clinical characteristics of study patients from whom methicillin-resistant Staphylococcus aureus
(MRSA) was isolated.
Characteristic
Demographic variable
Age group
Pediatric (⬍18.0 years)
Adult
Sex
Male
Female
Type of insurance
Public assistance
Private
Uninsured
Unknown
Clinical variable
Clinical syndrome
Bacteremia, endocarditis, or sepsis
Osteomyelitis or septic arthritis
Pneumonia
Skin and soft tissue infection
Urinary tract infection
Othera
Risk factor for HA-MRSA infectionb
Inpatient culture sample obtained ⬎48 h
after admission
Hospital stay in the past year
Surgery in the past 6 months
Hemodialysis in the past year
Indwelling catheter
MRSA isolated previouslye
Laboratory report
Self-report only
Lived in long-term care facility in the past
year
Location of care
Intensive care unit
Other inpatient unit
Emergency department
Outpatient
NOTE.
a
Patients, no. (%)
(N ⫽ 616)
224 (36.4)
392 (63.6)
301 (48.9)
315 (51.1)
429 (69.6)
149 (24.1)
20 (3.3)
18 (2.9)
63 (10.3)
33 (5.4)
46 (7.5)
354 (57.5)
22 (3.6)
98 (15.9)
135 (21.9)
255 (50.1)c
237 (43.4)d
39 (6.3)
79 (12.8)
80 (24.9)
11 (3.4)
18 (5.7)f
118 (19.2)
236 (38.3)
128 (20.8)
134 (21.8)
HA-MRSA, healthcare associated MRSA.
Includes asymptomatic skin or nasal colonization, cholecystitis, conjunctivitis, peritonitis, respiratory colonization, and upper respiratory infection.
b
Denominators for HA-MRSA infection risk factors exclude those patients interviewed who answered that they did not know information
requested of them and those patients about whom risk factor information
could not be determined from medical record review. For all 616 patients
it was determined whether MRSA had been isolated from them at University of Chicago Medical Center since 1994, but for 295 patients, it could not
be determined whether MRSA had been isolated from them at another
healthcare facility. The information regarding a stay in a long-term care
facility was determined only for those patients who lacked another healthcare risk factor.
c
Data were available for 509 patients.
d
Data were available for 546 patients.
e
Data were available for 321 patients.
f
Data were available for 318 patients.
Table 2. Genotypic and phenotypic characteristics of methicillinresistant Staphylococcus aureus isolates.
Characteristic
Genotypic variable
Clonal complex or sequence type
Clonal complex 1
ST1
Clonal complex 5
ST5
ST5 SLV
ST105
ST231
Clonal complex 8
ST8
ST8 SLV
ST72
Clonal complex 22
ST22
Clonal complex 30
ST30
ST36
Clonal complex 59
ST59
New sequence type: 1-31-1-1-12-1-40a
PVL gene carriage
Positive
Negative
SCCmec type
II
IV
Otherb
Phenotypic variable
Antibiotic resistancec
Ciprofloxacin
Clindamycin
By D-test and Vitek testing
By Vitek testing alone
By D-test alone
Erythromycin
Gentamicin
Trimethoprim-sulfamethoxazole
Rifampin
Linezolid
Vancomycin
Isolates, no. (%)
(N ⫽ 616)
26 (4.2)
210 (34.2)
2 (0.3)
4 (0.7)
15 (2.4)
341 (55.5)
2 (0.3)
2 (0.3)
7 (1.1)
1 (0.2)
3 (0.5)
2 (0.3)
336 (54.6)
280 (45.5)
220 (35.7)
387 (62.8)
9 (1.5)
275 (44.6)
269 (43.7)
216 (35.1)
53 (15.3)
564 (91.6)
39 (6.3)
2 (0.6)
10 (1.6)
0 (0)
0 (0)
NOTE. PVL, Panton-Valentine leukocidin; SCC, staphylococcal cassette
chromosome; SLV, single-locus variant.
a
Numbers denote the allotypes of 7 genes that determine sequence type.
A total of 7 MRSA isolates had multiple ccr genes and were thus considered nontypeable, 1 had no ccr complex identified, and 1 was tentatively
named SCCmec type VII (S. Boyle-Vavra, unpublished data).
c
Includes intermediately susceptible isolates as resistant. All 616 isolates
were tested for susceptibility to clindamycin, ciprofloxacin, erythromycin,
gentamicin, rifampin, linezolid, and vancomycin; 347 isolates were tested for
susceptibility to trimethoprim-sulfamethoxazole and underwent the D-test for
inducible clindamycin resistance.
b
Table 3. Identification of community-associated methicillin-resistant Staphylococcus aureus in accordance with 8
criteria, for the entire sample and for isolates stratified by patient age group and location of patient care.
