key: cord-0018758-33st52bo authors: Gray, P; Jenner, R; Norris, J; Page, S; Browning, G title: Antimicrobial prescribing guidelines for poultry date: 2021-03-29 journal: Aust Vet J DOI: 10.1111/avj.13034 sha: 0adb414d0de3a17466cd76cdde92a9f732fdb757 doc_id: 18758 cord_uid: 33st52bo nan Dr Peter Gray BVSc Peter Gray graduated with a Bachelor of Veterinary Science from Sydney University in 1983. He spent 2 years in a pet and aviary bird-focused private practice in western Sydney, and started with Inghams Enterprises in 1986 as a poultry veterinarian. During his ongoing work life at Inghams, Peter has had technical and veterinary roles that have involved him in all aspects of a poultry operation from importation, export, breeding, feed mills, hatching, growing, processing and further processing. His work has covered veterinary work in both chicken and turkey species, as well as welfare and food safety. He has always valued the learnings from many experienced colleagues both from within Inghams and the wider Australian Veterinary Poultry Association community. He has been a representative on industry and government committees, and is a qualified poultry welfare auditor with the Professional Animal Auditor Certification Organization (PAACO). Over the course of his working life, he has seen great change in the Australian industry where genetics, biosecurity, new vaccine strategies and improved management practices have seen an extensive reduction in antibiotic use in the poultry industry. He hopes these guidelines can play a part in continuing that positive trend while maintaining good welfare outcomes for the birds under our care. Rod Jenner is a consultant poultry veterinarian consulting to both the chicken meat and egg industries, and conducting projects on behalf of Agrifutures Australia and Australian Eggs Ltd. He has been in the poultry industry since graduation. Rod has served on a number of industry representative committees over the years, including the RIRDC chicken meat advisory committee, and has also served as President of the Australian Veterinary Poultry Association (AVPA), member of Therapeutics Subcommittee and Welfare Subcommittee of the AVPA, Queensland executive of the AVA, and divisional committee of the WPSA. Of recent years, Rod has progressed into teaching veterinary students in the area of commercial poultry medicine at the University of Queensland and James Cook University. Core principles of appropriate use of antimicrobial agents While the published literature is replete with discussion of misuse and overuse of antimicrobial agents in medical and veterinary situations there has been no generally accepted guidance on what constitutes appropriate use. To redress this omission, the following principles of appropriate use have been identified and categorised after an analysis of current national and international guidelines for antimicrobial use published in the veterinary and medical literature. Independent corroboration of the validity of these principles has recently been provided by the publication (Monnier et al 2018) of a proposed global definition of responsible antibiotic use that was derived from a systematic literature review and input from a multidisciplinary international stakeholder consensus meeting. Interestingly, 22 elements of responsible use were also selected, with 21 of these 22 elements captured by the separate guideline review summarised below. 10 Spectrum of activity Use narrow-spectrum in preference to broad-spectrum antimicrobials whenever appropriate. 11 Extra-label (off-label) antimicrobial therapy Must be prescribed only in accordance with prevailing laws and regulations.Confine use to situations where medications used according to label instructions have been ineffective or are unavailable and where there is scientific evidence, including residue data if appropriate, supporting the off-label use pattern and the veterinarian's recommendation for a suitable withholding period and, if necessary, export slaughter interval (ESI). Where possible optimise regimens for therapeutic antimicrobial use following current pharmacokinetic and pharmacodynamic (PK/PD) guidance. Minimise therapeutic exposure to antimicrobials by treating only for as long as needed to meet the therapeutic objective. Ensure that written instructions on drug use are given to the end user by the veterinarian, with clear details of method of administration, dose rate, frequency and duration of treatment, precautions and withholding period. 15 Target animals Wherever possible limit therapeutic antimicrobial treatment to ill or at-risk animals, treating the fewest animals possible. Keep accurate records of diagnosis (indication), treatment and outcome to allow therapeutic regimens to be evaluated by the prescriber and permit benchmarking as a guide to continuous improvement. Encourage and ensure that instructions for drug use are implemented appropriately 18 Monitor response to treatment Report to appropriate authorities any reasonable suspicion of an adverse reaction to the medicine in either treated animals or farm staff having contact with the medicine, including any unexpected failure to respond to the medication. Thoroughly investigate every treated case that fails to respond as expected. Post-treatment activities 19 Environmental contamination Minimise environmental contamination with antimicrobials whenever possible. 20 Surveillance of antimicrobial resistance Undertake susceptibility surveillance periodically and provide the results to the prescriber, supervising veterinarians and other relevant parties. Evaluate veterinarians' prescribing practices continually, based on such information as the main indications and types of antimicrobials used in different animal species and their relation to available data on antimicrobial resistance and current use guidelines. Retain an objective and evidence guided assessment of current practice and implement changes when appropriate to refine and improve infection control and disease management. Each of the core principles is important but CORE PRINCIPLE 11 Extra-label (off-label) Antimicrobial Therapy can benefit from additional attention as veterinarians, with professional responsibility for prescribing and playing a key role in residue minimisation, must consider the tissue residue and withholding period (WHP) and, if necessary, export slaughter interval (ESI) implications of off-label use before selecting this approach to treatment of animals under their care (Reeves 2010; APVMA 2018). The subject of tissue residue kinetics and calculation of WHPs is very complex requiring a detailed understanding of both pharmacokinetics (PK) and statistics, as both these fields underpin the recommendation of label WHPs. Some key points to consider when estimating an off-label use WHP include the following: 1 The new estimate of the WHP will be influenced by (1) the offlabel dose regimen (route, rate, frequency, duration); (2) the elimination rate of residues from edible tissues and (3) the maximum residue limit (MRL). 2 Approved MRLs are published in the MRL Standard which is linked to the following A PVMA website page: https://apvma.gov. au/node/10806 3 If there is an MRL for the treated species, then the WHP recommended following the proposed off label use must ensure that residues have depleted below the MRL at the time of slaughter. 4 If there is no MRL for the treated species, then the WHP recommendation must ensure that no detectable residues are present at the time of slaughter. 5 Tissue residue kinetics may be quite different to the PK observed in plasmaespecially the elimination half-life and rate of residue depletion. The most comprehensive source of data on residue PK is that of Craigmill et al 2006. 6 WHP studies undertaken to establish label WHP recommendations are generally undertaken in healthy animals. Animals with infections are likely to have a longer elimination half-life. 7 There are many factors that influence variability of the PK of a drug preparation, including the formulation, the route of administration, the target species, age, physiology, pathology and diet. 8 The following figure provides a summary of typical effects on elimination rates associated with drug use at higher than labelled rates and in animals with infections ( Figure 1 ). Management of disease outbreaks on a commercial poultry farm Commercial poultry veterinary medicine is a unique stream of veterinary science that focuses strongly on preventive medicine. Infectious disease outbreaks are most commonly the result of lapses in biosecurity, which are not always totally preventable and should never be unexpected. Biosecurity in this context is more than quarantine. It has external, internal and resilience components, which include vaccination, preventive medication, optimal nutrition, appropriate genetics, good husbandry and exemplary management. The methods used for diagnostic investigation are quite diverse, even though they are being applied to a single animal species, and often to the relatively uniform context of a commercial farm. Animal behaviour, or ethology, is the most frequently used diagnostic tool, and probably the least acknowledged skill used by a field veterinarian. Gross pathology, histopathology, epidemiology, microbiology, and serology are all important diagnostic tools, while the disciplines of immunology, pharmacology, therapeutics and veterinary medicine in public health are employed by commercial poultry veterinarians in the conduct of their role. Food industry. The number one consideration is always that the veterinarian is operating within a food production system. Every decision about treatment must incorporate considerations about the wholesomeness of the animal or product as a human food source. Food safety considerations are paramount Treatment options are severely limited Broiler chickens have a very short lifespan relative to antimicrobial treatment regimens. The prescribing veterinarian must be cognisant of the likely slaughter date of the flock before recommending treatments. The use and consequences of antimicrobial therapies must be clearly communicated with both the farmer and the owner/processor of the chickens to ensure that treatment will not contravene the advised WHP. Egg laying flocks are in constant production, so advice on WHPs precludes the sale or supply of eggs into the food sector for the duration of the WHP for any medication that has a WHP longer than 0 days (NIL). Backyard poultry flocks are commonly kept for enjoyment, egg production and occasionally for their meat. In most instances, movement of animals, eggs and meat is confined to the primary household. However, it is not uncommon for surplus eggs and chickens to be sold or given away to neighbours and work colleagues. Additionally, certain fancy varieties of backyard poultry may be extensively traded and sold between individuals. Therefore, the prescribing veterinarian must be aware of the medications that can be used safely in poultry and their associated WHPs. Inappropriate advice may have far-reaching implications Treating a flock, not an individual. Treatments are generally applied to an entire flock, rather than to an individual bird. It is costprohibitive to consider hospital pens in large-scale operations, but this can be feasible in smaller niche farms, or with high value stock (e.g. rare breeds, genetically superior stock, or during situations of severe shortage). However, even high value commercial stocks are generally replaceable, so it is unusual to treat an individual commercial bird. In contrast, in small backyard poultry flocks, it is common for owners to have a strong bond with their birds. In such instances, the birds may have become part of the family and the owners may be willing to go to extensive lengths to ensure their birds receive individual veterinary medical attention. When treating a flock with an antimicrobial agent, consideration needs to be given to the long-term commercial return, as well as the short-term response. • Valid grounds for antimicrobial medication include animal welfare, managing the risks of disease in susceptible flocks, the zoonotic potential of the disease and true economic loss when there is a no more effective way to control the disease. • Medication is not justified when it will be ineffective, for example for viral or nutritional diseases. • Medication is often not the best approach to disease control, even though in theory, it may be effective. It may be best to process birds early or, in mild cases, let the disease run its course. • Medication can sometimes be counter-productive, for example, when it may have an impact on live bacterial vaccines. • Medication is unwarranted if the intention is solely to provide non-specific cover over stressful periods, to be seen to be doing something, to bring peace of mind, or to use up excess drug stocks. Prudent use. It is important to remember that if antimicrobial therapy is being considered, mass medication in water or feed will not only target sick birds, but