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Community-associated methicillin-resistant Staphylococcus aureus

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Article  in  British Medical Bulletin · April 2010

DOI: 10.1093/bmb/ldq010 · Source: PubMed

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Published Online April 1, 2010

Community-associated methicillin-resistant
Staphylococcus aureus infections

Fiona J. Cooke †‡ and Nicholas M. Brown †*

†
Clinical Microbiology and Public Health Laboratory, Health Protection Agency, Addenbrooke’s
Hospital, Hills Road, Cambridge CB2 0QW, UK, and ‡Wellcome Trust Genome Campus, Hinxton,
The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA)

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has been recognized for over a decade, and usually refers to MRSA identified in
previously healthy individuals with no recognized MRSA risk factors. Infections
range from minor skin and soft tissue infections, through to severe pneumonia
and necrotizing fasciitis. This review summarizes the current data on the
epidemiology and molecular features of CA-MRSA, in addition to diagnosis and
therapeutic measures. We also refer to current national guidelines for the
management of these infections. Areas of agreement include the important
genotypic and phenotypic differences of community MRSA strains compared
with hospital strains. Areas of controversy include the precise epidemiological
definition of community-acquired/associated MRSA. Fortunately, true CA-MRSA
can be differentiated from hospital MRSA by molecular techniques, as discussed
herein. Recent interest has focused on the changing epidemiology of CA-MRSA.
Worldwide, CA-MRSA is now seen outside of the initial specific population
groups, and in the USA, the successful USA300 community strain is beginning to
spread back into hospitals. Reasons why USA300 remains relatively uncommon in
Europe are unclear. Topics timely for research include the investigation of the
epidemiology of infections and evolutionary genomics.

Keywords: community/MRSA/methicillin resistance/Staphylococcus aureus/

skin and soft tissue infections/necrotizing pneumonia, review/staphylococcus
chromosomal cassette/genomics

Introduction
Accepted: March 6, 2010
*Correspondence address. Community-associated methicillin-resistant Staphylococcus aureus
Clinical Microbiology and
Public Health Laboratory,
(CA-MRSA) was first recognized in the mid-1990s.1 The term was
Health Protection originally defined epidemiologically, and referred to strains of MRSA
Agency, Addenbrooke’s seen in patients presenting with infections in the community or present-
Hospital, Hills Road,
ing to hospital departments for the first time. Thus patients who had
Cambridge CB2 0QW, UK.
E-mail: nicholas.brown@ previously been admitted to hospital, or who were receiving prolonged
addenbrookes.nhs.uk antibiotic treatment, or who were resident in a care-home or healthcare

British Medical Bulletin 2010; 94: 215–227 & The Author 2010. Published by Oxford University Press. All rights reserved.
DOI:10.1093/bmb/ldq010 For permissions, please e-mail: journals.permissions@oxfordjournals.org
F. J. Cooke and N. M. Brown

facility, or had regular contact with hospitals (e.g. dialysis patients)/

healthcare workers were excluded.2 Indeed, some authors choose to
distinguish between hospital-acquired MRSA, healthcare-associated
MRSA and CA-MRSA, which is often helpful. The US Centre for
Disease Control and Prevention has published criteria to distinguish
CA-MRSA from healthcare-associated MRSA,3 and tight definitions of
various subgroups of CA-MRSA have been proposed.4
The initial reports of CA-MRSA infection tended to come from
specific patient groups, such as military recruits, sports teams and indi-
viduals living in close communities or involved in activities resulting in
skin abrasions.5 Some of the first countries to report community strains
were Australia, New Zealand, USA, UK, France, Finland and Canada.
However, in 1997, there were reports of four fatal cases in children

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from Minnesota and ND, USA, who did not fall into any recognized
risk groups.6 It also transpired that CA-MRSA strains were somehow
different from hospital strains, not just in terms of the epidemiology
and nature of infection, but also at a molecular level. The distinct
characteristics of CA-MRSA when compared with hospital MRSA, in
terms of clinical presentation, antibiotic susceptibility and molecular
characteristics including the expression of virulence factors such as the
Panton-Valentine leukocidin (PVL) toxin, are summarized in Table 1
and will also be discussed below.

