Veterinary pharmacovigilance. Part 2. Veterinary pharmacovigilance in practice -- the operation of a spontaneous reporting scheme in a European Union country -- the UK, and schemes in other countries

Veterinary pharmacovigilance, as it operates in the European Union (EU), covers a very broad remit, including adverse effects in treated animals, exposed humans and the environment, and in addition, it extends to cover the violation of maximum residue limits. The mainstay of veterinary pharmacovigilance is the spontaneous reporting scheme working along side other systems such as those reporting on residues surveillance. One of the most well established schemes in the EU is that operating in the UK and this paper examines the evolution of that scheme and some of its findings, data from other countries, and information available from the literature. It also tentatively examines the ways that pharmacovigilance can be used for regulatory purposes, and the contribution from pharmacoepidemiology.     

The O-antigen of Salmonella enterica serotype Enteritidis PT4: a significant factor in gastrointestinal colonisation of young but not newly hatched chicks

The lipopolysaccharide of Salmonella and other Gram negative pathogenic species has been implicated as a major virulence determinant and in this study we report the role of LPS of S. Enteritidis in the colonisation and persistent gastrointestinal infection of young poultry. The gene encoding the unique O-antigen ligase, waaL, was mutated by insertional inactivation in a well characterised S. Enteritidis strain, S1400/94. The waaL mutant, designated PCP, produced rough colonies on agar medium, did not agglutinate O9 antiserum, did not produce an LPS ladder on silver stained gels and was serum sensitive. PCP and a nalidixic acid marked derivative of S1400/94 (S1400/94 Nalr) were used to orally challenge young chicks, separately and together in competitive index experiments. At post-mortem examination of 1-day-old chicks challenged S1400/94 Nalr and PCP separately there were no significant differences in the numbers of S1400/94 Nalr and PCP bacteria in tissues sampled on days 1, 2, and 5. By day 42 after challenge S1400/94 Nalr bacteria were recovered in significantly higher numbers than PCP from the caecal contents (P < 0.001). In competitive index studies in the 1-day-old chick PCP colonised, invaded and persisted in lower numbers than S1400/94 Nalr. In 4-week-old chicks challenged separately, PCP bacteria were recovered from all tissues examined in significantly lower numbers than S1400/94 Nalr. In competitive index experiments in 4-week-old chicks, PCP was not detected at any site and at any time point. Therefore, the O-antigen of S. Enteritidis plays an important role in poultry infections although this role is less important in the newly hatched chick.     

Attaching and effacing lesions in the large intestine of an eight-month-old heifer associated with Escherichia coli O26 infection in a group of animals with dysentery

Escherichia coli O26:K60, with genetic attributes consistent with a potentially human enterohaemorrhagic E. coli was isolated from the faeces of an eight-month-old heifer with dysentery. Attaching and effacing lesions were identified in the colon of a similarly affected heifer examined postmortem, and shown to be associated with E. coli O26 by specific immunolabelling.     

Colonisation of the chicken caecum by afimbriate and aflagellate derivatives of Salmonella enterica serotype Enteritidis.

A semi-quantitative cloacal-swab method was used as an indirect measure of caecal colonisation of one-day old and five-day old chicks after oral dosing with wild-type Salmonella enterica serovar Enteritidis PT4 and genetically defined isogenic derivatives lacking the ability to elaborate flagella or fimbriae. Birds of both ages were readily and persistently colonised by all strains although there was a decline in shedding by the older birds after about 21 days. There were no significant differences in shedding of wild-type or mutants in single-dose experiments. In competition experiments, in which five-day old birds were dosed orally with wild-type and mutants together, shedding of non-motile derivatives was significantly lower than wild-type. At 35 days post infection, birds were sacrificed and direct counts of mutants and wild-type from each caecum were determined. Whilst there appeared to be poor correlation between direct counts and the indirect swab method, the overall trends shown by these methods of assessment indicated that flagella and not fimbriae were important in caecal colonisation in these models.     

