Review

Antibiotic resistance in
1. Introduction
2. Available antibiotics: their
mechanism of action and
development of resistance
3. Current practise: treatment
options for MRSA and GISA
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Queen's University on 05/12/13
Staphylococcus aureus and its
relevance in therapy
Abhijit M Bal† & Ian M Gould
†Aberdeen Royal Infirmary, Department of Medical Microbiology, Foresterhill, Aberdeen AB25 2ZN,
Scotland
Staphylococcus aureus is a major cause of infections. Only ∼ 20% of the
strains remain sensitive to penicillin. β-lactamase stable penicillins such as flu-
cloxacillin form the mainstay of treatment of staphylococcal infection. Meti-

infections cillin-resistant S. aureus (MRSA) are resistant to all β-lactam antibiotics.

4. Conclusions Glycopeptide antibiotics are effective against most MRSA strains but, in the
5. Expert opinion last few years, isolates of MRSA that have reduced susceptibility to glyco-
peptides (glycopeptide-intermediate S. aureus) have been isolated. Some
strains exhibit frank resistance to glycopeptides (vancomycin-resistant
S. aureus). Infections due to these strains are difficult to treat. This review
summarises the therapeutic options for MRSA, glycopeptide-intermediate
S. aureus and vancomycin-resistant S. aureus. Novel therapeutic strategies
such as immunotherapy and vaccines are also discussed.

Expert Opin. Pharmacother. (2005) 6(13):2257-2269

For personal use only.

1. Introduction

Staphylococci belong to the family Micrococcaceae and are broadly divided into two
main categories of clinical importance: Staphylococcus aureus, which are coagulase
positive; and a heterogeneous group of staphylococci that give a negative reaction
with coagulase test: the coagulase-negative staphylococci (CoNS). S. aureus is char-
acteristically associated with acute pyogenic infections whereas CoNS cause infec-
tions in susceptible hosts with certain predisposing conditions. The most common
species of CoNS that causes infection is Staphylococcus epidermidis. Besides the coag-
ulase test, it differs from S. aureus in being negative for mannitol fermentation reac-
tion and deoxyribonuclease test [1]. S. aureus produces a range of virulence factors
that include various enzymes and toxins.
Penicillin was introduced in 1941 during World War II and soon after its intro-
duction strains of S. aureus that produced the enzyme β-lactamase were isolated [2].
These strains inactivate penicillin by opening the β-lactam ring. This led to the
development of β-lactamase stable penicillins (flucloxacillin, meticillin, oxacillin,
nafcillin) around 1960 that were resistant to the action of β-lactamases. However,
meticillin-resistant S. aureus (MRSA) was reported in 1961 [3] and since then the
problem of infections with MRSA has rapidly grown. MRSA has altered penicil-
lin-binding proteins (PBPs) that have reduced affinity for all β-lactams. In the last
few years, there has also been growing concern with regards to the acquisition of
glycopeptide resistance in MRSA.
Most people acquire MRSA in a hospital setting. These strains establish an eco-
logical niche in the hospital environment and are easily transmitted between
patients. In recent years, community-acquired MRSA (CA-MRSA) strains have
emerged. Such strains are isolated from individuals with no history of direct or
indirect contact with hospitals or other healthcare settings.
Ashley Publications
www.ashley-pub.com
Resistant staphylococci pose a problem for clinicians and their patients. Due to the
limited therapeutic options, infections caused by these strains are usually difficult to

10.1517/14656566.6.13.2257 © 2005 Ashley Publications ISSN 1465-6566 2257

 Antibiotic resistance in Staphylococcus aureus and its relevance in therapy
treat. Second, invasive infection with MRSA is associated with
increased mortality [4], although this has not been substanti-
ated in all studies [5]. Third, by establishing an ecological niche
in the hospital, the resistant strains have the potential to spread
and colonise patients. Colonisation may subsequently lead to
infection. Finally, by increasing the duration of hospital stay,
they indirectly increase expenditure [6,7].
This review summarises the basis of antibiotic resistance in
S. aureus and the therapeutic options for such infections.
2. Availableantibiotics: their mechanism of
action and development of resistance
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Queen's University on 05/12/13
2.1 β-lactam antibiotics
S. aureus produces four different types of β-lactamase
enzymes. These enzymes act on the β-lactam ring and thereby
inactivate the antibiotic. Most clinical strains produce β-lacta-
mase and hence are resistant to penicillin. The β-lactamase
stable penicillin antibiotics are useful therapeutic options for
such infections.
Crosslinking of the peptidoglycan cell wall of bacteria is
carried out by a group of enzymes that have high affinity for
penicillin. These enzymes are known as PBPs. PBP 2 is an
important enzyme that is involved in crosslinking peptidogly-
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can in the cell wall of staphylococci. Staphylococci become
resistant to all β-lactam antibiotics due to the acquisition of
the mecA gene that codes for PBP 2′, a variant of PBP 2. This
abnormal enzyme carries out functions similar to that of PBP
2 but has low affinity for β-lactam antibiotics. S. aureus pos-
sessing the mecA gene is resistant to β-lactam antibiotics and
is known as MRSA. Mechanism of resistance in MRSA has
been extensively reviewed [8]. Briefly, the mecA complex
includes the mecA gene along with regulatory sequences
namely mecI and mecR.
The mecR gene encodes a cytoplasmic membrane receptor.
Binding of β-lactam antibiotics to this receptor generates a
signal cascade that leads to proteolysis of the product of the
repressor gene mecI. Loss of the repressor allows uninhibited
production of PBP 2′ encoded by the mecA gene. Strains that
possess the mecA complex but have a fully functional repres-
sor gene mecI remain susceptible to the β-lactam antibiotics.
