Antimicrobial resistance of Staphylococcus

pseudintermedius
Kristina Kadlec and Stefan Schwarz
Institute of Farm Animal Genetics, Friedrich-Loefer-Institut (FLI), Ho ltystrae 10, 31535 Neustadt-Mariensee, Germany
Correspondence: Kristina Kadlec, Institute of Farm Animal Genetics, Friedrich-Loefer-Institut (FLI), Ho ltystrae 10, 31535 Neustadt-Mariensee,
Germany. E-mail: kristina.kadlec@i.bund.de
Staphylococcus pseudintermedius, Staphylococcus intermedius and Staphylococcus delphini together comprise
the S. intermedius group (SIG). Within the SIG, S. pseudintermedius represents the major pathogenic species
and is involved in a wide variety of infections, mainly in dogs, but to a lesser degree also in other animal species
and humans.
Antimicrobial agents are commonly applied to control S. pseudintermedius infections; however, during recent
years S. pseudintermedius isolates have been identied that are meticillin-resistant and have also proved to be
resistant to most of the antimicrobial agents approved for veterinary applications.
This review deals with the genetic basis of antimicrobial resistance properties in S. pseudintermedius and other
SIG members. A summary of the known resistance genes and their association with mobile genetic elements is
given, as well as an update of the known resistance-mediating mutations. These data show that, in contrast to
other staphylococcal species, S. pseudintermedius seems to prefer transposon-borne resistance genes, which
are then incorporated into the chromosomal DNA, over plasmid-located resistance genes.
Introduction
First described in 2005 as a novel species,
1
Staphylococcus
pseudintermedius along with another two coagulase-posi-
tive staphylococcal species, Staphylococcus intermedius
and Staphylococcus delphini, forms the S. intermedius
group (SIG). Members of the SIG have been identied in a
variety of animal species, either as colonizers or as causa-
tive agents of diseases, very often skin infections.
26
Despite the fact that a correct species identication within
the SIG requires molecular tools, the aforementioned stud-
ies have conrmed that S. pseudintermedius is most
frequently detected in dogs. Thus, Devriese et al.
7
recom-
mended that a canine isolate should be classied as
S. pseudintermedius when it is identied by standard tests
to belong to the SIG. In the present review, we also include
older publications and address the corresponding isolates
as S. pseudintermedius if they originate from dogs. Iso-
lates from other animal species will be referred to as SIG
isolates in this review.
During recent years, the species S. pseudintermedius
has gained considerable attention because of the emer-
gence of meticillin-resistant S. pseudintermedius (MRSP)
isolates. The MRSP usually exhibit resistance to several
other non-b-lactam antimicrobial agents also. So far, most
of the publications on antimicrobial resistance in MRSP
have focused on isolates from dogs, and only few isolates
from other animals have been investigated. However,
resistant S. pseudintermedius isolates have been identi-
ed from several host species, including cats, horses, a
parrot, a donkey and humans.
6,811
In contrast to dogs,
S. pseudintermedius seems to be very rare in some of
these species. In horses, for example, a single S. pseud-
intermedius isolate was identied between 1995 and 2006
from3457 horse post mortemexaminations, amongwhich
coagulase-positive staphylococci were identied in 60
cases; the remaining isolates were Staphylococcus
aureus.
8
The presence of indistinguishable isolates in pets
and their owners has been conrmed.
12,13
Like other
staphylococci, S. pseudintermedius is a facultative patho-
gen, and resistant isolates have been identied as causa-
tive agents in clinical infections. In addition to canine
pyoderma, resistant S. pseudintermedius isolates have
been shown to cause complicated postoperative infec-
tions or skin infections in dogs and cats,
14
urinary tract
infections in cats
15
and various infections in human
patients.
1618
In contrast to the wealth of data on phenotypic antimi-
crobial resistance of S. pseudintermedius and SIG iso-
lates, comparatively little information is available on the
genetic basis of antimicrobial resistance. This report
reviews the current knowledge of the resistance genes
and the resistance-mediating mutations currently known
to occur in S. pseudintermedius and SIG isolates.