Biomicroscopy of the tear film: the tear film of the pekingese dog

Polarised light biomicroscopy was used to examine the normal pre-corneal tear film in 21 eyes of 12 pekingese dogs. The purpose of the study was to examine the influence of excessive exophthalmos on the pre-corneal tear film in the dog. The majority of the animals were found to have high levels of ocular surface contamination by particulate material and plaques of viscous mucus. Other abnormalities included surface lipid with an abnormal granular (three dogs) or 'curdled' (two dogs) appearance; excessive thinning of the lipid layer of the tear film; and the presence of dark globular structures in two dogs, which were presumed to be abnormal meibomian lipid. Break up of the tear film was observed in one dog. Grossly, a thread of viscous mucus was frequently observed along the margin of the lower eyelid. It is postulated that this thread forms because of the excessively exophthalmic conformation of the breed, which prevents the normal access of effete mucus and entrapped debris to the lower conjunctival fornix. The combination of the above factors in the pekingese is suggested as the mechanism whereby the tear film has a reduced stability, thus enhancing the risk from factors more usually considered to initiate corneal ulceration in the breed. The possible adverse effects of lid splitting for the mass removal of distichiae in exophthalmic dogs is discussed.     

Veterinary pharmacovigilance. Part 4. Adverse reactions in humans to veterinary medicinal products

Although seemingly rare, adverse reactions to veterinary products do occur. These may arise from inadvertent exposure during use or as a result of occupational accidents. They are often mild in nature and include adverse effects such as minor skin reactions. However, more serious reactions may occur, and they are not restricted to the effects of the veterinary medicines themselves. For example, high-pressure injection injuries may occur as a result of accidents occurring during animal vaccination operations. This paper reviews some of these events, mentions where appropriate the regulatory actions taken, and describes some of the measures used to minimise such effects in the future, and serves to bring the issues discussed here to the attention of pharmacologists, pharmacoepidemiologists and others who train those who use veterinary medicinal products.     

Prevalence of anthelmintic resistance on sheep farms in New Zealand

AIM: To establish the prevalence of anthelmintic resistance in parasitic nematodes on sheep farms in New Zealand.

METHODS: A cross-sectional prevalence study was conducted, using a standardised faecal nematode egg count (FEC) reduction (FECR) test (FECRT) for ivermectin, at a full (0.2 mg/kg) and half (0.1 mg/kg) dose rate, and albendazole, levamisole and albendazole-levamisole in combination, on 60 lambs (n=10 per group) on farms selected from throughout New Zealand. Farms that conformed with selection criteria were chosen at random (n=80) or with a history of suspected resistance to macrocy- clic lactone (ML) anthelmintics (n=32). Resistance to an an- thelmintic was inferred when there was <95% reduction in FEC 7-10 days after treatment. Larval cultures were performed for all control groups and for treated groups for which resistance was evident.

RESULTS: Of the farms randomly selected, 36% showed ≥95% FECR for all anthelmintics tested; resistance to ivermectin at 0.1 and 0.2 mg/kg liveweight was evident on 36% and 25% of these farms, respectively. Resistance to both ivermectin (0.2 mg/kg) and levamisole was evident on 8/80 (10%) farms, to ivermectin and albendazole on 10/80 (13%) farms, and to iver- mectin, levamisole and albendazole on 6/80 (8%) farms. The prevalence of resistance to a half dose of ivermectin tended to be more prevalent on farms with a history of suspected ML resistance (p=0.06). Resistance to albendazole was seen across all the main parasite genera, and to levamisole in Nematodirus, Ostertagia (= Teladorsagia) and Trichostrongylus species. Resistance to ivermectin was dominated by Ostertagia spp, although Cooperia, Nematodirus and Trichostrongylus species were also implicated.

CONCLUSION: Anthelmintic resistance in parasitic nema-todes of sheep is common in New Zealand. Not only was resistance to albendazole and levamisole common, but resistance to the ML, ivermectin, was at a higher prevalence than expected. Sheep farmers and advisors in New Zealand need to re-evaluate the way they manage parasites, and more research is urgently needed if the steady decline in anthelmintic susceptibility is to be halted.