Is it time to ban all antibiotics as animal growth-promoting agents?

THE LANCET

widely, and Devries and Haesebrouck2 have confirmed their presence in horses, dogs, and cats, which species have never received avoparcin, the related glycopeptide. Further, Casewell et al3 in the UK have shown that there does not seem to be a clear genetic relation between VRE recovered from chickens and those from hospital patients. These data have recently been supported by an examination of the genetic construct of VanA gene clusters from chickens and man conducted by Beighton and Casewell at Kings College School of Medicine and Dentistry, University of London. In the USA the Office of Technology Assessment reported at the end of 1995 that they were unable to show that the use of antibiotics in livestock was related to resistance in man and this confirms earlier studies that formed the basis of the decision in the USA and many other parts of the world not to follow the Swann recommendations. Your correspondents would do well to heed the comment made by the SCAN report, issued in July, 1996, “that to be convinced of danger for man resulting from the use of avoparcin in animals, it would prefer evidence to indications and proof to possibilities”. A J Mudd Roche Products, Heanor, Derbyshire DE75 7SG, UK

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van den Bogaard AE, Stobberingh EE. Time to ban all antibiotics as animal growth-promoting agents? Lancet 1996; 348: 619. Devries LA, Haesebrouck F. Susceptibility of enterococci and intestinal streptococci from pigs to the growth-enhancing antibiotics flavomycin and avoparcin. Proceedings of the 14th International Pig Veterinary Society Congress, Bologna, 1996. Seyed-Akhavani M, Hill RLR, Morrison D, Woodford N, Beighton D, Casewell MW. A molecular comparison of vancomycin-resistant E. Faecium (VREF) strains isolated from patients and chickens. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 1995.

SIR—I can understand some of van den Bogaard and Stobberingh’s1 concerns about the recommendations made by the Swann committee, which were mainly aimed at preventing the further development of multiantibioticresistant strains of salmonellae in calves from reaching man. The committee reported 27 years ago, and our knowledge and understanding have increased since those days, as have the number of antimicrobially active molecules used in human and veterinary medicine. With respect to “other promising molecules”, I would point out that tiamulin is a prescription-only veterinary medicine in EU countries and therefore can only be used under the direction of a veterinary surgeon, unlike in-feed growth promoters. Having been involved with the clinical development of the compound for the treatment and prevention of swine dysentery, 2,3 a mucohaemorrhagic diarrhoea of pigs caused by a spirochaete, Serpulina hyodysenteriae, I was concerned that it should be placed alongside and possibly confused with in-feed growth promoters that are prescription free. Growth promoters are extensively used in the feed of healthy pigs on a free-sale basis to improve nutritional efficiency. Tiamulin is the most effective therapeutic antibiotic in veterinary medicine for swine dysentery, as a result of the widespread development of resistance to tylosin and lincomycin4 and the withdrawal of several antimicrobial compounds following their safety reviews in Europe. To suggest that tiamulin should be withheld pending possible development of a similar molecule from the pleuromutilin family of antibiotics for human use, which would take several years to develop, would result in serious health and welfare problems for the pig population of Europe (about 115 million). The pleuromutilins were screened originally for human medicine in the early 1970s and dismissed on grounds other

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than their microbiological activity and subsequently developed for animal use. They were recently reviewed within Sandoz and again their development for human use was not pursued. The pleuromutilin family of antibiotics are being developed for and used only in veterinary medicine and therefore the potential risk of cross-resistance development to antibiotics used in man, with which they are structurally unrelated, is judged remote. D G S Burch Tiamulin Business Group, Biochemie, c/o Sandoz Pharmaceuticals UK Ltd, Frimley Business Park, Frimley, Surrey GU16 5SG, UK

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Van den Bogaard AE, Stobberingh EE. Time to ban all antibiotics as animal growth-promoting agents. Lancet 1996; 348: 610. Burch DGS, Heard TW, Tasker JB. Tiamulin injection for the treatment of swine dysentery. Vet Rec 1983; 113: 236–37. Burch DGS. Tiamulin feed premix in the prevention and control of swine dysentery under farm conditions in the UK. Vet Rec 1982; 110: 244–46. Prescott JF, Baggot JD. Lincosamides, macrolides and pleuromutilins. In: Antimicrobial therapy in veterinary medicine. Ames: Iowa State Press, 1993: 179–204.

