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Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed (1989)

Chapter: QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS

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Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 60
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 61
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 62
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 63
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 64
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 65
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 66
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 67
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 68
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 69
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 70
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 71
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 72
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 73
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 74
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 75
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 76
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 77
Suggested Citation:"QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN LIVESTOCK AND POULTRY FEEDS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Page 78

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60 TABLE IV- 1 COMMON ANTIBACTERIAL FEED ADDITIVES APPROVED BY U . S . FOOD AND DRUG ADMINISTRATION Addi tive Year Approyed Sul faquinoxal ine ( sul fonamide ) 19 4 7 Roxarsone ( arsen ical ) 1951 Chlortetracycl ine 19 5 1 Penic i l l in 19 5 1 Bac itracin 1953 Sodium arsenate ( arsenical ) 1953 Furazol idone 1953 oxytetracycl ine 1953 Erythromycin 19 5 5 Hyqromyc in B 1957 Neomycin a Novob iocin 19 6 1 Tylosin 19 6 1 Sul fametha z ineb 19 6 3 Sul fameraz ineC 1967 Oleandomyc in 1968 Lincomycin 19 7 0 Sul fathiazoleb 1971 Bambermycin 197 3 Virqiniamyc in 1974 source : u . s . Food and Drug Administrat ion , Divis ion o f Animal Feeds , Center for Veterinary Medic ine , December 1 9 8 7 ( persona l communicat ion ) . a Never official ly approved : has been marketed s ince be fore 1 9 5 8 . b For use in combination only . c For use in fish .

61 tetracycl ines used to medicate them . The food-animal population in the United states is very larqe--more than 2 0 t imes the human populat ion ( Table IV- 2 ) . I n 1 9 7 1 and 19 8 5 , for example , the total u . s . food-animal population was 3 , 5 2 2 and 5 , 12 2 mil l ion head , respectively ( Table IV-2 ) . The number of head of l ivestock ( exclus ive of poultry ) for the same 2 years was 2 3 7 and 2 0 6 mi l l ion . In the interveninq 14 years , production of red meat decl ined somewhat , and poultry production increased . The relationship o f the amount o f red­ to white-meat food produced is important in cons iderinq the maqnitude of human exposure to meat or poultry products contaminated with pathoqenic bacteria of farm-animal oriqin . An understandinq of the maqnitude can be had by inspect ion o f per-capita consumpt ion figures for meat and poultry in this country . The consumption o f red meat per cap ita ranqed from a h iqh o f 1 6 8 lb in 1 9 7 1 to a l ow of 1 5 3 . 2 lb in 1 9 8 5 . In the same period , the amount of poultry consumed increased from 4 9 . 0 to 6 9 . 7 lb . 6 ANIMAL CONSUMPTION OF FEED AND BACTERIAL CONTENT OF GASTROINTESTINAL WASTE To understand the number o f col i form orqanisms potent i a l l y exposed to ant imicrobials in animal feed , one need only examine Table IV-3 , which shows the larqe amounts o f feed consumed per head o f l ivestock or poultry annual ly . ( The amounts of medicated feed consumed are discussed l ater . ) Multiplyinq the amounts o f feed by numbers o f anima l s in production in the United States ( Table IV-2 ) yields an estimate of the larqe amounts of manure produced . Animal manure is a d irect source and a vector of bacterial contaminat ion of the farm , o f farm anima l s , of foraqe crops and feed , of farmers , of slauqhterhouse workers , and of meat or food by products ( such as milk and eqqs ) consumed by humans . 3 The spread o f bacteria can be enhanced by the coprophaqic habits o f some animal spec ies . As an example of the maqnitude o f the potential bacterial contaminat ion problem assoc iated with farm and feedl ot exposure of anima l s , the numbers o f col i form orqanisms and the l arqe amount o f manure produced by bee f cattle can b e c ited . A s inqle 9 0 0 - lb feedl ot steer produces about 9 lb ( 4 . 1 kq ) of manure sol ids da i ly ; each qram conta ins approximately 1 0 7 col i form orqanisms , for a total of 4 . 14 x 1 0 1 0 such orqanisms per day . 5 TOTAL ANTI BIOTIC PRODUCTION Accurate analys is of the impact o f antimicrob i a l s on farm anima l s ( on the ir infect ious bacterial fl ora , health , or

