Research on MRSA in animals: past, present and futureLuca GuardabassiAssociate Professor in Clinical MicrobiologyDVM, PhD, Diplomate ECVPH

This is not a review lecture!

If you look for an excellent review on MRSA in animals:

Talk overview

•

Publications

on

MRSA in animals

•

Origin

of

FA-MRSA ST398

•

Genetic

diversity

of

FA-MRSA

•

FA-MRSA vs

MRSA in companion

animals

•

MRSP

•

Future

research

Publications on MRSA in animals ranked by year (total = 106) Web of Science® accessed 20 April 2009

0

5

10

15

20

25

30

1972 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

First isolation of MRSA from cows

First isolation of MRSA from pets

First isolation of MRSA from horses

First isolation of MRSA from pigs

Publications on MRSA in animals ranked by country (top 10) Web of Science® accessed 20 April 2009

0

5

10

15

20

25

Netherl

ands

Canad

aGerm

any

United K

ingdom

United Stat

esDen

mark Italy

Belgium

KoreaJa

panSwitz

erlan

dOther

Publications on MRSA in animals ranked by type of study Web of Science® accessed 20 April 2009

Prevalence inanimalsDetection in animals

Human carriage

Genotypic analysis

Review

Animal infection

Human infection

Case-control study

Methods foridentificationEradication

0123456789

10

2009 2008 2007 2006 2005 2004 2003 1999 1997 1995 1994 1972

Pets Horses Livestock Food Other

Publications on MRSA in animals ranked by animal host Web of Science® accessed 20 April 2009

What is the origin of the FA-MRSA clone ST398?

CC9

CC398

CC30

Other information on S. aureus in pigs

From Devriese

1984. J. Applied

Bacteriol. 56, 215-220

•

Old

studies by Hajek

et al. (1970s) and Devriese

(1984) indicated

that

porcine

S. aureus

form a heterogenic

population•

3 major biotypes/ecovars

were

described

by Devriese

CC30CC9

CC30?

MLST

CC12

CC1/97?

S. aureus ST398 is likely to have pig origin but failure to detect the clone in the old Devriese collection suggests that it could be absent or low-prevalent in pigs in the 1970s.

Take-home message:

What is the diversity of FA-MRSA?

•

Marked geographical

differences in the distribution of

spa types:

• t011 and t108 predominant

in NL• t034 predominant

in DK

•

High

diversity

in SCCmec types (mainly

type IV, IVa

and V) frequent

associated

with

spa types

• t011 often

contains

SCCmec

type IV and IVa• t108

often

contains

SCCmec

type V

•

FA-MRSA are

currently

typed

by MLST and spa typing

but we

do not know

the

discriminatory

power of

these

methods

within

this

S. aureus lineage

Facts on diversity and evolution of CC398

MRSA ST9 from pig carcasses in Hong Kong: a new MRSA clone associated with pigs? Guardabassi et al. unpublished

Isolate Sampling date Resistance pattern spa SCCmec PFGE

K1 22 Feb 2008 3 t899 IVb A

G29 11 Mar 2008 4 t899 IVb B

55 27 Mar 2008 1 t899 IVb A

56 1 t899 V C

57 1 t899 V C

61 1 t899 V C

54 1 t899 V F

B40 15 April 2008 1 t899 IVb A

B46 1 t899 IVb A

B50 1 t899 IVb A

B51 1 t899 IVb A

B52 1 t899 IVb A

B22 1 t899 V C

B39 1 t899 IVb D

B37 2 t899 IVb B

B36 2 t899 IVb E

Resistance patterns:1: TE, C, CN, DA, E, CIP, SXT2: TE, C, DA, E, CIP, FD3: TE, C, CN, DA, E, CIP,

SXT, FD4: TE, C, DA, E, CIP,

SXT, FD

MRSA ST9 t899 was isolated the nasal cavity of 16% pig carcasses

MRSA ST9: a new MRSA clone associated with pig farming? Guardabassi et al. unpublished

