Microbiology (2015), 161, 2061–2068 DOI 10.1099/mic.0.

000178

Review Staphylococcus haemolyticus – an emerging

threat in the twilight of the antibiotics age
Tomasz Czekaj, Marcin Ciszewski and Eligia M. Szewczyk
Correspondence Department of Pharmaceutical Microbiology and Microbiological Diagnostics, Medical University
Tomasz Czekaj of Łódź, Pomorska 137, 90-235 Łódź, Poland
tomasz.czekaj@umed.lodz.pl
Staphylococcus haemolyticus is one of the most frequent aetiological factors of staphylococcal
infections. This species seems to lack the important virulence attributes described in other
staphylococci. However, studies have shown that the presence of various enzymes, cytolysins
and surface substances affects the virulence of S. haemolyticus. Nevertheless, none of them
has been identified as crucial and determinative. Despite this, S. haemolyticus is, after
Staphylococcus epidermidis, the second most frequently isolated coagulase-negative
staphylococcus from clinical cases, notably from blood infections, including sepsis. This raises
the question of what is the reason for the increasing clinical significance of S. haemolyticus?
The most important factor might be the ability to acquire multiresistance against available
antimicrobial agents, even glycopeptides. The unusual genome plasticity of S. haemolyticus
strains manifested by a large number of insertion sequences and identified SNPs might
contribute to its acquisition of antibiotic resistance. Interspecies transfer of SCCmec cassettes
suggests that S. haemolyticus might also be the reservoir of resistance genes for other
staphylococci, including Staphylococcus aureus. Taking into consideration the great adaptability
and the ability to survive in the hospital environment, especially on medical devices,
S. haemolyticus becomes a crucial factor in nosocomial infections caused by multiresistant
staphylococci.

Introduction noted (Corse & Williams, 1968; Gemmell & Dawson,

Coagulase-negative staphylococci (CNS) constitute the main 1982; John et al., 1978). Simultaneously, increasing num-
part of the human skin microbiome. For this reason, their role bers of CNS infections were observed as a result of progress
as pathogens was underestimated and their identification did in medicine. According to a study conducted in the USA
not include a distinction between species on a regular basis between 1980 and 1989, CNS contribution to hospital-
(Eng et al., 1982). Amongst the genus Staphylococcus, only acquired bacteraemia increased from 9 to 27% (Schaberg
coagulase-positive Staphylococcus aureus was considered et al., 1991).
as pathogenic and thoroughly analysed in many studies.
It was not until the late 1960s that one of the CNS, Staphy- Phylogenetically, staphylococci constitute a very coherent
lococcus saprophyticus, was associated with frequent urinary group. S. aureus versus Staphylococcus epidermidis and Sta-
tract infections (John et al., 1978). Later, in the 1970s, the phylococcus haemolyticus shows *75% average nucleotide
first CNS infections in patients with invasive and indwel- identity values, which proves their close genetic relatedness
ling medical devices were reported (Liekweg & Greenfield, (Konstantinidis et al., 2006; Lamers et al., 2012). That fact
1977; Rupp & Archer, 1994). is also indicated in the topology of a dendrogram based on
the 16S rRNA sequence in Bergey’s Manual of Systematic
Diagnostic protocols designed by Kloos & Schleifer (1975) Bacteriology (Vos et al., 2009) as well as in whole-genome
and the later introduction of molecular techniques enabled
sequencing projects comparing different staphylococci
a more accurate identification of the already known staphy-
strains (Takeuchi et al., 2005) and 134 isolates of
lococci species as well as new species (Kloos & Schleifer,
S. haemolyticus from geographically diverse origins (Cava-
1975). Differences in the frequency of isolation from clini-
cal materials, and in the virulence factors and antimicrobial nagh et al., 2014).
susceptibility amongst staphylococci species were also Nowadays, S. aureus, S. epidermidis and S. haemolyticus are
the most frequent aetiological agents of staphylococcal
Abbreviations: CNS, coagulase-negative staphylococci; HAI, hospital- infections (Takeuchi et al., 2005). However, their virulence
acquired infection; MRSA, meticillin-resistant Staphylococcus aureus; factors differ depending on the species. Moreover, the
MRSH, meticillin-resistant Staphylococcus haemolyticus. diversity between particular strains also seems to be