Such strains are in a preMRSA state. Mutations in the mecI
gene lead to a loss of repressor functions. However, it is
important to understand the role of other genetic elements
that lead to the expression of meticillin resistance. Niemeyer
et al. [9] reported PBP 2′ production even in the presence of
an intact repressor gene. This could be due to mutations in
other repressor genetic elements such as blaR2. Similarly, the
high meticillin resistance (hmr) genes play an important role
in stabilising the MRSA strains. Experiments have shown that
selective deletion of mecI gene leads to unregulated expression
of PBP 2′ [10], which can compromise cell wall integrity
because PBP 2′ by itself is a poor transpeptidase [11]. The hmr
genes, hmr A and B, seem to neutralise the effects of unregu-
lated PBP 2′ and lead to smooth cell wall synthesis. The hmr
2258 Expert Opin. Pharmacother. (2005) 6(13)
genes also seem to play an important role in the development
of tolerance of S. aureus to high concentrations of β-lactam
antibiotics, and in mediating the Eagle phenomena of para-
doxical susceptibility to lower concentrations and tolerance to
higher concentrations of antibiotics [12].
The mecI and mecR complex is a part of staphylococcal
cassette chromosome mec (SCCmec). S. aureus can be classi-
fied into five different SSC types; types I – V. The earliest
MRSA isolates belong to type I. SCCmec types II and III are
associated with resistance to antibiotics not belonging to the
β-lactam group: macrolides, clindamycin and tetracyclines.
The majority of hospital MRSA strains belong to SSCmec
types I, II and III [13]. The type IV mobile element is smaller
than the other types and does not contain any additional
genes that mediate resistance to other antibiotics [14]. How-
ever, CA-MRSA carrying SCCmec IV has emerged as one of
the most virulent strains. Such strains carry additional viru-
lence determinants such as genes for superantigens (entero-
toxin B and C), Panton-Valentine leukocidin (PVL) [15] and
exfoliative toxins [16]. MRSA strains that have the ability to
produce PVL are associated with necrotising pneumonia [17],
skin infections, such as furuncles, and subcutaneous abscesses
[18]. Miller and colleagues [19] have recently reported strains of
CA-MRSA belonging to the SCCmec IV group causing necr-
otising fasciitis in California, USA. All strains in their study
were capable of producing PVL and were sensitive to clin-
damycin, trimethoprim-sulfamethoxazole (TMP-SMX) and
rifampicin. SCCmec type V has recently been reported from a
CA-MRSA strain from Australia [13]. The recombinase gene
in SCCmec type V, ccrC, is distinct from the recombinase
genes ccrA and ccrB found in types I – IV.
2.2 Glycopeptides
Vancomycin and teicoplanin, the two glycopeptide antibiot-
ics extensively used in clinical practise, have bactericidal
activity against S. aureus. The emergence of glycopeptide-
intermediate S. aureus (GISA) and vancomycin-resistant S.
aureus (VRSA) heralds an ominous trend in the management
of MRSA infections. The nomenclature of strains has been a
matter of confusion. As per the criteria suggested by the
Clinical and Laboratory Standards Institute (CLSI), suscepti-
ble strains have a vancomycin minimum inhibitory concen-
tration (MIC) of ≤ 4 µg/ml and resistant strains have a MIC
of ≥ 32 µg/ml. Strains with MIC between 8 and 16 µg/ml are
defined as having intermediate susceptibility (vancomycin-
intermediate S. aureus [VISA]). The British Society for Anti-
microbial Chemotherapy (BSAC) guidelines define a suscep-
tible strain as that having a MIC of ≤ 4 µg/ml and a resistant
strain as having a MIC of ≥ 8 µg/ml. There is no category for
intermediate susceptibility. Japanese investigators have used
the term VRSA for strains of S. aureus that grow on brain
heart infusion (BHI) screening agar plate containing 4 µg/ml
of vancomycin within 24 h and the vancomycin MIC by
broth microdilution is ≥ 8 µg/ml [20]. Those strains that grow
on vancomycin-containing BHI agar and have a vancomycin

MIC of ≤ 4 µg/ml but give rise to subpopulations that grow
in the presence of vancomycin 5 – 9 µg/ml are termed
heteroresistant VRSA. It is difficult to ascertain the clinical
relevance of heteroresistant VRSA as many reported strains
were those that were obtained under selection pressure on
vancomycin-containing media and were not the original iso-
lates [21]. The nomenclature; S. aureus with reduced vanco-
mycin susceptibility (SA-RVS), has also been used to refer to
strains with vancomycin MIC of ≥ 4 µg/ml [22].
D-alanine-D-alanine is an important component of peptido-
glycan in the cell wall of Gram-positive bacteria. Glycopeptide
antibiotics strongly bind to this molecule thereby inhibiting its
incorporation in the peptidoglycan chain. This leads to the
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inhibition of cell wall synthesis and bacterial cell death.
The mechanism of development of resistance to the glyco-
peptide antibiotics is complex and not completely under-
stood. An increase in the cell wall thickness is postulated to
be an important mechanism for development of glycopeptide
resistance. Hanaki et al. [23] reported the findings of two clin-
ical isolates of MRSA. Strain Mu50 was resistant to vanco-
mycin with MIC 8 µg/ml (intermediate susceptibility as per
the CLSI guidelines), whereas strain Mu3 was susceptible
(MIC ≤ 4 µg/ml) but produced subclones with higher vanco-
mycin MIC in the presence of the drug. The cell wall thick-
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ness of Mu50 but not Mu3 strains was twofold that of the
control strain. These authors have also found that Mu50
strains had increased number of D-alanine-D-alanine residues
in the cell walls [24]. The increased numbers of such residues
could effectively ‘trap’ vancomycin and lead to resistance by
decreasing the amount of drug available at the cell mem-
brane. A second mechanism is the alteration of autolytic
activity. Most GISA strains show reduced cell wall autolysis,
which may also contribute towards increased cell wall thick-
ness. Increased synthesis of PBP 2 has also been reported for
GISA strains [25]. Theoretically, the PBP 2 molecules could
effectively compete with vancomycin for binding to the
newly synthesised peptidoglycan molecules.
