Effect of tetracycline treatment regimens on antibiotic resistance gene selection over time in nursery pigs.

BACKGROUND: The majority of antimicrobials given during the production of pigs are given to nursery pigs. The influence of antimicrobial use on the levels of antimicrobial resistant (AMR) genes is important to quantify to be able to assess the impact of resistance on the food chain and risk to human and animal health. RESULTS: This study investigated the response on the levels of nine AMR genes to five different treatment strategies with oxytetracycline, and the dynamics of gene abundance over time by following 1167 pigs from five different farms in Denmark. The results showed no significant difference between treatments and an increase in abundance for the efflux pump encoding tet(A) gene and the genes encoding the ribosomal protection proteins tet(O) and tet(W) tetracycline resistant genes following treatment, while tet(M) showed no response to treatment. However, it was also observed that the levels of tet(O), tet(W), and ermB in some farms would drift more over time compared to a single treatment-course with antibiotic. CONCLUSION: This study underlines the large variation in AMR levels under natural conditions and the need for increased investigation of the complex interactions of antimicrobial treatment and other environmental and managerial practices in swine production on AMR gene abundance.

A strain-, cow-, and herd-specific bio-economic simulation model of intramammary infections in dairy cattle herds.

Intramammary infections (IMI) in dairy cattle lead to economic losses for farmers, both through reduced milk production and disease control measures. We present the first strain-, cow- and herd-specific bio-economic simulation model of intramammary infections in a dairy cattle herd. The model can be used to investigate the cost-effectiveness of different prevention and control strategies against IMI. The objective of this study was to describe a transmission framework, which simulates spread of IMI causing pathogens through different transmission modes. These include the traditional contagious and environmental spread and a new opportunistic transmission mode. In addition, the within-herd transmission dynamics of IMI causing pathogens were studied. Sensitivity analysis was conducted to investigate the influence of input parameters on model predictions. The results show that the model is able to represent various within-herd levels of IMI prevalence, depending on the simulated pathogens and their parameter settings. The parameters can be adjusted to include different combinations of IMI causing pathogens at different prevalence levels, representing herd-specific situations. The model is most sensitive to varying the transmission rate parameters and the strain-specific recovery rates from IMI. It can be used for investigating both short term operational and long term strategic decisions for the prevention and control of IMI in dairy cattle herds.

Determinants of antimicrobial treatment for udder health in Danish dairy cattle herds.

Societal pressure to limit the use of antibiotics in livestock production systems, including dairy cattle systems, is consistently increasing. To motivate farmers to reduce antibiotic usage, it is important to understand the factors that determine whether a cow will be treated with antibiotics or not. If farmers' usual practices regarding antibiotic treatments are taken into account, they may be motivated to adopt control measures that can facilitate prudent use of antibiotics and are at the same time cost-effective. In this study, we analyzed database recordings of milk yield and somatic cell count from the routine milk recording scheme, clinical registrations of mastitis and PCR results, and cow factors such as days in milk and parity in relation to antibiotic treatments for 518 dairy herds in Denmark. Farm-wise logistic regressions were used to predict antimicrobial treatment based on these factors. The resulting regression coefficients of 422 herds were further analyzed by principal component analysis and clustering to determine the driving predictors for treatment in different groups of farms. The results showed that determinants that were most important for predicting antibiotic treatments vary from one farm to another. Health indicators such as PCR or somatic cell count were most indicative for treatment on some farms, whereas other groups seemed to depend more on production factors (milk yield) or later culling of the cows. This shows that farmers behave differently and differences can be identified in register data. This information can be considered when developing cost-effective herd-specific control measures of mastitis to promote prudent use of antibiotics in Danish dairy cattle farms.

Effect of Tetracycline Dose and Treatment Mode on Selection of Resistant Coliform Bacteria in Nursery Pigs.

