Summary

The increased flexibility offered by medicating water as compared to either parenteral or in~feed medication makes it an attractive alternative. Water medication has also been successfully used as an adjunct to these other methods of treatment, often as an immediate response to a herd outbreak, in situations where severely ill pigs are individually treated by a parenteral route, and control of disease in more mildly affected pigs is commenced before feed medication arrives. From a pharmacological point of view, when combining treatment methods, there are certain advantages in using the same antibiotic. There is likely to be an increasing number of' antibiotics which exist in formulations appropriate to each of these uses, thereby Facilitating the synchronised use of administration routes.

Introduction

Infectious pneumonias caused by viruses, mycoplasmas and bacteria constitute a major problem in countries all over the world. Estimates of economic loss attributable to infectious respiratory disease in pigs (Muirhead 1979; Kavanagh and Mortimer 1996) have been projected. The economic losses in production can be very substantial. In 1995, in Europe, there were 110.9 million pigs, which accounted for 742 million ECU of animal health sales, which is 23% of the total European animal health market. Forty-one percent of these animal health sales were antibacterial products (Anon 1997). In the survey described in this paper, it was found that most veterinarians recommend prophalaxis over and above waiting for the appearance of clinical symptoms and the use of vaccines for prophalaxis is common although not as universal as the use of antibiotics. Water medication is used routinely throughout the European Union. Efficacy, cost and convenience are the key parameters used by veterinarians in choosing this in preference to other methods of herd medication.

The design of the water delivery system, palatability of the medication, water quality and promptness of delivery are all important to maximise the effectiveness of medication in the water. Differences in water supply to newly weaned pigs have been shown to result in differences in growth rate of at least 18% and Feed Conversion Ratio (FCR) of at least 4%, while in growing pigs the effect on growth rate was found to be at least 5% and on FCR 5.5.% (Brooks and Carpenter 1989). These effects on the healthy pig are of significant economic importance to the producer and are increased in the clinically ill animal. It is therefore vital to consider water supply to animals together with any discussion of medication, both for the above reason and in order to maximise the intake of medication. This paper is a synthesis of a survey of practitioners from across Europe and data from a number of studies conducted by the author during the development of water medication product candidates.

Materials and Methods

A survey involving the interview of 266 pig veterinarians in eight European countries was conducted. The countries involved were Denmark, France, Germany, Italy, The Netherlands, Poland, Spain, United Kingdom and approximately 30 interviews were conducted (50 in Germany) in each. Because response rates to written questionnaires are typically low, oral interviews based upon a standard questionnaire but conducted in the local language were used.

Five separate animal studies were conducted, each involving 60 growing pigs with bodyweights at the beginning of the trial between 25 and 30 kg, divided into replicates of 8 - 12 pigs. The water intake of pigs was recorded throughout the trial period in each trial. Trials lasted 14 days. Water usage was measured using graduated header tanks directly connected to sueva cup drinkers, containing a nipple valve which released water into the pig's mouth on contact. Intake was calculated by subtracting the water remaining in the cups or collected in a bowl beneath the slats under the cup, from the total amount delivered from the tank.

Trial 1: A precise measurement of water intake in healthy pigs of unmedicated and medicated water at different inclusion levels was conducted.

Trials 2,3,4,5: Pigs were artificially infected with 4 field isolates of Actinobacillus pleuropneumoniae. Two involved serotype 3, whilst one of each of the other trials involved the use of serotype 9 and 5a. The effect upon water intake of these infections was monitored.

Results

The organisms found to be most commonly associated with outbreaks of bacterial pneumonias were Mycoplasmae, Pasteurellae and Actinobacilli.


In growing pigs it was found that in the majority of cases when presented with an outbreak of pneumonia, either the whole herd or all in contact pigs were treated.

Overall, the most used antibiotics as prophylactics were in order of volume; tetracyclines, macrolides, tiamulin combinations, followed by sulphonamides and penicillins.

The requirements of an ideal chemotherapeutic to deal with outbreaks of respiratory disease in pigs:

1. Relevant spectrum of anti-bacterial activity.
2. High bioavailability and relevant organ and cellular partitioning.
3. Easy to administer.
4. Cost effective.

Spectrum of activity

In terms of spectrum the major organisms being targeted are the Gram negative pathogens (Pasteurella and Actinobacillae) in addition to mycoplasma spp. Of the gram positives Streplococci and, on occasions, Staphylococci are also worth bearing in mind. In specific cases, but less commonly, other species may be implicated. In essence this defines the choice of chemotherapeutic. Based upon site history, or in some occasions a very clear pathological picture, a chemotherapy of specific activity may be chosen. More commonly the involvement of a number of these organisms in combination (often superimposed upon an initial viral infection) demands a broad spectrum approach as a prompt response in die face of an outbreak of respiratory disease. The spectrum of activity might be categorised as one with a good grain negative spectrum, activity against the mycoplasmae and preferably some gram positive activity.

