Review

Review
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Current challenges in treating
MRSA: what are the options?
Expert Rev. Anti Infect. Ther. 6(5), 601–618 (2008)
Natasha VDV Ratnaraja
and Peter M Hawkey†
†
Author for correspondence
Regional HPA Microbiology
Laboratory, Heart of England
NHS Foundation Trust, Bordesley
Green East, Birmingham,
B9 5SS, UK
Tel.: +44 121 424 1248
Fax: +44 121 772 6229
peter.hawkey@
heartofengland.nhs.uk
This review looks at the challenges facing the worldwide community with the increasing problem
of methicillin resistance in Staphylococcus aureus. The epidemiology and natural history of
community-associated methicillin-resistant Staphylococcus aureus and the challenge of control
is discussed. Options for treatment and review of key antimicrobial agents acting against
methicillin-resistant S. aureus, both currently in use and in development, are addressed. There
are a number of new agents, the place of which in therapeutic regimens is yet to emerge. The
review attempts to inform the reader of the probable position of these agents.
Keywords : ceftaroline • ceftobiprole • community-associated methicillin-resistant Staphylococcus aureus
• dalbavancin • daptomycin • iclaprim • linezolid • methicillin-resistant S. aureus treatment • oritavancin
• quinupristin–dalfopristin • telavancin • tigecycline • tomopenem
The development of resistance to antimicrobials has been regarded as a consequence of their
use since their introduction nearly 70 years ago
and is worsening [1] .
The incidence of methicillin-resistant
Staphylococcus aureus (MRSA) has significantly
increased since the first reports emerged in the
1960s. In 2006, the percentage of invasive
S. aureus infections in the UK hospital setting
due to MRSA was 43% [201] . The European
Antimicrobial Resistance Surveillance System
(EARSS) annual report for 2006 showed that
for 15 out of 31 participating countries, the
proportion of invasive S. aureus isolates that,
were MRSA was greater than 25%. Both
the UK and Ireland were included in those
15 countries. Statistically significant increases
in the proportion of S. aureus isolates that were
MRSA were also seen in Hungary, Portugal
and Malta [201] .
A meta-analysis by Cosgrove et al. comparing
outcomes of MRSA and methicillin-susceptible
S. aureus (MSSA) bacteremia showed that there
was a higher mortality associated with MRSA
bacteremia compared with bacteremias due to
MSSA [2] . It is, therefore, important to try and
prevent infections with MRSA and to treat them
appropriately when they arise.
Previously, MRSA was almost exclusively associated with healthcare facilities; however, MRSA
has now begun to emerge within the community in some countries [2,3] . The dissemination
of MRSA means that new methods of control
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10.1586/14787210.6.5.601
of infection need to be sought. This may be difficult in the community setting. Treatment of
MRSA infection, both hospital- and community-associated, needs to be effective. The ability
to treat in an outpatient setting is of paramount
importance to prevent large numbers of patients
being admitted to hospital for what are often
relatively minor and/or chronic infections. This
review will discuss the following:
• Differences between community-associated
MRSA (CA-MRSA) and hospital-associated
MRSA (HA-MRSA) and the challenges in
overcoming them;
• New agents to overcome MRSA in both the
community and hospital settings.
Emerging challenges in the hospital
& the community
Although occasional infections have previously occurred in the community, acquisition
of MRSA has traditionally been associated with
healthcare facilities. Infections with MRSA
within the community were rare, although
sometimes seen among intravenous drug users.
An outbreak of CA-MRSA among indigenous
Australians in Western Australia between
1989 and 1991 was one of the first reports of
an outbreak within the community setting [4] ,
with subsequent reports of similar infections
emerging from the South Western Sydney
Area Health Service region [5] . Between 1997
and 1999, the US CDC reported four cases of
© 2008 Expert Reviews Ltd
ISSN 1478-7210
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Ratnaraja & Hawkey
rapidly fatal MRSA infections in children, again occurring within
the community [6] . Since the late 1990s, an increasing number
of cases of CA-MRSA have been reported worldwide [7] , to the
extent that it is being considered in some parts of the world to
be epidemic [8,9] .
Many countries have reported cases of CA-MRSA, including the USA, Europe, New Zealand, Australia, Samoa, Canada
and Finland. The USA has particularly been affected, with
CA-MRSA (predominantly the USA300 clone but also the
USA400 and USA500 clones) comprising 60–75% of all isolates
of S. aureus in some regions [10] .
There are some notable differences between HA-MRSA and
CA-MRSA. Risk factors for the acquisition of HA-MRSA
include older age, prolonged hospitalization, antimicrobial
therapy, urinary catheterization, diabetes mellitus, intravenous
drug use, skin conditions such as eczema and psoriasis, being
on hemodialysis or continuous ambulatory peritoneal dialysis,
previous surgery and the insertion of invasive devices. The aging
population, with more contact with healthcare services and often
more antimicrobial use, represents a significant population at
risk of colonization and subsequent infection.
By contrast, CA-MRSA differs from HA-MRSA in that it
tends to affect younger, nonwhite or indigenous populations.
These patients usually have no significant prior medical conditions and no prior contact with healthcare settings. Any situation where there is close physical contact may result in outbreaks
or clusters of CA-MRSA, for example, within the military, in
prisons, among children in institutions, among indigenous
populations and in athletic teams [11–13] .
Although CA-MRSA is typically seen in the community,
transmission within the hospital setting has been described [14,15] .
Familial transmission has also been described [16] .
There is a diverse range of HA-MRSA infections, ranging from
superficial infections to life-threatening bacteremias and endocarditis. The presence of MRSA on prosthetic materials, such as central
venous catheters and prosthetic heart valves, may cause dilemmas over treatment due to poor penetration of some anti-MRSA
antibiotics and persistence of infection because of an inability to
remove some prostheses. Patients may also be asymptomatic, with
colonization of the skin, wound or ulcer. It is this group of patients
who represent a risk both to themselves and to others, as asymptomatic colonization may go unnoticed, allowing both for infection to
develop in a patient and for transmission to close contacts.
The clinical presentation of CA-MRSA infection varies, with
the most common presentation being skin and soft-tissue infections, such as folliculitis and other pustular lesions [3,8,11,13,17,18] .
However, virulence of this pathogen varies and more serious infections, such as necrotizing pneumonia, necrotizing fasciitis, pyomyositis, septic thrombophlebitis, the ‘pelvic syndrome’ (pelvic
abscesses and septic arthritis of the hips) and ocular infections,
can occur. There have been reports of bacteremia and endocarditis
due to CA-MRSA [12,13,19] .
It is the mecA gene that is associated with methicillin resistance. This is carried on the staphylococcal cassette chromosome (SCC) mec, a large mobile element found in a range of
602
staphylococci consisting of the mec and ccr gene complexes.
There are five main types of SCCmec: type I SCCmec, carrying
class B mec and type 1 ccr; type II SCCmec, carrying class A mec
and type 2 ccr; type III SCCmec, carrying class A mec and type 3
ccr; type IV SCCmec, carrying class B mec and type 2 ccr; and
type V SCCmec, carrying class C2 mec and type 5 ccr [20] .
In contrast to HA-MRSA, which is commonly associated with
types I, II and III SCCmec, CA-MRSA is usually associated
with the smaller, types IV and V SCCmec [3,7,18,21] . However,
there have been reports of CA-MRSA strains harboring SCCmec
types I, II or III [22,23] and a report of HA-MRSA strains containing SCCmec type IV [24] . This suggests that the differences between HA-MRSA and CA-MRSA are not as clear-cut
as previously thought.
