This is a CDC study of MRSA that I believe was originally published a while back but it's new to me --
Community-Associated Methicillin-Resistant Staphylococcus Aureus Isolates
Causing Healthcare-Associated Infections
Cynthia L. Maree; Robert S. Daum; Susan Boyle-Vavra; Kelli Matayoshi; Loren
G. Miller
Emerg Infect Dis. 2007;13(2):236-242. ©2007 Centers for Disease Control
and Prevention (CDC)
Posted 02/26/2007
Abstract and Introduction
Abstract
We noted a marked increase in healthcare-associated (HA)
methicillin-resistant Staphylococcus aureus (MRSA) infections caused by
isolates phenotypically consistent with community-associated (CA)-MRSA
strains. To study this trend, we retrospectively examined all HA-MRSA
isolates from patients in our institution during 1999-2004. An isolate was
considered an SCCmecIV phenotype if it had antimicrobial drug
susceptibilities consistent with typical CA-MRSA isolates. Our phenotypic
definition was validated in a limited subset of isolates by SCCmec genotype,
pulsed-field gel electrophoresis, and multilocus sequence typing. Among 352
patients with HA-MRSA isolates, SCCmecIV phenotype increased from 17% in
1999 to 56% in 2003 (p<0.0001). Antimicrobial drug-susceptibility phenotype
and genotype were consistent in 21 (91%) of 23 isolates. In a multivariate
model, the SCCmec type IV phenotype was independently associated with wound
culture source, later year of collection, and MRSA isolated earlier during
hospitalization. In conclusion, MRSA isolates phenotypically similar to CA
strains have become the predominant isolates associated with HA-MRSA in our
hospital.
Introduction
Methicillin-resistant Staphylococcus aureus (MRSA) is the most frequently
identified antimicrobial drug-resistant pathogen in US hospitals.[1] The
epidemiology of infections caused by MRSA is rapidly changing. In the past
10 years, infections caused by this organism have emerged in the community.
The 2 MRSA clones in the United States most closely associated with
community outbreaks, USA400 (MW2 strain, ST1 lineage) and USA300, often
contain pvl genes and, more frequently, have been associated with skin and
soft tissue infections.[2,3] Outbreaks of community-associated (CA)-MRSA
infections have been reported in correctional facilities, among athletic
teams, among military recruits, in newborn nurseries, and among men who have
sex with men.[4-7] CA-MRSA infections now appear to be endemic in many urban
regions and cause most CA-S. aureus infections.[5,6,8-10]
CA-MRSA isolates were first recognized by distinct resistance profiles of
antimicrobial drugs that lacked resistance to older antimicrobial
drugs.[11-13] Several groups have noted these distinct susceptibility
patterns appearing in isolates from hospitalized patients. Denis et al.
noted that since 1995, MRSA isolates in Belgian hospitals were losing
resistance to older antimicrobial drugs such as gentamicin and
clindamycin.[14] A Spanish hospital experienced a decrease in
gentamicin-resistant MRSA isolates (from 97% in 1998 to 20% in 2002) and a
simultaneous increase in MRSA isolates carrying the SCCmec type IV cassette
(from 0% prevalence in 2000 to 23% prevalence in 2002).[15] A French group
noted a similar finding in their hospitals over an 11-year period and found
a correlation between isolates that contained SCCmec type IV and
susceptibility profiles to =3 antimicrobial drugs.[16] However, these
investigations did not distinguish between cultures obtained from patients
hospitalized with CA infection and those with hospital-associated (HA)
infections. Thus, it is unclear whether these trends in decreased
antimicrobial drug resistance and increased number of MRSA isolates that
contained SCCmec type IV were due to increased hospitalization of patients
with CA-MRSA infections or to an increased prevalence of isolates containing
SCCmec type IV among HA-MRSA isolates.
Some MRSA strains associated with CA infection have been noted to cause HA
infections. Outbreaks of HA infections caused by isolates containing SCCmec
type IV have been reported from Australia and the United States. Affected
populations have included postpartum women and patients undergoing
prosthetic joint replacement.[17-19] Another recent report demonstrated that
CA strains had emerged as a substantial cause of HA bloodstream
infections.[20] However, these reports are anecdotal, and data examining
temporal trends are lacking.
