Jenny A. Nicholds, David French, Daniel Parker, and Peter O’Kane The poultry industry is different from many other livestock sectors in that it is unusual for the veterinarian to be presented with single animals to examine and treat. Due to the scale of farms, it is not unusual for a poultry barn to house up to 200,000 commercial layers or 80,000 broilers. Furthermore, poultry farms can have multiple houses so the number of birds on these epidemiological units can easily exceed 1,500,000 in the case of commercial layers and 400,000 in the case of broilers. At the hatchery level, depending on the type of equipment in place, one incubator can contain more than 120,000 eggs or developing embryos. Thus the poultry veterinarian’s main focus needs to be on disease prevention Historically, antimicrobials were widely used in both the prevention and treatment of diseases, but with more focus on responsible use of antimicrobials, poultry producers and veterinarians should consider biosecurity, hygiene, and management as their primary tools for disease prevention and target antimicrobial use for treatment of clinical infections. When husbandry, hygiene, and biosecurity procedures fail to prevent the introduction of a disease agent, appropriate antimicrobial therapy may become necessary to prevent pain and suffering in affected birds as well as economic losses to the producer. The poultry veterinarian will then be required to investigate, make a diagnosis, and if antimicrobial therapy is considered necessary, they must then determine the appropriate drug formulation, duration of treatment, and route of administration. Antimicrobial drug use in poultry can be divided into three categories: therapeutic, preventive/prophylactic, and growth promotion. Antimicrobial drugs in the therapeutic category are used to treat or cure a clinically detectable disease. Because sick birds often have reduced feed consumption or feed bins at the farm may be full, therapeutic antimicrobials are typically administered via the drinking water to ensure rapid intake and adequate uptake of the medication. Certain circumstances or disease conditions, however, may dictate administration in feed instead or concomitantly with water. Prophylactic or preventive antimicrobials are administered prior to the appearance of clinical signs of disease in a flock. The route of antimicrobial administration will depend on the timing or age of bird when the treatment is applied. Due to the structure and scale of the poultry industry, the hatchery is a critical control point in the management of health in poultry flocks. Hatching eggs from multiple flocks are often co‐mingled in the incubators and hatchers, so the microbiological status of the eggs and chicks from these eggs will be shared. If increased bacterial contamination has been identified in association with hatching eggs coming from a particular breeder flock, progeny from that flock and progeny of other flocks that were in the same hatchery may be treated preventively using in ovo (eggs) or subcutaneous (day‐old chicks or poults) injection of an antimicrobial until the underlying cause for such contamination is identified and corrected. Other routes for administration of prophylactic antimicrobials include oral administration via drinking water or feed. The last category of antimicrobial use, growth promotion, is the most controversial. Many antimicrobials were first approved for use in poultry based on their observed growth‐promoting effects: improved feed efficiency and growth rates. The improved production resulted in an economic benefit that was greater than the cost of the antimicrobial drug. Due to increasing concerns that the growth‐promoting use of antimicrobials had the potential for a negative impact on human health due to the development of antimicrobial resistance, there has been voluntary and regulatory removal of antimicrobial growth promoters from poultry production in many jurisdictions. With discontinued use, it became evident that much of the growth promotion effect was due to the control and prevention of subclinical enteric disease. In the US and Canada, some antimicrobials were authorized for both therapeutic use and growth promotion; however, the dose level per bird for growth promotion was generally lower than the therapeutic dose. Regulatory changes definitively preventing growth promotion use became effective in early 2017 and late 2018 in the US and Canada respectively. In the United Kingdom (UK) and European Union (EU), the use of antimicrobials for growth promotion was phased out through the 1990s and finally became illegal in the UK and EU on 1 January 2006. Since January 2022, in the EU antimicrobial medicinal products are not permitted for prophylaxis other than in exceptional circumstances. In considering these broad categories of antimicrobial use in poultry, the distinction between therapeutic and preventive categories is not always clear. The poultry