will be consumed by healthy birds. In addition, sick chickens tend to have reduced feed and water consumption, limiting their antimicrobial intake. Thus, mass antimicrobial therapy is not targeted therapy, but rather, is largely a preventive approach to limiting the spread of bacteria to healthy individuals. Treatment options are severely limited in Australia by the restricted number of registered veterinary medicines available for administration in feed or water, and by food safety considerations, placing more emphasis on the importance of preventive measures. Non-steroidal anti-inflammatory drugs are not registered for use in poultry and are never used in poultry medicine, so therapeutic options are limited to antimicrobials. There are relatively few alternatives to preventive antimicrobial therapy, but options include (with variable evidence of efficacy) medium-chain fatty acids, probiotics, prebiotics (for example, mannan oligosaccharide derivatives), acidifiers, essential oil extracts and many more. The use of antimicrobials in commercial poultry production is under considerable pressure and can be influenced by major customers, with a growing expectation to demonstrate good antimicrobial stewardship, and an emphasis on strategies to reduce use. Veterinary intervention is closely scrutinised, and there is an increasing requirement to justify approaches to flock health when they involve the use of antimicrobial agents. Backyard poultry: It can be difficult to design appropriate treatment regimens for backyard poultry due to the limited number of registered veterinary medicines available. Clients may place pressure on the prescribing veterinarian to provide medications that are not approved for use in poultry. This largely occurs when the birds are kept primarily as pets and their eggs are not consumed. It is important for the prescribing veterinarian to be aware that backyard poultry are classified as food-producing species and to investigate which antimicrobial agents can be used safely and legally. If unregistered medicines or off-label uses are prescribed, then the prescribing veterinarian must determine and recommend an appropriate WHP for eggs and meat. It is essential that a diagnosis, even if only presumptive, is made before considering medication. 2 Drug susceptibility and resistance All infectious organisms have an inherent pattern of susceptibility and resistance to specific drugs. Resistance to certain drugs may also be acquired. Acquired resistance may be determined by laboratory susceptibility tests or inferred by prior clinical experience and previous response to therapy on a particular farm, although it should always be remembered that prior clinical experience can be misleading, as clinical improvement of a flock may not have been a result of successful antimicrobial therapy. Sampling for susceptibility testing prior to antimicrobial use is essential. Bactericidal antimicrobials kill bacteria, thereby reducing the number of organisms, whereas bacteriostatic antimicrobials inhibit the metabolism, growth or multiplication of bacteria, thereby preventing an increase in the number of organisms. In practice, this generally makes little difference, as a functional immune system is essential for resolution of all infectious diseases, regardless of the mode of action of the drug used to treat them. Choosing a drug that will reach the site of infection at an effective concentration for enough time is an important consideration. Having selected a drug that is likely to be effective, an appropriate dose rate must be determined. Dose rates should be selected and calculated using the following guidelines: • Water and feed consumption can vary considerably, and is affected by flock health, ambient temperature, species, physiological status and management practices. Therefore, where information is available, antimicrobial dose rates based on bodyweight, in conjunction with known current water or feed consumption, provide the most accurate dosages. The exception is in young rapidly growing birds, where dose rate expressed as a concentration in feed or water provides a more practical calculation method. • Treatment should always commence at maximum recommended dose rates for the greatest efficacy. • Dose rate may need to be adjusted to allow for spillage or wastage, which can be considerable, especially in ducks. When calculating a dose to be delivered in water, it is necessary to know the: • Concentration of the active ingredient in the selected antimicrobial product 6 Onset of medication Normally treatment should commence as soon as a presumptive diagnosis is available when disease is acute and a high mortality rate is expected, for example, in fowl cholera (infection with Pasteurella multocida). For more chronic disease, it is appropriate to wait for the results of susceptibility testing. In theory, for time-dependent antimicrobial agents, the minimum inhibitory concentration (MIC) of a drug should be maintained or exceeded at the site of infection throughout the course of treatment to ensure that the infecting organism remains suppressed and is less likely to acquire resistance. It is critical to ensure that the amount of medicated water supplied each day is sufficient to eliminate the risk of birds running out of water during times when the manager is not on the farm (e.g. overnight). In acute disease outbreaks, medication should continue until mortalities stop and clinical signs are no longer apparent in the flock. Usually this takes at least 3 days, and mortalities may continue to rise for the first few days as severely affected birds succumb, especially if they are too sick to consume any medication. However, acute diseases are usually under control within 5-7 days, and if no response is apparent within 3-5 days, the diagnosis and treatment regimen should be reassessed. Some diseases may require ongoing medication in feed or water to suppress clinical disease and potential spread to other flocks. Oral administration is most effective for infections involving the digestive tract. Drinking water medication is usually more effective than in-feed medication, as it can be commenced and altered more quickly, and because sick birds may continue drinking even when they have ceased eating. There is also less risk of consumption by non-target birds/species. It is important that, as the medicated water is consumed, the dose is not diluted with fresh water. Birds should have no access to other water sources. The efficacy of many antimicrobials can be affected by the route of administration. Once powders are dissolved in solution, or liquids diluted, the drug can lose its activity. As a rule, medications should be prepared daily. Antimicrobials should not be mixed or administered concurrently, as one may interfere with the solubility, absorption or activity of another. The pharmacology of antimicrobial agents in poultry Within the critical context of antimicrobial stewardship, it is important to select drug and dosage regimens that reflect the five rightsright drug, right time, right dose, right duration and right route. 1 There are many physiological, pathological and pharmacological sources of variation in antimicrobial drug exposure within and between birds of the same and different species (e.g. chickens, ducks and turkeys), to which can be added sources of variation within and between routes of administration. There have been several recent reviews of antimicrobial use in poultry [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] and key findings are presented in this summary. The potential for distribution of antimicrobial agents into the eggs of laying birds is an important consideration when developing treatment plans for laying birds and this subject has been comprehensively evaluated. [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] As seen in Appendix 2, there are very few drugs approved for use in birds and even fewer for birds currently producing eggs for human consumption. This is primarily a consequence of the presence, often for prolonged periods, of residues of the antimicrobial agent or its metabolites in meat and/or eggs. The antimicrobial agents approved for use in birds in Australia represent well-established and aged classes that were developed for use from the 1940s to the 1970s. With the exception of avilamycin, the antimicrobial agents listed in Appendix 2 with antibacterial indications (amoxicillin, apramycin, bacitracin, chlortetracycline, erythromycin, flavophospholipol, lincomycin, neomycin, oxytetracycline, spectinomycin, sulfadiazine, sulfadimidine, tiamulin, trimethoprim, tylosin, virginiamycin) were available for use in poultry in Australia in 1989. Because of the age of the antimicrobial agents available for use and their availability in most cases from a range of generic sources, there has been very little recent investigation of their pharmacology or efficacy, or optimal dosage regimens 57-70 for these agents. When these antimicrobial agents were first approved for use in Australia, it was only necessary to establish the dose regimen based on clinical response to treatment in infection challenge studies and field confirmation studies. The trend in recent decades to define dosage regimens is much more sophisticated and frequently involves an integration of the pharmacokinetic (PK) behaviour of the drug in the target bird species with the pharmacodynamic (PD) response of the target pathogen, often established by in vitro microbiological methods (e.g. the MIC of a representative panel of isolate of the target pathogen). Very few PK/PD studies are available to re-examine the dosage regimens of currently approved antimicrobial agents, although the PK/PD profile of tiamulin in an experimental intratracheal infection model of Mycoplasma gallisepticum in young chickens has been described. 71 Although valuable information was obtained in this study, tiamulin is not widely used in Australia, as Mycoplasma gallisepticum is very effectively controlled by vaccination. Application of the mutant selection window approach to the evaluation of the killing of Mycoplasma gallisepticum has been investigated for danofloxacin, doxycycline, tilmicosin, tylvalosin and valnemulin. 72 However, none of these antimicrobial agents are registered for use in Australia and the efficacy of vaccination in control of mycoplasmoses in chickens obviates any need for their use. The most practical and common route of administration of antimicrobial agents in poultry in Australia is per os, with drugs being mixed in water or feed. There is only a single class of antimicrobial agent registered for injection in poultry (lincomycin-spectinomycin) and, although in ovo injection commonly used outside Australia, [73] [74] [75] no antimicrobial agents are registered for this route in Australia. Effective use of antimicrobial agents in water requires an understanding of the drug and its formulation, especially its stability and solubility, as well as knowledge of factors influencing water intake and thereby exposure of birds to the treatment. Inconsistent antimicrobial administration has been observed after intravenous infusion of drugs into individual patients, 76 so it can be assumed that drug delivery in water or feed to populations of birds will have many challenges, both in the medication and consumption of water and feed, and the systemic availability of administered drugs. At best, administration by the oral route to a population of birds can be expected to be associated with significant imprecision. 77 Key considerations about feed and water medication have been described by a number of authors 11, [78] [79] [80] [81] [82] [83] [84] [85] [86] and include a range of important factors affecting water consumption, including bird age (absolute water consumption increases with age, but consumption per kg live weight decreases), environmental temperature and heat stress, water temperature, electrolyte composition of the water, the feeding regimen and the lighting program (during dark periods birds do not usually drink and a peak of water consumption can occur just after lights are turned on). Other factors affecting water and feed consumption and drug availability are presented as follows in the sections on interactions and sources of variability. The metabolism of foreign compounds or xenobiotics, including antimicrobial agents, in birds has received some attention, 87-99 but is not nearly as well understood as the metabolism of drugs in mammalian species. One notable observation in birds is the ability of chickens to metabolise monensin and other ionophores, allowing them to be used with caution, but greater safety than in many mammalian species. 88 When the metabolism of monensin is impaired by coadministration of tiamulin, an inhibitor of Cytochrome P450 family 3 subfamily A (CYP3A) enzymes, monensin biotransformation is reduced, monensin accumulates, the margin of safety is eroded and toxicity can be observed. Not all ionophores are equally susceptible to the consequences of concurrent tiamulin exposurefor example, the safety of lasalocid 100 does not appear to be affected. Other impacts of drugs on the CYPs of poultry have been described and include effects associated with sulfadimidine, 101 sanguinarine, 102 and the interaction of butyrate and erythromycin. 