There is a strong association between CA-MRSA strains and
the Panton–Valentine leukocidin (PVL) toxin [25–27] , with many
strains (up to 80%) containing the gene encoding this [10] . The
PVL toxin is encoded by two genes, lukS-PV and lukF-PV,
and has previously been seen with some strains of MSSA. The
current rise in PVL-producing CA-MRSA strains may be due
to de novo SCCmec elements spreading among known PVLproducing CA-MRSA, as suggested by Monecke et al. [28] , or
it could be due to PVL phages disseminating among strains
of MRSA.
Multilocus sequence typing has shown that there are discreet clonal complexes containing PVL-positive MRSA (both
HA-MRSA and CA-MRSA) [25,26] . Clonal expansion and diversification within a clonal complex can produce differences in
virulence and pathogenicity, as shown by Kennedy et al. in the
USA300 clone [29] . Diep et al. showed through genomic sequencing that the USA300 clone had horizontally acquired the type I
arginine catabolic mobile element (ACME) from Staphylococcus
epidermidis [30] . It is thought that type I ACME promotes both
the growth and survival of, and enhances colonization of, human
skin, with USA300. Type I ACME is physically linked to type IV
SCCmec, suggesting that there may be a link between pathogenicity and antimicrobial resistance. Dissemination of the
USA300 clone from the community into the hospital setting
may be aided by both the presence of type I ACME and type IV
SCCmec [31,32] .
Historically, CA-MRSA strains tend to be more sensitive
to antimicrobials than HA-MRSA strains [3,7,33,34] . Strains of
CA-MRSA tend to retain susceptibility to non-β-lactam antimicrobials, such as trimethoprim/sulfamethoxazole, clindamycin,
gentamicin and tetracyclines. However, recent reports have suggested that multidrug-resistant strains are emerging. Diep et al.
described a high incidence of multidrug-resistant CA-MRSA
caused by clone USA300 in San Francisco, CA, USA [35] . Men
who have sex with men (MSM) sex appeared to be a risk factor
for acquisition, suggesting that sexual transmission of this strain
may occur. These new data are worrying, as we could be seeing the rise of multidrug-resistant, virulent and easily transmissible strains of CA-MRSA to the epidemic proportions seen with
HA-MRSA. Without the development of new agents, treatment
options will be limited for a condition that was often previously
Expert Rev. Anti Infect. Ther. 6(5), (2008)
Current challenges in treating MRSA
treated within the community with oral antibiotics [36] . Clonal
diversity and transmission will mean that there will no longer be
any real distinction between HA-MRSA and CA-MRSA.
The increasing prevalence of CA-MRSA is of concern, not
only because of its transmissibility but also because currently
there are no effective decolonization strategies for it [37] . Typical
decolonization regimes used to eradicate HA-MRSA have not
been studied extensively for use in CA-MRSA; however, the utility of mupirocin in such regimens may be limited by the emergence of CA-MRSA strains with high-level resistance to mupirocin, especially in subtypes of the USA300 clone, as described
by Han et al. at a health center in Boston in 2007 [38] . The
same study also showed clindamycin- and tetracycline-resistant
USA300 clones. A 2008 Cochrane review of antimicrobial drugs
for treating HA-MRSA found ‘insufficient evidence to support
use of topical or systemic antimicrobial therapy for eradicating
nasal or extranasal MRSA’ [39] . Due to a lack of clinical trials,
currently there is not enough evidence to support decolonization
therapy for CA-MRSA. With repeated skin infections, increased
risk of shedding of the organism from infected skin coupled
with a lack of an effective decolonization regimen could mean
persistence and/or transmission of MRSA within the community. The organism can be present on fomites such as personal
possessions and towels, again resulting in transmission to other
individuals. Inadequate hand hygiene can also facilitate transmission. Several members of a household may be colonized/
infected, making eradication or reduction of MRSA within the
community very difficult.
Decolonization can only work if there is an effective screening policy in place. Rapid tests are now available that allow for
the detection of MRSA in carriers on admission to healthcare
facilities, enabling prompt patient isolation and the institution
of decolonization regimes.
Currently, there is an overall lack of supportive evidence for
universal screening [40] . The reason for this may be multifactorial, with cost, availability and implementation of isolation/
decontamination and timing of screening all being important
considerations. It is difficult to control for so many variables in
a study.
There are three important limitations of screening. First, MRSA
decolonization therapy is not wholly effective (50–60% effective
for long-term clearance) and long-term and recurrent therapy, as
well as mass use, with mupirocin may lead to resistance.
Second, isolation and barrier nursing is essential in the prevention of transmission of MRSA. Current UK guidelines recommend that in new hospitals, at least 50% of all beds should be
in side rooms with en suites to prevent transmission of healthcare-associated infections (HCAIs) [41] . However, many hospitals in the UK are old, with nowhere near this number of
side rooms available. A similar situation exists in hospitals in
many other countries. The additional problems of Clostridium
difficile and other multidrug-resistant organisms means prioritization of side rooms for patients with the most transmissible
conditions. Understaffing of nursing and medical personnel,
bed occupancy often above the recommended 85% and patients
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with increasingly complex medical conditions all act to impede
successful barrier nursing and strict infection-control practices.
Eradication of MRSA can only be successful if there are adequate
resources to implement safe practices.
Third, while PCR is an effective and time-saving method of
screening for MRSA, its cost means that it may not be suitable for mass screening. Once universal screening is in place, no
doubt studies will be undertaken to determine if this is a costeffective exercise and a useful tool in the fight against MRSA.
The problem of CA-MRSA may mean that screening will need
to be extended to household contacts of known carriers. This
will have huge cost implications as well as presenting practical
issues of screening so many patients. Studies will need to be
undertaken to see if there is any benefit to be obtained though
screening this population.
It is likely that the controversy surrounding policies of universal MRSA screening as a tool to help reduce rates of MRSA
infection and transmission may persist until further robust
evidence is available.
Other approaches to prevent MRSA infection in the future
include the development of a vaccine against staphylococci.
Problems encountered with developing a vaccine include a failure
of whole-cell live or killed vaccines, as well as conjugate polysaccharide vaccines, to elicit an adequate and long-lasting immune
response [42,43] . The large number of virulence factors possessed
by the organism also hinders the development of an effective
vaccine, with single immunological targets having limited use
for this purpose [44] . Despite these limitations, the widespread
problem of MRSA means that there continues to be work into the
development of a suitable and long-lasting vaccine [44,45] .
The many problems surrounding MRSA mean that newer
strategies are required, both for the rapid diagnosis and for the
successful management of both CA-MRSA and HA-MRSA,
to prevent further dissemination into both the community and
hospital environments in epidemic proportions.
New agents to overcome MRSA
Traditionally, there has been a limited antimicrobial armamentarium for use against MRSA, with glycopeptides being the main
agents used. Known shortcomings of glycopeptides include poor
tissue penetration, poor oral bioavailability and a narrow therapeutic window, necessitating the monitoring of serum drug levels.
More recently, there have been reports of increasing MICs over
time, a phenomenon termed ‘vancomycin creep’ [46] . Although the
MICs remain within the susceptible range, the higher MICs may
be associated with higher rates of clinical failure [47] . The British
Society for Antimicrobial Chemotherapy Bacteraemia Resistance
Surveillance Programme has recently reported a rise in vancomycin
MICs for MRSA at various centers in the UK and Ireland [48] .
Problems in detecting this creep using routine methods of antimicrobial susceptibility testing (e.g., disk diffusion and automated
testing) means that this phenomenon may go unnoticed [49] .