veterinarian is faced with making a decision regarding treatment of a population; individual treatment is often not possible or practical. When disease is identified in a flock, not all birds will be clinically ill. The antimicrobial treatment will be therapeutic for those clinically affected birds and preventive for the remaining birds. This introduces the concept of metaphylaxis – treating part of the population that are not clinically ill but are in contact with sick animals. To further complicate the matter, growth‐promoting antimicrobials are known to kill or inhibit the growth of disease‐causing agents, including bacteria or coccidia. These products are particularly effective at prevention of necrotic enteritis, a condition triggered by enteric overgrowth of Clostridium perfringens (Grave, 2006; Smith, 2011). While the exact mode of action for growth promotion associated with the use of antimicrobials is debatable (Dibner and Richards, 2005; Neiwold, 2007), growth promotion is clearly a “side‐effect” of disease prevention. Antimicrobial use, in animals or humans and in any of the previously described categories, has the potential to select for bacterial strains that are resistant to the antimicrobial used (Roth et al., 2019). For this reason, antimicrobial use in food‐producing animals, particularly for growth promotion, has been and still is a focus of scientific, political, and consumer debate (Casewell et al., 2003; Phillips et al., 2004; Kelly et al., 2004; Cox and Popken, 2004; Cox, 2005; Phillips, 2007). The association of antimicrobial use in food animals with antimicrobial resistance impacting human health resulted in different approaches to the control of antimicrobial use in a number of countries. Over the past 50 years, use of antimicrobials in these categories has changed substantially, including since the last edition of this text. Steps have been taken in many countries to voluntarily and/or regulatorily reduce the use of Medically Important Antimicrobials (MIAs). The World Health Organization’s Critically Important Antimicrobials for Human Medicine (WHO CIA) list (WHO, 2017) defines MIAs that are used in human medicine and are divided into categories according to specific criteria (Table 34.1). The WHO List has recently been updated, WHO 2024; Table 23.2. Different countries have referred to this list in defining their own lists of MIAs and definitions vary by country (Scott et al., 2019; Table 23.2). The significant variation in approach between different countries across the globe is beyond the scope of this chapter. We will attempt to highlight some major differences between Canada, the US, and the UK. Table 34.1 Medically Important Antimicrobials – WHO categories in relation to Canada, US, and UK categories and the relevant poultry drugs implicated. a WHO (2018) Critically Important Antimicrobials for Human Medicine, 6th Revision, 2018. https://apps.who.int/iris/bitstream/handle/10665/312266/9789241515528‐eng.pdf?ua=1 b Category III reduction – everything you need to know, Chicken Farmers of Canada (no date). www.chickenfarmers.ca/category‐3‐reduction/ c CVM GFI #152 Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern. FDA (no date). www.fda.gov/regulatory‐information/search‐fda‐guidance‐documents/cvm‐gfi‐152‐evaluating‐safety‐antimicrobial‐new‐animal‐drugs‐regard‐their‐microbiological‐effects d British Veterinary Poultry Association. Antimicrobials Guidelines. 2021. www.ema.europa.eu/docs/en_GB/document_library/Other/2014/07/WC500170253.pdf e Scott HM, et al. 2019. Critically important antibiotics: criteria and approaches for measuring and reducing their use in food animal agriculture. Ann NY Acad Sci 1441:8. Products previously used for growth promotion have included penicillins, tetracyclines, avoparcin, virginiamycin, bacitracin, flavomycin, and avilamycin. In the UK in 1969, the Swann Report concluded that “the administration of antibiotics to farm livestock, particularly at sub‐therapeutic levels, poses certain hazards to human and animal health.” In particular, it led to resistance in enteric bacteria of animal origin (Swann et al., 1969). The outcome of this report was a recommendation that some antimicrobials that were important for therapeutic use (e.g., penicillins and tetracyclines) should no longer be used in feed for growth promotion. Following the ban on all growth-promoting antimicrobials in Sweden in 1986, and the ban on avoparcin and virginiamycin in Denmark in 1995 and 1998, the EU banned the use of avoparcin in 1997 and four other antimicrobials used for growth promotion in 1999, on the basis of the “Precautionary Principle.” These four antibiotics were bacitracin (a polypeptide), spiramycin and tylosin (macrolides), and virginiamycin (a streptogramin combination). Two remaining antimicrobial growth promoters licensed in the EU, flavomycin and avilamycin, were banned from use in 2006 (Dibner and Richards, 2005; Castanon, 2007). In the US, Food and Drug