This study describes the results of a randomized clinical trial investigating the effect of oxytetracycline treatment dose and mode of administration on the selection of antibiotic-resistant coliform bacteria in fecal samples from nursery pigs. Nursery pigs (pigs of 4 to 7 weeks of age) in five pig herds were treated with oxytetracycline for Lawsonia intracellularis-induced diarrhea. Each group was randomly allocated to one of five treatment groups: oral flock treatment with a (i) high (20 mg/kg of body weight), (ii) medium (10 mg/kg), or (iii) low (5 mg/kg) dose, (iv) oral pen-wise (small-group) treatment (10 mg/kg), and (v) individual intramuscular injection treatment (10 mg/kg). All groups were treated once a day for 5 days. In all groups, treatment caused a rise in the numbers and proportions of tetracycline-resistant coliform bacteria right after treatment, followed by a significant drop by the time that the pigs left the nursery unit. The counts and proportions of tetracycline-resistant coliforms did not vary significantly between treatment groups, except immediately after treatment, when the highest treatment dose resulted in the highest number of resistant coliforms. A control group treated with tiamulin did not show significant changes in the numbers or proportions of tetracycline-resistant coliforms. Selection for tetracycline-resistant coliforms was significantly correlated to selection for ampicillin- and sulfonamide-resistant strains but not to selection for cefotaxime-resistant strains. In conclusion, the difference in the dose of oxytetracycline and the way in which the drug was applied did not cause significantly different levels of selection of tetracycline-resistant coliform bacteria under the conditions tested.IMPORTANCE Antimicrobial resistance is a global threat to human health. Treatment of livestock with antimicrobials has a direct impact on this problem, and there is a need to improve the ways that we use antimicrobials in livestock production. We hypothesized that antibiotic resistance development following treatment of diarrhea in nursery pigs could be reduced either by lowering the dose of oxytetracycline or by replacing the commonly used practice of flock treatment with individual or small-group treatments, since this would reduce the number of pigs treated. However, the study showed no significant difference between treatment groups with respect to the number or proportion of tetracycline-resistant coliforms selected. The most important conclusion is that under practical field conditions, there will be no added value, in terms of lowering resistance development, by exchanging flock treatment for individual or small-group treatment of nursery pigs. The reason for the lack of an effect of single-animal treatment is probably that such animals share the environment with treated animals and take up resistant bacteria from the environment.

Epidemiological and economic consequences of purchasing livestock infected with Mycobacterium avium subsp. paratuberculosis.

BACKGROUND: Paratuberculosis (PTB) is a chronic disease which may lead to reduced milk yield, lower animal welfare and death in cattle. The causative agent is Mycobacterium avium subsp. paratuberculosis (MAP). The economic consequences are particularly important incentives in the control and eradication of the infection. One strategy to control PTB in a herd is to purchase animals from farms with a low risk of MAP infection. We wanted to investigate the epidemiological and economic consequences of buying livestock from different supplier farms of low, medium or high risk, as well as farms with unknown status. We also wanted to estimate the probability of spontaneous fadeout if the farmer of an initially MAP-free herd bought a specified number of infected animals in a single year, or continually bought infected animals. This was achieved through simulation modeling, and the effects of consistently introducing one, five or ten infected animals annually into an initially infection-free herd was also modeled. RESULTS: Our findings show that once infected, a farm can relatively safely purchase animals from other low and medium-risk farms without experiencing an increase in the prevalence, highlighting the importance of certification programmes. Furthermore, farms free of MAP are highly susceptible and cannot purchase more than a small number of animals per year without having a high risk of being infected. The probability of spontaneous fadeout after 10 years was 82% when introducing a single infected animal into an initially MAP-free herd. When purchasing ten infected animals, this probability was 46%. The continual purchase of infected animals resulted in very low probabilities of spontaneous fadeout. CONCLUSIONS: We demonstrated that MAP-free farms can purchase a small number of animals, preferably from certified farms, each year and still remain free of MAP. Already infected farms have little risk of increasing the prevalence on a farm when purchasing animals from other farms.

Modeling the growth dynamics of multiple Escherichia coli strains in the pig intestine following intramuscular ampicillin treatment.

BACKGROUND: This study evaluated how dosing regimen for intramuscularly-administered ampicillin, composition of Escherichia coli strains with regard to ampicillin susceptibility, and excretion of bacteria from the intestine affected the level of resistance among Escherichia coli strains in the intestine of nursery pigs. It also examined the dynamics of the composition of bacterial strains during and after the treatment. The growth responses of strains to ampicillin concentrations were determined using in vitro growth curves. Using these results as input data, growth predictions were generated using a mathematical model to simulate the competitive growth of E. coli strains in a pig intestine under specified plasma concentration profiles of ampicillin. RESULTS: In vitro growth results demonstrated that the resistant strains did not carry a fitness cost for their resistance, and that the most susceptible strains were more affected by increasing concentrations of antibiotics that the rest of the strains. The modeling revealed that short treatment duration resulted in lower levels of resistance and that dosing frequency did not substantially influence the growth of resistant strains. Resistance levels were found to be sensitive to the number of competing strains, and this effect was enhanced by longer duration of treatment. High excretion of bacteria from the intestine favored resistant strains over sensitive strains, but at the same time it resulted in a faster return to pre-treatment levels after the treatment ended. When the duration of high excretion was set to be limited to the treatment time (i.e. the treatment was assumed to result in a cure of diarrhea) resistant strains required longer time to reach the previous level. CONCLUSION: No fitness cost was found to be associated with ampicillin resistance in E. coli. Besides dosing factors, epidemiological factors (such as number of competing strains and bacterial excretion) influenced resistance development and need to be considered further in relation to optimal treatment strategies. The modeling approach used in the study is generic, and could be used for prediction of the effect of treatment with other drugs and other administration routes for effect on resistance development in the intestine of pigs.

