Drugs Prohibited from Extralabel Use in Food Animals

FARAD Digest Drugs prohibited from extralabel use in food animals

Michael A. Payne, DVM,PhD; Ronald E. Baynes, DVM,PhD; Stephen E Sundlof, DVM,PhD, DA8V'r; Anhur Craigmill, PhD;Alistair I. Webb, BVSC,PhD; Jim E. Riviere, DVM,PbD

T he Animal Medidnal Drug Use Clarification Act Diethylstilbestrol (DES}-From 1941 to 1971,US (AMDUCA), signed into law in 1994, amended the physiciansprescribed this potent nonsteroidalsynthetic Food Drug and Cosmetic Act to decriminalize most estrogento between0.3 and 3 million pregnantwomen instancesof ExtralabelDrug Use by veterinarians.I to prevent miscarriageor other reproductive diseases.' This privilege, however, is not can~ blanche; specific The drug continued to be useddespite considerable evi- conditions must be met btIore a veterinarian may dence,collected during the 19505,that raisedquestions legally use or prescribe drugs in an extraIabel fashion regardingefficacy for its label claims.' In 1971 a link for food-producing animals. These requirementsl-4 between in utero exposureto DES and a rare vaginal include a valid veterinarian-clIent-patient relationship cancer (clear cell adenocarcinoma)was estab)jshed.' and appropriate drug labeling and record keeping. Between35 and ~ of fetal~ femaleo&prlng Certain ~gs may not be prescribed or used even will develop precancerous lesions,' which undergo under AMDUCA auspices.Section 530.21 of the act clear- malignanttransformation in approximately1 in 1,000of ly states that the FDA CenteI' for Veterinary MedidDe those exposed,'In 1971, the FDA pub)jshed an alm (CVM) may prohiliit the extI2label use of approved new advising doctors against the use of DES in pregnant animal or human drugs for a number of reasons.Thus far, WOlDen.The FDA banned the use of DES in food ani- FDA-CVM has prohibited 8 drugs or drug classes,mak- malsin 1979.\0The 'drug hasapplications in human and ing their extI2label use in food animals illegal companionanimal medicine,but DES-containingprod- Veterinarians violating state or federal laws regu- ucts ale not currently being marketed. lating the transpon, sale, or use of drugs may face various sanctions, includl,ng warning letters, fines, tempo- Chloramphenicol-Reversible, dose-relatedbone rary or pennanent revocation of their state veterinary marrow suppression resulting from treatment with license, or incarceration. Extralabel use of any of the chloramphenicol has been detected in numerous prohibited drugs in food animals represents one of the species including humans. Of more concern is a FDA's highest priorities for regulatory attention. human-specific aplastic anemia, estimated to affect Because of the potential adverse human health between 1 in 10,000 to 50,000 exposed people. effects resulting from the use of these drugs in food Because this idiosyncratic toxicosis is often fatal, animals, FARAD will decline to routinely provide appearsto be non-doserelated, and could presumably withdrawal intervals for them. However, in the event of be triggered by residues, use of chloramphenicol in accidental exposure, FARAD bas consulted with veteri- food animals was prohibittd in 1984. Severalreports narians and regulatory officials to deterDline periods document human fatalities resulting from ophthalmic after which tissue and milk might be safely marketed. preparations containing chloramphenicol, with total This FARAD Digest provides background infor- exposure doses that could be achieved from food mation to more clearly define the regulatory require- residues.11Several veterinarians have been fined or ments regarding these compounds. The drugs are list- imprisoned for distributing or misbranding chloram- ed in the order in which they were prohibited. Except phenicol for use in food animals.11.UA number of onl, as described, these drugs should not be used in food injectable, and topical products containing chlonm- animals. phenicol are approved and available for use in small animals. The prohibition againstthe drug's use in food Prom the Food Animal Residue Avo~ Databank (FARAD), animals extends to all formulations of chlonmpheni- Environmental Toxicology Extension, College or AgricultUral and col including ophthalmic ointments. Florfenicol EDviroDmenta1Sd~, Unive:rStyof CaJifom1a,Davis, CA 95616 (Nuflor), a synthttic member of the chlonmphenicol (Payne.Cftigm111); FARAD, Center ror CutaDeOUSToxicolosy and family, is approvedfor use in beef cattlt in the United Residue Pharmacology,College or Veterinary Med1clne, NoM States.This compound lacks the p-NO2 group thought Carolina State University, Raleigh. NC 27606 (Baynes,Riviere); to be responsiblefor inducing aplastic anemia and has FARAD, Depanment or PbysioiOltcal Sciences, College or Veterinary Medtctne, University or Florida, Gainesville,PL 32610 not been associatedwith the syndromt.14Florfenicol (Webb); and the Center ror Veterinary Medtctne, Food and Drug may be usedin an extnl.bel fashion in food-producing Administntion, RockviDe,MD ~55 (SundJoC). species.

