Community-associated MRSA: a dangerous epidemic

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[email protected]

Community-associated MRSA:
a dangerous epidemic

Michael Otto ‘ … the lesson from the CA-MRSA acquisition of methicillin-resistance elements.
Interestingly, all CA-MRSA strains have the same
The National Institutes of epidemic is that of an increased type of resistance element that was probably
Health, Laboratory of acquired from Staphylococcus epidermidis, indicat-
Human Bacterial urge to put more resources into ing an important role for this less virulent skin
Pathogenesis, National commensal as a reservoir for the horizontal
Institute of Allergy & drug and vaccine development.’ transmission of genetic factors to S. aureus.
Infectious Diseases,
Hamilton, MT 59840, USA Although a relatively unspectacular, nonmotile ‘Within a very short period of time,
Tel.: +1 406 363 9283; coccus, Staphylococcus aureus is a dangerous CA-MRSA have become not only the
Fax: +1 406 375 9677; pathogen and a major public health concern. In most frequent causes of soft- and skin-
[email protected] addition to being a common food-poisoning tissue infections in the community, but
agent, it can cause serious skin and soft tissue are also replacing traditional MRSA
part of infections and life-threatening diseases. Further- strains in hospitals on a large scale.’
more, resistance to multiple antibiotics, most
notably to penicillin and methicillin, is common In contrast to this relatively clear theory
in S. aureus and makes treatment especially diffi- about the establishment of methicillin resist-
cult. However, the biggest current threat from ance, we are far from understanding what causes
this human pathogen is the pandemic spread of the exceptional virulence of CA-MRSA.
community-associated methicillin-resistant Epidemiological comparisons cannot help
S. aureus (CA-MRSA), a crisis affecting many much, because all CA-MRSA strains belong to a
aspects of our social life and second only to very limited number of clonally related back-
HIV/AIDS in scope and importance. grounds. Nevertheless, Panton–Valentine leuko-
cidin (PVL) was initially declared as the one
Infections with MRSA have traditionally been factor responsible for the extraordinary CA-
limited to healthcare settings and individuals MRSA virulence. However, it should be noted
with risk factors for infection. Therefore, it came that PVL is only one of many genes that are
as quite a shock when MRSA infections associated with CA-MRSA strains. Unfortu-
unrelated to hospitals were reported in healthy nately, a preconceived notion that PVL is
individuals beginning in the late 1990s: first in responsible for the prominence of CA-MRSA
children, later in professional football players rapidly developed, although solid molecular evi-
and other sports teams, prisoners and men who dence to support a function of PVL in
have sex with men (MSM). The strains that CA-MRSA pathogenesis has never been pro-
cause these infections are remarkable because duced. Contributing to the overall confusion, a
they combine antibiotic resistance with excep- recent study – the design of which addressed
tional virulence and transmissibility, a pheno- the toxicity of PVL – was erroneously inter-
menon unprecedented with S. aureus. Moreover, preted as proof for a role of PVL in CA-MRSA
while most S. aureus infections were previously pathogenesis [1]. Additionally, an alleged
thought to originate from nasal colonization, gene-regulatory role of PVL, suggested in the
transmission of CA-MRSA includes body-to- study as an explanation for how PVL confers
body and sexual contacts. Within a very short enhanced virulence, turned out to be incorrect [2].
period of time, CA-MRSA have become not In contrast, all studies that have used isogenic
only the most frequent causes of soft- and skin- CA-MRSA lukS/F-PV (encoding PVL)-deletion
tissue infections in the community, but are also strains, including studies using a series of ani-
replacing traditional MRSA strains in hospitals mal-infection models, have failed to find a role
on a large scale. for PVL in virulence, or any influence of the
leukotoxin on gene expression [3]. In addition,
Where did CA-MRSA come from so suddenly? experiments with human neutrophils, a primary
It is generally agreed that CA-MRSA have evolved
from highly pathogenic methicillin-susceptible
S. aureus (MSSA) strains in the community by the

10.2217/17460913.2.5.457 © 2007 Future Medicine Ltd ISSN 1746-0913 Future Microbiol. (2007) 2(5), 457–459 457