Multistrain models predict sequential multidrug treatment strategies to result in less antimicrobial resistance than combination treatment.

BACKGROUND: Combination treatment is increasingly used to fight infections caused by bacteria resistant to two or more antimicrobials. While multiple studies have evaluated treatment strategies to minimize the emergence of resistant strains for single antimicrobial treatment, fewer studies have considered combination treatments. The current study modeled bacterial growth in the intestine of pigs after intramuscular combination treatment (i.e. using two antibiotics simultaneously) and sequential treatments (i.e. alternating between two antibiotics) in order to identify the factors that favor the sensitive fraction of the commensal flora. Growth parameters for competing bacterial strains were estimated from the combined in vitro pharmacodynamic effect of two antimicrobials using the relationship between concentration and net bacterial growth rate. Predictions of in vivo bacterial growth were generated by a mathematical model of the competitive growth of multiple strains of Escherichia coli. RESULTS: Simulation studies showed that sequential use of tetracycline and ampicillin reduced the level of double resistance, when compared to the combination treatment. The effect of the cycling frequency (how frequently antibiotics are alternated in a sequential treatment) of the two drugs was dependent upon the order in which the two drugs were used. CONCLUSION: Sequential treatment was more effective in preventing the growth of resistant strains when compared to the combination treatment. The cycling frequency did not play a role in suppressing the growth of resistant strains, but the specific order of the two antimicrobials did. Predictions made from the study could be used to redesign multidrug treatment strategies not only for intramuscular treatment in pigs, but also for other dosing routes.

Pharmacokinetic-pharmacodynamic model to evaluate intramuscular tetracycline treatment protocols to prevent antimicrobial resistance in pigs.

High instances of antimicrobial resistance are linked to both routine and excessive antimicrobial use, but excessive or inappropriate use represents an unnecessary risk. The competitive growth advantages of resistant bacteria may be amplified by the strain dynamics; in particular, the extent to which resistant strains outcompete susceptible strains under antimicrobial pressure may depend not only on the antimicrobial treatment strategies but also on the epidemiological parameters, such as the composition of the bacterial strains in a pig. This study evaluated how variation in the dosing protocol for intramuscular administration of tetracycline and the composition of bacterial strains in a pig affect the level of resistance in the intestine of a pig. Predictions were generated by a mathematical model of competitive growth of Escherichia coli strains in pigs under specified plasma concentration profiles of tetracycline. All dosing regimens result in a clear growth advantage for resistant strains. Short treatment duration was found to be preferable, since it allowed less time for resistant strains to outcompete the susceptible ones. Dosing frequency appeared to be ineffective at reducing the resistance levels. The number of competing strains had no apparent effect on the resistance level during treatment, but possession of fewer strains reduced the time to reach equilibrium after the end of treatment. To sum up, epidemiological parameters may have more profound influence on growth dynamics than dosing regimens and should be considered when designing improved treatment protocols.

Mean effective sensitivity for Mycobacterium avium subsp. paratuberculosis infection in cattle herds.

