Identification and surveillance of antimicrobial resistance dissemination in animal production.

Antimicrobial resistance is a growing problem in human medicine, and concern has been expressed that use of antimicrobials in animals may be a contributing factor. Although the majority of human pathogens showing antibiotic resistance have no link with animals, the issue of animal use of antimicrobials remains controversial, particularly with respect to antibiotic growth promoters (AGP). The European Union (EU) has withdrawn as AGP some compounds that remain in use in the United Sates. This difference in availability allows comparisons to be made of antimicrobial resistance outcomes with and without use of an AGP. Such comparisons so far show little apparent measurable benefit to human health resulting from the EU removal of AGP, and there is evidence of increased use of therapeutic antibiotics in animals to treat an apparent increased incidence of clinical disease. Microbial risk assessments are important in judging quantitatively or qualitatively whether the risk of using a particular AGP is acceptable in terms of potential hazard to human health. Resistance surveillance is an essential part of such microbial risk assessments, but such surveillance should be carefully planned to avoid confounding factors that could invalidate any conclusions.

Veterinary use of antimicrobials and emergence of resistance in zoonotic and sentinel bacteria in the EU.

Antimicrobials are essential for treatment of sick animals, but even if used correctly, may eventually lead to antimicrobial resistance. While this represents a potential hazard to humans, the great majority of resistant human pathogens, especially the more important ones, are unrelated to animal sources. A survey of informed medical opinion suggested that of the human antimicrobial resistance problem, <4% was seen as potentially linked to animal sources. This proportion related largely to zoonotic bacteria which by definition have the capacity to carry resistance between species, although the evidence for resulting harm remains limited. A recent study compared resistance among chicken, pig and cattle isolates of Salmonella spp., Campylobacter spp. and Escherichia coli from a series of EU countries. When tested against antimicrobial agents, this survey showed variation of resistance between countries, between hosts and between organisms. Such variation may give insight into preferred methods of antimicrobial administration or disease control, but it is clear that the epidemiology of antimicrobial resistance induction and dissemination in animals remains complex and is yet to be fully understood.

A hypertonic infusion in the treatment of experimental shock in calves and clinical shock in dogs and cats.

A novel composite hypertonic solution for intravenous use was tested in two experimental models, one of endotoxic shock and one of shock linked with dehydration, both in anaesthetised calves. Endotoxic shock was induced with Escherichia coli lipopolysaccharide and was characterised by a low cardiac output, hypoxaemia, acidosis and anuria. Treatment with a small volume of the solution increased cardiac output, improved oxygen carriage, corrected acidosis and stimulated renal function. Experimental dehydration in calves was induced by intraperitoneal mannitol and frusemide diuresis, and was characterised by reduced circulating plasma volume, acidosis and poor peripheral perfusion. Treatment with the new solution corrected the acidosis and stimulated peripheral circulation significantly better than treatment with hypertonic or isotonic saline alone, and also expanded the calves' plasma volume. The new solution was also compared with conventional fluid therapy in clinical small animal practice. Twenty cats and dogs with clinical shock were treated with either small volumes of the hypertonic solution or large volumes of isotonic fluids. The animals treated with small volumes of the hypertonic solution responded better than the animals treated with large volumes of isotonic fluid.

A comparison of two oral rehydration solutions in experimental models of dehydration and diarrhoea in calves.

Two oral rehydration solutions (ORS 1 and ORS 2) were evaluated in isolated intestinal loops of anaesthetised calves, in an experimental model of dehydration in the calf, in calves with experimentally induced diarrhoea and in 164 calves with clinical diarrhoea. The studies in isolated intestinal loops indicated that water absorption was significantly greater from ORS 2 than from ORS 1. After the intraperitoneal administration of hypertonic mannitol combined with intravenous diuretics, the plasma volume of calves was reduced by about 30 per cent, and was more rapidly expanded after treatment with ORS 2 than ORS 1. The plasma volume remained significantly reduced (P less than 0.01) three hours after dosing with ORS 1 whereas after treatment with ORS 2 it was not significantly different from the initial value. Acidosis was corrected to a significantly (P less than 0.01) greater extent after treatment with ORS 2, and peripheral perfusion also returned to normal more rapidly in calves given ORS 2. In newly purchased calves in which diarrhoea was induced experimentally with an E coli challenge, base deficit and diarrhoea were corrected more rapidly in the calves receiving ORS 2. When the solutions were tested in the treatment of 164 clinical cases of diarrhoea and dehydration there was no statistically significant difference in mortality between the formulations, although the overall mortality was 4.8 per cent in the calves treated with ORS 2, compared with 8.6 per cent in the calves treated with ORS 1. It was concluded that ORS 2 performed better than ORS 1 especially in the expansion of plasma volume and the correction of acidosis.