000178 G 2015 The Authors Printed in Great Britain 2061

T. Czekaj, M. Ciszewski and E. M. Szewczyk

essential. S. aureus, the most virulent species, causes a admissions from 1984 to 1987 (Martin et al., 1989). Simul-
broad spectrum of infections, from minor skin diseases taneously, the widest spectrum of antimicrobial resistance
to systemic infections and sometimes septic shock (Otto, amongst CNS was observed in S. haemolyticus strains.
2012). S. epidermidis, due to its ability to produce extra- During the next decades, multiresistance of
cellular slime substances and proteins binding extracellular S. haemolyticus was reported with an increasing frequency.
matrix, can easily form biofilms (Arciola et al., 2002; Most of the analysed strains were resistant to the commonly
Rosenstein & Götz, 2013). The ability to form a biofilm used antiseptic agents and antibiotics, notably more fre-
was also associated with the existence of biofilm-associated quently than strains of any other species amongst CNS
protein Bap, encoded by the bap gene (Tormo et al., 2005). (Cavanagh et al., 2014; Hope et al., 2008). Many authors
S. epidermidis is predominant in blood infections, particu- reported S. haemolyticus strains as resistant to one or
larly in patients with artificial heart valves or with intrave- more antibiotics amongst penicillins, cephalosporins,
nous catheters commonly used in hospitals (Liekweg & macrolides, tetracyclines, quinolones, aminoglycosides, gly-
Greenfield, 1977; Rupp & Archer, 1994). In contrast to copeptides and fosfomycines (Holden et al., 2013; Lebeaux
the abundance of information available for S. epidermidis, et al., 2012; Shittu et al., 2004). In 2008, strains resistant to
little is known about biofilm formation of S. haemolyticus, the majority of available antimicrobial agents were
despite the importance of this species in nosocomial infec- described for the first time (Campanile et al., 2008). Multi-
tions (Barros et al., 2015). These infections are mostly resistant S. haemolyticus strains spread in the hospital
associated with immune-compromised patients and environment (Cavanagh et al., 2014; Rodrı́guez-Aranda
patients with implanted medical devices (Silva et al., et al., 2009). Ternes et al. (2013) showed that 55.9% of
2013). Most S. haemolyticus strains seem to lack the import- infants carried multiresistant CNS in their nasal cavity.
ant virulence attributes. However, some enzymes, cytolysins Amongst them the most frequently isolated species were
or surface substances are indicated in the literature as S. haemolyticus (38.3%) and S. epidermidis (38.0%).
factors contributing to its virulence (Daniel et al., 2014;
Flahaut et al., 2008; Simango, 2005), but none of them Multiresistant strains of S. haemolyticus also pose a serious
was identified as a crucial and determinative factor problem in animal pathology. They have been isolated both
(Fredheim et al., 2009). Despite this, S. haemolyticus is, from ruminants (Vanderhaeghen et al., 2014) and domestic
after S. epidermidis, the second most frequently isolated animals (Ruzauskas et al., 2014). Due to the possibility of
CNS from clinical cases, particularly from blood infections, transmission between animals, their owners and veterinary
including sepsis (Becker et al., 2014; Klingenberg et al., staff, animals can act as reservoirs of multidrug-resistant
2007; Liakopoulos et al., 2008; Silva et al., 2013). Therefore, strains of S. haemolyticus (Lloyd, 2007).
what is the reason for the increasing clinical significance of The scale of the phenomenon of the increasing resistance
S. haemolyticus? The most important factor might be the amongst S. haemolyticus strains for the most frequently
facility to acquire multiresistance against available antimi- used antimicrobials (b-lactams, macrolides, aminoglyco-
crobial agents. In a recent study, Barros et al. (2012) sides and quinolones) over the years is presented in Table 1.
noted that 75% of analysed S. haemolyticus isolates dis-
played multiresistance. This species also plays an important
role in the dissemination of resistance genes, contributing Meticillin-resistant S. haemolyticus (MRSH)
to the emergence of epidemic clones of a more virulent Meticillin resistance became the reason for a significant
nosocomial pathogen, S. aureus (Cavanagh et al., 2014; limitation in the use of b-lactam antibiotics. Some authors
Fluit et al., 2013). even describe the present times as the ‘post-penicillin age’.
S. aureus strains have been reported to be resistant to peni-
cillin since its discovery and introduction to the general
Multiresistance
population, due to their ability to produce b-lactamases.
The increasing number of CNS in hospital-acquired infec- In the 1950s, S. aureus strains producing penicillinase
tions (HAIs) is closely related to their antimicrobial resist- became widespread (Chambers, 1988). In 1959, meticillin –
ance and the ability to survive in a hospital environment. a semisynthetic, b-lactamase resistant antibiotic – was intro-
In the late 1980s, many studies were conducted in order duced to clinical use. At that time, natural resistance of
to determine the scale of the problem and the sources of S. aureus strains to meticillin was not observed and the pro-
multiresistance. The antimicrobial resistance profiles of blem of penicillin resistance seemed to be permanently
CNS have been monitored. Archer & Climo (1994) solved (Lebeaux et al., 2012; Sutherland & Rolinson, 1964).
indicated that the percentage of CNS resistant to meticillin, Nevertheless, strains with reduced susceptibility to meticillin
oxacillin and nafcillin amongst HAI strains increased from were reported shortly after the introduction of meticillin
20 to 60% between 1980 and 1989, according to The (Sutherland & Rolinson, 1964). In 1961, the first strain of
National Nosocomial Infection Survey, which included meticillin-resistant CNS was isolated in a clinical laboratory
data collected from selected hospitals in the USA. An even in the UK (Stewart, 1961). However, at that time, CNS
larger increase was reported at university hospitals in the were not regarded as particularly pathogenic to humans.
state of Iowa, where the frequency of bacteraemia caused Resistance to meticillin, described in the above-mentioned
by CNS increased from 5.2 to 42 cases per 10 000 study, was substantially higher in CNS than in S. aureus.

