ASSESSMENT OF ANTIMICROBIALS USAGE IN COMMERCIAL FARROW-TO-FINISH PIG HOLDINGS IN VOJVODINA REGION (SERBIA)

Antimicrobial use is considered to be the highest in pig production as compared with other animal husbandry sectors. In Serbia, antimicrobials have wide application at pig farms as therapeutic but also as a prophylactic treatment. Th e aim of the research study was the assessment of antimicrobial usage in diff erent stages of pig production in commercial farrow-to-fi nish pig holdings located in Vojvodina Province (Serbia). A total of eleven pig holdings located in the Vojvodina Province were included in this research. All investigated herds were single site farrowto-fi nish production systems with minimum of 300 sows in the site. Th e data on prophylactic and therapeutic measures on the investigated farms were obtained from offi cial farm treatment records provided by the veterinarians and/or farmers. Th e antimicrobials usage on pig farms was recorded by product, administration route and animal production category. Th e analysis of recorded data revealed that diff erent types of antimicrobials from almost all groups were applied. Breeding pigs (sows, boars) received less treatment as compared to growing categories. As regards the types of antimicrobials, frequent use of cephalosporins and polymyxins in growing piglets was detected. Th e group treatments were mostly preventive and the administration of an antimicrobial oft en lacked a precise previous diagnosis. Administration of high amounts of macrolides and pleuromutilins (tiamulin), quite oft en in combination with tetracyclines in the fattening stage was noticed. In conclusion, signifi cant level of prophylactic antimicrobial treatments in farrow-tofi nish pig farms in Serbia is evident. Th e present study was initiated as a fi rst step for comparing antimicrobial usage on herd level using available data.


INTRODUCTION
In the past, antimicrobial usage (AMU) in animal husbandry was frequently aimed at therapeutic but also at preventive treatment (McEwen and Fedorka-Cray, 2002). However, since recently, AMU in livestock systems has been associated with the problem of antimicrobial resistance (AMR) (Raasch et al., 2020). Th e ban of AMU as growth promoters was applied by the European Union (EU) in 2006 (Diana et al., 2019;Raasch et al., 2018). Pursuant to legal directives, continuous monitoring of AMR is performed in EU member countries (Echtermann et al., 2019). Today, the problem of AMR is considered one of the major global threats for the future as it undermines the possibility to eff ectively treat bacterial diseases in both humans and animals. Resistant bacteria that emerge among food producing animals can spread to humans, along the food production chain and in the environment (Silbergeld et al., 2008;Baquero, 2011), so reduction of AMU is therefore essential (Raasch et al., 2018). However, prophylactic AMU is still present in many countries in order to sustain animal health and welfare Diana et al., 2019).
Pig production is considered to be amongst the animal husbandry sectors with the highest AMU (Callens et al., 2012;Collineau et al., 2017). Prophylactic AMU aimed at preventing infections is a common practice on pig farms, especially during stressful periods for some categories (Prodanov-Radulović et al. . As compared to a multi-site production systems, farrow-to fi nish swine farms off er more supporting environment for interactions between pathogens, environment and management (Savić et al., 2015;Prodanov-Radulović et al., 2020). Th e aim of the research was the assessment of AMU in diff erent stages of pig production in commercial farrow-to-fi nish pig holdings located in Vojvodina Province (Serbia).

MATERIAL AND METHODS
Eleven pig holdings located in the Vojvodina Province were included into this research. To meet the criteria to be included in the study, the herds had to be single site farrow-to-fi nish production systems with minimum 300 sows in the site. All selected pig farms had their own veterinary service or at least one full-time veterinarian. Basic production characteristics were common to the majority of selected farrow-to-fi nish farms, i.e., the piglets were weaned at the age of 28-35 days, and then transferred to a weaning, and later to growing and fattening units. Herd visits took place between January 1 and November 30, 2019. During the herd visits, detailed data about AMU in all categories were collected. All herds were examined by the same investigator according to a standardized protocol. Th e data on prophylactic and therapeutic measures on the investigated farms were obtained from offi cial farm treatment records provided by the veterinarians and/or farmers. Th e following details were ascertained from farm records: number and category of pigs in the unit, production details, disease status and current veterinary health plan. Th e veterinarians were required to allocate the AMU to fi ve diff erent production groups in farrow-to-fi nish production: sows, boars, suckling and weaned piglets, fatteners. Based on the available records, the AMU on pig farms was recorded by product, administration route and production category.

