·Copyright 1935 by Medlcal Encydopedia Inc., New York, NY COPYRIGHT UNDER THE INTERNATIONAL COPYRIGHT UNION ALL RIGHTS RESERVED. THIS BOOK IS PROTECTED BY COPYRIGHT NO PART OF IT MAY BE DUMICATED OR REPRODUCED IN ANY MANNER WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER PRINTED IN THE UNITED STATES OF AMERICA Distributors outsid. U.S.An Intendenca Publisher, New York London ·CONTENTS Foreword by Henry Welch, Ph.D., and Fell Narti I beliem 21.D 7 Chapter 1 latrodudian 13 19 21 25 26 Chapter 11 Mochanism of the Antibiotic Growth Effect The Influence of Enotronmental Bacteria on the Grouth of Animals Dforphologic Changes Produced by Feeding Antblotia The Effects of Antibiotics on tho Growth of Germ-free Antmals Effects on Intestinal Flora Effect on Rumen of croorganisms Adlibharic-tolerant Intettral Oficroorganism as a Source of Unidentified Grouth Factors Growth of Animals Recotoing Hydrolyzed Penicillin Effects of Prolonged Usage of Dlotary Antibiotics 83 84 38 38 Chapter 111 Effect of Fooding Antibiotics on the Requirement for Nutrients Effects on Vilamin and Mineral Requirement Effect on Protetn Requirement Effects on N#rogen Motabolien 30 Chapter IV Antibiotics in Animal Production Antibiotica # Poultry Production Antibiotics in Suine Production 57 81 ·65 68 Effect on Cancer Quality Antibiotics in the Dlots of Ruminants Antiblottas in Beef Cattlo Farding Anttblotta in Lomb Perde The Effect of Dietary Antiblotla on Roproduction in Animals Egg Production in Poultry Antibiotics and Egg Productions fillers with Chronic Raspbratory Dlance 69 71 78 81 81 84 88 Chapter V Physiologic and Other Effects of Dietary Antibiotics Effects of Antibiotics on tho Endoartre System Antibiotics and Lloer Phydology Effect of Antiblotlar on Blood Formation Pharmacology of Antibiotica Effocts on Growth of Human Subjecte Mluocblancow Nutritional Effects Efects on Guinos Pigs Publa llealth Aspects of Ferding Antibiotics to Antrale Conclusions 89 80 93 94 85 97 Bibliography 121 Index ·Foreword One of the great economic developments in the feld of antibiotics is the use of those drugs in feeds for the promotion of animal growth. During the past few years there has been a steady increase in the amount of antibiotics – largely penicillin, chlortetracycline orytetracycling, and bacitracin - used for this purpose. In 1954 alone, somo 490 000 pounds of these drugs wero Incorporated into feeds randering the farmer tremendous savings. Bocauso antibiotics stimulate the growth of swine, chicks, and poults, they cut down the feed consumption of these animals, since they can be sent to slaughter much sooner and in a healthior con dition than they would have been prior to tho uso of these drags. A unique phonomonon - perhaps without prece dent in the history of medicno – is indeed the present use of the so-called antſbiotics as stimulants of growth and nutrition in both human beings and animals. The opposite phenomenon has already been recorded in history Damely tho use of such nutritivo elements as vitamins, mineral salts, and amino acids as therapeutic agents. Vitamins were known and developed primarily as a component of the normal diet of human beings and animals only recently were they synthenzed and developed us powerful therapeutic druge But never before has a medicinal drug been used in animal feeding or in the diet of humans to stimulate nutrition and promote the speed and extent of growth. ANTIDIOTICS IN PUTRITION 17 ·This now application for adtbiotics will surely not wly greatly widen the horizon of their nusefulness, but also markedly affect tho putitional and economic problems of the world probably so much so that antibiotics may to tho futuro becomo e soost valuablo ele ment to solvtog the over-growing disproportion be tween increasing world population and food supplies. The use of antibiotics lo putrition bus ako opened Dp now avenues for research into much bado phlosophical problems of blology us the fofucuco at es vironmental bacteria on animal growth the correlation between the blocheanical action af antbloties und the anatomical changes in the morphology of animals fed with these substances the philosophical question of garm frcom animal Hfo versus the growth of animals whose bodies, as well as their enyironment, are liter Ally soaked in bacteria, and finally the correlation be tween the prolonged administration of antiblodios to kalimals and their vitamin and mineral requtrement These and other vital problems will eventually bo solved thanks to the searching light projected by biotics and antibiotic research upon tho field of nutrh Lon. Wo ero indood fortunato that Dr Thomas H. Jules prepared the monograph on "Anttblotics in NofritionThis is the fourth la the monograph salos do Algaed to embrace the principal antibiotia and their application, not only in clinical medicino but for other allied folds of lefumess u well. Doctor Jukes is a planear to this field. He together with his colleagues, was the first to demonstrate the effectiveness of calor totracycline in stimulating the growth of chalckens. In tho preparation of this monograph, Dr Jukes has completely covered the dovelopment of the use of antibiotics ta putriHon. Following a brief Introduction to Chapter I, he discusses mi sono detall the sect anism of the entblotic growth effort. Ho cover the effect of fooding antibiotics on the requirement for other nutrients in Chapter Il Chapters IV und V plain the tiso of antibiotos in abmel production and the physiological and other effects of detary ontt biotics A bibliography of more than 400 references to tostimony to the thoroughness with which De Jules has covered the subject of indblodios in anlmal nutri- Hon. All of the studios dopo to date concerning the Antiblote effect on the growth of human subjects, and 8 ANTIBIOTICS MONOGRAPHS

·also included, and the public health aspects of feeding
antiblotics to animals is explored.
Tho correlation of this largo mas of data has been
a nonumental tash, but it is so well done that this
monograph will be of great value to public health and
research workers veterinarians, cconomic specialists,
and those interested in the impact of the over widening
use of antbiotics in our daily life
Doctor Jukes has written his monogmph in a clear
terso, castly readable style We consider it a very
worthwhilo and valuable addition to this series
HENRY WELCH, Ph.D.
Director Division Antefier,
fond Drug Adstrelony
laher-to-CAL Antibiotia &
Chenderophy Antiblatie
Medicine
FELIX MARTI DAÑIZ, MD
Lernetional Leater Aabhavad
Chemother And Editions
Antbloth Hadhi
ANTIBIOTICS IN NUTRITION
19

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·"OFTIN in our laboratory discussions for the last several years I have told the young research workers in my group that there should be much interest in raising young animals such as rabbits, guines pige, dogs and chicks from birth on pure food matc- Hals. By this latter expression I refer to food products which havo been freed completely from common microbes by Laboratory methods. Without Wishing to speak positively I wish to state that I would undertake this investigation if I had time with the expectation that life under these conditions would becomo imporulblo. By such an approach one could perhaps attempt to study the digestive process by the systematic addition of microbe-free nutritive materials or sloglo strains of microbes or mlied cultures of known microbea. Tho egg of the chicken lends itself without serious difficulty to this type of asperiment. The outside of the shell could be kept free from bacteria at the moment the chick hatched and then tho chick could be placed in a germ free environment ventilated by stello etr and starto food (water milk and grains) could readily be introducod from the outside. "Whether the result would be positive and would confirm the proconceived idea which I have put forward or whother it would be Degative or oven reversed, that is to say that lfc under these condt tions would be actually stimulated, it would be of great Interest to try such an apperiment." (PASTEUR, L., as quoted by Duclaus, Em Comptes rendus Volume 100, page 68, 1885) ANTIBIOTICS IN NUTRITION | IT

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·CHAPTER ! Introduction The use of antibiotics in the control of harmful bacteria is a culmination of year of searching for what has been aptly termed a magic bullet" 1 mbstance that will bli e parasito without harming its host. Antibiotics when added to the food of animals aro able to improve their nutrition by producing changes to the intestinal bacteria This effect was discovered accidentally the "magic bullet" reached an unseen target. The growth rate of young chickens was found to be increased by adding streptomycin, chlortetracycling, or chlortetracyclino fermentation residuesh, I to their diet Tho work with chlortetracyclino residues led promptly to studies with other species and it was found, perhaps Dot un expectedly that the growth promoting effoct was oven more marked when certain intestinal infections were present. It is now well established that tho growth rato of youmg animals is usually increased by adding relatively small amounts of certain antibiotics to the diet. This offect on growth occurs in apparently bealthy animals on dlets that are adequate in all known nutritional factors and the effect is also observed on certain defident diets. Many antibiotics are toode to animals but thero ero certain outstanding and familiar exceptions, which include three antibloties that are widely used in ani mal feeds chlortetracycline oxytetracycline t and penicillin. These throcrubstances are well known for their effectiveness in animals against many diseasoproducog bacteria and for the absence of harmful effects produced by their uiso fo therapeutic doses. They are commonly used in animal foods, and badtru cin is wed to some extent These four antibiotics together with streptomycin have been used in many aperimental nutritional studios since 1850 and this Tbo trudo mamo of Loderlo Laboratories Divtalon, American Cynaamid Co., for chlor tetracycline b Aureomycin t Tho trdo Date of Chur. Pilzer & Co, for orytetracyelloo is Tanmaydn. ANTIBIOTICS IN NUTRITION | 13 ·-CH2CONHCH-CH ] (Chale CO-N CH COOH Benzylpenicillin NH2 NH-C NH CH, HOCH CHO CH HEN HN CH CH C-NH-CH CHOH O 1 CH) CHO CHOH CH NHCHE HCOH CH 1 BOCH CH CH2OH CH3 Streptomycin CI CHE OH N(CH3)2 -OH OH -CONH2 OH 0 OH O Chlortetracycline CHE CHOH Ņ(Chsz OH OH CONH, OH 0 OH 0 Oxytetracycline Fre 1 Structural formulas of peoklito G (berry penicillin) streptooryan, chbartetor Cycloc, cod czytetracyclitoa 14 | ANTIBIOTICS HONOGLAFHS ·monograph will bo largely concerned with a review of these studics. The struotural formulas of chlortetracycling oxytetracycline, streptomycin, and penia- Un are shown in Aguro 1 Their distinctive structural chemistry excites interest to tho blochemical mechanism by which such widoly differing mbstances in hibit bacterial growth while not injuring the host to which they are adminis tered. The other antibiotic that is used as a supplement to feeds, bacitracto is e mixture of complex polypeptides. Bacitracin A has recently been reported by Craig und co-workers to bave the structuro SCH Isoleucine co phenylalanine – histidine - Aspartic