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Short Communications
Virulence genes and antimicrobial susceptibility in Pasteurellamultocida isolates from calves
K. Katsuda *, K. Hoshinoo, Y. Ueno, M. Kohmoto, O. Mikami
Pathology and Pathophysiology Research Division, National Institute of Animal Health, NARO, 3-1-5 Kannondai, Tsukuba, Ibaraki 305-
0856, Japan
1. Introduction
Bovine respiratory disease (BRD) is the most economic-
ally
important
disease
among
cattle.
Many
bacterial
species are associated with the pneumonia seen in BRD.
Pasteurella multocida is agents of BRD (Confer, 2009).Although improved vaccines are effective tools for the
control of BRD, poor environmental conditions are one
main reason for shortcoming in vaccination success. For
therapy of clinical cases, antimicrobials remain effective
tools
for
such
bacterial
infections.
The
increased
preva-
lence of antimicrobial-resistant bacterial pathogens has
become a major public health and animal health concern.
Continuous regional monitoring of antimicrobial suscept-
ibility is important for the selection of effective anti-
microbial agents for treatment of bovine pneumonia.
P. multocida possesses various virulence factors, includ-
ing capsule, lipopolysaccharide, fimbriae and adhesins,
toxins, iron-regulated and iron acquisition proteins, sialicacid metabolism proteins, hyaluronidase and outer mem-
brane proteins (Ewers et al., 2004; Harper et al., 2006).
These virulence factors play important roles in the
pathogenesis of P. multocida. Data on the antibiotic
resistance
profiles
and
virulence
factors
of P. multocida
from cattle differing in disease status may yield a better
understanding of pasteurellosis in cattle.
We investigated 378 isolates from clinically healthy
and diseased calves to discover their distribution of
capsular type, their phenotypic antimicrobial resistant
profiles and the presence or absence of 17 virulence genes.
Veterinary Microbiology 167 (2013) 737741
A
R
T
I
C
L
E
I
N
F
O
Article history:
Received 30 May 2013
Received in revised form 30 August 2013
Accepted 22 September 2013
Keywords:
Pasteurella multocida
Antimicrobial susceptibility
Virulence gene
Cattle
A
B
S
T
R
A
C
T
A total of 378 isolates ofPasteurella multocida from clinically healthy and diseased calves
were characterised for their susceptibility to 9 antimicrobial agents and screened by PCR
for the presence of antimicrobial resistance genes and 22 genes virulence-associated,
including capsule biosynthesis genes.
Of the 378 isolates, 102 (27.0%) were resistant to at least one of the 9 tested
antimicrobial agents. Resistance to oxytetracycline (21.7%) was the most frequently
observed phenotype among the isolates. The tet(H) gene were the primary determinant
detected. The resistance rates for thiamphenicol, ampicillin, kanamycin and florfenicol
were 13.2%, 5.8%, 9.0% and 0.5%, respectively. Cefazolin, ceftiofur, cefquinome and
enrofloxacin were effectiveantimicrobial agents, with no resistant isolates emerging over
the course of the investigation.
Most isolates were identified as capsular type A, only 6.3% belonged to capsular type D
and no other capsular type was identified. Four of the virulence-associated genes (pfhA,tadD, tbpA and HAS) exhibited associations to the capsular type, and three (pfhA, tbpA and
hgbB) were associated with the disease status of the animals. These virulence genes have
been considered as epidemiological markers and are hypothesised to have a strong
positive association with the outcome of disease in cattle.
2013 Elsevier B.V. All rights reserved.
* Corresponding author. Tel.: +81 29 838 7925; fax: +81 29 838 7925.
E-mail address: [email protected] (K. Katsuda).
