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Livestock Associated MRSA
Menace or Pussycat?
Tiger
Mirage

Peter Davies BVSc, PhD
University of Minnesota
“The larger the island of knowledge,
longer the shoreline of doubt”

the

Ralph Sockman

2
Outline





What are LA-MRSA?
What has been their impact on public health?
The plot thickens!
Where did they come fro...
Staphylococcus
aureus


Common inhabitant of warm-blooded animals




‘Normal flora’ (20-30% of people)

Common opportu...
Methicillin resistant S. aureus
(MRSA)


From 1961 emerged rapidly to be a major
problem of chronically ill in health car...
In biology, the truth is a moving target!

6
MRSA: ‘Changing paradigms’


1990s : global emergence of community
associated infections (CA-MRSA)







Predominan...
Proportion of clinical S. aureus isolates
that are MRSA

8
Holland – an issue emerges!


Very low MRSA prevalence





2004: 6mo girl screened before surgery for a congenital
he...
S. aureus subtyping methods
‘Livestock associated’


PFGE

Sma1 Untypable



MLST

ST398 (CC398)



SCCmec typing (I – ...
Matthew 7:7 - “Seek and ye shall find”

MRSA in market hogs (de Neeling et al,
2006)


National survey of slaughter pigs ...
Matthew 7:7 - “Seek and ye shall find”

Colonization of farm workers


ST398 found in 23% of pig farmers




760x gener...
MRSA in livestock:
An epidemic waiting to happen?
(Wulf and Voss, 2008)



Not just a “Dutch” problem



May become an i...
Blood in the water!

M

IS

IN
F

T
Y
M

O

RM

S
H

AT

IO
N
MRSA in animals – publication rate
12
10

Cattle

Pig, Sheep

Cat, Dog

8

Horse

N 6

4
2
0
70s 80s 9095

96

97

98

99
...
ST398 (livestock associated) MRSA
Generally accepted facts



Occurs in livestock in many countries




High MRSA preva...
ST398 colonization and transmission


ST398 appears a ‘poor persistent colonizer’ in most people


van Cleef et al (2011...
Burden of disease from ST398 MRSA
(review funded by National Pork Board)




89 papers/reports of ST398 associated clini...
Disease burden from ST398 S. aureus

Cumulative data from 89 publications (n = 2,553 cases)



2,056 screening isolates
...
Geographic distribution of S. aureus
causing invasive infections in
Europe
Grundmann et al 2010



357 laboratories servi...
Burden of disease from ST398 MRSA
in North America


Retrospective study of human isolates in Canada





5 ST398 out ...
ST398 genomic studies and virulence


> 30 known ‘virulence factors’ in S. aureus




Schijffelen (2010): full genome o...
Fatal ST398 infections



5 fatal cases reported
4 MSSA not MRSA





Spa type t571 (not common in swine)
No signific...
Public health risk of ST398 MRSA




Elevated occupational risk of infection not well
documented
Current evidence sugges...
ST398 MRSA in pigs in
Denmark (DANMAP 2012)

25
Human MRSA
infections in Denmark
(DANMAP 2012)

ST398

26
ST398 bacteremia cases
in Denmark (DANMAP 2012
<1% of bacteremic
S. aureus cases



Impact low








<1% of cases
...
The plot thickens – Part One

Not all ST398 S. aureus are ‘livestock associated’
28
Lethal pneumonia caused by an ST398
S. aureus strain
Rasigade et al (2010)


Observations









Fatal necrotizi...
More of the story
Davies P.R. et al, EID June 2011



t571 ST398 MSSA




Detected in 9 families from the Dominican Rep...
‘Animal independent’ ST398 clinical
infections in NY city (Uhlemann et al, 2012)


Studied outpatient MRSA isolates, non-...
The plot thickens - Part Two
ST398

ST5

t011, t108
t034, t567…
>30 spa types

t002

ST9
t899
t337

Not all ‘livestock ass...
LA-MRSA: not just ST398 in pigs








ST9 (t899, t337) - Asia, Italy, Spain, USA
ST5 (t002) - North America (US, ...
MRSA myopia


