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Survey of internal parasites in Western Australian pig herds. 2. Relationship to anthelmintic usage and parasite control practices.

The housing, management and internal parasite control practices used in piggeries in Western Australia was surveyed by interviewing the owner/manager of 100 randomly selected piggeries. At the time of the interview 20 faecal samples were collected from pigs and examined for evidence of internal parasites. Most herds (80%) in which anthelmintics were used, had evidence of nematode infection. Some pig producers were using an anthelmintic that was ineffective against nematode species present while some herds had nematodes that should have been controlled by the anthelmintic being used. Prevalence of nematode infection was higher in pigs run in paddocks than in pigs housed intensively. Washing sows prior to farrowing was associated with a lower prevalence of nematode infection. The findings suggested that pig producers should ensure that the anthelmintic used is effective against the nematodes present in their pigs. It was concluded that administering anthelmintics as a single dose in the feed may not be the most effective method of deworming pigs.

Animal Husbandry↗

Evaluation of gastro-intestinal nematode parasite control strategies for first-season grazing cattle in Sweden.

A three-year grazing experiment (1998-2000) was conducted with first-season grazing cattle (FSGC) on improved pastures in central-eastern Sweden. Comparison was made between five groups with 10 calves in each group where four of these were set stocked and either (1) untreated, (2) ivermectin bolus treated, (3) subjected to biological control with the nematophagous fungus Duddingtonia flagrans, or (4) treated with a copper wire particle bolus. The fifth treatment was an evasive grazing strategy, whereby untreated calves were turned out onto pasture used by older cattle the previous year and then these calves were moved to silage aftermath in mid-July. To introduce low-levels of parasite infection to the experiment, each animal received a 'priming dose' of approximately 5,000 Ostertagia ostertagi and 5,000 Cooperia oncophora infective third stage larvae immediately prior to the start of the first grazing year of the trial. Results showed that efficient and sustainable parasite control of FSGC was possible to achieve without the use of anthelmintics by using turnout pastures that the previous year had been grazed by older cattle, in combination with a mid-July move to aftermath leys. Biological control also proved beneficial but the efficacy was impaired if high faecal egg counts coincided with rapid dung pat degradation due to heavy rainfall. No indication of parasite control was observed with the copper wire particle bolus. It was also demonstrated that the impact of gastrointestinal (GI) parasitism varied between years and that the level of overwintering contamination is important but likewise, is unpredictable. Although faecal egg counts in 1999 were low, due both to a delayed turnout and drought for the major part of the grazing season, deposited eggs successfully developed to infective larvae and overwintered in large numbers. The population of overwintered infective larvae at the time of turnout in early May played an important role in the course of infection in 2000 and resulted in an average 65 kg advantage of the ivermectin treated calves compared with the untreated calves.Thus, this three-year grazing experiment has emphasised the importance of subclinical gastrointestinal nematode infections in FSGC in Sweden. In addition, the study has shown that adequate parasite control may be achievable without the use of anthelmintics.

Animal Husbandry↗

Prevalences of gastrointestinal parasites in sheep and parasite-control practices in NW Spain.

A coprological survey to know the presence of gastro-intestinal nematode parasites infecting sheep was done in Galicia (NW Spain), an area with Atlantic climate where sheep production is replacing cattle due to the Agricultural Community Politics of the European Union. From September 2001 to November 2002, 1710 faecal samples were randomly collected from 49 sheep farms and examined by using the flotation technique to determine the prevalence of gastro-intestinal nematode parasites. The sheep-level prevalence was 100%, and the genera identified were Chabertia, Cooperia, Haemonchus, Nematodirus, Oesophagostomum, Teladorsagia, Trichostrongylus and Trichuris spp. A questionnaire was distributed to the farmers (at the same time as sampling) about parasite-control practices during the year before sampling (2000). Ninety percent (95% CI 81%, 98%) of the farmers said they used antiparasitic drugs occasionally, but none of them asked for a coprological analysis prior to the treatment and the efficacy of the drugs was never evaluated. A higher median EPG was observed in the treated sheep (163) than in the untreated ones (26). Chemotherapy was the only parasite-control practice. Flocks that treated according to the farmer's previous experience had higher median EPG (236) than other flocks (185 following the prescription of their veterinary clinician and 232 based on the commercial agent's counsel). Typically, one benzimidazole-treatment per year was applied in autumn and non-veterinary counsel was used. Sheep treated with imidotiazoles had lower EPG (144) than other drugs (164 for the benzimidazoles and 166 for the macrocyclic lactones). We found a higher median EPG in the sheep receiving two treatments/year (175) than in those treated only once per year (156). These results suggest lack of knowledge about worm-control strategies and anthelmintic use or unwillingness to apply such knowledge.

