Download Methicillin-resistant Staphylococcus aureus (MRSA): focus on

Review: Methicillin-resistant Staphylococcus aureus (MRSA)
Methicillin-resistant Staphylococcus aureus (MRSA):
focus on community-associated MRSA
Thomas M File
TM File, Infectious Disease Section, Northeastern Ohio Universities College of Medicine,
Rootstown, OH; and Summa Health System, Akron, OH.
Correspondence to: TM File, 75 Arch St. Suite 105, Akron, OH 44304, USA
Email: [email protected]
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections are defined as occurring in patients
who have no association with the healthcare setting. CA-MRSA has emerged as a common cause of community infections in the
US and are distinct from MRSA strains classically associated with healthcare-associated infections from genotypic and phenotypic
perspectives. They are frequently susceptible to non-beta-lactam antimicrobials, express the SCCmec type IV or V gene and contain
the Panton-Valentine leukocidin virulence factor. They most commonly cause mild skin infections, but have been associated with
severe soft tissue infection and with necrotising pneumonia.
South Afr J Epidemiol Infect 2008;23(2):13-15
Introduction
CA-MRSA is the predominant cause of community-associated skin and
soft tissue infection regardless of the presence of such ‘risk’ factors.
In the past several years there has been a dramatic increase in the
prevalence of methicillin-resistant Staphylococcus aureus (MRSA) as a
cause of community-associated infections in otherwise healthy individuals
(community-associated MRSA, CA-MRSA) in the United States. In most
communities CA-MRSA is now the predominant cause of skin and soft
tissue infection. The CA-MRSA strain is also being recognised as a
cause of community-acquired pneumonia. This article will briefly review
the epidemiology, genotypic and phenotypic characteristics, clinical
manifestations, and approaches to therapy of this important pathogen.
Definition of CA-MRSA
A survey of available literature quickly reveals the lack of a universally
used classification system to define CA-MRSA. Related terms (eg.
community-acquired; community-onset) are often used interchangeably,
and different authors use varying degrees of specificity when describing
‘community’. The currently used system for the classification of MRSA
infections is listed in Table 1.
MRSA history
Table 1: Definitions for Staphylococcus aureus infections
Classification
Methicillin-resistant strains of S. aureus were first described in the early
1960s, shortly after the introduction of semi-synthetic penicillins. The
subsequent emergence of MRSA has historically been associated with
the healthcare setting and this pathogen is now a common cause of
nosocomial infections generally resistant to multiple antimicrobial drugs.
In fact, more than half of the infections caused by S. aureus in intensive
care units and more than 40% of S. aureus infections outside of intensive
care units in US hospitals are now attributable to MRSA, which causes a
variety of bloodstream, respiratory/urinary tract, and skin and soft tissue
infections.1
Community-onset
Cases with at least one of the following
healthcare risk factors: presence of an
invasive device at time of admission; history
of MRSA infection or colonisation; history of
surgery, hospitalisation, dialysis, or residence
in a long-term facility in previous 12 months
Hospital-onset
Cases with positive culture obtained
48 hours after admission to the hospital
Community-associated
Outside of the healthcare setting, MRSA infections have increasingly been
reported in the past decade in otherwise healthy, community-dwelling
individuals without healthcare-associated risk factors for disease
acquisition.2 Incidence of so-called community-associated or -acquired
(CA) MRSA infections was first reported in the early 1980s and has
since been on the rise.3 Outbreaks have been reported in several welldefined and characteristically ‘closed’ populations, including Alaskan
natives, American Indians, children, participants in team sports, military
personnel and correctional facility inmates. Crowded living conditions
and poor hygiene are additional risk factors. Presently, however,
South Afr J Epidemiol Infect
Definition
Healthcare-associated
Cases with no documented communityonset risk factors
Primary factors currently utilised in the categorisation of MRSA infections
are time of infection isolation and the genotypic/phenotypic characteristic
of the resistance patterns. Generally, MRSA infections isolated after
48-72 hours of admission to a healthcare facility, or those present at time
of admission in recently discharged patients or residents of long-term
care facilities are interchangeably referred to as ‘nosocomial’, ‘hospitalacquired’, ‘hospital-associated’, or ‘healthcare-associated’ (HA). Terms
used to describe cases of infection not involving a traditional healthcare
setting include ‘community-acquired’, ‘-associated’, and ‘-onset’. Of
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2008;23(2)
Review: Methicillin-resistant Staphylococcus aureus (MRSA)
among adults presenting to one of 11 emergency departments across
the US during August 2004. The USA strain accounted for 97% of the
