Observations on the History of the Development of Antimicrobials and Their Use in Poultry Feeds

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1 Observations on the History of the Development of Antimicrobials and Their Use in Poultry Feeds F. T. Jones*,1 and S. C. Ricke *Department of Poultry Science, University of Arkansas, Fayetteville, Arkansas 72701; and Department of Poultry Science, Texas A&M University, College Station, Texas ABSTRACT Antimicrobials are powerful tools, but controversy Fifteen compounds are listed for treatment of coccidiosis, and conflict often follow power. The develop- ment of antimicrobials was marked by personal attacks, 11 are listed as growth promotants, and six are listed for other purposes. Seven compounds are also used in human political intrigue, internal conflicts, and lawsuits. Such medicine. These compounds include bacitracin, chlotetracycline, erythromycin, lincomycin, novobiocin, oxytetra- controversy and conflict has continued. The early history of supplementing animal feeds with antimicrobials parallels the isolation and identification of vitamin B 12. Vitamin cycline, and penicillin. No published estimates of antimicrobial use in animals exist at present, and estimates of that use differ markedly. The Union of Concerned Scientists (UCS) estimates usage at 30.6 million pounds, nearly B 12 was isolated and characterized in 1948, but further research showed that several feed ingredients, including 50% (49.85%) higher than the Animal Health Institute dried mycelia of certain fungi, were more potent as (AHI) estimate of million pounds. AHI surveyed growth promoters in the diet of chicks than was vitamin their members (the manufacturers of antimicrobials) to B 12 alone. The growth-promoting component in fungal obtain their estimates, whereas USC calculated their estimates mycelia was shown to have antimicrobial activity. A total of 32 antimicrobial compounds are approved for use in broiler feeds in the U.S. without a veterinary prescription. using published data and the following general formula: antimicrobial use = number of animals treated average days treated average dose. (Key words: antibiotic development, feed antibiotic use, history of feed antibiotic use) 2003 Poultry Science 82: INTRODUCTION H. G. Wells is reported to have stated, Human history becomes more and more a race between education and catastrophe (Russo, 2002). To aid education in surging ahead of catastrophe, this introductory review to a symposium titled Current Applications, Future Prospects, and Alternatives for the Use of Antimicrobials in Poultry Production was undertaken to provide background information on the development of antimicrobials and their use in animal feeds. ANTIBIOTIC PIONEERS Modern chemotherapy is reported to have begun with the work of Paul Ehrlich, a German physician and researcher (Burdon and Williams, 1968). In 1909, following years of tireless work, Ehrlich produced Salvarsan or compound 606 because he discovered the compound during his 606th animal experiment. Salvarsan was the first chemical compound documented to cure a human disease (syphilis) (De Kruif, 1926). Ehrlich s success produced considerable fame, publicity, and stress for the shy scientist. Ehrlich and his work were also severely criticized by a variety of individuals, including other physicians who had, prior to Salvarsan, made their livelihood by continuing treatments for syphilis until the patient died. The nearly 6 yr of praise and criticism took its toll on Ehrlich s health. In 1914 Ehrlich was forced to testify as an expert witness in a libel suit brought by the hospital for which he worked. Because Ehrlich considered such testimony degrading, the experience left Ehrlich in very frail health, and 1915 he died as a result of a stroke (Marquardt, 1951). Inspired by Ehrlich s success, Gerhard Domagk (a German physician and pacifist) discovered in 1932 that a red dye (prontosil rubrum) (PR) protected mice and rabbits from infection by streptococci and staphylococci. In spite of his success, Domagk was unsure that PR would work on humans and had done little testing of the compound in humans. Soon afterwards Domagk s 6-yr-old daughter 2003 Poultry Science Association, Inc. Received for publication September 6, Accepted for publication November 11, To whom correspondence should be addressed: ftjones@uark.edu. Abbreviation Key: AHI = Animal Health Institute; APF = animal protein factor; FDA = United States Food and Drug Administration; PR = prontosil rubrum; UCS = Union of Concerned Scientists. 613