Animals↗

Assessment of parasite control and weight gain after use of an ivermectin sustained-release bolus in calves.

OBJECTIVE: To assess parasite control and weight gain after administration of an ivermectin sustained-release bolus over 135 days to calves grazing in the midwestern United States. DESIGN: Replicated pasture study. ANIMALS: 56 Bos taurus calves. PROCEDURE: Calves were matched for body weight and randomly allocated to remain untreated or to receive an ivermectin sustained-release bolus before turnout on day 0. Calves were grazed by treatment group on B pastures (4 replicates). Body weights and fecal egg counts were recorded on days- 1 and 28, and then at 28-day intervals until day 168. RESULTS: Parasitism was not clinically evident prior to or during the study. In treated calves, mean fecal egg counts were at or near 0 at all posttreatment evaluations. Although the mean egg count exceeded 20 ova/g only once in control calves, the cumulative egg output was > 42 million/calf. For the treated group, it was < 0.1% of this number. Mean total weight gain was 33.9 kg (74.6 lb) greater for ivermectin-treated calves than for untreated control calves (P < 0.02): a 34% increase. CLINICAL IMPLICATIONS: Fecal trichostrongyle eggs from calves can accumulate over a grazing season to provide enormous potential for augmenting pasture infectivity. An ivermectin sustained-release bolus (administered to calves being placed on pasture) controls parasitism, limits pasture infectivity, and can substantially influence growth by limiting the impact of subclinical parasitism.

Animals↗

A survey of ovine parasite control practices in Tennessee.

A sample of 126 sheep producers in Tennessee was randomly selected from the members of a statewide organization of sheep producers. Data about the participants' farms, sheep, parasite control practices and sources of information regarding ovine parasite control were obtained by a telephone survey. The response rate was 99%. The typical respondent kept 20 lambs, 20 ewes and 2 rams on three pastures totalling 20 acres. In order of decreasing frequency, anthelmintics were given according to a regular schedule, to coincide with breeding management procedures, or to treat clinical signs of parasitism. Proportions of producers deworming the various classes of sheep zero, one, two, three, four or more than four times annually were as follows: lambs--3, 28, 40, 16, 9 and 8%, respectively; ewes--3, 8, 20, 16, 34 and 22%, respectively; rams--1, 9, 19, 15, 38 and 19%, respectively. The majority of respondents planned to deworm lambs (89%) and ewes (82%) the same number of times in the following year. Of the producers who dewormed sheep two or more times during 1989, 39-49% (ranges include different proportions for lambs, ewes and rams) used the same anthelmintic exclusively, and 51-61% used two or more drug classes. Of the owners using a single anthelmintic exclusively, most (39-66%) used ivermectin, followed by levamisole (19-33%) and benzimidazoles (13-24%). One hundred and three of 124 (83%) producers intended to use the same anthelmintics in the future. Sixty-four of 124 (52%) producers had discontinued using at least one ovine anthelmintic. The most common reasons for discontinuance were dissatisfaction with the clinical response after treatment and inconvenience of administration. Sheep-oriented publications, other sheep producers and veterinarians were considered the most important sources of information about deworming programs and choice of anthelmintics.

Animals↗

Nematode parasite control of livestock in the tropics/subtropics: the need for novel approaches.