Administration (FDA) guidelines came into effect in 2017, preventing use of antimicrobials considered important for human medicine for growth promotion. This has effectively eliminated use of virginiamycin. According to the US classification of MIAs, bacitracin is the only remaining product with a growth promotion claim. Despite this claim, to the authors’ knowledge bacitracin is now seldom used for growth promotion and its main use is for disease prevention (e.g., necrotic enteritis). In Canada, a regulatory foundation for changes to the use of MIAs began in 2014 with the publication of the Federal Framework for Action. In early 2015 the Federal Action Plan on AMR and AMU in Canada was released, building on the Framework for Action (Government of Canada, 2015). Later that year, Health Canada and the pharmaceutical industry began work to phase out growth promotion claims on antimicrobial labels. Currently, all growth promotion doses and label claims have been removed but preventive and therapeutic label claims for virginiamycin and bacitracin remain. This initial wave of changes had minimal impact on feed medication for poultry as producers were not using the implicated products for growth promotion. Additional restriction on use of products formerly labeled for growth promotion has largely targeted preventive use and has been voluntary and/or in response to customer and/or consumer pressure and the need to fill a market demand for meat “raised without the use of antibiotics.” Since January 2022, the EU banned antimicrobials for prophylactic treatment for all animals, other than in exceptional cases limited only to individual animals or restricted numbers of animals. This effectively prohibits prophylactic use in commercial poultry as the numbers of birds in a commercial barn are seldom restricted. The terms prophylaxis and metaphylaxis are often poorly defined and easily confused. A short‐term targeted treatment in response to epidemiological evidence could appear similar to widespread, routine application of the same treatment to compensate for poor husbandry, but the former may be considered justifiable whereas the latter would not. The use of certain antimicrobials for disease prevention in poultry in the US and Canada is currently still permitted. It should be noted, however, that the market for poultry products raised without the use of antimicrobials for prevention or treatment has moved the respective industries away from antimicrobial use (Figure 34.1). Figure 34.1 Graphic representation of the percentage of broiler chickens raised by antimicrobial use marketing programs (full spectrum, reduced use, ionophores only, or no antibiotics ever) in the USA. A prohibition on preventive use in the United States was implemented in January 2012 with a ban on the extra‐label use of cephalosporins. This ban particularly targeted the extra‐label use of ceftiofur when administered in ovo for metaphylaxis in cases of known or anticipated E. coli challenge (FDA, 2012a,b). Such use was associated with E. coli isolations from poultry carcasses containing genes that rendered them resistant to third‐generation cephalosporins used in humans. While extra‐label use is prohibited, ceftiofur remains approved for subcutaneous administration to day‐old chicks and turkey poults in the USA. Since broiler chicks in the USA are generally vaccinated against Marek disease in ovo, and not handled for vaccination individually as day‐old chicks, the use of ceftiofur in broiler chicks has effectively been discontinued. In Canada, voluntary industry‐led changes in antimicrobial use (AMU) unfolded alongside the regulatory changes that impacted growth‐promoting use. The Chicken Farmers of Canada (CFC), a national farm animal group overseeing national programs of on‐farm food safety and quality assurance, voluntarily made changes to permitted use of MIAs. In 2014, the preventive use of Category I antimicrobials was eliminated. In 2018 the preventive use of Category II antimicrobials was also prohibited. Together, these measures effectively eliminated the use of ceftiofur, gentamicin or lincomycin‐spectinomycin as in ovo preventives for hatchery use and the use of virginiamycin in feed for prevention of necrotic enteritis. The CFC also plans to eliminate the preventive use of Category III antimicrobials, though the initial 2020 timeline for this has lapsed and an updated timeline has yet to be announced. Elimination of preventive use in this category will effectively eliminate in‐feed use of bacitracin for the prevention of necrotic enteritis. Thus far, use of category IV antimicrobials (bambermycin and ionophores) and uncategorized products (avilamycin) will continue to be permitted. The CFC AMU reduction strategy will also continue to permit use of antimicrobials for treatment of disease, the use of ionophores to prevent coccidiosis, and the use of chemical coccidiostats. At the turn of the century in Europe, there was growing