Injection sites and withdrawal times

Transcription

1 Injection sites and withdrawal times Jfm Nouws To cite this version: Jfm Nouws. Injection sites and withdrawal times. Annales de Recherches Vétérinaires, INRA Editions, 1990, 21 (suppl1), pp.145s-150s. <hal > HAL Id: hal Submitted on 1 Jan 1990 HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

2 Injection sites and withdrawal times JFM Nouws RVV-District 6, PO Box 40010, Nijmegen, The Netherlands (Pharmacokinetics of Veterinary Drugs, October 1989, Foug6res, France) Summary &horbar; Following parenteral antibiotic administration, various factors influence the persistence of residues at the injection site, for example, the antibiotic itself, the composition of the formulation, the degree of irritation induced and the species of animal medicated. Routine testing for the detection of such residues is lacking in the EEC and even the absence of residues in the urine is no guarantee of their absence at the injection site. International regulatory guidelines concerning the permitted residue levels and the permitted extent of irritation at the injection site have yet to be agreed upon. By establishing such limits, it is hoped that the presence of drug residues can be avoided and at the same time good veterinary practice can be facilitated. injection sites / residues I irritation I withdrawal time Résumé &horbar; Sites d injection et délais d attente. Après une injection d antibiotique, différents facteurs peuvent influencer la persistance des résidus au site d administration (le principe actif, la formulation, le degré d irritation et l espèce animale). Les tests de routine pour la détection de ces résidus n existent pas dans la CEE et la non détection de résidu dans les urines ne garantie pas leur absence au niveau du site d injection. Des recommandations internationales relatives aux tolérances et au degré d irritation au site d injection restent à déterminer. A ce niveau, on peut espérer que la présence des résidus sera évitée et que simultanément les bonnes pratiques vétérinaires seront améliorées. sites d injection / résidus / tolérance locale / délai d attente INTRODUCTION Subcutaneous (sc) and intramuscular (im) injections of many veterinary products (antimicrobials, vaccines, tranquillizers, etc) may cause severe local tissue irritation and lead to prolonged persistence of residues at the injection site (Nouws, 1984; Rasmussen, 1980a, b; Rasmussen and Svendsen, 1976). In the Netherlands, the frequency of injection sites detected and removed at slaughter in normal pigs is about 3%. For the pig industry, the annual economic loss of meat as a result of injection site condemnation is at least 6 million guilders. In this respect, it must be emphasized that only injection sites with visible signs of tissue irritation are detected and removed. There are of course formulations which cause little or no visible alteration at the injection site; in this case, however, high local drug concentrations may be present, which may give rise to technological problems in processing meat products and, although the risk is small, may pose a real public health threat in respect to human consumption.

3 In this paper, the problems of drug persistence and detection at the injection site for various groups of antimicrobial formulations are summarized, and the necessity of establishing quality criteria for such formulation is strongly proposed. DRUG FORMULATIONS /3-Lactam formulations In general, formulations of procaine (proc) benzylpenicillin persist for a relatively short period at the injection site (ie, less than 2 weeks) and little, if any, tissue damage is observed 7 d post injection (pi) (see table I). Ampicillin and amoxicillin trihydrate/ anhydrate, and benzathine benzylpenicillin (oily) formulations usually induce limited irritation, which is sometimes still visible 2 In this case, the injection site weeks pi. can appear oily or show evidence of white/ yellow granules in the fat and connective tissue. Beyond 2 weeks pi, a great deal of experience is needed to detect injection sites macroscopically. However, high drug concentrations may remain for 3-10 weeks (or even longer) after injection, especially in the case of the slowly absorbed benzylpenicillin formulations (eg, benzathine or benethamine salts; see duphapen@, table I), while an investigation of urine or organ residues at this stage may well prove negative. It must be emphasized that, with this type of formulation, therapeutic plasma levels of the antibiotic are maintained for 2-4 d, while on the basis of residue persistence at the injection site, preslaughter withdrawal times of 3-10 weeks are required. Unfortunately, with currently available screening methods (Bogaerts and Wolf, 1980; Nouws et al, 1988) adequate monitoring of recommended withdrawal periods in excess of 3 weeks for slowly absorbed penicillin formulations is impossible. A suitable alternative to the long-acting formulations in this respect would be the procaine benzylpenicillin formulations, which would have to be administered 2 or 3 times, but without the requirement for an excessively long withdrawal period. This point therefore raises serious doubts as to the necessity of using benzathine benzylpenicillin formulations, for example, in food-producing animals. Aminoglycosides (eg, dihydrostreptomycin, neomycin, gentamicin) Aminoglycoside antibiotic residues can be detected in the urine of domestic animals for around 2 weeks pi. Using special methods, residues can be detected in the kidneys, liver and sometimes at the injection site for at least 6 weeks. However, kidney examination with the EEC-4-plate method (Bogaerts and Wolf, 1980) gives negative results by 3 weeks pi, and thus a recommended withdrawal period of longer than 3 weeks cannot be monitored using standard methods (Bogaerts and Wolf, 1980; Nouws et al, 1988). The use of aminoglycoside formulations in food-producing animals will therefore carry the risk of small amounts of bound antibiotic being present in certain edible tissues. In this context, it would be preferable if the in vivo detection limit of the EEC-4-plate test for aminoglycosides (2-6 ppm) could serve as the tolerance level for this kind of drug in organs. Tetracycline formulations In the past, large variations between different formulations of oxytetracycline (OTC)

