The role of agriculture in the transmission of Methicillin-resistant Staphylococcus aureus

Intro:
Methicillin-resistant Staphylococcus aureus (MRSA) is an associate of the emerging
antibacterial-resistant superbugs. It carries characteristics which circumvent β-lactam
antibiotics (e.g. penicillin) and exposes the immune system to severe bacterial infections
(Schulz et al. 2018). Late research has identified the emergence of the livestock-associated
strain (LA-MRSA) within swine, which has been speculated to be due to extensive use of
tetracycline; an antibiotic used in agriculture (Dierikx et al. 2016). Its development infers an
intriguing epidemiological notion which differs from the well-established hospital-acquired
(HA-MRSA) and community-acquired (CA-MRSA) strains; their evolution understood greater
through environmental context. European countries have recorded a prevalence of LA-MRSA
since 2005, with 70% of swine farms in Denmark and the Netherlands testing positive
(Grøntvedt et al. 2016). Therefore, an investigation into the contribution of agriculture towards
the transmission of LA-MRSA may be of interest, with livestock trading and movements,
antibiotics, direct human-animal interactions and animal waste as potential causes and modes
of transmission. This bibliography analyses articles pertaining to the issue with varying focuses
within the area of agriculture and its hypothesised impact upon LA-MRSA.

Keywords: antibiotic resistance, pigs, outbreak, health, LA-MRSA

Schulz J, Boklund A, Toft, N, Halasa, T (2018) Drivers for livestock-associated

Methicillin-resistant Staphylococcus aureus spread among Danish Pig herds- a simulation
study. Nature Scientific Reports 8, 1 -11. doi: 10.1038/s41598-018-34951-1

The livestock-associated strain of Methicillin-resistant Staphylococcus aureus (LA-MRSA)

has the potential to transmit between livestock (i.e. pigs) and humans, and studies have
explored methods to control this risk. The aim was to find a correlation between movements
of livestock and the prevalence of LA-MRSA within Denmark; with the outcome contributing
to prevention strategies. A computational model was developed to establish a connection
between these movements and its spread between 2006 and 2015, which gathered data from
the Ministry of Environment and Food. It was found that pig movements alone could not be
responsible for the transmission of LA-MRSA and therefore no policy could be recommended

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to limit transmission. It suggested that other means of bacterial transmittance through animal
contact (both indirect or direct) may be responsible for its presence within humans.

This research conducted provides an alternative method of data collection and is

thorough as it records the movements of agriculture over a lengthy period of nine years.
It is not the most relative study as the data was collected via a simulation and does not
test the nature of the bacterium once transmitted. It does however, demonstrate that the
simple movement of pigs does not contribute to the transmission and that another area
of study should be researched. As it does not pertain to the main contention, this may
be suited in helping scope my research towards other forms of transmission such as
direct contact or food production.

Rating: 2/5

Angen Ø, Feld L, Larsen, J, Rostgaard K, Skov R, Madsem A M, Larsen A (2017)

Transmission of methicillin-resistant Staphylococcus aureus to human volunteers visiting
a swine farm. Applied Environmental Microbiology 83, 1 – 10. doi: 10.1128/AEM.01489-
17

Direct contact with swine has been suspected to contribute to the prevalence of LA-MRSA and
this investigation sought to study the imposed risk on individuals who associate with livestock.
It aimed to conclude whether individuals could acquire the strain following direct contact, and
airborne exposure to an LA-MRSA positive herd. Nasal and throat swabs were tested for the
presence of the strain concluding each visit, and results indicated that 94% of individuals
obtained the strain. However, its concentration decreased after two days to a null value. The
study denoted no major risk for subjects and that majority contracted the strain from air-borne
activities, rather than direct handling. This implicates that the transmission of livestock to
humans is minor due to the natural tendency to decrease after isolation from the source.

This article concluded that there was no risk for short-term exposure to an LA-MRSA
positive site, and the method of acquiring data was simple and direct. This aids the
exploration into whether direct contact could contribute to the transmission and this can
be used to clarify the role of agriculture. However, I found that a longitudinal study on

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 farmers would have been more beneficial to understand whether prolonged exposure could
harvest the strain.

