john wain laboratory for gastrointestinal pathogens gezi...
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The evolution of drug resistance in Salmonella
John WainLaboratory for Gastrointestinal Pathogens
GEZI, CfI, HPA, Colindale, UK
Research in Viet Nam showed that
transmission is linked to MDR but not to resistance
P = 0.006
Treatment was equally effective for both groups
Without plasmid With plasmid
AKU, Karachi
data – not all (FQ)
resistance is equal
Hassan et al, JIDC August 2008
www.jidc.org
S. Typhi
S. Paratyphi A
MDR in S. TyphiCases reported in England and Wales
0.0
10.0
20.0
30.0
40.0
50.0
60.0
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
Year
Perc
enta
ge r
esis
tanc
e
Ampicil l in Chloramphenicol Streptomycin
Sulphonamides Tetracycline Trimethoprim
MDR in S. Paratyphi ACases reported in England and Wales
0
5
10
15
20
25
30
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
Year
Perc
enta
ge r
esis
tanc
e
Ampicil l in Chloramphenicol Streptomycin
Sulphonamides Tetracycline Trimethoprim
Variation in IncHI1 plasmids – challenge for typing and evolutionary studies
Ins/delShared genes
•Ins/del
•Gene content
•Rearrangement
•SNPs
pHCM1 – 1993
pR27 – 1961
SNP discovery in core genesPlasmid Multi-Locus Sequence Typing
pHCM1218160 bp
HCM1.064
HCM1.043
HCM1.178ac
HCM1.259
HCM1.116
HCM1.099
SNPs in six loci
Can SNPs be used for plasmid typing?
ST5
ST2 ST4
UK
Pakistan
Vietnam
Mexico
Thailand
India
Jordan
ST1
ST6
ST5
ST8
ST3
ST2 ST4
Group 1
Group 2
58.6
56.4
32.2
78.3
29.7
58.6
ST1
ST6
ST7
1972
1972 -1993 1972
1993
1961
1993 - 2004
2002 - 2004
2003 - 2004
1993
19721993
1961
1993 - 1996
Phylogenetic trees based on plasmid SNPs
Not direct evolution but replacement
Paratyphi A
Vietnam data
D
C & E
Ins1056
56.4
29.7
78.2
32.258.6
Plasm idspHCM 1pSTY2pSTY3pSTY5KKG 28pSTY440R34444R31144R31542R91740R181
ST C D E IS10561 p p p a1 p p p a1 p p p a1 p p p a1 p p p a2 p a p a2 p a p a2 p a p a2 p a p a4 p a p a3 a a - a
pSTY6pSTY7JC T61K11632KC T51pST661pST721pAKU_1SPA-1308SPA-1464SPA-247SPA-251SPA-275SPA-287SPA-335SPA-416SPA-444SPA-460SPA-510SPA-842SPA-1074SPA-1326SPA-568SPA-688
6 a a a p6 a a a p6 a a a p6 a a a p6 a a a p6 a a a p6 a a a p7 a a a p7 a a a p7 a a a p7 a - a p7 a a a p7 a a a p7 a a a p7 a - a p7 a a a p7 a a a p7 a a a p7 a - a p7 a - a p8 a - a p8 a - a p8 a - a p8 a - a p
pR27 5 a a a a
SNPs Ins/Del
Gro
up 2
Gro
up 1
SNPs grouping confirmed by ins/del
Not antibiotic selection but competition between plasmids
pHCM1218160 bp
HCM1.064
HCM1.043
HCM1.178ac
HCM1.259
HCM1.116
HCM1.099
Ins1
056
Duy Phan et al. AAC January 2009
Ins1056
Group 2 plasmids occur in different haplotypes – but there is an absolute
association between H58 and ST7
Plasmid SNPs Chromosomal SNPs
Group 2
H58 Haplotype
Samples from VN 2000 - 2005
Quinolone resistance in S Paratyphi A (UK-ISC Travel) –
current research with UoB
0
10
20
30
40
50
60
70
80
90
100
19821983198419851986198719881989199019911992199319941995199619971998199920002001200220032004200520062007
Year
Perc
enta
ge r
esis
tanc
e
Ampicil l in Naladixic acid ANY Ciprofloxacin
Conclusions
• PMLST- A typing scheme for IncHI1 plasmids –it works.
• There is competition between plasmids but…• …the selective advantage is NOT the resistance
phenotype therefore..• …by using antibiotics are we selecting pathogens
with enhanced transmission potential.• More resistance does not always result in a
selective advantage – transmission is everything
Thank you MRC
Laboratory for Gastrointestinal Pathogens
More friends
Friends
Wellcome Trust Clinical Research Unit Viet Nam