sou · GLB3132d3 · 1998-01-01 00:00:00 — The bacteriological methods are the same as those employed by and co-workers (1981), i.e. culture on selective media containing nalidixic acid. The authors claim that very few faecal bacteria grow on this medium and the colonies of those that do can easily be differentiated visually from those of the infecting salmonella strain. No validation of this statement is presented. In these two studies tylosin, at both concentrations tested, gave a higher rate and a greater amount of salmonella excretion in the birds given this diet, compared to that of the control groups. Virginiamycin, at the concentrations tested, caused only a slight increase, or no increase, in the rate and amount of salmonella excretion. No studies addressing the issue of dose-response effects of spiramycin, tylosin or virginiamycin on salmonella colonisation have been found, nor any studies concerning effects on infectious dose. Taken together, it appears that tylosin and virginiamycin might effect salmonella colonisation, but available studies can not provide the basis for any proper assessment. No information has been found on spiramycin in this matter. E.7.2 Other enteric pathogens No data on influence of macrolides on colonisation with other enteric pathogens, such as #AMPYLOBACTER spp. or 9ERSINIA ENTEROCOLITICA has been Continuous administration of MLS antibacterials to animals might interfere with disease surveillance. Kempf and co-workers (1991) suggested that macrolide (spiramycin or tylosin) treatment might hinder the detection of -YCOPLASMA GALLISEPTICUM in cultures, or antibodies to this pathogen, in samples from subclinically infected chickens. (1992) reported a decrease in the isolation rate of 3ERPULINA HYODYSENTERIAE after introducing virginiamycin in the feed of pigs with clinical signs of infection. Such effects need to be considered for disease control based on surveillance programs, as they may substantially affect the efficiency and the benefit/cost ratio of the program. As spiramycin, tylosin and virginiamycin are safely used in clinical therapy, they are not expected to have any obvious toxic effects on the target species at growth promoting dosages. Spiramycin and tylosin were evaluated by () in 1994 and by the Joint FAO/() 1991 (1991). In table E.VII, provisional maximum residue limits (MRL) fixed by the Commission in 1995 for spiramycin and tylosin when used as veterinary products are shown. Corresponding values for spiramycin when used in cattle were not given at the time, but temporary MRLs for cattle as fixed by JECFA 1991 to 50, 300 and 200µg/kg for muscle, liver and kidney. MRLs are based on (acceptable daily intake). These limits are based on risk assessments and are set to ensure that residues in animal products do not harm the consumers of these products. Maximum residue limits of spiramycin and tylosin as veterinary products in foodstuffs of animal origin according to Commission regulation (EC) 1442/95 bovine, swine, muscle, liver, 1 Provisional MRL, expired 1, 1997. According to a study by and co-workers (1988), usage of tylosin and virginiamycin at dosages used for growth promotion did not result in residues even if no withdrawal time is practised. Published studies on residue aspects on spiramycin when given at growth promotion dosages have not been found. Spiramycin fed to pigs at approximately 8 times the maximum concentration permitted for growth promotion resulted in liver residues at zero withdrawal time of 10 times the MRL (FAO/WHO, 1991). Assuming a linear relationship, residues in swine liver, from spiramycin used for growth promotion, could be above MRL at zero withdrawal time (see chapter 5). The pharmacokinetics of spiramycin are not linear in swine (Sutter ET AL , 1992), which could result in higher residue levels than what might be expected. Similar experiments in poultry, with similar assumptions of a linear relationship, indicates that in poultry the MRL would not be reached with spiramycin at growth promotion dosages(FAO/WHO, 1991). For tylosin at growth promoting dosages, MRL is not expected to be reached (see chapter 5). Further investigations into possible residues from spiramycin as antibacterial feed additives () in target species are therefore necessary. Allergic reactions triggered by macrolide therapy in humans are rarely reported (Descotes ET AL , 1988; Periti ET AL , 1993). Occupational contact dermatitis and/or asthma is, however, not unusual in farmers (especially pig farmers), feed plant workers, veterinarians and people working in the pharmaceutical industry (and