Isolates meeting criterion, no. (%)
Stratified by patient
age groupa
Criterion
48-hour
Clindamycin susceptible
SCCmec IV
Non-MDRc
PVL⫹
ST8
SSTI
Lack of healthcare risk factors
Stratified by location of
patient careb
All isolates,
no. (%) meeting
criterion (N ⫽ 616)
Adult
patients
(N ⫽ 392)
Pediatric
patients
(N ⫽ 224)
Emergency
department
(N ⫽ 128)
Inpatient
setting
(N ⫽ 354)
Outpatient
setting
(N ⫽ 134)
481 (78.1)
347 (56.3)
387 (62.8)
385 (62.5)
336 (54.6)
341 (55.4)
354 (57.5)
212 (34.4)
284 (72.5)
169 (43.1)
188 (48.0)
179 (45.7)
152 (38.8)
168 (42.9)
184 (46.9)
77 (19.6)
197 (88.0)
178 (79.5)
199 (88.8)
206 (92.0)
184 (82.1)
173 (77.2)
171 (76.3)
135 (60.3)
NA
108 (84.4)
121 (94.5)
124 (96.9)
114 (89.1)
106 (82.8)
117 (91.4)
99 (77.3)
NA
158 (44.6)
180 (50.9)
172 (48.6)
147 (41.5)
155 (43.8)
153 (43.2)
70 (19.8)
NA
81 (60.5)
86 (64.2)
89 (66.4)
75 (56.0)
80 (59.7)
84 (62.7)
43 (32.1)
NOTE. See Patients, Methods, and Materials for details about criteria. MDR, multidrug resistant; ST, sequence type; NA, not applicable;
PVL, Panton-Valentine leukocidin; SSTI, skin and soft tissue infection.
P ⬍ .001, by ␹2 test, for comparison between pediatric and adult cases for each criterion.
P ⬍ .001, by ␹2 test, for comparison of the 3 locations of care for each criterion, except the 48-hour criterion.
c
Non-MDR isolates were resistant to ⬍3 of the following antimicrobials: clindamycin, ciprofloxacin, rifampin, gentamicin, erythromycin,
vancomycin, linezolid, and trimethoprim-sulfamethoxazole.
a
b
owing to the absence of the mecA gene, and 1 isolate was
coagulase-negative Staphylococcus. Two isolates came from patients who had no documentation of a S. aureus isolation in their
medical record, and 2 isolates were not available for study. Ultimately, 616 patient-isolate sets were included in the analysis
(table 1).
Of the 616 patients, 320 (52.0%) were interviewed and paper
medical records were reviewed for 296 (48.1%); electronic
records were reviewed for all 616. Two predominant MLST
types, ST8 and ST5, accounted for 342 (55.5%) and 211 (34.2%)
of the isolates, respectively (table 2). Nearly two-thirds of the
isolates carried SCCmec IV, including 11 (5.2%) of ST5 and 336
(98.5%) of ST8 isolates. A total of 9 isolates carried novel
SCCmec elements, and none carried types I, III, or V. Erythromycin resistance was detected in the vast majority of isolates
(564 [91.6%]). A D-test was performed on 347 isolates; 53
(15.3%) were positive for inducible clindamycin resistance.
None of the isolates tested were resistant to vancomycin or linezolid (table 2).
The percentage of isolates designated as CA-MRSA varied according to which criterion was applied (table 3). Surprisingly,
the lowest percentage of isolates were identified as CA-MRSA by
the “lack of healthcare risk factors” criterion, which classified
34.4% of isolates as CA-MRSA. The highest percentage of isolates was classified as CA-MRSA by the 48-hour criterion
(78.1%). The percentage of isolates designated as CA-MRSA by
each criterion was lower for adults than for children (P ⬍ .001)
(table 3). For each criterion except the 48-hour criterion, the
highest percentage of CA-MRSA cases was identified in the
emergency department and the lowest in the inpatient setting
(table 3). There were 91 isolates from patients who were known
to have had an MRSA infection prior to the 1-year study period.
Of these 91 isolates, 30 (33.0%) were susceptible to clindamycin,
38 (41.8%) carried SCCmec type IV, and 26 (28.6%) carried the
genes for PVL; 22 (24.2%) met all 3 of these criteria for identifying CA-MRSA. Thus, a history of previous MRSA infection
was often associated with the recovery of isolates that had features typical of CA-MRSA isolates.