There have been rare reports of vancomycin-resistant S. aureus
(VRSA), glycopeptide-intermediate S. aureus (GISA) and hetero­
geneous glycopeptide-intermediate S. aureus (hGISA) strains [50]
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and it seems possible that the increase in MICs may be associated with the emergence of these strains. In the case of hGISA,
glycopeptide therapy kills the dominant glycopeptide-susceptible
population, allowing the glycopeptide-resistant subpopulation to
predominate. hGISA infection is associated with a poorer outcome than MRSA infection [51] . A recent report from Detroit
(MI, USA) has shown a significant increase in the prevalence of
heterogeneous vancomycin-intermediate S. aureus (VISA) over
a 20-year period (from 2.27% between 1986 and 1993 to 8.2%
between 2003 and 2006) [52] . This time period correlates with the
start of the MRSA epidemic and the subsequent increase in vancomycin use. Glycopeptides are inadequate to treat these strains
and the development of alternative, effective agents is crucial for
the management of VRSA, GISA and hGISA infections.
In the 1990s, concern over the potential of MRSA to increase
to endemic levels and the known shortcomings associated with
glycopeptides encouraged the development of new agents to overcome this problem. We are now beginning to see the results of
this research. These new agents have improved efficacy against
MRSA, with greater tolerability and/or bioavailability than
vanco­mycin, which may help in reducing the mortality and
morbidity associated with these resistant strains.
A slow rate of emergence of resistance and lack of equally cheap,
alternative agents has meant that vancomycin has been the most
commonly used drug for the treatment of MRSA infections.
However, there are a number of shortcomings regarding vancomycin. First, it may not have sufficient tissue penetration and may
not achieve adequate levels in cerebrospinal fluid (CSF) or in hte
lung. In mechanically ventilated patients, it has been shown that
concentrations of vancomycin in epithelial lining fluid of the lung
is only 14–16% of that in serum [53,54] . Continuous infusion of
vancomycin also shows similar limitations; Moise-Broder et al.
showed that in patients undergoing cardiac surgery, tissue-toplasma ratios of vancomycin were only 0.3 in non­diabetic patients
and only 0.1 in diabetic patients [55] . In CSF, these levels are
enhanced by the presence of inflammation; however, a recent
study has shown that adequate levels of vancomycin may be
achieved when concomitant steroids are given [56] . Nevertheless,
there remains some concern about the reliability of vancomycin
in the treatment of CNS infections and pneumonia.
There is also a small but increasing number of strains of MRSA
that have either full or intermediate susceptibility to vanco­mycin
(VRSA, hGISA and VISA) [57,58] . In the case of VRSA, it is
thought that the organism acquires the vanA resistance operon
from vancomycin-resistant enterococci (VRE) in the presence
of concurrent infection with these organisms [59] . VISA infections tend to occur with prolonged vancomycin therapy and
are associated with resistant bacteria which possess thick cell
walls [60] . As discussed, hGISA has been described, involving a
small subpopulation that has a MIC of vancomycin within the
intermediate or resistant range [61] . Vancomycin tolerance can
also be seen. This is a state where the bacteria are suppressed but
not killed by vancomycin therapy. This can be determined in
the laboratory by a minimum bactericidal concentration:MIC
ratio of greater than 32 [62] .
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The shortcomings of vancomycin means that newer agents
are needed to overcome MRSA. The problem of developing
resistance among strains of CA-MRSA means that treatment
options within the community are becoming limited. Over
recent years, a number of novel agents have been marketed,
with other agents also being developed. These agents vary in
their pharmacodynamic and pharmacokinetic profile, as well as
tissue penetration and distribution. This allows different infections at a range of body sites to be treated, both in the in-patient
and outpatient settings.
Linezolid (Zyvox®, Pharmacia/Pfizer, Inc.)
This oxazolidinone, marketed by Pfizer, is the first of its class;
by binding at the 23S subunit of the 50S ribosome to prevent
formation of the 70S ribosomal complex, it inhibits the initiation
of protein synthesis. It is bacteriostatic against MSSA, MRSA,
coagulase-negative staphylococci (CoNS), enterococci (including VRE strains) and streptococci (including penicillin-resistant
and multidrug-resistant pneumococci). It demonstrates in vitro
activity against some Gram-negative organisms (Bacteroides spp.,
Moraxella catarrhalis and Pasteurella spp.) but is not generally
thought to be efficacious against most other Gram-negative bacteria due to its elimination via efflux pumps [63] . Linezolid has antianaerobic activity, being active against C. difficile, Clostridium
perfringens, Bacteroides and Fuseobacterium spp.
Linezolid was first approved for use in the UK in 2001 and
is currently licensed for pneumonia and skin and soft-tissue
infections (both complicated and noncomplicated) caused by
Gram-positive organisms. It has been shown to be at least as
efficacious as (and superior to in many studies) vancomycin
for the treatment of hospital-acquired and nosocomial pneumonia [63–67] . Linezolid is not currently licensed in the UK
for the treatment of MRSA bacteremia; however, there have
been reports of successful treatment of this condition with linezolid, either used alone or in combination with rifampicin
or fusidic acid [68,69] . Schorr et al. pooled and analyzed five
randomized trials comparing linezolid with vancomycin for
the treatment of secondary S. aureus bacteremia and found it
to be noninferior for this indication [70] . It has excellent tissue
penetration. Linezolid has reasonable penetration into the CSF
[71] and studies have shown it to be adequate for the treatment of
CSF shunt infections caused by CoNS and other Gram-positive
organisms [71,72] . There have been reports of both treatment failures (monotherapy) [73] and successes (linezolid used alone and in
combination with either rifampicin, gentamicin, fusidic acid or
amikacin) [74–76] for MRSA endocarditis associated with linezolid
use. Further data are required regarding the use of a bacteriostatic
agent for the treatment of endocarditis, as bactericidal drugs are
preferential treatment for this condition.
Linezolid has 100% bioavailability at the standard dose of
600 mg twice daily, making it an effective oral as well as intravenous agent against MRSA. After only 1–2 h of oral dosing,
maximal plasma levels are achieved. The half-life is 4.26–5.4 h
[77] . The drug is distributed well into tissues, demonstrating
only 31% protein binding [78,79] . However, reversible bone
Expert Rev. Anti Infect. Ther. 6(5), (2008)
Current challenges in treating MRSA
marrow suppression may occur as a side effect, most commonly
following prolonged therapy (greater than 14 days) [78,80] , and
necessitates regular monitoring of full blood counts. If myelo­
suppression occurs, discontinuation of the drug should be considered. Peripheral and optic neuropathies have also been described
in association with treatment durations greater than 28 days. Lactic
acidosis is a rare but serious side effect, not associated with either
duration or dosage of this agent. Linezolid is also a weak reversible, nonselective monoamine oxidase inhibitor and has been
associated with the serotonin syndrome [78,81–83] . Concomitant
therapy with other drugs should be reviewed carefully before
prescribing this antibiotic.
Linezolid is excreted mainly via the urine (with 30% of the
drug excreted unchanged), as well as nonrenal routes. It does
not require therapeutic drug monitoring and there is no need for
dosage adjustment in renal or hepatic impairment [71] .
In 2007, Pfizer and the US FDA released an alert because of new
safety concerns following the results of an as yet unpublished openlabel, randomized trial comparing linezolid with comparator antibiotics (vancomycin, oxacillin and dicloxacillin) for the treatment
of critically ill patients with intravascular catheter-related bloodstream and catheter-site infections. The study showed that treatment with linezolid resulted in higher mortality compared with the
comparator antibiotics. This difference in mortality was not seen
in pure Gram-positive infections, but was seen in those patients
with pure Gram-negative infections, in those with Gram-negative/
Gram-positive infections and in those treated with linezolid who
did not have an infection at the time of entering the study. The new
safety alert has stated that ‘linezolid is not approved for the treatment of catheter-­related bloodstream infections, catheter-site infections, or for the treatment of infections caused by Gram-negative
bacteria’ [202] . Linezolid should not be used as monotherapy in
mixed MRSA and Gram-negative infections.