Glycopeptide resistance in enterococci is due to the acquisi-
tion of van gene complexes (vanA – vanG) that mediate vary-
ing degrees of resistance to vancomycin and teicoplanin. VanA
gene mediates high-level resistance to both vancomycin and
teicoplanin. As these genes are borne on plasmids, antibiotic
resistance is easily transmissible and independent of selection
pressure. These strains have terminal D-alanine-D-lactate
instead of D-alanine-D-alanine resulting in 1000-fold lower
affinity to vancomycin. Chang et al. [26] isolated a strain of
MRSA that was highly resistant to vancomycin with an MIC
of 1024 µg/ml from a patient in Michigan. This strain pos-
sessed vanA gene complex mediating high-level resistance.
Tenover et al. [27] obtained an isolate from a patient in Penn-
sylvania. Their isolate also possessed the vanA gene sequence
but exhibited only a moderate level of vancomycin resistance
with an MIC of 32 µg/ml. Moreover, this isolate was sensitive
to teicoplanin, a finding not consistent with the presence of
vanA gene. The authors hypothesised that the comparative
Expert Opin. Pharmacother. (2005) 6(13)
Bal & Gould
low level of vancomycin resistance in the Pennsylvania isolate
may be related to the level of expression of the vanA genetic
element. A third VRSA isolate was recovered from urine of a
resident of a long-term care facility in New York state [28]. On
initial antibiotic susceptibility tests using Microscan panels,
the vancomycin MIC was found to be 4 µg/ml. However,
subsequent tests showed that the MIC was > 256 µg/ml by
using the Epsilometer test and 64 µg/ml using the broth
microdilution method as recommended by the CLSI. This
isolate also possessed the vanA gene. The detection of vanA
gene in MRSA strains is an ominous finding. VISA strains
consume more energy and nutrients to produce thicker cell
walls under selection pressure and hence have a lower rate of
growth [29]. However, this may not be true for VRSA strains
possessing the vanA gene. Moreover, such strains may not be
detected by routine antibiotic susceptibility methods. It is rec-
ommended that vancomycin agar screening plates should be
used for all MRSA isolates to detect resistant isolates.
Whether routine surveillance should be carried out to
detect VISA strains is debatable. It has been proposed that
VISA strains are very rare and screening all MRSA isolates for
this purpose may not be cost effective. However, in certain
patient populations, such as those on haemodialysis and
chronic ambulatory peritoneal dialysis, surveillance for VISA
may be useful as these patients receive long-term vancomycin
therapy [21].
There could also be differences between relative susceptibil-
ity of isolates to vancomycin and teicoplanin. The term GISA
incorporates both VISA and teicoplanin-intermediate
S. aureus. We have earlier reported several meticillin-sensitive
and -resistant strains of S. aureus that were sensitive to vanco-
mycin but resistant to teicoplanin on screening plates. Trans-
mission electron microscopy revealed thicker cell walls in
teicoplanin-resistant cells. These cells also expressed higher
levels of phosphoglycerate kinase [30]. The difference in sus-
ceptibility to vancomycin and teicoplanin is of clinical signifi-
cance as it influences the choice of therapy particularly
because teicoplanin is favoured in certain situations due to its
once-daily administration and reduced nephrotoxicity.
S. aureus with GISA phenotype characteristically belong to
the accessory gene regulator (agr) group II. The agr gene con-
trols the expression of surface adhesins during the exponential
phase of bacterial growth and expression of exoproteins during
the stationary phase. Components encoded by the agr gene
include AgrB (a transmembrane protein), AgrD (a peptide pre-
cursor), AgrC (a sensor protein that acts as a receptor for the
AgrD-derived peptide) and AgrA (a regulator protein activated
by AgrC) [31]. S. aureus can be classified into four agr groups
based on variations in AgrB, AgrC and AgrD proteins. Muta-
tion in the agr sequence is associated with the expression of
GISA phenotype [32]. It is hypothesised that in the presence of
vancomycin, the bacterial cells have a tendency to lose certain
agr functions through point mutations. Such mutations may
lead to a decrease in autolysis [33]. Loss of certain functions
attributed to the agr locus is also associated with persistent
2259
 Antibiotic resistance in Staphylococcus aureus and its relevance in therapy
bacteraemia due to MRSA. Fowler et al. [34] studied two groups
of patients; one group had persistent bacteraemia (≥ 7 days),
the other had resolving bacteraemia (≤ 4 days). Both groups
were clinically similar at baseline. MRSA strains causing persist-
ent bacteraemia were deficient in the production of δ-haemo-
lysin coded by the agr locus. This locus is also responsible for
downregulating the surface adhesin gene fnbA that codes for
fibronectin-binding protein A (fnbA) and mutations in agr may
thus lead to the overexpression of fnbA and increased adhesion
to host cells such as those lining the endothelium [35].