Epidemiology of CA-MRSA
The epidemiology of CA-MRSA is changing. Initial clusters occurred in
sports participants, the military and prisoners, and there were out-
breaks amongst children and adults living in close communities. Other
high-risk groups were identified including men who have sex with
men,7 the district nurse population,8 injecting drug users9,10 and the
homeless.11 Of concern, CA-MRSA is now increasingly recognized
outside these patient groups, and the epidemiologic characteristics of
patients with CA-MRSA infections are becoming more similar to
patients with community-associated methicillin-susceptible S. aureus
(MSSA) infections.12 In addition, several studies have suggested that
CA-MRSA strains may be encroaching on nosocomial settings, and are
causing infections with onset .72 h after admission to hospital.13,14
Of concern, a deterministic mathematical model has predicted that, in
the USA, CA-MRSA will become the dominant MRSA strain in hospi-
tals and healthcare facilities, as a result of the expanding community
reservoir of CA-MRSA and increasing admission to hospital of individ-
uals with CA-MRSA.15 The model also predicts that increased severity
of CA-MRSA (particularly PVL-positive strains) will lead to increased

216 British Medical Bulletin 2010;94

 Community MRSA

Table 1 Hospital versus community-associated MRSA.

Hospital MRSA Community MRSA

Typical patients Elderly patients, often debilitated Previously healthy people, often younger
Patients with chronic disease, e.g. Those involved in close contact activities,
diabetic skin ulcers e.g. sports teams or military service,
especially those resulting in skin
abrasions
Intensive care unit patients
Renal patients with indwelling lines
Clinical Device associated Tend to be more aggressive skin and
infections soft tissue
Wound infections Necrotizing pneumonia
Respiratory and urinary tracts Septic shock and bacteraemia in
more severe cases
Risk factors Indwelling devices, lines, prolonged Close physical contact, poor hygiene,

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hospitalization, long-term antibiotics shared sanitary facilities, crowded living
conditions (e.g. military recruits, prisons)
Transmission Nosocomial Predominately community acquired
Little spread among household Spreads within families and sports teams
contacts
Antibiotic Typical UK clones (EMRSA 15 and 16) Generally more susceptible to
susceptibility resistant to erythromycin, ciprofloxacin, non-beta-lactam agents, including
with or without aminoglycosides, ciprofloxacin
clindamycin, tetracycline, rifampicin,
fusidic acid.
Molecular SCCmec types I, II or III (except Mainly SCCmec type IV or V
characteristics EMRSA-15 in the UK, which has
SCCmec type IV)
PVL less common PVL more common

length of hospital stay and a larger nosocomial reservoir of CA-MRSA.

This will undoubtedly make control of MRSA infections in hospitals
an increasing challenge.
In the USA, two clones of CA-MRSA (USA300 and USA400) have
caused particularly aggressive infections over a wide geographical
area.16 These both harbour the PVL toxin genes (see below). A study
in 2006 found that MRSA was the most commonly identifiable cause
of the acute skin and soft tissue infections in adults presenting to
university-affiliated emergency departments in the USA, and USA300
accounted for 97% of all MRSA isolates.17 The origins and epidemiol-
ogy of USA300 have been comprehensively reviewed.18 These
American clones are not yet common in the UK or elsewhere in
Europe, reasons for which are unclear.19

Prevalence—how common are these strains?

The prevalence of nasal carriage of S. aureus in the community in the
USA has been studied as part of the National Health and Nutrition

British Medical Bulletin 2010;94 217

F. J. Cooke and N. M. Brown

Examination Survey.20 Nasal swabs were obtained from 9622 individuals

selected to be representative of the general US population for a variety
of social and demographic characteristics. Overall, 0.8% (95% CI:
0.4– 1.4%) were found to be colonized with MRSA. The carriage rate
for any S. aureus was 32.4% (95% CI: 30.7 –34.1%). Multivariate
analysis showed that the carriage of MRSA was associated with age
over 60 years and female gender, but was not associated with hospital
contact, as defined as an overnight stay in the previous 12 months. The
MRSA isolates were subject to further characterization. Two
Staphylococcus chromosome cassette (SCCmec) types were identified
(see below and Fig. 1), with approximately half of the isolates carrying
SCCmec type II and half SCCmec type IV. The presence of SCCmec
type varied with age of the individual. SCCmec type IV was associated