2062 Microbiology 161

 Staphylococcus haemolyticus – an emerging threat

Table 1. S. haemolyticus resistance to selected antimicrobials according to various studies since 1989

ND , No data included in the study.

Antibiotic Resistant strains (%) 1996/1997D 1997/1998d 2006–2008§ 2008–2010I

1989*

Penicillin ND 87.5 84.4 95.0 ND

Meticillin 80.0 72.3 70.5 ND ND
Gentamicin 79.0 67.9 58.4 73.0 92.9
Erythromycin 79.0 78.8 75.1 64.0 85.7
Tetracycline 75.0 ND ND ND 28.6
Trimethoprim 63.0 ND ND ND 57.1
Chloramphenicol 11.0 ND ND 25.0 ND
Ciprofloxacin ND 54.9 54.9 ND 92.9
Clindamycin 2.7 4.6 ND 47.0 ND
Fusidic acid ND 31.0 30.6 ND 50.0
Teicoplanin ND 11.4 12.7 ND ND
Vancomycin ND 0.0 0.0 ND ND

*N570 S. haemolyticus isolates from 60 patients in the USA, n551 hospitalized, strains isolated mainly from wounds, urine and blood; phenotypic
analysis (MIC) (Froggatt et al., 1989).
DN5184 S. haemolyticus isolates from hospitals in the UK; phenotypic analysis (MIC) (Andrews et al., 2000).
dN5173 S. haemolyticus isolates from hospitals in the UK; phenotypic analysis (MIC) (Andrews et al., 2000).
§N564 S. haemolyticus isolates from hospitalized patients in Rio de Janeiro, Brazil; phenotypic analysis (disc diffusion assay) (Barros et al., 2012).
IN514 S. haemolyticus isolates from European countries (Belgium, n52; Germany, n510; Spain, n52); genotypic analysis (Cavanagh et al., 2014).