Rating: 3/5

Dierikx C M, Hengeveld P D, Veldman K T, de Haan A, van der Voorde S, Dop P Y,

Bosch T, van Duijkeren E (2016) Ten years later: still a high prevalence of MRSA in
slaughter pigs despite a significant reduction in antimicrobial usage in pigs the
Netherlands. Journal of Antimicrobial Chemotherapy 71, 2414 – 2418. doi:
10.1093/jac/dkw190

The Dutch government proposed a scheme to reduce the presence of LA-MRSA within pigs
by implementing a 50% reduction in the administration of antibiotics. Specifically focusing on
‘slaughter pigs’, this study examined the prevalence of the superbug between 2009 and 2014,
with the latter period following the introduction of the scheme. Nasal swabs were collected
from 558 pigs across several slaughterhouses and using two methods, cultured to undergo a
process of genetic identification. Results indicated 99% of pigs were positive for LA-MRSA
despite the reduction of antibiotic administration however, the concentration was not measured
but merely its presence. These findings contribute to understanding the role of agriculture in
the transmission of LA-MRSA and located the potential for farm workers to contract the strain
through direct contact.

This was a really valuable article which examined the attempt at controlling the spread of
LA-MRSA rather than testing its presence alone. It would be helpful in formulating an
alternative discussion on the means of controlling outbreaks, and also provides evidence
which may complement or contrast other gathered studies.

Rating: 4.5/5

Grøntvedt C A, Elstrøm P, Stegger M, Skov R L, Andersen P S, Larssen K W, Urdahl A

M, Angen Ø, Larsen J, Åmdal S, Løvedt S M, Sunde M, Bjørnholt J V (2016) Methicillin-
resistant Staphylococcus aureus CC398 in humans and pigs in Norway: a “One Health”
perspective on introduction and transmission. Clinical Infectious Diseases 63, 1431 – 1438.
doi: 10.1093/cid/ciw552

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Previous studies have examined the transmission of LA-MRSA between livestock and humans,
but the acknowledgement of how it was first conceived within animals was of key interest. The
aim was to understand the introduction of the strain and its potential relationship to humans as
part of the greater ‘One Health’ initiative. Questionnaires surveyed demographic and medical
information, and previous databases of epidemiological information dating from 2008 to 2014
were collected. A phylogenetic analysis was performed, and results demonstrated that livestock
trading and transportation by humans contributes greatly towards the spread of LA-MRSA.
These findings suggest that human impact is responsible for its development, and therefore,
may be a potential area to control to prevent routes of transmission.

This research provided a more inquisitive perspective by examining the origin of LA-MRSA
by compiling phylogenetic information. Although this deviates from the analysis of
contraction between livestock and humans, it would be important to mention the evolution
of the bacterium. This could really benefit my research when investigating how agriculture,
as a human-made business, contributes to the global transmission of the bacterium.

Rating: 4/5

Fletcher S (2015) Understanding the contribution of environmental factors in the spread

of antimicrobial resistance. Environmental Health Preventative Medicine 20, 243 – 252.
doi: 10.1007/s12199-015-0468-0

A general outlook on contributing factors for the transmittance of antibacterial resistance was
reviewed. Despite attaining a holistic approach to superbugs, the use of antibiotics in areas such
as veterinary medicine and its potential to spread via alternative routes (e.g. animal waste and
food production) was investigated. The analysis of using antibiotics in livestock indicated a
key concern for manure to act as a transportation for the bacterium when delivered to ponds
and crops. Therefore, there is the potential for the superbug gene to be transferred to humans
via animal waste in agriculture; as well as animal-derived food products. This discussion
established the effects of antibiotic use in the environment as multidisciplinary and indicated
the need to review basic practices of agriculture.

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This review article summarised a very broad outlook on the causes of the antibiotic
resistant bacteria but encapsulated a great discussion on how animal associated products
may contribute to the transmittance (as opposed to direct contact). This could help with
other key ideas when discussion how agriculture has contributed to the evolution and
spread of LA-MRSA.