TABLE IV-2 ANIMAL PRODUCTION IN UNITED STATES { Thousands of Head Marketed or Produced for Marketing ) Year Cattie Calves Sheen Lambs Chickens Broilers Turkevs Hoas Hoas/oias a 1987 49 , 900 10 , 564 1986 49 , 995 10 , 477 - - 2 16 , 938 4 , 64 6 , 3 12 2 07 , 2 16 1985 48 , 7 39 10 , 488 1 , 610 6 , 456 2 5 1 , 957 4 , 478 , 749 185 , 282 86 , 583 52 , 298 1984 50 , 682 10 , 253 7 , 007 2 3 4 , 7 69 17 1 , 2 9 6 0\ 1 , 82 1 4 , 282 , 391 87 , 344 54 , 07 3 N 1983 48 , 089 10 , 443 1 , 820 7 , 104 2 3 1 , 82 1 4 , 18 3 , 6 6 0 170 , 72 3 89 , 129 56 , 694 1981 46 , 647 10 , 383 1 , 510 7 , 013 223 , 721 4 , 147 , 52 1 170 , 87 5 95 , 986 58 , 698 1979 48 , 358 10 , 151 1 , 347 6, 336 225 , 066 3 , 951 , 291 156 , 4 57 92 , 499 6 7 , 3 18 1977 56 , 378 12 , 62 1 1 , 450 7 , 361 235 , 856 3 , 9 3 9 , 897 136 , 890 80 , 939 56 , 539 197 5 54 , 3 15 12 , 2 3 9 1 , 812 9 , 039 238 , 576 2 , 9 50 , 099 124 , 165 7 3 , 627 49 , 2 67 197 3 48 , 3 69 1 1 , 652 2 , 198 10 , 879 2 3 6 , 7 10 3 , 008 , 667 132 , 2 3 1 8 2 , 4 10 60 , 614 197 1 49 , 14 3 12 , 0 8 6 2 , 2 02 12 , 627 2 2 0 , 195 2 , 94 5 , 348 119 , 657 98 , 644 62 , 4 12 Source : u . s. Department o f Agr iculture . 6 a a Combination o f p igs and overweight market hogs .

TABLE IV- 3 FEED CONSUMED BY LIVESTOCK AND POULTRY 1 9 7 1 - 19 8 3 ( Feed Consumed Per Head , Pounds , Equivalent Feeding Value o f Corn ) Year Qaia gAt tle Sheep �Qul ta Hogs ( Beginning Milk Bee f and Hens and . ( per October} Cows Othe r Ca t tle a LambS Pul lets Ch ickens Broi lers Turkeys 1 0 0 lb) 19 7 1 11 , 370 5 , 859 99 32 9.3 96 954 0\ 9 , 198 1 , 008 w 1973 11 , 570 5 , 774 7 , 708 2 , 02 1 100 32 9.7 94 660 1975 11 , 540 6 , 303 7 , 59 3 1 , 260 101 26 7.7 71 566 1977 12 , 1 2 9 8 , 8 64 6 , 52 4 1 , 442 103 24 8.6 79 633 1979 12 , 978 6 , 800 8 , 122 1 , 373 107 26 9.4 76 688 1981 1 2 , 18 1 6 , 248 8 , 759 1 , 409 108 26 10 . 0 84 62 0 1983 12 , 648 5 , 795 7 , 848 1 , 723 105 28 9.3 82 605 Source : Adapted from u . s . Depar tment of Agriculture . 6a a Feed consumed divided by the number of cattle on feed January 1 .

64 rates of growth ) requires rel iable data on the total amounts o f penici l l in and the tetracycl ines used annual ly in anima l s ( as feed additives , for growth promotion , for prophylaxis , and for treatment of infections ) and medical use in humans . The same information on other common feed-addit ive drugs would be use ful for purposes of comparison , but such deta iled information is not ava i l able . Although gross estimates o f production and use have been made , there is not good agreement between the figures from d i f ferent sources . However , the figures that are ava i l able to the committee provide a general bas i s for estimating the breadth of use of antib iotics in anima l s reared for human food . The u . s . International Trade Commiss ion provides information on the annual production of ant ib iot ics in the United States ( Table IV-4 ) . The data show total pounds produced for medicinal and nonmedic inal use in humans and anima l s . From 1 9 5 0 to 1 9 8 6 , the total annual ant ibiotic production in the u . s . increased by a factor o f about 49 ( from 0 . 9 to 4 4 . 4 mi l l ion pounds ) . Product ion f igures for 1 9 8 6 show an atypica l annual increase ( 3 9 % ) over the preceding year and may represent an aberration . However , the figure for 1 9 8 5 ( 3 1 . 9 mil l ion pounds ) is within the range for the previous 4 years ( 3 0 . 4 - 3 2 . 5 mi l l ion pounds ) and represents an increase by a factor of about 3 5 over product ion in 1 9 5 0 . The data in Table IV-4 show that the percentage of total product ion directed to animal feed and other uses increased from 1 6 % in 1 9 5 1 to 3 8 % in 1 9 5 9 . In the 1 9 6 0 s , an average o f about 4 0 % of the total ant ibiotic production was directed to animal feed and other uses . By the late 1 9 7 0 s , 4 2 -4 8 % of ant ibiotic product ion was directed to animal feed and other uses . Although in formation on the actual amount o f antimicrobial product ion used i n animal feed rather than other use is not ava i l able , an assumpt ion can be based on in formation presented l ater in thi s chapter--that the nonmedic inal represented the predominant use . In Table IV-5 , for 1 9 8 1 - 1 9 8 6 , the total production figures are ava i l able for classes of antimicrob i al s , but a direct breakdown into medic inal and nonmedicinal uses is not ava i l able . Although Tables IV-4 and IV- 5 are not directly comparable , they do show that large amounts o f ant imicrobials were used as feed additives . In 1 9 8 3 , for example , 3 1 . 9 mi l l i on pounds of ant ib iot ics was produced , o f which 2 2 . 5 mi l l ion pounds ( 7 1 % ) was tetracycl ines plus other non-P -l actam antibiot ics . In the same year , 7 5 % o f the ant ib iot ics ( other than penic i l l ins , cephalosporins and tetracycl ine s ) were directed to feed addit ive and other uses ( Tabl e IV-4 ) . Thus , 3 6 % o f the ent i re ant ib iotic product ion for 1 9 8 3 cons isted o f antibiotics ( other than P - l actams and tetracycl ines ) that were directed to feed additive and other uses . 7 Cons iderable amounts o f tetracycl ine and penic i l l in go into an ima l feed ,