concern regarding the development of antimicrobial resistance in human medicines and the use of antimicrobials in livestock industries was blamed for this increase. In some EU countries, legislation was introduced to reduce antimicrobial use in the livestock sectors. In the UK, the poultry industry recognized these consumer and legislator concerns and took the initiative in responsible use of antimicrobials, following WHO guidelines on highest priority critically important antimicrobials by banning the use of some antimicrobial classes (e.g., third‐ and fourth‐generation cephalosporins, glycopeptides, and ketolides) and restricting the use of other classes (e.g., fluroquinolones and macrolides), thus preempting the need for legislation. Furthermore, when the O’Neill report on antimicrobial resistance (O’Neill, 2016) recommended restrictions on the amount of antimicrobials used in agriculture to 50 mg/kg, the UK poultry industry was already well below this level. Following the 2016 finding of the Mcr‐1 resistance gene to colistin in China (Liu et al., 2016), the UK poultry meat and layer industries voluntarily restricted colistin use. Ionophores, which are used to control coccidiosis in poultry, are not considered to be MIAs but because of their activity against some Gram‐positive bacteria, they are considered antimicrobials in the US and Canada; for this reason, they cannot be used in “antimicrobial‐free” production. This is unfortunate because the ionophores are very effective at controlling coccidiosis and preventing subsequent disease in poultry. There has been debate about whether the use of ionophores will drive antimicrobial resistance in bacteria important for human health (Nilsson et al., 2012, 2016, 2019). However, there is scant evidence that this is the case (Naemi et al., 2020). In EU and UK, ionophore coccidiostats are approved as feed additives and not as veterinary medicines and therefore can be added to feed without veterinary prescription. The UK has not to date developed “antimicrobial‐free” or “no antimicrobial ever” labels and so ionophores are still widely used in poultry diets for coccidiosis control. There is good evidence that the removal of ionophore coccidiostats from poultry diets has both financial and environmental impact because of the reduction in feed efficiency (Parker et al., 2021). It is worth noting that based on this key difference in classifying the ionophores, the approach that each country has been able to take in terms of reducing antimicrobial use, specifically for the prevention and treatment of enteric disease, namely necrotic enteritis, has been impacted. Therapeutic antimicrobial uses have not as yet been banned in Europe but have been targeted in the US. Two fluoroquinolones that were approved as therapeutic antimicrobials for the control of colibacillosis in the US were banned in 2005 from use in poultry but not in cattle. The primary reason for this ban was to allay concerns regarding rising fluoroquinolone resistance rates in human cases of campylobacteriosis (FDA, 2005). In Canada, there have been no bans on antimicrobials for therapeutic use. Extra‐label drug use (ELDU) in Canada is not codified like the US; Canadian veterinarians have the privilege of prescribing ELDU as long as the drug is not banned by federal law for use in food animals. Health Canada defines ELDU as “the use or intended use of a drug approved by Health Canada in an animal in a manner not in accordance with the label or package insert” (Health Canada, 2014). While not recommended by Health Canada, it is possible for Canadian veterinarians to use the cattle injectable enrofloxacin formulation in poultry. In the United States, veterinarians may have some flexibility with how antimicrobials are administered via the water. ELDU is permitted with the exception of antimicrobials that have been banned from use for poultry (such as the fluoroquinolones) or in food production animals in general (such as chloramphenicol) so long as a prescription is utilized. Deviations from the label for dose and duration may be allowed, but the veterinarian is expected to take adequate precautions to ensure that those deviations do not cause violative residues. In most cases, antimicrobials that are added to the feed must be accompanied by a veterinary feed directive (VFD). There are a few exceptions to this rule where the antimicrobials are not considered to have any human significance (e.g., ionophores, bacitracin methylene disalicylate, bambermycin, anthelmintics). While US veterinarians have some degree of flexibility with water additive antimicrobials, they have no flexibility regarding dose, duration, species, or indications for use with antimicrobials that are added to feed. Such antimicrobials, whether a VFD is required or not, have to be used with no deviations from the label. In the UK, veterinarians can prescribe antimicrobials extra‐label, but a standard minimum withdrawal period of