103 It is clear that there are some unique features of avian metabolism and that there are important differences in drug metabolism within species of birds and, importantly, between species. 89 For this reason, caution is required when using a new drug or a well-established one in a new bird species. Transport proteins play an essential role in the absorption, distribution and excretion of drugs and toxins [104] [105] [106] [107] and are located throughout the body in the cytoplasmic membranes of cells of the gastrointestinal tract, liver, kidney and brain. It is likely, just as observed in mammals, that there are important differences within and between species of birds in the rate and extent of drug transport across membranes and consequent PK. Adsorption of drugs to the surface of chemical substances with particular properties can lead to reduced local and systemic availability. Examples include the interaction of bentonite and tylosin, 108, 109 mycotoxin binders and tetracyclines, 110 tylosin and salinomycin 111 and, potentially, biochar immobilisation of lipophilic substances. 112 Tetracycline solubility and chelation The bioavailability of chlortetracycline can be reduced by the presence of high concentrations of calcium and NaSO 4 113 and increased in a low pH environment, as may occur following administration of citric acid to chickens 114 or turkeys. 115 Drug-drug interactions A number of drug-drug interactions (DDIs) have been described in poultry between drugs not registered for use in birds in Australia, for example between doxycycline and diclazuril or halofuginone, 116 flunixin and doxycycline 117 and ionophores and florfenicol, 118 as well as between registered drugs, for example between monensin and sulphonamides. 119 The potential for DDIs should always be considered when more than one drug is used. As described above, the best known DDI is between tiamulin and the ionophores, 100 and has been seen with monensin 120 and salinomycin. 121 Drug-herb interactions A number of plants contain bioactive substances that can lead to interactions, such as that seen between silymarin and doxycycline in quail. 122 Hard water can interfere with absorption, leading to decreased plasma concentrations of enrofloxacin 123 (not registered for use in poultry in Australia) and reduced availability of oxytetracycline. 55, 124 Microbial degradation Lactobacillus species in the crop of birds have been associated with the degradation of orally administered erythromycin. 125, 126 Prandial status Although not registered for use in poultry in Australia, the bioavailability of doxycycline is substantially reduced in the presence of feed, 127 highlighting prandial status as a potential source of variation. However, it is usually neither practical nor desirable to administer oral treatments to birds that have been fasted. Water sanitisers can adversely affect the stability of antimicrobial agents, such as amoxicillin 128 and other antimicrobial agents. 129 Other sources of variability A large number of pharmaceutical, physiological, pathological and pharmacological factors have been described as having an impact on the PK and clinical outcomes of antimicrobial use, particularly in mammals. [130] [131] [132] [133] However, there are a growing number of examples of factors influencing PK and clinical outcome in poultry, with representative examples presented below. It should be recognised that most of the examples on sources of PK variation have been reported in studies of antimicrobial agents not registered for use in birds in Australia (all registered antimicrobial agents are set out in Appendix 2). However, the findings of these studies do highlight the diversity of sources of variation that need to be considered when designing dosage regimens or investigating poor responses to treatment. Delivery of drugs in water or feed to populations of birds of variable weight and health makes delivering a predictable, accurate and intended dose impossible. 77 Measures can be introduced to reduce the degree of imprecision, but there will always be birds receiving less than or more than the target dose. The age of birds can have an impact on PK 134 and has been shown to influence the bioavailability of enrofloxacin, which was increased by 15.9% in 8-week-old broilers compared with that in 4-week-old birds. 104 In contract, plasma concentrations of sulfaquinoxaline and sulfadimidine were higher in younger broilers than in older birds. 135 Age and growth of broilers has also been shown to have a significant impact on the PK of florfenicol. 136 Bacterial isolate variation When multiple isolates of Gallibacterium anatis were taken from various organs of layers, significant variation in antimicrobial resistance was observed. 137 This clearly can have an impact on clinical success if dose regimens are inadequate to control the full spectrum of resistances present. When monitored throughout the day, tylosin concentrations in plasma from broilers were subtherapeutic at night, an unfavourable finding for a time-dependant antibacterial agent. 138 It is likely that there was no water and feed consumption during the night. Sulfadimidine given orally to chicks was found to have dramatic differences in PK throughout the day, 139 sufficient to question the reliability of dosage regimens. Induced fatty liver in chickens led to significant changes in the PK of erythromycin, lincomycin and oxytetracycline. 140 Chickens have a small repertoire of bitter taste receptors (T2R) and the umami receptor (T1R1/T1R3) responds to amino acids such as alanine and serine. They lack a counterpart of the mammalian sweet sensing T1R2, so T1R2-independent mechanisms for glucose sensing might be particularly important in chickens. The avian nutrient chemosensory system is present in the gastrointestinal tract and hypothalamus and is related to the enteroendocrine system, which mediates the gut-brain dialogue relevant to the control of feed intake. 141 It may not necessarily be related to taste, but water intake has been shown to increase in birds fed lasalocid. 142 Formulation Modified formulations of doxycycline have been shown (not unexpectedly) to be associated with differing PK profiles in treated broilers. 143 Gender Differences in the PK of antibacterial drugs (including the sulphonamides) have been shown when comparing hens and cockerels. 144 Tobramycin was eliminated more rapidly in ducks than in drakes, 145 similar to observations with apramycin. 144 Disease Generally, antimicrobial agents are administered to birds that are affected by infection, from early subtle clinical stages to more obvious florid disease. While PK studies are frequently undertaken in normal birds, not surprisingly, the presence of disease can have a significant impact on PK and between and within bird variability in PK. The following examples illustrate the complexity and unpredictability of the effects of disease on the PK of various antibacterial agents. Most of the examples describe the use of antibacterial agents not registered for use in birds in Australia. However, the cases remain important as they demonstrate the importance of the impacts of disease on drug PK. • Amoxicillin administered to chickens with caecal coccidiosis was associated with a lower C max , a reduced AUC and lower bioavailability. 146 • Endotoxaemia in turkeys had dramatic effects on cardiovascular function, but the PK of amoxicillin was not influenced, though PK was impacted by the rapid growth of the birds. 147 • Infection of turkeys with Pasteurella multocida resulted in higher plasma levels of chlortetracycline (15 mg/kg) than in uninfected turkeys, and citric acid (150 mg/kg), a chelating agent of divalent cations such as calcium and magnesium, led to higher plasma levels in birds whether or not infected with Pasteurella multocida. 115, 148 • Danofloxacin (not registered) had a reduced C max in chickens infected with Pasteurella multocida, but the concentrations achieved adequately controlled infection. 149 • Infection of broilers with Escherichia coli was associated with a decrease in the Vd and the elimination half-life of florfenicol (not registered). 155 • Florfenicol (not registered) had reduced C max and AUC0-12 h values in lung tissue in Gaoyou ducks infected with Pasteurella multocida. 156 • Florfenicol (not registered) had a reduced C max after administration by IM or IV in Muscovy ducks infected with Pasteurella multocida. 157 • Infection of broilers with Salmonella gallinarum was associated with reduced clearance of kitasamycin (not registered). 158 • Muscovy ducks with induced renal dysfunction had increased plasma concentrations of levofloxacin (not registered). 159 • Infection of ducks with Pasteurella multocida was associated with increased plasma concentrations and slower elimination of orbifloxacin (not registered). 160 • Chickens with infectious coryza had higher plasma concentrations, and reduced clearance (and possibly reduced residue elimination) of sulphachloropyridazine (not registered)-trimethoprim. 161 The effective treatment of birds with antimicrobial agents requires an understanding of the multitude of factors that influence selection of the appropriate drug, administration according to a route and dose regimen that increases the likelihood of adequate drug exposure of treated birds, and minimisation of those factors that are associated with PK variability. The choice of antimicrobial agents is from a small formulary for treatment of birds with pathogens with evolving antimicrobial resistance status. In many respects, it is amazing that drugs from the 1980s, and before, continue to provide clinical benefit. However, in the absence of monitoring of the PK and pathogen status of individual birds, the vigilance of farm personnel and the veterinarian in assessing the response to treatment is critical. Production records Most commercial poultry farming operations have production records. These are useful indicators of the recent history of the flock. There are often also husbandry records that may provide clues about any recent husbandry or management factors that could influence the incidence and/or outcomes of disease. Vaccination programmes are also valuable sources of information. While some records may not be immediately available, a little time spent requesting and assessing further information is often well worth the effort. 162 An important consideration when investigating infectious diseases is to review the farm location and the placement of nearby farms. A quick view on Google Earth prior to your visit may assist in identifying potential risks, including nearby farms and dams on which wild waterfowl may reside. The other important records to review are the recent visitor entries, feed/gas deliveries, water sources and water sanitation. Prior to arrival, ask the farmer to keep recently deceased or currently affected birds for you, to maximise your chance of a rapid diagnosis. Ask if there have been recent disease outbreaks in the area, or previously on the farm. If there have been severe clinical signs or mortalities, recommend that the flock/farm be quarantined until the visit. Depending on the body system involved, there may be more specific details to be gathered. These will be covered, where appropriate, in each of the following chapters. Farm and shed conditions should be the first part of flock examination. Observing the general farm conditions, biosecurity standards, rodent management and wild bird activity can greatly inform the general assessment of the husbandry and management standards employed by the farmer. Inside the shed, indicators such as litter condition, air quality, temperature, humidity, lighting, and the availability of feed and water, are all important factors in disease investigation. Flock behaviour is a good indicator of its general health status. Observations include bird distribution (huddling), general flock activity levels, noise levels, and eating and drinking behaviours. In production systems where birds are not fed ad libitum, observing birds at feeding time is very useful. The examination progresses to considering individual animals, looking for typical cases within the flock. Individual birds are very adept at disguising signs of illness and injury, so it is prudent to take the time to examine several birds to look for consistent clinical signs. Once typical cases have been selected, 5-10 individuals can be selected for necropsy. Ideally, use cull chickens or recently deceased birds to reduce the risk of decomposition interfering with the gross and/or histological assessment, as well as microbiological diagnoses. On commercial farms, if the pathological signs of disease are not easily distinguished, the owner may allow some healthy birds