Factors interfering with persistent efficacy

Introduction

Sustained-release drugs have been known for a long time, mainly for antibiotics, insecticides and antiprotozoal drugs. With the advent of the avermectins, studies have demonstrated that a single therapeutic dose can persist in concentrations sufficient to be effective against incumbent nematode infections for prolonged periods after treatment.

The clinical significance of a prolonged efficacy is great. The sustained-release property may protect animals from reinfection by some nematode (and arthropod) species for several weeks, and will be of great value in the control of livestock pests under intermittent or constant challenge. The timing of an anthelmintic treatment may become less critical and the interval between treatments may be extended. It is, however, difficult to determine which is the optimal level and duration of persistence for an anthelmintic. The essential feature by which helminths differ from viruses, bacteria and protozoa is that the course of infections in the host does not conform to a standard pattern. Populations of helminths cannot increase in the host alone; each individual must undergo development outside the host before it can parasitize the host. The consequence is that the course and magnitude of worm populations are infinitely variable and determined not only by the host response, but also by climate and management (Michel, 1985). Furthermore, the maximum/optimal level of parasite reduction which could still ensure the success of preventive control schemes remains to some extent undefined. Therefore, different levels and lengths of persistence can be of interest depending on the required control.

The evaluation of persistence (nematodes)

The World Association of the Advancement of Veterinary Parasitology (WAAVP) guidelines (Wood et al., 1995) include two test designs to determine the persistent efficacy against helminths. In the first test design, there are weekly treatment intervals prior to a single parasite challenge. An alternative test protocol involves a daily intake of larvae. Infections are given beginning on the day of treatment and continue daily for periods up to the designed extent of protection to be studied. The second test can also be done using animals to graze heavily contaminated pastures for various periods after treatment. Although this protocol has been used on a more limited scale, it reflects more closely the practical situation where animals, after treatment, graze on contaminated pastures. VICHa recommends a study design using multiple daily challenges, as this most closely mimics what occurs in nature (Vercruysse et al., 2001).

Large variations in the persistent efficacy of a particular ML against a particular worm species have been reported. Potential reasons for these variable results include study design, and host- and parasite-related factors. The impact of trial design on persistent efficacy has been reviewed by Deroover et al. (1997). It was concluded that the efficacy values obtained a The International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) is an international programme of cooperation between regulatory authorities and the animal health industries of the European Union, Japan and the USA which aims to harmonize the technical requirements for the registration of veterinary medicinal products. Australia and New Zealand participate as active observers.

from different types of studies used to evaluate persistent efficacy are not always comparable, and the study type itself may influence the apparent end point of the persistent efficacy of an anthelmintic. The influence of host-related factors, such as breed, nutritional status and amount of body fat, remains largely unstudied (Armour et al., 1987). Persistent efficacy may also be influenced by parasite-related factors, such as inhibition proneness of the strain (Yazwinski et al., 1994a) or the level of infection. Vercruysse et al. (1998) reported that the persistent efficacy of doramectin injectable against C. oncophora appeared to be shorter when treated animals were challenged with a high infection level (10,000 L3 day-1), compared with a lower infection level (1000 L3 day-1). A possible explanation for the effect of the infection level on the duration of persistent activity is that the establishment, maturation and survival of the worms in the untreated animals are density dependent. Differences in larval intake can influence worm mortality and the course of an infection in parasite-nai've calves (Michel, 1985). However, recently, Vercruysse et al. (2000) found that the duration of persistent efficacy of ivermectin against Ostertagia was, at a moderate infection level, somewhat shorter compared with a high dose level, indicating that other, unknown factors also may affect the duration of persistent activity.

According to the WAAVP and VICH guidelines (Wood et al., 1995; Vercruysse et al., 2001), persistence claims can only be determined on the basis of actual worm counts and not on number of eggs per gram of faeces. One could argue that worm counts indicate better the direct effects on the host, while faecal egg counts give a better view of the extent of pasture contamination. However, to measure the persistent effect of an anthel-mintic by using faecal egg counts may be misleading. The relationship between worm counts and faecal egg counts is not necessarily linear and/or will vary substantially according to many, often unknown and/or uncontrolled, circumstances, for example the age of animal, parasite species, level of infection, reinfection pattern, inhibition and immunity development. The shortcomings of using faecal egg counts to assess persistent efficacy was illustrated by the observations done by Eddi et al. (1997). In his experiment, average faecal egg counts on day 56 post-treatment were either zero in doramectin-treated or very low in controls (46), ivermectin- (4) or fenbendazole-treated (25) groups. At the same time, however, mean total parasite counts, of which O. ostertagi was the predominant species, were: 250, 12,750, 2900 and 5600 parasites per animal, for the same groups, respectively. Ranjan et al. (1997) showed that although there was no difference in persistent efficacy between ivermectin and doramectin, based on faecal egg counts, animals receiving doramectin had 40% lower worm burdens 56 days after treatment. Entrocasso et al. (1996) and Meeus et al. (1997) could not detect significant differences between the persistent efficacy of the different MLs, based on faecal egg counts; this is in contrast to the many studies in which clear differences in duration of persistence were observed, based on worm counts. Also, results from some field evaluations of persistent activity based on post-treatment faecal egg counts (Entrocasso et al., 1996; Eysker et al., 1996; Meeus et al., 1997; Talty et al., 1998) suggest a longer persistent efficacy than those using worm counts. There is a suggestion that the MLs could have an effect on worm fecundity and/or immunity of the host (Meeus et al, 1997). Finally, the expression of group faecal egg counts may mask the real differences in infection prevalence. Therefore, in the following review on duration of persistent efficacy of the MLs, only results based on worm counts were considered. Reductions in faecal egg counts may have effects on the extent of pasture contamination and would be important in infections over a grazing season.

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