The observed MIC for meticillin in CNS reached 2000 mg the possibility of evaluating the contribution of
ml21, in comparison with the maximum of 20 mg ml21 for S. haemolyticus to the phenomenon of meticillin resistance.
S. aureus. In the following years, meticillin-resistant
Another important feature of staphylococci is their ability
S. aureus (MRSA) strains were isolated in other European
countries, as well as in the USA, Japan and Australia (Enright to survive in the hospital environment. According to a
et al., 2002). study conducted in South Korea in 2011, MRSH strains
were found on 51.4% of X-ray cassettes in a Radiology
It is well known that the mechanism of meticillin resistance Department. PFGE analysis showed a genetic similarity
determines the resistance to all b-lactam antibiotics: peni- between the isolated strains, which indicates their clonal
cillins, cephalosporins, carbapenems and monobactams spread in the hospital environment via medical devices
(Kollef, 2009; Widmer, 2008). In S. aureus (Hiramatsu
(Kim et al., 2012). Such an occurrence was also reported
et al., 2002), which is the subject of the majority of studies
previously in other studies (Degener et al., 1994; Tabe
on meticillin resistance, as well as in CNS (Bochniarz et al.,
et al., 1998), which showed that patients and hospital
2013), this mechanism is associated with the presence of
the mecA gene, encoding the modified transpeptidase peni- staff might also be a reservoir for multiresistant
cillin-binding protein PBP2a, which is natively responsible S. haemolyticus strains (Perl et al., 1999; Rahman et al.,
for the synthesis of pentaglycine bridges in peptidoglycan. 2012; Squeri et al., 2012).
Despite differences in the peptidoglycan structure between Molecular analysis demonstrated that mecA genes, part of
S. haemolyticus and S. aureus, its similarity is sufficient to SCCmec cassettes, are associated with meticillin resistance.
develop the same resistance mechanism (Billot-Klein These cassettes are mobile genetic elements which might be
et al., 1996). Analysis of mecA gene sequences in GenBank horizontally transferred. (Młynarczyk & Młynarczyk, 2008;
reference strains of S. aureus, S. haemolyticus and Zong et al., 2011). SCCmec cassettes are localized in the
S. epidermidis showed 99.95% similarity, which proves genomic bacterial DNA, at the 39 end of the orfX gene
the theory of the interspecies transfer of mecA gene. encoding ribosomal methyltransferase. Apart from the
b-Lactam agents bind native PBP2 protein and block its mec gene complex (mecA, mecR1, mecI), they comprise
activity, whereas they exhibit a much lower affinity to the the ccr gene complex encoding chromosomal recombinase,
modified PBP2a protein (John & Harvin, 2007). In the which enables the integration of cassette and chromosomal
1970s, meticillin resistance was more frequent amongst DNA, and sometimes also other genes encoding virulence
meticillin-resistant CNS than amongst MRSA. This factors or associated with resistance to various antimicro-
phenomenon is still current (John & Harvin, 2007). Unfor- bial agents (Hanssen & Ericson Sollid, 2006; Ito et al.,
tunately, even in current papers, the species of the investi- 2001). SCCmec cassettes consist of 10–60 kbp
gated CNS groups are often not specified, which hinders (International Working Group on the Classification of

http://mic.microbiologyresearch.org 2063
T. Czekaj, M. Ciszewski and E. M. Szewczyk