2 614 JONES AND RICKE (Hildegard) became seriously ill with a streptococcal infection and faced amputation of her arm (which was the standard treatment of the day for this illness). Domagk injected his daughter with PR, and she fully recovered from the infection without complication or amputation. Additional testing on human volunteers verified the fact that PR was effective. It was later discovered that the active compound in PR was sulfanilamide, the parent compound for modern-day sulfa drugs. In 1939, Domagk was offered the Nobel Prize in Medicine, but the German Nazi governing regime considered accepting such an award anti-german and instructed the Gestapo to interrogate him for 11 d. Domagk refused the award in 1939 but was able to collect his prize in 1947 after World War II (Cann, 1998). Alexander Fleming, an English bacteriologist who discovered penicillin, was likely motivated by his experiences as a World War I medic. Confronted by wounded soldiers consumed by gangrene and other incurable diseases, Fleming wrote, Surrounded by all those infected wounds, by men who were suffering and dying without our being able to do anything to help them, I was consumed by a desire to discover, after all this struggling and waiting, something which would kill those microbes. (Maurois, 1959). Although trained as a surgeon, Fleming never practiced medicine beyond medical school (Macfarlane, 1984). Instead, Fleming searched for methods to kill microorganisms within the human body. Initially Fleming discovered that bodily fluids and other materials inhibited microbes via a material he dubbed lysozyme. However, lysozyme was found to act on only less virulent bacteria. In 1928 Fleming observed that contaminating mold colonies inhibited the growth of staphylococci on agar plates and described the properties of the material he called penicillin (Wong, 2001a). When he reported his findings in a scientific journal a year later, the work was dismissed as a laboratory curiosity, possibly because Fleming had neither produced a purified extract of penicillin nor produced enough crude extract to do animal testing (Steinert, 2000). Although Fleming continued to work with penicillin, his supervisor opposed further penicillin research because he believed that vaccines would cure all diseases (Cann, 1998). The advent of World War II accelerated the commercial development of penicillin and involved Ernst Chain and Howard Florey (both of Oxford University, UK) who were able to produce sufficient quantities of penicillin for testing and later clinical use. In 1945 the Nobel Prize in Medicine was shared between Fleming, Chain, and Florey. Selman Waksman, a soil microbiologist, was inspired by the success of penicillin and was quoted as saying Drop everything, see what these English have done with a mold. I know the Actinomycetes will do better. Waksman initiated a search for new antibiotics from Actinomycetes. As is still the custom, Waksman assigned routine screening procedures to graduate students. One graduate student, Albert Schatz, isolated and tested the antibacterial activities of streptomycin, which was at the time the only antibiotic effective against tuberculosis. Waksman was awarded the 1952 Nobel Prize in Medicine and never mentioned Schatz. The patent awarded for streptomycin listed both Waksman and Schatz as inventors, but when the drug was licensed, Waksman sought to retain all the royalties. Schatz successfully sued Waksman for his share of the royalties, but many research organizations would not hire Schatz because he was viewed as bitter and envious (Wong, 2001b). Although many obvious lessons may be derived from the experiences of these antibiotic pioneers, only a few seem noteworthy at this juncture. Antibiotics are powerful tools, but controversy and conflict often follow power. The development of antibiotics was marked by personal attacks, political intrigue, internal conflicts and lawsuits. Such controversy and conflict has continued until today. Will the future be any different? ANTIBIOTICS IN ANIMAL FEEDS HOW IT BEGAN The early history of supplementing animal feeds with antibiotics parallels the isolation and identification of vitamin B 12. Thus, it is impossible to discuss the history of antibiotics in animal feeds without mentioning research work with vitamin B 12. Jukes (1972) reported that during the 1940s advances in genetics, nutrition, housing, and marketing systems made possible a rapid expansion of poultry production in the U.S. The increase in number of chickens increased demands for certain basic feed components at a time when the supply was short. Although replacements were found for certain feed components, none were found for fishmeal or other animal protein sources. The shortage of animal protein sources along with a rapid increase in supplies of vegetable protein sources, particularly soybean meal, resulted in an increased use of vegetable protein sources. Animal proteins contained an unidentified substance then called animal protein factor (APF), which was necessary for balanced swine and poultry rations. The shortage of animal protein sources now encouraged researchers to determine the nature of APF. Vitamin B 12 was isolated and characterized in 1948 and was determined to be APF (Ott et al., 1948; Rickes et