As with clindamycin, linezolid has been shown to reduce the
production of Panton Valentine leukocidin (PVL), α-hemolysin
and toxic-shock-syndrome toxin [84] , making it an important
agent in the treatment of Gram-positive causes of toxic shock
and also of necrotizing fasciitis and pneumonia.
Resistance to linezolid has been described in VRE [85,86] ,
with the mechanism being a G2576U ribosomal mutation at
the binding site [87] . Rare cases of linezolid-resistant strains of
S. aureus emerging during therapy have been reported [88] , and
an intrinsic linezolid-resistance gene in a strain of MRSA has also
been described. Transferable resistance has also been noted in
one case [89] . Nevertheless, overall, the high activity of linezolid
(MIC90 2 mg/l) means that it remains an excellent choice in the
treatment of MRSA infections.
Quinupristin–dalfopristin
(Synercid®, King Pharmaceuticals)
This streptogramin consists of a 30:70 ratio of two semisynthetic
pristinamycin derivatives, quinupristin and dalfopristin. This
combination allows for synergistic inhibition of bacterial protein
synthesis at the 50S ribosome. It is bactericidal against MRSA,
MSSA and Streptococcus pyogenes but is bacteriostatic against
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vanco­mycin-resistant Enterococcus faecium (VREF); most strains
of Enterococcus faecalis are inherently resistant to it [82,83] . The
half-life of synercid is 0.70–0.85 h [90] .
It is approved for use in the UK for serious Gram-positive infections, including hospital-acquired pneumonia, skin and soft-tissue
infections and infections due to VREF. Quinupristin–dalfopristin
is occasionally used for the treatment of VREF bacteremia but its
use in the treatment of endocarditis and pneumonia is limited by
concerns over its safety profile and potential drug interactions.
Resistance to quinupristin–dalfopristin in MRSA is rare [87] .
The SENTRY antimicrobial surveillance program has reported
resistance to quinupristin–dalfopristin in 10.0% of all E. faecium
isolated in Europe and in 0.6% of all E. faecium isolated in North
America [91] .
A further limitation of quinupristin–dalfopristin is that it has
poor bioavailability and can only be given by intravenous infusion through a central vein [79,83] , precluding its use in less serious
infections in patients who otherwise would not need a central
venous catheter.
The drug is mainly eliminated through bile in the feces. Renal
impairment may reduce clearance. Quinupristin–dalfopristin
has a considerable toxicity profile, including hepatotoxicity,
hyper­bilirubinemia, myalgias, arthralgias and, in up to 74%
of patients, thrombophlebitis [79,81,83] . The British National
Formulary recommends dose reduction in moderate hepatic
impairment and avoidance in severe hepatic impairment or if
the plasma bilirubin concentration is or becomes greater than
three-times the upper limit of reference range [92] . It is also contraindicated in breastfeeding. Quinupristin–dalfopristin inhibits
the activity of cytochrome P450 3A4 and, thus, can interact with
other drugs, including ciclosporin. Quinupristin–dalfopristin
does not itself induce QTc prolongation but can interfere with
the metabolism of other drugs that may cause this, necessitating close monitoring. The presence of other agents with greater
efficacy, less troublesome side effects and greater ease of administration means that quinupristin–dalfopristin is not usually
considered to be a first-line agent for MRSA infections.
Daptomycin (Cubicin®, Cubist Pharmaceuticals)
Daptomycin is a semisynthetic cyclic lipopeptide derived from
the fermentation products of Streptomyces roseosporus. This rapidly
bactericidal antibiotic has a novel mechanism of action, requiring physiological levels of Ca 2+. The lipophilic tail of dapto­
mycin inserts into the bacterial cell membrane. This results in
rapid membrane depolarization and potassium efflux, which
stops DNA/RNA and protein synthesis. Daptomycin has a long
postantimicrobial effect and its activity is concentration dependent [93–95] . The half-life of daptomycin is 7–9 h [96] . The current
recommended doses are 6 mg/kg once daily for bacteremia and
endovascular infections and 4 mg/kg once daily for complicated
skin and skin-structure infections (cSSSIs).
Daptomycin is only effective against Gram-positive organisms,
including MRSA, MSSA and VRE. It is also active against strains
of linezolid- and Synercid (quinopristin–dalfopristin)-resistant
strains of VRE [93,94,97,98] .
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Daptomycin is efficacious in, and currently indicated for use
in cSSTIs [99,100,101] . Fowler et al. recently published the results
of an open-label trial that showed a nonsignificant increase in
successful treatment of bacteremia and endocarditis (including
right-sided cases) due to MRSA and MSSA [102] . The authors
used gentamicin plus either an antistaphylococcal penicillin or
vancomycin as comparator agents. Many of the cases of persistent or relapsed bacteremia were attributed to complicated bacteremia associated with the presence of indwelling devices and/
or osteomyelitis. The findings of a systematic review by Falagas
et al. in 2006 confirm that further studies on the use of daptomycin for bacteremia and/or endocarditis are warranted [103] .
Microbiological failures have been described during prolonged
therapy with daptomycin and were associated with an increase
in MIC during the treatment phase [98,104,105] . The underlying
resistance mechanism for this is poorly understood.
Daptomycin is inhibited by pulmonary surfactants, precluding
its use in pneumonia [106] . It has been successfully used for the
treatment of bone and joint infections, although clinical trials
are lacking [98,107] .
Adverse effects include a dose-dependent rise in creatinine
kinase, which may be accompanied by myopathy, and derangement of hepatic transaminases [100,102] . Dose adjustment is required
for renal impairment. There are insufficient data regarding the
use of daptomycin in pregnancy or breastfeeding.
It has been shown that the MIC of daptomycin to MRSA increases
in cases of prior exposure of MRSA to vancomycin. It is thought that
heterogenous vancomycin resistance develops, producing a thickening of the bacterial cell wall that impedes the entry of the large
daptomycin molecule into the organism [108–110] . However, Wooton
et al. demonstrated that the bactericidal activity of daptomycin is
not significantly affected by this phenomenon [109] .
Daptomycin has a relatively low toxicity profile and its once-daily
dosing means that it has a place in prolonged and/or outpatient
therapy. However, in mixed Gram-negative and -positive infections,
another agent with a broader spectrum may be more appropriate.
It has the advantage over some of the newer anti-MRSA agents
of having Gram-negative activity, notably against Haemophilus
influenzae, Neisseria spp., Acinetobacter spp. (including multidrugresistant strains) and Enterobacteriacae [112–114] . It has variable
activity against Providencia and Burkholderia spp. but tends to
be active against other nonfermenting Gram-negative organisms.
In Pseudomonas aeruginosa and Proteus spp., resistance mainly
occurs via MexAB-OprM and AcrAB efflux pumps, respectively
[115–117] . It also shows good in vitro activity against some atypical
pathogens, such as Mycobacterium chelonae, Mycobacterium abscessus, the Mycobacterium fortutium group, Mycobacterium marinum,
Mycoplasma spp. (Mycoplasma hominis and Mycoplasmapneumoniae)
and Ureaplasma urealyticum [118] .
Tigecycline is currently indicated for the treatment of cSSSIs
and complicated abdominal infections caused by multiple-anti­
bacterial-resistant organisms. It has been shown to be an efficacious drug for the treatment of both skin and skin-structure
infections and intra-abdominal infections, and is as efficacious as
vancomycin/aztreonam and imipenem–cilastin in randomized,
double-blind studies [119–122] . Trials comparing tigecycline and
meropenem for the treatment of intra-abdominal infection are
ongoing, as are trials for the treatment of bloodstream infections.