At our institution, which is located in an area in which CA-MRSA infections
are endemic, we have noted a large increase in HA infections caused by MRSA
isolates that, by assessment of antibiotic susceptibility patterns, appear
to carry the SCCmec type IV element (e.g., susceptible to gentamicin,
clindamycin, and trimethoprim-sulfamethoxazole).[6,10,21] The aim of this
study was to quantify this trend over a 6-year period.
Methods
Population
To find patients with HA-MRSA infections, we identified all cultures
obtained =72 hours after hospitalization that grew MRSA, from January
1, 1999, through December 31, 2004, at Harbor-UCLA Medical Center, a
tertiary-care, urban, county hospital in Los Angeles County. At this
hospital, surveillance cultures for MRSA colonization are not routinely
performed; therefore, cultures positive for MRSA are likely to reflect
infection rather than colonization. For a given patient, we examined only
data from the first positive culture and excluded patients who had positive
cultures both =72 hours and <72 hours after admission. If a patient
had been hospitalized more than once during the study period, only data from
the first hospitalization were retained. A standardized instrument was used
to abstract data from the medical record of each patient. Information
obtained included demographics, admission date and time, hospital location,
antimicrobial drug susceptibility of the MRSA isolate, and time, date, and
source of the MRSA culture.
We obtained only MRSA blood isolates for molecular typing because the
clinical microbiology laboratory discards all other types of isolates after
identification is complete. In vitro susceptibilities were reported as
minimal inhibitory concentrations and performed with the VITEK system
(bioMérieux, Durham, NC, USA), according to the protocols of the Clinical
and Laboratory Standards Institute (CLSI). The investigation protocol was
reviewed and approved by the Institutional Review Board of Harbor-UCLA
Medical Center.
Molecular Characterization of Strains
Molecular typing was performed at the University of Chicago by investigators
who were blinded to the clinical details and antibiograms of the isolates.
SCCmec Typing
PCR was performed to detect mecA by using the primer pair mecAF/mecAR.[22]
SCCmec elements were distinguished by the molecular architecture of the ccr
and mecA complexes.[21,23,24] PCR typing of SCCmec types I-IV was performed
under the conditions previously described.[24,25] SCCmec type II (ccrAB
complex type 2 and mec complex class A), SCCmec type III (ccrAB complex type
3 and mec complex class A), and SCCmec type IV (ccrAB complex type 2 and mec
complex class B) were assigned according to published criteria.[25] PCR
primers used to detect mecI (primers mI3/mI4), the mecR1 membrane spanning
region (MS) (primers mcR3/mcR4), and the mecR1 penicillin-binding region
(PB) (primers mcR1/mcR5) were originally reported by Suzuki et al..[26]
Screening for ccrAB complex types 1, 2, and 3 (ccrAB 1, 2 and 3) was
accomplished with a multiplex PCR assay that uses a mixture of 4 primers
designed by Ito et al., consisting of a common forward primer (ß2) and
reverse primers, a2, a3, and a4 specific for ccrAB complexes
1, 2, and 3. Thermocycler conditions used have been described.[27] The
presence of the ccrAB gene complex allotype 4 (ccr complex 4) was assessed
in a separate reaction that used the primer pair ccrA4F and ccrB4R.[27]
Screening for the ccrC gene (ccr complex 5) was performed with a forward
primer (?F) in combination with the reverse primer ?R described by
Ito et al..[28] Prototype strains used for SCCmec typing were NCTC10442
(SCCmec I), N315 (SCCmec II), 85/2082 (SCCmec III), MW2 (SCCmec IV), and WIS
(SCCmec V). The control strain used for detection of ccrAB4 was S.
epidermidis strain ATCC 12228, which contains ccrAB4 in the
non-mec-containing SCCcomposite island.[24]
MLST
MLST was performed by PCR amplification and sequencing of 7 housekeeping
genes by using the primer pairs designed by Enright et al.[29] Denville
Taq-Pro Complete (Denville Scientific, Metuchen, NJ, USA) or the Taq DNA
Polymerase (Promega, Madison, WI, USA) was used for the PCR reactions. PCR
products were evaluated on an agarose gel and purified by using Millipore
96-well Montage (Billerica, MA, USA) plates according to manufacturer's
instructions. The purified templates were sequenced at the University of
Chicago Core Sequencing Facility and evaluated with the use of Vector NTI
software (Invitrogen, Carlsbad, CA, USA). Each sequence was submitted to the
MLST database website (www.mlst.net) for assignment of the allelic profile
and sequence type (ST).