EDITORIAL – Otto

target of PVL and a key cell type for defense pulsed-field gel electrophoresis type-USA300
against S. aureus, have led to the same con- harbor a mobile genetic element named arginine
clusion. Thus, all sound scientific data available catabolic mobile element (ACME) that adds an
to date indicate that PVL does not play a additional arginine deaminase locus to the
significant role in CA-MRSA disease. S. aureus genome [5]. This element might contrib-
ute to enhanced colonization due to the role of
It would have been convenient to be able to ammonia production in pH homeostasis on epi-
pinpoint the virulence of the most dangerous thelia. In fact, recent results demonstrate a signifi-
S. aureus strains to just one factor – which, by the cant difference in the survival of isogenic USA300
way, would have been in remarkable contrast with ACME-positive and -negative strains in a rabbit
everything that we have learned over the years on infection model, suggesting that the presence of
the multi-facetted causes of S. aureus virulence. ACME influences pathogen success [6].
Unfortunately, we have to accept that the initial
PVL euphoria was unfounded, which sets us back ‘...we have to think much more in terms
to the start. If not PVL, what then? Although of gene and protein expression, and not
unlikely, there is still the chance that a gene with
an unknown function, specific to the CA-MRSA only gene presence, when trying to
genomes, may emerge as the sole cause for this big elucidate the molecular basis of
difference in pathogen success. Furthermore, CA-MRSA pathogenesis.’
while the current facts do not suggest a significant
role of host factors for skin and soft-tissue infec- Of note, similar to the CA-MRSA-specific
tions, the possibility that some individuals may be methicillin-resistance element, the ACME ele-
more susceptible to CA-MRSA infection than ment was likely transferred to CA-MRSA from
others, especially to severe and/or recurrent infec- S. epidermidis, which is a specialist in skin colo-
tions, should not be excluded. For epidemic nization. Interestingly, the factors that now
CA-MRSA, it is much more likely that the key to emerge as potentially crucial for CA-MRSA viru-
pathogenesis will be bacterially determined, and lence, specifically acute virulence factors such as
more complicated. In that regard, some very lytic toxins and colonization/adhesion factors,
interesting recent progress has been made in iden- traditionally underlie contrasting regulation in
tifying factors that influence CA-MRSA viru- S. aureus and are thus not commonly expressed
lence. Importantly, these recent studies also concurrently. CA-MRSA strains might have
suggest that we have to think much more in terms evolved to combine the high-level expression of
of gene and protein expression, and not only gene colonization factors and toxins without adverse
presence, when trying to elucidate the molecular effects on growth.
basis of CA-MRSA pathogenesis.
Fortunately, and in contrast with many hos-
‘ … we are far from understanding pital-associated MRSA strains, CA-MRSA are
what causes the exceptional susceptible to antibiotics other than methicillin
virulence of CA-MRSA.’ and β-lactam antibiotics, leaving antibiotic
treatment as an efficient therapy method for
Novel cytolytic peptides of S. aureus with a CA-MRSA infection up to now. However, the
pronounced capacity to lyse human neutrophils current epidemic also raises the question about
have recently been identified. These peptides, therapeutic possibilities. Not only do
the S. aureus α-type phenol-soluble modulins CA-MRSA strains appear to cause severe and/or
(PSMs), are expressed at high levels in fatal infections to an extent not previously seen
CA-MRSA, whereas expression is low in stand- with S. aureus, such as necrotizing fasciitis and
ard hospital-associated MRSA [4]. Murine mod- the Waterhouse–Friderichsen syndrome, they
els of bacteremia, skin- and soft-tissue infection may also acquire resistance to additional anti-
and peritonitis established an exceptional role of biotics in the future. This would lead to a pub-
α-type PSMs in CA-MRSA virulence. Thus, one lic-health catastrophe as we are running out of
novel characteristic of CA-MRSA strains might effective antibiotics for S. aureus and a working
be the strong expression of virulence determi- vaccine for S. aureus infections is not in sight.
nants that interact with host defenses. In addi- Owing to the revised notion about the role of
tion, CA-MRSA may have acquired genes to PVL, a vaccine against staphylococcal infections
improve the establishment of an infection. The will not likely be improved by simply adding
most frequently found CA-MRSA strains of PVL to the formula, as some have suggested.
Rather, the lesson from the CA-MRSA

458 Future Microbiol. (2007) 2(5) future science group

Community-associated MRSA: a dangerous epidemic – EDITORIAL

epidemic is that of an increased urge to put Financial & competing interests disclosure
more resources into drug and vaccine develop- The authors have no relevant affiliations or financial
ment. As the molecular basis of CA-MRSA vir- involvement with any organization or entity with a finan-
ulence turns out to be multifactorial and likely cial interest in or financial conflict with the subject matter
due to the new combination and stronger or materials discussed in the manuscript. This includes
expression of virulence factors, finding efficient employment, consultancies, honoraria, stock ownership or
drugs against CA-MRSA will not be substan- options, expert testimony, grants or patents received or
tially different from previous efforts to find pending, royalties
anti-S. aureus drugs. The CA-MRSA epidemic
just shows us that we have to be fast. No writing assistance was utilized in the production of
this manuscript.

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