Antibiotics are agents that either kill or inhibit the growth of microorganisms, including substances produced by microorganisms and synthetic antibacterial compounds. The first antibiotic, penicillin, was discovered by the Scottish scientist, Alexander Fleming, in 1928, for which he shared the Nobel Prize in 1945 [1]. Antibiotics then became the first treatment for life-threatening infections caused by bacteria in humans. Severe protein feed shortages plagued American farmers from the early part of the twentieth century until the end of World War II, and low growth rates and feed efficiency led to meat shortfalls and high prices. In 1950, American farmers rejoiced at news from a New York laboratory: a team of scientists had discovered that adding antibiotic to livestock feed accelerated the animals’ growth and cost less than conventional feed supplements [2]. However, different antibacterial agents had different stimulating effects on pig gain rates. Especially, the effect of antibiotics on growth rate and intestinal flora were different in swine [3]. Since then, antibiotics have become an integral part of animal feeding programs, particularly in the pork and poultry industries. More than 1,000 experiments were conducted in the US between 1950 and 1985. Summarizing the results, they found that antibiotics were the most effective agents for improving growth and feed efficiency in young pigs, as well as the entire growing-finishing period, and reducing mortality and morbidity, particularly in young pigs. The mortality rate can be twofold higher under farm conditions than in a research station environment where the facilities are generally cleaner, the disease load is lower, and the environment is less stressful [4].

The natural weaning process of piglets is gradual and occurs at about 2 to 3 months of age. Weaning represents a shift from the piglet’s reliance on the sow’s milk to other food sources. However, in most developed countries and some developing countries, weaning is abruptly terminated early in life at 19 to 25 days of age. Early weaned piglets have to be reared artificially. Early weaning has been adopted to increase the reproductive efficiency of the sows, particularly with regard to maximizing the sows’ litter size at birth and maximizing the number of sows that deliver each year, followed by the successful rearing of early weaned piglets. However, early weaning occurs at a time when there are marked changes in the piglets’ intestinal structure and function, such as villous atrophy and crypt hyperplasia, which are generally associated with poor performance, as they are thought to cause a temporary decrease in the digestive and absorptive capacity of the small intestine [5]. Weaned piglets must rapidly adapt to dramatic changes in the social and physical environments, separation from maternal littermates, mixing with unfamiliar piglets, abrupt changes in diet from suckling the dam to ingesting solid feed from a feeder, and establishing a social hierarchy. Consequently, early weaning is very stressful for piglets. Studies have shown that the weaning process has deleterious effects on intestinal mucosal health, highlighted by increased intestinal permeability and agonist-stimulated secretory responses. Diarrhea is the nemesis of the early weaned piglet. Enteropathogens infect the small intestine, which results in secretory or malabsorptive diarrhea. High death losses from diarrhea have dampened the enthusiasm for early weaning of artificially reared piglets. Usually, the nursing piglet is protected from enteropathogens by antibodies bathing the gut from the dam’s colostrum and milk. Artificially reared early weaned piglets are protected from enteropathogens by feeding them diets containing additives, such as antibiotics. In addition, adding an antibiotic to the feed results in significant growth performance and improves food conversion rate. Antibiotic trials conducted by the Agricultural Research Council of Britain [1] indicated that Aureomycin and penicillin improve the growth performance and food efficiency of pigs by 10%. Most countries have begun to regulate finisher feeds containing antimicrobial agents because of residual antibiotics.

However, after more than 70 years of using antibiotics as supplements, there is worldwide concern that antimicrobial resistance has made drugs used to treat human disease less effective. Statistics indicate that between 1970 and 2000, the majority of pig diets (70% to 80% of starters, 70% to 80% of growers, and 50% to 60% of finisher feeds) contained antimicrobial agents [6]. About 13,000 tons of antibiotics were administered to animals in 2010 to promote growth of livestock in the USA [7]. In Japan, 175 tons of antibiotics were administered to promote growth of livestock in 2001. In 2007, China produced 210,000 tons of antibiotics and administered 97,000 tons to animals for promoting growth. Zhu et al assessed the type and concentrations of antibiotic resistance genes (ARGs) at three stages of manure processing in land disposal at three large-scale (10,000 animals per year) commercial swine farms in China [8]. In-feed or therapeutic antibiotics used on these farms included all major classes of antibiotics except vancomycin. They detected 149 unique ARGs among all of the farm samples; the top 63 ARGs were enriched 192-fold (median) to 28,000-fold (maximum) compared with their respective antibiotic-free manure or soil controls. This review will discuss the advantages and disadvantages of antibiotic feed additives with regard to pork production and possible substitutes as an alternative to antibiotics in pork production.