seven days for eggs and 28 days for meat is generally applied. As these restrictions are often impractical or financially prohibitive, veterinarians rarely elect to use these products extra‐label. The consequences of the ban on enrofloxacin and sarafloxacin use in poultry in the United States has been studied but not widely reported. The bans have removed effective treatments of bacterial disease from the poultry veterinarian’s arsenal and treatment options for Gram‐negative organisms are lacking. Veterinarians have valid concerns that antimicrobial bans cause serious animal welfare issues in the face of an untreatable disease outbreak. In a somewhat extreme example, the potentially difficult decision regarding early slaughter of entire flocks may need to be considered should no approved therapy exist. The outcomes or concerns relating to bans on antimicrobial use for growth promotion and/or prevention are better documented and understood. The EU bans on growth‐promoting antimicrobials initially led to significant animal and human health concerns. Clostridial related diseases, including necrotic enteritis and cholangiohepatitis, initially increased and required more therapeutic antimicrobial treatments. However, poultry diets were refined and these clostridial diseases are now much less common in the EU and UK poultry industries. However, the dietary changes and interventions required to mitigate the removal of antibiotic growth promoters (AGPs) have impacted the feed costs for poultry (Wierup, 2001; Casewell et al., 2003; Dibner and Richards, 2005; Grave et al., 2006). In the EU, ionophores are still used for the control of coccidiosis and these ionophores have some moderating effect on clostridial disease. Similar observations were made in the US when poultry‐producing companies voluntarily removed in‐feed antimicrobials in order to produce an “antibiotic‐free” product for specific markets (Smith, 2011). Of concern for human health in the EU was the increased use of therapeutic antimicrobials in poultry to treat clinical disease, primarily necrotic enteritis but also other forms of infectious enteritis (Casewell et al., 2003; Grave et al., 2006). Unlike the majority of in‐feed antimicrobials approved for growth promotion, many of the antimicrobials used for therapy were related to or were the same as those used in human medicine (Casewell et al., 2003; Phillips et al., 2004; Phillips, 2007). Another potential unintended consequence for human health was the importance of the AGPs in maintaining intestinal integrity. This is especially important during slaughter and processing of birds as the normal poultry intestinal tract can contain zoonotic pathogens. Inflammation and disease of the intestinal tract weaken the gut wall and increase the risk of intestinal breakage and the potential for greater contamination of the final product (Russell, 2003). While raw meat is not sterile, good intestinal health is vital in reducing the bacterial load on poultry products provided to the consumer; alternative strategies for gut health management are therefore important in the absence of AGPs. The use of antimicrobials considered critically important in human medicine for therapy of food animals will continue to be scrutinized. The benefits of these products for health, both human and animal, also need to be considered. Consumer and retailer pressure in some regions has resulted in removal of these antimicrobials from broiler diets and in some cases resulted in a ban on their use through other routes (e.g., in water or parenterally). Producers supplying export markets with poultry products may be required to discontinue use of antimicrobials if they wish to continue to supply certain markets where bans are in place, or where consumers demand that antimicrobial use is discontinued (Dibner and Richards, 2005). The general trend for the future is reduced and more responsible antimicrobial use. This ultimately means that when the question of whether or not to treat a flock is raised for the poultry veterinarian, there are more factors than ever to consider in the decision‐making process: effectiveness against the disease agent, pharmacokinetics and pharmacodynamics of the medication, withdrawal times, pathology and physiology, economics, animal welfare, impact on food‐borne pathogens, and impact on the ability to market the final product. Under current husbandry conditions in the poultry industry, segregation and medication of individual sick birds are not feasible. The low economic value of the individual bird makes it cost‐prohibitive to individually dose each bird in a house, which eliminates parenteral administration of antimicrobials. An additional argument against parenteral administration is that the stress on birds when individually handled can result in more rapid progression of the disease. Since sick birds continue to drink, therapeutic antimicrobials labeled for use in drinking water are most often used.