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with those in younger age groups, whereas the opposite was true for
SCCmec type II. Strains carrying SCCmec type IV were less likely to be
multiply antibiotic resistant, but were more likely to carry PVL or
enterotoxin B genes. There were also some ethnic differences in car-
riage rates. These characteristics are typical of those described for
CA-MRSA strains. However, the overall prevalence of PVL genes was
very low [6 of 75 (8%) MRSA strains and 9 of 372 (2.4%) total
S. aureus strains tested]. Also, pulsed-field gel electrophoresis (PFGE)
showed that only 6 of the 75 (8%) MRSA isolates belonged to the
MRSA300 lineage and therefore the carriage of specific clonal types
associated with severe infection in reported outbreaks was low. This
suggests that, at the time of this survey in 2001– 2002, these virulent
CA-MRSA strains were restricted to localized groups of younger indi-
viduals in specific social settings (sports teams, military recruits,
prisons, etc.) and were not widely prevalent in the general population.

Fig. 1 Comparison of the SCCmec typical of hospital and CA-MRSA. The legend helps
explain why SCCmecII (A) encodes resistance to multiple antibiotics, whereas SCCmecIV
encodes resistance to methicillin alone. Adapted from Nat Rev Microbiol 2009; 7:629– 412.
Orf X (open reading frame): SCCmec cassettes integrate into the integration site sequence
(ISS), which is located at the 30 end of orfX ccr: The Cassette chromosome recombinase (ccr)
gene complex is composed of one or two site-specific recombinase genes, (responsible for
the mobility of SCCmec), and surrounding orfs of unknown function. Tn554: this transpo-
son is present in SCCmecII but not SCCmecIV, and encodes resistance to the MLSB
(macrolide-lincosamide-streptogramin) antibiotics and spectinomycin. mec: This encodes
methicillin resistance, and is full length in SCCmecII but truncated in SCCmecIV. IS431: inser-
tion sequence 431 harbours an integrated plasmid pUB110 in SCCmecII, which encodes a
tobramycin resistance gene. This plasmid is not present in SCCmecIV.

218 British Medical Bulletin 2010;94

 Community MRSA

We are not aware of similar data for the general community

population in the UK, although there are MRSA prevalence data for
specific groups of, mainly elderly, people. A retrospective case – control
study performed using the UK General Practice Research Database
between 2000 and 2004 assessed the community acquisition of MRSA
in a population who had no hospital admission in the previous 2
years.21 The average incidence of MRSA acquisition was 15.2 cases per
100 000 population per year, which over the period of the study gives
a similar prevalence (0.7%) to that seen in the USA. However, individ-
uals ,18 years were excluded from the study and therefore there is no
information from an age group of particular interest in this setting.
Also, cases were identified retrospectively from clinical coding infor-
mation and therefore no MRSA isolates were available for laboratory

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characterization. Current estimates of prevalence of CA-MRSA in the
UK general population lie between ,0.1 and 1.5%.22,23

Clinical presentation
Staphylococcus aureus normally causes a spectrum of infections
ranging from common, mild skin and soft tissue infections to severe
haematogenous infection with multi-organ involvement. Outbreak
reports of CA-MRSA infection in specific groups have suggested that
these strains are more aggressive than has been seen previously with
S. aureus outside hospital. Severe skin and soft tissue infections
( perhaps starting with a ‘spider bite’ lesion), large and/or recurrent
abscesses, necrotizing pneumonia or bone and joint infections have
been typical. The presence of PVL and other toxin production is an
important element to this, although it should be recognized that these
toxins are not restricted to MRSA and are seen in MSSA too.
However, these outbreak reports may not necessarily be representative
of the spectrum of CA-MRSA infection seen more generally.
The prevalence, natural history and clinical impact of CA-MRSA
colonization were assessed in a population of 812 US Army soldiers.24
Nasal swabs were taken on recruitment and 8 –10 weeks later and the
soldiers were observed prospectively for evidence of infection.
CA-MRSA was defined as a strain with an antibiotic susceptibility
profile and molecular PFGE profile different from the prevailing hospi-
tal MRSA strains in an individual with no contact with hospital or
other risk factor for colonization with a hospital MRSA strain. At
the time of recruitment, the CA-MRSA colonization rate was 3%.
A further 28% of soldiers were colonized with MSSA. Nine of the 24
(38%) with CA-MRSA colonization developed skin and soft tissue
infection, compared with only 8 of 229 (3%) with MSSA and 12 of