Phenotypic analysis of antimicrobial
resistance in S. pseudintermedius and SIG
isolates
Various studies have dealt with the phenotypic analysis of
antimicrobial resistance of S. pseudintermedius and SIG
isolates.
6,9,10,12,1925
For this, different methods have
Accepted 3 April 2012
Sources of Funding: This study was self-funded.
Conict of Interest: No conicts of interest have been declared.
2012 The Authors. Veterinary Dermatology
276 2012 ESVD and ACVD, Veterinary Dermatology, 23, 276e55.
Vet Dermatol 2012; 23: 276e55 DOI: 10.1111/j.1365-3164.2012.01056.x
been used, including disk diffusion, broth microdilution
and, in selected cases and for specic antimicrobial
agents, the Etest. The use of the different methods
followed different performance standards, among which
the Clinical and Laboratory Standards Institute (CLSI) doc-
ument M31-A3
26
is most frequently used worldwide.
Moreover, different test panels of antimicrobial agents
and, for broth microdilution, different ranges of test con-
centrations for the antimicrobial agents have been used
in different studies. In addition, a wide range of inter-
pretive criteria have been used for the assessment of an
isolate as susceptible, intermediate or resistant to a spe-
cic antimicrobial agent. These observations underline
the problem of comparability of the results obtained in
different studies.
27,28
The CLSI document M31-A3 contains only a few veteri-
nary-specic clinical breakpoints applicable to canine
S. [pseud]intermedius, e.g. for ampicillin and cefpodox-
ime.
26
The interpretation of antimicrobial susceptibility
test results for other antimicrobial agents obtained from
S. pseudintermedius or SIG isolates usually relies on
breakpoints applicable to S. aureus, coagulase-negative
staphylococci or Staphylococcus spp. staphylococci in
general. In the absence of S. pseudintermedius-specic
interpretive criteria, it seems to be appropriate to use
breakpoints for S. aureus.
However, an exception is the identication of MRSP
isolates. Besides phenotypic oxacillin resistance, the
gene mecA has to be present to classify an isolate as
MRSP. For S. aureus and coagulase-negative staphylo-
cocci, the cefoxitin disk test is commonly used for predic-
tion of mecA-mediated resistance. A closer look at the
situation in MRSP has shown that the oxacillin break-
points recommended for S. aureus underestimate the
presence of mecA-carrying S. pseudintermedius, and the
breakpoints given for coagulase-negative staphylococci,
namely minimal inhibitory concentration (MIC) values of
0.5 mg L and inhibitory zones of 17 mm, when test-
ing according to the CLSI document M31-A3, are much
more appropriate.
22
Moreover, the cefoxitin predictive
test proved not to be useful for S. pseudintermedius.
22
A revised recommendation is going to be included in the
forthcoming CLSI document M31-A4.
Genetic basis of antimicrobial resistance in
S. pseudintermedius and SIG isolates
While many recent studies have focused on MRSP
isolates, comparatively little is known about the molecular
basis of antimicrobial resistance in meticillin-susceptible
S. pseudintermedius or SIG isolates. The following para-
graphs are intended to provide an update of the current
knowledge of the genes and mutations involved in the
resistance of meticillin-resistant and meticillin-susceptible
S. pseudintermedius or SIG isolates to various antimicro-
bial agents.
Resistance to b-lactam antibiotics
Based on CLSI recommendations, meticillin (oxacillin)-
resistant staphylococci are considered as resistant to all
b-lactam antibiotics. As such, resistance to the penicillin-
ase-stable penicillins meticillin and oxacillin has gained
particular attention. In laboratory testing, meticillin has
been replaced by the more stable oxacillin. Studies
conducted during the years 19861995 did not identify
oxacillin-resistant S. pseudintermedius or SIG isolates.
29
Moreover, no oxacillin-resistant isolate was detected
among 50 S. pseudintermedius isolates from cases of
canine pyoderma collected in 2002.
25
However, an
increasing number of MRSP isolates has been identied
during the last decade.
30,31
A retrospective investigation
showed an increase from about 5 to 30% among iso-
lates from the USA during the years 2001 to 2007,
respectively.