to be euthanased as well to enable direct comparisons. At this point, appropriate samples can be taken for laboratory investigation. Personal biosecurity, hygiene and the use of personal protective equipment should always be adopted when handling potentially infectious or zoonotic birds or samples from them. For advice on these matters, refer to the Australian Veterinary Association guidelines: https://www.ava.com.au/library-resources/other-resources/ veterinary-personal-biosecurity/ If a diagnosis can be made based on clinical signs and gross pathology, a treatment regimen can be commenced immediately. A presumptive bacterial infection would indicate the commencement of antimicrobial therapy only if there is enough time for treatment and the WHP can be complied with. The choice of drug is likely to be influenced by time constraints and food safety considerations as much as by susceptibility considerations. A good rule of thumb is that the recurrence of an identified problem is unsatisfactory! In commercial poultry medicine, preventive medicine is the ultimate goal. There is a wealth of knowledge and there are many tools available to assist a veterinarian in providing advice on disease prevention. Biosecurity, vaccinations, husbandry, nutrition and hygiene practices should all be discussed with a farmer in conjunction with treatment advice in the event of a disease outbreak. Field veterinarian's kit [162] Disposable overalls Water sanitation measurement device (strips measuring free chlorine/ meter/test kit) and/or oxidation-reduction potential meter The digestive tract of birds has a significant number of differences from that of mammals, primarily to allow rapid food consumption and storage, and simple digestion ( Figure 2 ). Each of the organs of the digestive tract of chickens has a specific role in the digestion and absorption of nutrients. The highly refined nature of commercial feedstuffs alters the functional homeostasis of the digestive tract of commercial chickens, leading to slight anatomical differences in organ size and shape from those of the backyard chicken. The composition of the gastrointestinal microbiota (the community of commensal, symbiotic and pathogenic microorganisms) is a key functional component of general and gastrointestinal tract health and productivity in poultry. The digestive tract has historically been the target of non-specific antimicrobial treatments aimed at improving the productivity of flocks, through manipulation of the microbial population. However, increasing awareness of the need for improved antimicrobial stewardship has seen this practice disappear. Many non-antimicrobial interventions (enzymes, organic acids, probiotics, prebiotics, essential oil extracts, yeast extracts) are now available to assist in the maintenance of a healthy gut microbiota, thus removing the need for antimicrobial therapies under normal growing conditions. [164] [165] [166] [167] However, 168 imbalances in the microbiota can and do occur, leading to both clinical disease and subclinical, production-limiting infections. Gastrointestinal tract health is such an important component of bird health and productivity that even subtle non-specific changes to gut health and physiology can have a significant bearing on flock health and performance. It is important for the clinician to have a very good understanding of normal gut morphology and physiology in order to detect mild pathological changes or altered intestinal contents. Wet droppings can be due to either digestive or urinary tract problems. It is important to differentiate between the two early in the case investigation. Before farm entry Look at mortality and production records. Review other farm records. Review current coccidiostat and worming programs. On farm Observe: • 1 A necropsy is the first step towards diagnosis of intestinal disease. With experience and practice, gross lesions are very often diagnostic, particularly for coccidiosis and parasitic burdens. 2 Direct smearclostridial overgrowth, presence of oocysts. 3 Faecal flotationoocyst evaluation. 4 Histopathology. 5 Polymerase chain reaction for differentiation of coccidial species. This is not necessary for a simple diagnosisthe treatment of all Eimeria species is similarbut is useful for monitoring the efficacy of vaccination. 6 Enzyme-linked immunosorbent assay for detection of mycotoxins (collect a feed sample if feed quality is suspected). 1 The history will be important for determining the differential diagnosis. This will include vaccination and flock history, along with overall flock and necropsy signs. 2 It can be prudent to delay treatment until a diagnosis and antimicrobial susceptibility has been established, but this can depend on the level of mortality, the prognosis and the time until slaughter. 3 Treatment is not warranted for viral infections. 4 Coccidiosis is very common in backyard flocks and young chicks will almost invariably be challenged at some point. Older birds will develop immunity and will sporadically shed coccidial oocysts into the environment, thus perpetuating the infection cycle. 5 Intestinal worms are also very common in backyard flocks and a regular treatment program should be encouraged. Background/nature of infection/organisms involved. Coccidiosis results from infection with members of the genus Eimeria. In the chicken, there are four common species, with a couple of less common species. Disease is generally seen in birds around 4-5 weeks of age, but can be seen in older flocks if exposure has been delayed, or if vaccinal immunity has waned. Secondary involvement of Clostridium perfringens can lead to necrotic enteritis. With each diagnosis of coccidiosis, particularly if it is caused by Eimeria maxima and Eimeria necatrix, it is worthwhile performing a direct smear of the intestinal mucosa to look for an overgrowth of Clostridium perfringens, using a gram stain to identify the organism. Treatment. The presence of a few coccidial lesions is a normal occurrence and does not indicate disease or warrant treatment. If coccidiosis is strongly suspected, it is often appropriate to commence a course of anti-coccidial medication based on pathology alone, as delaying treatment could result in high mortality rates because of the explosive course of the disease in intensively raised flocks. Treatment choice is not affected by species of Eimeria, although the response to the treatment can be impacted. Eimeria necatrix infections tend to take longer to respond to treatment due to the severity of the lesions. Anti-coccidials used. Amprolium combined with ethopabate is the treatment of choice for short-lived flocks such as broilers. Toltrazuril is suitable for longer-lived or more valuable birds. Note that there are label restraints for both treatment options that must be followed. Specific details on diseases, prevention and specific treatment choices can be found in Appendix 1. In food-producing species, it is critical that contraindications and WHPs are reviewed as described in the label requirements and guidance in Appendix 2. Background/nature of infection/organisms involved. Necrotic enteritis is caused by Clostridium perfringens. Necrotic enteritis is often found in association with coccidiosis and should be investigated in any suspect coccidiosis outbreak. Clostridium perfringens is a commensal in the chicken digestive tract under normal conditions, but it tends to overgrow and cause clinical disease when there is an excess of nutrients in the jejunum and ileum, which results in changes in the intestinal micro-environment. Treatment. If necrotic enteritis is suspected, then the treatment of choice until the diagnosis is confirmed would be amoxicillin at 20 mg/kg/day for three to five days, depending on the speed of recovery, whilst being aware of withholding periods as it will have good efficacy against Clostridium perfringens, has a short WHP and, since water soluble, can be applied immediately. Another treatment option is Zinc bacitracin in feed at 200ppm active ingredient for 5-7 days. However, as zinc bacitracin is not water soluble and requires in feed treatment this approach may not be practical in a sudden disease outbreak situation such as occurs with necrotic enteritis. Where previous flock history suggests that necrotic enteritis is not able to be controlled with other measures as outlined in Appendix 1 (eg dietary) then preventative treatment with either zinc bacitracin in feed at a rate of 40 ppm (active ingredient) or avilamycin at a rate of 10-15ppm (active ingredient) in feed may be required. The preventative treatment period will usually coincide with the times of coccidiosis challenge on the farm and is fed continuously through this risk period. Probiotics could also be considered as a potential alternative to antibiotics in these situations. The choice of preventative treatment option will depend on applicable poultry species and production type, along with previous successful prevention regimes. Zinc bacitracin can be used as per label directions in poultry with a nil withholding period for meat and egg production. Avilamycin can only be used in broiler chickens. Antibiotic treatment may be useful for necrotic enteritis prevention, but it is not a replacement for poor management, use of aggravating feed ingredients or inadequate coccidiosis control. NOTE: Virginiamycin is also registered for use as a preventative treatment for necrotic enteritis. As it has a 'HIGH' ASTAG rating this antibiotic should only be used as a treatment of last resort and used strictly according to label directions. Antimicrobials used. Specific details on diseases, prevention and specific treatment choices are shown in Appendix 1. In foodproducing species, it is critical that contraindications and WHPs are reviewed as described in the label requirements and guidance in Appendix 2. Background/nature of infection/organisms involved. Dysbacteriosis is an imbalance of the normal bacterial flora, causing mild enteritis with wet droppings, leading to wet floors and dirty feathering, and potentially poor performance. It is mainly seen in broiler flocks. Lesions at necropsy include undigested feed, watery intestinal contents, flaccid intestines with a poor tone and excess caecal volume with gassy contents. Treatment. Antimicrobial treatment is not recommended for dysbacteriosis. It is important to address the underlying cause. Background/nature of infection/organisms involved. Avian intestinal spirochaetosis (AIS) is caused by Brachyspira spp. (most commonly Brachyspira pilosicoli or Brachyspira intermedia). The typical presentation of AIS is a chronic diarrhoea causing stained vents and manure-stained eggs. It is a disease of long-lived floorbased flocks. As the presentation is chronic, it is generally not reported in broiler flocks. Specific details on diseases, prevention and specific treatment choices are shown in Appendix 1. In food-producing species, it is critical that contraindications and WHPs are reviewed as described in the label requirements and guidance in Appendix 2. Background/nature of infection/organism involved. Spotty liver disease is caused by Campylobacter hepaticus. It is a disease of longer-lived floor-living layer and breeder flocks and is rarely seen in caged birds or broilers. Clinical disease is almost invariably associated with a drop in egg production. The disease can occur throughout the year but tends to result in higher mortalities and greater drops in egg production in summer. Antimicrobial treatment, although effective, should not be relied upon for long-term control, as resistance to commonly used antimicrobials occurs rapidly. Specific details on diseases, prevention and specific treatment choices are shown in Appendix 1. In food-producing species, it is critical that contraindications and WHPs are reviewed as described in the label requirements and guidance in Appendix 2. Lincomycinspectinomycin at 100 g combined antibiotic activity/200 L in drinking water for 3-5 days. Background/nature of infection/organisms involved. Histomoniasis (or blackhead) is caused by a protozoan parasite, Histomonas meleagridis. Turkeys are highly susceptible, but disease is also seen in chickens. It is very rare in broilers. Lesions are commonly found in both the caeca (large caseous casts) and the liver (discrete circular lesions). It is often transmitted by the nematode Heterakis gallinae, so control of Heterakis gallinae will assist in control of histomoniasis in chickens. However, direct transmission occurs readily in turkeys. Treatment. There is no currently registered treatment for histomoniasis. Consider control of the vector (Heterakis gallinae) and earthworms to reduce the incidence of disease. Background/nature of infection/organisms involved. There is a wide range of nematodes and cestodes that can affect poultry, some of which are almost invisible to the naked eye. Intestinal worms should always be considered as a differential diagnosis, particularly in free-range flocks. Faecal flotation can be used to detect