2.3 Linezolid
Linezolid belongs to a novel class of antibiotics; oxazolidinones.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Queen's University on 05/12/13
It binds to the 50S ribosomal subunit and prevents the forma-
tion of the 70S ribosome complex. It is bacteriostatic against a
number of Gram-positive organisms including MRSA and van-
comycin-resistant enterococci (VRE) [36]. Its 100% bioavaila-
bility following oral administration makes it an attractive
therapeutic option for MRSA infections [37]. Resistance to line-
zolid has been reported in S. aureus strains. Tsiodras and col-
leagues [38] reported a case of MRSA peritonitis that was treated
with linezolid because the patient was allergic to vancomycin.
Although the initial isolates were linezolid-sensitive, subse-
quent isolates were resistant to the antibiotic. The resistant iso-
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lates showed Gly2576Thr mutations in DNA encoding the
central loop of domain V of 23S rRNA. Laboratory studies
indicate that reversion to susceptibility to linezolid is possible
in an antibiotic-free environment but several passages were
required to achieve reversion [39]. Thus, linezolid resistance can
be stable over long periods of time. Newer oxazolidinones in
development include ranbezolid [40] and AZD-2563 [41].
2.4 Quinupristin–dalfopristin
Quinupristin and dalfopristin are streptogramin antibiotics
derived from pristinamycin. The compound is bactericidal for
S. aureus. Each binds to a different site on the 50S ribosomal
subunit to form a stable complex. Resistance to strepto-
gramins is due to the modification of the ribosome target site,
enzymatic inactivation of the antibiotic or an efflux pump [42].
Methylation of the ribosomal binding site leads to quinupris-
tin resistance, although the susceptibility to dalfopristin can
still be retained. Plasmid-mediated resistance to quinupristin
is controlled by a specific hydrolase [43]. Quinupristin–dalfo-
pristin can still act as a bacteriostatic agent in face of resistance
to a quinupristin component [44]. Dalfopristin resistance can
occur secondary to an efflux pump mechanism or more com-
monly due to virginiamycin acetyltransferase-induced acetyla-
tion [45]. Resistance to dalfopristin confers resistance to the
streptogramin complex [46]. Bacteria are rarely resistant to
both compounds.
2.5 Daptomycin
Daptomycin was developed in the 1980s and is currently in
Phase III trials in the UK. The drug has already been given a
2260 Expert Opin. Pharmacother. (2005) 6(13)
fast track licence in the US by the FDA. Daptomycin belongs
to a novel class of antibiotics; the cyclic lipopeptides. It exerts
bactericidal action against Gram-positive bacteria [47] by
gradual depletion of membrane potential without rupture or
lysis of the membrane [48]. Absence of membrane lysis could
be therapeutically important as a lack of bacterial cell lysis
products in systemic circulation would be expected to pre-
vent a pro-inflammatory response and hence reduce mortal-
ity [49]. It forms ion channels in the bacterial cell membrane
leading to a loss of potassium ions and cell death. It also
affects the conductivity in lipid bilayer membranes through a
calcium-dependent mechanism [50]. Studies have shown that
the presence of calcium ions leads to a 10-fold enhancement
in the interaction between daptomycin and membrane phos-
pholipids [51]. Daptomycin resistant isolates have been diffi-
cult to obtain in the laboratory [52]. However, Mangili and
colleagues [53] recently reported a case of septic thrombo-
phlebitis of the portal vein due to MRSA. The patient was
treated for a prolonged period with daptomycin and resistant
strains developed during therapy.
2.6 Tigecycline
Tigecycline is a glycylcycline that binds to the 30S ribosomal
subunits of a bacterial cell. It has a broad spectrum with activ-
ity against both Gram-positive (including MRSA and VRE)
and Gram-negative (including those producing extended
spectrum β-lactamase enzyme) bacteria. The drug is available
for parenteral administration only. It is bacteriostatic, has a
long half-life, demonstrates a postantibiotic effect and has a
good tissue penetration [54]. The antibiotic is likely to be
licenced for use in Europe soon.
2.7 The newer glycopeptides (oritavancin,
dalbavancin and telavancin) and related compounds
(ramoplanin)
Newer glycopeptides still awaiting licence for general use have
useful activity against MRSA strains include oritavancin, dal-
bavancin and telavancin. All these compounds have bacteri-
cidal activity. Oritavancin has a long half-life and is active
against GISA strains [55]. It was also found to be active against
a laboratory engineered MRSA strain possessing vanA deter-
minant, and this has been extensively reviewed elsewhere [56].
Dalbavancin is a teicoplanin derivative characterised by a long
half-life, which allows once-weekly administration [57]. Experi-
mental data show that the generation of single-step high-level
resistance was rare [58]. Telavancin is a vancomycin derivative
that inhibits cell wall synthesis and the synthesis of cell mem-
brane phospholipids. It is active against MRSA and GISA
strains [59]. Ramoplanin, a glycolipodepsipeptide, has a dis-
tinct mechanism of action. It binds to and inhibits lipid inter-
mediate I and II at a site different from D-alanine-D-alanine
[60]. Briefly, peptidoglycan synthesis has two important com-
ponents. The first is the attachment of cell wall precursor mol-
ecules to a lipid carrier. This is followed by polymerisation. By

binding to the lipid intermediates, ramoplanin inhibits trans-
fer of precursor molecules whereas the glycopeptides inhibit
polymerisation [61]. As they act on different targets, cross-
resistance is unlikely. Ramoplanin is rapidly bactericidal for
MRSA strains [62].
3. Current
practise: treatment options for
MRSA and GISA infections
3.1 The glycopeptides: vancomycin and teicoplanin
Glycopeptide antibiotics are traditionally the treatment of
choice for invasive MRSA infections because, until recently,
resistance was not perceived as a problem. Vancomycin and
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teicoplanin are two commercially available glycopeptide anti-
biotics. Teicoplanin is more lipophilic, has better tissue pene-
tration, has a longer half-life but is highly protein bound and
is slightly less active against staphylococci than vancomycin.