This can help in the choice between different families of antibiotics. However data, such as Minimum Inhibitory Concentrations (MICS) and serum concentrations, do not always give a reliable indication of the efficacy in vivo (Reeve-Johnson 1997). In vitro methods do not take account of distribution of antibiotics between the body components, and at the cellular and sub-cellular levels (Carlier et aL 1987); Shryock and Scomeaux 1997). It has been proposed that in the case of macrolide antibiotics, for example, that accumulation in immuno-competent cells is an important mechanism in the in vitvo activity of the drug and that this explains field efficacy data which surpasses predictions based upon in vitro or even blood serum levels (Stoker 1996). Additionally, the final choice of antibiotic will be influenced by the previous usage patterns of antibiotics on the particular production unit in question.

Bioavailabiliy

This is an expression of the quantity of drug that is absorbed and 'available'to the biological system in question. When considering an animal, it is 100% for an intravenously administered agent. The 'bioavailable dose' is therefore "the dose obtained by the subject, as opposed to the notional dose in the quantity of product delivered as a dose" (Brander et al 1982). In oral preparations, this may be influenced by binding to organic matter or other moieties in the water as well as the structural characteristics of the compound itself. In the commercial situation, one practically h.?s a choice of two administration routes for pigs, namely by parenteral injection or by mouth. Oral administration may be either in the feed or in the drinking water. Oral bioavailability will be less than by parenteral administration for any given compound and, in some cases bioavailability is considerably reduced. However, this is usually proportionately compensated for by an increase in inclusion levels in the water or feed, sufficient to raise the tissue levels of the antibiotic in the body.

Ease of administration

In an acute outbreak, getting a sufficiently high dose into the body rapidly can be an important factor in the choice of administration method.

Of major consideration in the administration of a chemotherapeutic in the herd situation is the ease of administration with minimum disruption to either the herd or its management. Whilst parenteral injection might be ideal in the face of a severe and acute outbreak, where a rapid response is needed, the practicalities of administering by this route are a major inconvenience in most situations.

Feed and water medication are a practical way of mass medicating in prophylactic, metaphylactic regimes and indeed of treating an intercurrent outbreak of mild to moderate severity.

Cost-effectiveness

Although there was a wide variety of responses, it has been found that in general, when treating prophylactically, cost and convenience are high on the list of priorities in choosing an appropriate product. However, as disease becomes more severe, cost is traded off in preference for good clinical efficacy of treatment.

Factors influencing the effectiveness of chemotherapy delivered in the water

Intake

There is much individual variation in water intake in the normal healthy pig. In the pig suffering from pneumonia, water intake may be depressed, which decreases the ingested dose. Additionally, it is found that the individual variation also increased in sick pigs. It is also important at this stage to be sure to distinguish between water intake and water disappearance, as both sick pigs and pigs confronted with unpalatable substances in the water showed a greater tendency to 'play' with nipple drinkers and spill greater amounts of water while ingesting less.

However, water intake does not always decrease even with very high morbidity pneumonias m groups of pigs. Groups of 8-12 pigs, where each individual had been infected with the same strain of Actinobacillus pleuropneumonia, were closely monitored for water intake. The total water usage and spillage in each case were carefully measured to give actual intake under group conditions. Growing pigs with weights between 25 and 30 kg were used in the groups. Four European field isolates of infective strains of Actinobacillus spp. were investigated.

Delivery system

As with all fluids, water will tend to flow down a pressure gradient from high to low pressure.

Thus the pressure in a system with a header tank is directly determined by the height of the header tank. Doubling the height, doubles the pressure in a given water delivery system. The water flow (current) is inversely related to the resistance of the pipe system. Hence increasing the resistance of the pipes will also proportionately decrease flow.

In a mains driven watering system, the pressure is determined directly by the mains supply. In both cases, however, once the water is in the watering system in a pig house it obeys the principles of laminar flow through the pipes. In doing so it experiences resistance from the walls of the pipes so that the layers nearest the wall of the pipe flow slowest, while the layer in the centre flows most rapidly. The 'shearing' forces exhibited consequently affect the rate of flow.

This was first described by Poiseuille in 1842. He discovered that the rate of flow of a volume of water is directly dependent upon: (1) the pressure gradient, (2) the forth power of the radius of the tube - (and inversely upon the viscosity of the fluid).