The percentage of concordance was calculated to define the subset of patient-isolate sets that would be identified as CA-MRSA by
simultaneous application of any 2 of the criteria used to identify
CA-MRSA (table 4). A high percentage of patients were classified as
having had a CA-MRSA isolate recovered by application of any 2 of
the following criteria: SCCmec IV, non-MDR, PVL, ST8, and clindamycin susceptibility. In contrast, there was a relatively poor correlation between the SSTI criterion and each of the other 7 criteria.
The concordance between the “lack of healthcare risk factors” criterion and each of the other 7 criteria was also relatively poor (table
4); this remained true even when patients were stratified by location
of care, age group, or both.
The “lack of healthcare risk factors” criterion was applied to
the patient-isolate set as a screening test for identifying CAMRSA, here defined by the hypothetical gold standard of clindamycin susceptibility (table 5). The sensitivity of the “lack of
healthcare risk factors” screening test was only 52.8%. The specificity was 89.2%, the PPV was 86.3%, and the NPV was 59.4%.
These parameters showed some variation when the sample was
stratified by patient age group and location of patient care. Sensitivity and the PPV were lower for patient-isolate sets that involved adult patients and higher for patient-isolate sets that inWhat is CA-MRSA?
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Table 4. Percentage concordance in identifying community-associated methicillin-resistant Staphylococcus aureus, for any 2 of the 8 study criteria applied simultaneously.
Criterion
Clindamycin susceptibility
SCCmec IV
Non-MDR
PVL⫹
ST8
SSTI
Lack of healthcare risk factors
48-hour
Clindamycin
susceptibility
SCCmec IV
Non-MDR
PVL⫹
ST8
SSTI
68.5
72.1
73.4
68.0
68.5
67.7
56.3
89.6
92.9
87.8
88.6
73.2
68.7
93.8
91.7
90.9
74.2
66.7
89.5
89.6
75.5
67.4
89.8
74.7
72.4
73.2
68.7
66.2
NOTE. See Patients, Methods, and Materials for details about criteria. MDR, multidrug resistant; ST, sequence type; PVL,
Panton-Valentine leukocidin; SSTI, skin and soft tissue infection.
volved pediatric patients. The sensitivity was highest among
patient-isolate sets that involved patients treated in the emergency department and lowest among patient-isolate sets that involved patients treated in the inpatient setting. Not unexpectedly, the NPV was very low for patient-isolate sets that involved
patients treated in the emergency department, where the prevalence of clindamycin-susceptible isolates was highest (84.4%).
Compared with all other patients, emergency department patients were significantly more likely to be children (103 [80.5%]
vs. 121 [24.8%]; P ⬍ .001) and to be covered by a stateadministered health insurance program (103 [80.5%] vs. 326
[66.8%]; P ⫽ .003). When the SCCmec IV criterion was used as
the gold standard for identification of CA-MRSA, use of the “lack
of healthcare risk factors” criterion as a screening test produced
similar results (table 5).
We did not consider that children ⬍1 year of age had a
healthcare-associated risk factor simply because all of these patients
were born in the hospital. If all such children were considered to
have a risk factor for HA-MRSA infection, then use of the “lack of
healthcare risk factors” criterion would increase the number of pa-
tients designated as having HA-MRSA isolates recovered to 430
(69.8%). This designation would also decrease the sensitivity of this
criterion as a screening test for clindamycin susceptibility to 46.1%,
and it would decrease the sensitivity of the criterion as a screening
test for the SCCmec IV criterion to 44.4%.
Most of the 212 patient-isolate sets considered to be CA-MRSA
by the “lack of healthcare risk factors” criterion would also have
been considered CA-MRSA by any of the other 7 criteria examined
(figure 1A). However, of the 404 isolates considered HA-MRSA
(and the infections considered to be HA-MRSA infections) by the
“lack of healthcare risk factors” criterion, 35.9%– 67.1% would be
considered CA-MRSA by the other criteria (figure 1B). Importantly, of the patients identified as having HA-MRSA infection by
the “lack of healthcare risk factors” criterion, 166 (41.1%) had an
isolate recovered that was clindamycin susceptible, and 190 (47.0%)
had an isolate recovered that had a type IV SCCmec element.