The above discussion shows that antibiotics are the most effective at improving the growth and efficiency of young pigs. In 1950, American farmers rejoiced at the news that scientists had discovered that adding antibiotics to livestock feed accelerated animal growth and cost less than conventional feed supplements [2]. Since that time, antibiotics have provided great benefits to pork producers for several decades. However, warnings about bacterial resistance have overshadowed the benefits. The consumption of antibiotics in the pig industry will increase dramatically as the human population increases. This means that more antibiotic resistant bacteria will arise and spread among animals and the environment and cause more human disease.

The mechanism used by antibiotics to promote growth involves the ability to suppress or inhibit the growth of certain microorganisms. The direct effects of antibiotics in promoting growth can be explained by decreased competition for nutrients and reduced microbial metabolites that depress growth [39,40]. Bassaganya et al reported that poor health status associated with the dirty environment results in suppressed growth; pigs in a clean room had a greater cumulative average daily gain and average daily food intake than pigs in a dirty room [41]. Cromwell summarized data collected in the US between 1950 and 1985, indicating that responses to antibiotics under farm conditions may be twice as great as in a research station environment where the facilities are generally cleaner, the disease load is less, and the environment is less stressful. This was confirmed by Emborg et al, who analyzed data from 6,815 flocks collected from 1995 to 1999 and concluded that kg broilers produced per m² and percent dead broilers in total were not affected by the discontinued use of antibiotics where the facilities were recognized as cleaner [42]. However, the feed-conversion ratio increased marginally [43]. Similar results were also reported by Lain et al, who found that the level of antimicrobial use for treating diarrhea after weaning (and the incidence of diarrhea in weaned piglets) did not increase significantly after withdrawal of an antibiotic growth promoter from weaner feeds according to the farmer’s evaluations [44]. As early as 1955, Coates et al demonstrated that oral antibiotics do not have growth-promoting effects in germ-free animals [45]. Coates et al indicated that antibiotics reduce gut size and cause thinning of intestinal villi and the total gut wall. Many studies have found that antibiotic additives are more efficient in unsanitary conditions. Overall, scientists have demonstrated that the feeding environment significantly affects the antibiotic response. Antibiotics have less of an effect on rate of growth and feed efficiency in a clean feeding environment. Pigsty facilities have improved dramatically over the past several decades with animal welfare legislation aimed at improving the quality of the floors, living space, permanent access to fresh water, and setting a minimum weaning age. Meanwhile, research has focused on replacing antibiotics with organic acids, fermented mash, probiotics, prebiotics, minerals, oligosaccharides, enzymes, herbs/flavors, protein/amino acids, and management and husbandry techniques [46]. Pigs fed antibiotics or 0.5% ACTIVATE Starter DA was a dry organic acid blend composed of calcium salt of 2-hydroxy-4-[methylthio] butanoic acid, fumaric acid, benzoic acid, and carrier with 31% L-met activity) showed the same improvements in weight gain and feed efficiency as those fed a control diet [47]. The survival rate of coliforms is strongly influenced by pH (regeneration cycle of 70 min at pH 5, and 25 min at pH 7), regardless of the digesta origin. The following killing potency order was established for coliform bacteria: propionic<formic<butyric<lactic<fumaric<formic<propionic<lactic<sorbic<benzoic [48]. Adding some amino acids to the diet during the weaning period not only improves intestinal structure but also elevates the immunocompetence of the piglets. Diet formulation techniques can help the pig counteract some of the normal gut changes that occur at weaning. Low-protein, amino-acid fortified diets limit the amount of fermentable protein present in the gut and help reduce post-weaning diarrhea. In these cases, proper amino acid fortification and ratios relative to lysine are essential so as not to limit pig growth [49]. In recent years, pig toys, such as ‘porky play’, have gained popularity on European pig farms as a way of preventing stress, as pigs that play with simple toys have fewer chances of developing harmful behavior like ear and tail biting. Porky play distinguishes itself from other toys as it is made of biodegradable material with imidazolium oligomers with an antibacterial function. Riduan developed a series of imidazolium oligomers with a range of terminal alkyl groups that kills E. coli within 30 seconds [50].

In May 2015, the World Health Assembly endorsed the Global Action Plan on Antimicrobial Resistance, which calls on all countries to adopt national strategies within 2 years [51]. The European Commission decided to phase out and ban the marketing and use of antibiotics as growth promoters in animal feed on 1 January, 2006. Since then, the use of antibiotics is only allowed with a veterinary prescription for direct applications or as medicated feed [52]. In the US, the National Action Plan for Combating Antibiotic-Resistant Bacteria [53] stressed the need to slow the spread of antibiotic resistance through stewardship at all levels. Southeast Asian WHO countries committed to address the issue in the Jaipur Declaration [54]. The process is also under way in South Africa, started by the work of the global antibiotics resistance partnership and continued through a broad coalition of government and private sector leaders [55].

In line with recent research results, the effects of organic acids, fermented mash, probiotics, prebiotics, minerals, oligosaccharides, enzymes, herbs/flavors, protein/amino acids and improved management and husbandry techniques, especially clean and hygienic conditions, can completely replace antibiotics in all stages of the pork industry.