Screening for pvl Genes
Isolates were screened for the lukF-PV and lukS-PV genes encoding the
components of the PVL toxin by PCR amplification of a 433-bp product that
includes a portion of both the lukS-PV and lukF-PV ORFs by using the primer
pair luk-PV-1/ luk-PV-2 (final concentration 0.2 µM) designed by Lina et
al..[30] The thermocycler conditions have been described.[27]
Case Definition and Data Analysis
A standardized definition of CA-MRSA infection was created by the Centers
for Disease Control and Prevention (CDC) Active Bacterial Core Surveillance
sites.[31] Using this definition, we defined HA-MRSA infections as those
MRSA infections that did not meet the definition of CA-MRSA infections.
Specifically, we defined an MRSA isolate as HA associated if the original
entry criteria of hospitalization for =72 hours before culture
acquisition was met and if in the year before the present hospitalization,
the patient had had any 1 of the following: hospitalization, surgery,
residency in a long-term care facility, and hemodialysis or peritoneal
dialysis, or at the present admission had indwelling percutaneous devices or
catheters. A CA infection was defined as a culture-confirmed MRSA infection
without any of the above criteria. However, if the patient did not meet any
of the above criteria, had an infection at the time of admission, and the
culture of the infection on admission was taken =72 hours after
admission, then the infection was considered CA. An example of this
situation would be a deep tissue infection microbiologically diagnosed from
a surgical biopsy specimen 4 days after the patient's admission.
To validate our definition of HA-associated infection, we reviewed 105 (30%)
randomly selected charts of the patients with MRSA infections identified
=72 hours after hospitalization. The purpose of this validation was to
confirm that these cultures did not reflect CA infections that were
diagnosed late (>72 hours) in the hospital course. Of note, in the CDC
definition, an infection is considered HA if it occurs >48 hours after
admission. Yet, we chose =72 hours as a cut-off to more conservatively
capture HA infections, i.e., to minimize the miscategorization of CA
infections as HA infections.
We then defined MRSA strains as having the SCCmec type IV phenotype if the
isolates were resistant to oxacillin and susceptible to gentamicin,
clindamycin, and trimethoprim-sulfamethoxazole. All other isolates were
considered to be phenotypically non-SCCmec type IV.
Characteristics were compared between patients infected with the non-SCCmec
type IV phenotype isolates and those infected with SCCmec type IV phenotype
isolates by using a X2 or t test, as appropriate. No adjustments were made
for multiple comparisons. Temporal trends in the proportion of the SCCmec
type IV phenotype were compared with the Cochran-Armitage test of trends. A
multivariate analysis that predicted phenotypically SCCmec type IV isolates
was performed by using an unconditional logistic regression model and a
backward model selection method. A p value of =0.05 was defined as
statistically significant. Data analysis was done with SAS software version
8.2 (SAS Institute Inc., Cary, NC, USA).
Results
Population Characteristics
We identified 352 patients who had HA-MRSA cultures; 229 (65%) were men, and
the median age was 50 years (mean 49.5 years). In the subset of medical
records reviewed for validation of HA or CA status, none of the patients'
infections (0/105) fit our definition of a CA infection. The SCCmec type IV
phenotype was identified in 128 (36%) of these 352 patients. Compared with
the non-SCCmec type IV phenotype, patients with the SCCmec type IV phenotype
were younger (median age 48 vs. 54 years, p = 0.02) and had the defining
culture taken earlier in the hospitalization (median 8 vs. 15 days, p =
0.01). Finding an isolate with the SCCmec type IV phenotype was more likely
if the culture source was from a wound, blood, or source other than sputum
(odds ratio [OR] 2.9, 95% confidence interval [CI] 1.7-5.0, p<0.0001; OR
2.6, 95% CI 1.2-5.7, p = 0.02; and OR 1.2, 95% CI 0.6-2.3, p = 0.69) ( Table
1 ).