eggs or tapeworm segments and assess the severity of an intestinal worm burden. Treatment. Specific details on diseases, prevention and specific treatment choices are shown in Appendix 1. In food-producing species, it is critical that contraindications and WHPs are reviewed as described in the label requirements and guidance in Appendix 2. Ascaridia galli Levamisole at 28 mg/kg live weight. As a guide, assuming a medicated water intake of 35 mL/bird over the treatment period, use 800 g levamisole per 900-1000 L drinking water, or 8 g per 10 L water for a small number of birds. The amount of solution prepared should be the volume that will be consumed over 12 h. Remove other sources of water during the treatment period. Note there is a 7-day WHP for meat. Piperazine (adult worms only). The recommended dose for poultry is 200 mg/kg (1 g per 5 kg bodyweight). Use 1 kg of Piperazine Wormer to treat 2500 birds with a bodyweight of 2 kg. The volume of medicated water provided should be able to be consumed by the birds over a 6 to 8 h period. Discard any remaining medicated water after 6-8 h. Add the amount required to a small quantity of water first. When it is completely dissolved, add it to the medication tank, mixing thoroughly. When treating a severe worm infestation, repeat the dose 17-21 days later. John Glisson wrote 'Although much is known about the individual agents responsible for respiratory diseases in poultry, uncomplicated infections with single agents are the exception. Under commercial conditions, complicated infections with multiple aetiologies, with viruses, mycoplasmas and other bacteria, immunosuppressive agents, and unfavourable environmental conditions, are more commonly observed than simple infections'. This combination makes antimicrobial treatment in the face of a disease outbreak both challenging and often unrewarding. It is important to systematically step through all potential predisposing factors including: 1 Interactions between respiratory pathogens 2 Effects of immunosuppressive factors 3 Environmental factors 4 Management of vaccination (including adverse reactions) The respiratory system relies on cilia, mucus and phagocytic cells to protect against infections. High levels of dust and/or high ammonia reduce cilial motility and thus clearance of pathogens trapped in mucus, as well as the function of phagocytes. As a result, disease presentations can be complex, but can be subdivided into the following categories: Functions and unique features of the avian respiratory system As in mammals, the respiratory system in birds is involved in: In contrast to mammalian species, the lungs in birds do not expand. On inspiration air passes through the lungs and into the air sacs, and then on expiration returns through the lungs, taking excess heat and CO 2 and exchanging it with O 2 . The transfer of heat in the air sacs is responsible for a considerable proportion of a bird's heat loss under high temperature conditions. As a result, birds with respiratory disease are much more susceptible to mortality in hot, humid environments. Another unique feature is the intimate association of the air sacs with the some of the bird's bones. Consequently, respiratory infection may also result in a related osteomyelitis (Figures 3 and 4) . 1 The history will be important in determining a differential diagnosis. This will include the vaccination and flock history, along with overall flock and necropsy signs. 2 Most causes of respiratory disease are highly contagious, so quarantine of the affected flock is critical. 3 As mortality can be exacerbated by stress and poor ventilation, these adverse management factors should be minimised. 4 Many causes of respiratory disease can be prevented by vaccination, so vaccination should be considered as a key control strategy for future flocks, along with thorough cleanout and disinfection, strict biosecurity and improved management to ensure high air quality and lower stress. 5 Respiratory disease is very common in backyard poultry flocks. Outbreaks are most commonly attributable to poor biosecurity. It would be prudent to delay treatment until a microbiological diagnosis and antimicrobial susceptibility can be established, but this can be affected by concerns for bird welfare, WHPs, economic considerations, the level of mortalities, and the time until slaughter. If treatment is required before a diagnosis can be established, then the treatment of choice would be a tetracycline, as it will have a broad spectrum of activity against the bacterial agents that are most likely to be involved. Treatment is not warranted for any viral infection. Treatment will not eliminate most bacterial respiratory pathogens. Birds will generally remain carriers, so measures to minimise the risk of spread should be considered. Specific details on diseases, prevention and specific treatment choices are shown in Appendix 1. In food-producing species, it is critical that contraindications and WHPs are reviewed as described in the label requirements and guidance in Appendix 2. Chlamydia psittaci Chlortetracycline at 60 mg/kg for 5-7 days in drinking water, followed by chlortetracycline at 400-750 ppm in feed for a minimum of 2 weeks, depending on the severity of the disease. Oxytetracycline at 70 mg/kg for 5-7 days, followed by infeed medication. Note that this is NOT a suitable treatment for birds producing eggs for human consumption. Tylosin tartrate at 100 g/200 L of drinking water for 3-6 days depending on the severity of the disease (not registered for birds producing eggs for human consumption). In the case of food-producing egg layers and where secondary infection complicates the disease picture, use chlortetracycline at 60 mg/kg bodyweight for 3-5 days, depending on the severity of the disease. Infectious coryza (Avibacterium paragallinarum) Chlortetracycline at 60 mg/kg live weight can be used for 3-5 days, depending on the severity of the clinical signs. Relapse often occurs after treatment is discontinued and treatment with chlortetracycline at 100 ppm in feed for up to 28 days may be required. Amoxicillin a can be used at 20 mg/kg if there is resistance to tetracyclines and sensitivity to amoxicillin has been conformed in vitro. Prior to antimicrobial treatment, collect samples for culture and susceptibility testing. Tetracycline-oxytetracycline at 70 mg/kg for 5-7 days, or chlortetracycline at 60 mg/kg for 5-7 days. Note that oxytetracycline is NOT suitable for treatment of birds producing eggs for human consumption. Fowl cholera outbreaks can recur after cessation of treatment, so in the case of severe disease, chlortetracycline may be required in-feed at 100 ppm for up to 28 days Amoxicillin a at 20 mg/kg for 3-5 days Functions and unique features of the avian musculoskeletal system The avian skeletal system is similar to that of mammals but must balance the requirement for reduced weight to enable flight and the tensile strength needed for structural support. Consequently, the skeleton of a bird has some unique features. The bones of birds are lighter in weight than those of mammals. Some bones are hollow and are part of the avian respiratory system. These bones, called pneumatic bones, include the humerus, clavicle, keel, pelvic girdle, and lumbar and sacral vertebrae. Other important bones in the avian skeleton are the medullary bones. These include the tibia, femur, pubic bone, ribs, ulna, phalanges and scapula. Medullary bones are an important source of calcium when hens are laying eggs. Eggshells are primarily composed of calcium salts, and a hen's body mobilises approximately 47% of its body calcium to make an eggshell. When in production, a commercial laying hen cannot obtain enough dietary calcium to support daily egg production. Without medullary bones from which to draw calcium, the hen would produce eggs with very thin and weak shells ( Figure 5 ). 1 Lameness can have a nutritional, viral, bacterial or traumatic aetiology. 170 Therefore, it is important to ask questions about the feed source, access to feed, and changes in feed and its formulation. This applies to commercial and backyard flocks. 2 As bacteria (particularly Staphylococcus species) can enter the birds well before the onset of clinical lameness, a full history, including early chick quality, the donor source, scratching injuries, respiratory insults, gut health issues (including the quality of the water) and traumatic tendon damage should be recorded. 3 Donor flock information is important for assessing potential viral aetiologies and genetic predispositions. 4 Understanding the rapidity of the growth rate (particularly in broilers) and modifications (such as light programs) is important information. 5 It is important to determine the root cause of infection if Staphylococcus aureus or Escherichia coli are involved. They can enter the blood stream through the skin, the respiratory tract, the intestinal tract or during incubation or hatching. Amoxicillin a at 20 mg/kg for 3-5 days. Chlortetracycline at 60 mg/kg for 5-7 days. Culture and susceptibility testing are necessary to determine an appropriate antimicrobial for treatment because of variation in patterns of resistance. However, the most consistently effective treatment in ducks has been amoxicillin a at 20 mg/kg for 3-5 days. Amoxicillin a at 20 mg/kg live weight for 3-5 days can be used in broilers with respiratory colibacillosis. Chlortetracycline can be used at 60 mg/kg live weight for 3-5 days, depending on the severity of the clinical signs. Non As lameness due to bacterial infection can often be chronic, antimicrobial treatment will often not resolve the problem. Infection will often be secondary to other causes and the penetration of antimicrobials to the sites of infection is often poor. When individual birds are of high value or are considered pets, long-term antimicrobial therapy may improve some less severe cases. Label directions for food-producing animal usage must still be taken into consideration. The exception to this will be when Mycoplasma synoviae or Pasteurella multocida are involved. The vaccination history and other signs in the birds should help differentiate these from other causes, such as Staphylococcus aureus. Use of antimicrobials can often wait until culture and susceptibility are performed, so appropriate sampling is important. Nutritional stress can also trigger bacterial infections. This stress may be due to an inadequate diet, but any factor that inhibits feed intake in some or all birds in the flock can be responsible. Non-bacterial causes of lameness (e.g. nutritional/developmental) should not be treated with antimicrobials. Correcting the nutritional cause should be the priority. Specific details on diseases, prevention and specific treatment choices are shown in Appendix 1. In food-producing species, it is critical that contraindications and WHPs are reviewed as described in the label requirements and guidance in Appendix 2. Antimicrobial susceptibility testing should be performed to ensure that the most efficacious antimicrobial is used. A number of antimicrobials, including amoxicillin a , erythromycin, tylosin, oxytetracycline, and chlortetracycline have been used to treat acute and sub-acute staphylococcal infections. Clinically affected birds respond well early in the course of the disease, but once lameness is seen in birds, treatment efficacy decreases. Antimicrobial susceptibility testing should be performed to ensure that the most efficacious antimicrobial is used. Systemic diseases in poultry can be peracute, acute, sub-acute or chronic. In peracute and acute cases, the challenge when presented with a sudden increase in mortality is differentiation and recognition of exotic and new emerging diseases, so empirical treatment for suspected endemic bacterial pathogens should not be undertaken until exotic and new emerging diseases have been considered. However, if the cause is a primary bacterial infection (such as fowl cholera or erysipelas), then treatment at this stage can be the most successful of any antimicrobial therapy in poultry in terms of reducing morbidity and mortality. In chronic cases, the systemic infection can often be secondary to other factors, especially in the case of colibacillosis, and therefore treatment is often unrewarding until the primary factor is removed. 1 If high rates of mortality with a sudden onset are seen, quarantine should be implemented on the farm prior to the veterinary visit. 2 The veterinarian would be wise to inform government veterinarians of the situation to ensure that laboratory services are ready to perform exotic disease exclusion testing, if necessary. 