Peter Davies BVSc, PhDUniversity of Minnesota

PATHOGENS in

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Emerging diseases in intensive livestock production

Media Shoot first – ask questions later (maybe)

Blogosphere Just shoot and ask no questions Move on to next ‘crisis’

Guilty until proven innocent Habitual overstatement of public health

risks

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Diseases in the twilight zone

BSE Model prediction up to 50,000 human deaths

from variant CJD Lower limit of 5,000 Global tally after 15 years is around 200.

H5N1 avian influenza Guesstimates up to 150 million circulated 564 Laboratory confirmed cases (August 9, 2011) 330 fatalities.

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Discovery vs. emergence

Conventional microbiology reveals the tip of the iceberg

Today have very powerful diagnostic tools Closely related hosts (mammals,

homeotherms) likely to be colonized by ‘closely related’ organisms

Discovery involves much uncertainty Interspecies transmission Virulence in various species

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Diseases in the twilight zone

Influenza viruses MRSA Clostridium difficile Noroviruses Sapoviruses Intestinal spirochetes ….

Recent Emerging Disease Issues in Swine

What Where When* Swine Health* Human Health*

Media hype*

Clostridium difficile (pigs) Global 1986 +/- ++(?) ++

PRRS Global 1987 +++++ - -

Salmonella typhimurium DT104 Global 1993 +/- ++ ++++

PCV2 Global 1996 +++++ - -

Hepatitis E infection USA/global 1995 - +/- +/-

Menangle virus Australia 1997 + +/- -

Nipah virus Malaysia 1998 ++ ++ ++

Bungowannah virus Australia 2003 + - -

MRSA ST398 EU/global 2004 - +/- +++++

virulent Streptococcus suis type 2 China 2005 ? ++ ++

H1N1 pandemic influenza Global 2009 + ++++(?) +++++

Recent Emerging Disease Issues in Swine

What Where When* Swine Health* Human Health*

Media hype*

Clostridium difficile (pigs) Global 1986 +/- ++(?) ++

PRRS Global 1987 +++++ - -

Salmonella typhimurium DT104 Global 1993 +/- ++ ++++

PCV2 Global 1996 +++++ - -

Hepatitis E infection USA/global 1995 - +/- +/-

Menangle virus Australia 1997 + +/- -

Nipah virus Malaysia 1998 ++ ++ ++

Bungowannah virus Australia 2003 + - -

MRSA ST398 EU/global 2004 - +/- +++++

virulent Streptococcus suis type 2 China 2005 ? ++ ++

H1N1 pandemic influenza Global 2009 + ++++(?) +++++

S. aureus and C. difficile

Common commensals found in healthy people and animals

Opportunistic pathogens increasing in incidence and clinical severity

Recognized human pathogens long before animal reservoirs thought of epidemiological significance.

Important nosocomial agents - hospital infections principal concern

Community acquired infections more important in recent years.

Animal colonization raises risk of livestock as sources of community acquired infections.

Both isolated from pork

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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 papers

PFGE with the SmaI enzymeSoge et al. J. Antimicrob. Chemother. 2009;64:1148-1155

MRSA isolated from US West Coast public marine beaches

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Holland – an issue emerges!

Very low MRSA prevalence ‘Search and destroy’ policy Intensive screening and typing with sma1 PFGE

2004: 6mo girl screened before for 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

PFGE

MLST

SCCmec typing (I – VIII)

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) 44 of 54 (81%) of farms positive

All isolates a ‘single clonal group’ Nontypable (NT) by sma1 PFGE MLST: ST 398 3 closely related spa types predominant (t011, t108, t1254,

…)

Panton-Valentine Leucocidin (PVL) toxin negative Uniformly resistant to tetracycline

Use of tetracyclines may be selecting for MRSA?

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

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Colonization of farm workers

ST398 also isolated from pig farmers (Voss et al 2005) 23% of farmers positive on nasal swab 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)

EFSA farm prevalence study (dust samples)

*

MRSA spa types in swine barn dust (EFSA, 2010)

Predominant in North America

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ST398 MRSANot just a pig problem!