RESULTS
Th e data on the frequency of certain AMU according to the production categories: sows, boars, suckling and weaned piglets, fattening pigs were collected and analyzed. Prophylactic AMU in sows was most commonly based on a combination of lincomycin hydrochloride and spectinomycin sulphate (12.06%) but also combination of tiamulin hydrogen fumarate and oxytetracyclin (10.34%) (Figure 1). According to farm production data, appropriate powdered forms of these antimicrobials were mostly used in the period of late pregnancy, i.e., 7 to 14 days before farrowing. As regards the therapeutic treatment of sows, preparations of procaine benzyl penicillin and dihydrostreptomycin sulphate (15.51%) administered parenterally were used. Most fre-quently, they were administered in the fi rst 3 days aft er parturition in order to prevent puerperal infections and possible health complications. Also, the sows were frequently treated with tiamulin hydrogen fumarate and oxytetracyclinebased preparations in the form of dehydrate (13.79%). In all examined pig farms, there was no standard antimicrobial prophylactic protocol for breeding boars. Th e therapeutic treatment of boars was mainly applied in accordance with established clinical picture and relevant disease diagnosis. Th e combinations of tiamulin hydrogen fumarate and doxycycline hydrochloride (22.22%), as well as tiamulin hydrogen fumarate as the sole substance were most commonly administered in the therapy. Th e parenteral use of oxytetracycline dihydrate, fl uorophenicol and enrofl oxacin has also been reported ( Figure 2).   (12), Gentamicin sulphate (13) and Sulfadimidine + oxytetracycline hydrochloride + neomycin sulphate (14).
In sucklings, prophylactic treatment mostly included application of watersoluble colistin sulfate (13.51%). However, prophylactic usage of commercial preparations containing at the same time more than one active substances was established. Parenteral application involved the administration of a number of diff erent AMs, most frequently cefquin sulphate-based preparations (Figure 3).
In the category of weaned piglets, in the period just before or aft er the piglets are weaned, per os administration of amoxicillin trihydrate was frequently detected (14.89%). In the therapeutic treatment of weaned piglets, the combination of trimethoprim-sulfametoxasol was dominant (18.63%) followed by fl orfenicol (14.89%) and enrofl oxacin (Figure 4). In fattening pigs, tiamuline hydrogen fumarate-based preparations, alone or in combination with doxycycline hydrochloride, as well as the administration of oxytetracycline in the form of dihydrate were dominant in the prophylaxis. In the therapy of fatteners, oxytetracycline in the form of dihydrate and fl orfenicol were most frequently the antimicrobials of the fi rst choice ( Figure 5).