So whilst a doubling of header tank height will double the rate of flow, doubling the radius of the piping system will increase the rate of flow sixteen times!

This influences not only the initial design of a system, but the maintenance of one already installed. The effects of 'liming'and sedimentation in pipes will therefore also reduce delivery rates by a forth power relationship.

The method of presenting water to pigs is also very important (i.e. the choice of cups, nipples or troughs). It is crucial that these are appropriate to the age of pig (e.g. bite drinkers for adults do not suit piglets!) and that they are physically in good condition to work effectively and are comfortable to use. The number, position and height of the drinkers should also be appropriate to maximise intake.



These flow rates can be easily verified manually with stop watch and container of known volume. alatabili An illustrative example of work carried out on a novel macrolide antibiotic formulated for inclusion in the water shows that at the 0, lx and 2x doses the water intake is unaffected by palatability issues. However, at 4x and 8x the dose there is a dramatic decrease in water intakes by the pigs. Despite the decrease in water intake, the average intake of the chemotherapeutic in mg/10kg bodyweight was maximum at the 4x dose.

Rate of uptake

Most of the absorption takes place in the small intestine. After the gastric' phase of digestion, the stomach releases liquid into the small intestine, generally sooner than particulate matter. Absorption into the intestinal mocusa is also from the liquid phase. It is likely that water borne compounds may be absorbed more rapidly into the body than those which need to come out of the feed and into solution before absorption.

Promptness of treatment

Typically, it may take several days for a medicated feed to be ordered from a mill, formulated, mixed and transported to the farm. In terms of the pathogenesis of a disease, this constitutes a major delay. Additionally, feed medication will usually be ordered in bulk and administered until all (often many tons) have been used. Water medication is obviously much more flexible and can be started or stopped at short notice.

Method of delivery

This usually occurs by direct administration into a header tank of known volume, into an individual pen 'box' drinker, or by means of a water proportioning system. Some products currently used in the water (e.g. oxytetracycline) are not very readily soluble and solubility enhancing agents such as citric acid are often used to increase solubility. It has however been reported (Carr 1994) that the use of citrate based Compounds may dislodge sediment and result in blocked drinkers.

Ease of administration

Currently rnost antibiotics used are in the form of a soluble powder. Low solubility with amoxycillin, for example, can result in a homogenous lump of antibiotic floating unused in the header tank, or oxytetracycline leading to blockage of water proporfioners. Aqueous solutions of antibiotics therefore have an immediate advantage if easily miscible.

Stability

Lack of stability of a product will also affect effectiveness. Some products, e.g. ceftiofur, whilst effective when given parenterally, have not yet been formulated in forms sufficiently stable to withstand challenges of the environment by temperature, humidity, sunlight and other factors to which orally administered agents would routinely be exposed. As a consequence, insufficient levels of the active agent may be available to the pigs, preventing successful therapy.

At pig level there are 4 major impediments:

1. Palatability of the product.
2. Water delivery rate.
3. Inadequate number of drinking points (position, height and number).
4. Water quality (affects palatability and organic matter contamination may bind to therapeutic substance).

In order to reduce these factors a number of steps should be applied:

1. Ensure usage at recommended product inclusion.
2. Check flow rates at different points in system to 'troubleshoot' for problems.
3. Reassess drinkers at pig level.
4. Drain system between batches of pigs, scrub out header tank and use a line sanitiser.

References

Anon (1997). Dossier 14, FEDESA, Brussels, Belgium.
Brander, G.C., Pugh, D.M., Bywater, R.J. (1982) Eds. Veterinary Applied Pharmacology and Therapeutics, Balliere Tindall, London.
Brooks, P., Carpenter, J. (1989). Pig Farming Supplement, November 1989.
Carlier, M., Zenebergh, A., Tulkins, P. (1987). Journal of Antimicrobial Chemotherapy, 20, (Suppl. B): 47-56.
Carr, J. (1994). Elanco Technical Bulletin, 1994.
Kavanagh, N.T., Mortiiner, 1. (1996). Proceedings of the 14th IPVS Congress, Bologna, 715.
Muirhead, M. R. (1979). British Veterinary Journal, 13 5' 497-507.
Reeve-Johnson, L. (1997). Journal of Veterinary Pharmacology and Therapeutics: 20' suppl. 1: 1 10- 120.
Shyrock,T.R.,Scorneaux,B.(1997). JoumalofVeterinaryPharinacologyand Therapeutics, 20, suppl. 1: 127-180.
Stoker, J., Parker, R., Spencer, Y. (1996). Proceedings of the 14th IPVS Congress, Bologna, Italy, p. 656.

The Pig Journal (1998) 4_2 74-86. Republished with permission.
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