Pigs – widespread (but not China, UK, Ireland, Japan)

ST9

Calves – Holland Horses – Austria, Belgium, France, Germany,

Holland, Canada Chickens – Belgium Dogs – Austria, Canada Lack of host specifity may indicate zoonotic risk!

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MRSA in pigs in Ontario (Khanna et al, 2007)

Convenience sample of 20 Ontario herds 25% (71/285) of pigs positive 20% (5 of 25) farmers positive

Predominant (75%) spa types similar to ST398 Dutch isolates Spa type t034 predominant

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Livestock associated MRSA in USA

Two farms in Iowa (Smith 2007)

One positive – 70% of pigs (ST398)

Slaughter pigs (Davies et al, 2009)

539 pigs from 45 farms 25% of pigs MRSA positive Diverse spa types - t034 predominant

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Prevalence and characterization of MRSA in pigs and farm workers on conventional and antibiotic free swine farms in the USA

Collaborative Study – National Pork Board 54 farms across 3 centers (MN, IA-IL, OH_NC) 18 farms per state

9 conventional, 9 antibiotic free 24 pigs per farm; any human volunteers

Difficulties in finding farms 45 farms enrolled (24 conv., 21 ABF) 1084 pigs; 154 people

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MRSA on conventional and ABF swine farms

MRSA detected in pigs on 4 farms All 4 conventional farms in IA-IL All pigs negative in ABF farms

45 (4.2%) of 1084 pigs positive 29 (18.8%) of 154 people positive

24 of 40 (60%) people positive on two farms with highest pig prevalence

MRSA on conventional and ABF swine farms

32 spa type 539/t0342 spa type 2/NT2 other ‘LA’ (t011; t571

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MRSA in farm workers on conventional and ABF swine farms

17 spa type 539/t0345 spa type 2/NT1 other

Not LA type 539/t034

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MSSA isolates in MN

98 isolates of MSSA characterized in MN 92 from pigs, 6 from people Pig samples clustered on 4 farms (3 conv., 1

ABF) 65 (71%) of pigs isolates were spa type

539/t034 1 isolate from human

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Summary

MRSA detected in market hogs and occupationally exposed people

Spa type 539/t034 predominant Spa type 2/tunknown also detected in all studies

Similar to Canada

Lack of knowledge of S. aureus epidemiology in pigs Spa type 539/t034 in MN

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Exposure assessment – ST398

High risk of exposure in groups with direct livestock contact Major concerns about occupational risk Some exposure risk to direct family members

Currently no indication of significant community exposure

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Risk assessment

Consequences of occupational exposure Colonization vs. Infection

What is the burden of disease? Virulence Transmission

Diversity within ST398 lineage Animal vs. human isolates

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Questions?

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Current and future studies

Epidemiology of S. aureus in multiple site pig farms (NPB)

MRSA colonization and infection in swine veterinarians (NIOSH) 70 ‘volunteers’ Study duration of colonization over 18 months Prospective study of infection risk

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Occupational exposure

Consistent observations that people with occupational exposure to animal species more likely to be colonized with MRSA As yet minimal data indicating increased risk of

infection Interspecies transmission of S. aureus

Frequency, Quantity, Duration Burden of disease

Primarily occupational?

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Burden of disease from ST398 MRSA

Many reports don’t distinguish infection from colonization

Small number of serious infections Retrospective study of human isolates in

Canada 5 ST398 out of 3,687 (4 skin/soft tissue infections)

CDC has examined >12,000 isolates ST398 had not identified in a human clinical case

Current evidence suggests low pathogenicity?