Contents lists available at ScienceDirect
Veterinary Microbiology
jou rnal homepage : www.e lsev ier .com/locate /ve tmic
0378-1135/$ see front matter 2013 Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.vetmic.2013.09.029
http://dx.doi.org/10.1016/j.vetmic.2013.09.029http://dx.doi.org/10.1016/j.vetmic.2013.09.029http://dx.doi.org/10.1016/j.vetmic.2013.09.029http://dx.doi.org/10.1016/j.vetmic.2013.09.029http://dx.doi.org/10.1016/j.vetmic.2013.09.029http://dx.doi.org/10.1016/j.vetmic.2013.09.029http://dx.doi.org/10.1016/j.vetmic.2013.09.029http://dx.doi.org/10.1016/j.vetmic.2013.09.029http://dx.doi.org/10.1016/j.vetmic.2013.09.029mailto:[email protected]:[email protected]://www.sciencedirect.com/science/journal/03781135http://dx.doi.org/10.1016/j.vetmic.2013.09.029http://dx.doi.org/10.1016/j.vetmic.2013.09.029http://www.sciencedirect.com/science/journal/03781135mailto:[email protected]://dx.doi.org/10.1016/j.vetmic.2013.09.029http://crossmark.crossref.org/dialog/?doi=10.1016/j.vetmic.2013.09.029&domain=pdfhttp://crossmark.crossref.org/dialog/?doi=10.1016/j.vetmic.2013.09.029&domain=pdf -
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2. Materials and methods
2.1. Bacterial isolates
A total of 378 P. multocida field isolates collected on the
basis of one isolate per herd from cattle were investigated.
Of the 378 isolates, 140 were from nasal swabs of clinically
healthy cattle; the remaining 238 isolates were from lung
lesions of BRD-affected cattle. The isolates were collectedat
our
institute
between
2009
and
2012
and
originated
from
30
different
regions
in
Japan.
All
isolates
were
identified using API micro standardised strips (API 20NE;
bioMerieuxJapan Ltd., Tokyo,Japan) and by PCR detection
of the species-specific gene fragment kmt (Ewers et al.,
2006; Tang et al., 2009; Townsend et al., 1998). All isolates
were stored in 1 ml of tryptic soy broth (Becton, Dickinson
and
Company,
Sparks,
MD,
USA)
supplemented
with
20%
(v/v)
glycerol
at
80 8C. Prior to minimum inhibitory
concentration (MIC) determination, the isolates were
cultured on tryptic soy agar plates supplemented with
5% sheep blood (Becton, Dickinson and Company, MD,
USA).
2.2. Measurement of MICs and antimicrobial resistance gene
To determine the susceptibility of the P. multocida
isolates to antimicrobial agents, the agar dilution method
(dilution range: 0.125512.0 mg/ml) recommended by theClinical and Laboratory Standards Institute subcommittee
on Veterinary Antimicrobial Susceptibility Testing was
used
(CLSI,
2005).
The
following
quality-control
strains
were also tested: Staphylococcus aureus ATCC 29213,
Enterococcus faecalis ATCC 29212, Escherichia coli ATCC
25923 and Pseudomonas aeruginosa ATCC 27853. The
antimicrobial agents used in this study are listed in
Table 1. All isolates were analysed with PCR for the presence
of
specific
resistance
genes
for
florfenicol
(floR), thiamphe-
nicol (cat3A), tetracycline (tet(B), tet(G), tet(H), tet(L), tet(M)),
kanamycin (aphA1), and penicillins (blaROB-1, blaTEM-1, blaPSE-
1) was conducted as described previously (Kehrenberg and
Schwarz, 2001; Mak et al., 2009; White et al., 2000).
Production of lactamase was assayed using the chromogenic
disc method (Becton Dickinson Microbiology Systems)
according
to
the
manufacturers
instructions.
2.3. Virulence genes
Bacterial
DNA
was
extracted
using
the
InstaGene
Matrix
(BIO-RAD
Laboratories
Inc.,
CA,
USA)
according
to
the manufacturers instructions.
All isolates were analysed with PCR for the presence of
capsule biosynthesis genes and the virulence-associated
genes. PCR analysis of virulence-associated genes for
capsule biosynthesis (capA, capB, capD, capE and capF),
fimbriae
and
adhesins
(ptfA, fimA, hsf-2, pfhA, tadD, nanB
and nanH), iron-regulated and iron acquisition proteins
(tonB, tbpA, hgbA and hgbB), sialic acid metabolism (sodA
and sodC), hyaluronidase (HAS), and outer membrane
proteins (ompH, omp87 and psl) was conducted as
described previously (Ewers et al., 2006; Tang et al.,
2009; Townsend et al., 1998). Tab
le
1
AntimicrobialsusceptibilityofP
.mu
ltoci
daisola
tedfrom
cattle.