S. aureus considered ‘normal flora’ of pigs




No systematic study of S. aureus in pigs

Most studies fo...
Studies of S. aureus




Pilot study of ecology of S. aureus on swine
farms (NPB)
Longitudinal study of S. aureus and MR...
Pilot study of of S. aureus in swine


Detailed longitudinal study of two multiple-site
systems in Minnesota





Anat...
Pilot study of S. aureus ecology in
pigs


2 farms: conventional (convenience)






Nose – tonsil – skin (axilla) – ...
Spa types by sample source

38
Diversity of S. aureus on pig farms






All MSSA
15 spa types detected
>95% of isolates ST398, ST9
or ST5
Complex an...
S. aureus colonization and
infection in swine veterinarians



18 month longitudinal study 2012-2014
Nasal swabs collect...
Influence of time since pig contact




Prevalence higher if sampled
< 2days after last pig contact
Prevalence not affec...
Prevalence of MRSA/MSSA by month


Prevalence similar over
time





Verkade et al (2013)





MSSA: 54% - 84%
MRSA...
S. aureus spa types in veterinarians




Striking similarity to pig data
3 spa types > 50%
Vast majority are
 ST398
 ...
S. aureus colonization patterns (x =MRSA)





Most positive for S. aureus at some time
Diversity among isolates within...
S. aureus colonization patterns



Some consistently positive with same spa type
 ST398 (7): MRSA and MSSA
 ST5 (3): MS...
Summary – preliminary results


Patterns of colonization indicate








21% (14/67) of veterinarians are truly col...
Concepts of interspecies transmission
Complete host adaptation

No host adaptation
Human
flora

Human
flora

Swine
flora

...
LA-MRSA: models of host adaptation

ST398

48
LA-MRSA: models of host
adaptation

49
LA-MRSA: models of host adaptation


Diverse S. aureus flora
adapted to swine








ST398, ST5, ST9,…….

Likely sim...
THANK YOU!





Jisun Sun
My Yang
Leticia Linhares
Srinand Sreevatsan






Swine faculty and
graduate students
NPB...
HUGE
THANK
YOU
TO TEAM
NOSTRIL!island of knowledge,
“The larger the

the longer the shoreline of doubt”

52
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Dr. Peter Davies - Livestock Associated MRSA: Tiger or Pussycat?

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Livestock Associated MRSA: Tiger or Pussycat? - Dr. Peter Davies, Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, from the 2013 Allen D. Leman Swine Conference, September 14-17, 2013, St. Paul, Minnesota, USA.

More presentations at http://www.swinecast.com/2013-leman-swine-conference-material

Published in: Health & Medicine, Lifestyle
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Dr. Peter Davies - Livestock Associated MRSA: Tiger or Pussycat?