Rating: 4/5

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References

Angen Ø, Feld L, Larsen, J, Rostgaard K, Skov R, Madsem A M, Larsen A (2017)

Transmission of methicillin-resistant Staphylococcus aureus to human volunteers
visiting a swine farm. Applied Environmental Microbiology 83, 1-10. doi:
10.1128/AEM.01489-17
Dierikx C M, Hengeveld P D, Veldman K T, de Haan A, van der Voorde S, Dop P Y, Bosch
T, van Duijkeren E (2016) Ten years later: still a high prevalence of MRSA in slaughter
pigs despite a significant reduction in antimicrobial usage in pigs the Netherlands.
Journal of Antimicrobial Chemotherapy 71, 2414 – 2418. doi: 10.1093/jac/dkw190
Fletcher S (2015) Understanding the contribution of environmental factors in the spread of
antimicrobial resistance. Environmental Health Preventative Medicine 20, 243 – 252.
doi: 10.1007/s12199-015-0468-0
Grøntvedt C A, Elstrøm P, Stegger M, Skov R L, Andersen P S, Larssen K W, Urdahl A M,
Angen Ø, Larsen J, Åmdal S, Løvedt S M, Sunde M, Bjørnholt J V (2016) Methicillin-
resistant Staphylococcus aureus CC398 in humans and pigs in Norway: a “One Health”
perspective on introduction and transmission. Clinical Infectious Diseases 63, 1431 –
1438. doi: 10.1093/cid/ciw552
Schulz J, Boklund A, Toft, N, Halasa, T (2018) Drivers for livestock-associated methicillin-
resistant Staphylococcus aureus spread among Danish Pig herds- a simulation study.
Nature Scientific Reports 8, 1 -11. doi: 10.1038/s41598-018-34951-1

6
Abstracts

Summary One: Drivers for livestock-associated Methicillin-resistant Staphylococcus

aureus spread among Danish Pig herds- a simulation study

To gain insight into the rapid increase in the number of livestock-associated Methicillin-
resistant Staphylococcus aureus (LA-MRSA)-positive herds in Denmark, we developed an
individual-based Monte Carlo simulation model. We aimed to assess whether transmission of
LA-MRSA via pig movements could explain the observed increase in the number of positive
herds in Denmark, and to evaluate the effect of other between-herd transmission mechanisms.
Pig movements alone were not sufficient to mimic the observed increase in LA-MRSA-positive
herds in Denmark in any of the modelled scenarios. The model identified three factors that
played important roles in the between-herd spread of LA-MRSA: (1) the within-herd dynamics,
(2) the frequency and effectiveness of indirect transmissions, and (3) unexplainable
introduction of LA-MRSA to swine herds. These factors can act as starting points for the
development of LA-MRSA control programs in pig herds in order to limit the risk of its
transmission to humans.

Summary Two: Transmission of Methicillin-Resistant Staphylococcus aureus to Human

Volunteers Visiting a Swine Farm

Transmission of methicillin-resistant Staphylococcus aureus (MRSA) from animals to humans

is of great concern due to the implications for human health and the health care system. The
objective was to investigate the frequency and duration of MRSA carriage in human volunteers
after a short-term exposure in a swine farm. The experimental study included 34 human
volunteers staying 1 h in a MRSApositive swine farm in four trials. In two of the trials, the
influence of farm work involving pig contact was studied using a crossover design. The
quantities of MRSA in nasal swabs, throat swabs, and air samples were measured at different
time points and analyzed in relation to relevant covariates. This investigation showed that,
overall, 94% of the volunteers acquired MRSA during the farm visit. Two hours after the
volunteers left the stable, the nasal MRSA count had declined to unquantifiable levels in 95%
of the samples. After 48 h, 94% of the volunteers were MRSA-negative. Nasal MRSA carriage
was positively correlated to personal exposure to airborne MRSA and farm work involving pig
contact and negatively correlated to smoking. No association was observed between MRSA
carriage and face touching behavior, nasal methicillin-susceptible Staphylococcus aureus
(MSSA) carriage, age, or gender. The increase in human MRSA carriage among the volunteers
with pig contact seems to be dependent on the increased concentration of airborne MRSA of
the surrounding air and not directly on physical contact with pigs. MRSA was not detected in
any of the throat samples.

