Methicillin-Resistant Staphylococcus aureus: An Evolutionary, Epidemiologic, and Therapeutic Odyssey
Methicillin-Resistant Staphylococcus aureus: An Evolutionary, Epidemiologic, and Therapeutic Odyssey
Stan Deresinski () 0 1
0 Received 23 August 2004; accepted 10 November 2004; electronically published 24 January 2005. Redwood, CA
1 Division of Infectious Disease and Geographic Medicine, Department of Medicine, Stanford University, Stanford, and Santa Clara Valley Medical Center , San Jose, California
Methicillin-resistant Staphylococcus aureus, first identified just over 4 decades ago, has undergone rapid evolutionary changes and epidemiologic expansion. It has spread beyond the confines of health care facilities, emerging anew in the community, where it is rapidly becoming a dominant pathogen. This has led to an important change in the choice of antibiotics in the management of community-acquired infections and has also led to the development of novel antimicrobials. HISTORICAL BACKGROUND AND EPIDEMIOLOGY
It was only 1 year after an Oxfordshire constable, Albert
Alexander, became the first recipient of penicillin, that
Rammelkamp reported the identification of isolates of
Staphylococcus aureus resistant to this miracle drug .
Infections caused by penicillin-resistant S. aureus were
initially limited to hospitalized patients and were only
later detected in the community, where they eventually
became common . In an historical reprise, the
identification of methicillin-resistant S. aureus (MRSA) was
reported within 1 year after the 1960 introduction of
this semisynthetic penicillin, and once again, an
organism that was initially present only in hospitals later
became prevalent in the community [2, 3]. The spread
of MRSA from the hospital to the community was a
predictable event. The emergence in the past decade of
novel strains of MRSA in the community that are
genetically distinct from MRSA strains originating in the
hospital was perhaps less anticipated.
MRSA is currently the most commonly identified
antibiotic-resistant pathogen in US hospitals [4, 5].
Although 25.9% of S. aureus strains isolated from
outpatients were methicillin resistant , most of these
strains were recovered from individuals who were likely
to have acquired them in the health care environment
[6, 7]. Their association with health care may, however,
have been indirect; household contacts of individuals
with hospital-acquired MRSA (HA-MRSA) are at
significantly increased risk for MRSA colonization . In
a recent and dramatic evolutionary development,
however, infection with novel community-acquired strains
of MRSA (CA-MRSA) in previously healthy individuals
without either direct or indirect association with health
care facilities has emerged as a new and important
public health problem [9–11].
In some community settings, CA-MRSA have
become the prevalent form of S. aureus isolated from
cutaneous infections, especially among children. At a
Houston pediatric hospital, 74% of
community-acquired S. aureus strains isolated since 2001 have been
resistant to methicillin . Clusters and outbreaks in
adolescents and adults have been reported to occur in
Native Americans , homeless youth , men who
have sex with men , jail inmates , military
recruits , children in child care centers , and
competitive athletes . Although most infections
have involved skin and skin structures, potentially lethal
invasive infections have also occurred. The report in
1999 of the deaths of 4 previously healthy children in
Minnesota and North Dakota who did not have
previous contact with health care facilities unequivocally illustrated
the potential dangers presented by CA-MRSA .
Reversing and completing an epidemiologic cycle, CA-MRSA
are now being introduced from their site of origin in the
community into the hospital [19, 20]. At some hospitals, CA-MRSA
are displacing classic hospital-associated strains of S. aureus,
which is consisitent with the hypothesis that the former may
be more fit .
MOLECULAR EPIDEMIOLOGY OF METHICILLIN
The mechanism of resistance to methicillin was uncovered in
1981 with the the identification of reduced-affinity
penicillinbinding proteins in MRSA . The altered protein, PBP2a
(PBP2 in the United Kingdom), retains effective transpeptidase
activity while having reduced affinity for penicillin and other
available b-lactam antibiotics. PBP2a exhibit both a reduced
rate-constant for acylation by b-lactams and elevated
dissociation constants . These 2 factors, acting together, prevent
acylation of PBP2a and thus result in b-lactam resistance .