Agentsa
MIC(mg/mL)
MIC50
(mg/ml)
MIC90
(mg/ml)
No.ofresistantisolates(%)
0.1
25
0.25
0.5
1.0
2.0
4.0
8.0
16
32
64
128
256
512
>512
Clinicallyhealthy
(n=140)
Clinicallydiseased
(n=238)
Total
(n=378)
ABPC
22
18
40
140
118
18
0b
10
2
4
6
0
0
0
1.0
4.0
8(5.7
)
14(5.9
)
22(5.8
)
KM
0
0
2
2
22
32
102
150
34
0
0
2
6
26
16.0
32.0
12(8.6
)
22(9.2
)
34(9.0
)
OTC
0
6
20
104
166
0
0
0
10
34
36
0
0
2
2.0
128.0
29(20.7
)
53(22.3
)
82(21.7
)
TP
0
14
208
102
0
4
0
0
0
2
44
4
0
0
0.5
128.0
15(10.7
)
35(14.7
)
50(13.2
)
FF
10
64
286
16
0
0
2
0
0
0
0
0
0
0
0.5
0.5
0(0.0
)
2(0.8
)
2(0.5
)
CE
Z
2
66
54
192
60
4
0
0
0
0
0
0
0
0
1.0
2.0
0(0.0
)
0(0.0
)
0(0.0
)
CT
F
378
0
0
0
0
0
0
0
0
0
0
0
0
0
0.1
25
0.1
25
0(0.0
)
0(0.0
)
0(0.0
)
CE
Q
378
0
0
0
0
0
0
0
0
0
0
0
0
0
0.1
25
0.1
25
0(0.0
)
0(0.0
)
0(0.0
)
ER
FX
236
4
20
118
0
0
0
0
0
0
0
0
0
0
0.1
25
1.0
0(0.0
)
0(0.0
)
0(0.0
)
a
ABPC=Ampicillin,KM=Kanamycin,
OCT=O
xytetracycline,TP=Thiamphenicol,FF=FlorfenicolCEZ=Cefazolin,
CTF=Ceftiofur,CQN=Cefquinome,ERFX=Enrofloxacin.
b
Thecut-offs(indicatedbold)usedforthem
idpointoftheMICpeakswasdefinedastheresistancecut-offwhentheMICdistributio
noftheantimicrobialswasbimodal.
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2.4. Statistical analysis
Statistical analysis was performed with GraphPad
Prism1 software, version 5.0 (MDF Co. Ltd., Tokyo,Japan).
The results were considered statistically significant if
p 0.05.
3. Results
The MICs for 9 antimicrobial agents and the anti-
microbial susceptibilities of the P. multocida isolates are
listed
in
Table
1. Of
the
378
isolates,
102
(27.0%)
were
resistant to at least one of the 9 antimicrobial agents, and
the resistance rates ranged from 0.5% to 21.7%. Of the 102
resistant isolates, 49 isolates were resistant to 1 class of
antimicrobial (15 isolates were resistant to ampicillin
(ABPC), 32 isolates were resistant to oxytetracycline (OTC),
2
isolates
were
resistant
to
thiamphenicol
(TP)),
22
isolates
to
2
classes
(2
isolates
were
resistant
to
TP
and
kanamycin
(KM), 2 isolates were resistant to KM and OTC, 18 isolates
were
resistant
to
TP
and
OTC)
and
29
isolates
to
3
classes
(1isolate resistant to TP, KM and ABPC, 4 isolates resistant to
KM-OTC-ABPC, 24 isolates resistant to TP, KM and OTC).