al., 1948). However, further research showed that several feed ingredients, including dried mycelia of certain fungi, were more potent as growth promoters in the diet of chicks than was vitamin B 12 (Stokstad et al., 1949; Hill and Brannion, 1950; Sunde et al., 1950; Swenson, 1951). The growth-promoting component in fungal mycelia was shown to be antibiotics. This finding was an unexpected result, since only a few years before the feeding of sulfa drugs to rats and chicks was shown to produce a depression in growth rates (Black et al., 1941; Luckey et al., 1946). Moore et al. (1946) were apparently the first to show that inclusion of antibiotics in the feed of chickens caused increased weight gain. However, a number of investigators subsequently documented the growth stimulation

3 SYMPOSIUM: USE OF ANTIMICROBIALS IN PRODUCTION 615 TABLE 1. Antimicrobial compounds currently approved for use in broiler feeds without a veterinary prescription 1 Drug name Indications for use Human use Amprolium Coccidiosis None Arsanilic acid Growth promotion, feed efficiency None Bacitracin methylene disalicylate Rate of weight gain, feed efficiency None Bacitracin zinc Rate of weight gain, feed efficiency Yes Bambermycins Rate of weight gain, feed efficiency None Chlotetracycline Rate of weight gain, feed efficiency Yes Cyromazine Fly control None Decoquinate Coccidiosis None Diclazuril Coccidiosis None Erythromycin Prevention of infectious coryza Yes Halofuginone hydrobromide Coccidiosis None 2 Hygromycin B Worms None Lasalocid Coccidiosis None Lincomycin Rate of weight gain, feed efficiency Yes Maduramicin ammonium Coccidiosis None Monensin Coccidiosis None Narasin Coccidiosis None Narasin/nicarbazin Coccidiosis None Nicarbazin Coccidiosis None Nitarsone Blackhead None Novobiocin Stapylococcus infections Yes Oxytetracycline Rate of weight gain, feed efficiency Yes Penicillin Rate of weight gain, feed efficiency Yes Piperazine Worms None 3 Robenidine hydrochloride Coccidiosis None Roxarsone Rate of weight gain, feed efficiency None Salinomycin Coccidiosis None Semduramicin Coccidiosis None Sulfadimethoxine and ormetoprim 5:3 Coccidiosis None 4 Tylosin Rate of weight gain, feed efficiency None Virginiamycin Rate of weight gain, feed efficiency None Zoalene Coccidiosis None 1 Abstracted from Miller (2001). 2 This drug is not FDA approved but does have orphan drug status to treat systemic sclerosis. 3 This drug is no longer marketed in the U.S., but there are multiple anthelmitic human products in use in other countries. 4 This drug was formerly used in humans to treat urinary tract infections but is no longer used. effect of antibiotics in pigs and chicks (Groschke and Evans, 1950; Stokstad and Jukes, 1950; Whitehill et al. 1950). Although there were concerns expressed about antibiotic resistance (Elam et al., 1951a,b), resistance was believed to be strictly chromosomal in nature. Thus, the dangers of hypersensitivity reactions to residues in meat and fungal overgrowth in animals were thought to be of more concern than resistance (Ainsworth and Austwick, 1953). In 1951 the United States Food and Drug Administration (FDA) approved the use of antibiotics in animal feeds without a veterinary prescription. FEED ANTIMICROBIAL FACTS The data in Table 1 were composed from information obtained from the 2002 Feed Additive Compendium (Miller, 2001). A total of 32 antimicrobial compounds are approved for use in broiler feeds in the U.S. without a veterinary prescription. Fifteen compounds are listed for treatment of coccidiosis, 11 are listed as growth promotants, and six are listed for other purposes. Seven of the compounds listed in Table 1 (bacitracin, chlotetracycline, erythromycin, lincomycin, novobiocin, oxytetracycline, and penicillin) are also used in human medicine, but the remaining 25 compounds are not. However, the National Antimicrobial Resistance Monitoring System (NARMS), a joint effort of the Center for Disease Control, FDA, and USDA shows resistance patterns in animal pathogens (including poultry) have been relatively low and stable since monitoring began in 1996 (CDC, 2002). No unbiased estimates of antimicrobial use in animals exist at the present time, and published estimates of that use differ markedly. The Animal Health Institute (AHI) conducted a survey of their members and estimated antimicrobial use in animals in These data are shown in Table 2. It should be noted that the data in Table 2 include antimicrobial compounds marketed for food and companion animals. The 1999 AHI survey estimates the total use of antimicrobial compounds at million pounds (Carnevale, 2001). The Union of Concerned Scientists (UCS) estimates usage at 30.6 million pounds, nearly 50% (49.85%) higher than the AHI estimate (Benbrook, 2001). Methodology may explain these discrepancies. AHI surveyed their members (the manufacturers of antimicrobials) to obtain their estimates, whereas USC calculated their estimates using the following general formula: antimicrobial use = number of animals treated average days treated average dose (Benbrook, 2001; Carnevale, 2001). UCS obtained animal numbers from USDA and estimates