PBP2a is encoded by the mecA gene (for a glossary of genetic
terms, see Appendix) . The mobile mecA gene complex is
comprised of mecA together with its regulator genes, mecI and
mecR, and resides within a genomic island, the staphylococcal
cassette chromosome mec (SCCmec) that constitutes 1%–2%
of the ∼2.9 million–bp S. aureus chromosome [24–26] (figure
1). SCCmec also contains the insertion sequence, IS431mec, as
well as recombinases necessary for site-specific integration and
excision. Some SCCmec types also contain various additional
genetic elements, such as Tn554 (which encodes resistance to
macrolides, clindamycin, and streptogramin B) and pT181
(which encodes resistance to tetracyclines) .
The expression of PBP2a is induced by the binding of
blactam antibiotics to a cytoplasmic membrane
sensor-transducer receptor encoded by the mecR1 gene, triggering a signal
leading to the proteolytic release of the mecI repressor from
the operator region of the mecA gene [27, 28]. Phenotypic
resistance to methicillin is variably expressed, and population
analysis demonstrates that each MRSA strain has a
characteristic growth profile at each concentration of methicillin
examined . In contrast to this heterogeneously expressed
resistance to methicillin, homogeneous resistance requires the
interaction of additional factors, such as the femA–F genes that
are involved in peptidoglycan synthesis .
MOLECULAR EVOLUTIONARY HISTORY
Although PFGE is commonly used in hospitals to determine
the relatedness of isolates for epidemiologic purposes, this
method is insufficiently discriminatory for evolutionary studies
. The overall genetic background of S. aureus isolates is
unambiguously determined through multilocus sequence
typFigure 1. Diagram showing the staphylococcal cassette chromosome
mec type IV (SCCmec type IV) (adapted from ). SCCmec type IV lacks
antibiotic resistance elements directed at non–b-lactam antibiotics that
are present in SCCmec types characteristic of hospital-acquired
methicillin-resistant Staphylococcus aureus. ccrA2 and ccrB2 designate cassette
chromosome recombinases. WIS 1272 designates IS431mec insertion
sequences. mecA encodes PBP2a. orfX indicates an open reading frame.
DmecR1 is a signal transducer gene whose activation by b-lactam
antibiotics inactivates the mecI repressor gene product, allowing expression
ing by determination of the sequence of portions of 7
housekeeping genes . The mobile SCCmec elements, on the other
hand, are classified by analysis of their cassette chromosome
recombinase (ccr) and mecA gene complexes . SCCmec
types also differ with regard to their acquisition of resistance
determinants acquired as the result of integration of plasmids
and transposons . At least 5 SCCmec types (types I–V),
varying in size from ∼20 kb to 68 kb, have been identified 
(table 1). The smallest of these—SCCmec types I, IV, and V—
contain only recombinase genes and the structural and
regulatory genes for resistance to methicillin and lack the
transposable elements and genes encoding resistance to
non–b-lactam antibiotics carried by types II and III [33, 35]. SCCmec
types I-IV contain alleles of ccrA and ccrB, whereas type V,
which has to date been identified in a small number of
Australian CA-MRSA isolates, contains a novel ccr designated ccrC
. Two possible additional SCCmec types have recently been
identified among Australian CA-MRSA strains .
Genetic evolutionary analyses have demonstrated that the
mecA gene has been transferred into methicillin-susceptible S.
aureus (MSSA) on 20 occasions, having emerged in 5
phylogenetically distinct lineages (as well as reemerging within
indvidual lineages) [25, 31, 37]. It has been suggested that the
emergence of PBP2a initially resulted from a recombination
event involving the genes encoding an existing PBP and an
inducible b-lactamase . The donor strains that became the
source of PBP2a are likely to have been coagulase-negative
staphylococci, with Staphylococcus sciuri identified as a prime
candidate . A recent study of 44 methicillin-resistant
Staphylococcus epidermidis isolates from the blood of patients with
prosthetic valve endocarditis from 1973 to 1983 found that 2%
carried SCCmec type I, 34% carried type II, 28% carried type
III, and 36% carried type IV . The introduction of mecA
from the putative donor species into MSSA strains that are
Characteristics of staphylococcal cassette chromosome mec (SCCmec) types I–V.
elements (gene) on SCCmec
already successfully adapted to hospital environments and to
the community have, in turn, created successful epidemic
HAMRSA and CA-MRSA clones [31, 35, 41, 42].