isolates that were typed.7
these, ‘community-onset’ is generally used to refer to infections that
begin outside of the healthcare setting (regardless of the presence
of risk factors for MRSA), while infections occurring in a community
setting in the absence of risk factors for MRSA are considered by some
to represent cases of ‘true’ community-associated (CA) MRSA. Current
criteria set forth by the Centers for Disease Control and Prevention (CDC)
for distinguishing CA- from HA-MRSA include: 1) Diagnosis of MRSA
made in the outpatient setting or a positive culture for MRSA within
48 hours after admission to the hospital; 2) No medical history of MRSA
infection or colonisation; 3) No medical history in the preceding year of
dialysis, surgery, hospitalisation, or admission to a nursing home, skilled
nursing facility, or hospice, and 4) No permanent indwelling catheters or
medical devices that pass through the skin into the body.4
In 2004, 87 patients (10%) in a daptomycin skin infection trial were
MRSA-positive whereas in 2006, 579 patients (54%) in a telavancin trial
were MRSA-positive.8,9 These numbers underscore the increase in MRSApositive patients that are being enrolled for trials in skin infection. Since
these were controlled studies with several exclusionary criteria which
may be risk factors for CA-MRSA, it is reasonable to conclude that in nonstudy settings the rates of MRSA are higher than this. At our hospital, the
prevalence of CA-MRSA as a cause of community-onset skin infections is
approximately 70% (personal communication, T File, November 2007).
The distinction between CA-MRSA and HA-MRSA has become somewhat
blurred in the last few years as strains associated with the community
setting have been introduced into hospitals, resulting in nosocomial
infections and, in some cases, displacement of HA strains. In some
hospitals in the US, the predominant strain as a cause of nosocomial
infection is the CA-MRSA strain.
Community-acquired strains of MRSA are distinct from HA-MRSA
from genotypic, phenotypic, and epidemiological perspectives.3-5
Strains of CA-MRSA are more frequently susceptible to a variety of
non-β-lactam antimicrobials. Although a small percentage contains
SCC (staphylococcal chromosomal cassette) mec type V, these strains
predominantly carry SCCmec type IV, which is smaller in size than the
gene cassette found in most HA strains (type I-III). This observed SCC
size differential may allow for more efficient transfer of resistance among
different bacteria, a factor which may be relevant in the alarmingly rapid
emergence of CA-MRSA. The potential of CA strains to cause serious
illness is further emphasised by their production of a relatively greater
number of recognised staphylococcal virulence factors when compared
to HA-MRSA. Most notably, CA strains frequently carry the PantonValentine leukocidin genes which produce cytotoxins associated with
tissue necrosis and leucocyte destruction. Based on pulsed-field gel
electrophoresis (PFGE), almost all the CA-MRSA strains are from a single
clone: the USA 300 clone. These, and additional characteristics of both
MRSA types, are summarised in Table 2.
Clinical manifestations
Presently, the spectrum of disease caused by CA-MRSA is different in
distribution and pattern of infection than HA strains. Patients infected
with CA-MRSA tend to be significantly younger than those infected with
traditional strains of MRSA.10 Unlike traditional MRSA infections which
are often isolated from the bloodstream and the respiratory and urinary
tracts, CA-MRSA infections are typically found on skin and in soft tissue
and occur in settings involving crowding, contact, and compromised
hygiene. The great majority of skin infections due to CA-MRSA are mild
pustules and do not require hospitalisation; however, reports of severe
infection, such as necrotising fasciitis have been reported. Of interest,
because skin infections due to CA-MRSA often have a necrotic centre
(probably related to the effect of the Panton-Valentine leukocidin),
many infections have been mistaken for ‘spider bites’. In a populationbased surveillance study in Maryland, Georgia and Minnesota, of
1,647 patients with CA-MRSA, 77% had skin or soft-tissue infections,
10% had wound infections, 5% had respiratory tract infections
(3% sinusitis, 2% pneumonia), and 4% had urinary tract infections.11
In a study that compared CA-MRSA and HA-MRSA infections in
Minnesota, Naimi et al observed that hospital MRSA was associated
with the following infections: skin and soft tissue 36%, respiratory 22%,
UTI 20%, blood stream 9%, others 13%, whereas community MRSA was
associated with: skin and soft tissue 74%, otitis media 7%, respiratory
6%, blood stream 4%, others 9%.12
Epidemiology
The increase in prevalence of CA-MRSA has particularly occurred since
2000. In one study from an emergency department in Oakland, California
and conducted from October 2003 until February 2004, 137 patients with
skin and soft tissue infection were evaluated for CA-MRSA.6 Cultures of
nares and of the skin infection sites were obtained. Of 119 infection-site
cultures, 79 (66.4%) grew S. aureus of which 61 (77%) were MRSA.