High rates of therapeutic failures with monotherapy of
both glycopeptide antibiotics have been reported [63], perhaps
due to poor bactericidal activity. Therapeutic failure in serious
infections has been reported even with a combination of van-
comycin and an aminoglycoside [64]. Persistent MRSA infec-
tion in a biofilm may be difficult to eradicate and
combination therapy of vancomycin and rifampicin is recom-
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mended. Moreover, it is difficult to predict the outcome in
individual cases based on glycopeptide MIC of the strains.
Fridkin and colleagues [22] conducted a case control study
of patients infected with SA-RVS strains with vancomycin
MIC of ≥ 4 µg/ml. This included both the VISA strains (MIC
8 µg/ml as per CLSI guidelines) and non-VISA SA-RVS
(MIC < 8 µg/ml). The authors found no significant difference
between VISA and non-VISA SA-RVS infected patients with
regards to their clinical presentation. However, patients
infected with SA-RVS strains had a higher in-hospital mortal-
ity rate than control patients infected with MRSA. This
increase in mortality was independent of comorbid condi-
tions. Recurrent MRSA infection and vancomycin use were
the risk factors for acquiring SA-RVS. Infection with SA-RVS
strains was, however, rare and only 21 cases were reported in
the 4-year study period.
Vancomycin is potentially nephrotoxic and trough levels
need to be measured for both agents to ensure adequate serum
levels. Trough levels need to be as high as 20 µg/ml for deep-
seated infections such as infective endocarditis. However, newer
preparations of vancomycin are less nephrotoxic than older
ones. Given the fact that treatment with glycopeptide antibiot-
ics alone is not always successful against MRSA infections, a
second or even a third agent often needs to be added for treat-
ing serious invasive infections such as endocarditis, joint infec-
tions and CNS infections. Usual choices for additional agents
include gentamicin and rifampicin. Gentamicin is by itself
nephrotoxic and its toxicity may be increased in the presence of
another nephrotoxic agent such as vancomycin. Rifampicin is
bactericidal for staphylococci but resistance can easily emerge
during monotherapy. As the glycopeptide antibiotics are
Expert Opin. Pharmacother. (2005) 6(13)
Bal & Gould
administered parenterally, this entails a long-term venous access
and hence an increased duration of hospital stay particularly if
vancomycin is the preferred drug. Both these factors increase
the likelihood of nosocomial infections.
As GISA strains are infrequently isolated, clinical experience
in the management of these infections is limited. There are
anecdotal clinical reports claiming use of continuous infusion
with vancomycin in combination with other antibiotics [65] and
laboratory evidence of potential benefit with higher doses of
vancomycin (1.5 g b.i.d. instead of 1 g b.i.d.) [66] for the treat-
ment of GISA infections. Ploy and colleagues [67] reported a
case of MRSA bacteraemia in a patient with leukaemia. The
strain was found to be susceptible to vancomycin but there was
no clinical improvement with either vancomycin or teico-
planin. Repeat cultures grew a strain that was intermediately
resistant to both these agents and was selected from an original
heterogeneous population of GISA. Charles et al. [68] found
that clinical failure with vancomycin was more likely in patients
infected with GISA than with glycopeptide-susceptible MRSA.
Several anecdotal reports of glycopeptide failure have also been
cited in the literature [69]. Reports of treatment failures have
stimulated interest in newer agents active against such strains.
3.2 Newer glycopeptides in the treatment of MRSA
infections
Oritavancin was found to be as effective as vancomycin for the
treatment of MRSA skin and soft tissue infection [70]. Seltzer
et al. [71] evaluated the efficacy of once-weekly dalbavancin for
skin and soft tissue infections. Success rate of 94% was achieved
with two doses of dalbavancin compared with 76% for the
standard regimen. Darouiche and Mansouri [72] injected rabbits
with dalbavancin or vancomycin and followed this by implant-
ing subcutaneous central venous catheters. The catheters were
then inoculated with a strain of S. aureus. The rate of device
colonisation was 53% in the vancomycin group and 28% in the
dalbavancin group, although this difference was not statistically
significant. However, several factors need to be considered
before the new generations of glycopeptides are licenced for
clinical use. Potential disadvantages of their long half-lifes such
as development of resistance and management of anaphylactic
reactions need to be addressed. Romano and colleagues [73]
studied the effect of ramoplanin on S. aureus colonisation of
catheters in a mouse model. Following bacterial inoculation
near the insertion site, uncoated catheters were colonised with
104 – > 105 colony-forming units whereas ramoplanin-coated
catheters had counts ranging from < 10 – 100 at 24 – 48 h.
Ramoplanin could be a useful therapeutic alternative in future.
3.3 Linezolid
Wunderink et al. [74] retrospectively analysed data from two
prospective trials comparing linezolid and vancomycin, each
with aztreonam, for empirical treatment of nosocomial pneu-
monia. The combined data included 1019 patients of whom
339 patients had S. aureus pneumonia and 160 had MRSA
pneumonia. Patients in the MRSA subset had better survival
2261
 Antibiotic resistance in Staphylococcus aureus and its relevance in therapy
rates when treated with linezolid than when treated with van-
comycin (80 versus 63.5%; p = 0.03). After adjusting for base-
line variables, the combination of linezolid and aztreonam was
found to be superior to vancomycin and aztreonam with
patient survival as the end point (odds ratio [OR] = 2.2;
p = 0.05). However, this study has its limitations as the benefit
of linezolid was seen only on subset analysis. Moreover, the
prospective studies had individually not shown a statistically
significant difference in survival in the two groups of patients.