Evidence indicates that the ancestral MRSA genotype,
ST250MRSA, is a strain originating in Denmark and possessing
SCCmec type I, most extant isolates of which were obtained in
the 1960s . (By convention, strains are named by their
sequence type [ST] and the presence or absence of methicillin
resistance. Thus, this strain is a methicillin-resistant S. aureus
of a sequence type designated as 250). ST250-MRSA arose as
the consequence of the acquisition of the mec gene by the
methicillin-susceptible strain ST250-MSSA, which had itself
arisen from ST8-MSSA by a chromosomal point mutation .
ST250-MRSA is no longer a major cause of epidemic MRSA
infections, but ST247-MRSA (the “Iberian clone”), which
evolved from ST250-MRSA by a single point mutation, remains
an important hospital pathogen in Europe and has been
reported to have caused an outbreak in a New York City hospital
. As indicated above, there have since been multiple
introductions of mec into S. aureus . The emergence of
CAMRSA strains, in particular, has repeatedly occurred as a result
of the introduction of SCCmec type IV into a variety of genetic
MSSA backgrounds . In the United States, one of the
resultant clones, ST8-MSSA (USA 300) has proven increasingly
EPIDEMIOLOGIC SUCCESS AND VIRULENCE
CA-MRSA strains differ in a number of important ways from
the 6 major pandemic clones of MRSA that account for nearly
70% of epidemic HA-MRSA strains . These differences are
found in the composition of the gene cassette coding for
methicillin resistance, in the carriage of plasmids encoding resistance
to antibiotics of other classes (as well as resistance to heavy
metals), and in their associated virulence factors.
The earliest strain of MRSA in which SCCmec type IV has
been identified was isolated in 1981 . Despite this
apparently recent emergence, an analysis of a large number of MRSA
isolates detected SCCmec type IV in twice as many clones as
any of the other types, suggesting its greater promiscuity and
successful persistence . This may be the result of greater
efficiency of transfer and/or a lesser fitness cost to the recipient
clone, possibly because of its smaller size and lack of the “excess
baggage” included in other SCCmec types [26, 35, 41]. Although
HA-MRSA has been reported to replicate more slowly than
MSSA , a CA-MRSA clinical isolate harboring SCCmec type
IV has been demonstrated to replicate more rapidly than
HAMRSA isolates with other SCCmec types [41, 42]. In contrast,
transformation of an SCCmec type I element into S. aureus
strains yielded highly oxacillin-resistant transformants with a
reduced growth rate . This relatively greater fitness of
CAMRSA strains carrying SCCmec type IV may account for its
remarkable success in displacing other MRSA strains in some
hospitals after its introduction from the community .
MOLECULAR BASIS OF VIRULENCE
Sequencing of the genome of CA-MRSA strain MW2, which
caused fatal sepsis in a 16-month-old girl from North Dakota
, identified 19 putative virulence genes not found in 5
simultaneously examined HA-MRSA strains . These
included genes for several superantigens, such as enterotoxins B
and C, as well as the amphipathic leukotoxin, the
PantonValentine leukocidin (PVL). PVL, first described in 1932 ,
is a bicomponent synergohymenotropic (synergistic
membrane-tropic) toxin that was present in !5% of unselected S.
aureus isolates but is present in the majority of CA-MRSA
isolates studied [49, 50]. CA-MRSA isolates from Australia, on
the other hand, infrequently carry the genes encoding PVL .
PVL is encoded by contiguously located cotranscribed
genes, lukS-PV and lukF-PV, inserted near the att site .
These genes are transmitted by a temperate phage designated
øPVL [51, 52]. Their gene products, 33 kDa and 34 kDa in
size, respectively, assemble as hetero-oligomers and
synergistically exert cytolytic pore-forming activity specifically
directed at the cell membranes of polymorphonucelar
neutrophils and monocytes and/or macrophages [49, 50]. Injection
of PVL into the skin of rabbits causes dermal necrosis ,
suggesting that it may play a role in the severity of skin and
skin-structure infections in humans. In addition, an
association between PVL-containing strains of MRSA and virulent
necrotizing pneumonia has been reported .