BACKGROUND: Mycobacterium avium subsp. paratuberculosis (MAP) infections in cattle are generally challenging to detect and cost-effective test strategies are consequently difficult to identify. MAP-specific antibody ELISAs for milk and serum are relatively inexpensive, but their utility is influenced by a number of factors such as herd size, herd composition and diagnostic sensitivity. The sensitivity of the test increases with the age of the tested animal, and therefore the general, or "mean effective sensitivity" (defined as the mean of the sensitivities for all animals within a population, MES), for detecting MAP within a herd is dependent upon the age distribution of the herd. For this study we used a dataset of cattle from 4,259 dairy herds and 4,078 non-dairy herds. The aim was to investigate the MES for groups of cattle considered to be reasonable entities for MAP surveillance and control, in order to assist the decision-makers in planning and optimizing these programs economically. We compared six different groups of cattle (three dairy and three non-dairy) in Denmark by calculating the MES for each herd in each group. RESULTS: The distribution of MES showed a large variation within and between groups, and in some groups we found a bimodal distribution of MES. Dairy herds generally showed higher MES than non-dairy herds. Dairy herds in a control programme for paratuberculosis showed a MES similar to all other dairy herds from which animals > 2.0 years were tested (both groups had a median MES = 0.60). For the non-dairy groups, the sensitivity became much higher when animals < 2.0 years and herds with less than 25 cattle were excluded, resulting in a median MES of 0.65. CONCLUSION: The results showed that MES could indicate the effectivity of testing different cattle groups for MAP, given that the data used are unbiased.

The thermodynamics of general and local anesthesia.

General anesthetics are known to cause depression of the freezing point of transitions in biomembranes. This is a consequence of ideal mixing of the anesthetic drugs in the membrane fluid phase and exclusion from the solid phase. Such a generic law provides physical justification of the famous Meyer-Overton rule. We show here that general anesthetics, barbiturates, and local anesthetics all display the same effect on melting transitions. Their effect is reversed by hydrostatic pressure. Thus, the thermodynamic behavior of local anesthetics is very similar to that of general anesthetics. We present a detailed thermodynamic analysis of heat capacity profiles of membranes in the presence of anesthetics. Using this analysis, we are able to describe experimentally observed calorimetric profiles and predict the anesthetic features of arbitrary molecules. In addition, we discuss the thermodynamic origin of the cutoff effect of long-chain alcohols and the additivity of the effect of general and local anesthetics.

Digital twin simulation modelling shows that mass testing and local lockdowns effectively controlled COVID-19 in Denmark.

BACKGROUND: Following the COVID-19 pandemic, it is important to evaluate different mitigation strategies for future preparedness. Mass testing and local lockdowns were employed during the Alpha wave in Denmark, which led to ten times more tests than the typical European member state and incidence-based restrictions at the parish level. This study aims to quantify the effects of these interventions in terms of hospital admissions and societal freedom. METHODS: This study assesses the effectiveness of these strategies via counterfactual scenarios using a detailed, individual-based simulation model that replicates the entire Danish population. The model considers multiple factors, including evolving societal restrictions, vaccination roll-out, seasonal influences, and varying intensities of PCR and antigen testing across different age groups and degree of completed vaccination. It also integrates adaptive human behavior in response to changes in incidences at the municipality and parish levels. RESULTS: The simulations show, that without mass testing in Denmark, there would have been a 150% increase in hospital admissions, and additional local lockdowns equivalent to 21 days of strict national lockdown. Without the policy of local lockdowns, hospitalizations would have increased by 50%. CONCLUSIONS: In conclusion, the combination of mass testing and local lockdowns likely prevented a large increase in hospitalizations while increasing overall societal freedom during the Alpha wave in Denmark. In future epidemics, mass testing and local lockdowns can likely prevent overwhelming healthcare systems in phases of high transmission and hospitalization risks.

This study looked at how Denmark handled the COVID-19 pandemic, specifically focusing on mass testing and local lockdowns during the Alpha-wave. Compared to other European countries, Denmark conducted ten times more tests and implemented restrictions at the parish level based on local incidence. Using a detailed simulation model, the researchers explored what would have happened without these measures. Without mass testing, hospital admissions would have increased by 150%, and without local lockdowns, they would have gone up by 50%. Furthermore, mass testing prevented 21 days of strict national lockdown. In essence, mass testing and local lockdowns in Denmark prevented a substantial rise in hospitalizations while allowing more overall societal freedom. This highlights the importance of these strategies for future pandemic preparedness.

The ALEX algorithm - estimating average lifetime antimicrobial exposure of danish slaughter pigs in a fast, automated and robust way.

Calculating and estimating antimicrobial exposure at specific batch level is key to understanding consumption patterns of antimicrobials in the Danish pig sector. Understanding consumption and trading patterns can assist in developing treatment plans at national levels and might lead to reducing antimicrobial resistance levels. The ALEX algorithm is a fast, automated and robust algorithm developed to estimate the average lifetime antimicrobial exposure of Danish slaughter pigs. The algorithm estimates antimicrobial exposure in the different life stages of the pig (piglet, weaner and finisher) together with the type of production network (the number of farms within a network and ownership of these). We present the algorithm and give two examples of usage. Furthermore, we compare the ALEX algorithm with an acknowledged exposure estimation algorithm, and we present a sensitivity analysis.