Authors’ reply SIR—Not everybody would agree that the resistance situation has improved since Swann, because we are now encountering some micro-organisms that are so multiresistant that it is difficult, and may be soon impossible, to combat these with the available antibiotics. During the past half century, the wide usage of each new antibiotic has led eventually to the emergence of genes encoding resistance to it. The level of resistance in the intestinal flora of populations with high use of antibiotics is considerably greater than in populations with lower antibiotic usage.1 Apart from developing countries, hospitals, daycare centres, and intensive farming units are populations with high antibiotic usage. The greater the number of resistant intestinal microorganisms, the greater the chance of transfer of their resistance genes to pathogenic bacteria. Most infections arise in the community, and all transferable resistance in hospitals must once have been introduced from elsewhere. In this respect one could consider resistance in (nosocomial) pathogens as the tip of the iceberg. Therefore, it has been suggested that a low level of carriage of resistant strains should become a public health goal, as have normal blood pressure and lower serum cholesterol concentrations.1 Because resistant bacteria and resistance genes are not checked by national or natural barriers, and might even overcome species barriers, a low level of resistance in intestinal flora should be thought of as a distinguishing quality and safety mark for food animals. This goal can be reached only by reducing the use of antimicrobial agents in these animals. In the Netherlands more antibiotics are used as growth promoters than for veterinary reasons. Stopping this practice would diminish the total amounts used in animals at least by 50% without hampering veterinary care. Because our knowledge of bacterial genetics has considerably increased since Swann, it does not, in view of the spread of resistance, seem to make sense anymore to differentiate between therapeutically used antimicrobials and antibiotics used as growth promoters in animal feeds. We therefore said that there is no reason to prohibit usage of avoparcine alone, but that the whole system of increasing the reservoir of resistance genes in food animals by continuously feeding antibiotics should be reconsidered. The expert panel on the avoparcine issue of SCAN could not reach consensus, and it stated that there was not yet sufficient evidence to take action, but it has banned approval as growth promoters other glycopeptides

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sharing cross resistance with vancomycin or teicoplanin, until the avoparcin case has been resolved by further studies. SCAN will review its decision within 2 years. Tiamulin is not approved as a growth promoter in the EU, but it is in the USA.2 We do not object to the therapeutic use of tiamulin, but are against its use for the prevention of bacterial diseases, which means feeding it life long to fattening pigs to control disease symptoms—ie, to maintain growth.3 Antibiotic treatment should aim at elimination of the causative organism. That this, if sufficient high doses of tiamulin are given, is possible has been shown in Denmark for swine dysentery.4 As well as the abolition of feeding antibiotics to improve growth, the veterinary use of antibiotics should be lowered by improving animal husbandry methods, introducing preventive vaccination programmes, and strict adherence to a veterinary antibiotic policy.5 *A E van den Bogaard, E E Stobberingh Department of Medical Microbiology, University of Maastricht, NL-6200 MD Maastricht, Netherlands

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Lester SC, Pilar M, Wang F, Perez Scale I, Gang H, O’Brien TF. The carriage of E coli resistant to antimicrobial agents by healthy children in Boston, in Caracas, Venezuela and In Put, China. N Engl J Med 1990; 323: 285–89. Prescott JF, Baggot JD. Lincosamides, macrolides and pleuromatilins. In: antimicrobial therapy in veterinary medicine. Ames: Iowa State Press, 1993: 201. Kyriakis SC, Tsinas AC, Saoulidis K, Sarris KJ. Studying the effect of a salinomycin/thiamulin combination against swine dysentery. Vet Med 1995; 90: 701–05. Szanzer J. Eradication/control programmes in Denmark for swine dysentery. Proceedings of the symposium on the safe usage of tiamulin for the prevention of swine dysentery. Netherlands: Nuland, 1996: 5. Bogaard AE van den. A veterinary antibiotic policy: a personal view on the perspectives in the Netherlands. Vet Microbiol 1993; 35: 303–12.