RESISTANCE TO ANTIBIOTICS OTHER THAN
In contrast to the multidrug resistance usually seen in
HAMRSA strains, antibiotic resistance in CA-MRSA strains is often
limited to b-lactams. The small size of SCCmec type IV may
preclude its carriage of additional genetic material, in contrast
to the characteristic presence of additional genetic material in
SCCmec type II and SCCmec type III [25, 26]. This does not,
however, preclude chromosomally encoded resistance or the
presence of resistance plasmids in strains carrying any of the
mec types. For instance, some CA-MRSA strains isolated in
western Australia contain a 41.4-kb plasmid encoding resistance
to tetracycline and trimethoprim, as well as resistance to
mupirocin and cadmium [55, 56]. Fluoroquinolone resistance is
frequent in CA-MRSA carrying SCCmec type IV isolated from
homeless youth in San Francisco . Nonetheless, in contrast
to HA-MRSA strains, most CA-MRSA isolates remain
susceptible to tetracyclines, clindamycin, and
trimethoprim-sulfamethoxazole (TMP-SMZ) .
AVAILABLE ANTIBIOTICS FOR THE
TREATMENT OF MRSA INFECTION
Vancomycin. Compared with b-lactam therapy, vancomycin
therapy has been associated with slower clinical response and
longer duration of MSSA bacteremia, and it has been
associated with more frequent complications in patients with
endocarditis [58, 59]. Failure of vancomycin therapy may be
observed in the treatment of patients with bacteremia due to
strains of MRSA that have MICs of vancomycin well within
the range considered susceptible . Heterogeneous
vancomycin resistance, which is not readily detected by routine
clinical laboratory methodology, is also associated with failure
of vancomycin therapy [61, 62]. The appearance of
vancomycin-intermediate S. aureus and, more recently,
vancomycin-resistant S. aureus is of further concern .
Quinupristin/dalfopristin. This combination is active in
vitro against MSSA and MRSA . It is bactericidal against
S. aureus, although in the presence of constitutive expression
of macrolide-lincosamide-streptogramin resistance, it is only
bacteriostatic . In a randomized trial, patients with
nosocomial MRSA pneumonia who received
quinupristin/dalfopristin had a clinical response rate of 19.4%, compared with
40% in vancomycin recipients .
Linezolid. Linezolid and vancomycin yielded comparable
results in hospitalized patients with MRSA infections at a variety
of anatomic sites in a randomized, open-label trial , as well
as in the treatment of skin and skin-structure infections caused
by gram-positive organisms . A retrospective subset analysis
of 2 prospective randomized clinical trials found evidence
suggesting that linezolid was superior to vancomycin in the
treatment of hospital-acquired pneumonia due to MRSA [69, 70].
Daptomycin. Daptomycin is a novel lipopeptide antibiotic
with bactericidal activity against S. aureus that binds, in a
calcium-dependent manner, to the bacterial cell membrane,
disrupting membrane potential . Daptomycin has received
approval from the US Food and Drug Administration for the
treatment of complicated skin and skin-structure infections due
to susceptible gram-positive pathogens . Daptomycin
therapy failed in a trial involving patients with community-acquired
pneumonia; daptomycin not only has limited penetration into
pulmonary epithelial lining fluid, but its activity is inhibited
by pulmonary surfactant [72, 73].
Tetracyclines. In vitro susceptibility results involving
tetracycline derivatives must be interpreted with caution, because
S. aureus isolates that are tetracycline-resistant but that have
relatively low MICs of doxycycline and/or minocycline may, in
fact, harbor inducible efflux genes [74, 75]. Minocycline has
been shown to have bactericidal activity similar to that of
vancomycin against a single strain of MRSA in an animal model
of endocarditis . Of 14 patients with MRSA infection who
were treated with doxycycline or minocycline, either alone or
in combination with rifampin, 3 (21%) experienced treatment
TMP-SMZ. TMP-SMZ was less active than vancomycin in
a rabbit model of MRSA endocarditis and less rapidly
bactericidal than nafcillin in a rabbit model of MSSA meningitis
[78, 79]. A randomized trial of treatment of S. aureus infections,
47% of which were due to MRSA, concluded that treatment
with TMP-SMZ was inferior to treatment with vancomycin
. An extensive literature review, however, concluded that
TMP-SMZ “may be effective for the treatment of infections
due to low bacterial burdens of susceptible strains of S. aureus”
[81, pg. 340].