65 TABLE IV-4 U . S . ANTIBIOTIC PRODUCTION 1 9 5 0 - 19 8 6 a Medicinal Total Use Nonmedicinal Use Port ion o f Added to Ant ibiotic In Animal Product i on Humans Feed and Added to u.s. Annual and for Other Annual Animal Feed Production , Chanqe , Anima l s , Uses , Chanqe , and Other � � lb ' � lb � lb ' Uses. ' 1986 44 . 4 +39 b b b b 1985 31. 9 + 5 b b b b 1984 30 . 4 - 5 b b b b 1983 31. 9 - 2 b b b b 1982 32 . 5 + 6 b b b b 19 8 1 30. 6 +2 4 b b b b 1980 24 . 6 - 2 b b b b 1979 25 . 2 - 2 14 . 6 10 . 7 -13 42 1978 25 . 7 +11 13 . 4 12 . 3 +22 48 1977 23 . 1 +13 14 . 0 10 . 1 + 1 43 1976 20. 5 +12 10 . 4 . 10 . 0 +12 48 1975 18 . 3 -11 9.4 8.9 +2 0 48 1974 20 . 5 - 1 13 . 2 7.4 -10 36 197 3 20 . 8 +2 5 12 . 6 8.2 +2 1 39 1972 16 . 6 - 7 9.8 6.8 - 4 41 19 7 1 17 . 9 + 6 10 . 8 7.1 - 3 40 19 7 0 16 . 9 +28 9.6 7.3 +2 6 43 1969 13 . 2 +28 7.4 5.8 +35 43 1968 10 . 3 + 8 6.0 4.3 + 2 42 1967 9.5 - 2 5.2 4.2 0 45 1966 9.7 29 5.4 4.2 +50 43 1965 7.5 +15 4.7 2.8 + 8 37 1964 6.5 - 3 3.9 2.6 + 4 40 1963 6.7 + 6 4.2 2.5 + 9 37 1962 6.3 +24 4.0 2.3 +28 36 19 6 1 5.1 + 9 3.3 1.8 + 6 35 1960 4.7 +27 3.0 1.7 +2 1 36 1959 3.7 + 6 2.3 1.4 +56 38 1958 3.5 + 9 2.6 0.9 0 26 1957 3.2 +19 2.4 0.9 +12 26 1956 2.7 +29 2.0 0.8 +60 28 1955 2.1 - 9 1.6 0.5 0 25 1954 2.3 +10 1.8 0.5 +25 21 1953 2.1 +24 1.6 0.4 +33 21 1952 1.7 +13 1.5 0.3 +50 15 1951 1. 5 +67 1.3 0.2 16 1950 0.9 0.9 b

66 TABLE IV-4 FOOTNOTES a 1 9 5 0 - 1 9 7 8 data from National Research counci l ( NRC ) re p o r t , The Ef fects o n Huma n Hea l th o f S ubtherapeutic Use of Ant imicrob i a ls in An ima l Feeds 4 a ( NRC data is based on re ports o f the u . s . International Trade Commiss ion [ ITC ] 7 ) 197 9 - 19 8 6 data cul led from ITC reports ? ( anima l - feed antibiotic data breakdown not presented by ITC for 1 9 8 0 - 198 6 ) . Amounts o f sul fonamide& produced not included . Only chemical s included in ITC production figures ; not included are finished pharmaceutical preparations and products in form of p i l l s , tablets , and capsules . In ITC data , amounts of antibiotics produced d i f fer from reported amounts sold ; e . g . , in 19 8 6 , 4 4 . 4 mi l l ion pounds of antibiotics produced and 1 1 . 3 mi l l ion pounds sold . D i fference between reported production and sales attributed to inventory changes , losses in process ing , and captive consumption converted into ethical and proprietary pharmaceutical products by primary manufacturer . Many pharmaceutical manufacturers not included in ITC reports if not primary producers of medic inal chemical ( i . e . , the i r drug requirements are met by purchases from U . S . or foreign producers ) . Amounts of antibiot ics produced annual ly assumed to provide better estimate of amounts used than ITC est imates of amounts sold , because finished dosage- form products made under captive use not included in estimates o f amounts sold . b F igures not ava i l able .

67 TABLE IV-5 u . s. PRODUCTION OF INDIVIDUAL CLASSES OF ANTIBIOTICS , 1 9 8 1- 1 9 8 6 �[Os;lY.QtiQD, HilliQDS Qf :fQUDQ§ 198 1 1982 1983 1984 1985 1986 Cephalosporins 1.1 1. 1 1.4 1.4 a 1.7 Penic i l l ins 7 . 4b 7 . 4b 6 . 1b a 6 . 8c 7 . 7c S emisynthet ic 2.3 2.1 1.9 2.0 pen ic i l l ins d Tetracycl ines 6.8 7.2 7.2 a a a Others 13 . 0 14 . 7 15 . 3 27 . 0 2 5 . 1e 35 . of Total sul fonamides 3.9 3.1 2.8 a a a Total 30 6 . 32 . 5 31. 9 30 . 4 31. 9 44 . 4 S ource : Adapted by the committee from u . s. International Trade Commiss ion ( ITC ) Reports . 7 a F igures not ava i l able . b Pen i c i l l ins other than semisynthetic penic i l l ins . c Includes a l l penic i l l ins . d Includes ampicil l in , amoxicil l in , dicloxac i l l in , cl oxaci l l in , and oxac il l in . e Includes tetracycl ines and cephal osporins . f Includes tetracycl ines .