Staphylococcal Cassette Chromosome Elements, 2009; Staphylococci strains resistant to glycopeptides were not
Shore & Coleman, 2013). At present, 11 types of SCCmec reported during the first 20 years following its introduction
cassettes and many subtypes have been identified in into clinical use, (Srinivasan et al., 2002). Resistance to
S. aureus strains. However, due to ongoing research and vancomycin and teicoplanin is still quite rare amongst
continuously increasing knowledge in this field, this list staphylococci, but many studies have indicated that
will certainly be extended in the near future. What is S. haemolyticus might play an important role in this
more, it is sometimes impossible to associate the cassette’s phenomenon. S. haemolyticus was the first Gram-positive
type to that described in the literature (International bacteria reported as being resistant to glycopeptides,
Working Group on the Classification of Staphylococcal before any other staphylococci and enterococci (Kristóf
Cassette Chromosome Elements, 2009), especially during et al., 2011). This species has been also suggested as being
the analysis of SCCmec cassettes in CNS strains. The largest more active than other CNS in generating clones with
diversity of SCCmec sequences is observed amongst increased glycopeptide (especially teicoplanin) MICs (Bia-
S. epidermidis, S. haemolyticus and Staphylococcus hominis vasco et al., 2000).
strains. In these cases, entire cassette sequencing is often
In 1987, the first case of peritonitis caused by
required in order to determine the similarity to those
S. haemolyticus with reduced susceptibility to vancomycin
described in the literature (Takeuchi et al., 2005).
in a dialysis patient was reported (Schwalbe et al., 1987).
The most frequently identified SCCmec cassette type in Amongst CNS, it was S. haemolyticus that was documented
S. haemolyticus strains is type V. Types IV and VII have as being resistant to teicoplanin for the first time (Biavasco
also been reported. Although these cassettes are present et al., 2000). It was suggested that S. haemolyticus is unique
in a relatively small number of strains, S. haemolyticus is amongst CNS and especially predisposed to resistance to
indicated to be the reservoir of SCCmec elements for glycopeptides, because of its extraordinary genome plas-
other staphylococci, due to its facility to transfer genes to ticity and tendency to frequent DNA rearrangements
other species (Fluit et al., 2013; Szczuka & Kaznowski, (Takeuchi et al., 2005). According to various studies, the
2014). At the neonatal intensive care unit in Örebro Uni- percentage of hospital-isolated S. haemolyticus strains
versity Hospital in Sweden in 2008, a case of SCCmec with reduced susceptibility to teicoplanin is increasing
type V cassette transfer from MRSH to meticillin-suscep- (Bannerman et al., 1991; Cercenado et al., 1996; Goldstein
tible S. aureus was reported (Berglund & Söderquist, et al., 1990). What is alarming is that the strains were also
2008). The study conducted by Ternes et al. (2013) indi- isolated from infants in neonatal intensive care units (Per-
cated that the prevalence of SCCmec amongst CNS is eira et al., 2014). At the University Hospital in Leiden in
high and that hospitalization increases the prevalence sig-
The Netherlands, the susceptibility of CNS to teicoplanin
nificantly. Whilst 60% of CNS strains isolated from
was compared over the years. Between 1985 and 1994,
patients’ physiological microbiome at the moment of
the percentage of CNS strains with reduced susceptibility
admission to the hospital possessed the mecA gene, the per-
to teicoplanin increased from 2 to 20% (Sloos et al.,
centage of mecA-positive CNS strains at the moment of dis-
1998). The data show that the rapidity of the selection pro-
charge from the hospital increased to 83.6%.
cess for teicoplanin-resistant strains is very high. The case
of a teicoplanin-resistant strain isolation from a Hickmann
Resistance of S. haemolyticus to the last-chance catheter was reported after the first course of treatment
antimicrobial drugs with this antibiotic (Cunningham et al., 1997). The most
As a consequence of the increasing resistance to meticillin, alarming cases are associated with infections caused by
the search for new antimicrobial drugs designed to treat CNS strains resistant to both teicoplanin and vancomycin
infections caused by meticillin-resistant strains was com- (Fajardo Olivares et al., 2011; Sieradzki et al., 1998). They
menced. A new class of antibiotics, glycopeptides (e.g. van- also emerged after long-term treatment with teicoplanin
comycin introduced into the clinic in 1958 and teicoplanin in infections caused by S. epidermidis strains (Aubert
introduced into the clinic 1984), inhibits the synthesis of et al., 1990; Blans & Troelstra, 2001). The wide use of gly-
cell walls by interfering with peptidoglycan synthesis copeptides in the hospital environment led to the selection
(Berglund & Söderquist, 2008; Srinivasan et al., 2002). of strains with reduced susceptibility to these antibiotics,
Resistance to glycopeptides results from the acquisition and with MIC values *4–8 mg l21 for vancomycin and/or
expression of operons that substitute a terminal D -lactate 8–16 mg l21 for teicoplanin (Nakipoglu et al., 2005;
or D -serine for the D -alanine, which reduces the vancomy- Natoli et al., 2009; Tabe et al., 2001). The first cases like
cin-binding affinity (Rice, 2012). Another mechanism of these were reported in 1979 and 1983, when CNS were
glycopeptide resistance involves a vanA operon contained regarded as bacteria with a low pathogenic potential (Sie-
on a transposon residing on a conjugal plasmid. However, bert et al., 1979; Tuazon & Miller, 1983). Although the
this mechanism has been mostly described for the genus increase in resistance to glycopeptides in S. aureus strains
Enteroccocus (Qureshi et al., 2014). is suggested by some authors to be connected with the
In the early 1980s, CNS were regarded as genetically unable phenomenon of MIC creep (incremental increases in glyco-
to develop resistance to vancomycin (Veach et al., 1990). peptide MICs for strains over time), it is believed that such