Seasonal variation in the transmission rate of covid-19 in a temperate climate can be implemented in epidemic population models by using daily average temperature as a proxy for seasonal changes in transmission rate.

From march 2020 to march 2022 covid-19 has shown a consistent pattern of increasing infections during the Winter and low infection numbers during the Summer. Understanding the effects of seasonal variation on covid-19 spread is crucial for future epidemic modelling and management. In this study, seasonal variation in the transmission rate of covid-19, was estimated based on an epidemic population model of covid-19 in Denmark, which included changes in national restrictions and introduction of the α -variant covid-19 strain, in the period March 2020 - March 2021. Seasonal variation was implemented as a logistic temperature dependent scaling of the transmission rate, and parameters for the logistic relationship was estimated through rejection-based approximate bayesian computation (ABC). The likelihoods used in the ABC were based on national hospital admission data and seroprevalence data stratified into nine and two age groups, respectively. The seasonally induced reduction in the transmission rate of covid-19 in Denmark was estimated to be 27 % , (95% CI [ 24 % ; 31 % ]), when moving from peak Winter to peak Summer. The reducing effect of seasonality on transmission rate per + 1 ∘ C in daily average temperature were shown to vary based on temperature, and were estimated to be - 2.2 % [ - 2.8 % ; - 1.7 % ] pr. 1  ∘ C around 2 ∘ C; 2 % [ - 2.3 % ; - 1.7 % ] pr. 1  ∘ C around 7 ∘ C; and 1.7 % [ - 2.0 % ; - 1.5 % ] pr. 1  ∘ C around a daily average temperature of 11  ∘ C.

Transmission Dynamics of Corynebacterium spp. Within Two Danish Dairy Cattle Herds.

Intramammary infections (IMI) can cause mastitis, a prevalent and costly infectious disease in dairy cattle worldwide. The IMI is caused by a range of bacteria, including Corynebacterium spp. Knowledge of the transmission dynamics of pathogens is generally sparse but essential to support decision-making; such as input to bioeconomic models. In this observational study, we explored the transmission dynamics of Corynebacterium spp. in two different Danish dairy cattle herds by testing monthly quarter-level milk samples of all lactating cows for 1 year. We estimated the prevalence for herd 1 and 2 to 24 and 11.7%, respectively, and the mean quarter-level incidence to be 8 and 6.5% per month, respectively. We compared a model for indirect transmission via the environment with a model with the direct contagious transmission and found that the latter model best explained the data. We estimated the daily mean quarter-level transmission rate to be 0.016 and 0.018 cases/quarter-day for herd 1 and 2, respectively. The mean recovery rate was 0.012 and 0.016 for herd 1 and 2, respectively. Consequently, the basic reproduction number for herd 1 and 2 was 1.27 and 1.10, respectively. This study highlights that Corynebacterium spp. can be prevalent within a herd and transmit directly between cows. Thus, future studies should investigate cost-effective control measures against Corynebacterium spp.

Mixed effect modeling of tetracycline resistance levels in Danish slaughter pigs.

Mathematical and statistical modeling can be a very useful tool in understanding and fighting antimicrobial resistance (AMR). Here we present investigations of mixed effect models of varying complexity in order to identify and address possible management factors affecting the tetracycline AMR levels in Danish pig farms. Besides antimicrobial exposure during pigs life cycle, the type of production seems to also have an influence. The results concludes that not only fully integrated farms (CHR integrated) but also farms in a production network with a single ownership (CVR integrated) might have a preventive effect on levels of tetracycline AMR compared to more complex trading patterns.

Advances in automatic identification of flying insects using optical sensors and machine learning.

Worldwide, farmers use insecticides to prevent crop damage caused by insect pests, while they also rely on insect pollinators to enhance crop yield and other insect as natural enemies of pests. In order to target pesticides to pests only, farmers must know exactly where and when pests and beneficial insects are present in the field. A promising solution to this problem could be optical sensors combined with machine learning. We obtained around 10,000 records of flying insects found in oilseed rape (Brassica napus) crops, using an optical remote sensor and evaluated three different classification methods for the obtained signals, reaching over 80% accuracy. We demonstrate that it is possible to classify insects in flight, making it possible to optimize the application of insecticides in space and time. This will enable a technological leap in precision agriculture, where focus on prudent and environmentally-sensitive use of pesticides is a top priority.