leucino Add glutamic acid Isoleucino :- Orolthino - lyzino - isoleudno It is nephrotoxic when injected' but appears to bo absorbed very poorly from the gastrotntestinal tract. The antblotics are a group of soluble orgadlo substances that aro produced by microorganisms and that are characterized by their property of inbibiting at low concentrations the growth, activity or multiplication of other maro organisons Antblote liko mbstances aro also produced by tho flowering plants and by animals Such plants u garlic, hops, and tomatoes contain antibacterial compounds termed respectively "allime, lupulon, and "tomating," whilo lyrokymo, a protein with antibacterial properties, is present in egg whito and in the secretions of the eye These substances aro not included among tho antibiotics because the definition of this term is restricted to compounds that are produced by microorganismos Howover the extensive occurrence of antlbacterial sub- Hunces in more complex organisms serves to emphasizo their widespread nature. This is a useful reminder of tho fact that tho Introduction of small Чатtities of antibiotics into the diet of animals is not necessarly an entirely novel procedure. The discovery and development of the useful antibiotics have been based on expirical peening procedures that were designed to find an antibacterial substance that was harmless to animals It may be presumed that such a substanco must block certain essential enzyme systems in the bacterial cell without apo preciably affecting any of the essential systems in tho cells of the host. Tho 1 ANTIBIOTICS IN NUTRITION | 15 ·mechanism of this blochemical selectivity has been studied from various stand points. There may be differences to the blochemical mochanisms of bacteria As compared with animals so that it is possible to block the metaboliom of a pathogenic microorganism without harming the host, or there may be difer onces to pannaablity to thet an injurious substance can enter the bacterial coll but not the oolls of the host. Penicillin has been reported to exert it toodo effects on microorganisms only mder conditions where theft growth is possibla 10 Celot found that penicilin fnhibitod the formation of combined glutemato fn Staphylococcus aurow cells while peptido glutamato accumulated in the medium Bedincin wu found to behavo similarly to penldllin.11 In contrast, chlortetracycling and chloramphenicol tended to fohibit tho formation of tho peptido rather than the uptako of glutamate. Penicillin has also been found to produce changes in tho mo tabolian of Ducloc edd.1 Stroptomycn appaen to inhibit the onloscetate. Pyruvate condensation in Escherichia coli and Umbrelt et af havo muggested that animal cells are not similarly affected because they are less permeable to tho antibiotic. Other blochemial reactions in the bacterial cells wero unaf fected even by high concentrations of streptomyofn. It is ovident from these and other opamples that differences between tho antihlotla caist with respect to their antibacterial mochanisms as well as to their chemical structures. Tho only known biochemical property common to tho antblotics under consideration is their antibacterial effect They do not for anamplo, al poses a singlo and distinctive chemical group, which might bere a growth promoting effect on animals. The strong tnference to that any such effect is secondary to the antibacterial action of antibioties on the microorgiions in the digestivo tract Before the discovery of the growth-promoting effect of antblotlas on ant mals, many fnvestigations were made of the results produced by adding out fonamides to purliod diets It was found that under such conditions de cancios of blotin, folic add, and vitamin K were procłuced. 11-1However these deidondos did not appear when these three substances were added to partiled diota or when nts recefvod diets of natural foods to which sulforumides TVEID addod. The results were taken to indicate that rats were able to obtain a supply of blotin, folo add, and vitamin K from a nondietary source when the rats were maitatood on a purlied diet that was deficient in these three vitamins and that this nondietery source originated in a bacterial fermentation that took place in the intestinal tract. It could be deducod that sulfonamides could do press or change the fntestinal bacteria for a manner that interfered with the production of these vitamins, which vo Deoded by the host animal Horrever 16 | ANTIBIOTICS MONOQIAPHS ·the sulfonamides do not loteriero with the assimilation of vitamins that aro added to the diet. The reason that deficiencies of biotin folic acid, and vitamin I developed was because they were not added to punied diets for rats, slace deficiencies of theso vitamins had dot appeared before sulfonamides were added. In contrast, thiaminc riboflavin, pyridorine and pantothenic acid wero added to the diets because if these additions were not mado deficiencies developed a cn in the absence of sulfonamides. The concept of a symblotic relationship between animals and tho bactorla In their gastrointestinal tract is an old one. Tho studies with rats on diets with sulfonamides emphasized this relationship and experiments with ruminants shoued that these animals WTTC even more versatile, for it was found that they could largely disperse with certain water-solable vitamins, which were shown to be produced by fermentation in the rumen 10 Furthermore simple oltrogo- Nous compounds such as urca, can be transformed by the rumen microorgankins Into amino acids, which could replace part of the protein requirement of ruminants. In contrast with these benefical activities of the microorganisms of the digestive tract, there are many familiar examples of pathogenlo bacteria and protozoa that can lovade the alimentary canal to produco clinical disease Tho sulfonamides and antibiotics have made somo of their greatest contributions to medicine for controling enteric diseases produced by organisms of this typo A few investigators in tho 1910s described aperiments with rats and chicks in which antibacterial substances produced increases in tho growth rate of tho animals. Martin" found that the mortality of young rats was provented and their growth rate was increased by feeding 1 mg of sulfanilamide dally but It was not clear whether an infection was present Mooro and co-workers found that succinylsulfathiazolo and streptomycin increased the growth of chicks on a purified diet. Theso authors made the foportant suggestion that the dietary supplements tohibited intestinal bacteria that were producing todo materials or weto rendering certain dietary vitamini unavailable to the animal, but that the possibility that tho agents were actlog systernically could not be overlooked. Morehouse and Mayfield found that 3-nitro-4-hydroxyphonylar solo add increased the growth of chicks and turkeys when added to natural dicts. This observation was made during studies of the coccidiostatic effect of this substance. A pharmacologic study of chlortetracyclino by Hanned and coworkers' led to an observation that the addition of this antibiotic to the det micreased tho growth rate of chick The effect was attributed to the elimination of some infection. All these studier in which the growth rate of animals was Improved by antlbacterial substances appeared to indicate that the effect was ANTIBIOTICS IN NUTRITION | 17 ·due to suppression of harmful microorganisms, and indood such an effect would not be surprising in view of tho association of weight loss with clinical disesse. Nevertheless, the possibility had been suggested by Mome and co-workert that uidentified intestinal bacterla could have an fohlbitory effect upon growth without causmg clinical disease. Investigations in oor laboratory which were first reported to 1019 4* showed that a growth-promoting effect was produced in chicks when crudo prepare tions of Streptomyces aurcofaciens cultures were added to the diet. These a periments were carried out with chicks that were being used to say the vitamin B1, content of S aurcofactenus fermentations. Tho chicks were appar ently healthy and were kept in cages that were frequently cleaned. Furtha more, the cages wero rilized Ath staum at four week intervals. Even with these precautions, the crude fermentation materials containing chlortetracycltoo produced more rapid growth than could be obtainod with crystallino vitamin B,2 or liver extract. Samples of the fermentation materials, which had been carmined to the chick growth test and had been found to contain the new growth factor wero sent early in 1949 to other fovestigators facluding Catron, Couch, Cunha, Kilder McGinnle, and Singsen, who confirmed tho observations during the rummer of 1949 and who alto showed that other species, such as turkeys and pigs, showed a marked growth response to the formentation mu tarials. The response was then found to be duo to the presenco of chlortetn cycline in the fermentation materials. Unespectedly small amounts of chlortot racycling and other antibiotics were found to produce an effect on growth.1487 These amounts were so small, 5 to 10 parts per million of diet, that it was economically feasible to mcorporate them in commercial dieta for fum inimale The nature and mechanism of the growth promoting effect produced in young animals by antiblotics hus erated the fnterest and attention of many vestigators and some of ther findings will be discussed to succeeding chapters 18 | ANTIBIOTICS HONOGRAPHS ·CHAPTER 11 Mechanism of the Antibiotic Growth Effect The action of antibiotics in increasing the growth rate of young animals may be termed for convenienco the "antibiotic growth effect. The most obvious explanation of the cliect is to postulate that it is due to the action of antibiotics on the intestinal bacteria. In support of this are the following observations 1 A number of difcrent antibiotics will produce the effect on growth but they have no special chemical properties in common Furthermore, their enti bacterial effects are cacted through different mechanisms It is thereforo un likely that these antibiotics would all have a stimulatory offoct on animal cells and it is much moro probable that the effect on growth is secondary to changes to the intestinal bacteria, since many of these bacteria are known to bo sus cepuble to the common antibiotics. 2. There have been many observations that the antibiotic growth effect may diminish ar disappear entirely when steps are taken to koop bacteria away from tho animals. Exceptions to theso findings have been noted. However if the growth effect is due to the direct effect of the antibiotio upon tho animals, it should bo consistently obtainable in clean surroundings which is not tho case. 8. Very little is known of the normal effects of the Intestinal bectorla on the nutrition of tho host animal. For camplo, it has been shown that feeding antibiotics brings about an increase in the storago of vitamin A in the liver.**.