Summary Three: Ten years later: still a high prevalence of MRSA in slaughter pigs
despite a significant reduction in antimicrobial usage in pigs the Netherlands

Objectives: In 2005, 39% of pigs and 81% of the slaughter batches at Dutch slaughterhouses
were MRSA positive. The objective of the present study was to investigate whether the 50%
reduction of antimicrobial usage in finishing pigs in 2014 compared with 2009 in the
Netherlands has led to a lower MRSA prevalence among Dutch slaughter pigs. Methods:
Nasal swabs from eight slaughter batches of on average 10 animals at seven slaughterhouses
were taken and cultured using method 1, which was used in 2005, and method 2, using high-
salt pre-enrichment. Suspected isolates were confirmed by PCR for two Staphylococcus

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aureus-specific DNA fragments and the mecA gene. A subset of MRSA isolates were further
investigated using spa typing, multiple-locus variable number of tandem repeat analysis
(MLVA) and antimicrobial susceptibility testing. Results: Using methods 1 and 2, we found
461 of 558 (83%) and 552 of 558 (99%) of the pigs to carry MRSA in their nares,
respectively. All 56 slaughter batches were MRSA positive. All MRSA isolates belonged to
the livestock-associated MLVA complex 398, had a non-WT phenotype for tetracycline and
spa type t011 predominated. Conclusions: A very high prevalence of nasal MRSA carriage
was found in Dutch slaughter pigs and therefore the reduction in antimicrobial usage at the
national level has not yet had an effect on the MRSA carriage rate of pigs entering the
slaughterhouse. Therefore, there is still an increased risk of MRSA carriage for personnel
working at pig slaughterhouses, particularly those having contact with living animals.
Method 2, using high salt pre-enrichment, detected more MRSA-positive pigs and is
currently the preferred method for screening of MRSA in livestock in the Netherlands.

Summary Four: Methicillin-resistant Staphylococcus aureus CC398 in humans and pigs

in Norway: a “One Health” perspective on introduction and transmission

Background. Emerging livestock-associated methicillin-resistant Staphylococcus aureus

(MRSA) persist in livestock populations and represent a reservoir for transmission to
humans. Understanding the routes of introduction and further transmission is crucial to
control this threat to human health. Methods. All reported cases of livestock-associated
MRSA (CC398) in humans and pigs in Norway between 2008 and 2014 were included. Data
were collected during an extensive outbreak investigation, including contact tracing and
stringent surveillance. Whole-genome sequencing of isolates from all human cases and pig
farms was performed to support and expand the epidemiological findings. The national
strategy furthermore included a “search-and-destroy” policy at the pig farm level. Results.
Three outbreak clusters were identified, including 26 pig farms, 2 slaughterhouses, and 36
humans. Primary introductions likely occurred by human transmission to 3 sow farms with
secondary transmission to other pig farms, mainly through animal trade and to a lesser extent
via humans or livestock trucks. All MRSA CC398 isolated from humans without an
epidemiological link to the outbreaks were genetically distinct from isolates within the
outbreak clusters indicating limited dissemination to the general population. Conclusions.
This study identified preventable routes of MRSA CC398 introduction and transmission:
human occupational exposure, trade of pigs and livestock transport vehicles. These findings
are essential for keeping pig populations MRSA free and, from a “One Health” perspective,
preventing pig farms from becoming reservoirs for MRSA transmission to humans.
Keywords. LA-MRSA; humans; pigs; epidemiology; control.

Summary Five: Understanding the contribution of environmental factors in the spread

of antimicrobial resistance

The overuse and abuse of antibiotics have contributed to the global epidemic of antibiotic
resistance. Current evidence suggests that widespread dependency on antibiotics and complex
interactions between human health, animal husbandry and veterinary medicine, have
contributed to the propagation and spread of resistant organisms. The lack of information on
pathogens of major public health importance, limited surveillance, and paucity of standards
for a harmonised and coordinated approach, further complicates the issue. Despite the
widespread nature of antimicrobial resistance, limited focus has been placed on the role of
environmental factors in propagating resistance. There are limited studies that examine the
role of the environment, specifically water, sanitation and hygiene factors that contribute to

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the development of resistant pathogens. Understanding these elements is necessary to identify
any modifiable interactions to reduce or interrupt the spread of resistance from the
environment into clinical settings. This paper discusses some environmental issues that
contribute to antimicrobial resistance, including soil related factors, animal husbandry and
waste management, potable and wastewater, and food safety, with examples drawn mainly
from the Asian region. The discussion concludes that some of the common issues are often
overlooked and whilst there are numerous opportunities for environmental factors to
contribute to the growing burden of antimicrobial resistance, a renewed focus on innovative
and traditional environmental approaches is needed to tackle the problem.