Fluoroquinolones. Although most CA-MRSA strains are
reported to be fluoroquinolone susceptible, this is not true in
some locales [36, 57]. Fluoroquinolone resistance emerged very
rapidly in HA-MRSA in the years after widespread utilization
of agents of this class; at one institution, fluoroquinolone
resistance increased from 7% before 1988 to 83% in 1990 .
In vitro passage of both fluoroquinolone-susceptible MSSA and
MRSA in the presence of either ciprofloxacin or levofloxacin
is associated with the frequent selection of clones resistant to
these antibiotics . Furthermore, fluoroquinolones select
MRSA from among heterogeneously methicillin-resistant
populations in vitro , and fluoroquinolone use is associated
with an increased risk of nosocomial acquisition of MRSA (but
not of MSSA) . The fluoroquinolones with C8
substitutions, such as gatifloxacin and moxifloxacin, appear to be more
potent against S. aureus than are older drugs of this class, and
they may be less likely to select resistant mutants, an effect that
may be strengthened by the addition of rifampin [86–88].
Clindamycin. Clindamycin has been used successfully in
the treatment of invasive CA-MRSA infections in children [89,
90]. Inducible resistance to clindamycin, however, is not
detected by routine susceptibility testing, but requires the use of
other methods (e.g., a double-disk diffusion test) [90–93].
Flattening of the zone in the area between the disks to resemble
the letter “D” indicates the presence of inducible resistance
(figure 2 and table 2).
Rifampin. Rifampin selects resistant mutants from among
both MSSA and MRSA strains at a frequency of 10 6 to 10 8,
but this may be prevented by using rifampin in combination
with a second active drug .
Topical agents. MRSA strains that are resistant to
mupirocin, mutants of which can be selected in vitro at frequencies
of 10 7 to 10 8, are reported with increasing frequency .
MRSA isolates with elevated MICs of triclosan have been
identified [96, 97].
OVERVIEW OF CHOICE OF SYSTEMIC
For some infections that require parenteral therapy and are due
to MRSA strains that are multidrug resistant, the treatment
choices may be restricted to vancomycin, daptomycin, linezolid,
and quinupristin/dalfopristin therapy. The potential superiority
of linezolid therapy over vancomycin therapy in treating
nosocomial pneumonia due to MRSA has been noted [69, 70].
Daptomycin is ineffective in the treatment of pneumonia
(Cubist Pharmaceuticals, data on file). The bacteriostatic activity of
linezolid may prove to limit its effectiveness in circumstances
in which bactericidal activity is required .
Choices for treatment of infections due to CA-MRSA may
include, in addition to the drugs mentioned above, TMP-SMZ,
tetracyclines, clindamycin, and fluoroquinolones. The
widespread use of fluoroquinolones for treating these infections
may, if history repeats itself, lead to the rapid emergence of
resistance to this class of antibiotics. Tetracycline therapy,
contraindicated in children and in those who are pregnant, may
prove to be effective, but further clinical data are required.
TMP-SMZ appears to be effective in treating infections of
limited extent and severity. Linezolid is an effective agent for which
use has been limited by its cost. Antibiotic therapy is not always
required: a retrospective analysis has found resolution of
CAMRSA infection in children with subcutaneous abscesses !5
cm in diameter who underwent incision and drainage in the
absence of administration of an antibiotic to which the
pathogen was susceptible .
INVESTIGATIONAL AGENTS WITH ACTIVITY
Semisynthetic glycopeptides. Oritavancin is a semisynthetic
glycopeptide derivative that is active against some
vancomycinresistant, gram-positive bacteria [99, 100]. A randomized trial
of oritavancin in the treatment of skin and skin-structure
infections demonstrated results comparable to those observed
with a vancomycin-based regimen . Its mean terminal
plasma half-life ( SD) of 151 39 h allowed it to be given
in a total of 3 daily doses [101, 102].