Linezolid has also been used for the treatment of MRSA joint
infections. Bassetti et al. [75] retrospectively evaluated the effi-
cacy of linezolid for prosthetic joint infections. Of the 20
patients, 14 had MRSA, 5 had meticillin-resistant CoNS and
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1 had Enterococcus spp. isolated from joint aspirates. The dura-
tion of administration of linezolid was 6 – 10 weeks with up
to 1 week of intravenous therapy. At 1 year of follow up, there
were four clinical failures. Unfortunately, bone marrow toxic-
ity is a known adverse effect of linezolid and it is more pro-
nounced following prolonged duration of therapy. Senneville
and colleagues [76] identified certain risk factors that increase
the likelihood of marrow toxicity following prolonged courses
of linezolid. These included > 58 years of age (OR = 20.5) and
low pretreatment haemoglobin of < 10.5 g/dl (OR = 16.49).
Additional risk factors included alcohol abuse and diabetes
For personal use only.
mellitus. Prolonged therapy is also associated with peripheral
neuropathy [77]. There are also several reports of optic neurop-
athy that is reversible provided therapy is withdrawn early [78].
In view of these adverse effects, the maximum duration of
therapy as recommended by manufacturer is 28 days. Line-
zolid has also been used for skin and soft tissue infections [79]
and urinary tract infections [80] caused by MRSA. It has been
widely used as a therapeutic option for infection with GISA.
Yanagihara et al. [81] studied the efficacy of linezolid against
VISA lung infections in a mouse model. Linezolid signifi-
cantly improved the survival rates in mice. Howden and col-
leagues [82] reported a series of 25 patients seriously infected
with SA-RVS (defined in their study as strains with popula-
tion analysis profile/area under curve ratio of ≥ 0.9) strains.
Most (18 of 25) of their patients were treated with linezolid
and therapy was effective for 4 of 8 patients with SA-RVS
endocarditis despite an apparent lack of bactericidal activity.
3.4 Quinupristin–dalfopristin
Yanagihara and colleagues [83] also compared the efficacy of
quinupristin–dalfopristin with vancomycin in a murine
model of haematogenous pulmonary infection with MRSA
or GISA strains. Their experiments demonstrated the superi-
ority of quinupristin–dalfopristin over vancomycin for both
infections using the number of viable bacteria in the pulmo-
nary tissues as an end point. Sander et al. [84] used quinupris-
tin–dalfopristin for 12 patients in an intensive care unit who
had MRSA or meticillin-resistant S. epidermidis infections
and had treatment failure with vancomycin. The treatment
was successful in seven patients. In a multi-centre trial,
> 70% of patients had a successful clinical outcome following
2262 Expert Opin. Pharmacother. (2005) 6(13)
treatment with quinupristin–dalfopristin [85]. These patients
were either intolerant to or had failed previous therapy. Mac-
rolide resistance does not have any effect on the efficacy of
quinupristin–dalfopristin [86].
3.5 Daptomycin
Daptomycin has excellent bactericidal activity against Gram-
positive bacteria and may prove successful in serious invasive
MRSA infections such as infective endocarditis. It may also be
useful in refractory infections. Scheetz and colleagues [87]
recently described a case of MRSA bacteraemia in an individ-
ual with end-stage renal failure. The blood cultures yielded
MRSA despite treatment with vancomycin and with the sub-
sequent addition of gentamicin and rifampicin. The patient
was then successfully treated with a combination of daptomy-
cin and oxacillin. There are in vitro reports of synergy between
daptomycin and β-lactam agents [88]. Recently, daptomycin
has been successfully used in the treatment of prosthetic valve
endocarditis due to MRSA associated with a perivalvular aor-
tic abscess in a patient in whom surgery was not an option
[89]. Daptomycin has also been approved by the US FDA for
the treatment of complicated skin and soft tissue infections.
3.6 Tigecycline
In a recently concluded Phase III trial, tigecycline was com-
parable to vancomycin plus aztreonam for skin and soft tissue
infections, and to imipenem–cilastatin for intra-abdominal
infections [90]. Nausea and vomiting were the most frequent
adverse effects of tigecycline. Results of the Phase II trials
have been published. In patients with skin- and skin-struc-
ture-related infections, tigecycline 50 mg b.i.d. led to a clini-
cal cure in 74% (95% confidence interval 60.3 – 85.0%) and
microbiological eradication in 69% (95% confidence interval
54.2 – 82.3%) of patients. It also had an acceptable safety
profile [91].
3.7 Newer quinolones
WCK-771 has demonstrated bactericidal activity against MRSA
strains [92]. The drug was also active against quinolone-resistant
strains of MRSA [93]. However, more studies are required before
newer quinolones can appreciably alter the existing therapeutic
guidelines for infections due to resistant staphylococci.
3.8 Newer cephalosporins
LB-11058 is a new synthetic cephalosporin with a high
affinity for PBP 2′. It was found to be highly effective in a
rat model of endocarditis [94]. Similar products in develop-
ment include RWJ-54428 [95], S-3578 [96], BAL-9141 [97]
and BMS-247243 [98]. Miller and colleagues [99] evaluated
the activity of CB-181963 against meticillin sensitive
S. aureus (MSSA) and MRSA isolates in both the planktonic
and biofilm environment. This new molecule was active
against biofilm-associated MRSA, although it could not
eradicate the biofilm. Resistance was not generated in any of
the tested isolates and the anti-MRSA activity correlated

with elevated binding to PBP 2′. Ceftobiprole is another
novel cephalosporin with high affinity for PBP 2′. It is bacte-
ricidal for both MRSA and GISA. In a rabbit model, it was
as effective as vancomycin for MRSA endocarditis and more
effective than vancomycin for VISA endocarditis [100]. Phase
III clinical trials have been initiated to study the usefulness
of ceftobiprole in MRSA infections.