3 If exotic or zoonotic disease is suspected, ensure that laboratory staff are aware and that birds are transported and submitted to the laboratory in biosecure containers. The history will be important for determining the differential diagnoses. This will include vaccination and flock history, as well as clinical signs in the flock and the necropsy findings. In cases where there is a rapid onset of mortality and a primary bacterial disease is suspected, then treatment with antimicrobials prior to the return of laboratory results is justified on welfare grounds, as the antimicrobial therapy can effectively and fairly rapidly minimise mortalities. Refer to Appendix 1 for the preferred choice of antimicrobial. However, laboratory samples must be taken prior to treatment to confirm the diagnosis and determine the susceptibility of the organism responsible. Specific details on diseases, prevention and specific treatment choices are shown in Appendix 1. In food-producing species, it is critical that contraindications and WHPs are reviewed as described in the label requirements and guidance in Appendix 2. Refer to Appendix 1 for further information, including dose rates, duration of treatment, preferred treatment choice/s and any contraindications. Because of the potentially devastating impact of acute systemic bacterial disease, once an outbreak is controlled with antimicrobials, a future preventive control program must be discussed. This discussion should be held with the diagnosing veterinarian, and a Necropsy 5-10 birds with typical clinical signs or 5-10 birds that have recently died and note findings. Depending on the findings, collect: • Swabs of heart blood from 5-10 affected birds and place into bacterial transport medium • The femur from 5-10 affected birds • Samples from affected tissues (e.g. lung/liver) from 5-10 affected birds If avian influenza or Newcastle disease are suspected, collect swabs from the palatine cleft or trachea and cloacal swabs from 10 affected birds (into viral transport medium). If sudden deaths are seen, collect a sample of feed and any retention samples from the previous week. First choice treatment Second choice treatment Amoxicillin a at 20 mg/kg live weight for 3-5 days can be used in chicken and turkey breeders and broilers. Chlortetracycline at 60 mg/kg bodyweight for 3-5 days. Spotty liver disease (Campylobacter hepaticus) Chlamydia psittaci Refer to Section 9 Fowl cholera (Pasteurella multocida) Escherichia coli (colibacillosis) Do not treat with antibiotics in most cases of colibacillosis. Instead, try to investigate and correct the root cause. If treatment is undertaken, in young birds trimethoprim/ sulphonamide combinations can occasionally have a Colibacillosis in young birds can be treated with lincomycin-spectinomycin at 100 g combined antibiotic activity/200 L of drinking water. Colibacillosis in older birds can be treated with chlortetracycline at 60 mg/kg live weight for government veterinarian may assist in development of future biosecurity plans. These plans should include biosecurity measures, cleaning and disinfection, rodent control and possible vaccination strategies. This is critical to ensure that antimicrobials are not relied upon as a future preventive strategy. Reproductive tract disorders can have several sequelae, including loss of production, loss of egg quality (both external and internal), and reduced fertility and/or hatchability. A good understanding is needed of the development of both an egg and an embryo in order to gain insights into the location and timing of developmental abnormalities. Records of production are usually readily available and are extremely useful tools when investigating egg production problems. Specific records related to egg production include: • Hen-day egg production rates • Hen-housed egg production rates • Egg weights • Fertility (%) • Hatchability (%) • Egg recovery rates (percentage of first grade eggs) • Eggshell defectsthin shells, pale shells, other shell deformities • Shell-less egg residues noticed in sheds Request that the farm keep: • Dead birds aside for you • Deformed eggs aside for assessment Structure and features of the female reproductive system 1 Ovaryconsists of a cluster of developing ova or follicles, and is fully developed at birth, but follicles only start to develop at the commencement of sexual maturity. Follicles develop sequentially, usually one every 24 h, which allows for daily production of a single ovum, or egg. 2 Infundibulumthe infundibulum is like a patent funnel that engulfs the follicle and feeds it into the oviduct. Fertilisation of the ovum occurs in the infundibulum. 3 Magnumthis is the largest part of the oviduct, and it is here that thick albumen is laid down. 4 Isthmusthis is where inner and outer shell membranes form. 5 Tubular shell glandthis is where shell calcification commences. 6 Shell gland pouchthe majority of shell deposition and, finally, shell pigment is laid down in this section of the oviduct. 7 Vaginathe shell cuticle is deposited on the fully formed egg as it passes through the vagina during the process of laying. 8 Cloacais the single cavity receiving faeces, uric acid and eggs prior to discharge. 9 Ventthe external opening of the digestive and urogenital tracts. 10 Vestigial (persistent) right oviductthis blind sac serves no functional purpose, but often fills with clear, water-like fluid ( Figure 6 ). The reproductive system of a layer or breeder hen is highly active, cycling daily to produce an egg as often as every 24 h. Hens can store sperm for up to 10 days, so daily mating is not required. Semen is stored in sperm storage tubules in the oviduct. Fertilisation of the ovum occurs after ovulation, in the infundibulum. 1 Dietary and environmental changes can have significant effects on reproductive performance in hens and should always be considered when investigating egg production problems. beneficial impact on early omphalitis/yolk sac infection. Treat with trimethoprim/sulphadiazine at a dose rate of 25 mg sulphadiazine/kg and 5 mg trimethoprim/kg per day for 3-5 days if the birds are less than 2 weeks old, or 12.5 mg sulphadiazine/kg and 2.5 mg trimethoprim/kg per day for 3-5 days if the birds are older than 2 weeks of age. In older birds amoxicillin a can be used at 20 mg/kg live weight for 3-5 days in broilers with respiratory colibacillosis or birds with reproductive tract colibacillosis. 3-5 days, depending on the severity of the clinical signs. Refer to Section 10 Riemerella anatipestifer Refer to Section 9 Salmonella species Refer to Section 8 2 Reproductive disease is seen most frequently, but not exclusively, in high egg production commercial poultry breeds over 2 years of age. 3 Reproductive disease is common in backyard poultry. 4 Some of the most commonly seen reproductive diseases in clinical practice include egg yolk coelomitis, egg dystocia, pyometra, oviductal prolapse, and ovarian and oviductal neoplasia. The history will be important for determining the differential diagnoses. This will include vaccination and flock history, as well as clinical signs in the flock and the necropsy findings. It would be prudent to delay antimicrobial treatment until a bacteriological diagnosis and susceptibility can be established. Most causes of reproductive system disease are non-infectious, so a thorough investigation of non-infectious causes is warranted. Primary bacterial causes of reproductive disease are very uncommon and a decision to use antimicrobials should only be made once a specific diagnosis has been made. Depending on the underlying cause, treatment may consist of medical or surgical therapy. Euthanasia is often required for neoplastic causes of reproductive disease because of the frequent occurrence of metastasis. Primary egg production drops In all instances of egg production drops, husbandry, lighting, feed and water intake, nutrition and environmental stresses must be considered early in the investigation Differential diagnosis Specific details on diseases, prevention and specific treatment choices are shown in Appendix 1. In food-producing species, it is critical that contraindications and WHPs are reviewed as described in the label requirements and guidance in Appendix 2. Refer to Section 9 The avian immune system shares many similarities with that of mammals, but also has some fundamental differences. The avian system has a cell-mediated and a humoral immune system, essentially as in mammalian systems. The thymus, bursa of Fabricius and bone marrow are primary lymphoid organs, while the spleen, mucosal associated lymphoid tissues germinal centres, and diffuse lymphoid tissues are secondary lymphoid organs. Birds do not have lymph nodes. The thymus, where T cells develop, is a lobulated organ located in the neck, running parallel to the cervical artery and jugular vein. The bursa of Fabricius is an organ that is unique to birds and is the site of B cell development, differentiation and maturation. Located dorsal to the rectum, this organ contains stem cells and is highly active in young birds, but atrophies after about 6 weeks. There are diffuse lymphoid accumulations in the head and associated with the respiratory system and gastrointestinal tract, such as the Harderian gland, located behind the eyes, and the Peyer's patches, in each of the caeca, just proximal to the junction of the caecum with the colon. If no clear gross lesions are identified, or confirmation of diagnosis is required, then collect samples of the brain and/or affected nerves for histopathology. Swab typical lesions and submit swabs for laboratory testing by polymerase chain reaction and/or culture and susceptibility testing. Collect swabs of the heart blood from 5-10 affected birds and place into bacterial transport medium. Collect blood samples from 10 birds for serology to detect evidence of viral infection. Collect feed samples for testing if vitamin deficiencies are suspected. increase the susceptibility of birds to secondary bacterial, viral and fungal infections. The presentation of a primary immunosuppressive disease is often complicated by secondary infections, making diagnosis of the primary disease more complex, but also more important. Treatment of secondary infections can be unrewarding if the primary cause of disease is not managed correctly. The secondary pathogen most frequently encountered because of immunosuppressive disease is Escherichia coli. Persistence of immunosuppressive viruses in the environment will result in ongoing secondary infections in subsequent flocks. It is therefore imperative to implement preventive measures, such as thorough cleaning and disinfection of facilities, and vaccination, to minimise the impact of these viruses on subsequent flocks. One of the more common disease entities encountered in poultry practice is that of poor chick health and vitality, and early chick mortality. Day-old chicks are highly susceptible to environmental and infectious disease challenges and can succumb rapidly. It is generally accepted that mortality issues in the first 3-4 days are more likely associated with the source hatchery, or the source breeder flock. In this instance, investigations should go beyond the individual affected flock to other flocks derived from the same breeder flocks or hatchery. This will often provide important information about the cause of the problem. Brooding conditions are also critical to the successful early development of a chick. Mortalities starting after 4 days of age can often be attributed to brooding issues, primarily either environmental stresses or poor hygiene. Specific details on diseases, prevention and specific treatment choices are shown in Appendix 1. In food-producing species, it is critical that contraindications and WHPs are reviewed as described in the label requirements and guidance in Appendix 2. Treatment of young chicks is often unrewarding as it is difficult to entice them to drink or eat, leading to rapid loss of vitality and unsatisfactory intake of medication. For this reason, the most humane option for the welfare of sick young chicks is often euthanasia. Necropsy 10-20 cull chicks with typical clinical signs or 10-20 chicks that have recently died and note findings. Submit whole live chicks to the diagnostic laboratory. Swab typical lesions or sample tissues and submit swabs and/or tissues for laboratory testing by polymerase chain reaction and/or culture and susceptibility testing. The history will be important for determining the differential diagnoses. This will include a total review of brooding conditions, vaccination history and the flock history, as well as clinical signs in the flock and the necropsy findings. It would be prudent to delay antimicrobial treatment until a bacteriological diagnosis and susceptibility can be established. Omphalitis (navel ill, yolk sac infection, mushy chick disease) Diseases of turkeys, ducks and other poultry When dealing with unfamiliar species or unfamiliar disease scenarios, it is prudent to use first principles, then investigate and treat based on the premise that all species of poultry are similar at a base level, but refer to Appendix 2 for a list of known or possible exceptions. From that base, knowledge can be acquired from the owner, from references and textbooks and from experienced poultry and avian veterinarians to assist with diagnosis and treatment. However, it should be noted that products