  1. 1. Livestock Associated MRSA Menace or Pussycat? Tiger Mirage Peter Davies BVSc, PhD University of Minnesota
  2. 2. “The larger the island of knowledge, longer the shoreline of doubt” the Ralph Sockman 2
  3. 3. Outline     What are LA-MRSA? What has been their impact on public health? The plot thickens! Where did they come from?   Recent research in pigs and swine veterinarians What are LA-MRSA? 3
  4. 4. Staphylococcus aureus  Common inhabitant of warm-blooded animals   ‘Normal flora’ (20-30% of people) Common opportunistic pathogen in humans      Insignificant to fatal Broad clinical manifestations Skin and soft tissue infections Invasive: pneumonia, septicemia and death Bacteremia: 80% fatality rate prior to antibiotic era
  5. 5. Methicillin resistant S. aureus (MRSA)  From 1961 emerged rapidly to be a major problem of chronically ill in health care institutions    Resistance linked to antimicrobial use in hospitals Hospital Associated MRSA (HA-MRSA) ‘The truth’ prior to 1995  Not a concern for broader community  No epidemiologic role of animal reservoirs 5
  6. 6. In biology, the truth is a moving target! 6
  7. 7. MRSA: ‘Changing paradigms’  1990s : global emergence of community associated infections (CA-MRSA)      Predominantly SSTI CA-MRSA ‘clones’ distinct from ‘hospital’ strains ‘Quantum change in the epidemiology of MRSA’ 2004…: detection/emergence of LA-MRSA Novel lineage not reported previously among HA-MRSA or CA-MRSA 7
  8. 8. Proportion of clinical S. aureus isolates that are MRSA 8
  9. 9. Holland – an issue emerges!  Very low MRSA prevalence    2004: 6mo girl screened before surgery for a congenital heart defect   Intensive screening and typing with sma1 PFGE ‘Search and destroy’ policy – isolation/decolonization MRSA isolate not typable with Sma1 PFGE 2 other screening isolates not typable by Sma1 PFGE  All 3 ‘cases’ epidemiologically linked to pigs Studies of MRSA prevalence in pigs, farmers and pork 9
  10. 10. S. aureus subtyping methods ‘Livestock associated’  PFGE Sma1 Untypable  MLST ST398 (CC398)  SCCmec typing (I – XI)  Spa typing III, IV, V  Ridom t034, t011, t108……...  egenomics 539, ………………..….. 10
  11. 11. Matthew 7:7 - “Seek and ye shall find” MRSA in market hogs (de Neeling et al, 2006)  National survey of slaughter pigs in Holland   All isolates a ‘single clonal group’     39% of 540 pigs positive (nasal swabs) Nontypable (NT) by sma1 PFGE MLST: ST 398 3 closely related spa types predominant (t011, t108, t1254,…) Uniformly resistant to tetracycline  Use of tetracyclines may be selecting for MRSA? 11
  12. 12. Matthew 7:7 - “Seek and ye shall find” Colonization of farm workers  ST398 found in 23% of pig farmers   760x general population prevalence Dutch health authorities changed MRSA screening procedures    (Voss et al 2005) People exposed to pigs and calves considered high risk Isolated and screened before hospital admission ST398 MRSA isolated from pork 2007) (van Loo et al., 12
  13. 13. MRSA in livestock: An epidemic waiting to happen? (Wulf and Voss, 2008)  Not just a “Dutch” problem  May become an important source of CA-MRSA  Epidemiology different to ‘classic MRSA strains’  Inter-human spread is possible  Probably ‘just a matter of time until an outbreak’ 13
  14. 14. Blood in the water! M IS IN F T Y M O RM S H AT IO N
  15. 15. MRSA in animals – publication rate 12 10 Cattle Pig, Sheep Cat, Dog 8 Horse N 6 4 2 0 70s 80s 9095 96 97 98 99 00 01 02 03 04 05 06 07 2010 >50 Years 15
  16. 16. ST398 (livestock associated) MRSA Generally accepted facts  Occurs in livestock in many countries   High MRSA prevalence in livestock farmers, veterinarians, slaughter plant workers    Pigs, cattle, avian, horse, ..? 20-50% in farmers (vs. ~ 0.5 - 2% in population) Mainly LA-MRSA Lingering questions   Are they truly colonized? What is the consequent risk to health? 16
  17. 17. ST398 colonization and transmission  ST398 appears a ‘poor persistent colonizer’ in most people  van Cleef et al (2011)   Research workers (short term exposure) Veal farmers in Holland Graveland et al (2011) ST398 less transmissible than non-ST398 MRSA  4-6x less transmissible in Dutch hospitals’ (Bootsma, 2010) Wassenberg (2011)  ‘insufficient to lead to an epidemic’ 17