22
High rates of meticillin-resistant S. pseud-
intermedius were seen, with 17% in isolates from 2003
2004
32
and 15.6% in isolates from 2005.
33
The rst case
of a meticillin-resistant S. pseudintermedius in Europe
was published in 2007.
24
Meticillin-resistant S. pseudin-
termedius is regarded a nosocomial bacterium in veteri-
nary clinics, in a similar way to healthcare-associated
meticillin-resistant S. aureus (MRSA) in human hospital
settings.
19,34
Meticillin resistance is based on the expression of the
mecA gene, which codes for the alternative penicillin-
binding protein PBP2a. The mecA gene is located on a
mobile genetic element, the staphylococcal cassette
chromosome mec (SCCmec) element. The types of these
SCCmec elements present in MRSP seem to differ from
those identied in MRSA. Two of these SCCmec ele-
ments from MRSP were sequenced completely and
proved to be novel types of SCCmec elements. The one
found in S. pseudintermedius KM1381 was composed
exclusively of parts previously identied in SCCmec ele-
ments of types II and III; it was designated as type II
III.
35
The SCCmec element found in S. pseudintermedius
KM241 also showed partial homology to SCCmec type III
but, based on the structural differences and the novel ccr
gene complex ccrA5 ccrB5, was considered to represent
a novel type, designated SCCmec VII
35
and subsequently
renamed SCCmec
KM-241
.
19
In contrast to the SCCmec
elements of types II or III,
36
the SCCmec elements of
types IIIII and VII did not carry integrated Tn554-like
transposons or small resistance plasmids, such as the
aadD-carrying kanamycin neomycin resistance plasmid
pUB110 or the tet(K)-carrying tetracycline resistance plas-
mid pT181. The analysis of 103 canine MRSP isolates
from Europe and North America identied the hybrid
SCCmec element IIIII in 75 (72.8%) isolates, while the
remaining isolates either had SCCmec types III (n = 2), IV
(n = 6), V (n = 14) or VII (n = 4) or were not typeable
(n = 2).
19
The analysis of feline MRSP from Europe and
North America identied the SCCmec element IIIII in the
11 isolates from Europe, whereas the single isolate from
Canada had an SCCmec element of type V.
9
Two recent
studies on MRSP among dogs and cats admitted to a vet-
erinary hospital during a 17 month period also identied
the SCCmec element of type IIIII in all 69 canine and
three feline MRSP isolates.
10,20
Resistance to penicillinase-labile penicillins, such as
penicillin G, ampicillin or amoxicillin, seems to be fre-
quent in S. pseudintermedius. An investigation of 116
canine isolates from Germany and the USA identied 72
(62.1%) as ampicillin resistant.
37
A similar percentage
was seen among isolates from France, where 31 (62.0%)
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2012 ESVD and ACVD, Veterinary Dermatology, 23, 276e55. 277
Antimicrobial resistance of Staphylococcus pseudintermedius
of 50 isolates were found to be b-lactamase producers.
25
Microarray studies of MRSP isolates revealed that the
gene blaZ, which codes for a narrow-spectrum b-lactam-
ase, is present in most of the MRSP isolates, e.g. in 102
(99.0%) of 103 canine MRSP and all 12 feline MRSP iso-
lates from Europe and North America.
9,19
The gene blaZ
was also detected by PCRin MRSP (n = 12) and meticillin-
susceptible S. pseudintermedius (MSSP; n = 3) from
dogs and in MRSP fromcats (n = 2).
23
Resistance to tetracyclines
So far, four different tetracycline resistance genes have
been identied in S. pseudintermedius and SIG isolates.
The genes tet(K) and tet(L) code for efux pumps
of the major facilitator superfamily, whereas the
genes tet(M) and tet(O) code for ribosome protective
proteins.
38
Analysis of 301 S. pseudintermedius and SIG isolates
from dogs, cats, horses, mink and pigeons identied tet-
racycline resistance in 105 (34.9%) isolates. Among
them, the tet(M) gene was present in 89 (84.8%), the
tet(K) gene in ve (4.8%), the tet(O) gene in one (0.9%),
the genes tet(K) and tet(M) in eight (7.6%) and the genes
tet(L) and tet(M) in two (1.9%) isolates.