Because parasites are more abundant, small ruminants in the tropical/subtropical regions of the world experience much greater ravages from internal parasitic disease than those in the temperate regions. In the tropics/subtropics, the limiting ecological factor influencing the severity of parasitism is rainfall, as temperatures almost always favour hatching and development of the free-living stages. Attempts to expand sheep and goat production by replacing traditional village production systems, which rarely involve anthelmintic treatment, with large-scale intensive commercial enterprises invariably induce complete reliance on anthelmintics to control nematode parasites. This has led to the widespread development of high level, multiple anthelmintic resistance throughout the tropics/subtropics, and in certain regions this has reached the ultimate disastrous scenario of total chemotherapeutic failure. Immediate concerted efforts are needed to resolve this crisis. Significant benefits are likely to emerge from research into non-chemotherapeutic approaches to nematode parasite control, such as grazing management, worm vaccines, breed selection and biological control. However, it is likely that none, in isolation or collectively, will completely replace the need for effective anthelmintics. What is needed is the integration of all methods of parasite control as they come to hand, with the underlying aim of reducing the use and thus preserving the effectiveness of anthelmintics. Although cheap and simple procedures, based on sound epidemiological principles, can achieve dramatic benefits in worm control, they have been poorly adopted by livestock owners. Clearly then, the greatest need is for technology transfer and education programmes, but these activities are generally found to be chronically under-resourced.

Animal Husbandry↗

Effectiveness of a slow-release, morantel tartrate anthelmintic bolus for controlling parasitic gastroenteritis in replacement dairy heifers.

Two experiments were done to evaluate the effectiveness of a slow-release, morantel tartrate, anthelmintic bolus for controlling parasitic gastroenteritis in replacement dairy heifers. In experiment 1, good control of nematode contamination of pasture was indicated by lower worm burdens in tracer calves that grazed with 15 heifers treated orally with a single bolus and by significantly decreased numbers of nematode eggs in the feces of the 15 treated heifers, as compared with numbers of eggs in the feces of 15 nontreated control calves. Significant differences in weight gain were not seen between treated and nontreated heifers, probably due to low amounts of larval exposure, the small number of heifers evaluated, and parasitic resistance in the heifers, which may have developed as a result of prestudy exposure to contaminated pasture. In experiment 2, done 1 year after the 1st experiment, using the same pastures that were used in experiment 1, young heifers were used. Many of the heifers were parasite naive at the beginning of the experiment (ie, nematode eggs were not found before the experiment). Treatment with the bolus was effective in controlling parasitic gastroenteritis in the heifers and in controlling nematode contamination of pasture. Compared with nontreated heifers, treated heifers had significantly higher cumulative weight gains, a significant decrease in plasma pepsinogen concentrations, and a significant decrease in worm egg excretion. The number of worms acquired by tracer calves that were grazed with treated heifers was significantly less than for tracer calves that were grazed with nontreated heifers.

Animals↗

Economic benefits of parasite control in cattle.

The economic losses often associated with parasitism in cattle are universally accepted. The degree of economic significance related to these losses, the burdens of parasites required to cause such losses, and the specific control measures needed to avoid these losses are, however, topics of serious debate and outright disagreement among parasitologists and veterinarians. This is because most cattle have parasite burdens that are truly subclinical, with no obvious signs of parasitism but significant losses in potential production. These losses are often very insidious in nature and often difficult to prove statistically in a consistent manner. This discussion focuses on the need to: (1) define the benefits related to parasite control in cattle; (2) develop clear and effective parasite control recommendations that will allow the producer to realize these benefits; (3) effectively transfer this information to the cattleman.

Animal Feed↗

Immunological aspects of nematode parasite control in sheep.

Gastrointestinal nematode parasitism is arguably the most serious constraint affecting sheep production worldwide. Economic losses are caused by decreased production, the costs of prophylaxis and treatment, and the death of the infected animals. The nematode of particular concern is Haemonchus contortus, which can cause severe blood loss resulting in anemia, anorexia, depression, loss of condition, and eventual death. The control of nematode parasites traditionally relies on anthelmintic treatment. The evolution of anthelmintic resistance in nematode populations threatens the success of drug treatment programs. Alternative strategies for control of nematode infections are being developed, and one approach is to take advantage of the host's natural or acquired immune responses, which can be used in selection programs to increase the level of resistance in the population. Vaccination can also be used to stimulate or boost the host's acquired immunity. The induction of protective resistance is dependent on the pattern of cytokine gene expression induced during infection by two defined CD4+ T-helper cell subsets, which have been designated as Th1 or Th2. Intracellular parasites most often invoke a Th1-type response, and helminth parasites a Th2-type response. Breeds of sheep resistant to infection have developed resistance over a much longer term of host-parasite relationship than genetically selected resistant lines. The immune components involved in these different responses and types of host-parasite relationships will be reviewed. The potential for using vaccines has been investigated, with variable results, for several decades. The few successes and potential new antigen candidates will also be reviewed.

