Spread and control of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) in Danish pig herds

Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) is an opportunistic human pathogen with main reservoir in pigs. Since LA-MRSA first was identified in Denmark in 2007 among isolates collected at two Danish pig farms in 2003, the occurrence have increased dramatically and reached a prevalence of 88% positive farms in 2016. Meanwhile a similar increase in human infections have been observed; most infections are still observed among people with livestock contact, but the development in number of infections among people without livestock contact have followed a similar increasing trend. Given the high prevalence of LA-MRSA positive farms, total eradication of LA-MRSA in the Danish pig population does not seem feasible, and thus a strong need for exploring options to control the spread of LA-MRSA in Danish pig herds exists. At present it is still not known how LA-MRSA managed to spread so quickly in the Danish pig population and a lot still needs to be understood regarding which factors that determine whether a farm becomes LA-MRSA positive or not. In the first part of this thesis two studies were conducted with the aim of identifying herd-level risk factors for: 1) herds testing MRSA positive (study 1), and 2) more specifically for herds changing status from negative to positive during 2014-2016 (study 2). The studies were based on data harvested in questionnaire-based phone interviews with farmers and supplemented with data for antimicrobial use, movement of pigs and location of neighbouring farms extracted from three national registers. Three risk factors already identified in other studies were confirmed. LA-MRSA positive status was associated with large herd size and with number of pig suppliers. In addition, sow herds tested LA-MRSA positive less frequently than herds without sows, and therefore data from sow herds were analysed separately. In univariable analysis, the following factors were associated with sow herds testing LA-MRSA positive: use of wet feed in the sow units; higher weights of piglets at weaning; availability of a delivery room on the farm; cleaning of aisles after pigs were moved; number of pigs per weaner section; number of pigs purchased in the past year, and factors related to rodent control and human traffic in the herd. In herds without sows, the univariable analysis showed that the presence of other animal species on the farm; negative pressure ventilation; full sectioning; frequent visits from the veterinarian; peroral use of tetracyclines for weaners; number of pigs purchased in the past year, and factors related to rodent control and human traffic in the herd were significantly associated with LA-MRSA status. Similar to what have been observed in other studies, many of the factors significantly associated with LA-MRSA status in study 1 was also significantly associated with herd size, and thus it was not possible to identify whether herd size itself or the related factors were the “true” risk factors. The number of observations in study 2 was small, but three variables (the number of pig suppliers, use of group medication in water vs. administration through feed, and having a company contract for mouse control) were associated with changing LA-MRSA status in the univariable analysis. Before the implementation of a national control strategy can be decided upon, it is also essential to understand how LA-MRSA spreads and persists within a pig herd, once it has been introduced. In the second part of this thesis a mechanistic model for spread of LA-MRSA within an pig herd was therefore build and subsequently used for studying transmission dynamics and within-farm prevalence after simulating different introductions of LA-MRSA on a farm. With the current parameterisation of the model, spread of LA-MRSA throughout the farm mainly followed the movement of pigs. The later in the production process LA-MRSA was introduced, the longer it took to spread to the whole farm. After spread of LA-MRSA had reached a steady state, the prevalence of LA-MRSA shedders was predicted to be highest in the farrowing unit, and lowest in the mating unit, independent of where and how LA-MRSA was introduced. Thus the farrowing unit might the area with most potential for intervention against spread of LA-MRSA. Introduction of a low number of intermittently shedding pigs was predicted to frequently result in LA-MRSA not establishing itself in the herd. Increasing the duration of carriage led to an increased median prevalence, less variance and fewer iterations where LA-MRSA did not become established in the herd. When removing the possibility of pigs becoming persistent shedders, LA-MRSA more frequently faded out and did not become established within the herd. Not much is known regarding successful interventions against LA-MRSA within pig herds. Consequently the mechanistic model for spread of LA-MRSA within a farm were used for simulating on-farm interventions within four different areas: 1) Reduced antimicrobial consumption, 2) Reduced number of pigs within each section, 3) Reduced mixing of pigs from different litters, batches or pens, and 4) Improved internal biosecurity. It is believed that a reduction in the within-farm LA-MRSA prevalence will result in less spread between farms and reduce the risk of transmission to humans working on the farm. Reducing the transmission rates after LA-MRSA had become fully established within the herd, resulted in a marked prevalence decrease in the prevalence of LA-MRSA positive pigs within the different stable units, albeit LA-MRSA rarely disappeared completely. This indicates that while reducing antimicrobial consumption might be an important step towards reducing the LA-MRSA occurrence within the herd, other preventive or intervention measures should also be implemented in order to completely clear a herd from LA-MRSA. Implementation of the other interventions after LA-MRSA had become established within a herd only resulted in marginal changes in the median within-herd prevalence. However, in relation to being able to achieve or maintain a low level of antimicrobial consumption, these factors might still be of importance. The results of the sensitivity analysis indicated that the assumptions regarding the existence of pigs persistently shedding MRSA have a noticeable influence on the model results. A secondary of objective of building the simulation model was to identify knowledge gaps regarding spread and control of LA-MRSA. Several knowledge gaps related to infection dynamics exist, including influence of the environment, LA-MRSA load and persistent carriage. Regarding control of LA-MRSA, the main problem is currently a lack of evidence for major effect of any type of intervention other than reducing antimicrobial consumption. In conclusion, the work presented in this thesis have resulted in: 1) Confirmation of already known risk factors for farms testing LA-MRSA positive (herd type, herd size, number of pig suppliers) and identification of a number of potential new risk factors, albeit many of these were related to herd size, and it therefore was impossible to conclude, whether herd size itself or these factors were the true risk factors. 2) Construction of a mechanistic model for spread of LA-MRSA within a pig herd that can be used for simulating LA-MRSA within herd dynamics following different introductions. The code for the model is publicly available, and the herd part of the model can potentially be re-used together with epidemic models for other pathogens. 3) Simulation of within-herd interventions: Reduced antimicrobial consumption, reduced number of pigs within each section, reduced mixing of pigs, and improved internal biosecurity, of which only reduced antimicrobial consumption had a marked effect on the within-herd prevalence. More intervention scenarios can be simulated, when data becomes available. 4) The observation that once LA-MRSA has become established within a herd, it will spread to all compartments within the farm and be very hard to get rid of.