Validation of the SCCmec Phenotype Definition
Of the 352 cultures, 35 were recovered from blood and were potentially
available for genetic analysis. We were able to subculture 24 of the blood
isolates. We could not perform SCCmec typing on 1 of the 24 growing
isolates. The 23 remaining isolates were representative of each year of the
6-year period except 1999, when no isolates could be recovered.
Twelve isolates carried the SCCmec type IV element, and 9 also carried the
pvl genes ( Table 2 ). Eleven isolates carried the SCCmec type II element;
none carried pvl. The clinical definition of the SCCmec IV phenotype was
fulfilled by 11 (92%) of the 12 isolates that carried the SCCmec IV element.
The exception was an isolate that contained SCCmec IV that was resistant to
gentamicin, clindamycin, and trimethoprim-sulfamethoxozole. The definition
of the non-SCCmec IV phenotype was fulfilled by 10 (91%) of 11 isolates
carrying the SCCmec II element. Phenotypic case definition of SCCmec type
was highly correlated with the genotype confirmation of the SCCmec type
phenotype (p<0.0001 by Fisher exact test).
Trend and Multivariate Analysis of the SCCmec type IV Phenotype
The proportion of MRSA isolates with the SCCmec type IV phenotype increased
from 17% in 1999 to 56% in 2003 (p<0.0001, Figure 1). The proportion of
isolates that were of the SCCmec type IV phenotype in 2004 (52%) was little
changed from 2003 (Figure 1). In the multivariate model, independent
predictors for having an SCCmec type IV phenotype isolate were wound source
of culture (referent group was sputum source, OR 2.6, 95% CI 1.5-4.6, p =
0.001), culture obtained in less time after admission, (OR 0.88 per week,
95% CI 0.8-0.98, p = 0.02), and year of culture acquisition (p<0.0001) (
Table 1 ).
Figure 1.
Percentage of methicillin-resistant Staphylococcus aureus (MRSA) isolates
among healthcare-associated MRSA isolates that are SCCmec type IV phenotype,
1999-2004.
Discussion
In many urban centers worldwide, infections due to MRSA account for a large
proportion of CA-S. aureus infections; in some communities MRSA accounts for
more than half of CA-S. aureus infections.[6,8-10,32] There have been
reports of strains frequently associated with community outbreaks causing HA
infections, but they have been mostly limited to case reports or case
series.[17-19] To our knowledge, ours is the first investigation quantifying
the rise of MRSA isolates typical of CA disease to become the predominant
strain of HA-MRSA (i.e., accounting for >50% of MRSA strains) within the
hospital setting. Remarkably, at our institution the number of HA-MRSA
isolates that have a CA phenotype, which previously was uncommon, now is
>50%.
Our analysis found 3 significant risk factors for an SCCmec type IV
phenotype MRSA culture. First, patients with MRSA cultures from a wound
source were more likely to have the SCCmec type IV phenotype. This finding
may be understandable, given that the most common clinical syndrome
described with CA-MRSA infections has been skin and soft tissue
infections.[10,33] In addition, 75% of CA-MRSA isolates that were genotyped
carried the pvl gene, which has a strong association with skin and soft
tissue infections.[33] A second risk factor for the SCCmec type IV phenotype
was a shorter length of hospital stay before MRSA culture. This association
may be due to the increased severity of illness and coexisting conditions in
patients with a longer hospital stay, factors that have been commonly
associated with the traditional (non-SCCmec type IV) HA-MRSA infections.
However, measures of severity of illness and coexisting conditions were not
captured in this investigation. A third risk factor was a later year of
culture collection; the likelihood of SCCmec type IV phenotype peaked in
2003. The rise of these isolates in our hospital may be from CA-MRSA
isolates brought in from colonized persons from the community. CA-MRSA
infections in Los Angeles County have rapidly become common and now exceed
the frequency of those caused by CA-methicillin-susceptible S. aureus.[34]
Alternatively, the rise of SCCmec type IV isolates may be a result of spread
throughout our hospital by the usual means of dissemination in a healthcare
setting (e.g., hands of healthcare workers, contaminated environment)[35] or
possibly by a combination of factors.