Tandem repeat successions in spa types associated with ST9 and ST398

spa type

Tandem repeat sequence MLST allelic profile

ST

t899 07-16-23-----------------02-34 3-3-1-1-1-1-10 9t337 07-16-23-23-02-12-23-02-34 3-3-1-1-1-1-10 9t3198 07-16-16-23-23-02-02-12-23-02-34 3-3-1-1-1-1-10 9t011 08-16-02---------25-34-24-25 3-35-19-2-20-26-39 398t034 08-16-02-25-02-25-34-24-25 3-35-19-2-20-26-39 398t0108 08-16-02---------25-----24-25 3-35-19-2-20-26-39 398t567 08-------------02-25-----24-25 3-35-19-2-20-26-39 398t571 08-16-02-25-02-25-34-----25 3-35-19-2-20-26-39 398

Transmission of methicillin-resistant Staphylococcus aureus strains between different kinds of pig farms. Van Duijkeren et al. 2007

Prevalence of methicillin-resistant Staphylococcus aureus among veterinarians: an international study Wulf et al. 2008. Clin. Microbiol. Infect. 14: 29-34

MRSA ST398 epidemiology in Holland van Loo

et al. 2007 Emerg. Infect. Dis.

FA-MRSA ST398 is likely to have acquired SCCmec in distinct locations and geographical dispersal could be limited. While we are studying FA-MRSA ST398, other FA-MRSA clones are emerging in livestock.

Take-home message:

What are the differences between FA-MRSA and MRSA in companion animals?

MRSA clones in animals

CC22 (ST22)Clone in pets (human origin)

CC398 (ST398)Clone in livestock (animal origin)

CC8 (ST8 and ST254)Clone in horses (human origin)

Epidemiology of FA-MRSA Current assumption: zoonosis

Evidence that FA-MRSA is a zoonotic agent

1. Human infections have been reported in farmers

and their family members in various countries

2. FA-MRSA carriage is significantly higher in

farmers and veterinarians than in the community

3. The specific FA-MRSA clone (ST398) was unknown

in human medicine prior to its recent emergence

in livestock

MRSA ST398 epidemiology in Holland van Loo

et al. 2007 Emerg. Infect. Dis.

Controversial aspects:

1. The FA-MRSA clone CC398 does not seem to be

particularly virulent – low morbidity/mortality in

humans

2. Cases of human infections have been reported in

Sweden, a country with low prevalence of FA-

MRSA in pigs, among individuals without contact

to animals

3. In Denmark, exposure to pets, horses and cattle

(but not to pigs) has been shown to be a

significant risk factors for FA-MRSA carriage in

vets (Moodley et al. 2008)

Epidemiology of MRSA in companion animals Current assumption: antrhopozoonosis

Evidence that MRSA in companion animals is an anthropozoonotic agent

1. The MRSA clones emerged in companion animals

have been known for many years in human

medicine

2. S. aureus is not a normal commensal in dogs and

cats (<20% are colonized by MSSA)

3. MRSA carriage in companion animals is usually

transient

Controversial aspects:

1. MRSA occurring in animals are highly pathogenic to

man, certainly more pathogenic than FA-MRSA

•

ST22 (EMRSA-15) is the most common cause of MRSA

bacteremia in the UK

•

ST8 (US300 or CA-MRSA-5) is the dominant CA-MRSA

clone in the USA

2. Human infection linked to MRSA carriage in

companion animals have been reported among

owners (Manian et al. 2003) and veterinary staff

(Weese et al. 2006)

3. High MRSA carriage rates are found in veterinarians

working with companion animals

MRSA prevalence in people exposed to animals Weese

& van Duijkeren. 2009 Vet

Microbiol.

PFGE sma

100

50

PFGE sma

63

64

58

57

65

66

67

61

60

59

62

54

55

56

North

North

West

West

North

North

North

East

East

East

East

South West

South West

South West

t064

t064

t064

t064

t451

t451

t451

t032

t749

t032

t032

t032

t032

t032

CC8

CC8

CC8

CC8

CC8

CC8

CC8

CC22

CC22

CC22

CC22

CC22

CC22

CC22

B3

B3

B1

B1

B2

B2

B2

A1

A1

A1

A1

A1

A1

A1

Human

Human

Equine

Human

Equine

Equine

Equine

Canine

Human

Human

Canine

Human

Canine

Canine

Molecular typing of MRSA from companion animals and veterinarians in the UK and Ireland Moodley et al. 2006, J. Antimicrob. Chemother.