28 Vet Med Today:FARAD Digest JAVMA, \101215. No.1, July 1,1999 Nitroimidamles--Laboratory studies of members than 20 months. Currently, use of any sulfonamide of this drug class (which include dimetrtdazole, other than SDM in dairy cattle older then 20 months is metronidazole, and ipronidazole) have demonstrated illegal Additionally. exttaJabeluse of SDM in lactating mutAgenicity and carcinogenicity.I' After undergoing dairy cattle is prohibited (for example,use of a higher reductive activation in vivo, metabolites from these doseor slow-releaseSDM bolusesin dairy cattle is not compounds attAck DNA basepairs resulting in loss of permitted). helical structure, strand breakage,and possible inhibi- tion of DNA repair mechanisms. Oral exposure to Nitrofurans-As with the nitroimidazolesand sul- nitroimidazole compounds has causedcarcinogenesis fonamides, the can:tnogenicity and mutagenicity of in rodents and mutagenic urinary metabolites in nitrofurans bas been documented in laboratory stud- humans. D1metrldazole was approved in the mid- ies. Feedingtrials with nitrofurazone havedemonsttat- 19605 for the treatment of histomoniasis (infectious ed the development of fibroadenomasin mammary enterohepatitis, blackhead) in turkeys. Despite avail- glands of rats and benign mixed tumors and granulosa able label alternatives, the FDA-CVM documented cell tumors in ovariesof mice.DFurazolidone has been widespreadextralabel use of the drug to treat and pre- shown to causebronchial adenocarcinomasin mice fed vent swine dysentery Food safety concernsled to with- the compound for life.H Thesedrugs are also believed drawal of its approval in 1987,1' to cause occupational allergic contact dermatitis in Metronidazoleis approvedin humansfor the treat- humans.JSOn the basis of concernsrelated to caIctno- ment of trichomoniasis, amebiasis, giardiasis.. and genicity, approval for all human nitrofurazone prod- anaerobicbacterial infections. Shon-tenn exposure in ucts, except for dermatologic preparations,were with- human patients does not appear to increase risk of drawn in 1974.» Nitrofurazone and furazolidone had developing cancer.IT The drug has found extensive been approved for a variety of protozoal and other extralabelveterinary use for indications similar to those infections in poultry and swine. On the basis of car- in humans,particularly in the treatmentof giardiasisin cinogenicity and the absenceof a reliable detection companion animals. Metronidazole and ipronidazole method, the FDA withdrew approval for systemic ani- (the latter also once labeled for histomoniasis) have mal nitrofuran products in 1991.17A number of nitro- beenused to eliminate the bull carrier-stateof the vene- furan-containing products are still availablefor topical real diseasetrichomoniasis. With no approved veteri- use in dogs,cats, and horses.A limited number of top- nary nitroimidazole labels, the use of any member of ical nitrofurazone products Jabe.edfor .pinkeye in cat- this drug classin food animals is illegal. tle, sheep and goats",and "surface wounds, cuts and abrasionson all1ivestockwwere recently available.As a Sulfonamide use in dairy cattle-As with the result of a FDA-CVM sponsoredstudy demonstrating nitroimidazoles, concerns about suHonamideresidues meat and milk residuesfollowing label use,. manufac- have arisen as a result of observedcarcinogenicity in turers of these products a~ to remove their food laboratory animals. In 1988, the FDA National Center animal indications. The parenthetic reference to for Toxicologic Resean:hreponed an in~ in thy- "approved topicalWnitrofurans in AMDUCA will be roid follicular cell carcinomasand hepatocellular ade- omitted in the near future. Product with .oldw Jabels, nomas in rodents given large dosesof sulfamethazine already in distribution, may be depleted through nor- (SMZ),18.l9These studies were of panicular concern to mal sale channeJs.Following this, with no approved regulatory