Animal Husbandry↗

Bermudagrass management in the Southern Piedmont USA. V: Gastrointestinal parasite control in cattle.

Parasite-free pastures would improve cattle health and performance, resulting in possible economic return to producers. Our objective was to determine the effect of a single series of anthelmintic treatment of steers prior to stocking on Coastal bermudagrass pastures, during five consecutive summers, on the parasite burden in cattle. The site for this experiment had been conventionally cropped for several decades, with no exposure to cattle, and would be expected to be relatively free of nematode larvae. The experimental design was a randomized complete block (landscape features) with a split plot arrangement of treatments where main plots were pasture fertilization treatments (mineral, clover plus mineral, and broiler litter) and split plots were low and high forage mass. Anthelmintic treatment included pour-on ivermectin on day -21, albendazole on day -7, and injectable ivermectin 48 h prior to stocking of pastures, with the cattle remaining in drylot during the 48-h period prior to being placed on the experimental paddocks. All steers received only one series of treatments during any given year. Yearling Angus steers (Bos taurus) were managed in a put-and-take grazing system with three "tester" steers assigned to each paddock and "grazer" steers added or removed at 28-day intervals. From 1994 to 1998, steers grazed the paddocks for a 140-day period from mid May until early October each year. Fecal samples for worm egg counts were obtained on day 0 and at 28-day intervals, thereafter. On all sampling days after day 0, samples were obtained only from tester animals. Over the 5-year period, the mean eggs per gram of feces (epg) gradually increased from 0 (following treatment) to a mean of 2.2 (range from 0.7 to 3.0) by the end of the grazing season (the last sampling date) in October. Although the epg were not zero, they were below threshold levels that would allow development of a parasite burden in cattle. In traditional management systems, cattle graze parasite-contaminated pastures; therefore, parasites negatively impact growth and productivity throughout the entire grazing period. Periodic anthelmintic treatments simply give a temporary reprieve from those parasitic infections. Conceptually, using the current grazing system, it should be possible to maintain these pastures in a parasite-free status indefinitely; however, from a drug resistance perspective, it would be most applicable in sod-based rotation systems where cattle graze from two to five years before land is returned to row-crops. By removing the effect of parasites, cattle can grow without the physiological constraints that gastrointestinal parasites place on appetite, digestion, nutrient utilization, and general well being.

Albendazole↗

Wildlife parasites: lessons for parasite control in livestock.

For sustainable livestock production it is suggested that the parasitologist take a leaf out of Nature's book in the search for solutions to the mounting problems concerning parasite control. While the farmer has come to regard all parasites affecting livestock as entirely without benefit, indigenous parasites and diseases are normal and play an essential role as interacting components of a natural environment in an ecosystem such as the 19,000 km2-sized Kruger National Park, Republic of South Africa. The parasites help to select their hosts for fitness and are assisted by predators and intra-species territorial aggression which continually eliminate the weak individuals from the system. It is essential to guard against the introduction of foreign parasites or infectious agents which have no real ecological niche or role in an established ecosystem, however, as they cause untoward interactions, sometimes of a violent nature. The policy must be to block off or, failing that, to control or eliminate these foreign parasites and diseases as far as possible. Often, when Man intervenes in an ecosystem, it leads to stress, overcrowding and stagnation and predisposes to disease and death. Intensification of the system, as in farming units, denies Nature the chance to manage on its own, because of clashing interests with Man. Frank parasitism and disease should almost invariably be seen as indicators of an imbalance in the ecosystem and should be rectified. Chemicals and vaccines should be used to produce sufficient food for all, but without exploiting Nature, or else Nature will be unable to continue catering for Man's needs.

Animals↗

Mapping soil-transmitted helminths in Southeast Asia and implications for parasite control.

Establishing the current status and distribution of soil-transmitted helminths is essential for developing and implementing parasite control. Although Southeast Asia is known to have a high prevalence of infection, a precise estimate of the total disease burden has not been fully described. Here, we use Geographical Information Systems (GIS) to collate and map recent published surveys on soil-transmitted helminth epidemiology and distribution for this region. Distinct geographical variation was observed, which is suggested to reflect climatic variation, as well as behavioral differences. However, for much of the region few data are available, and therefore it proved necessary to generate predictions of the distribution of soil-transmitted helminths using remotely sensed (RS) satellite sensor environmental variables. A significant finding was the importance of land surface temperature in influencing the distribution of Ascaris lumbricoides and Trichuris trichiura. Spatial analyses using RS satellite sensor data were then used to generate predictive maps of infection risk. This information provided the basis for an estimate of the population at risk of infection and the numbers requiring treatment. These applications of GIS and remote sensing provide a good basis for developing control of soil-transmitted helminths in the region.