Of the 616 isolates recovered from unique patients, 304 isolates (49.4%) were clindamycin susceptible and carried both the
PVL genes and the SCCmec type IV element. A slightly smaller
group of 286 isolates (46.4%) had these 3 characteristics as well
Table 5. Use of the “lack of healthcare risk factors” criterion as a screening test for identification of
community-associated methicillin-resistant Staphylococcus aureus, in accordance with 2 theoretical gold
standards.
Study group, gold standard criteria
Isolates from all patients (N ⫽ 616)
Clindamycin susceptibility
SCCmec IV
Isolates from adult patients (n ⫽ 392)
Clindamycin susceptibility
SCCmec IV
Isolates from pediatric patients (n ⫽ 224)
Clindamycin susceptibility
SCCmec IV
NOTE.
1240
●
Diagnostic discrimination of the
“lack of healthcare risk factors” criterion
Isolates that
satisfied the
criterion, %
Sensitivity, %
Specificity, %
PPV, %
NPV, %
56.3
62.6
52.8
50.9
89.2
93.5
86.3
92.9
59.4
53.0
43.1
48.0
33.6
68.8
93.1
93.5
77.6
80.6
66.3
61.1
79.5
88.8
68.2
66.8
72.6
93.1
90.4
98.6
37.8
27.6
NPV, negative predictive value; PPV, positive predictive value; SCC, staphylococcal cassette chromosome.
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David et al.
Figure 1. Concordance between isolates identified as communityassociated methicillin-resistant Staphylococcus aureus (CA-MRSA) and
healthcare-associated MRSA (HA-MRSA) by the “lack of healthcare risk
factors” criterion and the percentage of isolates identified as CA-MRSA and
HA-MRSA by the 7 other study criteria. A, Classification of the 212 isolates
that were identified as CA-MRSA by the “lack of healthcare risk factors”
criterion, in comparison with the other 7 study criteria. Of these 212 isolates,
the majority were also classified as CA-MRSA by each of the 7 other criteria
(i.e., 182 [85.8%] of the isolates were susceptible to clindamycin, 197 [92.9%]
carried the staphylococcal cassette chromosome [SCC] mec type IV element,
197 [92.9%] were not multidrug resistant [MDR], 189 [89.2%] carried the
Panton-Valentine leukocidin [PVL] toxin genes, and 180 [84.9%] had the
sequence type 8 [ST8] genotype). In addition, 178 [84.0%] of the patients
from whom the isolates were recovered had skin and soft tissue infection
(SSTI) identified as their clinical syndrome. B, Classification of the 404
isolates that were identified as HA-MRSA by the “lack of healthcare risk
factors” criterion, in comparison with the other 7 study criteria. Of these 404
isolates, many also had traits characteristic of CA-MRSA (i.e., 166 [41.1%]
were susceptible to clindamycin, 190 [47.0%] carried a type IV SCCmec
element, 186 [46.0%] were not MDR, 145 [35.9%] carried the PVL toxin
genes, and 162 [40.1%] had the ST8 genotype). In addition, 174 patients
[43.1%] from whom the isolates were recovered had SSTI identified as their
clinical syndrome.
as the ST8 genotype. Thus, a large group of the MRSA isolates we
analyzed shared all 4 of these criteria for CA-MRSA. Of these 286
isolates, 121 (42.3%) would be considered HA-MRSA by the
“lack of healthcare risk factors” criterion.
DISCUSSION
The CDC criteria that define CA-MRSA rely on a lack of exposure to the healthcare environment to identify cases of CA-
MRSA infection. The criteria accurately predicted the identification of a subset of about one-third of the MRSA isolates
identified in our surveillance that had the ST8 genotype and were
clindamycin susceptible, SCCmec IV– bearing, and PVL⫹—
isolate-specific traits most commonly believed to designate CAMRSA isolates.
The epidemiology of the remaining two-thirds of the MRSA
isolates is more complex. The presence of the traditionally recognized HA-MRSA risk factors (i.e., exposure to the healthcare
environment) identified nearly all of the patients from whom
isolates were recovered that had the ST5 genotype and were clindamycin resistant, SCCmec II– bearing, and PVL⫺—attributes
commonly believed to define HA-MRSA isolates. However,
many patients who had exposure to the healthcare environment
also had MRSA isolates recovered that had the ST8 genotype and
were clindamycin susceptible, SCCmec IV– bearing, and PVL⫹.
This apparent paradox was not due to the nosocomial spread of
isolates with these traits at the University of Chicago, as these
isolates represented only a small minority of those acquired ⬎48
hours after hospitalization. Rather, our data indicate that the
MRSA isolates with these traits must be circulating in the community and must be being transmitted to individuals living in the
community, both those who have had exposure to the healthcare
environment and those who have not had such exposure.