  18. 18. Burden of disease from ST398 MRSA (review funded by National Pork Board)   89 papers/reports of ST398 associated clinical cases through 2012 Data recorded      Numbers of isolates from screening vs. clinical infections Clinical presentations  bacteremia; pneumonia; skin or soft tissue infection, etc. Number of cases with invasive infections (not SSTI) Fatalities History of animal contact 18
  19. 19. Disease burden from ST398 S. aureus Cumulative data from 89 publications (n = 2,553 cases)   2,056 screening isolates 497 (19.5%) clinical     203 unspecified 125 ‘invasive’ 5 fatal Invasive disease   Many cases MSSA not MRSA Livestock exposure very inconsistent  Yes:10% No:26% Unknown: 64% 19
  20. 20. Geographic distribution of S. aureus causing invasive infections in Europe Grundmann et al 2010  357 laboratories serving 450 hospitals in 26 countries (2006-2007)   ST 398 spa types (t011, t034, t571, t1255, and t2383) identified on 12 occasions   2,890 MSSA and MRSA isolates from invasive infections None harbored the mecA gene. No cases of ST398 MRSA invasive disease
  21. 21. Burden of disease from ST398 MRSA in North America  Retrospective study of human isolates in Canada    5 ST398 out of 3,687 MRSA isolates 4 skin/soft tissue infections (Golding et al 2010) CDC has examined >12,000 MRSA isolates in USA   ST398 not identified in a human clinical case (June 2011) MN DOH – no ST398 among 7,000 isolates tested (2012) 21
  22. 22. ST398 genomic studies and virulence  > 30 known ‘virulence factors’ in S. aureus   Schijffelen (2010): full genome of ST398/t011 strain    Likely underpins the diversity in clinical expression Just 2 virulence factors found ‘ lack of virulence factors may explain the infrequency of serious clinical infections with ST398’ Argudin (2011): 100 ‘non-human’ ST398  Many resistance determinants but few virulence factors 22
  23. 23. Fatal ST398 infections   5 fatal cases reported 4 MSSA not MRSA    Spa type t571 (not common in swine) No significant livestock contact One MRSA with livestock contact   Spa type t011 (common in swine) 85yo man with lung carcinoma and COPD 23
  24. 24. Public health risk of ST398 MRSA   Elevated occupational risk of infection not well documented Current evidence suggests low transmissibliity       No reports of outbreaks Current evidence suggests low virulence? Significantly less invasive disease in Europe Serious infections uncommon General lack of virulence determinants Few fatalities 24
  25. 25. ST398 MRSA in pigs in Denmark (DANMAP 2012) 25
  26. 26. Human MRSA infections in Denmark (DANMAP 2012) ST398 26
  27. 27. ST398 bacteremia cases in Denmark (DANMAP 2012 <1% of bacteremic S. aureus cases  Impact low      <1% of cases Only 2 MRSA cases Trend concerning No animal contact in bacteremia cases Are they livestock associated?  and how? 27
  28. 28. The plot thickens – Part One Not all ST398 S. aureus are ‘livestock associated’ 28
  29. 29. Lethal pneumonia caused by an ST398 S. aureus strain Rasigade et al (2010)  Observations        Fatal necrotizing pneumonia in a previously healthy 14yo girl ST 398 - spa type t571 Panton-Valentine Leukocidin (PVL) positive Tetracycline susceptible Methicillin susceptible (MSSA) No livestock contact Inference  “spread of S. aureus ST398 among livestock is a matter of increasing concern because strains of this sequence type were able to acquire PVL genes” 29
  30. 30. More of the story Davies P.R. et al, EID June 2011  t571 ST398 MSSA   Detected in 9 families from the Dominican Republic living in Manhattan, NY (Bhat et al., 2007) Predominant MSSA type at Beijing hospital (Chen et al 2010, Zhao et al 2012)     Case report from Colombia (Jimenez et al 2011) All with no apparent livestock contact 30% of ST398 bacteremia cases in 89 publications reviewed were t571 MSSA Some ST398 variants could be independent of livestock?
  31. 31. ‘Animal independent’ ST398 clinical infections in NY city (Uhlemann et al, 2012)  Studied outpatient MRSA isolates, non-invasive MSSA cases, and bloodstream MSSA isolates   ST398 t571: 5% of non-invasive MSSA; 2.5% of MSSA bacteremias    No ST398 among outpatient MRSA cases “Clinically important clone that differs significantly at the genome level from its livestock associated counterpart” Only reported ST398 infections in USA are t571 MSSA without known livestock contact Distinct ‘pig clade’ and ‘human clade’ of ST398 t571 31