Early results of a Phase III multicenter, double-blind trial comparing tigecycline against imipenem–cilastin for the treatment
of hospital-acquired pneumonia showed that it did not achieve
noninferiority in ventilator-associated pneumonia [123] . Further
studies are warranted to assess its utility in the treatment of
hospital-acquired and ventilator-associated pneumonia.
To date, tigecycline has not been associated with any significant
adverse effects, dose-dependent nausea and vomiting being the
most common [113] . Vouillamoz et al. recently showed that no
adverse interactions occur when tigecycline is used in combination with other antimicrobials, which may make it a useful drug
in the treatment of mixed multidrug-resistant infections [124] . To
date, there have not been any reports of tigecycline resistance in
MRSA isolates.
Tigecycline (Tygacil®, Wyeth Pharmaceuticals)
Ceftobiprole (Zeftera™, Johnson & Johnson
Pharmaceuticals/Basilea Pharmaceutica)
Tigecycline, a derivative of minocycline, is a bacteriostatic glycylcycline, a new class of antimicrobial agent. Modification of the
side chain enhances binding to the 30S ribosomal subunit, with
subsequent inhibition of protein synthesis. This modification
also makes it less susceptible to the Tet(A-E) and Tet(K) efflux
pumps, the latter of which are predominantly associated with
resistance to tetracycline in staphylococci [111,112] .
Tigecycline has a half-life of 36 h and less than 15% of the
unchanged drug is excreted in the urine. It exhibits extensive
protein binding (~68%) that increases with increasing dose and
has a large volume of distribution (>10 l/kg). The recommended
dose of tigecycline is 100 mg then 50 mg intravenously twice
daily [113] .
Tigecycline has a broad spectrum of activity, being active against
MRSA, penicillin-resistant pneumococci, vancomycin-susceptible
and -resistant enterococci, b-hemolytic streptococci and Listeria
monocytogenes, as well as tetracycline-resistant strains of MRSA.
606
This novel broad-spectrum bactericidal cephalosporin has been
shown to be effective against MRSA. It is currently the most
studied of its class for activity against this organism. It is highly
active against MRSA, with a high affinity for PBP2´ [125–130] . It
also has a high affinity for PBP2x, the penicillin-binding protein
which is associated with resistance in pneumococci [130,131] . It is
available in intravenous formulation and has a half-life of 3–4 h.
The dosing regimen is 500 mg three-times daily.
Conversion of the water-soluble prodrug, ceftobiprole medocaril, to the active drug, ceftobiprole, in plasma is rapid. It distri­
butes into the extracellular compartments. The drug is excreted
renally, almost entirely unchanged, necessitating dose adjustment
in renal impairment [125,128,130] .
Ceftobiprole is potent against MRSA, VISA and penicillinresistant pneumococci, with poor activity against E. faecium.
However, unusually for a cephalosporin, it has bactericidal
Expert Rev. Anti Infect. Ther. 6(5), (2008)
Current challenges in treating MRSA
Review
Table 1. Profile of new and current agents for the treatment of MRSA.
Drug name Class
Site of action Half-life Stage of
Bactericidal
(h)
development
or
bacteriostatic
for MRSA
Resistance
mechanism
Clinical use
Linezolid
Oxazolidinone
Bacteriostatic
23S subunit of
50S ribosome
4–5
Currently
licensed for use
worldwide
G2576U
ribosomal
mutation at
binding site
cSSSIs including
diabetic foot
infections due to
MRSA and
uncomplicated skin
and skin-structure
infections; HAP/CAP;
infections associated
with vancomycinresistant
Enterococcus faecium
Synercid
Streptogramin
Bactericidal
50S ribosome
0.7–0.8
Currently
licensed for use
worldwide
Streptogramin- cSSSIs; HAP,
vancomycin-resistant
resistance
E. faecium bacteremia
genes vatD,
vatE and vgbA
and the
macrolideresistance
gene ermB
(E. faecium)
Daptomycin
Cyclic lipopeptide
Bactericidal
Cell membrane 7–9
Currently
licensed for use
worldwide
Possibly
thickening of
bacterial cell
wall with
vancomycin
therapy
Tigecycline
Glycylcycline
Bacteriostatic
30S ribosome
36
Currently in use, No reports of
ongoing clinical resistance
so far
trials for
HAP/VAP
cSSSIs; complicated
abdominal infection
Ceftobiprole
Novel
cephalosporin
(β-lactam)
Bactericidal
PBP (especially
PBP2’ and
PBP2x)
3–4
Under review by Undefined at
present
regulatory
authorities in
Canada, the EU
and Switzerland
HAP/VAP; cSSSIs
Ceftaroline
Novel
cephalosporin
(β-lactam)
Bactericidal
PBP2’
0.6–2.4
Phase III trials
cSSSIs; HAP/VAP
Dalbavancin
Secondgeneration
glycopeptide
Bactericidal
Bacterial cell
wall
123–210
Not described
US FDA
fast-track status
Phase III trials
cSSSIs
Oritavancin
Secondgeneration
glycopeptide
Bactericidal
Bacterial cell
membrane
100
Phase III trials
Not described
cSSSIs
Telavancin
Lipoglycopeptide
Bactericidal
Bacterial cell
wall and
membrane
7–11
Phase III trials
Not described
cSSSIs
Undefined at
present
cSSSIs; right- and
left-sided
endocarditis;
staphylococccal
bacteremia
CAP: Community-acquired pneumonia; cSSSI: Complicated skin and skin-structure infection; HAP: Hospital-acquired pneumonia; MRSA: Methicillin-resistant
Staphylococcus aureus; PBP: Penicillin-binding protein; VAP: Ventilator-associated pneumonia.
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607
Review
Ratnaraja & Hawkey
Table 1. Profile of new and current agents for the treatment of MRSA (cont.).
Drug name Class
Site of action Half-life Stage of
Bactericidal
(h)
development
or
bacteriostatic
for MRSA
4
Resistance
mechanism
Clinical use
Fast-track status
Phase III trials
for cSSSIs,
Phase II trials for
HAP/VAP and
intravenous-tooral switch
Resistance is
rare;
mechanism
has not been
described
cSSSIs; HAP
Iclaprim
Diaminopyrimidine Bactericidal
Bacterial folate
pathway
Ranbezolid
Novel
oxazolidinone
Bacteriostatic
23S subunit
Not
of50S ribosome available
Completed
Phase I trials
Target
modification
Intravenous catheterrelated infections
Tomopenem
1β‑methyl­
carbapenem
Bactericidal
PBPs 1, 2 and 4 2
Phase II trials
Not described
As yet undetermined
CAP: Community-acquired pneumonia; cSSSI: Complicated skin and skin-structure infection; HAP: Hospital-acquired pneumonia; MRSA: Methicillin-resistant
Staphylococcus aureus; PBP: Penicillin-binding protein; VAP: Ventilator-associated pneumonia.
activity against E. faecalis (both vancomycin-resistant and -susceptible strains) at therapeutically achievable concentrations.
Its broad spectrum means that it is active against many Gramnegative pathogens, including H. influenzae, Neisseria gonorrhoeae, Moraxella catarhalis and extended-spectrum-β-lactamase
(ESBL)-negative Enterobacteriaceae. It is also active against nonfermenting Gram-negative pathogens, such as P. aeruginosa and
Acinetobacter baumannii. Ceftobiprole is not stable to metalloβ-lactamases and is hydrolyzed by ESBL-producing organisms. It has some activity against Gram-positive (Actinomyces,
Clostridium, Fuseobacterium and Veillonella spp., among others)
but not Gram-negative anaerobes [125–129,132,133] .
Ceftobiprole has been granted fast-track status by the FDA for
the indications of healthcare-associated pneumonia and cSSSIs.