3.9 Other antibiotics
TMP-SMX could be a viable alternative for treating minor-to-
moderately severe S. aureus infections [101]. The drug is bacte-
ricidal for MRSA strains [102]. Elwell and colleagues [103] deter-
mined the susceptibility of several MRSA isolates from
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Queen's University on 05/12/13
patients. All the strains were resistant to sulfamethoxazole but
the combination of TMP-SMX was synergistic. TMP-SMX
could also be an effective alternative for GISA infections [104].
In a report from Israel, as many as 92% of MRSA isolates were
susceptible to this combination [105]. However, experimental
data have not always supported the use of TMP-SMX for the
treatment of invasive S. aureus infections [106]. Studies should
be carried out to evaluate the benefits of using TMP-SMX for
S. aureus infections. Clindamycin has been successfully used in
the treatment of invasive CA-MRSA infections including
pneumonia, septic arthritis and osteomyelitis [107]. As per the
For personal use only.
draft recommendations of the MRSA Working Party compris-
ing of experts working for the BSAC, Hospital Infection Soci-
ety and Infection Control Nurses Association, tetracyclines are
recommended as the drugs of choice for urinary tract infec-
tion due to MRSA, with trimethoprim and nitrofurantoin as
alternatives [201]. These recommendations are still under con-
sultation and can be accessed on the internet. The Working
Party also suggests considering chloramphenicol for MRSA
infections of the CNS (meningitis and brain abscess) provided
the strain is sensitive. Chloramphenicol, clindamycin and
tetracycline have bacteriostatic activity.
3.10 Combination therapy for MRSA and GISA infections
Combination therapy using vancomycin and β-lactam antibi-
otics has been suggested for the treatment of GISA infections.
Climo and colleagues [108] showed in vitro synergy between
vancomycin and oxacillin in a significant proportion of
MRSA isolates and all three GISA isolates. Interestingly, syn-
ergy was noted in isolates with higher vancomycin MIC
(≥ 4 µg/ml). This view has recently been challenged. Using
experimental conditions, such as longer incubation and a
higher inoculum that enhance the expression of resistance,
Goldstein and colleagues [109] observed antagonism between
β-lactam antibiotics and vancomycin but not teicoplanin. In
fact, the combination of β-lactam antibiotics and teicoplanin
was synergistic. Combination of intraventricular vancomycin
and intravenous linezolid has been successfully used for the
treatment of ventriculoperitoneal-shunt associated ventriculi-
tis due to GISA [110]. Vancomycin and linezolid combination
has also been used to treat GISA endocarditis [111]. In a rabbit
model of experimental endocarditis, Jacqueline and colleagues
Expert Opin. Pharmacother. (2005) 6(13)
Bal & Gould
[112] showed that a combination of linezolid and imipenem
had synergistic activity against MRSA and GISA strains.
However, only two strains were tested in their experiment.
Combination therapy has other benefits as it could compen-
sate for the inherent tendency of MRSA strains to become less
susceptible to vancomycin in face of vancomycin therapy. In a
retrospective study, Burnie and colleagues [113] reported 42
cases of MRSA bacteraemia from Manchester, UK. The mor-
tality was 4% in patients with dual therapy comprising of
vancomycin and rifampicin, compared with 38% in those
who received dual therapy but in whom repeat isolates were
found to have acquired rifampicin resistance, and 78% in
those who had infection with strains that had primary resist-
ance to rifampicin or in whom rifampicin was contraindicated
(p < 0.0001). The strains were serially passaged in the labora-
tory and exposed to increasing concentrations of vancomycin.
Serial passage of both rifampicin-sensitive and -resistant
strains selected isolates that had higher MIC for vancomycin.
A similar phenomenon could occur in the body tissues. It is
possible that the addition of a second agent, such as
rifampicin, helps to reduce the absolute number of bacteria in
tissues and delays the selection of isolates with higher
vancomycin MIC thereby reducing mortality.
3.11 Immunotherapy, vaccines and other novel
strategies
IFN-γ can appreciably enhance the killing of MSSA or MRSA
under experimental conditions [114]. The availability of
immunotherapy would be a novel alternative, as treatment
would involve indirectly enhancing the efficacy of circulating
immune cells through the recognition of pathogens; therefore,
the development of resistance should not be a matter of con-
cern. A recent study [115] explores the possibility that DNA
vaccination with mecA sequence could lead to protective
immunity against MRSA. The vaccination predictably leads
to the development of anti-PBP 2′ antibodies, and mice
injected with such a vaccine were shown to have a fivefold
increase in phagocytosis of MRSA but not MSSA. Passive
immunisation with human immunoglobulins has also been
successfully used in a murine model of staphylococcal pneu-
monia [116]. Lysostaphin, a peptidase, specifically cleaves the
Gly–Gly bonds of the peptide crossbridge in the cell wall of
S. aureus. A combination of lysostaphin and vancomycin was
found to be more effective than vancomycin alone in the
treatment of experimental MRSA endocarditis in a rabbit
model [117]. Lysostaphin was also found to be superior to van-
comycin in animal models of GISA endocarditis [118] and
MRSA eye infections [119]. S. aureus also possesses a group of
proteins known as fibrinogen binding proteins (ClfA, ClfB
and Efb) that bind to the substrates in tissue matrix. These
proteins also have antithrombotic activity that further impairs
wound healing. Mice vaccinated with plasmid-encoded clfA
DNA vaccine mount a strong immune response [120]. When
S. aureus cells are incubated in the immunised sera, their
subsequent ability to bind fibrinogen is reduced. Moreover,
2263
 Antibiotic resistance in Staphylococcus aureus and its relevance in therapy
such cells are rapidly phagocytosed by macrophages through
the crystallisable fragment (Fc) receptors that bind to the Fc
portion of the antibodies whose antigen binding fragments
(Fab) are bound to the bacterial cells. Targeting the capsular
polysaccharide of S. aureus is also an area of intensive research.