Exactly why the SCCmec type IV strains are successful in hospital settings
such as ours and others[20] is unknown. Some evidence indicates that SCCmec
type IV strains may be more "fit" than SCCmec types II/III that contain
HA-MRSA isolates. Compared with methicillin-susceptible S. aureus, isolates
containing SCCmec type II/III replicate more slowly in vitro.[36] Okuma et
al. found that CA-MRSA isolates that contain SCCmec type IV replicate more
rapidly than these traditional HA-MRSA strains and argued that CA-MRSA may
have enhanced ecologic fitness compared with SCCmec type II/III isolates,
perhaps due simply to a shorter doubling time.[37] Given the vulnerable
population within the hospital setting, it is unclear how infections with
isolates that contain SCCmec type IV will differ in symptoms and severity
from those caused by traditional HA-MRSA isolates. On the basis of our study
and other somewhat similar reports,[20] concern is rising that USA300
strains may overtake the traditional HA-MRSA strains in many hospital and
healthcare settings.
Our investigation had some limitations. First, the analysis was
retrospective and thus it was not possible to prospectively identify
patients with HA infections and compare them with patients with CA
infections. Although, by means of a chart review of a subset of patients who
were selected by the criteria of a MRSA culture obtained =72 hrs after
admission, none of these infections fulfilled the CDC definition of a
CA-MRSA infection.[31]
A second limitation was that our case definition was based on phenotypic
criteria because nonbloodstream isolates had been discarded and the SCCmec
type could not be validated. Traditionally, most HA-MRSA isolates in the
United States carry SCCmec type II (and to a lesser extent, SCCmec type III)
that encodes resistance to ß-lactam antimicrobial agents bleomycin,
macrolide-lincosamide-streptogamin B, aminoglycosides, and
spectinomycin.[38] Gentamicin resistance occurs in most strains that carry
the SCCmec type II element but is conferred by the aac6´-aph2´´ gene
elsewhere on the chromosome and is frequently carried by transposon
Tn4001.[11,16] Therefore, to select for isolates that did not confer a
phenotype typical of healthcare-associated or non-SCCmec type IV-containing
isolates, the SCCmec type IV phenotype was defined as isolates that were
resistant to oxacillin and susceptible to gentamicin, clindamycin, and
trimethoprim-sulfamethoxazole.
Some banked isolates did not grow, and in 1 isolate we could not detect an
SCCmec element. Of note, stored isolates may lose their SCCmec elements over
time,[39] which may explain our findings. Nevertheless, over the 6-year
observation period of our investigation, among isolates, the phenotype and
genotype definition of SCCmec type were in agreement for >90% of isolates.
Thus, we were able to validate our case definition of an HA-MRSA isolate
with SCCmec type IV phenotype using both chart review and SCCmec typing.
A third limitation of our investigation was that we were able to recover
only bloodstream isolates, a subset of strains that are small and
potentially nonrepresentattive. Whether the relationship of phenotype to
genotype is similar for bloodstream and nonbloodstream infections is
unclear. A fourth limitation is that all of the patients were from 1
institution and, therefore, may only reflect local trends. However, as
previously mentioned, reports of isolates associated with the CA-MRSA
infections causing HA infections are growing.[17-20]
In summary, we found that over a 5-year span, MRSA with a CA-MRSA phenotype
has become the most common cause of HA-MRSA infections in our institution.
This finding has important implications for MRSA epidemiology, infection
control practices, and empiric antimicrobial drug selection.
Findings from this investigation were presented in part at the 45th Annual
International Conference on Antimicrobial Agents and Chemotherapy,
Washington, DC, USA, December 2005.