Animals↗

Survey of anthelmintic resistance in Western Australian sheep flocks. 2. Relationship with sheep management and parasite control practices.

Owners of 116 farms, whose flocks had been tested for anthelmintic resistance, were interviewed to determine their use of various sheep management and parasite control practices and their knowledge and adoption of recommended procedures for the prevention and control of resistance. Farmers knowledge of current recommendations related mainly to changing drenches and drench groups. Other aspects of the recommended program including reduction of drenching frequency and the use of alternative management strategies were not considered as important by farmers. For most questions a high proportion of farmers (greater than 20%) had no opinion. Associations between various strategies for nematode control and resistance of Trichostrongylus and Teladorsagia to thiabendazole and levamisole were examined. These relationships differed between anthelmintics and nematode genera. A number of factors were related to resistance of one or both nematode genera to one or both anthelmintic groups. These factors included flock size, percentage of ewes in the flock, cattle number, main sheep production activity, grazing strategy, frequency of drenching, changes in the frequency of drenching, number of summer drenches and the method of estimating dose rates. It was concluded that the methods employed to control anthelmintic resistance may vary with the nematode, its resistance status and the anthelmintic to which it is exposed. Modifications to the previously recommended program have been proposed which incorporate selection of the anthelmintic to be used following a test for anthelmintic resistance.

Animal Husbandry↗

The Asian center of international parasite control (ACIPAC): five years of achievement. I. Introduction.

ACIPAC has made an effort to promote the concept of the school-based approach to malaria and STH control, mainly through human resource development, which could be eventually extended to any other health promotion program. Implementation of SSPP resulted in the establishment of national policies on parasite control and/or school health in some partner countries. It also provides a good opportunity for the formulation of partnerships among health and education sectors and international partners, although it did cause some problems concerning the enrollment of persons of authority from partner countries, and the staff of JICA resident offices as well. As described in the Joint Evaluation Report, ACIPAC is expected to further contribute to human resource development and to strengthening human resource and information networking at regional and global levels.

Asia↗

Herd immunity to helminth infection and implications for parasite control.

Despite much research on immunological responses to helminth parasites, knowledge of the dynamic interplay between levels of herd immunity in humans and the rates of exposure, establishment and mortality of parasites remains limited. We describe here a simple mathematical model for the population dynamics of helminth infections which mirrors the development of a degree of acquired immunity within populations which are genetically heterogeneous with respect to immunological responsiveness. We interpret observed patterns in the age-specific intensity of infection and attempt to understand the possible effects of control measures based on chemotherapy and vaccination. Mass chemotherapy can, in some circumstances, reduce the level of herd immunity such that average worm burdens in the adult age classes rise above their precontrol levels. When certain individuals or groups are predisposed to heavy infection, selective or targeted drug treatment can have significantly greater impact than mass or random application. Conversely, model predictions suggest that effective parasite control by vaccination (if and when vaccines become available) is difficult to achieve in communities that are genetically heterogeneous in their ability to mount protective responses to infection.

Age Factors↗

Parasite control in transhumant situations.

Transhumance is defined as 'seasonal moving of livestock to regions of different climate'. It is an integral part of livestock production in many parts of the world and takes several forms including moving of livestock from lowland to mountainous pastures or from dry to humid areas. The impact of transhumance on parasite populations of livestock and on parasite control is described, mainly using examples from Europe. The epidemiology of trichostrongylidosis of cattle, mainly caused by Ostertagia ostertagi and Cooperia oncophora, is characterised by prolonged survival of overwintered infective larvae until the end of June. Cattle moved to such contaminated pastures in a transhumant grazing system are exposed to these larvae and may be protected, during the second half of the grazing season until autumn, by a late application (June/July) of an intraruminal drug-release device. Community pastures used in a transhumant system with mixed grazing of young cattle originating from various farms may enhance transmission of dictyocaulosis. Therefore, specific prophylactic measures are required. Hill sheep nematode populations may differ from those in lowland sheep in that Haemonchus contortus generally plays a minor role in hill sheep in which Ostertagia circumcincta and Nematodirus spp. predominate. Infections with Fasciola hepatica and Dicrocoelium dendriticum can be acquired on mountainous pastures by cattle, sheep and other livestock grazing in a transhumant system as intermediate hosts of these parasites may find suitable habitats in these regions. There is evidence that in the prealpine and alpine area both parasites are mainly transmitted in two-season cycles. Further examples for the impact of transhumance on parasite-host inter-relationships include cysticercosis in cattle, echinococcosis, psoroptic manage in sheep, tick-borne fever of cattle, and hypodermosis in cattle. These are described and discussed.