* and that a stmilor increase takos place when the animals are placed in a highly anſtary environment without antibiotics." This may imply that the effect on Vitamin A is secondary to changes in the gut wall, which tho antibiotic has produced by its action on the intestinal microflora, Indeed, such Bodings may be a clue to hitherto unrecognized blochemical activities of the intestinal 4 The growth promoting effects of certain antibiotics when injected may be due to their excretion into the intestine This has been shown to occur lo bacteria. ANTIBIOTICS IN NUTRITION | 19 ·calves moder conditions where growth was improved following of chlortetracyclhoe, 31 5. Tho antibiotic growth effect can bo produced by certain et do not readay enter the blood srcam who gtven by mouth T] streptomyun' and becitract. It is of interest that becitrea lus to produce e growth responso in chicks when added to the dietu b implanted subcutaneously for injected bacitraan bas been rep encreted in the utmot rather than the bllo so that it is possiblo the bactricía may not reach tho totestino. In contrut, much antibloti tetracyclino and penicillin, which have been found to produce sponses when infected, , # Haro known to be secreted into thoi tho blo. » & A large number of lavestigations have showa that antibiodh requirement for certain B vitamins fa taimals on dilets deficient in ming. The B vitamins differ from each other with respect to the che pbysiology but they share the common property of belog produ intestinal bacteria, and there aro indications that antibiotic-toleran these bacteria will produco lncreased amoumts of B vitrindas ** 7 Antibiotics diappear rapidly from the tower of enloals administration I stopped, " Howover wdar certain caperimental tho dletary effect of untibiotics in spartog vitamin B1, may persist! after their withdrawal from the diet thus suggesting that a firaly chango for the intestinal flora has taken place. & Soveral investigators havo reported that the growth of wsup. anfools gradually tends to improve from apartment to expertoest! where other animals so receiving antibiotics, bodicethog tho elim certain harmful bacteria from the environment 8 No growth effect was found when entblotics were trajected his ing chick embryogh er word fod to germ free chicha at lovels that the growth rate of contaminated anlmala 10 Tho beneficial effect of Antblotka on dietary lives necroots in to disappear after several woola of foeding, suggesting that the fol was due to a change in the Intestinal flors, which later became toler antibiotic to that the chango wus reversed." Tho Intives of Environmental Bocera as the Growth of Animals The effect of sudbiodies to improving growth of animals led to the ·sion that bacteria that inhibited growth might be normally present in the intestuoal tract. If this assumption utro COTTOCt, the inhibitory effcct should be absent in animals that are free from bacters, and such animals should not show a growth response to antibiotics. Evidence to test tho assumption was sought from several approaches from the concept of "discoso level, from comparing animals in "clean and heartly contaminated surroundings from measuring the growth of chich embryos, and from studying "gorm frco chicks and turkeys. The Discus Leocl Concept Experiments with S aurcofacket fermentation products in the diets of saine mere carried out to 1948 and 1950 by a number of investigators locluding Cunha ct al,Catron, 47 Terrill and Krider" and Carpenter - Striking effects were noted in the control of diarrhea and in the fmprovement of growth In many herds, bloody dlorthea was endemic and yielded to treatment with the antibiotic supplement so that the affliction largely disappeared and growth was markedly incrcased. These observations led to ad emphasis by various fnvestigators on the postulation that the antiblotto growth effect in pigs varied with tho discaso level,'' ken a term that was first totro duced by Catron," which he has defined as the degree or amount of feed lot contamination with bacteria or virus infostation that causes pigs to scour" The definition could probably bo extended to include other spedes of animals In addition to pigs and other pathologic manifestations in addition to dlar thee. This proposal is now well substantiated and it is supported by observa tions on other fum animals, such as turkeys, chickens, and calves It soems evident that certain subacuto infections can often occur in young animals and that these infections aro accompanied by slow growth and often by diarrhea. Certain antibiotics will relieve these conditions when added to the diet so that a marked Increato in growth rato is observed when antibioties are administered. However it is also evident that a somewhat less marked effect of antibiotics on growth can be produced in animals that appear to be healthy u fudged by : completo absence of external clinical signs It is not clear whether the growth promoting effect of antibiotics on these apparently healthy animals differs only qualitatively from the clfect of antibiotics on the growth of animals that are suffering from frank infections However the preponderance of evidence is that both phenomena are part of the samo picture and the effect of antibiotics m both cases is to eliminate harmful bacteria. Relation of Cloon and Dirty Endironments to tho Antiblotic Growth Effect The finding that a high disease level magnified the antibiotic growth effect in pige lands to tho possibility that the effect may disappear in animals if the bacterial contamination of the environment is kept low A report by Coates and ANTIBIOTICS IN NUTRITION | 21 ·to fitlate tho proliferation of a thriving and abundant microilor. Taken os 1 whole, the findings demonstrate that under somo sanitary conditions, and per hupu by chance, it is possiblo to stop certain antibiotic-rusceptiblo und growthdepressing microorganisms from becoming established in the Intestinal tract of esperimental animals. This is shown by tho fact that these animals IRY grow as well without as with antibiotic supplementation untill an outilde source of Infection is introduced. Horrever the random tendency of natural contamb nation can lead to a different result so that animals that are kept scrupuloutty clean may nevertheless acquire and harbor a microflora whose growth-depress ing action is eliminated by feeding an kotiblotic. The experimental findings to which antibiotics were fed to animals in clean and dirty environments have led to the conclusion that the antiblotic growth offoct may be due to the PUP premion of a growth-depressing microflora that is usually present in healthy Animals but that may sometimes bo absent under spodlal wanitary conditions Antiblotia and the Growth of Chick Embryos The doveloping chick en bryo grows rapidly in tho absence of an intestinal flora and its weight locreases twenty-four fold during the perlod between the seventh and soventoenth days of incubation. This is a greater rate of increase then takes place at any time after hatching We concluded that a living organim whore tigues wero prally Tablo U1 Wolght of Chick Embryos ot 17 Dayt as Affectod by Infections of Antibiota Amount Infostud Whole og Surrtral ratio Avoropo weight Embryo Gm Gm Antitolotic 12 19:30 54) 12.0 Chlortotrocycline Ponicilin 12 20.30 8.7 126 104 6.0 22.30 50.6 1.2 Stroptoarydn 20.30 $4.6 12.5 40 23:30 512 12.2 26.36 7 13.3 Nano ( dolod water) The antibiotic was duided into the equal desen, which wolofactod on turvo svetosivo day 24 ) ANTIBIOTICS HONOGRAPHS ·01 ctating to rapidly might bo usually sendtive to the cffects of a growth-stimo lating substance. Accordingly chichen eggs containing Hving embryos were injected with sterile solutions of antibiotics and the incubation period was continued. The injections were started on the seventh day and on the loven teenth day the cmbryos Neto separated from tho membranes and weighed." No growth-promoting effect of the antibiotics Hous found, and no evidence of toxelty as fudged by deformities or depression of growth was observed except that tho embryos on the higher level of penidlin WCTO SOnnewhat smaller than the others (tablo III) The results indicated that the antibiotics tested did not focrease the growth rato of embryonic tone and the observation helps to sopport the idea that the antibiotic growth effect is overtod through the intestinal flora, since these are absent from the developing chick embryo Lepino ad co-workers found that slight but consistent diminutions in the prolifera tion of chick embryo heart and long fibroblasts and epithelial cells in vitro WETO caused by chloramphenicol or chlortetracycline, 10 mg/ml. of culturo mediam. Higher levels of the antibiotics produced marked inhibitory effects on the growth of these tissuo cultures. In axperiments with brain Heue, 10 Ag/ml of chlorumphenicol and 100 pg/ml, of chloramphenicol ar chlortetra cycline Inhibited call migration while 10 ng/ml of chlortetracycline had no offect. Morphologic Change Produced by Ferding Antiblotlas Gordon" mado a number of comparisons of the morphology of gorm-freo chicks with chicks exposed to ordinary contamination, with and without antiblotic feeding Penicillin and oxytetracyclino were tho antiblotics that were used. A marked reduction, 33 to 50 per cent of the weights of tho small intestino was noted in tho germ froo animals and in the antibiotic fod conventional animals, by comparison with the conventional donantibiotic-fod antmals. Simultaneously thero was a less marked lacrease la tho weight of the thymus gland. No differenco between the antibiotio-fed and nogantibiotic-fed Germ-freo animals was observed with respect to the weights of those organs. The author concluded that antiblotlas created "germ-free-like conditions in the conventional animals It is indeed striking that without reducing the total bacterial count in the intestine of chicks the antibiotics will produce morphologic conditions similar to those in germ-froo animals. This observation points strongly to the probability that antibiotlosensitivo bacterla, which produce a tissuo reaction, are barmally present to tho digestive tract. ANTIBIOTICS IN NUTRITION | 25 , ·Tablo V Summary of Results with Gorm-free Animo's In which the Wolghts at 4 work with and without Antibiotic Supplomontation Wore Compared Lovol po kg of dlet ung No. of experiments showing Animals Increasod w Docroond met Antibiotic 45 Chiclas 0 1 70 Chicks 0 Streptomycin Straptomycin Penkullin Ponicillin 11 Chicles 0 1 1 11 0 Ponicillin 46 1 Ponldinn 46 3 2 Turkeys Chicla Turkey Chicks Turkey Chiclas 25 3 0 Oxytetracyclone Oxytetracyclino Oxytetracyclino 25 0 50 1 Talon Luckoy and co-workortth. 