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

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Wellcome Trust Clinical Research Unit Viet Nam