39
In a study by
Kim et al.,
40
29 of 144 tetracycline-resistant isolates were
tested for the presence of tet genes, with the following
results: tet(M), n = 18; tet(M) and tet(K), n = 4; tet(M)
and tet(L), n = 6; and tet(L), n = 1. The gene tet(K),
which is commonly found on small plasmids in other
staphylococci from humans and animals,
41
was identied
in a single canine S. pseudintermedius isolate to be
located on a 4.5 kb plasmid. This plasmid, designated
pSTS2, was virtually indistinguishable in its restriction
map from the S. aureus prototype plasmid pT181.
37
Further analysis of tetracycline-resistant canine S. pseud-
intermedius (n = 6) and equine SIG isolates (n = 3) identi-
ed the tet(M) gene on different-sized chromosomal
HindIII fragments in all nine isolates.
39
The tet(M) gene
has been identied as part of conjugative transposons,
such as Tn916 and Tn1545.
42
More recent studies on
canine and feline MRSP revealed that 72 (69.9%) of 103
canine and all 12 feline isolates were tetracycline resis-
tant. In these isolates, the genes tet(K) (50.5%), tet(M)
(17.5%) or, occasionally, tet(K) and tet(M) (1.9%) were
detected.
9,19
Resistance to macrolides and lincosamides
So far, ve different genes that confer resistance to
macrolides and or lincosamides have been identied in
S. pseudintermedius and SIG isolates. Among them are
the gene lnu(A), which codes for a lincosamide nucleot-
idyl transferase, the gene msr(A), which codes for an
ABC transporter that can export macrolides and strep-
togramin B antibiotics, and the genes erm(A), erm(B) and
erm(C), all of which code for rRNA methylases that confer
combined resistance to macrolides, lincosamides and
streptogramin B antibiotics.
Previous studies identied the Tn917-associated
erm(B) gene as the predominant erm gene in canine and
feline S. pseudintermedius.
43,44
This gene was detected
as the sole macrolidelincosamide resistance gene in 10
and 21 canine feline S. pseudintermedius isolates from
respiratory tract infections or skin ear mouth infections,
respectively, collected in the BfT-GermVet study.
44
More-
over, it was also the sole macrolidelincosamide resis-
tance gene in most canine and feline MRSP isolates from
Europe and North America.
9,19
In six canine MRSP iso-
lates from the USA and Canada, the gene erm(B) was
present together with the gene lnu(A).
19
In two canine
feline S. pseudintermedius isolates from skin ear mouth
infections of the BfT-GermVet study, the gene erm(B)
was found together with the gene msr(A).
44
Another two
canine feline S. pseudintermedius isolates from respira-
tory tract infections harboured the gene erm(A),
44
which
is usually linked to the spectinomycin resistance gene
spc in transposon Tn554.
45
A constitutively expressed
erm(A) gene was also detected on a 70 kb plasmid in a
SIG isolate from a carrier pigeon.
46
The erm(C) gene was
detected on 2.5 kb plasmids in two canine S. pseudin-
termedius isolates.
37
These plasmids were indistinguish-
able in their restriction maps and closely resembled the
erm(C)-carrying plasmid pNE131.
47
Resistance to chloramphenicol
Chloramphenicol resistance in S. pseudintermedius and
SIG isolates is usually based on the expression of chlor-
amphenicol acetyltransferase (cat) genes. Among the
three cat genes known to occur in staphylococci,
41
the
cat gene originally identied on the 4.5 kb plasmid pC221
is very common. Small cat
pC221
-carrying plasmids, rang-
ing in size between 3.1 and 4.1 kb, were identied in
canine S. pseudintermedius.
37,48,49
These plasmids clo-
sely resembled pC221 in the parts comprising the plas-
mid replication gene and the cat gene, but differed in the
remaining parts of the plasmids. Kim et al.