agencies,as they coincided with reports of food animal labels,the use of any member of this drug sulfonamide residuesin up to 13% of swine carcasses classin food animalswill be illegal and up to 73% of retail milk samples,30.1lIn swine tissue and milk, SMZ was by far the most common sul- Clenbuterol- This synthetic sympathomimetic is fonamide detected, becauseof the compounds wide- approved in a number of foreign countries and is spreaduse, high oral bioavailability, long half-life, and administeredas either a bronchodilator in horsesor as stability in the environmenL a uterine relaxant in cattle and sheep.A ~2 adrenergic A review of the causes and prevention of SMZ agonist with lipolytic activity, this compound has been residues in swine is beyond the sco~ of this article, used illepDy in food animals to increaseweight gain but excellent referencesare available,-.n Detection of and lean"'body mass. Such illicit use is reponed to have milk residueswas particularly disturbing becausethere resulted in > 1,000 emergency h~italizations and are no SMZ products labeled for lactating cattle. several deaths in people in Europe. 'I In Spain and Oearly, theseresidues were the result of extralabeluse. France, numerous humans have developedsymptolDS New labeling for SMZ products, aggressiveeducation of toxicosis, with muscle tttmors, tachycardia, and efforts by the dairy industry, and intensified enfon:e- hean palpitations being the most commonly reponed. ment actions by regulatory agenciesresulted in a dra- Episodesare usually associated,with consumption of matic decreasein SMZ residuesin milk. Another con- liver, the edible tissue containing the highest residue sequenceof the SMZ issue was the now familiar drug concenttations.n.DSeveral factors may contribute to labeling and storage requirements, which were added the high residue concenttations detected in poisoned to the PasteurizedMilk Ordinance in 1989, Only 1 of humans. The dosagerequired for anabolic effects in the 3 sulfonamides that have label indications for lac- animals is 5 to 10 times higher than that usedfor treat- tating cows, suL~dimethoxine (SDM), is currently ment of respiratory therapyD.» and cooking only being marketed. The FDA defines a lactating cow as decreasesdrug residues minimally;- Becausemuscle any dairy cow (regardless of lactation status). older depletion and fat redeposition commencesfollowing

JAVMA,Vol 215, No.1, July 1, 1~ Vet Med roc8¥: FARAD Digest 29 drug withdrawal (the "p-agonist reverseefl'ect-)4), pro- United Kingdom.G Although theseand other data have ducersmay be tempted to market animalswith little or not been sufficiently conclusive to prevent approval of no withdrawal interval saraOoxacinfor chickens or enroOoxacinfor chickens Inappropriate use of clenbuterol is not limited to and beef cattle, it prompted FDA-CVM to prohibit Europe. Two veterinarianswere recently convicted on extralabel use of these compounds in 1997.46 chargesof conspirin§ to smuwe clenbuterol into the Fluoroquinolone products labeled for either humans us from Canada.' Total tines in these cases or companion animals may not be used in food ani- approached5100,000 and included an S-month prison mals. Any deviation from a food animal label (such as term. In addition, there have also been a disturbing use with a different spedes, dosage,route of adminis- number of regulatory actions involving Americanshow tration, or diseaseindication) is similarly illegal. In the animals.