  32. 32. The plot thickens - Part Two ST398 ST5 t011, t108 t034, t567… >30 spa types t002 ST9 t899 t337 Not all ‘livestock associated’ MRSA are ST398 32
  33. 33. LA-MRSA: not just ST398 in pigs        ST9 (t899, t337) - Asia, Italy, Spain, USA ST5 (t002) - North America (US, Canada) ST1 - Denmark, USA, Switzerland, Italy ST72 - USA, Korea ST97 – Italy, Spain ST49 – Switzerland …… 33
  34. 34. MRSA myopia  S. aureus considered ‘normal flora’ of pigs   No systematic study of S. aureus in pigs Most studies focused on MRSA    MRSA ‘Tunnel vision’ ‘Gotcha’ epidemiology (and journalism) Need to understand S. aureus epidemiology to understand LA-MRSA 34
  35. 35. Studies of S. aureus   Pilot study of ecology of S. aureus on swine farms (NPB) Longitudinal study of S. aureus and MRSA colonization and infection in swine veterinarians   NIOSH (UMASH center) 68 swine veterinarians 35
  36. 36. Pilot study of of S. aureus in swine  Detailed longitudinal study of two multiple-site systems in Minnesota    Anatomical site Age/stage of production Prevalence and diversity of S. aureus in pigs, people, environmental, air samples   Spa typing MSLT of selected isolates
  37. 37. Pilot study of S. aureus ecology in pigs  2 farms: conventional (convenience)     Nose – tonsil – skin (axilla) – feces – (vagina) S. aureus prevalent in all anatomical sites    2 cohorts per farm Sows – suckling – nursery – finishing Nose, tonsil and skin highest (59 – 66%) No MRSA detected Multiple spa types on both farms  Multiple spa types within pigs 37
  38. 38. Spa types by sample source 38
  39. 39. Diversity of S. aureus on pig farms     All MSSA 15 spa types detected >95% of isolates ST398, ST9 or ST5 Complex and dynamic
  40. 40. S. aureus colonization and infection in swine veterinarians   18 month longitudinal study 2012-2014 Nasal swabs collected monthly from 68 swine vets      Self collected and mailed S. aureus and MRSA Characterized by MLST and spa typing Survey of pig contact and clinical infections >95% compliance for swabs and surveys over 13 months 40
  41. 41. Influence of time since pig contact   Prevalence higher if sampled < 2days after last pig contact Prevalence not affected by delay in sample processing 41
  42. 42. Prevalence of MRSA/MSSA by month  Prevalence similar over time    Verkade et al (2013)    MSSA: 54% - 84% MRSA: 4% - 11% MSSA: 72% MRSA: 44% Suggests less MRSA in USA 42
  43. 43. S. aureus spa types in veterinarians    Striking similarity to pig data 3 spa types > 50% Vast majority are  ST398  ST9  ST5 43
  44. 44. S. aureus colonization patterns (x =MRSA)    Most positive for S. aureus at some time Diversity among isolates within veterinarians over time Spa types correspond with predominant pig isolates 44
  45. 45. S. aureus colonization patterns  Some consistently positive with same spa type  ST398 (7): MRSA and MSSA  ST5 (3): MSSA only  ST9 (2): MSSA only 45
  46. 46. Summary – preliminary results  Patterns of colonization indicate      21% (14/67) of veterinarians are truly colonized Transient contamination is more common Positivity associated with recent pig contact The veterinary nose: surveillance tool or selective culture medium? MSSA variants of common LA-MRSA types globally are common in US pigs and swine veterinarians   Suggests prolonged association with swine Host adaptation and virulence 46
  47. 47. Concepts of interspecies transmission Complete host adaptation No host adaptation Human flora Human flora Swine flora No interspecies transmission Some host adaptation Common interspecies transmisssion Swine flora Equal propensity to colonize both species Marked host adaptation Rare interspecies transmisssion
  48. 48. LA-MRSA: models of host adaptation ST398 48
  49. 49. LA-MRSA: models of host adaptation 49
  50. 50. LA-MRSA: models of host adaptation  Diverse S. aureus flora adapted to swine     ST398, ST5, ST9,……. Likely similar in other animals Likely varied propensity for interspecies transmission Likely varied virulence in other species 50
  51. 51. THANK YOU!     Jisun Sun My Yang Leticia Linhares Srinand Sreevatsan    Swine faculty and graduate students NPB UMASH “The larger the island of knowledge, the longer the shoreline of doubt” 51
  52. 52. HUGE THANK YOU TO TEAM NOSTRIL!island of knowledge, “The larger the the longer the shoreline of doubt” 52

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