DISCUSSION
Th e analysis of recorded data in farrow-to-fi nish pig holdings revealed that AMU was common practice during all production phases, i.e., diff erent types of antimicrobials from almost all groups were applied. Th e selected holdings are situated in Vojvodina Province, where majority of commercial pig production takes place, indicating that the obtained results gave a good insight into AMU in pig production in Serbia. Breeding pigs (sows, boars) received less treatment as compared to growing categories. According to the farmers, the aim of prophylactic treatment of sows was preventing the occurrence of disorders in late pregnancy and potential gastrointestinal infections in newborns. During other phases of sow production, AMU depended on the overall health status and/or current health issues, for instance respiratory and /or reproductive infections, lameness etc. In all examined herds, no preventive treatments of boars were reported, and, this was also the category with the lowest overall AMU. Contrary to that, suckling and weaned pigs received the most of the treatments. In newborns and at weaning, antimicrobials were commonly administered orally, as prophylactic group-treatments aimed at preventing diarrhea.
Group-level treatments are the common way of AMU in pig production. Th e majority of these treatments are prophylactic, administered to groups of pigs at critical time-points in production such as weaning (Callens et al., 2012;Corinne et al., 2016). Based on the experience, most farmers recognize the critical time points, when their pigs get ill (Raasch et al., 2018). Indeed, on all evaluated pig farms, the weaning period was indicated as the period when signifi cant health problems were notifi ed (diarrhea caused by Escherichia coli, infections with Streptococcus suis, respiratory infections). Th e process of weaning introduces a number of stress factors that may infl uence the immune function and intestinal microfl ora of weaned pigs. Th ese disturbances might challenge the risk of diff erent enteric disorders (Sjolund et al., 2016). According to Postma et al. (2016) a higher weaning age was associated with a lower necessity for AM therapy.
Th e pig industry uses more antimicrobials than any other livestock sector, especially during the weaning period, when pigs face several challenges and stressors including changes in the diet, separation from the sow and re-mixing. Th e practice of prophylactic AMU to a group is a way of reducing the risk of disease in weaned pigs. However, excessive use or misuse of broad-spectrum AM poses a serious threat for public health (Diana et al., 2019). Group treatment represented the most common way to treat growing pigs in the herds at strategic time points when pigs were prone most likely to contract disease (Sjolund et al., 2016). In our study, commercial in-feed medication was recorded in all participating farms. Indeed, in Vojvodina Region, feed mills frequently have the manufacturing authorization to produce commercial in-feed medication (Došen et al., 2014). Th is method of AMU in Serbia is still frequent, despite being almost obsolete in some EU countries (Echtermann et al., 2019). In-feed medication is ideal for prophylactic use, but once pigs get clinically ill, in-feed medication can be ineff ective. A properly functioning water supply is an ideal route for mass medication of pigs (Došen et al., 2014).
As regards the antimicrobials considered especially critical to human medicine (Callens et al., 2012;Sjolund et al., 2016), we established a relatively frequent use of cephalosporins in growing pigs. In most EU countries, the use of cephalosporins in pigs has been highly regulated or even banned (Echtermann et al., 2019). According to our research results, frequent application of polymyxins (colistin) is particularly worrying because reduction of its use is highly recommended. Moreover, guidelines explicitly state that colistin is a last-resort drug in human medicine, which should not be used as a substitute for good management practices (Sjolund et al., 2016). Frequent use of polymixins indicates that diarrhea still continues to be a major challenge in pig production (Prodanov-Radulović et al., 2015b).
Th e group-treatments in fattening stage were mostly of preventive nature and oft en lacked a precise previous diagnosis. High amounts of macrolides and pleuromutilins, quite oft en in combination with tetracyclines were observed in this age group. Farmers reported that fattening pigs were commonly treated for respiratory disorders. However, therapeutic treatments of individual pigs were not always recorded, and it was diffi cult to obtain reliable retrospective information on the therapeutic AMU in fatteners. According to the results of previous study (Prodanov-Radulović et al., 2014b; Prodanov-Radulović et al., 2020), swine dysentery and respiratory infections were most frequently diagnosed during the fattening stage.
It is suggested that improved biosecurity in pig farming could lead to a better health status and thus to a reduced AMU (Laanen et al., 2013). Th e correct management of diseased animals results in a lower risk of within-herd spread of infection, which in turn leads to reduced infection pressure and a mitigation of AMU (Callens et al., 2012;Collineau et al., 2017). Having in mind the obtained results, and in order to successfully reduce AMU, on-farm action is needed. It is obvious that current farrow-to-fi nish production systems provide more opportunities for multiple interactions between pathogens, as compared to multi-site production systems ( Commercial pig production in Serbia implies classical, old-type farrowto-fi nish farm structure (Došen et al., 2014;Prodanov-Radulović et al., 2020) and there is no central AMU database that could be used to set benchmarks for antimicrobial consumption. Having in mind the results of our previous epidemiological survey (Prodanov-Radulović et al., 2018), a biosecurity guidance for pig holdings should be created with the aim of upgrading biosecurity measures and therefore improving pig health resulting in the decrease of AMU.

CONCLUSION
Signifi cant level of AMU in farrow-to-fi nish pig farms in Serbia in prophylactic treatments is evident. Development of a national program for monitoring of AMU is highly required. Moreover, initiation of control and regula-tion measures for prescription and distribution of antimicrobials coupled with farmers' education is of crucial importance.