Two multicenter, randomized, double-blind trials have recently
been completed. The first compared ceftobiprole with vancomycin plus ceftazidime for the treatment of cSSSIs [134] and the
second compared ceftobiprole with vancomycin for the treatment
of cSSSIs caused by Gram-positive bacteria [135] . Both studies
showed noninferiority against the comparator antimicrobial
regimens. Nausea and taste disturbances were the most common
symptoms reported.
A recent Phase III trial comparing ceftobiprole with ceftazidime plus linezolid showed noninferiority in both the clinically
evaluable and intention-to-treat patient groups for the treatment
of hospital-acquired pneumonia; however, noninferiority was not
achieved in the ventilator-associated pneumonia subgroup [203] .
Ceftobiprole has obtained regulatory approval from Health
Canada for the treatment of cSSSIs, including diabetic foot infections, and is currently being reviewed by regulatory authorities in
the EU and Switzerland.
The broad spectrum of activity of ceftobiprole makes it a welcome addition to the armamentarium of agents that can overcome
MRSA. However, the three-times daily infusions, each lasting
1–2 h, and lack of oral formulation, may make it less amenable
to use in outpatient therapy.
608
Ceftaroline (Forest Laboratories, Inc.)
Ceftaroline is another novel cephalosporin that is currently under
development. It is administered clinically as an N-phosphono prodrug. As with ceftobiprole, it exhibits a high affinity for PBP2´
and has potent activity against MRSA and vancomycin-resistant
staphylococci, as well as many streptococci and Enterobacteriaceae
[136–138] . It has variable activity against E. faecalis and minimal
activity against anaerobes and nonfermenting bacteria (especially P.
aeruginosa). Mustaq et al. found that this drug may be susceptible
to hydrolysis by classical TEM and SHV β-lactamases as well as
ESBLs, although this is reversible with clavulanate [136] .
Owing to its poor bioavailability, ceftaroline must be given
intravenously [79] . It has a half-life of 0.6–2.4 h, necessitating
frequent dosing [79,139] . The optimal dosing regimen has yet to
be determined.
Experimental in vivo studies using a rabbit model have been performed, showing that ceftaroline is more efficacious than vanco­
mycin or linezolid in the treatment of endocarditis. It was also shown
to be the most efficacious agent against a strain of GISA [139] .
A multicenter Phase II trial recently showed noninferiority of
ceftaroline versus vancomycin plus aztreonam for cSSSIs [140,141] .
Phase III trials are in progress, including one comparing ceftaroline
with ceftriaxone for the treatment of community-acquired pneumonia. Early results from this trial look promising, showing some
superiority over ceftriaxone [142] .
Earlier this year, Novexel and Forest Laboratories announced
an agreement to develop Novexel’s novel intravenous β-lactamase
inhibitor, NXL 104, with Forest’s ceftaroline [204] . Phase I trials of
this ceftaroline/NXL 104 combination are expected to start in 2009.
If successful, this combination may eliminate the major drawback
associated with this otherwise promising antimicrobial.
Dalbavancin (Zeven®, Pfizer, Inc.)
Dalbavancin is a semisynthetic derivative of A-40926, a teicoplanin-like glycopeptide. It is a bactericidal second-generation
glycopeptide, formed by modifying the functional groups and
Expert Rev. Anti Infect. Ther. 6(5), (2008)
Current challenges in treating MRSA
sugar moieties of A-40926 but maintaining the d-alanyl-d-alanine
binding site. Dalbavancin acts by disrupting the formation of the
bacterial cell wall.
Dalbavancin has a unique pharmacokinetic profile with a
half‑life of 123–210 h, which allows effective once-weekly dosing. Because of poor oral bioavailability, it is only available in an
intravenous formulation. Dalbavancin has a volume of distribution of 10 l, high protein binding (>95%) and a systemic clearance
of 0.05 l/h. A total of 33% of the intact drug is excreted via the
urine [143,144] .
Following administration of a first dose of 1 g, the weekly dose of
dalbavancin is 500 mg. It has a similar spectrum of activity to teicoplanin and other glycopeptides, being active against staphylococci
(MSSA, MRSA and CoNS) and enterococci (including vanB- and
vanC- but not vanA-positive strains). Dalbavancin is potent against
GISA, linezolid-resistant strains of S. aureus, penicillin-resistant
and -susceptible strains of pneumococci and viridans streptococci
[144,145] . In vitro MIC90 values for dalbavancin against MRSA and
MSSA isolates, and methicillin-resistant and -sensitive isolates of
CoNS, are similar or lower than that for vancomycin or teicoplanin
[146] . Dalbavancin is also active against Gram-positive anaerobes,
Clostridium spp. and many fastidious aerobes. It is inactive against
Clostridium clostridioforme and some Lactobacillus spp. and lacks
any activity against Gram-negative organisms [145] .
Dalbavancin has been shown in vitro to have superior activity
against MSSA and MRSA compared with vancomycin [147] . It has
been shown to be as efficacious as linezolid for the treatment of
cSSSIs (including those due to MRSA) when given as a 14-day
course; clinical success was seen in 90% of the dalbavancin arm
and 92% of the linezolid arm at the test-of-cure visit in the 2005
randomized, double-blind study by Jauregui et al. [148] .
In 2005, Raad et al. published the results of a Phase II openlabel randomized controlled multicenter study of 75 patients with
catheter-related bloodstream infections caused by Gram-positive
organisms, including MRSA, MSSA, CoNS and enterococci [149] .
They compared a 14-day course of treatment of dalbavancin with
twice-daily vancomycin. Treatment with dalbavancin was associated with a significantly higher success rates than treatment with
vancomycin.
Dalbavancin has only been associated with mild side
effects, mainly headaches and gastrointestinal symptoms [144] .
Hypokalemia and, rarely, hypotension have been reported [149] .
Currently, there have been no reports of an association between
dalbavancin use and C. difficile-associated diarrhea. Dalbavancin
is not a substrate for the cytochrome P450 system and there are
no known significant drug interactions [145] .
The unique pharmacological profile and excellent safety profile
make dalbavancin an attractive option for the treatment of MRSA
infections, especially in the outpatient setting. In the long run, it
may lead to significant savings due to shorter in-patient stay.
Oritavancin (Targanta Therapeutics)
Oritavancin is modified from vancomycin by substitution of the
vancosamine of the disaccharide moiety by an epivancosamine
[83,151] . It acts by disrupting transmembrane potential and is rapidly
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Review
bactericidal, with concentration-dependent activity and a postantibiotic effect [82,150] . Oritavancin has a half-life of approximately
100 h [84] .
Similar to vancomycin, oritavancin is active against many
Gram-positive organisms, including MRSA, glycopeptide-resistant enterococci (including vanA-positive strains), streptococci,
Pepostreptococcus spp., Propionibacterium spp., Clostridium perfringens and Corynebacterium jeikeium, but is more potent and consistently exhibits lower MICs of less than 1 mg/l. It is active against
penicillin-intermediate and -resistant strains of Streptococcus pneumoniae and is unaffected by methicillin resistance in both coagulase-positive staphylococci and CoNS. Oritavancin has no activity
against Gram-negative organisms, including anaerobes [150–154] .
It has been shown that in bacteremia, the percentage of time that
the free oritavancin is above the MIC is important for the microbiological response [152,155] . Oritavancin achieves good concentrations in
both plasma and blister fluid, making it a suitable candidate for the
treatment of cSSSIs [154] . It is slowly eliminated from the body, taking 7 days for 6% of a single dose to be eliminated. Oritavancin has
a long half-life at approximately 100 h [153] and it is expected that the
recommended dosing regimen will be once daily or once on alternate
days. This will enable it to be used in the outpatient setting.
Oritavancin has been shown to be as efficacious as either vanco­
mycin or a β-lactam for the treatment of S. aureus bacteremia [156] .
