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