68 so it is clear that , on the basis of production data , the true figure for the percentage of antibiotic production goi ng into feed additives probably l ies somewhere between 4 2 % and 4 8 % ( Table IV-4 ) . Pen i c i l l ins and tetracycl ines together make up 4 2 % of the total 1 9 8 3 antibiotic production . Of the other antibiot ics , which account for 5 8 % of the total production for the same year , only a few are approved for use as feed additives ( see Table IV- 1 ) . Total sul fonamide production o f 2 . 8 mi l l ion pounds i n 1 9 8 3 was not included i n the previous ly c ited antimicrobial-use data . Information is not ava i l able as to what port ion o f sul fonamide production was directed to animal feed uses . Although preci se f igures on the amounts of individual ant ibiotics used in feed are not ava i lable from the ITC data , it appears that a large percentage ( 4 2 -4 8 % ) o f the total antibiot ic production in the United States is used in animal feed ; penic i l l ins and tetracycl ines represent a s i zable fraction thereof . FDA , in using 1 9 7 9 data from ITC , has estimated that approximately 5 5 - 6 0 % of the penici l l in and tetracycl ine consumed in the United States i s used in animal feed in subtherapeutic dosages ; an additional percentage is used for therapeutic purposes ( FDA , Personal correspondence , Offi ce o f Planning and Evaluation , 2 1 May 19 8 6 ) . ANTIBIOTIC USE IN fARMS AND FEEDLQTS Actual percentages of each type o f ant ib iot ic used in farms and feedlots would be more informative than the forego ing calculations of total antib iotics used . A s umma ry analys is of amounts used in farms and feedlots for the period 1 9 8 0 - 1 9 8 5 has been attempted ( see Tabl e IV-6 ) with data from IMA America , Ltd . , private organ i z at i ons ( on purchases o f feed antibacterials by feed manufacturers , l ivestock supply stores and distributors , etc . ) , the Animal Health Institute (AHI ) , ITC , researchers , trade associations , and the companies that manufacture drugs for use in animals . The figures in Table IV- 6 , the best ava i l able to th is committee , show l ittle variation in this period in total feed use ( amount sold to the feed trade ) of ant ibacteria l s : 9 . 7 - 1 1 . 7 mi l l ion lbsjyr . Tetracycl ine accounted for 5 7 % o f this volume in 1 9 8 0 and 4 9 % in 1 9 8 4 and 1 9 8 5 . Penic i l l in accounted for only 5-8 % o f the total . The total use o f tetracycl ines and penic i l l in i n feed i n thi s period gradually decl ined . The forego ing f igures on annual sales o f ant ibacteri a l s for l ivestock and poul try feeds can b e rel ated to the total annual product ion o f a l l antib iotics ( for a l l use s ) and t o the total annual production o f the tetracycl ines and penicil l in . For exampl e , in 19 8 3 , 3 1 . 9 mi l l ion pounds of ant ib iotics was produced and 9 . 9 mi l l ion pounds was sold to

TABLE IV- 6 ANNUAL SALES OF ANTI BACTERIALS FOR LIVESTOCK AND POULTRY FEEDS , 19 8 0 - 1 9 8 5 Production for all Annual Sales for Livestock and Poultrv Feeds Use �:--- Total Tetracvcl ines Penicil l in Others 10 6 106 106 1 0 6 10 6 10 6 10 6 106 106 Year lJL_ lb llL ksL lc llL ksL lc lc lJL_ kg_ kg_ 19 8 0 24 . 6 11 . 2 5. 1 46 6.4 2.9 57 0.9 0.4 8 .llL 3.9 1.8 35 19 8 1 30 . 6 9.7 4.4 32 5.2 2.4 54 0.7 0.3 7 3.8 1.7 39 19 8 2 32 . 5 10 . 8 4.9 33 5.3 2.4 49 0.7 0.3 6 4.9 2.2 45 0\ \D 19 8 3 31.9 9.9 4.5 31 5. 1 2.3 52 0.6 0.3 6 4.2 1.9 42 1984 30 . 4 11 . 7 5.3 38 5.7 2.6 49 0.7 0.3 6 5.3 2.4 45 19 8 5 31. 9 11 . 0 5.0 34 5.4 2.4 49 0.6 0.3 5 5.1 2.3 46 Source : Modi fied from a presentat ion ( unpubl ished ) to the committee by H . w . Jamison o f the Animal Health Institute ' s Antibacterial Research Criteria Task Force , March 2 1 , 19 8 8 , ent itled "Estimating the Volume of Antibacterials Used in Livestock and Poultry Feeds . " a From Table IV-4 . b Percent of total antibiotic production . c Percent of total annual sales for l ivestock and poultry feed .