Efficacy of clavulanate-potentiated amoxycillin in experimental and clinical skin infections.

The efficacy of clavulanate-potentiated amoxycillin was compared with amoxycillin alone in experimental staphylococcal infection in dogs and in a controlled trial in clinical cases of skin infection in dogs and cats. The experimental infection was produced by subdermal inoculation with beta-lactamase producing (amoxycillin resistant) staphylococci absorbed in cotton dust. This produced discrete, localised lesions with no systemic involvement. In a cross over study, six animals were randomly allocated to treatment with either amoxycillin alone (10 mg/kg, dosed twice daily) or a formulation of clavulanate-potentiated amoxycillin (12.5 mg/kg, of a 1:4 ratio, dosed twice daily). The lesions of the animals treated with clavulanate-potentiated amoxycillin resolved more quickly than those treated with amoxycillin alone. The difference was significant (P less than 0.05) for both lesion diameter and inflammation score after day 6 of treatment. A trial was carried out in clinical cases of skin disease which were randomly allocated to twice daily treatment with either amoxycillin alone (10 or 20 mg/kg), or with clavulanate-potentiated amoxycillin (12.5 or 25 mg/kg of a 1:4 ratio). The required duration of treatment was shorter (P less than 0.5) for the potentiated amoxycillin treatments, and the success rate (judged by cure or substantial improvement) was higher (P less than 0.05) for this group, especially (P less than 0.01) where amoxycillin resistant organisms were isolated. It was concluded that clavulanate-potentiated amoxycillin was an effective treatment of skin infections both under experimental and clinical conditions.

Clavulanate-potentiated amoxycillin: activity in vitro and bioavailability in the dog.

Clavulanic acid is an inhibitor of beta-lactamase (penicillinase) and when used with amoxycillin the resulting combination becomes active against most bacteria resistant to amoxycillin through production of beta-lactamase. A total of 551 bacterial isolates from dogs and cats were examined by disc sensitivity testing, which showed that there was amoxycillin resistance particularly among staphylococci (50 per cent), Klebsiella species (97 per cent) and Escherichia coli (28 per cent). A combination of potassium clavulanate and amoxycillin reduced the incidence of resistance to 0.3, 3 and 7 per cent, respectively. Minimum inhibitory concentrations were determined for a number of the isolates and showed marked reductions in the presence of potassium clavulanate. A formulation containing amoxycillin trihydrate and potassium clavulanate (4:1) was dosed to beagles at 12.5 mg/kg. Concentrations of the drugs in blood, tissue fluid and skin showed that both drugs were sufficiently well absorbed and distributed to allow a prediction of efficacy against infections caused by beta-lactamase producing bacteria.

Absorption in calves of amoxicillin, ampicillin, and oxytetracycline given in milk replacer, water, or an oral rehydration formulation.

Oxytetracycline, amoxicillin or ampicillin suspended in milk replacer, water, or a glucose-glycine-electrolyte solution (GGES) was orally given to calves (n = 64). Oxytetracycline suspended in milk replacer gave lower relative bioavailability than when suspended in water (P less than 0.01) or in GGES (P less than 0.001). Seemingly, the 63% binding (only partly reversible) of oxytetracycline suspended in milk replacer was responsible for low serum concentrations, whereas the greater water absorption from the GGES was responsible for improved uptake of antibiotic. Amoxicillin suspended in milk replacer had a delayed absorption, compared with that suspended in water, but the relative bioavailabilities from milk replacer and water were similar. In contrast, peak serum concentration and bioavailability were higher (P less than 0.05) when amoxicillin was suspended in GGES than when suspended in water. Binding of amoxicillin with milk replacer was comparatively low (16%) and was reversible. Ampicillin suspended in GGES gave a higher peak serum concentration (P less than 0.05) than when suspended in milk replacer. It, therefore, appeared that these antibiotics were more bioavailable when suspended in GGES than when suspended in water or especially in milk replacer. Oxytetracycline was bound particularly strongly to milk replacer.

