Antimicrobial growth promoters are substances that, when added to feeds at subtherapeutic dosages for an extended period of time, produce improvements in growth rate and feed conversion efficiency, mortality, and morbidity.
The era of antimicrobial growth promoters began in the late 1940’s when scientists found that chicks fed a dried fermentation mash of Streptomyces aureo-faciens grew faster and to a greater final weight than those fed a diet supplemented with liver extract. The component of the fermentation mash responsible for the stimulation of growth was identified as chlortetracycline. Soon after the ability of chlortetracycline to enhance growth was confirmed in turkeys and swine, sev-eral other drugs were added to the list of the compounds that could enhance growth and improve feed efficiency when used at levels ranging from 2 to 50 ppm in feed. Since the process by which farm animals convert feed protein into edible protein for the consumer is not particularly efficient, the extensive and continuous use of antimicrobial growth promoters as feed additives was rapidly become a major feature in modern intensive livestock production systems.
In nonruminating animals, antimicrobial growth promoters act primarily in the digestive tract, exerting a beneficial effect on the composition of microorga-nisms inhabiting the gut. It has long been known that a well-balanced intestinal flora obstructs the way to pathogens trying to enter the body. Antimicrobials also act to slow down bacterial metabolism, thus reducing, the rate at which the intes-tinal flora break down feed proteins to substances such as ammonia and biogenic amines, which are toxic to the animals and interfere with the absorption of nu-trients through the intestinal wall. Antimicrobials help to increase, therefore, the availability of nutrients and improve intestinal absorption. At the same time, they 179
also exert a positive effect on metabolism, increasing the rate at which animals lay down protein, thus improving weight gain and feed efficiency.
In ruminants, the extent or importance of changes in the small intestine similar to those observed in nonruminants has not, so far, been documented. In the case of ruminants, however, the beneficial effects of antimicrobial growth promoters lies more clearly in their ability to influence the balance of microbial species inhabiting the rumen. A higher level of rumen propionate is produced in treated animals at the expense of acetate and sometimes of butyrate production, and there are significant reductions in energy losses due to the ruminal production of methane. The total effect is to make rumen fermentation more efficient, thus increasing the metabolizable energy content available for lean meat production.
In the United States, permitted antimicrobial growth promoters include several antibiotic and synthetic antibacterial agents. The former group is com-posed of three aminoglycoside antibiotics including neomycin, streptomycin, and bambermycin; three macrolide antibiotics including erythromycin, oleandomycin, and tylosin; three polyether ionophore antibiotics including lasalocid, monensin, and salinomycin; two tetracycline antibiotics including chlortetracycline and oxy-tetracycline; three peptide antibiotics including avoparcin, bacitracin, and virgin-iamycin; and a series of miscellaneous antibiotics including lincomycin, penicillin procaine, avilamycin, and tiamulin. Within the latter group, several compounds such as arsenical compounds, nitrofurans including furazolidone and nitrofura-zone, sulfonamides including sulfamethazine, nitrofurans including furazolidone and nitrofurazone, sulfonamides including sulfamethazine, sulfathiazole and sul-faquinoxaline, and quinoxaline-1,4-dioxides are included.
In the European Union, significant changes in use of the permitted antimi-crobial growth promoters have occurred during the last decade. Currently, only four antibiotics including monensin, salinomycin, bambermycin, and avilamycin, and two synthetic antibacterials including carbadox and olaquindox, and autho-rized. It is important to note that continued use of the antimicrobial growth pro-moters is constantly under review throughout the world because of consumer discontent.
Since many of the above-mentioned compounds possess major anti-infec-tious activity in addition to their role as growth promoters, their application in animal farming has already been discussed in previous chapters. Hence, this chapter concentrates on the remaining compounds within this group, namely the organic arsenicals, peptide antibiotics, quinoxaline-1,4-dioxides, and miscella-neous substances.
6.1 ORGANIC ARSENICALS
Certain organic arsenicals are incorporated in pig and broiler feeds to improve weight gain and feed efficiency and to combat enteric infections. Arsanilic acid
FIG. 6.1 Chemical structures of commonly used organic arsenicals.
and its sodium salt are most commonly used, particularly in pigs, whereas roxar-sone and the related compound 4-nitro-phenylarsonic acid are used mainly in broilers (Fig. 6.1). The exact mode of action of these compounds is not yet understood but it is assumed that it is associated with their antibacterial activity.