Seventy six percent of the cases met the clinical definition of CA-MRSA
and 99% of the strains of MRSA were positive for the SCCmec IV gene
and 94% were positive for the Panton-Valentine leukocidin. A more
recent study found that MRSA was the cause of 59% of skin abscesses
Table 2: Characteristics and comparison of microbial properties between healthcare-associated and community-acquired strains of MRSA
Strain
SCCmec gene
Antibiotic resistance
PFGE type
Toxins
PVL genes
Infection spectrum
HA-MRSA
Type I
Type II
Type III
Multidrug-resistant
USA 100
Fewer
Rare
Bloodstream, respiratory tract, urinary tract
CA-MRSA
Type IV
Type V
Resistance typically limited to β-lactams
and erythromycin, although multidrug
resistance can occur
USA 300
More
Common
Commonly:
Skin & soft tissue
Occasionally:
Necrotising fasciitis, necrotising pneumonia
CA-MRSA, community-acquired methicillin-resistant S. aureus
HA-MRSA, healthcare-associated methicillin-resistant S. aureus
SCCmec, staphylococcal cassette chromosome mec
PFGE, pulsed-field gel electrophoresis
PVL, Panton-Valentine leukocidin
South Afr J Epidemiol Infect
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Review: Methicillin-resistant Staphylococcus aureus (MRSA)
CA-MRSA is also being recognised as a cause of community-acquired
pneumonia (CAP). However, at present, pneumonia due to these strains
is uncommon, but is important to recognise because of potentially
serious consequences, which include necrotising pneumonia, shock,
and respiratory failure, as well as formation of abscess and empyema.13
Most of the reported cases have occurred during the winter season and
have been associated with preceding influenza. A CDC study reported
17 patients with CAP due to MRSA. Fifteen of these patients were
due to CA-MRSA.14 The average age of all cases was 20.6 years and
47% were male. Five patients had an underlying co-morbid disease.
Several of the patients were suspected of having preceding influenza
and only one had documented evidence of prior influenza vaccination.
The overall mortality rate of these patients was 29%. Twelve of the
patients presented with very severe CAP and required admission to an
intensive care unit, illustrating the severe nature of these infections.
In an additional retrospective study conducted from 59 US hospitals
during 2002-2003, MRSA was identified as the aetiology in 8.9% of CAP,
26.5% of healthcare-associated pneumonia, 22.9% of hospital-acquired
pneumonia, and 14.6% of ventilator-associated pneumonia, illustrating
that MRSA is a major pathogen for all types of pneumonia.15
oral administration. There has been mounting evidence over the past
decades that the minimum inhibitory concentrations of vancomycin for
MRSA have increased and may be associated with decreased clinical
response. Agents effective for MRSA which are under development or
not yet marketed at the time of this writing include: the lipoglycopeptides
- telavancin and oritavancin; the penicillin-binding protein-2a-targeted
β-lactams - ceftobiprole and ceftaroline, and a folic acid inhibitor
- iclaprim.
While CA-MRSA is still an uncommon cause of CAP, the excess mortality
of inappropriate antibiotic therapy would suggest that empirical coverage
should be considered when CA-MRSA is a concern. A concern with
CA-MRSA is necrotising pneumonia associated with Panton-Valentine
leukocidin and other toxin production. Vancomycin does not decrease
toxin production whereas linezolid has been shown to affect toxin
production in a laboratory setting and may warrant its consideration
for treatment of these necrotising pneumonias. Of the other presently
available agents in the US, daptomycin should not be used for CAP since
this agent is inactivated by surfactant. There is little data on pneumonia
available for the other agents. The recent Infectious Diseases Society of
America/American Thoracic Society CAP guidelines recommend adding
vancomycin or linezolid when CA-MRSA is a concern for severe cases
of CAP.18
Therapy
The most effective approach of management for CA-MRSA remains to be
defined. The predominance of CA-MRSA has increased the importance of
obtaining cultures of even mild skin infections. For minor skin infections
without associated systemic signs, such as fever or haemodynamic
instability, treatment can be successfully managed with incision and
drainage. Whether or not antimicrobial therapy is beneficial in such
infections has been unclear. Initial studies suggested that pustules
which were incised and drained resolved with or without the use of
effective antimicrobials. However, more recent studies have suggested
a better outcome if antimicrobials are administered which are effective
against CA-MRSA.16,17 The difficulty in interpreting such reports is that
to date they have been retrospective, observational studies. Presently
a prospective randomised, clinical trial is being performed under the
direction of the National Institutes of Health.