1 somowbat varlablo but tho overtall asperience with these two drogs tadiaated e nogativo response. The lovels of antibiotica in tho diet nungod from 23 mg. of chloramphenicol to 50 mg of orytetracyclino per Kg. of diet and tho number of chicks per experimental group was necessarily small ranglog from 2 to 6 Similar resulta proto obtatoed with turkeys which received 50 mg. of penicillin per Kg. of diet so that the author concluded that "no stimulation be seen when garm-free birds aro fed antibiotics" More recently Luckey found that in three out of four experiments with a lower lovel of orytetracyclino, 25 mg/Kg, of diet, the birds receivtog the antibiotic grow more rapidly than the unsupplemented birds and slight for creases in tho growth rate, 3 to 7 per cent greater than the controls, were noted to two experiments in which a lower level of penicillin, 11 mg/Kg, of diet, was fed while in three crperiments with turkeys receivtag 48 mg of penldlin par kg of dlot, the wedghts of the supplemented birds were respectively 1, 7 and 13 per cont bigher than those of the controls. Ho baferred that the difer ence between these and the earlier results was that the lovels of orytetracyclino 28 | ANTIBIOTICS MONOGRAPHS ·and penicillin used in 1952 Tero higher and thencforo growth-depressing How aer the small number of birds involved and the great variability in the indi vidual weights malo it impossiblo to arrive at a definito conclusion that a growth effect was obsertd at these lover levels of antiblotics It secins un Hhely that levels of 50 mg of oxytetracyclinc or poulaillin would have a specfic depressing effect on the growth of germ frce birds when much higher levels of these antiblotics do not slow the growth of birds under ordinary conditions. The variability encountered in these capcrtuents may bo seen in table IV in which the welghts of all the germ-frco birds receiving oxytetracy dide as described by Lachey are summarized. A condensed summary of the results doscilbed in Luckoys two commun! cations on antibiotics and the growth of germ free birds is given in table V Table V shows that the antibiotic-fed birds pero heavler than the controls at 4 weeks to 11 of tho 18 cxperiments. This would seem to lead to the conclusion that there was about an equal chance of the antibiotic increasing or decreas- Ing growth, and the over-all result appears to confirm tho conclusion reached by Luckey in 1952 Effects on Intestinal Flora Many studies have been made of the bacteriology of tho mtestinal contents of animals fed antbloties to efforts to throw some light upon tho antibiotic growth effect. The results havo varled greatly and Sloburth and co-workers? pointed out that variations may be due to diferent basal diets, different baoterlologic procedures, the age of the birds studied and the types and lovols of antbloties usod. Furthermore, their investigations showed that extremo varia tions in the cecal and fecal microflora were found oven from day to day Emmples of the differences Doted by various investigators may be soen in tablo VL These differences and to numerous that we hesitate to rovlow the Literature in detall or to attempt to draw generalizations with respoct to the various bacterial types Thus Kratzer and co-workersfound a five- to ten fold tncreaso in the number of yeasts in the cacheta of chicks and turkey poults fed streptomycin, while Williams and co-workersfound little or no change in the yeast count of chicks fed chlortetracycline Sieburth and co-workers' drew attention to the marked reduction in Intestinal clostridin produced by feedmg antibiotics and this was confirmed by Elam and co-workers and by Williams and co-workers " Hoiveer Williams and co-workers found that feeding live cultures of hemolytic toxdin producing clostridia did not reduco the growth of recetving antblotics, and do growth-dep essing effect was chicks that we ANTIBIOTICS IN NUTRITION | 29 ·found when cell-free clostridia torns were fed to oupplendented morų chicks fod antibiotics. Elam and co-workorso found that feeding fecal costat depraised tho growth of chiclo in clean quarters but not in old quartere hal: later communication, Steburth and co-worken” concludod that little cance could be attached to the observation that the tourin-producing close the are greatly reduced by antiblotic supplementation, because the populber these organismos is small in comparison with other types. These authors nota that a consistent reduction in tho numbers of bacteria was found caly 1 material obtained in the smell intestine and not in other regions of the end gestivo tract. They studlod tho orygen uptako end carbon diando erabie of the intestinal contents in vitro, and thoy found that theso values were lo ered in the case of chicks fed a supplement of chlortetracycline, perhaps o dicating a decreased use of nutrients by the microffore, which might peranto greater utilization of putrients from the diet by the host animal Tho mexcotort blood vessels along the small intestino wezo potod to be more dilated to the birds receiving tho antibiotic supplemented diet. Smyser and associategie found that dietary peniallin produced during weeks a steady increase in tho nambers of Clantridium perfringens in the face of chuck. This observation seemed to rule out the possibility that the ground effect was related to a suppression of CL porfringens Chlortetracycline pro duced only slight changes in the cormt. Another source of difficulty in carrying out investigations of the effectue dotary antibiotics on fatestinal bacteria La becense the presenco of the art blotic in fntestinal contents may provent the growth of the bacteria wote platod opt. 164 Foct on Rumen Microorganisms A oumber of lovestigators have made observations on the effect of ent' blotia on the ramen microflora. Loosll and co-workersloo did not observo u striking difference in tho total bacterial count or to the morphologlo typer bacteria present based on stained slide camination to studies with Holster calves fod chlortetracyclino. In esperiments with beef hatfars, Neumann adu co-workerslo stated that the types of organisms found to the animals recetas chlortetracyclino were much less diverso then to the controls, which suggested that tho normal bacterial flore had been disturbed. Kester and Knodiso found that rumon samples taken from calves fed arytetracyclioo showed coordstently lowerod ability to digest cellulose in vitro e compared with the samples from control calves. These differences diappeared when the entblotic supplemen 32 ) ANTIBIOTICS MONOGRAPHS ·# Indicalor microorganisms in the rumen when chlortetracycline was fed to dairy calirs. The supplemented animals weto superior to tho controls with respect to gains in body weight, feed intake, and cliiciency of feed otilization These investigators and hesier and Knodt reported that the antibiotio supplementation had no significant effect on the thiamine and rlboflavin levels of the rumen contents although Chance and co-workerslo found that the amount of riboflavin in the rumen contents has lower when 0.5 Gm of chlortetracycline was fed dally Uian when the antibiotic-free nation was fed. In another Investí gatlon Chance and co-horhersitº reported that a definito increase occurred in the total bacterial count of the rumen contents and feces when chlortetracy dine was included in the motion. The number of rumen streptococci decreased in the tivo fistulated animals that were used in tho study Horn and co-work ene, w in studies with ycarling steers, reported that the rumon contents of an! mals recehang chlortetracycline showed a decreased ability to digest Aber In vitro and similar observations wero made by Radisson and co-workers 11 how ever these investigators noted that, when alfalfa hay was added to the culturo medlom, no depresang alect of chlortetracycline on celluloso digestion oc curred, indicating that alfalfa hay contained a factor that provented chlortotra gelino from depressing the digestion of cellulose in vitro by cultures of rumen bacteria. It is evident that studies of cellulose digestion in vitro do not neces arily reflect the behavior of the rumen bacteria in the living animal Rusoff et al.1) did not find differences between control calves, chlortetracycline in- I fected calves, and those fed chlortetracycline orally with respect to the rumen contents. Measurements were made of plI and tho content of eight of tho B vitamins in the rumen fluid together with an examination of tho rumen flora and the degree of fiber digestion in vitro Lodge and co-workers114 found that the digestion of cellulose in vitro by the rumon microorganisms was lower in the case of cow that had received a daily supplement of 240 mg of chlor tetracycline from an carly age The presence of chlortetracyclino was demonstrated in the ramen liquid. Theso authors also noted that the addition of of chlatetracycline per ml of formentation mixture soverely inhibited cellulose digestion in vitro by the microorganisms from the control cows but liulo effect on tho digestion of cellulose by the microorganlams ob tained from the antblotilo-fed cows perhaps indicating the establishment of chlortetracyclino-tolorant cellulolytic microorganisms in the antiblotic-fed ani Huhtanen and co-workeryll havo described techniques for studying tho digestion of Abor in vitro by rumen microorganisms Depressions of the digestation was discootmund Hibbs and co-workerslae found changes in tho ratlogs L6 had very mals. ANTIBIOTICS IN NUTRITION ( 33 ·Omg to tion of fiber wero observed when antibiotics woro added However no depression of the digestion of celluloso es present in alfalfe was observed114 to result frat feodtog chlortetracycline to sheep thus recalling the results reported by Radissom,113 Studies of the effect of chlortetracyclino on the ruinen microorganismos WCTO reported by Mann and co-workers U7 The antibiotio was fod ta doses of 40 to young calves for several weeks following which the animals were slaughtered and the contents of their patches and abomasums were camined. Tho chlartetracycline-fod calves showed no marked bacteriologic differences from the controls and the authors commentod that there was little difference between the supplemented and control calves in the final elopment of typical viablo streptococcal population of the rumon Tho supplemented calves had larger and less acld rumen content than the controls and reached a runen PH that was considered to be sudtablo for fnterstvo some bacterial and protozoan action at a much earlier age Antiblotic tolerant Intestinal Microorganisms DI Q Source of Unidontland Orowth factors Following the addition of an antibiotic to the diet, microorganions that aro tolerant to the presenico of the antiblotic la cultura media may be recovered from the intestinal contents 110 One possible explanation of the antibiotic growth effect to antoals could be that these tolerant microorganisms produce vitamin like growth factors that to not present in suffdent quantities in the dlet to cable marmum growth of the host animal to take place and that are pot produced by the intestinal flare at a sufficient rate in the absence of antibiotics in the det. There have been soveral Investigations of this possibllity Kratzer and co-workers the found that the number of yeasts Increased five to tenfold in the intestinal tract of young hokeys that recevod streptomycin. Theo yeasts were plated out and grown in large flasks following which they were harvested and fed to chicles and turkeys There was no consistent growth response and, although slight increases were found in some asportinenta, they were loss than those obtained with antibiotic supplements A fresh attack on this problem was made by Romoser and co-workers100 who noted that E. coll and Aerobacter aerogenes increased to mumbers in the ceca of penicillin fod chickt. These penitllin redatant organisms vero isolated, grown in mes cultures under various candidons, and fed to chida. In soane erpartments the cultures were lyophilized Tho chids received basal drets that were considered suitablo for obtatning responses to unloor growth 34 | ANTIBIOTICS MONOGRAPHS ·factors.