40
identied
chloramphenicol resistance in 29 (18.1%) of 160 canine
S. pseudintermedius isolates. In 17 of these 29 isolates,
a cat
pC221
was identied, which was often linked to a
pS94-like streptomycin resistance gene. This combination
of a cat
pC221
gene with a str gene had been observed
before in other staphylococcal species.
50,51
The cat
pC221
gene was also detected in 59 (57.3%) of the 103 canine
isolates and in 10 (83.3%) of the 12 feline MRSP isolates
from Europe and North America.
9,19
Resistance to aminoglycosides
Different genes, all coding for aminoglycoside-inactivating
enzymes, have been identied in S. pseudintermedius
and SIG isolates. The gene aacA-aphD, also named
aac(6)-Ie-aph(2)-Ia, which confers resistance to gentami-
cin, tobramycin and kanamycin, has been identied in
canine MRSP isolates.
19,52
Kanamycin resistance was
also conferred by the gene aphA-3, also named aph(3)-
III.
19,43
In the study by Boerlin et al.,
43
a gene cluster
carrying the gene aphA-3, the gene sat4 coding for a
streptothricin acetyltransferase and the gene aadE, also
named ant(6)-Ia, coding for a streptomycin adenyltrans-
ferase, was identied. This gene cluster showed homol-
ogy to the respective part of transposon Tn5405.
43
In
close proximity to the right-hand terminus of this Tn5405-
homologous segment, the MLS
B
resistance gene erm(B)
was identied. This structure was seen in the chromo-
somal DNA of 20 erythromycin- and aminoglycoside-
resistant S. pseudintermedius isolates.
2012 The Authors. Veterinary Dermatology
278 2012 ESVD and ACVD, Veterinary Dermatology, 23, 276e55.
Kadlec and Schwarz
The analysis of MRSP for aminoglycoside resistance
genes identied the aacA-aphD gene in 91 (88.3%) of the
103 canine and in 11 (91.7%) of the 12 feline isolates
from Europe and North America. The resistance genes
aphA-3, sat4 and aadE were simultaneously present in 93
(90.3%) of the 103 canine and in 11 (91.7%) of the 12
feline MRSP isolates. The erm(B) gene was also present
in all but one canine isolate from Germany. These obser-
vations suggested that despite the wide geographical dis-
tribution, the vast majority of the MRSP isolates of dogs
and cats carried the erm(B) gene linked to a Tn5405-like
element.
Resistance to trimethoprim
Susceptibility testing to the combination sulfonamide tri-
methoprim is very common. In contrast, trimethoprim
resistance is rarely tested, because this antimicrobial
agent is not commonly available for therapeutic interven-
tions. Observations made in the BfT-GermVet study
showed that sulfamethoxazole trimethoprim MIC values
of 4 76 mg L are seen only when staphylococcci are
resistant to both folate pathway inhibitors. Isolates resis-
tant to sulfonamides and susceptible to trimethoprim or
vice versa usually show distinctly lower sulfonamide tri-
methoprim MIC values.
53,54
So far, the molecular basis
for sulfonamide resistance has not been identied in
S. pseudintermedius. For trimethoprim resistance, the
gene dfrG has been detected in all 93 (90.3%) trimetho-
prim-resistant canine and in all 11 trimethoprim-resistant
feline MRSP isolates.
9,19
The gene dfrG codes for a
trimethoprim-resistant dihydrofolate reductase. It was
described rst in 2005 in a nosocomial S. aureus
isolate.
55
Resistance to uoroquinolones
In a study from France, 393 S. intermedius isolates were
collected in the years 1995, 1997 and 1999, and MICs to
enrooxacin were determined.
56
The MIC values of the
majority of isolates ranged from 0.063 to 1 mg L, with
only two isolates showing higher MIC values of 2 or
64 mg L. Both isolates were detected in 1999 and did
not show resistance to b-lactams.
56
Among the canine
and feline MRSP isolates from Europe and North Amer-
ica, 90 (87.4) of the canine and 11 (91.7%) of the feline
isolates were classied as uoroquinolone-resistant by
ciprooxacin MIC values of 4 mg L.
9,19
Descloux et
al.