Of the 11 known serotypes, capsular serotypes 5 and 8 are
predominant. Some strains are non-typeable. However, carbo-
hydrates are poor antigens and are usually coupled with pro-
teins to enhance their immunogenic potential. StaphVAX, a
bivalent antigen that incorporates antigenic determinants
from serotype 5 and 8 coupled with protein exotoxin A from
Pseudomonas aeruginosa is now in Phase III clinical trials [121].
Interest has also been renewed in certain plant extracts that
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Queen's University on 05/12/13
could be clinically useful for the treatment of S. aureus infec-
tions. Alkyl gallates, which are derived as extracts from the tara
plant native to South America, have been shown to enhance
the susceptibility of both MSSA and MRSA to β-lactam anti-
biotics. This synergistic activity was shown only with β-lactam
antibiotics [122]. Extracts of the tea tree oil have been used to
treat MRSA osteomyelitis [123]. However, further research
needs to be carried out before plant extracts and herbal medi-
cines can make sufficient impact on the management of
MRSA infections.
For personal use only.
3.12 Strategies that reduce colonisation with MRSA
Colonisation with MRSA is a risk factor for the development
of infection both in the community [124] and the hospital [125].
The eradication of carrier state could, therefore, lead to a
decrease in the incidence of infection. Usual sites of colonisa-
tion include anterior nares, throat, axilla and groin. Topical
eradication regimes have been evaluated for the eradication of
carrier state. Mupirocin has been a popular choice for the
eradication of nasal carrier state. A randomised placebo-con-
trolled trial clearly showed the benefits of using mupirocin for
eradication of S. aureus. Mupirocin treatment successfully
eradicated S. aureus from 93% of patients as opposed to a
15% success rate for those whom received placebo. Rate of
decolonisation was not statistically different between MSSA
and MRSA (p = 0.08). However, at day 90, only 61% of indi-
viduals in the mupirocin group remained decolonised [126].
Results have not been very encouraging in studies that have
focused exclusively on MRSA carriage. Harbarth and col-
leagues [127] studied the usefulness of intranasal mupirocin in
eradicating MRSA carriage. The eradication rate from all sites
was 25% for those receiving mupirocin compared with 18%
in those given placebo, and the difference was not statistically
significant (p = 0.4). Subgroup analysis on nasal MRSA car-
riage revealed a success rate of 44% in those on mupirocin
2264 Expert Opin. Pharmacother. (2005) 6(13)
and 23% in those on placebo. This difference too did not
reach statistical significance either (p = 0.06). Various oral
antibiotic combinations, such as novobiocin plus rifampicin
or TMP-SMX plus rifampicin, have been used for the eradi-
cation of MRSA from nasal and extra-nasal sites [128], particu-
larly the throat. However, there is insufficient evidence to
support eradication from extranasal sites although the strategy
is commonly used [202].
4. Conclusions
S. aureus has managed to stay a step ahead of developments
in therapeutics and medicine. It has successfully evaded anti-
biotics; penicillin followed by β-lactamase-stable penicillins
and now the emergence of glycopeptide resistance is being
seen. Strategies needed to counter such pathogens should
involve decreasing the use of inappropriate antibiotics; the
use of combination therapy; the use of antibiotics for only
the minimal duration necessary; more attention to infection
control procedures to limit the spread of bacteria; advances in
the pharmaceutical industry in its search for newer mole-
cules; non-pharmaceutical therapeutic strategies, such as vac-
cines, and immunomodulators; and advances in basic
research to understand pathogenesis.
5. Expert opinion
MRSA infections are difficult to treat and expert management
is usually required. The authors recommend combination
therapy in serious invasive infections and the choice of antibi-
otics depends on the site of infection. Newer licenced antibi-
otics should be used when there are sufficient indications to
justify their use. Their inappropriate use should be discour-
aged to prevent the emergence of resistance. Rapidly bacteri-
cidal agents are urgently needed for the treatment of deep-
seated infections such as infective endocarditis and prosthetic
joint infections. Mild infections can often be treated with a
combination of oral antibiotics such as trimethoprim plus
doxycycline. Nitrofurantoin on its own may be used for lower
urinary tract infections. Clinical trials need to be carried out
to compare newer antibiotics with the existing ones before
any firm guidelines can be issued. Novel therapeutic strategies
such as immunotherapy and vaccines may be important adju-
vants to existing treatment. More active control of MRSA
needs to be practised in hospitals to prevent the development
of further problems with multiresistant strains. These strains
may develop from the virulent CA-MRSA and plans for their
control also need to be urgently drawn up.

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Affiliation
Abhijit M Bal† MD DNB MNAMS &
Ian M Gould BSc, MBChB, PhD, FRCP,
FRCPath
†Author for correspondence
Aberdeen Royal Infirmary, Department of
Medical Microbiology, Foresterhill, Aberdeen
AB25 2ZN, Scotland
Tel: +44 (0)1224 554954;
Fax: +44 (0)1224 550632;
E-mail: a.bal@abdn.ac.uk
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