British Medical Bulletin 2010;94 219

F. J. Cooke and N. M. Brown

559 (2%) soldiers not colonized with either. Eight of the 9 soldiers
with CA-MRSA infection had a PVL-positive CA-MRSA strain.
From a study using a combination of population-based surveillance
in Atlanta and Baltimore and laboratory-based surveillance in
Minnesota, 1647 cases of CA-MRSA infection were identified.25
Again, cases were ascribed to the community if there were no estab-
lished risk factors for hospital acquisition. The incidence of CA-MRSA
infection was highest in children ,2 years. Abscesses, cellulitis or
other skin and soft tissue infections were most common (77% infec-
tions), whereas 6% infections were invasive (bacteraemia, meningitis,
or bone and joint infection). Pneumonia was present in 2%. As an indi-
cator of severity, 22% of the patients required hospital admission as a
direct result of the infection.

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The distribution of CA-MRSA infection is different from that seen
with typical hospital MRSA strains. Naimi et al. (2003) compared the
epidemiology of 131 CA-MRSA infections with 937 healthcare associ-
ated MRSA infections.26 The CA-MRSA infections occurred in a sig-
nificantly younger age group (median 23 years versus 68 years) and
were more likely to affect skin and soft tissue compared with hospital
MRSA infections. They were less likely to affect the chest or urinary
tract.
However, this situation is rapidly becoming more complex. Infection
with hospital strains of MRSA occurring in patients in the community
has been recognized for some time. Many of these patients have risk
factors for these infections, which often include recent contact with
hospital or other healthcare services. Hence, the designation of these as
‘healthcare-associated’ infections. Now, community strains of MRSA
are appearing in hospitals. As part of ongoing surveillance of invasive
MRSA infections in 9 US states, 100 MRSA isolates from both commu-
nity and hospital settings were characterized using PFGE.16
Hospital-acquired MRSA strains were predominately USA100, but
28% were USA300, previously considered the archetypal community
strain in the USA. As noted above, several nosocomial outbreaks of
CA-MRSA have now been described worldwide27 and CA-MRSA
strains are now an important cause of MRSA bacteramia in some US
hospitals.14

Molecular typing of MRSA

Of the multiple techniques that exist for molecular typing of S. aureus,
the commonly used ones are toxin gene profiling, antimicrobial resist-
ance typing, accessory gene regulator (agr) typing, PFGE, multilocus
sequence typing (MLST), multilocus restriction fragment typing,

220 British Medical Bulletin 2010;94

 Community MRSA

staphylococcal protein A gene typing (spa typing), amplified fragment

length polymorphism analysis and genotyping (e.g. of the SCCmec
element). MLST has proved particularly useful in elucidating the evol-
utionary origin of clones, and has demonstrated considerable global
variation in predominant genetic background types among CA-MRSA
strains. For example, most cases in the USA belong to clonal complex 8
(CC8), and are designated sequence type 8 (USA300:ST8) and ST1
(USA400:ST1). In Europe ST80 strains predominate28 whereas in
Australia ST93 strains are common. Some continent-specific clones
described in the early 2000s, such as clone ST8, have now spread all
over the world.28 There are also specific clones circulating in certain
populations, e.g. clone ST1-SCCmec type IV (see below), which has a
broad range of bacteriophage and usually harbours genes for entero-

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toxins A and H (sea; seh) but does not encode the PVL toxin, is circu-
lating amongst the IDU population in England and Wales.29 This is
truly a dynamic process, with new clones constantly emerging (e.g.
ST377) on new genetic backgrounds. For a more detailed description
of the molecular epidemiology of the epidemic waves of CA-MRSA,
see the review by Chambers and DeLeo.2