Unpublished Phase III trial data have shown equivalence with vancomycin and cephalexin for the treatment of cSSSIs [157,158] . After
a delay in the submission by Intermune for a new drug application
for oritavancin due to adverse events (rash and phlebitis), further
Phase III trials are ongoing.
Resistance to oritavancin has not been demonstrated among
strains of S. aureus, including VISA, although reduced susceptibility to oritavancin has been seen in vitro among VanA and VanB
strains of enterococci [82,150] .
If safety concerns are eliminated, oritavancin may be a promising alternative to traditional glycopeptides for the treatment of
MRSA infection.
Telavancin (Theravance, Inc.)
Being a semisynthetic analog of vancomycin, telavancin is a rapidly bactericidal lipoglycopeptide. It blocks the transpeptidation
and transglycosylation steps involved with peptidoglycan chain
formation. It also acts directly on the bacterial cell membrane,
changing its permeability [79,82,151,159] .
Telavancin shows enhanced activity against streptococci (including penicillin-resistant and -sensitive strains of S. pneumoniae) compared with vancomycin and is active against enterococci, including
vanA-positive organisms [82,151,159–163] . It is also more potent against
MRSA, MSSA (albeit to a lesser extent compared with that shown
against streptococci) and GISA compared with vancomycin and
linezolid [163] .
This rapidly bactericidal drug that exhibits concentrationdependent killing has a half-life of 7–11 h and a long postantibiotic effect [79,163] . The recommended dose is 10 mg/kg
intravenously once daily. It has poor oral bioavailability and so
must be given intravenously.
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Review
Ratnaraja & Hawkey
Telavancin distributes well into the tissues following intra­
venous administration and is highly effective for the treatment
of skin and soft-tissue infections. Stryjewksi et al. recently published the results of two parallel, randomized, double-blind,
active-controlled Phase III studies that showed noninferiority
of telavancin compared with either vancomycin or antistaphylococcal penicillin for the treatment of cSSSIs caused by Grampositive organisms [160,162] . Adverse events included nausea, taste
disturbance, insomnia and headache.
There have been some concerns about QTc elevation during
therapy with telavancin. The FAST 2 study, a Phase II trial
designed to assess the safety and efficacy of telavancin in patients
with cSSSIs, confirmed that a 12.5-ms QTc prolongation was
seen in patients receiving this drug [160] . The clinical significance
is uncertain and more trials are warranted to see if this effect of
therapy will preclude its inclusion in the armamentarium against
MRSA and other Gram-positive infections.
Iclaprim (Arpida Ltd)
Similar to trimethoprim, iclaprim selectively inhibits bacterial
dihydrofolate reductase (DHFR), which is an essential enzyme in
the bacterial folate pathway. However, this novel diaminopyrimidine differs from trimethoprim in that it is active against trimethoprim-sensitive DHFRs (seen with S. aureus and S. pneumoniae)
[164–166] . It also has an extended spectrum of activity, being active
against MRSA, VRSA, MSSA and strains of S. aureus resistant
to macrolides, quinolones and/or trimethoprim. Iclaprim is also
active against Enterobacter spp., Neisseria spp., H. influenzae, M.
cattarrhalis, Chlamydia pneumoniae and streptococci, but exhibits
variable activity against S. pneumoniae [164–167] . It is not considered to be effective against Pseudomonas spp. and has variable
activity against anaerobes. Iclaprim also shows a high level of synergism when combined with sulphonamides (sulfamethoxazole
and sulfadiazine) [165] . It has a bioavailability of approximately
40% and can be given both orally and intravenously. Iclaprim has
a half-life of approximately 4 h. A total of 70% of drug excretion
is via the kidneys [167] .
Iclaprim has been used in two unpublished Phase III trials of
cSSSIs, ASSIST-1 and ASSIST-2 [166,167] . These showed non­
inferiority of iclaprim to linezolid patients with cSSSIs (25% due to
MRSA). Data on ASSIST-1 are on Arpida’s website [205] . Iclaprim
has received fast-track status from the FDA for the treatment of
cSSSIs, including infections caused by MRSA. Phase II trials investigating the efficacy of intravenous iclaprim in the treatment of
hospital-acquired, ventilator-associated and healthcare-associated
pneumonia began in December 2007.
In January this year, the FDA approved a Phase II intravenousto-oral switch trial. If this and subsequent trials are successful, the
addition of another oral agent active against MRSA could help
reduce the costs and adverse effects associated with the in-patient
treating of these infections.
So far, iclaprim appears to be associated with minimal adverse
effects, with nausea, headache, constipation and diarrhea being
the main symptoms. The rate of spontaneous resistance in
S. aureus to iclaprim is approximately 10 -10 [164] .
610
The oral formulation and tolerability of iclaprim combined
with clinical efficacy against MRSA mean that it will be especially useful for prolonged outpatient therapy for the treatment
of MRSA infections. The results of ongoing clinical trials are
eagerly awaited.
Ranbezolid (RBX 7644, Ranbaxy Laboratories Ltd)
This new oxazolidinone, developed by Ranbaxy (recently taken
over by Daiichi Sanyko), is currently under investigation for use
against MRSA and penicillin-resistant pneumococci. Early studies have shown that ranbezolid has similar or lower MICs against
staphylococci to linezolid. It is bacteriostatic against MRSA
and also effective against MSSA, enterococci, M. catarrhalis,
pneumococci and both Gram-negative and -positive anaerobes
[151,168–170] . Mathur et al. have shown that ranbezolid is effective
at reducing MRSA, MSSA and CoNS in biofilms [171] . It may
be that ranbezolid may play an important role in the treatment
of intravenous catheter-related and other prosthetic infections
caused by Gram-positive organisms.
There are currently very little data regarding ranbezolid in
the literature.
Tomopenem (RO4908463/CS-023,
Daiichi Sankyo Co. Ltd)
This novel 1β-methylcarbapenem is currently under development. The addition of a guanidine-pyrrolidine side chain
bestows high affinity for the PBP1, PBP2 and PBP4 seen with
S. aureus [172] . This confers activity against MRSA, in contrast
to older carbapenems, while retaining activity against MSSA,
ESBL-producing Escherichia coli, Klebsiella spp,, P. aeruginosa
and other Gram-positive and -negative bacteria [172,173] .
Tomopenem has a prolonged half-life of 2 h. Approximately
70% of the drug is excreted unchanged in the urine, with no
renal tubular secretion. It has a volume of distribution of 15–17 l
and less than 10% protein binding. As with other carbapenems,
there is concentration-dependent killing at low, but not at high,
concentrations. MacGowan et al. have shown that tomopenem
appears to have a superior antibacterial effect against MRSA
compared with vancomycin [172] .
Clinical trials are currently in progress. If successful, monotherapy with tomopenem could treat mixed infections due to
both ESBL-positive and -negative Gram-negative organisms, as
well as MRSA.
Expert commentary
The spread of MRSA, both in the community and in the
healthcare environment, is of worldwide concern. The challenge is prompt identification and optimal treatment of such
infections. Screening may or may not prove to be helpful in
reducing transmission of, and infections due to, MRSA.
New agents have been developed with the following in mind:
efficacy against MRSA and other multiresistant organisms, tolerability and safety, formulation and potential for the development
of resistant strains. Of those that are likely to be licensed within
the next 5 years, as expected, no one agent completely satisfies all
Expert Rev. Anti Infect. Ther. 6(5), (2008)
Current challenges in treating MRSA
the above requirements. Thus, a decision must be made on the
most suitable agent for an individual patient, the site of infection and the setting for administration (healthcare or outpatient).