70 the feed trade for use i n l ivestock and poultry feeds . Tetracycl ines and penicil l in accounted for 5 8 % of the 9 . 9 m i l l ion pounds . In the same year , of the 7 . 2 mi l l ion pounds of tetracycl ines produced , 5 . 1 mi l l ion pounds ( 7 1 % ) was sold for use in l ivestock and poultry feeds ( Tables IV- 5 and IV- 6) • SUBTHEBAPEUTI C USE OF ANTIBACTERIAL DRUGS IN ANIMAL FEED The current FDA-approved uses of the tetracycl ines and penici l l in in animal feeds are for growth enhancement , disease prevention , and treatment of disease . In the f irst two of these categories ( commonly des ignated " subtherapeutic" ) , these antibiotics are used at 2 0 0 grams or less per ton for 2 weeks or more . 4 Some combinations with other ant ibacterial s ( tetracycl ine at 1 0 0 gjton [ gjton = grams drug per ton o f feed ] , sul fametha z ine at 1 0 0 gjton , and penici l l in at 5 0 gjton ) have been approved by FDA for use i n pigs that we igh up t o 7 5 lbs . The Center for Veterinary Medic ine ( see Footnote # 1 , page 1 of Pre face ) cons iders any extended use of ant ib iot ics in feed at 2 0 0 gjton or less beyond 2 weeks as " subtherapeutic use , " whether it is for growth enhancement or disease prevention . "Use l evels are general ly 2 0 0 gjton or l ess of penici l l in or tetracycl ine , but dosage un its wil l vary by species . Levels approved for claims of growth promotion and disease prophylaxis are usua l ly lower than those approved for disease treatment ; however , there is some overlap in the claims for dose levels of 2 0 0 gjton or less . " There is more concern in the agency with the length of t ime the antibiotic is used in feed than in the level of drug . ( FDA , personal correspondence , Apri l 2 6 , 1988 . ) Although the need for such information i s criti cal , there are n o actual data ( only estimates ) o n the amounts of penici l l in or tetracycl ine used subtherapeut ica l ly in animal feed . Experts in veterinary medicine from the Anima l Health Institute and el sewhere testi fied to this committee that use of the prophylactic dosage of antibacterial agents is common and important for successful and profitable rearing of l ivestock . It appears that hog farmers use antibacterial feed addit ives rather cons i stently during the early periods in ra i s ing swine . That involves such use of ant ibacterial additives for about 1 0 weeks in feeder pigs ( approximately one hal f of the ir l i fe span ) , divided into several stages . The f i rst stage often cons ists of the tetracycl ine­ sul fametha z ine-penici l l in combination or a tyl osin­ sul fametha z ine combination . After that stage , tetracycl ine ( 2 5 - 5 0 gjton ) , tyl osin alone , bacitracin , or bambermycin is used . In cattle it i s common to feed a tetracycl ine­ sul fametha z ine combination per head ( 3 5 0 mg of each drug to

71 each animal ) per day for 4 - 6 weeks a s the cattl e go into feedlots . The intent of such administration is primarily " prophylact ic . " Although penici l l in and the tetracycl ines are approved by FDA for use in several classes of poultry , they are not used commonly in broi lers . I n its efforts to obtain broader and more up-to-date information about the use of antibiotics by the d i fferent animal industries , the committee made inquiries to the National Broi ler Counci l ( NBC ) , the Texas Cattle Feeders Association ( TCFA ) , and the National Pork Producers Association ( NPPA) . NBC in 1 9 8 4 surveyed 3 0 companies representing 7 7 . 8 % of the industry ' s broiler product ion for that year . None of the companies reported us ing penici l l in or the tetracycl ines to increase rate of growth and feed e f f i ciency . However , they did indicate that those antibiotics were widely used in disease prevention and treatment programs . Of the 3 0 companies surveyed , 18 ( 6 0 % ) reported using penic i l l in i n disease prevent ion or treatment programs , 2 8 ( 9 3 % ) reported us ing chl ortetracycl ine , 2 3 ( 7 7 % ) reported us ing oxytetracycl ine , and 1 0 ( 3 3 % ) reported us ing tetracycl ine . The use of the antibiotics for disease prevention is summarized in Tabl e IV-7 . A survey by the TCFA in 1 9 8 6 involved 1 0 2 feedyards that produce 7 5 % of the feed cattle in the TCFA area ( New Mexico , Oklahoma , Texas ) . Responses from nutritionists responsible for more than 11 mil l ion head of cattl e ( approximately 4 2 % of a l l the feed cattle produced annual ly in the United States , assuming a total feed cattle production of 2 6 mi l l ion a year) indicated that none of the anima l s receives cont inuous l ow­ dose tetracycl ines in feed ( penic i l l in is not approved for such use ) . However , the survey did not address the use of subtherapeutic concentrations for disease prevent ion . The NPPA has not conducted a recent survey on the use of penicil l in or tetracycl ines in swine feed . However , Virgil Hays ( personal communication , 1 9 8 8 ) has cal culated the amount o f tetracycl ine used in swine feed for the committee ( Table IV-8 ) . According to u . s . Department of Agriculture f igures , approximately 8 6 . 5 mi l l ion pigs ( see Table IV-2 ) with an average we ight of 1 1 0 kg were marketed in 19 8 5 . On the bas i s o f the numbers in Tabl e IV-8 and the survey estimate of 6 . 6 g o f tetracycl ines per pig , it is poss ible to derive a figure for the total amount of tetracycl ines used in the rearing of swine in that year : 8 6 . 5 mi l l ion ( head of swine ) x 6 . 6 g ( tetracycl ines per pig) = 0 . 5 7 mil l ion kilograms ( 1 . 2 5 m i l l ion pounds ) of tetracycl ines . I f al l swine feed were medicated with tetracycl ines , the total would be 1 . 7 mi l l ion kil ograms ( 3 . 7 mi l l ion pounds ) . Because 5 . 4 mi l l ion pounds o f tetracycl ines were estimated to have been used in l ivestock and poultry feeds in 1 9 8 5 ( Table IV- 6 ) , the figure of 1 . 2 5 mil l ion pounds used in pig production represents approximately 2 3 % of the total tetracycl ines used in an imal