35
identied numerous base pair exchanges in the
genes gyrA, gyrB, grlA and grlB of S. pseudintermedius
isolates with enrooxacin MICs of 4 mg L. Some of
these base pair exchanges resulted in amino acid substi-
tutions at positions previously identied to play a role in
(uoro)quinolone resistance; Ser84Leu and Glu88Gly in
gyrA and Ser80Ile and Asp84Asn in grlA.
35
The same
exchanges, Ser84Leu and Glu88Gly in gyrA as well as
Ser80Ile and Asp84Asn in grlA, were seen in MRSP iso-
lates from Japan tested for their resistance to three uro-
roquinolones (ooxacin, enrooxacin and levooxacin). In
addition, Ser84Phe in gyrA and Asp84Glu in grlA were
detected in isolates classied as resistant or intermediate
to all three agents. In one isolate resistant to only ooxa-
cin, the exchange Ser81Pro was present in grlA.
57
Among
136 canine S. pseudintermedius isolates from Italy, two
were uoroquinolone resistant and one of them showed
single amino acid substitutions in gyrA (Ser84Leu)
and grlA (Ser80Arg).
58
The same two exchanges were
detected in three resistant S. pseudintermedius isolates
from Korea, while isolates considered as intermediate
showed solely the exchange in grlA.
59
In eight ciprooxa-
cin-resistant MRSP isolates from Spain (MIC of
32 mg L), these two substitutions were also identied.
60
In addition, the seven isolates belonging to the MLST
type ST71 showed (in contrast to the remaining ST92
isolate) an additional exchange in gyrA Glu714Lys.
60
Resistance to rifampicin
Comparatively little is known about rifampicin resistance
in canine S. pseudintermedius. Isolates resistant to rifam-
picin occur very rarely. Among 103 MRSP isolates from
dogs, only two isolates showed high rifampicin MIC
values of 64 mg L.
19
A single in-depth study on the
genetics of rifampicin resistance in MRSP isolates is
currently available.
61
The two MRSP isolates of the multi-
centre study
19
showed amino acid substitutions at
positions 513 (Gln513Arg) or 522 (Ala522Asp) in the
rifampicin resistance-determining region of RpoB.
61
During the screening of nine individual dogs, all rifampi-
cin-resistant MRSP isolates showed mutations at one or
two of the amino acid positions 508 (Ser508Asn), 509
(Ser509Pro), 513 (Glu513Leu), 516 (Asp516Asn), 522
(Ala522Asp), 526 (His526Arg, His526Pro, His526Tyr) and
531 (Ser531Leu). In most MRSP isolates, only a single
amino acid exchange was observed.
61
Resistance to fusidic acid and mupirocin
Resistance to both fusidic acid and mupirocin seems to
be very rare. Loefer et al.
62
investigated 71 MSSP and
12 MRSP isolates for their MICs to fusidic acid and mup-
irocin. The MSSP and MRSP isolates varied in their MICs
of fusidic acid between 0.068 and 0.062 mg L, respec-
tively. Likewise, low mupirocin MICs of 0.064 and 0.06
0.5 mg L were recorded for the MSSP and MRSP
isolates, respectively.
62
None of the 103 canine MRSP
isolates had an elevated MIC value of fusidic acid.
19
A sin-
gle study is available in which fusidic acid resistance
based on the gene fusC was detected in two S. pseudin-
termedius isolates.
63
Conclusion
As outlined in the previous sections, a number of antimi-
crobial resistance genes have been detected in S. pseud-
intermedius (Table 1). Most of these resistance genes
have also been identied in other staphylococcal species
or bacteria of other Gram-positive genera and species.
This observation underlines the ability of S. pseudinter-
medius to acquire genetic material from other bacteria.
