dr. peter davies - livestock associated mrsa: tiger or pussycat?
DESCRIPTION
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-materialTRANSCRIPT
Livestock Associated MRSA
Peter Davies BVSc, PhDUniversity of Minnesota
Menace MirageTiger or Pussycat?
“The larger the island of knowledge, the longer the shoreline of doubt”
Ralph Sockman
2
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
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
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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
In biology, the truth is a moving target!
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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
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Proportion of clinical S. aureus isolates that are MRSA
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Holland – an issue emerges!
Very low MRSA prevalence Intensive screening and typing with sma1 PFGE ‘Search and destroy’ policy – isolation/decolonization
2004: 6mo girl screened before surgery for a congenital heart defect
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
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S. aureus subtyping methods
PFGE
MLST
SCCmec typing (I – XI)
Spa typing Ridom
egenomics
‘Livestock associated’
Sma1 Untypable
ST398 (CC398)
III, IV, V
t034, t011, t108……...
539, ………………..…..
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National survey of slaughter pigs in Holland 39% of 540 pigs positive (nasal swabs)
All isolates a ‘single clonal group’ 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?
Matthew 7:7 - “Seek and ye shall find”MRSA in market hogs (de Neeling et
al, 2006)
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Colonization of farm workers
ST398 found in 23% of pig farmers (Voss et al 2005) 760x general population prevalence
Dutch health authorities changed MRSA screening procedures People exposed to pigs and calves considered
high risk Isolated and screened before hospital admission
ST398 MRSA isolated from pork (van Loo et al., 2007)
Matthew 7:7 - “Seek and ye shall find”
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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’
MYTHS
MISINFORM
ATION
Blood in the water!
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MRSA in animals – publication rate
0
2
4
6
8
10
12
70s 80s 90-95
96 97 98 99 00 01 02 03 04 05 06 07
Years
Cattle
Cat, Dog
Horse
Pig, Sheep
2010>50
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ST398 (livestock associated) MRSA
Generally accepted facts
Occurs in livestock in many countries Pigs, cattle, avian, horse, ..?
High MRSA prevalence in livestock farmers, veterinarians, slaughter plant workers 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?
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ST398 colonization and transmission
ST398 appears a ‘poor persistent colonizer’ in most people
Research workers (short term exposure) van Cleef et al (2011)
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’
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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
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
Geographic distribution of S. aureus causing invasive infections in Europe Grundmann et al 2010
357 laboratories serving 450 hospitals in 26 countries (2006-2007) 2,890 MSSA and MRSA isolates from invasive
infections ST 398 spa types (t011, t034, t571, t1255, and
t2383) identified on 12 occasions None harbored the mecA gene.
No cases of ST398 MRSA invasive disease
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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)
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ST398 genomic studies and virulence
> 30 known ‘virulence factors’ in S. aureus Likely underpins the diversity in clinical expression
Schijffelen (2010): full genome of ST398/t011 strain 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
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
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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
ST398 MRSA in pigs in Denmark (DANMAP 2012)
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Human MRSA infections in Denmark (DANMAP 2012)
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ST398
ST398 bacteremia cases in Denmark (DANMAP 2012
Impact low <1% of cases Only 2 MRSA
cases Trend concerning No animal contact
in bacteremia cases
Are they livestock associated?
and how?27
<1% of bacteremic S. aureus cases
The plot thickens – Part One
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Not all ST398 S. aureus are ‘livestock associated’
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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”
More of the storyDavies 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?
‘Animal independent’ ST398 clinical infections in NY city (Uhlemann et al, 2012)
Studied outpatient MRSA isolates, non-invasive MSSA cases, and bloodstream MSSA isolates
No ST398 among outpatient MRSA cases
ST398 t571: 5% of non-invasive MSSA; 2.5% of MSSA bacteremias
“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
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The plot thickens - Part Two
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ST398t011, t108
t034, t567… >30 spa
typesST5t002
ST9t899t337
Not all ‘livestock associated’ MRSA are ST398
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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 ……
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MRSA myopia
S. aureus considered ‘normal flora’ of pigs No systematic study of S. aureus in pigs
Most studies focused on MRSA ‘Tunnel vision’ ‘Gotcha’ epidemiology (and journalism)
Need to understand S. aureus epidemiology to understand LA-MRSA
MRSA
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
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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
Pilot study of S. aureus ecology in pigs
2 farms: conventional (convenience) 2 cohorts per farm Sows – suckling – nursery – finishing
Nose – tonsil – skin (axilla) – feces – (vagina) S. aureus prevalent in all anatomical sites
Nose, tonsil and skin highest (59 – 66%) No MRSA detected
Multiple spa types on both farms Multiple spa types within pigs
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Spa types by sample source
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Diversity of S. aureus on pig farms
All MSSA 15 spa types detected >95% of isolates ST398,
ST9 or ST5 Complex and dynamic
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 months40
Influence of time since pig contact
Prevalence higher if sampled < 2days after last pig contact
Prevalence not affected by delay in sample processing
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Prevalence of MRSA/MSSA by month
Prevalence similar over time MSSA: 54% - 84% MRSA: 4% - 11%
Verkade et al (2013) MSSA: 72% MRSA: 44%
Suggests less MRSA in USA
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S. aureus spa types in veterinarians
Striking similarity to pig data
3 spa types > 50% Vast majority are
ST398 ST9 ST5
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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 isolates44
S. aureus colonization patterns
Some consistently positive with same spa type ST398 (7): MRSA and MSSA ST5 (3): MSSA only ST9 (2): MSSA only
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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
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Concepts of interspecies transmission
Humanflora
Swineflora
Complete host adaptation
No interspecies transmission
Humanflora
Swineflora
No host adaptation
Equal propensity to colonize both species
Marked host adaptation
Rare interspecies transmisssion
Some host adaptation
Common interspecies transmisssion
LA-MRSA: models of host adaptation
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ST398
LA-MRSA: models of host adaptation
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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
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“The larger the island of knowledge, the longer the
shoreline of doubt”
Jisun Sun My Yang Leticia Linhares Srinand Sreevatsan
Swine faculty and graduate students
NPB UMASH
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THANK YOU!
“The larger the island of knowledge, the longer the
shoreline of doubt”52
HUGE THANK YOUTO TEAM NOSTRIL!