Table 1. Patients With Healthcare-Associated MRSA Isolates, 1999-2004, and
Predictors of SCCmec Type IV Phenotype*
Characteristic Patients with HA-MRSA, isolates, % (no.) SCCmec phenotype,%
(no.) Predictors of SCCmec type IV phenotype
Type IV Type II/III Bivariate anaylsis Multivariate analysis
Odds ratio
(95% CI) p value Odds ratio
(95% CI) p value
Total (352) 36 (128) 64 (224)
Sex
F 35 (123) 36 (44) 64 (79) 0.87 >0.05
M 65 (229) 37 (84) 63 (145)
Age, y
Mean 50±19 SD 47±1.7 SE 51±1.3 SE 0.02 >0.05
Median (range) 50 (<1-97) 48 (<1-87) 54 (<1-97)
Time from admission to specimen collection, d
Mean 19±21 SD 15±1.9 SE 21±1.4 SE 0.01 0.88 (0.8-0.98)? 0.02
Median (range) 12 (4-184) 8 (4-174) 15 (4-184)
Culture specimen source
Blood 10 (35) 46 (16) 54 (19) 2.6 (1.2-5.7) 0.02 2.2 (0.97-5.0) 0.058
Sputum 34 (188) 25 (29) 75 (89) Reference Reference
Wound 38 (133) 49 (65) 51 (68) 2.9 (1.7-5.0) <0.0001 2.6 (1.5-4.6) 0.001
Other 19 (66) 27 (18) 73 (48) 1.2 (0.6-2.3) 0.69 1.1 (0.5-2.2) 0.82
Year culture specimen collected
1999 52 (15) 17 (9) 83 (43) Reference <0.0001? Reference <0.0001
2000 57 (16) 19 (11) 81 (46) 1.1 (0.4-3.0) NS§
2001 65 (19) 28 (18) 72 (47) 1.8 (0.7-4.5) 1.8 (0.9-3.7)
2002 47 (13) 43 (20) 57 (27) 3.5 (1.4-8.9] 3.2 (1.5-6.9)
2003 63 (18) 56 (35) 44 (28) 6.0 (2.4-14.3) 5.2 (2.5-10.5)
2004 68 (19) 52 (35) 48(33) 5.1 (2.1-12) 4.4 (2.2-8.8)
*MRSA, methicillin-resistant Staphylococcus aureus; HA, healthcare
associated; CI, confidence interval; SD, standard deviation; SE, standard
error; NS, not significant; boldface indicates significance.
?Multivariate analysis results reflect time in weeks.
?Measured with the Cochran-Armitage test of trends.
§Was not a significant predictor in the multivariate model.
Table 2. Summary of Genetic Testing for 24 Healthcare-Associated MRSA Blood
Isolates*?
No. isolates SCCmec mecI mecR1(PB) pvl MLST Clindamycin Gentamicin TMP-SMX
SCCmec type phenotype?
8 IV - - + 8 S S S IV
1 IV - - + 1 S S S IV
2 IV - - - 8 S S S IV
1* IV - - - 8 R R R II
5 II + + - 5 R R S II
4 II + + - 5 R S S II
1 II + + - 8 R S S II
1§ II + + - 5 S S S IV
1¶ - - - - 5 R S S II
*MRSA, methicillin-resistant Staphylococcus aureus; PB, penicillin-binding
region; MLST, multilocus sequence typing; R, resistant; S, susceptible;
TMP-SMX, trimethoprim-sulfamethoxazole.
?All isolates were associated with mecA and ccr2 genes.
?Phenotype: as defined by the study case definition, according to
antimicrobial drug susceptibilities (see Methods).
§SCCmec phenotype did not match genotype.
¶SCCmec was not located for this isolate.
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Reprint Address
Loren G. Miller, Harbor-UCLA Medical Center, Division of Infectious Disease,
1000 W Carson St, Box 466, Torrance, CA 90509, USA: Email: lgmiller@ucla.edu
.
Cynthia L. Maree,* Robert S. Daum,? Susan Boyle-Vavra,? Kelli Matayoshi,?,1
Loren G. Miller*?
*David Geffen School of Medicine at the University of California, Los
Angeles, California
?University of Chicago, Chicago, Illinois
?Los Angeles Biomedical Institute at Harbor-UCLA Medical Center, Torrance,
California
1Current affiliation: University of Southern California School of Pharmacy,
Los Angeles, California
Disclosure: C.L.M. reports having received grant support from Pfizer
Pharmaceuticals. L.G.M. reports having received lecture and consulting fees
from Pfizer Pharmaceuticals. C.L.M.'s effort was supported by a grant from
the National Institute of Allergy and Infectious Diseases (NIAID) (T32
AI07481-09). R.S.D.'s and S.B.V's efforts were supported by a grant from
NIAID (AI40481-01A1), the Centers for Disease Control and Prevention (CDC)
(RO1 CCR523379), and the Grant Health Care Foundation. L.G.M.'s effort was
supported by grants from CDC (RO1/CCR923419) and the National Institutes of
Health (K23AI0183).
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