However, in contrast to other staphylococci,
29,41,64,65
plasmids do not seem to play an important role as carriers
of antimicrobial resistance genes. Apart from a few
exceptions,
37
resistance plasmids have rarely been
detected in S. pseudintermedius and SIG isolates. In
contrast, S. pseudintermedius seems to prefer transpo-
son-borne antimicrobial resistance genes. Most of
the determined antimicrobial resistance genes in
2012 The Authors. Veterinary Dermatology
2012 ESVD and ACVD, Veterinary Dermatology, 23, 276e55. 279
Antimicrobial resistance of Staphylococcus pseudintermedius
S. pseudintermedius and SIG isolates are associated with
transposons, as follows: blaZ, Tn552; tet(M), Tn916 and
Tn1545; erm(A), Tn554; erm(B), Tn917 and Tn551; aacA-
aphD, Tn4001; and aphA-3, sat4 and aadE, Tn5405.
41,64
In S. pseudintermedius, these transposons integrate into
the chromosomal DNA and are replicated as part of the
S. pseudintermedius genome. Comparative studies of
horizontal gene transfer using S. aureus, S. pseudinter-
medius and Staphylococcus hyicus strains as recipients
showed that plasmid transfer to S. pseudintermedius
occurred at much lower frequencies than to S. aureus or
S. hyicus, whereas a presumed transposon transfer
directly to the chromosome occurred at almost equal fre-
quencies in all three species.
66
These observations sug-
gest that S. pseudintermedius might have developed
ways and means to protect itself from extrachromosomal
DNA. The analysis of the recently nished whole genome
sequences of S. pseudintermedius isolates
67,68
will pro-
vide insight into the presence of restriction modication
systems or similar systems that might execute such a
protective function.
As shown in the studies of Perreten et al.
19
and Kadlec
et al.,
9
the accumulation of resistance genes and resis-
tance-mediating mutations, currently found especially in
contemporary MRSP isolates from dogs and cats, ren-
ders these isolates resistant to virtually all antimicrobial
agents available for therapeutic interventions in veterinary
medicine. As such, the control of MRSP infections has
become a real challenge for the veterinary practitioner.
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Table 1. Antimicrobial resistance genes and resistance-mediating
mutations in S. pseudintermedius and S. intermedius group isolates
Class of
antimicrobial
agents
Resistance
gene Resistance mechanism
b-Lactam
antibiotics
mecA Alternative target with low afnity
to b-lactam antibiotics
blaZ Inactivation of penicillins by
hydrolysis
Tetracyclines tet(M) Target protection by ribosome
protective protein
tet(O) Target protection by ribosome
protective protein
tet(K) Efux system (major facilitator
superfamily)
tet(L) Efux system (major facilitator
superfamily)
Macrolides and
lincosamides
erm(A) Methylation of 23S rRNA
erm(B) Methylation of 23S rRNA
erm(C) Methylation of 23S rRNA
msr(A) Efux system (ABC transporter)
lnu(A) Inactivation of lincosamides by
nucleotidylation
Chloramphenicol cat
pC221
Inactivation by acetylation
Aminoglycosides aacA-aphD Inactivation of gentamicin,
tobramycin and kanamycin by
acetylation phosphorylation
aphA-3 Inactivation of kanamycin by
phosphorylation
sat4 Inactivation of streptothricin by
acetylation
aadE Inactivation of streptomycin by
adenylation
Trimethoprim dfrG Alternative insensitive target
(dihydrofolate reductase)
Fluoroquinolones n.a. Mutations in the genes gyrA, gyrB,
grlA and grlB
Rifampicin n.a. Mutations in the gene rpoB
Fusidic acid fusC Target protection by binding to
elongation factor G
n.a., not applicable.
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280 2012 ESVD and ACVD, Veterinary Dermatology, 23, 276e55.
Kadlec and Schwarz
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Re sume
Staphylococcus pseudintermedius, Staphylococcus intermedius et Staphylococcus delphini forment le
groupe S. intermedius (SIG). Au sein du SIG, S. pseudintermedius repre sente la principale espe` ce patho-
ge` ne implique e dans une grande varie te dinfections, principalement chez les chiens et dans une moindre
mesure dans dautres espe` ces animales et chez lhomme.
Les agents antimicrobiens sont fre quemment utilise s pour contro ler des infections a` S. pseudintermedius.
Cependant, au cours de ces dernie` res anne es, les souches de S. pseudintermedius identie es comme
re sistantes a` la me ticilline se sont e galement ave re es e tre re sistantes a` la plupart des agents antimicrob-
iens valide s a` usage ve te rinaire.