Genetics of CA-MRSA
Methicillin resistance arises due to acquisition of the mecA gene encod-
ing the altered penicillin-binding protein PBP2’, which has reduced affi-
nity for beta-lactam antibiotics. On the chromosome, mecA is situated
within the Staphylococcal chromosome cassette (SCCmec). This mobile
genetic element also contains regulatory genes, the insertion sequence
IS431mec and cassette chromosome recombinase (ccr) genes, which
carry out integration and excision of SCCmec (Fig. 1). Most strains of
community MRSA harbour SCCmec types IV, V or VII, while most
hospital MRSA harbours SCCmec types II and III, although one major
exception is the dominant UK hospital-associated clone EMRSA-15,
which harbours SCCmec type IV. SCCmec type IV is smaller than the
other types, partly because it contains fewer antibiotic resistant deter-
minants. The small size may enable horizontal transfer of SCCmec IV
among a bacterial population.1 Subtyping of SCCmec is based on
sequencing the region upstream of the ccr genes, known as L-C, and
the epidemic USA300 and USA400 clones harbor SCCmec subtype
IVa.
Whole genome sequencing of two isolates of CA-MRSA is available:
MW2 (which caused fatal septicaemia and septic arthritis in a
16-month-old girl in the USA in 1998),30 and FPR3757 (a multidrug
resistant USA 300 strain)31 (www.genomesonline.org). Comparative

British Medical Bulletin 2010;94 221

F. J. Cooke and N. M. Brown

genomics with strains of MSSA and hospital-acquired MRSA has

enabled exploration of possible mechanisms of evolution, and ident-
ified regions affecting virulence and drug resistance. For example, the
MW2 chromosome contains a number of additional virulence genes
compared with MSSA, mainly within horizontally acquired genomic
islands. Comparison with community strain MSSA476, which caused
severe invasive disease in an immunocompetent child in the UK,32
points towards the acquisition of SCCmec IV by MSSA strains in the
community as the main event in the emergence of community
MRSA.33

PVL toxin and other virulence factors

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There are strong epidemiological associations between PVL and highly
transmissible, virulent, strains of CA-MRSA and other S. aureus and
this is particularly true for cases of necrotizing pneumonia presenting
from the community. However, overall, less than 2% of all S. aureus
(MRSA and MSSA) submitted to the HPA reference laboratory
harbour the genes encoding for PVL (http://www.hpa.org.uk). There
has been some debate recently concerning its significance as a virulence
factor in skin and soft tissue infections, and various alternative patho-
genicity factors (e.g. arginine catabolism mobile element (ACME),
a-toxin, regulation of gene expression, newly described cytolytic pep-
tides) have been proposed.

Diagnosis
In addition to clinical presentation and lack of traditional risk factors,
an antibiogram demonstrating susceptibility to ciprofloxacin sparks
initial suspicion of CA-MRSA in diagnostic laboratories. However,
ciprofloxacin susceptibility cannot be used as a definitive marker, as
work by the HPA staphylococcal reference unit has demonstrated that
the sensitivity and specificity of this finding as a maker of CA-MRSA
was 97 and 84%, respectively (http://www.hpa.org.uk). The clinical
and molecular epidemiology of PVL-encoding ciprofloxacin-susceptible
MRSA in England and Wales has been recently summarized.34 Of
interest, specific lineages of CA-MRSA (sequence types ST8 and ST80)
can be ciprofloxacin resistant, and ST5 lineages tend to be ciprofloxa-
cin susceptible, whether hospital or community acquired.
As could be predicted from the evolving molecular epidemiology of
CA-MRSA, these strains have also been able to acquire a variety of
antibiotic resistance determinants. CA-MRSA has been considered

222 British Medical Bulletin 2010;94

 Community MRSA

generally to be more susceptible to various classes of antibiotic, apart

from the beta-lactam agents, whereas hospital MRSA strains are often
multiply resistant. This situation is rapidly becoming more varied. For
example, a clone of USA300 has been described in the male homosex-
ual population in San Francisco, which is characterized by carriage of
a conjugative plasmid conferring multiple antibiotic resistance desig-
nated as pUSA03.7 Ellington et al.35 have also recently described poly-
clonal multiple antibiotic resistance in strains of PVL-producing MRSA
referred to the HPA staphylococcal reference unit, including the emer-
gence in the UK of ST772, which often had links to India or
Bangladesh (designated the Bengal Bay strain).