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1015202530354045

Holland

Denmark

Ger

man

y

Austri

aChina

Belgiu

m

Canada

Hong K

ong

Scotla

ndIta

ly

Sweden

Spain

Clinical cases = 122

Invasive = 27

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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 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”

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No pigsNo MRSA

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“One Health” means more than one

inference

‘.. concern because strains ST398 strains were able to acquire PVL genes’

But…. Livestock strains almost uniformly tetracycline

resistant and PVL negative Spa type t571 uncommon in animal isolates

Could adaptation of ST398 to livestock hosts include loss of human virulence factors

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The rest of the story

Davies et al, EID June 2011

t571 ST398 MSSA detected in 9 families from the Dominican Republic living in Manhattan

with no apparent contact with livestock (Bhat et al., 2007)

t571 the sole MSSA spa type in Dutch study of ST398 clinical isolates, including 3 independent cases of nosocomial bacteremia

with no apparent livestock contact (van Belkum et al., 2008)

t571 the predominant (11%) MSSA type at a Beijing hospital

Livestock contact unlikely (Chen et al 2010)

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Emergence of unusual bloodstream infections associated with pig-borne-like Staphylococcus aureus ST398 in France. (van de Marquet et al., 2011)

Study of t571 MSSA strains from cases of bloodstream infections in France

The 30 isolates differed from pig-borne strains Isolates shared similarities with strains from

humans in China and virulent USA300 strains

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Understanding LA-MRSA is embryonic Naïve perceptions of complex epidemiology

All MRSA found in livestock are ST398 Livestock are the only reservoirs of ST398

ST398 isolates of diverse genotype and geographic origin may also be epidemiologically distinct

Requires systematic investigation of S. aureus epidemiology in animals and humans.

The rest of the story……

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Community dissemination of MRSA ST398 Cuny et al (2009)

Study of German farming community where MRSA ST398 prevalent on pig farms

Nasal swabs from Pig farmers and family members Swine vets and family members 462 pupils (10 to 16 yo) in villages in the high

density pig farming area

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Nasal colonization with ST 398 Cuny et al (2009)

Group N Pct Pos

Pig farmers 113 86%

Farmer family members

116 4.3%

Swine Veterinarians 18 45%

Vet family members 44 9%

Schoolchildren* 462 0.007% (3)

*All 3 positive children lived on pig farms

Prevalence Ratio= 20

Prevalence Ratio= 5

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Communities in pig dense areas in Holland (van Cleef 2010)

Mailing in 3 selected municipalities in the Netherlands where livestock MRSA prevalent

Adults complete questionnaire and nose swab (n = 583)

One of 534 persons without livestock-contact positive (0.2%)

13 of 49 of farm residents/workers positive (26.5%) Conclusions:

High prevalence of livestock-associated MRSA in people with direct contact with farm animals.

Not spread into the wider community

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Exposure assessment – ST398

High risk of exposure in groups with direct livestock contact Major concerns about occupational risk Some exposure risk to direct family members

Currently no indication of significant community exposure

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Risk assessment

Consequences of occupational exposure Colonization vs. Infection

What is the burden of disease? Virulence Transmission

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Transmission of ST398 MRSA among people

Studies of transmission in Dutch hospitals (Bootsma, 2010)

ST398 is 5.9 times less transmissible than non-ST398 MRSA in Dutch hospitals’

‘Spreading capacity per admission insufficient to lead to an epidemic’

‘Nosocomial transmission of ST398 MRSA is 72% less likely than non-ST398 MRSA strains’

Wassenberg (2011)

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Distribution of LA MRSA and other MRSA clinical isolates in Europe (van Cleef et al., 2011)

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Diversity of genome of human and LA ST398 MRSA strains (Hallin et al., 2011)

‘LA-MRSA strains represent a homogenous lineage distinct from co-local HA- and CA-MRSA strains characterized by a lack of human-associated

virulence and adhesion determinants Absence of detectable enterotoxin gene

among ST398 LA-MRSA strains from a wide host range is reassuring regarding their foodborne pathogenic potential.’

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Duration of colonization

Research workers (short term exposure) van Cleef et al (2011)

33 of 199 exposures led to positive culture on farm Only 3 of 33 retested positive after 24 hours

Evidence suggests most short term exposure leads to short term ‘colonization’

Veal farmers in Holland Graveland et al (2011)

Rapid decline in prevalence during absence of animal contact LA-MRSA poor persistent colonizers in most humans.