Independent of their origin, some MRSA clones (namely CC398, CC8 and CC22) are able to transfer between hosts. Such clones have clearly acquired the capacity to adapt to different hosts and should be regarded as ”extended host-spectrum MRSA clones”.

Take-home message:

What is MRSP and why is it an emerging problem in veterinary medicine?

ethicillin

What is MRSP?

RSP

esistant

taphylococcusseudintermedius

•

It is a S. pseudintermedius resistant

to all β-lactams (penicillins & cephalosporins)

•

It is called

methicillin-resistant

because

the gene involved (mecA) is the same as in MRSA

• As MRSA it is generally

multi-resistant

and spreads

clonally

• Often

occurs

in the form of hospital outbreaks

M

<Udfyld sidefod-oplysninger

her>

How frequent are MRSP in small animals?

•

Reported

for the first

time in Brasil in 1998

•

MRSP emerged

in Europe

in 2006 and rapidly

spread in Sweden, Germany, Switzerland, Holland and Italy

•

In some

areas

of the US, MRSP account

for over 20%

of clinical

isolates

of S. psudintermedius

•

In Europe, the prevalence

is lower, approximately

5%

in some

countries

Prevalence of resistance in 100 MRSP isolates from 8 countries (CLSI breakpoints) The

MRSP ENTHUSIASTS, unpublished

data

Resistance %Kanamycin 98TMP 95Fluoroquinolones 94Clindamycin 94Gentamicin 92 Sulfonamides 78Tetracyclines 77 Chloramphenicol 70 Fusidic

acid

LinezolidVancomycin

0 00

If you are lucky…

Genetic diversity of in 100 MRSP isolates from 8 countries The MRSP ENTHUSIASTS, unpublished data

Spa type MLST Frequency Countries

t02 71 71% Sweden, Holland, Germany,

Italy, Switzerland, Denmark

t06 68 18% USA, Canada, Holland

Other Other 11%

MRSP is a true veterinary problem with serious implications for animal health. Probably the most serious resistance problem ever seen among animal pathogens.

Take-home message:

What is next?

•

Longitudinal studies at the farm level•

Transient vs. permanent carriage

•

Transmission and prevalence

within

farms

•

Epidemiological studies•

Secondary

transmission from farms to the

community

•

Vertical

vs. horizontal

transmission in animal

production

•

Identification

of

risk

factors promoting

MRSA in animals

•

Mathematical

models

•

Population structure studies•

Understanding

evolution of

FA-MRSA

•

Genetic studies•

Identification

of

key

factors for host-MRSA

interactions

•

Mode of

SCCmec

acquisition

There a still a number of questions to be answered and actions to be taken….

•

In vitro and in vivo experimental studies•

Assessment

of

host-range

•

Assessment

of

antimicrobial

effects

•

New tools•

PCR for rapid identification

of

MSSA/MRSA CC398

•

PFGE using

non-SmaI

endonuclease

(e.g. XmaI)

•

Control measures•

Rational antimicrobial

use

•

Phage

therapy•

Bacterial

antagonism

•

Farm decontamination•

Vaccination?

•

Intervention studies, etc,etc…

There a still a number of questions to be answered and actions to be taken….

We publish a lot of papers on MRSA but many crucial questions are still to be answered. We should try to answer the numerous questions and ultimately to solve problems rather than pointing them out.

Take-home message:

Two EU projects on FA-MRSA start in 2009

University Medical Centre Utrecht

University Claude Bernard Lyon

Universidade Nova de Lisboa

Utrecht University

University of Edinburgh

National Medicines Institute

DTU-Food Denmark

University of Amsterdam

Novolytics

http://www.fp7-pilgrim.eu/

Royal Veterinary College UK

Radboud University NL

University of Copenhagen DK

Universtè

Libre de Briussels BE

Erasmus University Medical Center

St. George Medical Schoold UK

National Institute of Public Health NL

Statens Serum Institut DK

Centrum vor Onderzoeg BE

Institute of Chemical Technolgoy CZ

Aguacure

Accelopment

PILGRIM CONCORD

THANK YOU!