Conversely, if the presence of the ST8 genotype, clindamycin
susceptibility, the SCCmec IV element, and PVL positivity are
assumed to define CA-MRSA isolates, only some patients from
whom such isolates were recovered fulfilled the CDC’s definition
for CA-MRSA infection. Use of the CDC definition, therefore,
underestimates the community-based disease burden caused by
MRSA isolates with these traits. For example, a healthcare risk
factor– based screening tool for MRSA isolates in populationbased surveillance in Atlanta, Baltimore, and 12 hospital laboratories in Minnesota determined that only 8%–20% of MRSA
patient-isolate sets were CA-MRSA [38]. Had we used a similar
definition, we would have excluded 164 isolates that were
clindamycin-susceptible, 26.6% of our total. We would also have
excluded 190 isolates that carried SCCmec IV, 30.8% of our total.
What, then, is CA-MRSA? For a clinician contemplating the
prescription of clindamycin for an SSTI that occurs in an ambulatory patient, there will be uncertainty about the wisdom of this
choice if the patient does not fulfill the CDC definition of CAMRSA infection, although many isolates from patients who do
not satisfy this definition will be clindamycin susceptible. For an
epidemiologist, a temporal definition (e.g., culture sample collected ⬎48 hours after hospital admission) or a healthcare risk
factor– based definition may designate a subset of patients whose
MRSA isolates that might be of interest. However, we have demonstrated that such a definition will not correlate with a definition based on molecular typing or antimicrobial susceptibility.
For a molecular biologist who is interested in the subset of isoWhat is CA-MRSA?
●
JID 2008:197 (1 May)
●
1241
lates that are PVL⫹, SCCmec IV– bearing, or bear some other
genetic trait, still other definitions may be of interest.
We have shown that a history of exposure to the healthcare
environment is poorly predictive of the genotypic and phenotypic characteristics of the MRSA isolates that cause infections.
This is so because the epicenter of the MRSA epidemic is no
longer in healthcare institutions; it has moved to the community, and these infections affect both individuals who have exposure to the healthcare environment and individuals who do not
have such exposure. Therefore, a single definition of CA-MRSA
cannot fulfill all purposes. Investigators who use the term must
carefully expostulate the definition they use and explicitly consider the different meanings given to the term “CA-MRSA.”
Our data also demonstrate that a disproportionate burden of
the MRSA isolates that had genotype ST8 and were clindamycin
susceptible, SCCmec IV– bearing, PVL⫹ came from children,
which is consistent with an earlier communication from our
center [34]. This suggests that children with MRSA infections
may be more likely to be exposed to a reservoir of MRSA strains
with these traits, compared with adults. Further research is
needed to assess the importance of this finding.
By the CDC’s risk factor– based definition, a history of a previous MRSA infection classifies a patient-isolate set as HAMRSA. We found that patients with such a history frequently
had MRSA isolates recovered that had genotype ST8 and were
clindamycin susceptible, SCCmec IV– bearing, and PVL⫹, thus
demonstrating the lack of close association between this risk factor and recovery of MRSA strains that had genotype ST5 and
were clindamycin-resistant, SCCmec II-bearing, and PVL⫺,
which are historically associated with HA-MRSA infection.
There are several limitations to our study. It was conducted at
a single center in the midst of a changing epidemic of MRSA
infections in the community. However, the south side of Chicago has been a focus of epidemic CA-MRSA disease for almost
a decade [5]. We were not able to interview every patient. However, thorough reviews of the paper medical records were conducted for those who were not interviewed, and additional information was collected from the electronic records of all
patients. It is unlikely that more complete interview data would
have yielded a greater number of patients categorized by the
“lack of healthcare risk factors” criterion as having HA-MRSA
infection.
Epidemiologists have promulgated criteria to define the nosocomial transmission of many pathogens. These criteria remain
valuable to infection control activities in healthcare facilities.
The CDC’s definition of CA-MRSA is an inverse criterion; it is
now used to describe community transmission of a pathogen
that was previously nearly exclusively limited to healthcare settings. In the late 1990s, early in the CA-MRSA epidemic, the
CDC’s definition was useful because it helped to define a new
epidemiological phenomenon. However, the “community ver1242
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David et al.
sus nosocomial” paradigm is no longer optimal for distinguishing genotypically distinct groups of MRSA isolates.
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