From discovery to development: Current industry perspectives for the development of novel methods of helminth control in livestock

Abstract

Despite the extraordinary success in the development of anthelmintics in the latter part of the last century, helminth parasites of domestic ruminants continue to pose the greatest infectious disease problem in grazing livestock systems worldwide. Newly emerged threats to continuing successful livestock production, particularly with small ruminants, are the failure of this chemotherapeutic arsenal due to the widespread development of anthelmintic resistance at a time when the likelihood of new products becoming commercially available seems more remote. Changing public attitudes with regards to animal welfare, food preferences and safety will also significantly impact on the ways in which livestock are managed and their parasites are controlled. Superimposed on this are changes in livestock demographics internationally, in response to evolving trade policies and demands for livestock products. In addition, is the apparently ever-diminishing numbers of veterinary parasitology researchers in both the public and private sectors.

Industries, whether being the livestock industries, the public research industries, or the pharmaceutical industries that provide animal health products, must adapt to these changes. In the context of helminth control in ruminant livestock, the mind-set of ‘suppression’ needs to be replaced by ‘management’ of parasites to maintain long-term profitable livestock production. Existing effective chemical groups need to be carefully husbanded and non-chemotherapeutic methods of parasite control need to be further researched and adopted, if and when, they become commercially available. This will require veterinary parasitology researchers from both the public and private sectors to work in close co-operation to ensure ‘sustainability’ – not only of the livestock industries that they service – but also for their very own activities and enterprises.

Introduction

There is no question of the importance of helminth infection in production livestock, whether for the industrial countries, or the developing countries, of the world. For example, recent surveys conducted in three of the largest sheep producing countries, namely Australia, South Africa and Uruguay, ranked nematode parasites as the most important of all the infectious diseases in sheep, with annual losses estimated to be US$ 222m (McLeod, 1995), US$ 45m (I.G. Horak, personal communication) and US$ 42m (Nari et al., 1997), respectively. A recent exhaustive review (Perry et al., 2002), commissioned by the major international donors to projects in the developing world, which estimated the effects of livestock disease on the poor owners of livestock, concluded that sic “on a global basis, gastro-intestinal parasitism emerges with the highest index as an animal health constraint to the poor”. Clearly the problem is there, and the industry is responsive.

However, I believe it is necessary at the outset to qualify what is meant by the term ‘industry’. In this setting, naturally one thinks immediately of the pharmaceutical industry which is traditionally linked with the business of developing and marketing parasiticides, but in another forum it could well mean the producer organizations representing the production livestock industries. The priorities and the means to achieve parasite control for the livestock industries that the latter bodies represent are much broader and are not necessarily chemically focussed.

Regarding parasites of livestock, superficially the missions of the livestock industry and the pharmaceutical industry may well appear to be dichotomous, with threats to the livestock industry in parasite control, likely to be considered as opportunities by the pharmaceutical industry. However, in this changing world nothing remains static, and this is particularly so with matters relating to livestock production, profitability, parasites and public perceptions. Although I come from a background of having little ‘inside’ experience on priority setting by livestock producer bodies – and even less with regards to the pharmaceutical industry – I do have the benefit of being ‘around for a long time’ working in the production livestock/nematode parasite research milieu. During my career as a veterinary parasitologist I have witnessed substantial changes in the positioning and re-alignment of attitudes of the pharmaceutical industry, livestock producer bodies, publicly funded research institutions and the consumers in response to economic and political imperatives of contemporary issues impacting on the management of production livestock throughout the world, and by implication on helminth control practices.

The last century will go down as the ‘chemotherapeutic era’, heralded by the commercial release of a vast range of wonder drugs used to control diseases of man, his crops and his livestock. Some examples of such drugs in chronological sequence of their appearance onto the marketplace are shown in Fig. 1. Although anthelmintics were ‘the last horse out of the box’ so to speak, there has been an ever increasing potency and spectrum of activity of new classes of drugs and at the same time ever decreasing dose rates—from 600 mg/kg for phenothiazine to 0.2 mg/kg for the macrocyclic lactones (McKellar and Jackson, 2004; see Fig. 2). Without wishing to be flippant, it does tend to foster an expectation that the next class anthelmintics will require efficacies exceeding 100%, at less than zero dose rate, to be commercially viable?