34
Antimicrobial Therapy in Poultry
Categories of Antimicrobial Drug Use in the Poultry Industry
Antimicrobial Drug Use in the Poultry Industries of Canada, United States, and UK
WHOa
Canadab
USc,e
UKd
Critically Important and highest priority – ceftiofur, macrolides (erythromycin, tilmicosin, tylosin) polymyxins, quinolones, and fluoroquinolones (enrofloxacin)
Critically Important and high priority – aminoglycosides (gentamicin, apramycin, neomycin, streptomycin), penicillins (aminopenicillins; amoxicillin, ampicillin)
Category I, Very High Importance – ceftiofur, enrofloxacin
Critically Important – ceftiofur, fluoroquinolones, erythromycin, trimethoprim sulfa
Category A: Avoid: not authorized for use in veterinary medicine
Category B: Restricted:
ceftiofur, fluoroquinolones
Highly Important – lincosamides (lincomycin), antistaphylococcal penicillins – narrow spectrum (penicillin G), streptogramins (virginiamycin), sulfonamides and dihydrofolate reductase inhibitors and combos (sulfas, pyrimethamine, trimethoprim), tetracyclines (chlortetracycline, oxytetracycline, tetracycline), amphenicols (florfenicol)
Category II, High Importance – virginiamycin, penicillins, tylosin, aminoglycosides (except topical agents) – gentamicin, lincosamides and extra‐label use of trimethoprim‐sulfadiazole
Highly Important – penicillin G, gentamicin, neomycin, tetracycline, chlortetracycline, oxytetracycline, virginiamycin
Category C: Caution:
aminoglycosides (except spectinomycin), aminopenicillins in combo with beta‐lactamase inhibitors (amoxicillin‐clavulanic acid, ampicillin‐sublactam), lincosamides, pleuromutilins, marcolides
Important – aminocyclitols (spectinomycin), polypeptides (bacitracin), pleuromutilins (tiamulin)
Category III, Medium Importance – bacitracin, sulfonamides, aminocyclitols (spectinomycin) and topical aminoglycosides (neomycin), aminoglycosides not used in human medicine: apramycin, tetracyclines
Important –
no poultry drugs listed
Category D: Prudence:
aminopenicillins without beta‐lactamase inhibitors (amoxicillin, ampicillin), tetracyclines, narrow‐spectrum penicillins, spectinomycin, antistaphylococcal penicillins, potentiated sulfas (trimethoprim sulfa)
Antimicrobial classes currently not used in humans – aminocoumarins (noboviocin), arsenicals (roxarsone, nitarsone), orthosomycins (avilamycin), phosphoglycolipids (bambermycin, flavomycin), ionophores (lasalocid, monensin, narasin, salinomycin)
Category IV, Low Importance – flavophospholipols (bambermycin), ionophores
Uncategorized – avilamycin
Not listed as medically important –
bacitracin, avilamycin, ionophores
Not categorized as medicines:
ionophores
Growth Promotion
Preventive Use
Therapeutic Use
Consequences of Antimicrobial Bans
Factors Influencing Antimicrobial Administration in the Poultry Industry
Husbandry and Economics
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