Drug resistance in veterinary helminths

doi:10.1016/j.pt.2004.07.010

Trends in Parasitology

Volume 20, Issue 10, October 2004, Pages 469-476

https://doi.org/10.1016/j.pt.2004.07.010 Get rights and content

At present, there is no effective alternative to chemical control of parasitic helminths where livestock are grazed intensively. Resistance to anthelmintics has become a major problem in veterinary medicine, and threatens both agricultural income and animal welfare. The molecular and biochemical basis of this resistance is not well understood. The lack of reliable biological and molecular tests means that we are not able to follow the emergence and spread of resistance alleles and clinical resistance as well as we need. This review summarizes some of the recent findings on resistance mechanisms, puts forward some recommendations for limiting its impact and suggests some priorities for research in this area.

Section snippets

The extent of the problem

In small ruminants, anthelmintic-resistant nematodes are already a serious problem [1]. In Australia, for example, the prevalence and severity of resistance now threatens the profitability of the entire sheep industry [2]. Resistance has arisen to all of the major families of broad-spectrum anthelmintics [3], the benzimidazoles (BZ), levamisole (LEV) and the other nicotinic agonists, in addition to the avermectins and milbemycins (AM) (including ivermectin, doramectin and moxidectin). Nematodes

Mechanisms of resistance

Drug resistance can arise in a limited number of ways (Box 3): (i) a change in the molecular target, so that the drug no longer recognizes the target and is thus ineffective; (ii) a change in metabolism that inactivates or removes the drug, or that prevents its activation; (iii) a change in the distribution of the drug in the target organism that prevents the drug from accessing its site of action; or (iv) amplification of target genes to overcome drug action. Those mechanisms implicated in

How to deal with anthelmintic resistance

Anthelmintic resistance is a major problem that we do not really understand, and it is here to stay – there is no evidence for reversion to anthelmintic susceptibility, even where the drug has been withdrawn [30]. In the short to medium term, there are no realistic alternatives to the continued use of current chemicals for parasite control. Pasture management can reduce the number of anthelmintic treatments required, but cannot replace them entirely [45]. Effective vaccines, new cost-effective

Management in endemic regions

The aim of management is to make parasite control sustainable. This implies the use of a range of control measures and a stabilization of resistance. At the same time, the economic cost of parasitism (due to production losses, and the costs of prevention and treatment) must be kept down. While they continue to work, anthelmintics remain the most cost-effective method of parasite control and so will remain in use. Although there might be some benefits in using mixtures of chemicals, existing

Research priorities

A recent Biotechnology and Biological Sciences Research Council-sponsored workshop* produced a list of research priorities in anthelmintic resistance for the short to medium term (Figure 1). Generally, research is needed in four main areas: (i) the development of better tests; (ii) the mechanisms of drug action and of resistance; (iii) the generation of suitable

Concluding remarks

Anthelmintic resistance in veterinary parasites is a major problem worldwide. Little is known about how this resistance has arisen and how to reverse it. Until novel methods of worm control are developed, we need to implement strategies to maximize the effective lifetime of our current compounds. Such strategies will be based on a sound understanding of the biology, in its broadest sense, of resistance and more research in this area is urgently needed.

References (57)

N.C. Sangster et al.
Pharmacology of anthelmintic resistance
Parasitol. Today
(1999)
I. Fairweather et al.
Fasciolicides: efficacy, actions, resistance and its management
Vet. J.
(1999)
R.K. Prichard
Genetic variability following selection of Haemonchus contortus with anthelmintics
Trends Parasitol.
(2001)
M.S.G. Kwa
Benzimidazole resistance in Haemonchus contortus is correlated with a conserved mutation at amino acid 200 in beta tubulin isotype 1
Mol. Biochem. Parasitol.
(1994)
A. Silvestre et al.
Mutation in position 167 of isotype 1 beta-tubulin gene of Trichostrongylid nematodes: role in benzimidazole resistance?
Mol. Biochem. Parasitol.
(2002)
G. von Samson-Himmelstjerna
Comparative use of faecal egg count reduction test, egg hatch assay and β–tubulin codon 200 genotyping in small strongyles (cyathostominae) before and after benzimidazole treatment
Vet. Parasitol.
(2002)
C.A. Winterrowd
Benzimidazole-resistant beta-tubulin alleles in a population of parasitic nematodes (Cooperia oncophora) of cattle
Vet. Parasitol.
(2003)
D. Kerboeuf
P-glycoprotein in helminths: function and perspectives for anthelmintic treatment and reversal of resistance
Int. J. Antimicrob. Agents
(2003)
N.C. Sangster
Binding of [H-3]m-aminolevamisole to receptors in levamisole- susceptible and -resistant Haemonchus contortus
Int. J. Parasitol.
(1998)
D.M. Yates
The avermectin receptors of Haemonchus contortus and Caenorhabditis elegans
Int. J. Parasitol.
(2003)

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Trends in Parasitology

Drug resistance in veterinary helminths

Section snippets

The extent of the problem

Mechanisms of resistance

How to deal with anthelmintic resistance

Management in endemic regions

Research priorities

Concluding remarks

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