Cette revue porte sur les bases ge ne tiques des proprie te s de re sistance aux antimicrobiens de S. pseudin-
termedius et des autres membres du SIG. Un re sume des ge` nes de re sistance actuellement connus, leur
association avec les e le ments ge ne tiques mobiles ainsi quune mise a` jour des re sistances me die es par
mutation connues jusqua` ce jour sont rappele s. Ces donne es montrent que contrairement aux autres
espe` ces de staphylocoques, S. pseudintermedius semble pre fe rer les ge` nes de re sistance porte s par
des transposons inse re s au sein du chromosome, au-dessus de ge` nes de re sistances porte s par des
plasmides.
Resumen
Staphylococcus pseudintermedius forma junto con Staphylococcus intermedius y Staphylococcus delphini
el grupo S. intermedius (SIG). Dentro de los SIG, S. pseudintermedius representa la especie pato gena ma s
importante y esta implicada en una amplia variedad de infecciones, principalmente en perros, pero tambie n
en otras especies animales y en seres humanos.
El uso de agentes antimicrobianos es comu n para el control de infecciones por S. pseudintermedius. Sin
embargo, durante los u ltimos an os, se han identicado aislados de S. pseudintermedius resistentes a
meticilina y a la mayor parte de a los agentes antimicrobianos aprobados para uso veterinario.
En esta revisio n se realiza un ana lisis de los fundamentos gene ticos de la resistencia a antimicrobianos en
S. pseudintermedius as como en otros miembros del grupo SIG. Se resumen todos los genes conocidos
relacionados con la resistencia, as como su asociacio n con elementos gene ticos mo viles. Tambie n se
incluye una actualizacio n de todas las mutaciones, conocidas hasta el momento, relacionas con mecanis-
mos de resistencia. Estos datos demuestran, en contraste con lo que ocurre en otras especie de estalo-
cocos, que S. pseudintermedius parece preferir genes de resistencia en transposones, que despue s se
incorporan al ADN cromoso mico, frente a genes localizados en pla smidos.
Zusammenfassung
Staphylococcus pseudintermedius bildet zusammen mit Staphylococcus intermedius und Staphylococcus
delphini die S. intermedius Gruppe (SIG). Innerhalb der SIG repra sentiert S. pseudintermedius die wichtig-
ste pathogene Spezies, die vor allem beim Hund an vielen verschiedenen Infektionen beteiligt ist. Das ist
auch in einem geringeren Ausma bei anderen Tierspezies und beim Menschen der Fall.
Antimikrobielle Wirkstoffe werden ha ug angewendet, um S. pseudintermedius Infektionen zu kon-
2012 The Authors. Veterinary Dermatology
282 2012 ESVD and ACVD, Veterinary Dermatology, 23, 276e55.
Kadlec and Schwarz
trollieren. Insbesondere in den letzten Jahren wurden S. pseudintermedius Isolate identiziert, die
Methicillin-resistent waren und sich auch als resistent gegenu ber den meisten antimikrobiellen Wirkst-
offen, die veterina rmedizinisch zugelassen sind, erwiesen haben.
Dieses Review befasst sich mit der genetischen Basis der antimikrobiellen Resistenz von S. pseudinter-
medius und anderen Spezies aus der SIG. Eine Zusammenfassung der momentan bekannten Resistenz-
gene und ihre Verbindung mit mobilen genetischen Elementen, sowie ein Update der bisher bekannten
Resistenz-vermittelnden Mutationen werden pra sentiert. Diese Daten zeigen, dass S. pseudintermedius
im Gegensatz zu anderen Staphylokokken-Spezies scheinbar Resistenzgene, die in Transposons lokalisiert
sind, und in die chromosomale DNA integriert werden, gegenu ber Plasmid-lokalisierten bevorzugt.
Antimicrobial resistance of Staphylococcus pseudintermedius
2012 The Authors. Veterinary Dermatology
2012 ESVD and ACVD, Veterinary Dermatology, 23, 276e55. e55