2064 Microbiology 161

 Staphylococcus haemolyticus – an emerging threat

a phenomenon has not occurred in CNS (Ahlstrand et al., SNPs per genome. A significant genetic diversity was
2011). observed, amongst others, in the region of the SCCmec
cassette. In 2014, a team of researchers from Norway and
Infections caused by multiresistant S. haemolyticus strains
the UK published conclusions regarding sequencing 134
might be associated with implantations and sometimes
clinical strains of S. haemolyticus, isolated between 1988
the only way to prevent a systemic infection is to remove
and 2010 in eight countries from different geographical
an implant (Daniel et al., 2014). As a rule, in the case of
regions (Belgium, Germany, Japan, Norway, Spain, Swit-
infections caused by staphylococci resistant to glycopep-
zerland, UK and USA) (Cavanagh et al., 2014). The
tides, treatment should be based on linezolid – a synthetic
chemotherapeutic of the oxazolidinones drug class (Perry majority of them (77%) were multiresistant, defined as
& Jarvis, 2001). Linezolid blocks protein synthesis by bind- resistant to at least three antibiotics. This study suggested
ing to 23S rRNA and preventing the creation of the trans- that multiresistant strains spread clonally between
lation initiation complex (Livermore, 2003; Long & Vester, countries. Multiresistant strains displace the susceptible
2012; Quiles-Melero et al., 2013). Resistance to linezolid strains in hospitals as a result of selective pressure in the
amongst CNS is currently negligible; however, the first environment (Holden et al., 2013; Miragaia et al., 2007;
cases of S. haemolyticus strains resistant to linezolid have Zhang et al., 2013). An alternative hypothesis assuming
been reported in India and in various countries in an independent emergence of the multiresistant strains in
Europe (Gupta et al., 2012; Mazzariol et al., 2012; different geographical regions seems to be less probable
Mendes et al., 2014a, b, c; Rajan et al., 2014; Tarazona (Cavanagh et al., 2014).
et al., 2007). Recent research performed in Italy on
S. haemolyticus strains showed that resistance to linezolid
Conclusion
is associated with a G2576T mutation (Mazzariol et al.,
2012), which leads to linezolid’s reduced affinity for the CNS often constitute underestimated aetiological factors of
ribosome. The same mutation has been described pre- human infections. One of the most important species in
viously for S. aureus (Tsiodras et al., 2001). A double this group is S. haemolyticus. Despite the fact that it does
mutation of the rRNA gene (C2190T and G2603T) con- not possess as many virulence factors as S. aureus and
nected with linezolid resistance was also reported in 2015 hence its potential to cause severe infections is lower, the
(Cidral et al., 2015). key role in the evaluation of a threat posed by
S. haemolyticus is its multiresistance. The unusual
genome plasticity manifested by a large number of inser-
Specificity of the S. haemolyticus genome tion sequences and identified SNPs might contribute to
In 2005, Takeuchi et al. (2005) sequenced the entire its acquisition of antibiotic resistance, and also resistance
genome of multiresistant S. haemolyticus strain JCSC1435 to the ‘last-chance’ antimicrobial drugs. It is suggested
consisting of 2685015 bp and three plasmids: 2300, 2366 that S. haemolyticus might be the reservoir of resistance
and 8180 bp. The obtained sequence was compared with genes (and SCCmec cassettes) for other staphylococci
the genomes of S. aureus and S. epidermidis reference (including S. aureus). Taking into consideration the great
strains. A unique feature of the S. haemolyticus JCSC1435 adaptability and ability to survive in the hospital environ-
chromosome is that it contains as many as 82 insertion ment (including on medical devices), S. haemolyticus
sequences. Two insertion sequence groups (ISSha1 and becomes a crucial factor in HAIs caused by multiresistant
IS1272-SH) comprised 68% of the insertion sequence staphylococci. Future studies leading to our further under-
elements. IS1272-SH of S. haemolyticus exhibited 85% standing of the mechanisms of transfer of resistance genes,
nucleotide identity to IS1272-SA of S. aureus and 81% including SCCmec cassettes, to other staphylococci species
identity to IS1272-SE of S. epidermidis. Moreover, should become a priority, especially in view of the increas-
IS1272-SH was almost identical to the insertion sequence ing resistance to the majority of available antimicrobial
fragment found in type I and IV SCCmec MRSA, which agents and increasingly difficult treatment of infections
indicates that it might have been transferred from caused by multiresistant strains.
S. haemolyticus to S. aureus via SCCmec cassette transfer.
The presence of so many insertion sequences is presumably
the reason for the frequent genome rearrangements in References
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