Animal Husbandry↗

Seasonal variation of Opisthorchis viverrini infection in cyprinoid fish in north-east Thailand: implications for parasite control and food safety.

Reported is the seasonal pattern of Opisthorchis viverrini metacercariae in cyprinoid fish in north-east Thailand. Samples of fish were collected in 1991-92 at monthly intervals from two areas-Khon Kaen Province, where the opisthorchiasis transmission rate was high, and Mahasarakham Province, where the rate was low. Metacercarial loads in both study areas had similar seasonal patterns. High burdens occurred in the late rainy season and winter (July to January) with low burdens during the summer (March to June). The average burden for Puntius leiacanthus in Khon Kaen was 1.68 metacercariae per fish (127.43 per kg), higher than for all species of cyprinoid fish from the low transmission area. The intensities of infection among P. leiacanthus and Cyclocheilichthys armatus collected in Mahasarakham were comparable, but lower than the intensity of Hampala dispar (0.75 metacercariae per fish) concurrently sampled from the same area (P < 0.05). There was no significant difference in metacercarial load per kg between fish species from Mahasarakham. The results indicate that seasonal variation in metacercariae was a common phenomenon in areas with both high and low endemicity of infection. Also, the metacerarial load in fish was positively associated with infection levels among humans.

Animals↗

Production and immunological responses associated with controlled-release-capsule vs 5-drench preventive anthelmintic programmes for parasite control in lambs.

AIMS: To determine whether: a) using a controlled-release anthelmintic capsule (CRC) instead of a programme of 5 oral drenches administered at 3-4 week intervals, would delay the development of anti-parasite immunity in lambs; b) the use of ivermectin instead of albendazole, administered either as a CRC or as a programme of 5 oral drenches, would delay the development of anti-parasite immunity in lambs; c) lambs treated with CRCs would have higher liveweight gains than lambs drenched orally 5 times at 3-4 week intervals, and; d) delayed onset of anti-parasite immunity is associated with reduced liveweight gains in the period following anthelmintic treatment. METHODS: Three field trials were conducted, 1 on a research farm and 2 on commercial sheep farms, in which groups of 30 lambs were treated with either a CRC containing albendazole, a CRC containing ivermectin, 5 oral drenches with albendazole, or 5 oral drenches with ivermectin, administered at 3-4 week intervals. Liveweights and faecal nematode egg counts (FECs) were recorded in all trials. Immunoglobulin-G (IgG) antibody levels to Ostertagia circumcincta and Trichostrongylus colubriformis adult and larval antigens were measured in Trials 1 and 3, and fleece weights and resistance of animals to nematode challenge infection were measured in Trial 1. RESULTS: CRC-treated lambs had higher levels of antibodies to O. circumcincta infective-stage larvae (L3) than orally drenched lambs in Trial 3, but no other immunological differences due to mechanism of delivery were detected. Antibody levels were lower in lambs treated with ivermectin than albendazole, as a CRC or oral drench in Trial 1, but this was not associated with any measurable effects on FEC or productivity. No significant differences (p>0.05) were detected between drench types (albendazole vs ivermectin) or delivery mechanisms (CRC vs oral drenching) in any of the production parameters measured, in any of the trials. Albendazole-CRCs failed to control FECs in all 3 trials. CONCLUSIONS: Although some differences between treatments in antibody levels were detected these were not associated with measurable differences in level of parasitism or productivity of lambs. CRC use did not appear to offer substantial gains in productivity over a structured programme of 5 oral drenches administered at 3-4 week intervals.

Journal Article↗