registered for chickens may not be registered for other species. Check the label for the registration status and contraindications in the species you are wishing to treat. There are some products used in one species that may be toxic for another. For example, salinomycin is toxic for turkeys. There are several disease entities that occur in a wide range of species, so it is worthwhile referring to Appendix 1 and the specific system sections for references to diseases encountered. Each disease is covered either in the specific system involved or in Appendix 1. Antimicrobial decision tree Use of antifungal disinfectants such as enilconazole. Feed and litter antifungal additives may be helpful in control, but ensure they meet food safety requirements. Effective treatment for avian aspergillosis and other fungal infections is not available. To investigate the source of fungal infections, microbiological monitoring of the hatchery and the litter source can be helpful, as long as results are interpreted in the light of normal source environmental levels. Avian tuberculosis (Mycobacterium avium) All ages susceptible, but more likely in older birds. All species. Weight loss. Irregular, discrete, greyish yellow or greyish white nodules in spleen, liver and intestine. Quarantine/biosecurity (infection risk for birds placed in previously contaminated premises or in-contact with infected birds). Source clean stock (quarantine new additions to the aviary for 60 days and retest with avian tuberculin). Treatment unsuccessful. More likely to be seen in backyard and zoo birds. Crop mycosis (candidiasis; Candida albicans) All ages, but young more severely affected. Chickens, turkeys, geese, pigeons, guinea fowl, pheasants, quail. Poor growth, stunting. Crop/oral mucosal thickening with white to off-white, raised lesions. May present as a pendulous crop. Opportunistic endogenous mycosis that results from disturbance of microflora or immunosuppression. Correct management factors, such as water and feed hygiene, husbandry and nutrition. Copper sulfate at a 1:2000 dilution in the drinking water may be helpful, but effectiveness is questionable. Antimicrobials are contraindicated. Cannibalism (feather/ vent pecking) All ages, but especially young adults. Chickens, turkeys (there is a genetic predisposition in some strains). Vary from pecking without removal of feathers to plucking of feathers. Egg production may drop. Pecking of the vent can also be observed soon after birds come into lay and can be responsible for 80% of all prolapses and may trigger salpingitis and egg peritonitis. Chickens -broiler strains. Caseous plaques in subcutaneous tissue of skin over the abdomen or between thigh and midline. Lesions develop rapidly. More common in males. Predisposed by skin scratching. Longer treatments maybe required for elimination of the organism and retesting maybe required prior to processing. Absorption of oxytetracycline and chlortetracycline may be reduced by calcium in the diet and the level of active drug may be reduced by heat treatment of feed. Zoonotic potential and notifiable in some states. Higher than labelled dose rates or duration may require extension of the withholding period and is the responsibility of the veterinarian. Normally young birds, but all ages affected depending on time of exposure. All, but coccidial species involved will vary between hosts. Mortality, diarrhoea, poor feed conversion and growth rate. Depending on the Eimeria species and the level of infection, gross lesions in the intestine will vary from haemorrhage and ballooning to inapparent. Vaccination, often at the hatchery using gel technology (used primarily in breeders and layers, but also an increasing number of broilers). Should be well controlled with coccidiostats if used at the correct levels in feed. Recommendation: Amprolium/ ethopabate in water is the primary treatment of choice in chicken broilers when in-feed medication control is insufficient. When in a concentration of 216 g amprolium/L and 14 g ethopabate/L, a rate of 500 mL-1000 mL/900 L drinking water for 5-7 days may be required, depending on the severity of the disease. Pathogen/disease This product is registered for all poultry with a nil withholding period for meat, but cannot be used for egg layers where eggs are used for human consumption. Amprolium alone (without ethopabate) (200 g/kg) can be used at 5 g/4 L for 5-7 days followed by 3 g/4 L for 5-7 days to treat an outbreak. This product can be used in chicken egg and meat birds, as well as in ducks, turkeys and pigeons. There is a nil withholding period for eggs and meat. Toltrazuril (Baycox) in water is more effective in stopping an outbreak of mortality due to coccidiosis, but it is registered only for chickens, has a withholding period of 14 days for meat, and cannot be used for birds that will be laying eggs within 8 weeks of treatment. Treatment is 3 L/1000 L for 2 consecutive days. Sulphaquinoxaline can also be used, but also has a withholding period that may make it unsuitable for meat birds. There is also a risk of vitamin K deficiency. It is the least preferred treatment. Colibacillosis (Escherichia coli) Any age, but especially young birds. All species. Review feed and water hygiene. Most Salmonella species infections in birds cause no pathology, mortality or illness and the concern relates more to food safety. Adult birds. Chickens. Delayed and/or reduced egg production and wet faeces. Biosecurity to prevent organism entry, especially to prevent wild bird contact, including via the water and feed supply. Avoid mixed farming enterprises. Good rodent control. Difficult to diagnose Brachyspira and assess whether antimicrobials have a positive impact on faecal moisture content. Treatment with antimicrobials should be based on confirmed diagnosis. Antimicrobials are rarely used for this condition in Australia, but if treatment is warranted, chlortetracycline as an in-feed treatment at 400 ppm for 7 days, followed, if necessary, by inclusion in-feed at 200 ppm for up to 28 days is a suitable option. Some evidence that essential oils have had a positive effect on infections of pigs with Brachyspira species. 174 Spotty liver disease (Campylobacter Adult birds around point of lay. Spotty liver disease is an acute, randomly distributed, focal, necrotic hepatitis causing mortality in up to 10% of a flock and a 10%-15% fall in egg production. Biosecurity improvements appear to have had some success. These include measures such as: • using specific boots and clothing for the shed. Once sites are contaminated with the bacteria and they become endemic. Birds often develop disease early in lay and clinically affected flocks will require antimicrobial therapy with tetracyclines. An alternative approach to medication noted by some veterinarians is, • improving cleaning of sheds and ensuring good terminal disinfection. • water acidification and chlorination. Reducing management/stress factors, such as improving cooling of sheds, reduces incidence. Preventive medications are NOT appropriate. Feed additives such as probiotics, prebiotics, phytogenics, short chain and medium-chain fatty acids in feed have not resulted in a significant improvement. outbreak. This will reduce mortality and treatment will probably not be required. The meat WHP for broilers is also applicable to meat chickens previously used as laying hens or broiler breeder. b Always read label carefully and follow label directions for use. c All actives can be associated with adverse effects, especially at higher than labelled dose rates. However, special note should be taken of label cautions for nicarbazin (use in hot weather), sulfaquinoxaline and tiamulin (drug interactions). Antibacterial agents approved for use in non-food-producing avian species: carnidazole, dimetridazole, doxycycline, ronidazole. Use in food-producing birds is extra-label. Note: not all registered antimicrobial agents are used or available for use. IMPORTANCE (ASTAG 2018): importance for human medicine; nhu, no human use. 175 Target Bird: Pullets -rearing hens prior to point of lay; Pullets -check label, only some products can be used in pullets, Hens -hens in lay. Withholding period for Eggs: DNU -do not use in egg laying birds; DNU* -withholding period in pullets is product specific. Funding for these guidelines was provided by the Australian Veterinary Association (AVA), Animal Medicines Australia (AMA), and Agrifutures Australia as part of the Agrifutures Chicken Meat Program. These guidelines would not have been possible without the considerable expertise and efforts of the Expert Panel authors: Dr Peter Gray, Dr Rod Jenner, Dr Stephen Page, Professor Jacqueline Norris, and Professor Glenn Browning. Additional in-kind contributions were made by the Australian Veterinary Association, Animal Medicines Australia, and NSW Department of Primary Industries. Antimicrobial stewardship in veterinary medicine, in antimicrobial resistance in bacteria from livestock and companion animals Review of antimicrobial therapy of selected bacterial diseases in broiler chickens in Canada Antimicrobial therapy of selected diseases in turkeys, laying hens, and minor poultry species in Canada Formulation and (bio)availability problems of drug formulations in birds Antimicrobial drug use in poultry Antimicrobial therapy (including resistance) Quantitative and qualitative analysis of antimicrobial usage at farm and flock level on 181 broiler farms in nine European countries The use of antimicrobial agents in broiler chickens Guidelines for antimicrobial use in poultry Practical and pharmacological considerations for the administration of antibacterial drugs in poultry. A review Drug administration to poultry Depletion of tylosin residues in feathers, muscle and liver from broiler chickens after completion of antimicrobial therapy Oxytetracycline transfer into chicken egg yolk or albumen Transference of dietary veterinary drugs into eggs Transfer and distribution profiles of dietary sulphonamides in the tissues of the laying hen Pharmacokinetics of veterinary drugs in laying hens and residues in eggs: a review of the literature Residues of veterinary drugs in eggs and their distribution between yolk and white Withdrawal times of oxytetracycline and tylosin in eggs of laying hens after oral administration Drug residues in poultry meat: a literature review of commonly used veterinary antibacterials and anthelmintics used in poultry Residues of aminoglycoside antibiotics in eggs after medication of laying hens Sulphonamide residues in eggs following drug administration via the drinking water Residues of macrolide antibiotics in eggs following medication of laying hens Excretion of oxytetracycline in eggs after medication of laying hens Excretion of tetracycline and chlortetracycline in eggs after oral medication of laying hens Residues of sulfadiazine and doxycycline in egg matrices due to cross-contamination in the feed of laying hens and the possible correlation with physicochemical, pharmacokinetic and physiological parameters Comparative pharmacokinetics and bioavailability of amoxycillin in chickens after intravenous, intramuscular and oral administrations Pharmacokinetics and bioavailability of spectinomycin after i.v., i.m., s.c. and oral administration in broiler chickens Kinetic disposition, systemic bioavailability and tissue distribution of apramycin in broiler chickens Pharmacokinetics of amoxicillin in broiler chickens Plasma disposition and tissue depletion of chlortetracycline in the food producing animals, chickens for fattening Pharmacokinetics and oral bioavailability of sulfadiazine and trimethoprim in broiler chickens A study in the pharmacodynamics of oxytetracycline in the chicken The pharmacokinetics of avian therapeutics Pharmacotherapeutic aspects of medication of birds Pharmacokinetic aspects of penicillins, aminoglycosides and chloramphenicol in birds compared to mammals. A review Serum concentrations and tissue residues of spectinomycin in chickens Pharmacotherapeutics for veterinary dispensing Some pharmacokinetic aspects of four sulphonamides and trimethoprim, and their therapeutic efficacy in experimental Escherichia coli infection in poultry Pharmacokinetics and tissue residue profiles of erythromycin in broiler chickens after different routes of administration Pharmacokinetics of gentamicin and apramycin in turkeys roosters and hens in the context of pharmacokineticpharmacodynamic relationships Pharmacokinetics of drugs in avian species and the applications and limitations of dose extrapolation Comparative pharmacokinetics and bioavailability of tylosin tartrate and tylosin phosphate after a single oral and i.v. administration in chickens Pharmacokinetics and clinical assessment of amoxicillin for the control of necrotic enteritis in broiler-breeders under field conditions Pharmacokinetics of tylosin in broiler chickens Pharmacokinetic parameters of amoxicillin in pigs and poultry Pharmacokinetics of doxycycline in turkeys and comparison between feed and water