**2. Usage of antimicrobials in dairy cattle production**

Antimicrobials are one of the modern interventions utilize by veterinarians and farmers to improve animal health and also the quality of animal products. The usage of antimicrobials has significantly ameliorated the well-being of animals, which results in better health and higher productivity of the animals [15]. In dairy cattle production, the usage of antimicrobials is highly indicated, mostly in treating diseases affecting the dairy cattle, such as mastitis. Besides disease treatment, antimicrobials have also been used to prevent diseases and promote growth in the dairy cattle production [16, 17].

### **2.1 Treatment and disease prevention in dairy cattle**

Bovine mastitis, usually caused by *Staphylococcus aureus*, is the most commonly treated diseases in dairy cattle. In fact, it has become the biggest consumers of antimicrobials in dairy cattle production due to its massive economic impact to the industry [18]. In UK dairy cattle production, an annual loss of €9.03 billion or an average of €279 per case was reported due to summer mastitis, a type of mastitis that occurs during the warmer months [19]. Meanwhile, the total economic cost is much higher in US dairy, which is \$444 for an average mastitis case [20]. There are a few costs that contribute to the economic impacts due to mastitis such as milk production losses, drug treatments and diagnoses, discarded milk, culling and also labour costs, but production losses are the major constituent of the economic impact of mastitis [21, 22]. Clinical mastitis and subclinical mastitis can result in significant milk production losses, but subclinical mastitis has a higher prevalence and it is difficult to estimate its economic impacts due to the variability in case definition and screening intensity [20, 23]. Clinical mastitis can be identified based on the clinical examination on dairy cattle for local or systemic signs of mastitis such as swelling and redness of the udders or abnormal milk secretions. It is harder to characterize subclinical mastitis as milk secretions are not visually abnormal, thus it is usually diagnosed based on the inflammatory markers and somatic cell counts in the milk. Antimicrobial treatment of mastitis in dairy cattle depends on the etiology of the disease. Appropriate antimicrobials such as β-lactams like penicillin and third-generation cephalosporin, aminoglycosides like amikacin and gentamicin, and fluoroquinolones are used in treating mastitis. Dairy cattle mastitis has been more susceptible to a wide range of antimicrobials and less prone for the selection pressure of AMR than the same isolates in humans. This is due to the use of intra-mammary infusion treatment compared to the conventional parenteral treatment with the former has a limited bacterial exposure and the later has a huge risk of exposing the infected udder to other bacteria from a different environment [18]. Besides, the blood-milk barrier in bovine udder also limits the distribution of specific antimicrobials away from the infected sites [18], thus preventing bacterial selective pressure to occur in other sites. Besides mastitis, endometritis is another disease that affects dairy cow which requires antimicrobial treatment occasionally. Bovine endometritis is a post-partum uterine disease that affects the uterine endometrium. It can also be classified into clinical and subclinical cases by evaluating the vaginal mucus using an intravaginal device followed by a scoring system for clinical endometritis [24], and the proportion of polymorphonuclear leucocyte in the endometrial cytological slide, with >5% of cells will be characterized as subclinical endometritis [25], respectively. It has a detrimental effect to the economics due to the reduced reproductive performance in diseased cattle [25]. Generally, a broad spectrum antibiotic therapy will be chosen to fight against the main pathogens that cause bovine endometritis, such as *Actinobacillus pyogenes* and some Gram-negative

anaerobes. Intrauterine cefapirin and oxytetracyclines can be used in endometritis for its good penetration to the endometrium.

However, sometimes the usage of antimicrobials in infected dairy cattle can be too late to treat the infected cattle back to health. Cases of subclinical mastitis will not be clinically obvious to detect, thus missing the right timing to administer antimicrobials to get rid of the pathogens. Besides, some dairy cattle that recovered completely from subclinical mastitis with antimicrobials can still have a low milk production and not increase for years [26]. Therefore, it is always better to prevent a disease from occurring in the herd rather than treating it. It is also rational to do so because it reduces the economic losses due to mastitis. Prevention use or prophylactic use of antimicrobials in dairy cattle refers to the administration of antimicrobials in healthy dairy cattle considered to be at risk, before the onset of any infectious diseases. The dairy cattle production in the USA has more than 90% of dairy farmers practised dry cow therapy at the end of lactation on the dairy cattle to prevent intra-mammary infections during the dry period [27]. The application of antimicrobials shows a significant reduction in the rate of intra-mammary infections during the dry period [27, 28]. Furthermore, antimicrobials can also be used for control treatment, also known as metaphylaxis, to prevent the spread of disease in the dairy cattle. It is usually given as a mass treatment to the healthy groups when part of the group is diagnosed with clinical disease, to prevent disease progression and spread in the herd. Conclusively, antimicrobials play an important role in the treatment, prevention and control of disease in dairy cattle production.

#### **2.2 Growth promotion in dairy cattle**

Growth promoters are any substances given to animals as supplements or nutrients to enhance their growth rate, without the specific intention of treating, preventing or controlling diseases. They were once used widely and uncontrollably in the food-producing animal industry like in dairy cattle production [29]. The growth-promoting effect of antimicrobials was discovered back in the 1940s when experimented chickens showed promising signs of growth after feeding with fermentation by-products of penicillin and streptomycin [30]. The practice of using antimicrobials then becomes widespread in the food-producing animal industry for the eagerness of farmers to obtain high profits in a shorter time by maximizing animal growth rates. In dairy cattle production, antimicrobials are used as feed additives in dairy cattle to enhance their digestive tract activity. Antimicrobials suppress competitive microorganism in the digestive tract that competes nutrients with the host or produces undesirable toxic substances to the host. This provides an optimum environment in the digestive tract of the dairy cattle that allows them to absorb all the food intake completely and effectively. The increase in nutrient utilization thus enhances the growth rate of dairy cattle. However, the public health concern about the usage of antimicrobials as growth promoters rises as prolonged use of antimicrobials increases the risk of AMR. To prevent AMR from jeopardizing the future of human medicine, many countries have taken action to reduce or ban the usage of antimicrobials as growth promoters in animals. Sweden became the first country to ban all usage of growth-promoting antimicrobials in food-producing animals in 1986 after the recommendations of the UK Swann Commission regarding the prohibition of antimicrobials as animal growth promoters in 1969. In 1997, the use of avoparcin was prohibited in the EU as evidence showed the use of avoparcin, a glycopeptide, closely related to vancomycin causes selection of the resistance gene (VanA). The EU further prohibited all use of antimicrobials for growth-promoting benefits in animals in 2006 in order to control the emergence of AMR.

The prohibition of antimicrobial usage for growth promotion in food-producing animals still remains a controversial debate [31–33]. It is still unconvinced about the potential issue of AMR from using antimicrobials as growth promoters in animals because the dose used is small than the therapeutic dose to select for resistance [33]. On the other hand, there are also some opinions about the prohibition on growth promoters that might actually increase the prophylactic usage of antimicrobials as some users might try to "play with the rules" [4].