* Little or no chick growth responso was obtained when either organism was added to tho diet in tho absonce of an antiblotic but a significant growth response was obtained to penicillin alone and a greater response to the com bination of pealallin and cultures of tho organisms as dietary supplements. It was considered in view of the small amount (022 per cent) of the supplement that tho results wero due to cffects of tho viablo organisms rather than to unidentified growth factors in the cultures, and the possibility was raised that the organisas alded" the antibiotic in roducing the number of Inhibitory in testinal bacteria. However do experiments with heat inactivated cells were included Along smiler lines Anderson and co-workeri'l 19 in Isolated varlous strains of E. colt from penialia fed chicks and fed the cultures to other chick CDs. Ono strain of E coll produced a growth response in the presence of peni cillin but not in its absence whilo a second strain somewhat improved growth under both conditions. In another experiment only one out of five supplements, the culture filtrate, Increased the growth rate of the chicks and then only in the presence of penicillip Similar preparations were testod with turkey poult but no dgnificant wedght increases were found except that responses were obtained to penicillin itself in a further reports the conclusion was drawn that the growth response of chicks to antibiotics was associated with an increase in intestinal coliforms becauso the growth response and the fncrease took place simultaneously Roberts has reported that the growth of chicka was increased by ether E coll or fish solubles and Blaylock and co-workors11 found that elther of these supplements produced a growth increase of 11 per cent in chicks during the first thrco weeks. The control diet for such espeti ments ought to be supplemented with the anfermented culturo modium, for the medium may contain supplements that improve the diet Tho coroparatively small growth responses that are obtained with experimental animals when sources of unknown factors such as bacterial and yeast cultures, are added to the diet present certain difficulties of laterpretation Much depends on tho basal diet that is used to evaluato "unknown growth factors in materials such as Ash solubles, liver yeast, and distillers solubles. The diet should bo completo and balanced with respect to the known growth requirements of the anlmal, fo doding amino acids, vitamins, and minerals. Recently Scott et all and Couch and co-workers 14 have found that chicks will show a growth response to the ash of certain sources of unknown growth factors and similar results have been obtained in our laboratory There is no evidenco that antiblotic-adapted forms of E. coli or other intetinal bacteria are better sources of nutritional factors than those bacterial forms that normally inhabit tho intestinal tract. ANTIBIOTICS IN NUTRITION | 35 ·The results with E coli and other intestinal organisms when fed to either antibiotic-supplemented a unsupplemented animals indicate that cultures of these organisms will not consistently produce a growth responso when added to the diet. Furthermore, when feeding the culturo produces a growth respariso in the absence of antibiotics in the diet, the responso may be less than the response to adding an antblote. It is possible that antblotic-tolerant status of Intestinal organisms may displace harmful bacteria from the digesthio tract The fnvestigations just dtodis, 1probably indicato that beneficial nutritional offocts may be produced by antibiotic-tolerant intestinal orgulans Growth of Animals Rocalving Hydrolyzod Panldilo The offoct of penicillamine (B B-dimethyloysteine) on nats fod a low-choline diet was desalbod by Wilson end du Vigneaud. 19 They found that tho L isomer was tordo and Its fofurlous effects were counteracted by cholino and ethanol amine. The D-Isomer which is a hydrolytic product of penicillin, was not to do Experiments in our laboratories with chicas showed only a slight growth response to an enzymatic hydrolyzato of penicillin (tablo VII) The responso appeared to bo not moro than 10 per cont of that given by tho umhydrolyzed antibiotic. L-ponídlamine was found to depress growth markodly when added at a lovel of 3 Gm./kg. to a purtiled diot containing choline. Elem and co-workers123 reportod that peniallin, Inactivated by autoclaving, produced a growth responso when injected into chicks but not when added to Tablo VI Effod of Procaine Ponkilla and panid tuinose-Hydrolyzod Poniatima, on the Growth of Chiclo Supplement por ka of diet Gm Weights at 25 days Gon Nono 226, 229 329 324 306, 125 2 mg procalne pondlun 5 mg procalno peddlin 5 mg hydrolyzed peidlin 10 mg hydrolyzed ponkalln 277 282 278 294 Thoro wore 10 chicla in each of duplicato group 36 | ANTIBIOTICS MONOGIAPHS ·Table V71 Microbiologk and Chick Assays of Ponkilin in Food Por cont of ponidlin romaining Microblologic Chick assay assay Treatment of food Shamed 5 minutes 43 64 46 Stected 15 minutos 21 29 56.50 14 Steamed 30 minutes 18 20 20 32 30 23 29 12 19 Storod 2 woals at 34 C. Stored 4 wuela ot 34 C Stored 4 weeks at 34 Ct Storod 4 woelos at 34 CI 48 67 17 40 Dibonzylothylonodomino penkalan Procaine pantallin two different comples the diet. An examination of their results show that the response with the infected hydrolyzato was obtained in ono axperiment but not in a second experiment Fell and Stephenson 189 reported that openicillamino produced a growth responso when fajected but not when added to the dlot howover in their ar periments peakslin did not produco a growth response when added to the diet Taylor and Gordon 16 carried out 3 experiments with pigs in which peni chin toactivated by three different methods was compared with activo peni cillin for its growth-promoting effect on pige. The pigs receiving penicillin grow at a rate of 143 per cent greater than the controls and with inactivo penldllin the growth rate was 94 per cent more than the controls Na penici- In was detected in tho gut, serum, or urine of the esperimental animals. Williams and co-wocherzli found that inactivated penicillin retained not more than a small part of the ability of tho original antibiotic to promote the growth of chicks It was found possible to plot e dosage response curve to lovels of penicillin on a purified pucrose-casein dlet so that feeds containing penicillin could be usmayed with chicks Chid dlets containing 25 of 50 mg./kg of peni cillin were stored under various conditions or steamed and wero assayed microbiologically and with chicks. The rates of faactivation of penicillin were ANTIBIOTICS IN NUTRITION | 37 ·very similar when measured by either procodure us shown in tablo VIIL The chick Asteys gave slightly higher values but there were rather wide variations to the chick assays. The conclusion from the results in tablo VIII is that the hydrolyzato did not have more than a small portion of the activity of the original penidlin when tested with chicks. It is possiblo that hydrolyzed peni diin, oven though inactive for the test organism Micrococcus pyogeno var aurous, might retain some slight activity against some of the intestinal bacteria Recently we have compared the growth response to poplalin and D-penidemboo with chicks on the sucroso-casaln diet and D-pondellamino was famd to produce a growth response correspondtag to about 3 por cent of that Produced by procaine penicillin. Effects of Prolongod Usage of Dletary Anttbloties Reduction of the Antibiotic Growth Efect Following the Prolonged Up of Antblotlar to Diets When antbloties aro routloely wed in the diets of miomls, ono can speculato that prolonged use, year after your might produco selectivo changes in the environmontel bacteria so that antibiotio redistant formas would gradually become more common. If somo of these resistant bacteria wero path ogenlo or barmful, then one would expect that tho Rotblotic growth effect would disappear and that animals would grav at a rato corresponding to the rato seen in simlar animals before the introduction of antibiotio feodłog Actually tho recorded observations have been to the opposite direction and tho prolonged use of antblotics has often resulted in a gradual fomprovement in the growth rate of unsupplemented animals to quarters where antiblodies have boen routinely used for soveral year. Perhaps certain growth-dopresetog bacterial farms tend to disappear from the environment to that the increased growth rato of animals is oventually seen to both the supplemented and unsupplemented groups. It is also posible that anttblotio-resistant becterla may produce increased quantities of certain midentified growth factors. Tho pool slbikty of an environmental clean-up duo to antblotio foeding came to our attention to 1949 and 1850 when the response to anůbiotics in chicos in our laboratory appeared to diminish over a Img soules of copertments, although tho chicos receiving antiblotio supplements continued to reach a Freight of 300 Gm or moro at 25 days Walbel and co-workerslot compared the weights of chicks at 8 weeks of with the percentage growth response of chlortetracycline or penicila to a series of experiments lasting from August, 1850 to July 1953. The quantitative response to antibiotics tended to vary frversely with the growth of the control 38 ) ANTIBIOTICS MONOGLAPHS ·+4아 +30F +20 PERCENT GROWTH RESPONSE TO ANTIBIOTIC o + to o mo ofo O lo -10 2T3 200 so WEIHT OF BASAL AROP AT THREE WEEK-ov FIGURE 2 groups and the average weight of the control groups in the third yer of the study was greater than during the first two year. A wide variety of diets was used. A scatter diagram of these results is in figuro 2 Libby and Schalbleia summartzed their findings with 3.900 chicks in 146 comparisons between groups of birds that wero fed antibiotics or arsonic acids and groups that received the wsupplemented control diets. Tho rerults are shown in tablo IX. A steady increase in growth rate and a decrease in mortality of the imsupplemented birds wero noted. The authors pointed out that the results do not support a concept that tho continued use of antiblotics in feeds can lead to tho proliferation of resistant strains of organisms that can cause antibiotics to become ineffective lastead, the authors state, the continuous use of antibiotics over a long period produces an environment with a lonored arm load or disease potential. After long time usage these growth TOTOtants ANTIBIOTICS IN NUTRITION | 39 ·Tablo LX Growth Rosponses to Dietary Anitbloties and Assonk Acids in Succesetre Years Compared with Control Group In Exqporlmonts with Chiclans Increase in weight of fupplemented birds by Increase in comparison with control wolght of conbirds, % trol birds with roupoct to 1950 Antiblothes Antonke odds 1951 control, 46 Mortality to 6 whes. of oge % Porlod 1956-1951 14.0 (2) 0 8.5 1951-1957 7.4 B.2 190 (15) 12.8 (32) 100 (4) 3.3 (19) 1952-1933 15-3 4.6 3.8 (5) 32 (9) 1953-1954 191 2. Takon from Libby and Schable Number of comparisons de parentheses are still capable of suppressing tho gorm load, but less of a challenge Ls prosented. Thus, binds that are grown on the premises whero birds have or havo had antibiotics or artonlo acids in their feads benefit to some atent from the Improvement in environment Tho reduction in the mortality of chicks that