Dalbavancin has a terminal plasma half-life of 9–12 days
. A total of 2 doses given 1 week apart in the treatment
of skin and skin-structure infections resulted in a 94% cure
rate, compared with a 76.2% cure rate in those patients
randomized to receive standard-of-care . A third drug of this
class, telavancin, with a terminal plasma half-life of 7 h in young
volunteers and 11 h in elderly subjects, was effective in a
neutropenic mouse thigh model and is also in clinical trials [104–
Glycylcyclines. The minocycline derivative tigecycline has
bacteriostatic activity against both MSSA and MSRA, including
tetracycline-resistant strains [99, 108, 109]. In a randomized
dose-comparison study, clinical cure rates were 67% and 74%
in patients with skin and skin-structure infections who received
25 mg and 50 mg daily, respectively .
Novel b-lactams. A series of b-lactamase–stable
cephalosporins with high affinity for PBP2a are in clinical development
. The PBP2a affinity of BMS-247243 is 100-fold greater
than that of methicillin or cefotaxime, and the drug is
bactericidal against MRSA at twice the rate of vancomycin .
Other drugs of this class in development include the
zwitterionic cephem RWJ-54428 , CB-181963 , BAL5788
, a prodrug of BAL9141 [116, 117], and S-3578 .
ME1036 (formerly CP5609) is a C2-modified carbapenem with
high affinity for PBP2a and with an MIC90 of 2.0 mg/mL against
MRSA . SM-197436, SM-232721, and SM-232724 are
novel methylcarbapenems that are also active in vitro against
Fluoroquinolones. DW286, a naphthyridone, is among
several fluoroquinolones in development that have in vitro
activity against MRSA . Active against MRSA strains that
are resistant to other fluoroquinolones, it selects
fluoroquinolone-resistant mutants at a lower frequency than do older
agents (as may another fluoroquinolone, ABT-492) [122, 123].
Oligosaccharides. Evernimicin is a complex sugar
derivative with a novel mode of action [124, 125]. A related
compound, avilamycin, has been used in animal feed, raising the
specter of rapid emergence of resistance to this class of drugs
Miscellaneous antimicrobials. The rifamycin rifalazil
retains activity against some isolates that are resistant to rifampin
. Epiroprim is a dihydrofolate reductase inhibitor with
activity against some trimethoprim-resistant strains of S.
aureus; its combination with dapsone results in in vitro activity
against S. aureus that is greater than that of TMP-SMZ .
Iclaprim is another dihydrofolate reductase inhibitor with
activity against MRSA .
Other examples of modifications of existing molecules with
antistaphylococcal activity include the oxazolidinones
ranbezolid [130, 131] and eperezolid [129, 132], as well as N-acylated
ornithine analogues of daptomycin . Among drugs with
novel targets are the peptide deformylase–inhibitors NVP-PDF
713 [134, 135] and BB-83698 .
A number of naturally occurring cationic proteins have in
vitro activity against S. aureus , and some have been
demonstrated to have activity in animal models of infection .
Lysostaphin is active in vitro against S. aureus  and was
effective in a rabbit model of MRSA endocarditis . Its use
in a patient with S. aureus infection and neutropenia was first
reported in 1974 . Specific bacteriophage has been
demonstrated to be effective in protecting mice against lethal S.
aureus infection [142, 143].
Targeting virulence factors. RNAIII-inhibiting peptide
inhibits S. aureus pathogenesis by disrupting quorum-sensing
mechanisms . The accessory gene regulator (agr) is an
important regulator of virulence that is, at least in part, related
to quorum sensing ; a truncated thiolactone peptide has
been found to be a potent inhibitor for all 4 agr-specificity
groups of S. aureus .
S. aureus immune globulin intravenous (human) (Altastaph;
NABI Biopharmaceuticals) is a hyperimmune, polyclonal,
intravenous immunoglobulin product derived from the plasma
of human donors who have previously been vaccinated with
S. aureus polysaccharide conjugate vaccine (StaphVAX; NABI
Biopharmaceuticals), a bivalent conjugate capsular
polysaccharide covalently bound to recombinant exoprotein A, which has
been demonstrated to provide temporary protection against the
occurrence of S. aureus bacteremia in patients receiving
hemodialysis [147, 148]. Patients with S. aureus bacteremia and
persisting fever are currently being enrolled in a phase I/II trial
. Also in progress is a phase II prevention trial involving
infants with low birth weights .