- With the recent us approval of clenbuterol case of the approved beef cattle formulation of (Ventipulmin Syrup) as a treatment for chronic enroOoxacin(BaytrlllOO), this prohibition extends to obstructive pulmonary disease(COPD or Kheaves")in all nonbeef-prorluction animals, including lactating horses,the FDA will be monitoring fOTillegal food ani- and nonlactating dairy cows, heifer replacements,and mal residuesand unusual salespatterns of the drug:7 veal caIves.41Enrofloxacin may not be stored in dairy fann drug cabinets. Dipyrone-A pyrazolon derivative, dipyrone has historically been used in humans and animaJsas an Glyco~pt1des-The only glycopeptide antibiotic antipyretic, anti-inflammatory,and analgesic,The drug available in the United States is the human product has been associated with serious toxic effects in vancomycin (Vancocin). Becauseof its gram-positive humans, including dose-independent teratogenicity, spectrum and associatedrenal and ototoxicity. this increasedbleeding times, and a potentially fatal agran- compound has found limited application in humans ulocytoSis,-- Prompted by these concerns, the FDA except in the treattnent of Clostridium dilJidlt colitis removed approval for all dipyrone-containing human and infections with beta Iactam-resistantgram-positive medical products in 1977,MDipyrone products labeled cocci. Most important, vancomycin is often the treat- for companion animals (but which the FDA had never ment of last resort for methicillin-resistant approved)continued to be sold, On the basisof surveys StllphylOC«aAsanus (MRSA) infections in humans. indicating food animal use, the absenceof an assay Although only demonstrated in the laboratory; wide- method, and lack of animal safety,residue, and efficacy spread transfer of vancomycin resistancefrom strains data, regulatory discretion allowing veterinary product of Enttrococcusspp to MRSA could provoke a health marketing ceasedin 1995,- Becauseproducts are not care crisis in the form of a common, highly virulent, availablefor either humansor animals,dipyrone is not and unuutable infection.40 Particularly worrisome are typically included on lists of extralabel prohibitions Danish and German data demonstrating vancomycin published by FDA-CVM. Old stockpiles of the drug, resistant Enterococcusspp in the fecesand food prod- however,do occasio.na11Ysurface. Any use of dipyrone ucts of poultry and swine fed the glycopeptide in food animals remains a violation of the Food Dnlg avopamn... Avoparcin, a compound chemically simi- and CosmeticAct and receivesthe sameregulatory pri- lar to vancomycin, has been used in Europeananimal ority as other compoundsdescribed in this article. feeds as a growth promoter since the mid-1970s. On the basis of these and other data, FDA-CVM in 1997 Fluoroquinoloncs-Although antibiotic use has issuedan order prohibiting the extralabeluse of aUgiy- been shown to contribute to microbial drug resistance copeptidesin food animals.46 in food animals, the frequency.magnitude, and impor- The restriction of fluoroquinolone and glycopep- tance of such resistancein humans remains a hotly tide use representsa novel exerciseof FDA-CVM dis- contestedissue. A review of relevantreseatth is beyond cretionary authority: restriction based not on the the scope of this article, but excellent summaries are drug'sdirect toxicity, but on its potential for increasing available."" Of particular concern has been the ques- human pathogenresistance. Besides these types of pro- tion of increasing virulence of Salmonella sp, a hibitions, various other efforts now underway may pathogen estimated to account for between 500 and help mitigate the drug resistanceproblem. A collabora- 4,000 human deaths in the United Statesannually.41.4] tive FDA, CDC, and USDA surveillance program will One study observeda risk of death or hospitalization monitor changesin drug resistancepatterns from both to be 20-fold higher for resistant than nomaistant human and animal isolates.