medication Blood level studies in chickens, turkey poults and swine with tiamulin, a new antibiotic Drug plasma levels following administration of trimethoprim and sulphonamide combinations to broilers Plasma disposition and renal clearance of sulphadimidine and its metabolites in laying hens Pharmacokinetics of sulfamethoxazole and trimethoprim association in hens Administration of doxycycline hydrochloride via drinking water to turkeys under laboratory and field conditions Serum levels of penicillin, dihydrostreptomycin, chloramphenicol, aureomycin and terramycin in chickens Pharmacokinetics and relative bioavailability of tiamulin in broiler chicken as influenced by different routes of administration Pharmacokinetics of oxytetracycline in broiler chickens following different routes of administration Preliminary clinical pharmacological investigations of tylosin and tiamulin in chickens Antimicrobial use and antimicrobial resistance indicators-integration of farm-level surveillance data from broiler chickens and Turkeys in British Columbia Treatment of a field case of avian intestinal spirochaetosis caused by Brachyspira pilosicoli with tiamulin Effects of tylosin on bacterial mucolysis, Clostridium perfringens colonization, and intestinal barrier function in a chick model of necrotic enteritis Efficacy of tiamulin alone or in combination with chlortetracycline against experimental Mycoplasma gallisepticum infection in chickens Efficacy of Linco-Spectin water medication on Mycoplasma synoviae Airsacculitis in broilers Effect of a single injection of lincomycin, spectinomycin, and linco-spectin on early chick mortality caused by Escherichia coli and Staphylococcus aureus Efficacy of Linco-Spectin medication on mycoplasma meleagridis airsacculitis in turkey poults Efficacy of lincomycin-spectinomycin water medication on Mycoplasma meleagridis airsacculitis in commercially reared turkey poults The effect of apramycin on colonization of pathogenic Escherichia coli in the intestinal tract of chicks Comparison of the efficacy of four antimicrobial treatment schemes against experimental Ornithobacterium rhinotracheale infection in turkey poults pre-infected with avian pneumovirus Efficacy of neomycin sulfate water medication on the control of mortality associated with colibacillosis in growing turkeys Comparative evaluation of therapeutic efficacy of sulfadiazine-trimethoprim, oxytetracycline, enrofloxacin and florfenicol on Staphylococcus aureus-induced arthritis in broilers Oral administration of antimicrobials increase antimicrobial resistance in E. coli from chicken-a systematic review The drug tolerant persisters of Riemerella anatipestifer can be eradicated by a combination of two or three antibiotics Pharmacokinetic/pharmacodynamic profiles of tiamulin in an experimental intratracheal infection model of Mycoplasma gallisepticum Determination of the mutant selection window and evaluation of the killing of Mycoplasma gallisepticum by danofloxacin, doxycycline, tilmicosin, tylvalosin and valnemulin The injection of turkey hatching eggs with tylosin to eliminate Mycoplasma meleagridis infection Injecting antibiotics into turkey hatching eggs to eliminate Mycoplasma meleagridis infection In ovo applications in poultry: a review Are nursing infusion practices delivering fulldose antimicrobial treatment? Dose imprecision and resistance: freechoice medicated feeds in industrial food animal production in the United States Poultry drinking water primer Oral medication via feed and water -pharmacological aspects Problems with oral administration of antimicrobially effective substances in animals-the situation with poultry Occurrence and characterisation of biofilms in drinking water systems of broiler houses Use of antimicrobial agents in livestock Feed and water consumption and performance of male and female broilers fed salinomycin and maduramicin followed by a withdrawal ration Technical problems of drug therapy through drinking water Species differences in pharmacokinetics and pharmacodynamics The ratio of the water and food consumption of chickens and its significance in the chemotherapy of coccidiosis Studies on comparative drug metabolism by hepatic cytochrome P-450-containing microsomal enzymes in quail, ducks, geese, chickens, turkeys and rats Implications of hepatic cytochrome P450-related biotransformation processes in veterinary sciences Cytochrome P450-dependent monooxygenase activities and their inducibility by classic P450 inducers in the liver, kidney, and nasal mucosa of male adult ring-necked pheasants Cytochrome P450 enzymes in chickens: characteristics and induction by xenobiotics Effect of age on hepatic cytochrome P450 of Ross 708 broiler chickens Hepatic CYP isoforms and drugmetabolizing enzyme activities in broiler chicks Oxidative monensin metabolism and cytochrome P450 3A content and functions in liver microsomes from horses, pigs, broiler chicks, cattle and rats Drug metabolism in birds Avian cytochrome P450 Veterinary Toxicology Avian forms of cytochrome P450 The monooxygenases of birds, reptiles and amphibians The activity and compatibility of the antibiotic tiamulin with other drugs in poultry medicine-a review Effect of sulfamethazine on mixed function oxidase in chickens Alteration of avian hepatic cytochrome P450 gene expression and activity by certain feed additives Effects of dietary sodium butyrate on hepatic biotransformation and pharmacokinetics of erythromycin in chickens Age-related P-glycoprotein expression in the intestine and affecting the pharmacokinetics of orally administered enrofloxacin in broilers Expression of MDR1, MRP2 and BCRP mRNA in tissues of turkeys Expression of drug efflux transporters in poultry tissues Implications of ABC transporters on the disposition of typical veterinary medicinal products In vitro model to assess the adsorption of oral veterinary drugs to mycotoxin binders in a feed-and aflatoxin B1-containing buffered matrix Interaction between tylosin and bentonite clay from a pharmacokinetic perspective In vitro adsorption and in vivo pharmacokinetic interaction between doxycycline and frequently used mycotoxin binders in broiler chickens Influence of mycotoxin binders on the oral bioavailability of tylosin, doxycycline, diclazuril, and salinomycin in fed broiler chickens The use of biochar in animal feeding Comparison of low dietary calcium and sodium sulfate for the potentiation of tetracycline antibiotics in broiler diets Pharmacokinetics of chlortetracycline potentiation with citric acid in the chicken The pharmacokinetics of chlortetracycline orally administered to turkeys: influence of citric acid and Pasteurella multocida infection Pharmacokinetic and tissue distribution of doxycycline in broiler chickens pretreated with either: diclazuril or halofuginone Pharmacokinetic interactions of flunixin meglumine and doxycycline in broiler chickens Effect of three polyether ionophores on pharmacokinetics of florfenicol in male broilers The effect of hepatic microsomal cytochrome P450 monooxygenases on monensin-sulfadimidine interactions in broilers Biochemical background of toxic interaction between tiamulin and monensin Compatibility of a combination of tiamulin and chlortetracycline with salinomycin in feed during a pulsed medication program coadministration in broilers Simultaneous administration of silymarin and doxycycline in Japanese quails suggests probable herb-drug interaction Influence of hard water on the bioavailability of enrofloxacin in broilers Hard water may increase the inhibitory effect of feed on the oral bioavailability of oxytetracycline in broiler chickens Effects of erythromycin-inactivating Lactobacillus crop flora on blood levels of erythromycin given orally to chicks Degradation of macrolide-lincosamidestreptogramin antibiotics by Lactobacillus strains from animals Pharmacokinetics and bioavailability of doxycycline in fasted and nonfasted broiler chickens Antibacterial activity of amoxicillin in vitro and its oral bioavailability in broiler chickens under the influence of 3 water sanitizers Influence of chlorine, iodine, and citrate-based water sanitizers on the oral bioavailability of enrofloxacin in broiler chickens Patient variation in veterinary medicine: part I. Influence of altered physiological states Population variability in animal health: influence on dose-exposure-response relationships: part I: drug metabolism and transporter systems Population variability in animal health: influence on dose-exposure-response relationships: part II: modelling and simulation Patient variation in veterinary medicine-part IIinfluence of physiological variables Impact of age and growth of chickens and turkeys on pharmacokinetics of anti-bacterial drugs: a brief review Blood and tissue content of sulfamethazine and sulfaquineoxaline in broilers following medication with drinking water. A contribution to mass medication in poultry The influence of rapid growth in broilers on florfenicol pharmacokinetics -allometric modelling of the pharmacokinetic and haemodynamic parameters Antimicrobial resistance profiling of Gallibacterium anatis from layers reveals high number of multiresistant strains and substantial variability even between isolates from the same organ Circadian serum concentrations of tylosin in broilers after feed or water medication Effect of the period of the day on the pharmacodynamics of sulfadimidine in chickens. 4. Studies on sulfonamides Pharmacokinetic changes of several antibiotics in chickens during induced fatty liver Nutrient sensing, taste and feed intake in avian species Effects of coccidiostats and dietary protein on performance and water consumption in broiler chickens Plasma concentrations resulting from florfenicol preparations given to pigs in their drinking water Pharmacokinetics of antibiotics and sulphonamides in hens and cocks. Sex-related differences Pharmacokinetics of tobramycin in ducks and sex-related differences Pharmacokinetics and oral bioavailability of amoxicillin in chicken infected with caecal coccidiosis The influence of growth and E. coli endotoxaemia on amoxicillin pharmacokinetics in turkeys Oral absorption of chlortetracycline in turkeys: influence of citric acid and Pasteurella multocida infection Plasma and tissue pharmacokinetics of danofloxacin in healthy and in experimentally infected chickens with Pasteurella multocida Comparative pharmacokinetics of danofloxacin in healthy and Pasteurella multocida infected ducks Pharmacokinetics of difloxacin in healthy and E. coli-infected broiler chickens Disposition kinetics of doxycycline in chickens naturally infected with Mycoplasma gallisepticum coli infection modulates the pharmacokinetics of oral enrofloxacin by targeting P-glycoprotein in small intestine and CYP450 3A in liver and kidney of broilers Tissue distribution and disposition kinetics of enrofloxacin in healthy and E. coli infected broilers Pharmacokinetics of florfenicol in healthy and Escherichia coli-infected broiler chickens Comparative pharmacokinetics of florfenicol in healthy and Pasteurella multocida-infected Gaoyou ducks Pharmacokinetics of florfenicol in normal and Pasteurellainfected Muscovy ducks Pharmacokinetics and tissue residues of kitasamycin in healthy and diseased broilers Comparative pharmacokinetics of levofloxacin in healthy and renal damaged muscovy ducks following intravenous and oral administration Comparative pharmacokinetics of orbifloxacin in healthy and Pasteurella multocida infected ducks Pharmacokinetic aspects of a sulphachloropyridazine trimethoprim preparation in normal and diseased fowl Rational use of chemotherapeutics Post Grad Committee in Veterinary Science in association with Australian Veterinary Poultry Association New issues and science in broiler chicken intestinal health: emerging technology and alternative interventions Use of antibiotics in broiler production: global impacts and alternatives Alternatives to antibiotics for maximizing growth performance and feed efficiency in poultry: a review EMA and EFSA joint scientific opinion on measures to reduce the need to use antimicrobial agents in animal husbandry in the European Union, and the resulting impacts on food safety Botanical alternatives to antibiotics for use in organic poultry production Infectious skeletal disorders in poultry A wire-flooring model for inducing lameness in broilers: evaluation of probiotics as a prophylactic treatment Critical review: future control of blackhead disease (histomoniasis) in poultry Mycoplasma gallisepticum infection In vitro sensitivity of poultry Brachyspira intermedia isolates to essential oil components and in vivo reduction of Brachyspira intermedia in rearing pullets with cinnamaldehyde feed supplementation Importance ratings and summary of antibacterial uses in human and animal health in Australia The work of Project Manager Dr Amanda Black is gratefully acknowledged, as are the contributions of the project Steering Committee members Dr Phillip McDonagh, Dr John Messer, Professor James Gilkerson, and Dr Melanie Latter.