References
1. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January
1992 through June 2004, issued October 2004. Am J Infect Control 2004; 32(8): 470-485
2. Salgado CD, Farr BM, Calfee DP. Community-acquired methicillin-resistant Staphylococcus aureus:
a meta-analysis of prevalence and risk factors. Clin Infect Dis 2003; 15; 36(2): 131-139
3. File TM Jr. Impact of community-acquired methicillin-resistant Staphylococcus aureus in the
hospital setting. Cleve Clin J Med 2007; 74(Suppl 4): S6-S10
4. Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus
infection in the United States. JAMA 2007; 298: 1763-1771
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methicillin-resistant Staphylococcus aureus isolates of diverse genetic backgrounds. J Infect Dis
2002; 186(9): 1344-1347
6. Frazee, et al. High prevalence of methicillin-resistant Staphylococcus aureus in emergency
department skin and soft tissue infections. Ann Emerg Med 2005; 45: 311-320
7. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistant Staphylococcus aureus infections
among patients in the emergency department. NEJM 2006; 355: 666-674
8. Arbeit RD, Maki D, Tally FP, et al. The safety and efficacy of daptomycin for the treatment of
complicated skin and skin-structure infections. Clin Infect Dis 2004; 38: 1673-1681
In general, CA-MRSA strains are usually susceptible in vitro to trimethoprim/sulfamethoxazole, clindamycin and minocycline or doxycycline
and these agents can usually be used for mild-moderate infection. One
potential caveat concerning trimethoprim/sulfamethoxazole, however,
is that it may not adequately cover for Streptococcus pyogenes; thus,
if S. pyogenes is also likely, an alternative agent or combination with
penicillin is recommended. In addition, isolates resistant to erythromycin
and susceptible to clindamycin should be evaluated for inducible
clindamycin resistance using the ‘D test’. Clinicians are advised to
consult their reference laboratory to determine if ‘D testing’ is routine or
must be requested. If inducible resistance is present, an alternative agent
is recommended. The newer fluoroquinolones, such as levofloxacin,
moxifloxacin and gemifloxacin usually have good activity for methicillinsusceptible S. aureus (MSSA) but are generally not effective for MRSA.
If active in vitro, oral rifampin can be added for antimicrobial efficacy,
but it should never be used as monotherapy because of the possibility
of rapid emergence of resistance. At present, the only FDA-approved
antimicrobials for MRSA are parenterally administered vancomycin
(although rare isolates of vancomycin intermediate-resistant strains
have been recently described), quinupristin/dalfopristin, linezolid,
daptomycin, and tigecycline. Of these, only linezolid is available by
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Minnesota. Clin Infect Dis 2001; 33: 990-996
13.File TM Jr. Community-associated methicillin resistant Staphylococcus aureus: not only a cause
of skin infections, also a new cause of pneumonia: editorial review. Curr Opin Infect Dis 2005; 18:
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14.Hageman JC, Francis J, Uyeki TM, et al. Emergence of methicillin-resistant Staphylococcus aureus
as a cause of community-acquired pneumonia during the influenza season, 2003-2004 [abstract
LB-8]. Program and abstracts of the 42nd annual meeting of the Infectious Diseases Society of
America. Boston, Sept 30-Oct 3, 2004
15.Kollef MH, Shorr A, Tabak YP, et al. Epidemiology and outcomes of healthcare-associated pneumonia:
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16.Ruhe JJ, Smith N, Bradsher RW, et al. Community-onset methicillin-resistant Staphylococcus
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2007; 44: 777-784
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skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus. Antimicrob
Agents Chemother 2007; 51: 3298-3303
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