- In addition, CDC has Salmonellainfections.44 The emergenceof the multi- funded a limited number of projects examining on- drug resistant Salmonellatyphtmurium DT-I04 strain farm methods to minimize resistance development. has similarly fostered international attention on the Lastly,a number of professional,industry, and regula- question of zoonotic pathogenresistance.45 Because the tory organizationshave formed committeeswhose pur- fluoroquinolones have remained a mainstay for treat- pose is to develop proceduresthat will define prudent ment of antibiotic-resistant Salmonella infections in use of antimicrobials in food animals. humans, the advisability of using this classof antibiotic in food animals hasbeen questioned.Espedally con- ExtraIabeI use of medicated feed-Another pro- troversial has been data collected by the Centers for hibition generatedby concernsof antibiotic resistance Disease Control and Prevention (CDC) suggestinga relatesto the extralabel use of medicatedfeed. Section possiblelink betweenOuoroquinolone Use in food ani- 530.11 of AMDUCA specifically prohibits the Mextrala- mals and increasing human pathogenresistance in the bel use of an approved new animal drug or human

30 Vet Med Today:FARAD Digest JAVMA. ~ '1~ Nn, 1t.(.,1 1C¥¥\ drug in or on an animal feed.". As a matter of enforce- the VIgilia. Association of maternal stilbestrol therapy with tUmor ment discretion, FDA-CVM generally has not objected appearance in young women. New Engl] Med 1971;284:878-881. 8. Crum CP. Female genital tract. In: Cotran RS, Kumar ~ to mixing a drug with an individual animal'sfeed, but Robbins SL, eds. Pathologic basts of diSeDse.5th ed. Philadelphia: WB extralabel massmedication in feed is prohibited ~with- out limitation or exception." This prohibition extends Saunders Co, 1~;1~1045. 9. Melnick S. Cole P, Anderson D, et al. Rates and risks of to all drugs; not just those discussedin this article. diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix. An update. N Engl] Med 1987;316:51+-516. Other dairy prohibitions-The Grade-A Pas- 10. DES ban now in effect.] Am ~ MedAssoc 1979;175:334. teurized Milk Ordinance states that unapproved or 11. Settepani JA. The hIzaJd of using chlonmphenicol in food animals.] Am ~ Mt.dAssoc 19M;184:93G-931. improperly labeled drugs will not be used to treat dairy 12. Sentencing in chloramphenicol cue. FDA ~ 1990;5:10. animalsand will not be stored in "the milkhouse, milk- 13. VeterinaNn sentenced on chloramphenicol charge. ] Am ing barn, stable, or parlor.,,49With the exception of ~ Mt.d Assoc 1991;199:317. SDM, none of the drugs or drug classeslisted in this 14. YIlnls AA. Chloramphenicol: relation of structure to activi- article may be legally labeled for dairy cattle and, if ty and toxicity. Annu Rev Ph4rmGColTaxicoll988;28:83-100. found during an inspection, would trigger regulatory 15. Parkhie MR. Hazards of exmlabel use of dimeaidazole.] Am Vtt Mt.d Assoc 1986;189:270-271. action. In addition to dipyrone, there are 2 drugs that 16. Why veterinary drugs are not always available. FDA ~ are not currently on the AMDUCA prohibited list but 1996;11:4. which result in "debits" if found during a dairy inspec- 17. Beard CM, Noller KL, O'Fallon WM. Lack of evidence for tion. Theseare dimethyl sulfoxide and colloidal silver. cancer due to use of metronidazole. N Eng] Med 1979;301:519-522. The use of ionophore compounds (ie, monensin, lasa- 18. National Center for Toxicological Resean:h. Chnmic toxicity locid) in lactating dairy cattle rations is prohibited. and can:inogmicity studies of sulfamcthaVne in B6C3Fl mice. Technical report for apcrimtllt numbt:r 418. Jefferson, Ark: National Center for Toxicological Resean:h, 1988. Status of aminoglycosides--A number of veteri- 19. National Center for Toxicological Resean:h. Chnmic toxicity nary organizationshave establishedor support policies and can:lnogmesls studies Oft sulfamcthatine in Fischer 433 rats. that discouragethe extralabel use of aminoglycosides. Technical report for expcrlmmt mmIbcr 420. Jefferson, Ark: National Theseorganizations include the Academyof Veterinary Center for Toxicological Resean:h, 1988. Consultants, the Society for Theriogenology, the 20. Bevill RE Causes, detection, and correction of sulfonamide residues in swine. In: Crawford LM, Franco DA, eds. Animal dntgs and American Association of Bovine Practitioners, the human