we have observed during tho last 4 yr adds support to the postulation that a reduced gern load develops. As can bo soen la column 5, prior to the inclusion of antibiotics and arsenioals for chick nations, the mortality of battery-raised chicks up to 8 wk of ago was about 8.5 percent, whereas the mortality of birds to theso sanno batteries in recent years has declined to less than 3 percent. In addition, ferver oull chicks and less variability in growth rate within pens are now boing noted. *From the practical point of viow this study indicates that antibiotics and arsonic adds would be of greatest value in promoting growth (1) when first used in a poultry-feeding onterpriso end (H) under the cuvironmental condi- Hons usually marrounding farm feeding If once used and then discontinued, feeding performanco may still be somewbat improved, because tho contamina to lovel has been lorrered." Experiments with pigs havo also shown that the growth of unsupplemented controls may tend to improve from year to year in murroundings whero anti biotics are fed, thus Catron has found in en published summary of x fivo 40 | ANTIBIOTICS MONOGRAPHS ·year study (1949 to 1953) involving 690 pigs that the average daily gains of antibiotic-fed pigs fn successive years were 1.04, 100 100 1.67 and 157 lb, uhllo the contesponding figures for imsupplemented pigs wero 133, 1.44, 158, 1.57 and 1.57 lb Hanson and Ferrin"" obtained the following results in fuccessivo years with prodaning pigs kept from weaning to 200 lb in the dry lot. The baml diet was changed somewhat between 1851 and 1853 so that the results from one y car to tho next were not directly comparable however tho results indicated that the general use of antibiotics for thrco years had controlled certain Intestinal infections so well that these infections wero not a prob. kom in 1853. A similar trend is indicated in a report by Richardson!! who used individually fed Lettermato plgs in four successive capements each of which lasted between 14 and 21 week. The average dally galo in pounds of the un supplemented controls roso from 1.38 in 1852 and 1953 to 1.61 in 1934 while the correspooding groups that received chlortetracyclino gained respectively 16, 20 8 and 4 per cent more than the controls in successive experiments thus showing a decrease in the antblotic growth responso duo to improvement by the unsupplemented controls. No responde pus obtained to oxytotracycline. These caperiments with chickens and pigs in which tho anublotlo growth effect wu shown to diminish in a series of experimets to tho samo rearing quarters while the growth of tho unsupplemented controls improved aro of great interest. The results indicato that the antibiotic growth effect is not due to a direct action on the animal but is due to a suppression of harmful bacteria and that the antibiotics or their effects may becomo "spread around the animal quarters so that the suppression may gradually extend throughout the Tablo X Rosults in Successivo Years with Promaning Plas Kopt from Weaning to 200 lb in the dry lot124 Avorage daily gain lb 3 to 8 weeks Whhout antibiotic With antiblotic Weaning to 200 iba. Without with antibiotic antibiotic Year 1951 0 37 0.64 140 1.63 1952 0 43 071 143 1.63 1953 0.63 073 1.74 1.79 ANTIBIOTICS IN NUTRITION | 41 ·premises. An additional possibility is that certain antibiotlo-tolerant bacteria, which become established through tho use of diets containing antibiotics, may have a beneficial effect on nutrition. Clearly it is time to question the soundnes of the diro prediction that the prolonged fooding of antibiotics would ezt courage the widespread development of resistant strafns of dangerous bac terla13 fn tho poultry rearing industry From the practical standpotat, the effects of feeding antibiotics to growing farm animals for prolonged periods have led to the spected benefits in the elimination of certain ondemio types of undlagnosed morbidity Slinger and Pepper la noted that syndrome involving poor growth, high mortality dermatitis, and diarrhea to young turkoys was overcome by the uso of antibiotics and furthermore, that this syndrome, which was ono of the major problems involved in rearing pou In Ontario, has largely disappeared following the inclusion of antibiotics in cortunercial dietu. The continuous administration of streptomycin and orytetracyclino at high lovels (0.02 and 0 04 per cent) on the diet of aged rats, beginning at the age of 11 mooths, was not found to be beneficial es regards longevity in studies by Franch et al. 144 The Averago life span of the supplemented animals of both poses was docreased by about 10 per cent. It was thought that, by analogy with thor results on high fat dlet, an increased efficiency of food utilization might havo been responsiblo for tho doleterious effoot. However an cumination of the rosults indicates that tho difference in tho lfo spen between treated and comtrol animals did not reach significance at the 5 per cent loval. No beneficial or deleterious effects of the antblotc supplementation were shown by gross and histologic examination. 42 | ANTIBIOTICS WONOGIAPHS ·Effect of Feeding Antibiotics CHAPTER 11: On the Requirement for Nutrients Improvements to the utilization of protein and of certain vitamins and minerals have been noted to be associated with the feeding of antiblotla in some experiments. These improvements are separate from the antibiotic growth effect, which bos been obtalaed on diets that were adequately furnishod with the known requirements for growth and to somo cases also with additional amounts of certain vitamins and sources of growth facton' such as liver Antibiotics have been shown in Dany Investigations to enhance the uhina tion of certain putrionts, shown by a lower requirement for the nutrient for the production of marmum growth in tho presence of the antibiotic, by a greater growth response to the antibiotic at ruboptimal lovels of the nutrient than when an optimal loval of the nutrient is supplied, by a greater growth response to a small increment of the nutrient in tho presence of the entbloto than in Its absence, by fcreases in the touo lovels of the nutrient, or by it increased urinary excretion or deposition in the egg when tho antiblotio was fed. It appears in the case of some of tho vitamins that antibiotics improve their uptake from the gut or thetr synthesis by tho intestinal bacteria, or both. It also oppears that the uptake of calcium and manganeso may be improved by anti bloties In the case of the protein requirement, the dtuation is moro obscure In some investigations it has appeared that tho protein requirement or the requirement for a speciio amino acid for madnon growth was lowered by adding Antibiotics and in other no protelo sparing effect was noted. These differences may roflect variations in the intestinal bacteria of the animals in the various esperiments. There is a large amount of experimental evidenco that establishes an effect of antibloties in Improving the efficiency with which food is cooverted to an ANTIBIOTICS IN NUTRITION | 43 ·Increase in body wolght in growing animals. This effect may be an indicata of an improvement of the uptake of various natrients from the intestinal tre and this to turn can lead to measurable effects of dietary antiblotias on the roquirement for protein, vitamins, and energy depending upon the mame in which the postabsorptve utilization of tho nutrients takes place. Effects on Vitamin ond Minorol Roquiremont B Compla Vltamin Emerson and Smith 19 produced a blotin deficiency te rats by adding streptomyca to a purified diot. This deficiency can also bo PC duced by adding sulfonamides to purified diets for rate. Streptomycin appear to differ from somo of the other antibiotics in this effort. In 1918 we made a unsuccessful attempt to produce folic acid deficiency in rats on a purifled die by adding a high lovel of chlortetracyclino. The first preparations of antiblotics that were widely used la anbnal feed contained chlortotracycline and vitamin Bus and the response that this combina tion producod In Roimals on "all vogoteblo" diets led to the wldo Impression that there wou sourio interrelation between the antſbloto and vitamin Bua In the growth response In romo fnvestigations It was shown that an antiblotio appla ment had a sparing offect upon the vitamin Bua requirements of chicks or pſg but in other axperiment tho growth response to the antibiotic and the vitalo appeared to be independent of each other Sparing effocts on other vitamtos wcro repartod by many investigator Common and co-workery140 found that blood lovels of riboflavin and cul. chum to chicks were fncreased when chlortetracyclino was fod, perhaps indicating that the absorption of theso substances from the intestino was improved by tho antibiotic. Biely and March"4 reported that chlatetracycline had a sparing effect on iboflavta, niacin, and fallo add to the growth of chico Saude evtdence for a sparing effect of chlortetracycline on the riboflavin requirements of chickus on purified diets was noted in our laboratory“ Oleson and ca workedy14 found & sparing effect of chlortotracycline on the vitamin Bu rom quirements of chicks whillo Stolstad And Jukeylo found that chlatetracyalino roduced the vitamin By requirement of chicks in some experiments but that in others. The high martality of young chicks associated with a deficiency of vitambo Bra was reduced by feeding chlotetracycline. Walbol and co-workerriti found that penldilla or chlortetracycline markedly increased the growth of chick fed diets containing suboptimal amounts of thiamine, but, when tho lovel of thiamine to tho diet was adequate, the growth response was ovely slight, thus indicating a spering effect on the thiambre requirement Tho 44 ) ANTIBIOTICS MONOGRAPHS ·anthors suggested that synthesis of thiamino by the intestinal flora might have been improved by the antibiotic. In another publication Waibol and coworkers16 observed that the addition of penallın to tho diet of laylng hans resulted in locreased deposition of blotin and follc acid in the egg yolk Liniswiler et all45 Doted that mis on inadequato lovels of pyridodne showed a somewhat greater growth response to chlortetracycline then rats on adequate levels of the vitamin, thus indicating a sparing effoct of tho antblotic on the requirement of vitamin Be Theso Investigations were extended con siderably by Lib and Batmann147 who compared the growth promoting offects of various antibiotics for rats on diets deficient in B vitamins Tho orpurimental data were not condusive because the growth promoting effects of the antibiotics were in most cases measured only at suboptimal levels of tho vitamlos however in the case of pantotheplo acid there was como evidence of a sparing action Chlortetracyclme was found by McDaniel and Daft118 to accentuato the signs of vitamin B, deficiency fi rats whillo penicillin had a bencidal effect on growth and survival and in reduciog tho severity of dermatitis This is in contrast with the findings for chlortetracyclino soported by Linkswller et al 1+ Coates and co-worker, 14 studied tho vitamin requirements of chicks on purified diets deficient in the wrious meanbers of the vitamin B complex as Influenced by the addition of pencillin to the diets No