Tefibazumab (Aurexis; Inhibitex) is a humanized monoclonal
antibody directed at the microbial surface components
recognizing adhesive matrix molecule (MSCRAMM) clumping
Table 2. Macrolide-lincosamide-streptogramin resistance in methicillin-resistant
Mechanism of resistance
Susceptible or resistant (inducible);a
NOTE. Data are adapted from .
a Resistant strains have inducible resistance. Determination of resistance requires specific testing (e.g., use
of a double-disk diffusion test).
factor A  that is currently being evaluated in a phase II
trial in patients with S. aureus bacteremia . INH-A21
(Veronate; Inhibitex) is a donor-selected human polyclonal
immunoglobulin preparation that is also enriched in antibody to
staphylococcal MSCRAMM proteins and that is undergoing
clinical trial evaluation for the prevention of infection in infants
with very low birth weights . Another cell surface
component, teichoic acid, is the target of BYSX-A110, an IgG1
chimeric monoclonal antibody that is in clinical trials for the
prevention of staphylococcal infections in infants with low birth
Aurograb (NeuTec Pharma) is a single-chain antibody
fragment lacking the immunoglobulin Fc domain targeted at
EMRSA-15, a 61-kDa ABC transporter expressed by epidemic
strains of MRSA that is in clinical therapeutic trials in the
United Kingdom [155, 156].
Pooled intravenous immune globulin preparations neutralize
a number of staphylococcal superantigen toxins and, as a
consequence, are commonly used in the therapy of toxic shock
syndrome . The identification of a conserved epitope on
staphylococcal enterotoxins that appears to be critical to their
activity raises the possibility of another approach to
superantigen neutralization . PVL can also be neutralized in vitro
by commercial intravenous immunoglobulin preparations
The story of antibiotic resistance and virulence in S. aureus
is, as has been stated by others, one of “depressing
evolutionary progression” [37, pg. 92]. The emergence of
CAMRSA, the rapid introduction of SCCmec type IV into
multiple genetic backgrounds, and the epidemiological success of
the resultant strains indicate that this problem will continue
its inexorable march [37, 160, 161]. Mathematical modeling
demonstrates difficulty in the epidemiologic control of MRSA
in the face of its increased prevalence in the community and
the increasingly daunting tasks for hospital infection-control
programs . An effective vaccine will be the only effective
Potential conflicts of interest. S.D. is a member of the speakers bureau
of Pfizer and is a consultant for Therapeutic Human Monoclonals.
Cassette chromosome recombinase (ccr) A gene
necessary for the mobility of SCC that enables its site-specific
integration into and precise excision from the S. aureus
Genomic island Genomic islands (often abbreviated as
GIS or GEIs) are horizontally acquired chromosomal regions
of DNA carrying several genes encoding traits associated with
increased adaptability or fitness under specific conditions. They
are termed pathogenicity, fitness, symbiosis, metabolic, or
resistance islands, depending on the functions encoded .
Housekeeping gene A gene involved in basic functions
required for cell viability and constitutively expressed in most
cells. Housekeeping genes evolve much more slowly than do
tissue specific genes that encode proteins necessary only in
selected types of cells.
Insertion sequence A DNA sequence involved in the
mobilization of genetic information to and from vectors such as
mec gene complex Gene complex composed of mecA and
its regulator genes, mecI and mecR.
mecA The gene encoding PBP2a, responsible for resistance
to methicillin and other b-lactam antibiotics.
mecI The mecA repressor gene.
mecR1 A signal transducer gene that encodes a
transmembrane receptor that responds to covalent binding of a
blactam antibiotic and its extracellular sensor domain. Binding
initiates events that lead to inactivation of the mecI gene
repressor product by a protease, allowing expression of mecA.
Staphylococcal chromosome cassette (SCC) SCC (or
SCCmec) is a mobile, 52-kb DNA cassette containing the gene
that encodes resistance to methicillin (mecA), as well as those
genes (ccrA and ccrB in most cases) that encode the integration
and excision necessary for its recombination in the
staphylococcal chromosome, in addition to insertion sequences.
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