hcalth. Lancaster, Pa: Technqmic Publishing Co, 199-4;63-80. AmericanVeterinary Medical Association, and a number 21. Sundlof SE Drug and chemical residues in livestock. ~ of state veterinary medical associations.These position Clin North Am FoodAntm Pract 1989;S:411-499. statementsare nonbinding and should not be confused 22. Rehm WI; Teelmann K, Weidekamm E. General aspects of with the legal prohibitions describedin this article.. metabolism, residues and toxicology of sulfonamides and dthydrofo- late reductase inhibitotS. In: RIco A. ed. Dnag miaes in animals. Orlando, F1a: Academic Press Inc, 1986;65-109. Treatment of companion animals-The prohibi- 23. Huff JE. Eusds SL, Haseman JK. OCCUnatce and relevance tions described in this anicle pertain to food-producing of chemically induced benign neoplasms in long-term cardnogenic- animals only and not companion species, such as dogs ity studies. Cancer Mctastasis Rev 1989;8:1-22. and cats. FARAD receives a few inqu~ related to the 24. AU BH. Some pharmacological and toxicological properties use of these compounds in companion animals that also of furazolidone. Vet Res COImIUm 1983;6:1-11. are a members of a food producing species (ie, horses, 25. Conde-Salazar L, Guimaraens D, Gonzalez MA, et al. Occupational allergic contact dermatitis from nitrofurazone. Contact llamas, pot bellied pigs). As long as they are never offered DcrmDlitis 1995;32:307-308. for slaughter, the FDA-CVM does not normally consider 26. Ust of drug products that have been withdrawn or removed these to be food animals. Because the ultimate fate of from the market for reasons of safety or effectiveness. Ft.d Reg such treated animals is often beyond the conttol of the 1998;63:540822- S4089. veterinarian, a practitioner should reflect on the amount 27. Nitrofuran approval withdrawn. FDA Vtt 1991;6:1-2. of liability that he or she is willing to accept. Practitioners 28. Smith DJ, Paulson GD, Larsen GL. Distribution of radiocar- bon after intramammary; inu.uterine, or ocular treatment of lactat- who have used a prohibited substance in a companion or ing cow with carbon-14 nitrofurazone.] Dairy Sd 1998;81:979-988. pack animal that subsequently enters the food supply 29. denbuterol a concern.] Am Vtt Mt.dAssoc 1~;205:1380. would be subject to enforcement actions under the Food 30. Study reveals European beef is tainted. Beef BItS Bull Drug and Cosmetic Act. 1993;16:2. 31. Keller WC. Illegal use of clenbutaol in food animals. FDA References Vet 1991;6:9-11. 1. Ext~label drug use in animals; final rule. Fed Reg 32. Sauer MJ. Pickett RJH, Uver S, et a1. Distribution and elim- ination of clenhuterol in tissues and fluids of calves following pro- 1996;61:57732-577%. 2. Helpful tips for exttalabd drug use: gmeraltnformation.] longed oral administration at a growth-promoting dose. ] Vet Am Va Med Ass« 1998;212:968-969. Phanlldcolnu 1995;18:81-86. 3. Helpful tips for extralabd drug use: recoJdkeeping, recoJd 33. Meyer HHD, Rinke LM. The pharmacokineticsand residues accessand product labels.] Am \tt Med Assoc1998;212:666-667. of clenbuterol in veal calves.] Allim Sci 1991;69:4S38-4544. ~. Extralabd drug UK (ElDU). AMDUCA g1ddtDIcebrochvn. 34. Elliott CT, Crooks SRH.McEvoy JGD. et al Observationon Schaumburg,Ill: American Veterinary Medical Assodation, 1998. the effects of long-term withdrawal on can:asscomposition and 5. Edelman DA. DES/Dtaltylstilbestrol-IICW perspectives. residue concentrations in clenbuterol-medicated cattle. ~ Res Boston:MTP Pnss Ltd, 1986;~3-44. Commun1993;17:459-468. 6. Dieckmann WJ. Davis ME. Rynkiewicz LM, et al. Does the 3S. Veterinariansentenced for smuggling clenbuterol] Am Vet administration of diethylstil~l during pregnancy have thera- Med Assoc1999;214:319. peuticvaJue?Am] ObstetGynecoI1953;66:1062-1OB1.. 36. Veterln8rians can help restore ethics in livestock show 7. Herbst AL, Ulfelder H, Poskanur DC. Ad~ocarctDOtnaof rings.] Am \tt 1oIedAlsoc 1993;206:933.