Prediction Models in Veterinary and Human Epidemiology: Our Experience With Modeling Sars-CoV-2 Spread.

The worldwide outbreak of Sars-CoV-2 resulted in modelers from diverse fields being called upon to help predict the spread of the disease, resulting in many new collaborations between different institutions. We here present our experience with bringing our skills as veterinary disease modelers to bear on the field of human epidemiology, building models as tools for decision makers, and bridging the gap between the medical and veterinary fields. We describe and compare the key steps taken in modeling the Sars-CoV-2 outbreak: criteria for model choices, model structure, contact structure between individuals, transmission parameters, data availability, model validation, and disease management. Finally, we address how to improve on the contingency infrastructure available for Sars-CoV-2.

Evolution of TEM-type extended-spectrum ß-lactamases in Escherichia coli by cephalosporins.

OBJECTIVES: This study was conducted to examine the molecular mechanisms responsible for the evolution of TEM-type extended-spectrum ß-lactamases (ESBLs) following selective pressure from four third-generation cephalosporins, namely ceftazidime, cefotaxime, ceftriaxone and ceftibuten. In addition, selective enrichment for ESBL detection in environmental samples was investigated. METHODS: Using experimental evolution, resistant variants were isolated and mutations in TEM-1 were examined by DNA sequencing. Resistance levels and the development of cross-resistance were determined for ESBL-producing isolates by Etest and disk diffusion assay. Selective plating with or without prior growth in selective broth was used to examine the approach of selective enrichment for ESBL detection. RESULTS: The third-generation cephalosporins ceftazidime, cefotaxime and ceftriaxone selected for ESBLs, whereas ceftibuten did not. All ESBL variants additionally remained susceptible to ceftibuten. DNA sequencing of the TEM-1 coding sequence of mutants revealed mutations not previously isolated through selection. This indicates that the potential for ESBL evolution is much broader than can be inferred from sequence analysis of clinical samples alone. The results also indicate that selective enrichment for enhanced detection of ESBL-producers may give unreliable results owing to the selection of spontaneous mutations in narrow-spectrum ß-lactamases resulting in TEM-type ESBL-producers. CONCLUSION: These results help explain the molecular changes responsible for evolution of TEM-type ESBLs and meanwhile question the appropriate use of selective enrichment for detection of ESBLs in environmental samples.

Continuing occurrence of vancomycin resistance determinants in Danish pig farms 20 years after removing exposure to avoparcin.

Vancomycin-resistant Enterococcus spp. is a major health problem worldwide and livestock have been implicated in constituting a reservoir for the transmission of vancomycin resistance to zoonotic pathogens. Vancomycin resistance determinants can be situated on mobile genetic elements and transferred between bacterial species The livestock reservoir must therefore be included in a risk assessment of the vancomycin resistance burden. Avoparcin, a vancomycin analogue, has not been used in Danish pig production for over 20 years and vancomycin has never been used. The objective of this study was to screen faecal samples from Danish pig farms for nine selected vancomycin resistance determinants. We found at least four different vancomycin resistance determinants in all screened Danish pig farms (665 finisher farms and 78 sow farms). The vancomycin resistance determinants present in vanB or vanG clusters were found at significantly different levels in sow and finisher farms. However, vanA was not detected in any of the farms. In conclusion, vancomycin resistance determinants are still present in Danish pig production 25 years after the ban on avoparcin use.

Evaluating the impact of transmission mode, calibration level and farmer compliance in simulation models of paratuberculosis in dairy herds.

Simulation models can predict the outcome of different strategies for the control and eradication of paratuberculosis (PTB) in dairy herds. Two main transmission modes have previously been used to simulate the spread of PTB: direct (contact between animals) and indirect (through the environment). In addition, previous models were calibrated to either low or high within-herd prevalence levels, which we refer to as normal and low hygiene levels, respectively. We simulated both direct and indirect transmission with the same model in both normal and low hygiene level scenarios. The effectiveness of a test-and-cull strategy was dependent on the calibration level of the simulation model, and eradication occurred less frequently with the more biologically plausible indirect transmission mode. The results were compared to within-herd prevalence records from 314 dairy herds. The prevalence in 50% of the herds varied less than 0.9% per year on average, and less than 4% in 90% of the herds. We therefore conclude that the normal-hygiene scenario best describes most dairy herds in Denmark. Finally, we simulated different levels of farmer compliance with a test-and-cull strategy and found that a 60% compliance level was not sufficient to reach eradication within 10 years.