sparing offoct was found for thiamine, nboflavin, Pyridoxne, or pantothienlo acid but tho require ments for blotin und follo acid were reduced. In the case of niacin, tho require ment appeared to be increased. Nelson and Scott160 found no effect of chlor tetracycline or penicillin on the niacin requirement of chicks on a purified diet. They noted that tho antibiotic growth effect diappeared when the diet was severely defident to placin, which was in contrast with our findings, ** although we noted that the antibiotic growth effect disappeared or was greatly diminished when chick were soverely deficient in riboflavin, pantothenic acid, or folic acid. Tho food intake is extremely low mader highly doficient conditions so that very littlo growth takes place Sarottin found that the anal administra Hon of 4 to 6 Gm. of streptomydo dally was followed by a marked decrease in the urtoary eaction of blotin in human subjects The effects on the cxcration of other B vitamins were variable and not marked. The quantitativo urinary cecretion of certeln products of tryptopbano metabolism was not changed by the administration of streptomycin. In studies with rats, Halovy and coworken 162 found that streptomycin reduced tho urtnary excretion of folic acid and blotin. Tho follc acid content of the liver and the amount of biotin in the contents of the oecum were reduced Varying effects were produced by the other antibioties chlortetracycline had a slight sparing effect on nlacho, follc ANTIBIOTICS IN NUTRITION | 45 ·aad, and biotin, oxytotracycling, on nladn and follo add, but do offects on the requirement for these vitamins were found for penodlin. In en investiga time by Sauberlicht on the requirement of weanling rats for certain B vita mins, sparing effects on the requtrement for thiamino and pantothento acid were obtained with chlortetracycline and penicilin and the requtroment fa pyridadne was spared by penicillin as fudged by the fact that marked growth responses were obtafood to tho andblodies on the deficient diets while their Inclusion in tho completely vitamin supplemented diet had no effect upon growth of the animals. In contrast, sulfametazine depressed growth on both the supplemented and deficient purified diets. Schendel and Johnsonll studied the offects of penicillin and chlortetracycline op nuts rocelying suboption levels of thiamine and pantothenic add administered both orally and subcutaneously Markod increases in growth wero produced by tho antiblottes and the growth responses were absent when the dicts were adequately supplemented with thlamine and pantothenic add. The results were not affected by tho modo of administration of tho vitamins. The amount of pantotheofc adid in the intestinal contents of rats on the deficient diet was increased when chlortetracyclino was given Along similar lines, Chot and co-oor ker?found that the oral administration of any of several antſbiotics increased the apparent formation of vitamin Bue by the intestinal bacteria as indicatod by a rise in the butanol-solublo radioactive fraction following the administration of cobalten The effects of antibiotics on the requirement of animals for vitamin B1 Lavo been studied with varying results. Soveral reports havo shown definito lmprovements produced by feeding antibiotics on the hatchablity of hens eggs or on growth of rats, chicks, or pigs when the animals were fod Big deficient diets while in other investigations no changes were produced. Johansson and co-workersh? 14 found that growth responses wero produced in rats by adding chlortetracyclino and vitamin Bus singly or in combination to a diet defident in vitamin Bua Tho responses appeared to be independent of each other and no Increase in the apparent vitamin Bis content of the kidney and liver time was produced by feoding chlortetracycline, but increases werd found, not unexpectedly when 25 mg/Kg, of diet of Bus were added of interest was the observation that chlortetracyclino produced increases in the vitamla Bes activity as determined with E coll 113-3 in the supernatant liquld obtained by ruspending the contents of tho color and cecum in water sod centrifuging off the solids. However E coll 113-3, responds to cobalt-containtng Bislike substances that will not alloviato vitamin Big defidency in animals Cravioto-Munoz et alih found that chlortetracycline produced a marbed growth response in rats on a Burdeficient, purified diet to an extent that lead 46 | ANTIBIOTICS MONOQIAPHS ·these authors to state that chlortetracycline could replace vitamin B1, in tho diet of the mat. Autoclaved chlortetracyclino was loeffective No unsupple mented group was included. The effect of antibiotics on the vitamin B1, requirements of pigs has varied in different aporiments. For example Catron and co-workersbe found that chlortetracycline and vitamin Bs, both increased the growth rate of pigs on a com-soybean diet and that the growth response to the vitamin was the same In the presence of absence of the antibiotic, whllo in another investigation 10 vitamin B12 produced a 14 per cent growth increase in the absence of chlor tetracycline and no increase in its prosence. Sheffy and co-workers,14 in a study with baby pigs on a semisynthetic milk, recorded the following daily guins no rupplement, 0.26 lb vitamin B1, 0,38 lb chlortetracycline 0 40 lb Bu plus chlortetracycline, 047 Ib These results indicated a sparing effect of chlortetracyclide on the vitamin Bus requirement. On the other hand, baby pigs that were highly deficient in vitamin Bis did not show a growth response to chlortetracycline in a study by Wahlstrom and Johnson, 16 Monson et alto made an interesting study with chicks that received diets containing insufficient amounts of folic acid, which were supplemented with antiblotics They found that collform organisms, which produced increased amounts of cellular folic acid in vitro appeared in the duodenum and lleum following the administra tion of antibiotics. Simultaneously the folic acid content of the liver of the chicks was increased. This may bo a further indication that antibiotic-resistant Intestinal bacteria aro in part responsible for the beneficial nutritional effects of dietary anúbiotics. It is ovident from various investigations already described, which may be theo u representative of the large volume of work to this field, that dietary antiblotios in many cases improve tho nutrition of animals with respect to the B vitamins, but in other cases the antibiotics are without any effect on the B vitamin requirement. A few exceptions have been noted, especially the case of streptomyco which appears to reduce the synthesis of blotin in the in testino. Antibiotics Improve the production of B vitamins by the intestinal bacteria or the absorption of B vitamins into tho blood stream. Sorne effects of dietary antiblotics lo modifying the requirements for animals for B compla vitamins were expected in view of the well known relationship of the intestinal and rumen microflora to synthesis of these vitamins, There was loss basis for specting an effect on the utilization of minerals and fat solublo vitamins However esperimental work soon uncovered such relation ships Vlamin A and Carotene Burgess and co-workers found that dietary ANTIBIOTICS IN NUTRITION | 47 ·penicillin improved the utilization of vitamin A and caroteno in chicks. Sig nificant increases were found in the vitamin A content per Gm. of liver and in the blood lovel of carotenolds when penidlin wus fed and the chicks werd compared with control birds at 28 days of ago. Along similar lines, Coates and co-workerslo noted that the liver storage of vitamin A was improved by foeding ponicllia to chicks and that the convoraon of B-carotene to vitamin A in the intestinal wall was increased. The same effects were produced by placing tho chicks in isolation units, which provented contact with Infections Further for vestigations in this fiold were made by Almquist and Maurer who employed a diet containing only vegetable sources of vitamin A activity in contrast to the diet used by Burgess and co-workers, which contained both carotenoids and fish of sources of vitamm A activity The findmgs are shown in tablo XI, llver Vitamin A was increased shghtly by the lowest lovel of ontblotio fed ad Tablo X VHamin A and Carotono in Chick Livers as Rolated to Fooding of antiblotka, 0 Supplement per Ko of dlot Liver Vitamin A U/Gm.) 8 wŁ 10 wk Livor caroteno wo./Gm.) 8 wk TO wk Average body wt Grm 8 wk 10 None 45 2.6 5.6 980 1363 55 94 31 7.6 989 13:39 4.5 mg antibiotic mlxturat 55 mg chlortetracycline 110 mg chlortotracycline 115 8.8 1070 73.87 113 115 4.8 7.2 1076 1446 *Practical diot containing only plant sources of vitamin A actitty approximately 11 | U/Gm. Chlortatracydino plus ponidiin higher lovels led to further clovations for both liver vitamin A and carotena. It was concluded that maintenance of a healthier intestinal condition in the presence of an antibiotic was responsiblo for improved convenim or absorp Hon of carotene or both. It is of interest to compare the effect of antibioties to proventing liver necross, an effect that is also produced by vitamin E, with that affect on vitamin A metabolism. Vitamin E has boca roported in rooma 48 | ANTIBIOTICS MONOGRAPHS ·investigations to improve the utilization of vitamin A, possibly by protecting it against oxidation. No sparing effect of chlortetracyclino on vitamin A was found in caper! ments with rats by Hartsook et alte and chlortetracyclino appeared to enhance the vitamin A deficiency syndromo when added to a diot free from the vitamin, A3 fudged by earlier appearance of the sgos of the daficiency and a shorter time of survival. In contrast Muray and Campbells found that the addition of chlortotra cycline to a vitamin A free dłet for rato increased their response to graded doses of vitamin A acctate. The man increase of many tests was 24 per cent The effect tras also observed when chlortetracyclino applomentation was begun 24 hours after the last dose of vitamin A, which mado it appear that tho improved utlization was not due to an increase in absorption of vitamin A from the intestine. The timo required for depletion of the liver stores of vitamin A was lengthened by dietary chlortetracycline The storage of vitamin A in tho llveru of pigs fod various supplements was measured by Barbes and co-workenz.10 They found that on the basal diet tho livers contained 128 units/Go. of vitamin A, with chlortetracyclino added, 193 and 19 6 units/Gm. with peniellin, 131 units/Gm. and with a misturo of penicillin and streptomycin residuo 13.2 units/Gm. Chlortetracycline but not penicillin increased the liver storage of vitamin A Penicillin wu found to produce Incroases in the vitamin A content of the Liver of chicks on a normal diet and to increase tho lovels of carotenoide, ascorbic edd, and phospholipid phosphorus in their blood plasma. 