JAVMA.Vol 215, No.1, July 1,1& Vet Med T*v: FARAD Digest 31 37. FDA approves raWted use of cleJlbutcrol product Cor mission of andmiaom.J-1aiIC8Dt SaImoueDa: InvestiptlOlll of u.s. bones. FDA ~ 1998;13:5-7. outbraks, 1971-1983. SdDtCe 1984;225:83~5. 38. Arellano f; s.aiI1aD JA Metamizole: ~ of tIS 45. Akkina j2. Hogue AT. Angulo Fj. et at Epidemiologic theNpeutic role. fur J alii PhGr-=Dl1990;38:617-619. aspects, control, and Imponance of multiple-drug resistant 39. Center for VeteriDary Medicine. GYM ~a opinion on SalIIIDIIell4lypblmurium DTI04 In the United Stales. J Am ~ Wed dlpy~ prodllcts. RockviUe, Md: Center for Veterinary Medicine. ASS« 1998;214:790-798. Dec 6. 1995. 46. ExtrIIabd animal dru& use; nuoroquiDOlones and gIy- 40. US Office of TechooIozy AssessmmL Impacts oj Glldhtotk- copeptides; order of prohibttion. fed Reg 1997;62:27944-27947. mistat NcUrl4. Washington. DC: US Office of Technology 47. Center for Veterinary Medldne. ExtralGbeI use of Baytril 100 ~~ut. 1995;OTA-H-629. pruhlJ,\kd. fncl1ldlftJ use 1ft dairy cattle or Ye4l calves. RockvIl1e, Md: 41. Chin GJ. MarxJ.eds. frontiers in biotechnology; antibiotic Callei' for VfleriDary MedidDe. Sept 22, 1998. resistance. Science 1994;264:360-388. 48. AndIDicrobi8l SUtcepdb\1ity I£Stin& In progress. J Am ~ 42. Buzby Jc. Roberts T. ERS estimates U.s. foodbome diJaIe Wed ASS« 1997;210: 14.5-H7. cwts. Food Rev 1995;18:37-42. 49. NtcholsjG. Item 16 r(l)-cvrmtt tnfOnllGttOlL MeInDrGnda of 43. Auplo FJ. T8uxe Iv; Cohen ML Stpi6caDa: and soun:es tlljonllatiOft M-I-92-IO. Washington. DC: US Food and Drug of antimicrobt8l- Iaist8nt DOntypboidal ~ infections in Administration. Callei' £or Food Safety and Applied Nntrition, Dec hUm8ns in the UDited Stales: the need for prudent use of antimicro- bial agents. includiug restricted use of Ruoroquluolones. in food anl- 3. 1992. 1n8ls, in PnlCetdirlgs. Am Acad Vet Phumacol Ther 1998;63-78. 44. Holmberg SD. Wells jG. CoIleDML ADiIMl-to-man a8DS- "

Correction: FARAD Digest

In the FARAD Digest tided "PrImer on estimating withdrawal times after extralabel drug use" (JAVMA,Oct I, 1998, pp 966-968), the first sentenceof the last para- graph of the left-hand column on page967 should haveread "...and from alOO-g ini- dal dose..." rather than 10-g initial dose. .

32 Vet Med Tod8y:FARAD Digest JAVMA. Vol 215, No.1, July 1,1-