The use of fourth-generation cephalosporins, ceftobiprole and
ceftaroline, may be limited by this drug class’ association with
C. difficile-associated diarrhea.
The concern over multidrug resistance in both Gram-positive
and-negative organisms means that research into new antimicrobials
will need to continue well beyond the next 5 years.
Five-year view
It is anticipated that many changes will happen over the next
5 years. There is likely to be a growing worldwide problem with
CA-MRSA, with increasing virulence and multiresistance.
Evidence of spread into healthcare settings is worrisome, and
CA-MRSA may soon become endemic within the UK, much
like HA-MRSA has become.
Although still rare, there may be a small increase in the number
of VISA/GISA and VRSA infections, limiting the utility of this
glycopeptide for treating staphylococcal infections. As is already
happening for certain infections, vancomycin may eventually be superseded by newer agents with greater tolerability
and efficacy.
There is already a greater willingness to treat patients in the
community, for the patients’ convenience and also to reduce
in-patient length of stay. Because of the risk of catheter-related
infections, oral formulation is usually preferred. Unfortunately,
poor bioavailability means that most antimicrobials have to be
given intravenously.
Linezolid can already be given orally and it is likely that the
place for oxazolidinones in the future will be for short courses of
therapy in the outpatient setting. Further studies are needed to
see if linezolid is more effective than vancomycin for the treatment of MRSA pneumonia. If it is, we could see more patients
treated as outpatients for this condition. As with clindamycin,
linezolid also plays a part in the treatment of necrotizing fasciitis. There do not seem to be any new agents on the horizon with
an anticytokine effect as seen in these two drugs. Therefore, it
is likely that there will always be a place for linezolid on the
hospital formulary.
Iclaprim is another antimicrobial that can be given orally and,
if Phase III intravenous–oral switch trials are successful, this will
be a welcome agent for the treatment of MRSA infections in the
outpatient setting.
Another way to treat infections in patients in the community
is to give a drug with a long half-life, enabling once-weekly
dosing. The expected launch of once-weekly dalbavancin in
2009 could mean a revolutionary change in the management
of MRSA cSSSIs. Not only will this approach be better psychologically for the patient, healthcare costs will be reduced and the
risk of developing further HCAIs will also be minimized. For
outpatient therapy with dalbavancin to be successful, adequate
numbers of staff are required to administer the drug, and failure
to provide this could limit its utility as an anti-MRSA agent in
the community.
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Review
As virulence becomes more of a concern, especially with community-acquired strains of MRSA, it is important to have agents
that are at least as, or more, efficacious than glycopeptides.
In late 2007, daptomycin was launched in the UK for the treatment of bacteremia and right-sided endocarditis due to S. aureus
and it is likely that over the next 5 years we will see its inclusion
on many hospital formularies for this indication. This may mean
that both the complication and relapse rates associated with
MSSA and MRSA bacteremia will be significantly reduced, a
welcome change in the current UK environment ,where MRSA
appears to be endemic. Its once-daily formulation means that it
too could be used successfully in the outpatient setting.
Tigecycline is already used in many hospitals. If trials examining at its use for intra-abdominal sepsis are successful, it may soon
become first-line therapy for this indication, especially in patients
with penicillin allergy. There may also be a role for tigecycline in
the treatment of hospital-acquired pneumonia.
The broad spectrum of activity of ceftobiprole means that
mixed MRSA and ESBL non-producing Gram-negative infections could be treated with a single agent. As a β-lactam drug, it
is usually well tolerated and so could possibly be used as empirical
therapy when MRSA infection is suspected. Ceftobiprole may
select for C. difficile infection and, with the rising incidence of
ESBL-producing Enterobacteriacae, these factors may limit their
future use.
Ceftaroline, especially in combination with NXL 104, shows
much promise for use in cSSSIs. If Phase III trials are successful, the next 5 years could see its inclusion onto many hospital
formularies for the treatment of hospital-acquired pneumonia
and cSSSIs due to multiresistant organisms. As with ceftobiprole,
there is concern that selection of C. difficile infection may be a
future problem.
The new glycopeptide derivatives, telavancin and oritavancin,
show much promise, especially with the latter’s proven efficacy
against vanA-positive enterococci. If safety concerns regarding both
of these drugs are not proven, it is likely that these anti­microbials
will also be of use in the fight against MRSA.
The future for quinupristin–dalfopristin looks uncertain; it is
disadvantaged by its inferiority in ease of administration and also
efficacy in relation to resistance.
Over the next 5 years, it is anticipated that there will be some
exciting new agents available for MRSA treatment.
Tompenem looks promising with regards to its broad-range
activity against both Gram-positive and -negative organisms. The
results of clinical trials are eagerly awaited.
It remains to be seen if screening for MRSA will be effective
at reducing MRSA transmission and infection within healthcare facilities and, possibly, within the community. Again, both
isolation facilities and increases in laboratory personnel need to
be sufficient for this approach to be successful. More thorough
economic healthcare evaluations are needed.
The next 5 years will show the results of drug development
started in the 1990s. It is hoped that new approaches to treat
MRSA will be successful in reducing the growing endemicity of
MRSA already seen in many parts of the world.
611
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Ratnaraja & Hawkey
Acknowledgements
The authors would like to thank Dr Katie Hardy, Regional HPA
Microbiology Laboratory, Heart of England NHS Foundation Trust,
Bordesley Green East, Birmingham, B9 5SS, England.
Financial & competing interests disclosure
PM Hawkey has received research funding and/or speaker support from
Astra Zeneca, Basilea, Beckton Dickinson, MSD, Novartis, Pfizer and
Wyeth. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
No writing assistance was utilized in the production of this
manuscript.
Key issues
• Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a worldwide problem.
• The characteristics of community associated-MRSA appear to be changing with clonal diversity, increased transmissibility within both
the hospital and community setting, increased virulence and drug resistance.
• The use of glycopeptides to treat MRSA is limited by poor tissue and CNS penetration, vancomycin tolerance and an increasing number
of strains with full or intermediate susceptibility to these agents.
• Newer agents have been marketed to overcome the shortcomings of glycopeptides.
• Linezolid has been shown to be an effective agent for the treatment of nosocomial pneumonia and complicated skin and soft-tissue
infections due to multiresistant Gram-positive organisms and, as an oral agent, is ideal for treatment within the community. Newer
oxazolidinones in development show similar potential.
• Tigecycline, ceftobiprole, ceftaroline and tomopenem all have a broad spectrum of activity with excellent tissue penetration, making
them ideal agents for the treatment of complicated skin and skin-structure infections.
• Daptomycin has been shown to be efficacious in the treatment of bacteremia and endocarditis due to MRSA and
methicillin‑susceptible S. aureus.
• Dalbavancin, oritavancin and telavancin all show promise as agents that circumvent problems seen with vancomycin for the treatment
of Gram-positive infections.
• The once-weekly formulation of dalbavancin makes it ideal for use in the outpatient setting.
• Iclaprim may also prove to be a welcome addition to the armamentarium against MRSA if intravenous–oral switch trials are successful.
• Further economic and clinical evaluation is needed to see if screening for MRSA on admission to healthcare settings can reduce
transmission and infections due to this organism.
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•
Peter M Hawkey
Regional HPA Microbiology Laboratory,
Heart of England NHS Foundation Trust,
Bordesley Green East, Birmingham,
B9 5SS, UK
and
Division of Immunity and Infection, The
Medical School, University of
Birmingham, Birmingham, B15 2TT, UK
Tel.: +44 121 424 1248
Fax: +44 121 772 6229
[email protected]
Affiliations
•
Natasha VDV Ratnaraja
Consultant Microbiologist, Department of
Microbiology, Sandwell and West
Birmingham NHS Trust, Dudley Road,
Birmingham B18 7QH, UK
Expert Rev. Anti Infect. Ther. 6(5), (2008)