Oral vitamin K prophylaxis for newborn infants: safe enough? SIR—Vitamin K prophylaxis has been a matter of debate for some years. Two studies have reported an increased risk of cancer in children receiving intramuscular vitamin K in the newborn period.1,2 However, these findings have not been confirmed by others.3 In Switzerland, before these studies were published, the acceptance—by parents, midwives, obstetricians, and paediatricians—of intramuscular vitamin K was declining.4 In Switzerland, and in many other European countries, but not in the USA, intramuscular vitamin K was changed to oral application. The change to oral prophylaxis may have improved vitamin K acceptance. In Switzerland the recommendation is to give 2 mg vitamin K on postnatal days 1 and 4, whereas in other European countries three doses are recommended. To facilitate resorption, particularly in infants with cholestatic liver disorders, a new micellar form of oral vitamin K (Konakion MM paediatric, Roche, Switzerland) was introduced in January, 1995.5 We report three exclusively breastfed infants with severe coagulopathy caused by vitamin K deficiency despite appropriate oral micellar vitamin K prophylaxis. Two of them had biliary atresia. The first child presented with severe intracranial haemorrhage and the second one with haemorrhagic pleural effusions leading to dyspnoea. The third child, who also presented with severe intracranial bleeding, had no cholestatic liver disease. Computed tomography demonstrated angiomatosis of the choroid plexus as the source of the haemorrhage. The three infants were 7 to 8 weeks old at the time of presentation. The

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prothrombin time in all of them was severely prolonged (>60 s). The vitamin K dependent factors were all low (<6%), and the vitamin K independent factors were normal. Coagulopathy was corrected with Prothromblex (Immuno, Austria) or fresh frozen plasma as well as intravenous vitamin K. Therefore prothrombin time remained normal in all three children. It is important to note that these three cases could have been prevented by intramuscular vitamin K and that the new micellar form given on days 1 and 4 does not sufficiently facilitate resorption in patients with cholestatic liver disease. We suggest that current recommendations should be reevaluated to change to intramuscular dosage or to increase the number of oral doses. *O Baenziger, C P Braegger, S Fanconi *Division of Intensive Care Medicine, University Children’s Hospital 8032 Zürich, Switzerland; and Division of Gastroenterology and Nutrition, University Children’s Hospital

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Golding J, Paterson M, Inlen LJ. Factors associated with childhood cancer in a national cohort study. Br J Cancer 1990; 62: 304–08. Golding J, Greenwood R, Birmingham K, Mott M. Childhood cancer, intramuscular vitamin K and pethidine given during labour. BMJ 1992; 305: 341–46. Ekelund H, Finnström O, Gunnarskog J, Källén B, Larson Y. Administration of vitamin K to newborn infants and childhood cancer. BMJ 1993; 307: 89–91. Tönz O, Schubiger G. Neonatale Vitamin-K-Prophylaxe und VitaminK-Mangelblutung in der Schweiz. Schweiz Med Wochenschr 1988; 118: 1747–52. Schubiger G, Tönz O, Grüter J, Shearer MJ. Vitamin K concentration in breastfed neonates after oral or intramuscular administration of a single dose of a new mixed micellar preparation of phylloquinone. J Pediatr Gastroenterol Nutr 1993; 16: 435–39.

Anticoagulation therapy: bleeding and thromboembolic complications SIR—The Italian researchers (Aug 17, p 423)1 are to be commended for their community-based study of the bleeding complications of warfarin. Despite cumulative evidence for the efficacy of warfarin in diminishing the incidence of stroke in non-rheumatic atrial fibrillation under strictly controlled conditions, clinicians in primary care have concerns about the safety of anticoagulation.2 However, general practitioners will find little reassurance in the Italian study: the safety of warfarin is perceived to be a function of side-effects, whose classification is characterised by a secondary care perspective. The safety profile of any drug depends on the frequency of its side-effects, which frequency in turn is a function of how those side-effects are operationally defined. For example, the ISCOAT investigators classify haemorrhage requiring more than two units of blood as major. Suppose, for example, that they had decided to classify as a major side-effect only those haemorrhages requiring up to four units, as other researchers in this area have done.3 With such classifications, the frequency of major side-effects would diminish, improving the safety profile of the drug. Palareti and colleagues classify side-effects as major, minor, and insignificant. Primary care doctors might well have some concern that blood loss requiring up to two units might deserve a more substantial accolade than minor, but it is with the classification of insignificant side-effects that they have the greatest concern. The researchers include, as insignificant events, epistaxis, microscopic haematuria, and occasional haemorrhagic bleeding. The insignificance of these events ultimately is a retrospective judgment. At the onset of any blood loss—whether it is from the nose, the bladder, or the vagina—the patient who is receiving

Vol 348 • November 23, 1996