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Management/treatment
UK guidelines for the management of MRSA infections presenting in
the community have been published recently by the British Society for
Antimicrobial Chemotherapy (BSAC).36 These complement recent gui-
dance for management of PVL-associated S. aureus infection from the
Health Protection Agency (http://www.hpa.org.uk/web/HPAwebFile/
HPAweb_C/1218699411960) and BSAC guidelines for the prophylaxis
and treatment of MRSA.37 A comprehensive review of the guidelines is
outside the scope of this article, but a number of key principles are
stated. Although CA-MRSA reports often stress the severity of infection
in some individuals, most infections are mild skin and soft tissues infec-
tions and can be managed in the community in the same way as infec-
tions due to other S. aureus strains. Mild infection and small abscesses
(,5 cm) may not require systemic antibiotic therapy, but incision and
drainage of abscesses is important. At present, CA-MRSA is uncom-
mon in the UK, but it is important that clinicians are aware of factors
that would make it more likely (Box 1). In such cases, appropriate
samples should be taken for culture and for susceptibility testing to
guide antimicrobial therapy. Where this is required, options for oral
empirical treatment in the community include doxycycline (not in chil-
dren), rifampicin, fusidic acid and trimethoprim (either alone or as
co-trimoxazole). Rifampicin and fusidic acid cannot be given alone,
but combinations of rifampicin with one of the other agents have been
recommended.36 If susceptibility is confirmed, erythromycin, clarithro-
mycin or clindamycin would be alternative options. It should be noted
that tetracyclines and trimethoprim are not optimal choices for empiri-
cal treatment of Group A streptococcal infection and that cover for this
organism should be considered initially (Table 2).

British Medical Bulletin 2010;94 223

F. J. Cooke and N. M. Brown

Box 1 Factors increasing likelihood of CA-MRSA, rather than hos-

pital MRSA.

The presence of a ‘spider bite’-like red, painful papule with a

black necrotic centre in a geographical location where spider bites
are uncommon.
Severe skin and soft tissue infection (carbuncles, furuncles, other
abscesses) in a young person.
Recurrent skin and soft tissue infection or clusters of infection in
households or social groups.
Poor response to treatment with a beta-lactam antibiotic.
History of exposure to multiple courses of antibiotic in the recent

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past, especially quinolones or macrolides.
Severe pneumonia in a young person accompanied by haemoptysis
and hypotension.
Recent travel to the USA or other area where CA-MRSA strains
are more common.

Table 2 Antibiotic options for treatment of CA-MRSA.

Oral Intravenous

Empirical therapy
Doxycycline (not in children) Vancomycin
Rifampicin* Teicoplanin
Fusidic acid* Daptomycin (not for pneumonia)
Trimethoprim Linezolid
Definitive therapy, i.e. susceptibility is confirmed
Erythromycin Combinations of above antibiotics with another
agent, such as rifampicin, should be considered
in critically ill patient.
Clarithromycin
Clindamycin

*Rifampicin and fusidic acid cannot be given alone, but combinations of rifampicin with one of the
other agents have been recommended.36

In the hospital setting, where intravenous therapy is required, vanco-

mycin, teicoplanin, daptomycin (not for pneumonia) or linezolid are
options. For severely ill patients, particularly those with necrotizing
pneumonia, combinations of antibiotics have been proposed, usually
including rifampicin. In addition, linezolid and high-dose clindamycin
have proposed as a combination, because they suppress the production
of PVL and other toxins. Clearly, in severe infections there are limited
trial data to support the use of one regimen over another and rec-
ommendations are largely based on expert advice. In addition, the use

224 British Medical Bulletin 2010;94

 Community MRSA

of adjunctive therapy, such as intravenous immunoglobulin, has been

successful in some case reports, but its contribution is currently
uncertain.

Summary
CA-MRSA has appeared, diversified and spread throughout different
population groups in a relatively short period. This illustrates the
dynamic and highly adaptable nature of the organism, and suggests
that the epidemiology and molecular nature of this infection is likely to
continue to evolve. While it remains relatively uncommon in the UK as

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compared with the USA, clinicians should be alert to potential risk
factors of infection with community rather than hospital MRSA, as
this can have significant prognostic and treatment implications.

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