They are also efficacious in the egg-producing industry and were previously approved for use in laying hens, although presently these drugs are no longer approved for this purpose. However, their use in animals is, generally, rather limited and the risk–benefit ratio is questionable because these drugs can produce toxicosis known as peripheral nerve demyelination.
Organic arsenicals are poorly absorbed from the gastrointestinal tract and are excreted mainly in feces (1). After their absorption, organic arsenicals are distributed throughout the body and rapidly excreted in the urine without being metabolized to a great extent. Elimination of the parenterally administered com-pounds is nearly complete within 24–48 h, while several days are required for elimination of the compounds from the gut.
When animals do not have constant access to organic arsenicals, there is a high possibility that significant levels of arsenic residues will not appear in tissues. However, excessive feeding of these compounds can result in arsenic concentrations as high as 3–10 ppm in liver and kidney and 1–2 ppm in blood (1). Feeding organic arsenicals to laying hens also produces a substantial increase in arsenic residues in eggs, especially in the yolk. It is interesting to note that arsenic residue concentrations in incurred tissues increase in a dose-dependent manner and, therefore, a maximum limit of arsenic transfer is not normally reached (2).
Arsanilic acid is added to swine and poultry feeds at a dosage rate of up to 100 ppm for growth-promoting purposes. It is also effective for prophylaxis and treatment of many outbreaks associated with E. coli infections in swine. To treat scour in swine, arsanilic acid is administered in the feed, at a level of 250 ppm for up to 3 weeks. Arsanilic acid may also be administered to poultry for treatment of coliform septicemia at a level of 250 ppm in the feed for 5–8 days.
Roxarsone has been used by the poultry industry due primarily to its ability to improve growth, feed conversion, and pigmentation to broilers. At least 50%
of the poultry industry has used roxarsone as a growth promoter, although the drug also exhibits anticoccidial activity similar to that of arsanilic acid (3). Roxarsone is not approved for use as anticoccidial in the United States, but it is approved for use in chicken and turkey feeds as a growth promoter. It is added in poultry feeds at a rate of 50 ppm and in swine feeds at 25–37.5 ppm.
When diets that contained 11–88 mg/kg arsenic originating from the incor-porated roxarsone were fed to layer hens for 4 weeks, arsenic residues in liver, eggs, and the excreta significantly increased with increasing arsenic levels in feeds (4).
6.2 PEPTIDE ANTIBIOTICS
Peptide antibiotics are compounds containing amino acids that are covalently linked to other chemical entities and consist of more than one component. In contrast to naturally occurring proteins that are built up fromL-amino acids only, peptide antibiotics usually containD-amino acids. Avoparcin, bacitracin, efroto-mycin, enraefroto-mycin, thiopeptin, and virginiamycin constitute the main members within this group of drugs (Fig. 6.2). They are usually added to animal feeds at low concentrations, and produce residues in tissues at very low or undetectable levels. Unfortunately, the metabolic pathways of most peptide antibiotics have not been still elucidated. Within the European Union, these antibiotics are regu-lated under a separate legislation (Directive 70/524/EEC).
Avoparcin is a narrow-spectrum glycopeptide antibiotic composed of two components. It is used solely for growth-promoting purposes, although it is also primarily active against gram-positive bacteria. Avoparcin is administered as a feed additive to improve the rate of weight gain in chickens, turkeys, pigs, and calves, and to enhance milk production in lactating cattle (5). It is also recom-mended at dosages of 15–40 ppm in the feed for beef cattle to improve live weight gain by 5–15%.
In ruminants, avoparcin has a dual action. It acts in the rumen by enhancing fermentation, and in the intestine by improving the absorption of nutrients. Fol-lowing feeding to animals, avoparcin is virtually unabsorbed from the gastrointes-tinal tract and is rapidly eliminated in the form of the parent compound. As a result, no withdrawal period is required.
Bacitracin is a linear-ring peptide antibiotic produced by Bacillus subtilis and Bacillus licheniformis. Commercial formulations of bacitracin comprise a mixture of many closely related compounds classified into bacitracin A, B, C, D, E, F, and G (5). The main components are bacitracin A, B1, and B2, constituting 57%, 22%, and 13%, respectively, of the mixture, whereas bacitracin F constitutes less than 2%. Bacitracin F is actually a degradation product of bacitracin A that
FIG. 6.2 Chemical structures of commonly used peptide antibiotics.