72 TABLE IV-7 USE OF PENICILLIN OR TETRACYCLINES FOR DISEASE PREVENTION IN POULTRY , 1 9 8 4 Dur a t ion No . of Drug Companies A Route Dosage use . days Penicil l in 3/ 14 Feed 5 0 - 1 0 0 gjton 3 -14 Penici l l in 4/ 18 Water 1 0 0 - 1 6 0 KU/gal b 3 -14 Chlortetracycl ine 9/ 2 8 Feed 1 0 0 - 5 0 0 gjton 2 -7 Chlortetracycl ine 9/ 2 8 Water 1 0 0-4 0 0 mgjqal 2 -7 Oxytetracycl ine 6/ 2 3 Feed 1 0 0 -2 0 0 g/ton 3-14 Oxytetracycl ine 8/ 2 3 Water 1 0 0 -4 0 0 mqjga l 3-14 Tetracycl ine 5/ 1 0 Water 2 0 0 - 1 , 0 0 0 mgjqa l 3 -7 Source : Data from J . P . Pretanik , National Bro i l er Counc i l , 1 9 8 8 ( personal communication ) . a No . Companies • ( number of companies reporting thi s use ) / ( number of companies reporting) . b KU • thousand units .

73 TABLE IV-8 ESTIMATES OF TETRACYCLINE USED IN REARING SWINE Feed , Tetracycline . gA�--­ Use kg All Diets Suryey Estimate In sow breeding and 44 2.7 0 . 17 gestation : estimate used 2 1-day breeding period In lactation : assumption 15 1.6 0 . 17 of 1 0 0 gjton Starter : assumption of 23 2.5 0 . 47 100 gjton Grower : assumption o f 96 5.3 1 . 92 s o gjton Finisher : assumption o f 280 7.7 3 . 87 2 5 gjton Total per pig 4 58 19 . 8 6 . 60 Source : Data from Virgil Hays , Univers ity o f Kentucky , 1 9 8 8 , ( personal communication ) . a As basel ine for comparison , amount o f tetracycl ine is calculated for medication of a l l diets . On bas i s o f surveys done i n the state of I l l inois and those done by Univers ity o f Nebraska in 19 8 3 , and more recently by Hays ( 19 8 8 ) of seven maj or suppl iers of feed for swine , figures have been cal culated in right-hand column . The committee recogn i z es that accuracy of figures cannot be val idated in practice . However , in absence of recent comprehens ive survey data , the committee views these as best est imates of amounts of tetracycl ine used in swine .

74 and poultry feed . According t o Virgil Hayes ( personal communication , 1 9 8 8 ) , triple-drug medication that includes the tetracycl ines in the feed of growing swine is used routinely , thus subtherapeutic dosing is frequent and widespread . Estimates of antimicrobial consumption indicate their use in farm animals is predominantly in subtherapeutic concentrat ions . In December 1 9 8 4 , Gusta fson testi fied before the Subcommittee on Investigations and OVers ight of the u . s . House of Representatives Committee on Science and Technology . Gusta fson presented estimates ( Tabl e IV-9 ) derived primarily from industry sources , that , of the 8 , 3 1 6 , 0 0 0 kg ( 18 . 3 mi l l ion pounds ) of antib iotics used in anima l product ion , 8 8 % was used i n subtherapeut ic concentrations : o f the latter amount , 2 8 % was for growth promot ion . Of the 2 , 64 0 , 0 0 0 kg o f the tetracycl ines admini stered t o farm anima l s ( Tabl e IV-9 ) , 2 , 4 0 3 , 0 0 0 kg ( 9 1 % ) was used in subtherapeutic concentrations . Only 7 % and 2 % , respectively , of a l l the tetracycl ines administered to cattle and swine were for therapeut ic purposes , but 85% of the tetracycl ines given to poultry was used therapeut ica l ly . In addition to reviewing the above estimates made by Gusta fson in 1 9 8 4 , the committee sought and received estimates made by AHI that would have involved data from the same sources as were ava i lable to Gusta fson ( Tabl e IV- 6 ) . In those estimates , the total sales of antibacteri a l s for l ivestock and poultry feeds was 5 . 0 mil l ion kil ograms in 1 9 8 5 , contrasting with the figure of 8 . 3 mil l ion kil ograms reported by Gusta fson ( Table IV-9 ) . The d i fference i s substantial and is not readily expl icabl e . However , it should be noted that the total figures for annual use ( or sales ) of tetracycl ines in l ivestock and poultry are very s imi lar : 2 . 6 mi l l ion ki lograms in the Gusta fson est imates and 2 . 4 mi l l ion kilograms in the AHI estimates , prorated for total u . s . ant ibiotic production in 1 9 8 5 ( Tables IV- 6 and IV- 9) . The AHI estimates are related to " antibacteria l s " and the Gusta fson estimates to " antibiotics , " so the d i fferences might be due to inclus ion in the latter category of ant ibiotics that are coccidiostat& ( e . g . , monens in ) , rather than ant ibacterial agents . As a result of the a forement ioned d i f ferences , the committee is uncerta in as to which est imates should be used as a ba sis for comparison of trends in annual use . The estimates o f tetracycl ine use in feed for individua l animal and avian species show some poss ible discordances . The estimates by Hays of tetracycl ine use in swine ind icate that 1 . 7 mi l l ion kil ograms would be used i f al l swine feed were medicated with this drug . This figure would be close to the 1 . 6 5 m i l l ion kilograms in the 1 9 8 5 est imate of Gusta fson . However , not a l l swine are medicated with tetracycl ines during growth . In addition , the previously noted NBC and TCFA surveys both indicate recent marked reduct ions in the