Diarrhoea treatments--fluid replacement and alternatives.

Treatments for diarrhoea in animals include antibiotics, antisecretory drugs, adsorbents and fluid therapy. Of these, antibiotics have a role in bacterial disease, but are probably often used in cases where they contribute little. Other drug approaches (antisecretory, adsorbents, etc.) may in the future be useful, but those so far available do not appear very effective. Fluid therapy, especially by the oral route, is rational, is effective in both bacterial and viral diarrhoea, and should be the treatment of first choice.

Comparison between milk deprivation and oral rehydration with a glucose-glycine-electrolyte formulation in diarrhoeic and transported calves.

Treatment of diarrhoeic calves by oral administration of a glucose-glycine-electrolyte solution (GGES) was compared with milk deprivation (water given instead) and with no treatment (milk-fed controls). The diarrhoea followed challenge with enteropathogenic Escherichia coli. The GGES group showed a significantly lower mortality (5 per cent) in comparison with the controls (37 per cent). The milk-deprived group had a slightly lower mortality (30 per cent) in comparison with the controls. The milk deprived group showed a significantly prolonged duration of diarrhoea in survivors compared with the control group, while the GGES group did not differ significantly from the controls. Calves arriving on farms were allocated randomly to either GGES or to an alternative control treatment (usually partial milk deprivation). The incidence of diarrhoea during the subsequent two weeks was significantly less in the GGES group. Clotting of milk by rennet was impaired by addition with either water or an alkaline electrolyte solution but was enhanced by dilution with GGES.

Oral fluid replacement by a glucose glycine electrolyte formulation in E coli and rotavirus diarrhoea in pigs.

A glucose glycine electrolyte solution (GGES) was investigated to determine its suitability for oral rehydration in diarrhoea in pigs. Piglets with diarrhoea following experimental infection with eneteropathogenic Escherichia coli were given access in cube drinkers to either GGES or water. The mortality in the GGES group (11.6 per cent) was significantly (P less than 0.05) less than in the controls (24.0 per cent), and weight gain in severely diarrhoeic piglets was greater in the GGES group. Gnotobiotic piglets were challenged with pig rotavirus and either given access to GGES or milk. The GGES was either in restricted volume or ad lib. Restricted access to GGES prevented much of the weight loss due to the diarrhoea and ad lib access to GGES allowed relatively uninterrupted weight gain in comparison with controls. In naturally occurring cases of diarrhoea on farms, access to GGES reduced mortality to weaning from 19.7 per cent to 7.2 per cent (P less than 0.05). Weight gain per day was also greater in piglets which scoured for three days or more, indicating the rehydrating effect in reducing net fluid loss. Thus GGES treatment was of value in treatment e&ects of diarrhoea due to either E. coli or rotavirus.

The ability of cholestyramine resin and other adsorbents to bind Escherichia coli enterotoxins.

Several adsorbent materials were evaluated for their ability to bind Escherichia coli enterotoxins. Cholestyramine, a strong anion-exchange resin, bound the heat-labile and the heat-stable types of enterotoxin and reduced significantly their effects in some animal models. However, its efficacy in the treatment of diarrhoeic piglets appeared to be adversely affected by the presence of milk in the alimentary tract.

Biological evaluation of a methanol-soluble, heat-stable Escherichia coli enterotoxin in infant mice, pigs, rabbits, and calves.

Escherichia coli P16 was shown to produce two heat-stable toxins (ST) with differing biological activity. The toxins were separated by methanol extraction, and the first, STa, was methanol soluble, partially heat stable, active in neonatal piglets (1 to 3 days old) and infant mice, but inactive in weaned pigs (7 to 9 weeks old); the second, STb, was methanol insoluble, active in weaned pigs and rabbit ligated loops, but inactive in infant mice. It is therefore suggested that use of suckling mice as indicators of ST production will fail to identify certain ST-producing strains.