Therefore by virtue of their remarkable efficiacy, broad spectrum activity, ease and safety of use, and relative cheapness, these modern wonder drugs fostered the notion that disease scourges could be kept permanently in check, if not eradicated, by their frequent use.

The 1960–1980s were the halcyon days for livestock producers and for those pharmaceutical companies who were fortunate to have marketable broad spectrum anthelmintic products during this time. For example, the forerunner to the true anthelmintic ‘wonder’ drugs was thiabendazole and large-scale field research studies in Australia by the discoverers, Merck Sharp and Dohme, demonstrated the economic benefits of suppressive (monthly) drenching of sheep (see Fig. 3A). Not to be outdone, the next anthelmintic ‘big gun’ to appear on the marketplace was the imidothiazole, levamisole and ICI, the distributors of this drug to the sheep industry in Australia, recommended that at times farmers considered they had a problem with barbers pole worm (Haemonchus contortus), then they could save a lot of money by half-dosing, because Nilverm^® (levamisole 7.5 mg/kg) was so highly effective against this parasite (see Fig. 3B). Suppressive, and often half-dosing with these new drugs, became very much in vogue for the treatment of parasites of sheep during the 1960–1980s, at least in Australia.

So these were great days, not only for the veterinary pharmaceutical industry, where seemingly the only problem that they had was supplying enough drench to farmers clamouring for these products, but also for the sheep industry, which in Australia was approximately twice the size of current estimates. However, one would have expected that matters would not have been so rosy for non-drug-related veterinary parasitology research. Because at that time, a generally held notion was that control of worms in livestock could be achieved by the simple expedient of one or several treatments with the new anthelmintic wonder drugs – problem solved – and by implication no need for further research on parasites.

However, quite to the contrary, the 1960–1980s were precisely the time when veterinary parasitology flourished and many research institutions throughout the world reached their zenith during these decades. This apparent paradox could be attributed to the fact that the world economy was generally buoyant and governments of countries in the developed world with significant livestock industries, provided substantial core funding which underpinned activities at their research institutes. The need to write funding proposals to support the activities of veterinary parasitology researchers was virtually unheard of during these days and as a consequence, research often was of an altruistic, serendipitous nature. However, it certainly was the ‘golden era’ for both basic and applied veterinary parasitology research, resulting in the development of a vast information bank in a wide range of disciplines, such as: host/parasite immunology, physiology, pathology, epidemiology, ecology, etc.

At the same time, the pharmaceutical industry was pretty much doing their own thing, focused of course on the research and development (R&D) of new chemical actives. Some of the large multinational companies developed enormous R&D facilities (state of the art laboratories, field stations, etc.), scattered throughout the world, but concentrating on countries with large grazing livestock industries. Although much of their work was shrouded in secrecy (and still is of course for obvious commercial reasons), there was no shortage of elaborate and expensive new product launches – with the WAAVP conferences being a favoured forum – when scientists from the private and public sectors ‘rubbed shoulders’, and the chosen few from the public sector were very pleased indeed to be spoilt with drug company largesse which was legendary during this time. However, events were to change.

Attitudes started to harden against ruminant livestock and by association veterinary parasitology research. These were based on perceptions that ruminant livestock caused adverse environmental effects, such as on land degradation, green-house gas emissions and competition for food supply in a hungry world which could best be served by increasing plant rather than animal protein for human nutrition. Added to this was the sustained pressure from competition with synthetic fibre and cotton producers, which led to the virtual collapse of the wool industry towards the end of the last century. Also the very success of the pharmaceutical companies in producing modern anthelmintic wonder drugs, solved the problem of worm parasites in livestock—at least in the minds of many who controlled the financial destiny of veterinary parasitology research.

As a consequence of these negative influences, there was a severe and sustained reduction in veterinary parasitological research and extension to the grazing livestock industries. The mid 1990s onwards has witnessed the virtual dismantling of some of the bastions of applied veterinary parasitology research throughout the world. Of course this was not uniform, with some institutions being relatively unaffected and a very few actually expanding, but some have effectively disappeared leaving regions or countries virtually bereft of veterinary parasitology expertise. Unfortunately this has come at a time when I believe they are most needed.