75 TABLE IV-9 ESTIMATED 19 8 5 ANNUAL ANTI BIOTIC USE IN THERAPY , DISEASE PREVENTION , AND GROWTH PROMOTION All Antibiotics . tbousands of kilograms Subtherapeutic Use Disease Growth Tberapeutic Use Prevention Promotion Total cattle 4 58 1 , 100 3 40 1 , 898 swine 2 50 3 , 57 8 1 , 391 5 , 219 Poultry 304 580 3 15 1 , 199 Total 1 , 012 5 , 258 2 , 04 6 8 , 3 16 Tetracycl ines ( Chl ortetracycl ine and Oxytetracycl ine ) , thousands of kilograms Subtherapeutic Use Disease Growth Tberapeutic Use Prevention Promotion Total cattle 50 589 130 7 69 swine 30 9 50 701 1 , 651 Poultry 187 33 220 Total 2 67 1 , 57 2 831 2 , 64 0 Source : Correspondence from R . H . Gusta fson (American Cyanamid Company ) to E . Eastman ( Subcommittee on Invest igat ions and OVers ight , House Committee on Science and Technology ) , January 24 , 1 9 8 5 ( personal communicat ion ) .

76 use o f tetracycl ines for growth promotion . However , the committee bel ieves that the tetracycl ines are widely used in poultry product ion for disease prevention . In cattle­ rais ing , data on the extent of use o f prophylaxis are not reported . Although use of tetracycl ine for growth promot ion in poultry and cattle has reportedly decreased , it is unknown whether the prophylactic use of subtherapeutic concentrat ions has remained constant or has increased correspondingly . Thus , it is very difficult to quanti fy current subtherapeut ic use of tetracycl ines ( and penicil l in ) on u . s . farms and feedlots . I n summa ry , exact data on ant ibiotic use in animal feed are not obtainable . The best avai l able estimates indicate that 3 1 -4 6 % of the total annual production of ant ibiot ics ( 3 1 . 9 m i l l ion pounds ) in the United States is used in anima l s for a l l purposes . ( Even higher figures have been suggested ) . A range of 9 . 7 - 1 1 . 7 mi l l ion pounds ( 4 . 4 - 5 . 3 mil l ion kilograms ) was used annual ly from 1 9 8 0 through 1 9 8 5 ( Tabl e IV- 6 ) . In the same years , tetracycl ine use in l ivestock and poultry totaled 5 . 1- 6 . 4 mi l l ion pounds , and penici l l in use 0 . 6 - 0 . 9 mi l l ion pounds . Although data are l imited , it appears that about twice the amount of antibacteri a l s i s used for disease prevention as for growth promotion . The committee is aware that strict compl iance with the regul ations in the United States governing subtherapeuti c use of antimicrobials is not always achieved in common practice . On the farm , pl anned brief periods of antimicrobial use and the amount of medication and duration of its administration might sometimes be below or exceeded the spec i f ications . For example , concentrations of antimicrobials actual ly ach ieved in feed might vary widely from the spec i f ied regul atory l imits , because of miscalculation or improper mixing of drug and feed either on the farm or by the feedmi l l . The true period of med ication might be longer or shorter due to the t ime taken to consume the amount of feed in storage or for other reasons . For purposes of analys i s , the committee has considered a l l use of antimicrobials as speci fied for both growth enhancement and disease prevention as being in the category of subtherapeutic use . That is also the view taken by FDA ( M . F . Lowe , 1 9 8 8 , personal communicat ion ) . The approach seems reasonable , in that , with the except i on o f the rep o rt o f Gusta fson , the re is l itt l e quant itat ive i n fo rmation to d i st i ngu ish use for growth promot i on from use f o r d i s e a s e prevent i o n . Gusta f s on ' s estimates indicated that 8 8 % o f a l l a nt i b i ot i c u s e i n l ivestock and poultry was subtherapeutic . Tetracycl ines account for almost S O % of total ant ibacterial use in l ivestock and poultry feeds ( Tabl e IV- 6) . In the est imates of Gusta fson ( Tabl e IV-9 ) , subtherapeut ic use of tetracycl ines accounts for 2 9 % o f a l l antibiotic use i n cattl e , swine , and poultry for a l l purposes . I f data in Tables IV-4 , IV- 5 , and IV-9 are - - - - -