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5 have been observed in respect to local tissue irritation and persistence of the antibiotic at the site of injection (Hall et al, 1989; Luthman and Jacobsson, 1982; Mevius et al, 1986; Nouws, 1984; Petzer et al, 1984; Xia et al, 1983). Table I presents more recent data on this subject. As can be seen, both 10% and 20% formulations may cause pain and extensive local irritations (hemorrhages and edema, muscle degeneration, necrosis and abscess formation). All the 20% (the so-called long-acting ) formulations hitherto tested cause considerable irritation and result in the persistence of OTC at the injection site for at least 2 weeks pi. With the so-called longacting formulations, a prolonged drug persistence at subtherapeutic levels in plasma is observed; this is the result of the persistence and prolonged absorption of OTC from the injection site, which in turn is a consequence of the excessive local irritation (Nouws, 1984; Petzer et al, 1984; Xia et al, 1983). There are, however, formulations that cause minimal, if any, irritation (and with a correspondingly short OTC persistence) at the injection site. It is also worth noting that the use of such formulations may result in the disappearance of organ and injection-site residues, while urine residues remain detectable (see engemycin 10%, table I). This phenomenon may occur as a result of OTC release from a deep tissue compartment (eg, bone). Macrolides Formulations containing macrolide antibiotics (tylosin, spiramycin, erythromycin) can also cause considerable local irritation, and prolonged persistence of residues at the injection site may be expected. In addition, because of the high binding affinity to proteins, residues may persist for a long period in liver and kidney tissue (see table I: tylosin). With respect to macrolide formulations, more comparative research is needed. Other antimicrobial formulations Chloramphenicol and sulfonamide/trimethoprim formulations often cause excessive irritation at the injection site, sometimes painful, following im injection. Thirty days post injection, remnants of necrotic tissue are still observed macroscopically (sometimes with sharp demarcation zones). At that time, sulfonamide (but no trimethoprim) residues could be detected at the injection site (Rasmussen and Svendsen, 1976). Further comparative research is required in this field. GENERAL ASPECTS AND CONSIDERATIONS As shown, drug persistence at the injection site depends mainly upon the formulation characteristics. Another factor affecting persistence is the species medicated; in sheep, for instance, tissue irritation is generally less than in calves or pigs (symptoms of pain, however, may be more pronounced in sheep than in calves or pigs). Thus the extent of tissue irritation cannot be automatically extrapolated from one species to another. Other factors influencing drug persistence are the injection volume (the larger the volume the greater the irritation) and the site of injection; in this latter respect, more rapid absorption has been recorded following injection into the neck or shoulder musculature. In this context, it is important not to give repeat injections of irritating formulations at the same site, since this will result in even