The
final
2
isolates
were
resistant
to
4
classes
of
antimicrobial
agents
(resistant
to
TP,
ABPC,
OTC
and
florfenicol (FF)). The resistance rates for ABPC, KM, OTC and
TP were 5.8%, 9.0%, 21.7% and 13.2%, respectively. There
were only 2 isolates resistant to FF (0.3%), and no isolates
were resistant to enrofloxacin (ERFX) or cephalosporin
drugs (cefazolin (CEZ), ceftiofur (CTF), and cefquinome
(CEQ)).
Of
the
82
oxytetracycline-resistant
isolates,
75
isolates
harboured tet(H) and 4 isolates harboured tet(B).
The remaining 3 isolates were negative for all the tet genes
tested
in
this
study.
Of
the
22
ampicillin-resistant
isolatesthat produced b-lactamase when assayed using thechromogenic disc method, 16 isolates harboured the
blaRob-1 gene; the remaining 6 isolates were negative for
all
the bla genes tested in this study. Of the 50
thiamphenicol-resistant isolates, 47 harboured the cat3A
gene. All isolates that showed resistance to kanamycin
were positive for the aphA1 gene. Two florfenicol-resistant
isolates possessed the floR gene. Although we compared
the antimicrobial susceptibility to the clinical status of the
source
animals,
there
is
no
significant
difference
between
2
clinical status; clinically healthy and clinically diseased.
The most prevalent capsule biosynthesis genes
detected
in
the
378
P.
multocida
isolates
were
capA
(354isolates, 93.7%) and capD (24 isolates, 6.3%). None of the
isolates harboured the capB, capE and capF genes. And
there is no association between capsular type and clinical
status (Table 2).
Genes encoding adhesins (ptfA, fimA, and hsf-2), iron
acquisition
factors
(tonB and hgbA), porin and outer
membrane proteins (psl, opmH and omp87), superoxide
dismutases (sodA and sodC), neuraminidase (nanB and
nanH) and hyaluronan synthase gene (HAS) were each
found in more than 88.0% of the isolates. In contrast, 3
genes (pfhA, tbpA and hgbB) were detected from 52.4% to
76.2%
(Table
2).
The
combination
of
virulence
genes
and
capsular
typeswas assessed with a Chi-square test. The most remarkableTab
le
2
Perc
entdistributionofvirulenceassociatedgenesinP
.mu
ltoci
daisolatesfrom
cattle.
Cl
inicalstatusa
No.ofisolates
viru
lenceassociatedgenes
psl
ompH
omp87
ptfA
fimA
hsf-2
pfhA*
tadD
nanB
nan
H
tonB
tbpA*
hg
bA
hg
bB*
sodA
sodC
HAS
Cl
inicallyhealthy
140
100
100
100
100
100
98.6
30.0
90.0
100
85.7
100
51.4
96.4
40.0
100
100
92.9
Cl
inicallydiseased
238
100
100
100
91.6
100
89.1
65.6
88.2
100
89.9
100
90.8
95.0
74.0
100
100
92.4
To
tal
378
100
100
100
94.7
100
92.6
52.4
88.9
100
88.4
100
76.2
95.5
61.4
100
100
92.6
Ca
psuletypebyPCR
No.ofisolates
ps
l
ompH
omp87
ptfA
fimA
hsf-2
pfhAb
tadD*
nanB
na
nH
tonB
tbpA*
hg
bA
hg
bB
sodA
sodC
HAS*
A
354
10
0
100
100
94.6
100
92.7
55.4
94.1
100
88
.7
100
80.5
95.5
61.3
100
100
97.7
D
24
10
0
100
100
95.8
100
91.7
8.3
12.5
100
83
.3
100
12.5
95.8
62.5
100
100
16.7
a
ClinicallyhealthymeansP
.mu
ltoci
daisolate
dfrom
upperrespiratorytractandclinicallydiseasedmeansP
.mu
ltoci
daisolatedfrom
lowerrespiratorytract.
b
Significantassociations(p
0.0
1).
K. Katsuda et al./ Veterinary Microbiology 167 (2013) 737741 739
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associations were present between pfhA, tadD, tbpA, and
HAS (p 0.01). These virulence genes revealed a clear
association with capsule type A isolates. The distributions
of these virulence genes among isolates from animals of
differing health status were compared with a Chi-square
test. Three genes (pfhA, tbpA and hgbB) were significantly
more prevalent (p 0.01) in isolates from animals showing
clinically
diseased.