77 comb ined , i t appears that subtherapeutic use of tetracycl ines ( 2 . 4 mill ion kilograms ) accounts for 17 t of total annual production of a l l antibiotics ( approximately 14 mil l ion kilograms in 19 8 3 ) and 7 3 t of a l l tetracycl ines produced for a l l purposes ( 3 . 3 mil l ion kilograms in 1 9 8 3 ) . Data on subtherapeutic use of tetracycl ines for the l ast 3 years are not ava i l able , and it is not poss ible to calculate the percentages of total antibiotic production or of total farm and feedlot use that they account for today . Antibiot ic use in animals , in quantitative terms , is an important pressure for sel ection of ant ibiotic res istance in enteric bacteria on the farm and in feedlots . Subtherapeut ic use in animal feed appears to be greater in quantative terms in thi s regard than antibiotic use for therapy , and tetracycl ine accounts for about hal f the amount of antibacteria l s used in this fashion . Although distinct ion between the growth-promotion and di sease-prevention uses of subtherapeut ic concentrations would be helpful , no accurate data is ava i labl e . Furthermore , disease-prevent ion uses apparently are routine when there is suspic ion of disease in some anima l s in a group or the durations of medication might be prolonged beyond speci fied regul atory time periods in severe cases or s imply because of mistakes . REFERENCES 1. Counci l for Agricultural Science and Technol ogy . Ant ibiotics in Animal Feeds . Report No . 8 8 . Ames , I owa : Council for Agricultural Science and Technol ogy , 198 1 . 2. Hays , v . w . Benef its and risks of antibiotics use in agriculture , pp . 7 4 -8 7 . In w . A . Moats , Ed . Agricultural Uses of Antibiotics . American Chemica l s Society S ymposium Series 3 2 0 . Washington , D . C . : American Chemical Society , 19 8 6 . 3. Loehr , R . c . Agricultural waste management : Problems , Processes and Approaches . In D . H . K . Lee , E . w . Hewson , and D . Okun , Eds . Environmental Sciences . New York : Academic Press , 1 9 7 4 . 4. Mil ler Publ ishing Co . The Feed Addit ive Compendium . Minnetonka , Minnesota : Mi l l er Publ i shing Co , 1 9 8 7 . 4a . National Research Counc i l . Committee on the E ffects on Human Health of Subtherapeut ic Use of Antimicrobials in Animal Feeds . Effects on Human Health of Subtherapeutic Use of Ant imicrobials in Animal Feeds . Washington , D . C . : National A cademy Press , 19 8 0 .

78 5. OVercash , M . R . , F . J . Humenik , and J . R . Miner . Livestock Waste Management . Vol . 1 , Table 2 6A . Boca­ Raton , Florida : CRC Press , 1 9 8 3 . 6. u.s . Department of Agriculture , National Economics Divis ion , Economic Research Service . Food Consumption , Prices , and Expenditures 19 8 5 . Bul let in No . 7 4 9 . u . s . Department of Agriculture , January 1 9 8 7 . 6a . u.s. Department of Agriculture . Nat ional Agricultural Statistical Service . Agriculture Statistics 19 8 6 . Washington , D . C . : u . s . Government Printing Off ice , 1 9 8 6 . 1. u. s . International Trade Commission . Synthet ic Organic Chemical s : United States Production and Salas , 1 9 5 0 - 1 9 8 6 . Washington , D . C . : u . s . Government Print ing Office .

v ANTIMICROBIAL RESI STANCE IN HUMANS AND ANIMALS fREQUENCY OF DRUG BESI STAHCE IN CLINICAL I SOLATES OF SALMQNEIJA SPP . fROM HQMANS AND ANIMALS IN THE QNITED STATES Thousands of cl inical laboratories throughout the United States isolate occas ional strains of salmonel l ae from humans , test their susceptibil ity to antimicrobial agents , and send the isolates--but not the susceptibi l ity test results --to state reference laboratories for serotyping . S imilarly , a paral lel set o f veterinary service and re ference l aboratories process animal isolates o f salmonel lae s imilarly . This whol e elaborate salmone l l a reporting apparatus l ists about 4 5 , 0 0 0 total isolates per year . These salmone l l a test results , however , are scattered through the f i l es o f thousands of l aboratories , and even the re ference l aboratory f i l es rarely have both susceptibil ity and serotype results . Thus , an expensive system obscures a maj or part of its only product , epidemiol ogic informat ion . To survey the prevalence of res istance in salmonel l ae , it is there fore necessary to repeat work that has al ready been done , to col lect serotyped isolates from reference laboratories to retest the ir susceptibil ity and to f i l e the results together . Table V- 1 summari z es an example of such work carried out 8 years ago as background for a study o f res istance plasmids in salmone l l ae . Susceptib i l ity testing was performed on several thousand human isolates o f salmonellae col lected and serotyped by the Massachusetts state Laboratory and several thousand animal isolates col lected and serotyped from a l l parts of the United states by the National Veterinary Laboratory , in Ames , I owa . In this chapter and throughout the report the committee has included data on the antibiotic res istance pro f i l e of bacterial isolates collected from various veter inary l aboratories throughout the United States over several years . The history of ant ibiotic exposure was not ava ilable in most cases . The committee has made the assumpt ion that the ant ibiotic res istance profile of the isolates is indicative of exposure of the animal host to the spec ific ant ibiotics l isted in the pro f i l e . There is an inherent problem in this assumpt ion that is clearly recogn i z ed : the ant ibiotic res istance profile of an isolate cannot be used with absolute certa inty to determine direct exposure o f a 79

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