6 greater local irritation and much longer persistence. A further point which should be stressed is the fact that, in diseased animals, drug absorption is reduced (thus the effect of irritating components in the formulation may be even more pronounced). This may explain why in diseased animals injection site irritation is often greater (even for excellent formulations) than in healthy animals and establishment of accurate withdrawal times is hardly possible. In short, from the standpoint of drug persistence, as well as from a therapeutic and good veterinary practice point of view, non-irritating formulations are required. These should also show excellent bioavailability with an as-short-as possible period of drug persistence in the body. Thus, it is desirable to license and to use only those formulations which exhibit a drug persistence of less than 3-4 weeks at the injection site. It must be borne in mind that prescribed withdrawal times of longer than 4 weeks are impractical in that they are diffi- i- cult to control effectively. Formulations with such long withdrawal times do nothing to enhance good veterinary practice ; they merely cause residue problems. Good veterinary practice from a residue point of view means using formulations which possess good bioavailability characteristics, are non-irritant, and persist for only a short period in the body; at present, a large number of formulations do not fulfill these criteria. As regards the criteria, each country currently has its own registration policy. It would be highly desirable if international standards concerning levels of irritation and drug persistence at the injection site could be established in the near future. In would also be re- this context, guidelines quired detailing methods of investigating injection sites (eg, the minimum and maximum injection site weight ( g) to be examined) and how to objectively quantify the level of irritation. On the other hand, the consequences of such an approach would be to provide a stimulus and challenge to the pharmaceutical industry to develop only those formulations which would provide the optimum therapeutic effects, with a minimum of residue problems. In conclusion, we should, first of all, be using formulations which currently fulfill the above criteria and, secondly, in the longterm, we should be improving our other formulations as a prerequisite for minimizing drug residues and irritation at the site of injection in food-producing animals. REFERENCES Bogaerts R, Wolf F (1980) A standardized method for detection of residues of antibacterial substances in fresh meat. Fleischwirtschaft 60, Hall WF, Kniffen TS, Bane DP, Bevill RF, Koritz GD (1989) Plasma concentrations of oxytetracycline in swine after administration of the drug intramuscularly and orally in feed. J Am Vet Med Assoc 194, Luthman J, Jacobsson SO (1982) Comparison of two oxytetracycline formulations in cattle. Acta Vet Scand 23, Mevius DJ, Nouws JFM, Breukink HJ, Vree TB, Driessens F, Verkaik R (1986) Comparative pharmacokinetics, bioavailability and renal clearance of five parenteral oxytetracycline- 20% formulations in dairy cows. Vet Q 8, Nouws JFM (1978) Tissue distribution and residues of some antimicrobial drugs in normal and emergency-slaughtered ruminants. Thesis, State University of Utrecht, NL Nouws JFM (1984) Irritation, bioavailability, and residue aspects of ten oxytetracycline formulations administered intramuscularly to pigs. Vet Q 6, Nouws JFM, Broex NJG, den Hartog JMP, Driessens F (1988) The new Dutch kidney test. Arch Lebensmittelhyg 39, Petzer IM, Giesecke WH, van Staden JJ (1984) A comparative investigation on tissue com-

7 patability in cattle of several oxytetracycline formulations for intramuscular administration. Proceedings 13th World Congress on Diseases of Cattle, Durban, (Coubrough RI, ed) Hoechst Pharmaceuticals Ltd, Johannesburg, Rasmussen F (1980a) Tissue damage at the injection site after intramuscular injection of drugs in food-producing animals. tn: Trends in Veterinary Pharmacology and Toxicology. (van Miert ASJPAM, van Frens J, van der Kreek FW, eds) Elsevier, Amsterdam, Rasmussen F (1980b) Tissue damage at the injection site after intramuscular injection of drugs. Vet Sci Commun 2, Rasmussen F, Svendsen 0 (1976) Tissue damage and concentration at the injection site after intramuscular injection of chemotherapeutics and vehicles. Res Vet Sci 20, Xia W, Nielsen P, Gyrd-Hansen N (1983) Oxytetracyclines in cattle. A comparison between conventional and a long-acting preparation. Acta Vet Scand 24,