4. Discussion
Monitoring
the
antimicrobial
susceptibility
trends
of P.
multocida is an important aid to veterinarians in selecting
the most efficacious therapeutic agents. The results of the
present study indicate that CEZ, CTF, CEQ, ERFX and FF are
very active against the P. multocida isolates tested. On the
basis of the MIC breakpoints of these agents, all but two of
the
isolates
would
be
considered
susceptible
to
these
antimicrobial
agents.
OTC
showed
poor
activity
against P.
multocida compared with other classes of antimicrobial
agents;
this
is
not
unexpected.
Tetracycline
(19,031.9
kg/year), penicillin (7,180.4 kg/year) and aminoglycoside
(3,195.0 kg/year) are the main antimicrobial agents used
for
cattle
in
Japan,
as
tetracyclines
account
for
one-half
of
the
antimicrobials
used
for
cattle
in
Japan
(Asai
et
al.,
2005). These findings agree well with results presented in
previous reports (Portis et al., 2012; Watts et al., 1994). The
results of PCR-based determination of antimicrobial
resistance genes, some isolates were negative for all
known specific resistance genes in this bacterium
(Schwartz,
2008).
The
genetic
background
of
antimicrobial
resistance
remained
unclear
for
these
isolates.
Further-
more, molecular analyses aimed at uncovering the
resistant
mechanisms
should
be
carried
out
in
futurestudies.
We have confirmed that P. multocida isolates in capsular
type A are more common than those in capsular type D.
Consistent
with
this
finding,
it
has
been
reported
that
capsular type A isolates are one of the principal causes of
bovine respiratory diseases (Frank, 1989) and are highly
adapted to bovine hosts (Ewers et al., 2006). In contrast to
all the other virulence genes investigated in this study, 4
virulence genes (pfhA, tadD, tbpA, and HAS) were obviously
associated
with
certain
capsule
types
(capsule
type
A).
Although there were only 24 isolates belonging to the
capsule type D in this investigation, similar findings have
been
reported
previously
(Ewers
et
al.,
2006;
Tang
et
al.,2009).
Except for the pfhA gene, P. multocida regularly
harboured fimbriae- and adhesin-related genes indepen-
dently of the clinical status of cattle. In this investigation,
the distribution of the pfhA gene was associated with
clinical
status.
In
a
past
study
(Verma
et
al.,
2013), all
isolates possessed thepfhA gene independently of capsule
type and disease status. In contrast, Ewers et al. (2006)
reported a significant association between the presence of
thepfhA gene in P. multocida isolates and the clinical status
of cattle. We investigated 4 iron-regulated and iron-
acquisition
related
genes
(tonB, hgbA, tbpA, hgbB). Irre-
spective
of
their
clinical
status,
nearly
all
isolates
had
thetonB and hgbA genes. A higher prevalence of the tbpA gene
and hgbB gene were observed in isolates from diseased
cattle than in isolates from healthy cattle. These results
agree with a recent study reporting that these two genes
were significantly associated with bovine clinical status
(Ewers et al., 2006).
In conclusion, resistance to antimicrobial agents,
including penicillin, chloramphenicol, tetracyclines and
aminoglycosides,
was
observed
in
P.
multocaida
isolatescollected from cattle. Therefore, continuous monitoring of
antimicrobial susceptibility is necessary to determine the
current susceptibility status of P. multocida. Several
virulence
genes
(tbpA, hgbB, and pfhA) have been con-
sidered as epidemiological markers and are hypothesised
to have a strong positive association with the outcome of
disease in cattle. The results of this investigation provide
useful information for understanding the antimicrobial
resistance patterns, capsular types and virulence gene
prevalence
of P. multocida isolate from cattle.
Conflict of interest
All authors declare that there are no financial or other
relationships
that
might
lead
to
a
conflict
of
interest.
Acknowledgements
We thank Natsuko Andou and Syuuko Sawajiri for
excellent
technical
assistance
in
this
study.
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