Weismann, 1973; Gollins, 1989; , 1989; Caraffini ET AL , 1994; Danese ET AL , 1994). Hypersensitivity to tylosin and/or spiramycin, indicating a certain but not absolute cross- reactivity, has been reported (and Weismann, 1973). Airborne antigen is thought to be the main cause of these reactions. There is no information available on the prevalence of hypersensitivity to virginiamycin, but there can be no doubt that both tylosin and spiramycin are capable of functioning as antigens and that people continuously exposed to dust containing these substances may become allergic. Frequent use of macrolides in animal feed may therefore be regarded as a professional hazard for farmers and other people in contact with this feed. E.8.3 Other immunological effects An apparent reduction of the response to vaccination following administration of macrolides has been noted in two studies. In a study by (1990), chickens, vaccinated against disease virus (NDV), were challenged with NDV and subsequently treated with spiramycin. This resulted in a twice as high mortality in treated and vaccinated birds as compared to non-treated, vaccinated birds. The spiramycin was given as a subcutaneous injection at a high dose, which must be regarded as a rather extreme challenge. In one study by (1985), virginiamycin was given in the feed at a concentration of /kg in a floorpen experiment. Immunological response to vaccination with NDV, in the form of antibody production, was measured. The NDV titers in the group receiving virginiamycin were depressed as compared to the non-treated group. In a corresponding experiment with caged birds the results were inconclusive. No challenge experiments were made. No explanations of the mechanisms behind these findings have been provided by the authors. No other, similar reports have been found. In many countries the control of NDV infections depends on vaccination programs. In view of this, these observations certainly merit further investigation. Like other , if the use of spiramycin, tylosin or virginiamycin reduces the amount of feed consumed per kg weight gain in the target animal, they would also be expected to reduce nitrogen output per kg weight gain. The effect of tylosin and tylosin fermentation wastes on microbial activity in soil has been investigated (Bewick, 1978). Tylosin from waste was detected in leachates and after 10 weeks had been leached from the soil. Addition of pure tylosin to potting compost in concentrations expected from fertilising soil with the wastes (2, 20 or 40 /ha) resulted in a decrease in microbial respiration for 5-7 weeks after the addition of the antibiotic. In an experiment by Jagnow (1978), the degradation of spiramycin added at 10 ppm to chicken manure was investigated. After 4 weeks, of the added spiramycin had been degraded. However, when the manure was mixed with soil in the ratio 1:3, degradation of spiramycin was complete within a week. Gavalchin and (1994) studied the degradation of tylosin and erythromycin in sandy loam from a non-agricultural area mixed with chicken faeces at different temperatures. Sterile soil-faeces mixtures were used as controls. At 20 and , inactivation of tylosin occurred rapidly and after 5 days the detection limit was reached. At however, of the initial concentration was still present after 30 days of incubation. No degradation of either antibiotic occurred in the sterile controls. This indicates that the degradation process is due to microbial degradation of the antibiotic, probably by enzymatic inactivation. In the experiment, non-agricultural soil was used and the antibiotics were mixed in faeces from non-medicated birds. As the prevalence of bacteria carrying resistance genes coding for macrolide degrading enzymes can be expected to be higher in both faeces from animals given the substance in question and in agricultural soil previously fertilised with macrolide containing manure, the degradation process can be expected to be more efficient. However, during the degradation period the microbial respiration is expected to be lowered as observed by Bewick (Bewick, 1978), presumably due to impairment of sensitive microbiota. Spiramycin, tylosin and virginiamycin all belong to important antibacterial . Increased resistance to spiramycin, tylosin and virginiamycin would hamper the therapeutic use of substances from these in both animals and humans. Exposure of bacteria to spiramycin, virginiamycin and tylosin selects for resistant strains, usually carrying one or several transmissible resistance determinants. 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