4 616 JONES AND RICKE TABLE 2. U.S. Animal antimicrobial use in ,2 Usage Total use Antimicrobial class (million lbs) 3 (%) Aminoglycosides Fluoroquinolones Ionophores/arsenicals Penicillins Sulfonamides Tetracyclines Other antibiotics Total Adapted from Carnevale (2001). 2 Values include antimicrobials used in food and companion animals. 3 Values represent pounds of active ingredient. of the number of animals treated via the National Animal Health Monitoring System (NAHMS) as well as National Academy of Science reports. Then UCS developed antimicrobial use estimates during each major growth stage using NAHMS data and the FDA Green Book. Feed consumption data were developed from widely accepted estimates of feed efficiency and weight gain (Benbrook, 2001). The UCS estimates seem to assume that every animal production unit experiences exactly the same conditions, when, in fact, unique conditions arise in each animal production situation. It is uncertain whether the UCS estimates are of the active ingredients contained within antimicrobial products or if the estimates include diluents. It is unclear how UCS determined how product cost and personal preferences affected antimicrobial use patterns. Apparently UCS assumed that if animal producers could use a product, they would use that product. Furthermore, UCS estimated trends in antimicrobial use per animal by comparing 1985 estimates with late 1990s data and suggested that there was a 307% increase in antimicrobial use in poultry. However, estimate tables include the following footnote: 1985 use assuming the number of beef cattle, swine and poultry produced in 1984 equaled late 1990s herd/flock size (Benbrook, 2001). In view of the fact that USDA estimates of broiler numbers in 1984 were 4.28 billion birds and 7.08 billion in 1999, clearly the assumption stated is false. Although AHI estimates of animal antimicrobial use contain some imprecision in that they contain products used in companion animals, the total use in 1999 is listed at million pounds. AHI estimates that nearly half (47.5%) of the compounds used are not used in human medicine and are unrelated to human drugs. Furthermore, the report estimates that million pounds (86.3%) of antimicrobials sold in 1999 were used to prevent and treat diseases, while 2.8 million pounds (13.7%) were used for growth promotion (Carnevale, 2001). No information was provided on how these estimates were obtained. In summary, the development of antimicrobial compounds was not without political difficulties, opposition, and controversy. Such problems have continued to this day. Antimicrobial use in animal feeds was discovered by accident while researchers were attempting to determine the nature of APF, which was finally identified as vitamin B 12. Of the 32 antimicrobial compounds approved for use in U.S. broiler feeds without a veterinary prescription, 15 compounds are listed for treatment of coccidiosis, 11 are listed as growth promotants, and six are listed for other purposes. Seven compounds (bacitracin, chlotetracycline, erythromycin, lincomycin, novobiocin, oxytetracycline, and penicillin) are used in animal feeds and human medicine. No unbiased estimates of antimicrobial use in animals exist at the present time, and published estimates of that use differ markedly. REFERENCES Ainsworth, G. C., and P. K. C. Austwick Response to the proposed amendments to the penicillin act. Vet. Rec. 65:166. Benbrook, C. M Quantity of antimicrobials used in food animals in the United States. A presentation to Amer. Soc. Microbiol. Accessed: Black, S., J. M. McKibbin, and C. A. Elvehjam Use of sulfaguanidine in nutrition experiments. Proc. Soc. Exper. Biol. Med. 47: Burdon, K. L., and R. P. Williams Microbiology. 6th ed. MacMillan, London. Cann, A Domagk, Fleming, Waksman and the third man. dfwt6html. Accessed: Carnevale, R Antibiotic resistance and food producing animals Views of the industry. Accessed: Center for Disease Control and Prevention Diseases and Pathogens Under Surveillance. narms/pus.htm Accessed: De Kruif, P Microbe Hunters. Blue Ribbon Books, New York. Elam, J. F., L. L. Gee, and J. R. Couch. 1951a. Effect of feeding penicillin on the life cycle of the chick. Proc. Soc. Exp. Biol. Med. 77: Elam, J. F., L. L. Gee, and J. R. Couch. 1951b. Function and metabolic significance of penicillin and bacitracin in the chick. Proc. Soc. Exp. Biol. Med. 78: Groschke, A. C., and R. J. Evans Effect of antibiotics, synthetic vitamins, vitamin B 12 and an APF supplement on chick growth. Poult. Sci. 29: Hill, D. C., and H. D. Brannion The use of an animal protein factor supplement in practical poultry ration. Poult. Sci. 29:

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