144 High" found that chlortetracycling, 50 mg/Kg, of diet, tncreased tho deposition of vitamin A from caroteno la the liver and kidnoys. Rats receiving 80 mg. carotene as tho solo source of vitamin A dopositod 80 mg, of vitamin A In tho liver and widneys while chlortetracyclino-fod rats deposited 63 mg Tho storage of preformed vitamin A was not affected by the antibiotic. Penicillin had no eflect on storage of vitamin A from carotono-fed rats. Theso results ure slollar to those reported by Barber and co-workers with piggi lo that chlortetracycline but not penicillin increased Ilvet vitamin A storago on diet containing carotene The results with chicks differ for both Coates and Burgess reported increases in tho lives vitamin A of chicks following the addition of penicillin to a diet containing carotene. Vitamin D Calcium and Phosphorus Investigations by Ross and Yacowitzi* indicated that penicillin appeared to decreaso the vitamin D require moat for normal bone calcification. An Increase in bono ush of chick at thrco woek wu observed to be produced by adding penidhiin to a diet containing ANTIBIOTICS IN NUTRITION 1 49 ·pealcllin improved tho utilization of vitamin A and caroteno in chicho. Significant increasts wero found in the vitamin A content per Gm. of liver und in the blood level of carotenolds when ponicillin was fed and the chicks ao compared with control birds et 28 days of age. Along omflar Iones, Coutes vod co-workers to noted that the liver storago of vitamin A was improved by feeding ponicillin to chicks and that the conversion of B-caroteno to vitamin A in tho intestinal wall pes Increasod. Tho xme affects were produced by placing the chicks in Isolation units, which prevented contact with infoctions. Further tovestigations in this field were made by Almquist and Maurer who employed a diot containing only vogotable sources of vitamin A activity in contrast to tho diot used by Burgess and co-workers, which contained both crotenoids and fish ofl sonerces of vítamín A activity The findings are shown in tablo XI liver vitamta A wus increased slightly by the lowest level of antblotio fed und Tabl. XI Vitamin A and Carotone In Chick Livon os Rolatod to Feeding of antibiotic Supploment per kg of diet Livor vitamin A LU/Gm.) Awk 10 wk Livor caroteno (40./Gm.) 8 wk. 10 wk Arorogo body w Gm 8 wk TO wk 45 83 2.6 5.6 980 1363 55 94 3.1 76 989 1389 Nono 4,5 mg antibiotic mixturot 55 mg. chlortetracycline 110 mg chlortetracydino 715 &.8 1070 138 113 115 48 7.2 1006 1446 *Practical diet containing only plant sources of vitamin A oddvity approalmatoly 11 | U/Gm. Chlortetracydine plus pontilin. higher lovels led to further clevations in both liver vitamin A and carotena. It way concluded that maintenance of a healthier fintestinal cooditour in tho presence of an antibiotic was respondble for tmproved conversion or absorp- Hon of carotene or both. It is of interest to comparo the effect of antibiotics to proventing liver necrosis," an offect that is also produced by vitamin E, with their effect on vitamin A metabolism. Vitamin E has been reported to como 48 | ANTIBIOTICS MONOGRAPHS ·Per cent tovestigations to improve the utilization of vitamin A, possibly by protecting it against oxidation No sparing effect of chlortetracyclino on vitamin A was found in experi ments with rats by Hertsook ot alll and chlortetracyclino appeared to onhanco the vitamin A doficiency syndromo when added to a dict free from the vitamin, as fudged by earlict appearance of tho signs of the deficiency and a shorter timo of survival, In contrast Murray and Campbelli found that the addition of chlortetra cycline to a vitamin A free diet for rats increased that response to graded doses of vitamin A acetate. The mean Increase of many tests was 24 Tho effect was also observed when chlortetracycline supplementation was begun 24 hours after the last doso of vitamin A, which made it appear that the improved utilization was not duo to an tractcase to absorption of vitamin A froan tho Intestine Tho time required for depletion of the liver stures of vitamin A was lengthened by dietary chlortetracycline. The storage of vitamin A in the livers of pigs fod various supplements was measured by Barber and co-workery 10 They found that on the basal diet tho Hvers contained 128 units/Gm. of vitamin A with chlortetracyclino added, 19.3 and 19 6 units/Gm. with penicillin, 191 units/Gm, and with a mlituro of penicillin and streptomycin residue, 13.2 units/Gm. Chlortetracycline but not penicillin increased tho liver storago of vitamin A Penicilin was found to produce fricreases to the vitamin A content of tho liver of chicks on a normal diet and to increase the levels of carotenoids, escorbic acid, and phospholpld phosphorus in their blood plasma l High1's found that chlortetracycline 50 mg/Kg, of diet, incroased tho deposition of vitamin A from carotene in the livor and kidneys. Rata rocciving 80 mg. carotene u tho colo sourco of vitamin A deposited 50 mg of vitamin A In tho liver and Wdnoys while chlortetracycline-fed rats deposited 63 mg The storage of preformed vitamin A was not affected by the antiblotic. Penicilin had no effect on storage of vitamin A from caroteno-fed rats. Theo results are slotlar to those reported by Barber and co-workers with piggle in that chlortetracyclino but not penicillin increased liver vitamin A storago on a diet contaloing carotene. The results with chicks differ for both Coates and Burgess reported increases in the liver vitamin A of chicks following the addition of penicillin to a diet containing caroteno. Vitamin D Calcium and Phosphorus Investigations by Ross and Yacon witzi indicated that penicillin appearod to decrease tho vitamin D require mont for normal bone alcification. An Increase in bono ash of chicks at thrco works wus observed to bo produced by adding penicillin to a dlet containing 144 ANTIBIOTICS IN NUTRITION | 49 ·suboptimal levels of vitamin D These results mey bo compared with earlier observations by Migicovsky and co-workertler who found that penicilio bere creased the uptake of caldum" when fed to chicks on a low calcium diet Gabuten and Shaffer le found that dietary penicillin facrossed the breaking strength of eggs and the blood calcium lovel fn hans and Bogdonoff and Shaffner 1" roported that chlortetracyclino, cuytetracycline penicilin, and bacitracin increased the plema caldum level of male chicks when added to a diet containing 26 per cent calcium. Penicillin was also fed with lower levels of calcium and was found to increase the plastia calcium lovel. Lindbled and co-workers?to found that the growth response of chleb and tukoy poults to chlortetracyclino was greater or higher than on lower levels of calchum and phosphorus. Blanganexo Motabollsm. Manganeso is needod for growth and the proven tion of a bone deformity tarmed "perosis in chloks and poults. An affect of chlatetracyclino on the utilization of manganese was described by Pepper and co-worker. 191 They found that the amount of manganeso requtrement to pro veut porosis in chicks was lowered by adding chlortetracycline at a lovel of 10 mg/kg of diet. Effod on Protoln Requirement A largo number of caperiments have been carried out to ſavestigate the offoct of dietary antblotics on the level of prototn required by poultry and swine for medmum growth. Tho economic fimportance of this question is obvlous, for the supply of proteins af high biologic valuo may Ilmit tho numbers of poultry and plgs that can bo produced on a nationwido bads. In some a partments it was found possiblo to produce marimum growth with slightly lower lovels of protein in the presence of dietary antiblotics than in thetr absence. Other Investigatioos bavo indicated that no difference in the protein requirement was produced by feeding antibiotics, Tho proten requirement for maximum growth of chicks was found Machiin and co-worharyin to bo 19 per cent with a diet containing chlortetra cyolino and 21 per cent {f tho antibiotic was omitted. Weakloy and coworkerrin concluded that badtracin, chlortetracycling, and penicillin all had a sparing effect on the protein requirement of chicks Chlortetracycline and penldllin nero found to improve the growth of chickens at four different levels of protoin, and there was evidence that the om of both protein kod Indicator the energy was improved by tho antibiotics, but 50 | ANTIBIOTICS MONOGRAPHS ·protein level for maximum growth was lowered. 114 Scott and co-workergini concluded that in their experiments the protein requirement of chicks was not changed by addiog 15 mg of chlortetracycline per Kg of dict. Growth and nitrogen retention wero measured in chicks on various lovels of protein with and without penicillin by Saxena and co-workers. 1T6 The increase in weight that accompanied ponidillin fceding was the same at all lovels small but not dgnificant increases in nitrogen retcntion were found in the birds roctiving the penidlin supplement at the lowost lovel of protein (15 per cent) Turkeys showed an improved response to penicilin us tho lovel of fishmeal in the diet was increased 15 and tho greatest feed cibciency was obtained with penldllo and tho bighest level of fishmeal. Slinger and co-workers!deducod that tho requirement for lysino was increased, simultaneously with the growth rate, by adding antibiotics to a diet containing 20 per cent protein. The lysino dei clency which manifests itself in young turloys by the appearance of whito feathers was not seen when the antibiotic-upplementos diet contained 28 per cent protelo. Biely et allt' found that chlortetracycline and penicillin did not affect the protein requirement of chicks or their requirement for lyzing or tryptophano bat did reduco the mortality on the tryptophanodefident diet. Matterson and co-workerslº found that chicks fed a ration containing chlor tetracycline required at least 21 per cent of protein for best results as measured by growth and feed offciency There was no indication that the antibiotlo reduced the protein requirement. Whilto-Stevens and Zelbelin approached tho problem from the standpoint of the lovels of both protein and antibiotic. Their results with chicks showed that 10 parts per million of chlortetracyclino was more effective as judged by growth on tho low than on the high protein diet, whilo higher lovels of chlortetracycline were most off at the higher protein lovels, the optimum being 22 per cent protein with 100 parts per million of chlortetracycline Studies with pigs have led to retults very dmilar to those reported for chick. There is somo evidence for a slight lowering of the protoin requirements for matnum growth, but in many experiments tho antibiotic growth effect has been observed at varytng protein levels without ovidenco of interaction. It has also been noted that feeding an antibiotic may improve nitrogen retention. It is customary in fcoding pigs to reduce tho protein content of their diets stepwise daring the growing period and this practico complicates an evaluation of the effect of entblotic supplementation on protein requirement. Catroo and co-workerslo investigated the effects of chlortetracycline on the growth of pigs receiving varlous levels of protein from weaning to 200 lb The results are summa ed in table XII Each protein level was reduced by step of 3 ANTIBIOTICS IN NUTRITION 1 51 ·Table XII Rolation of Chbostonocycline 10 mg/lb of Dhet on Average Dally Galn and Food Unitization in Growing Pos* Initiat 200 Chlortot Avoropo daily wt gain, b. racycline In diet Initialt-75 75-150 150-200 AY Feed dolly par 100 L gain Proton levek of gain 20 to 17 to 14 1.21 1.81 1.51 390 + 1.31 179 194 1.68 354 18 to 15 to 12 - 1.29 1.58 1.81 1.56 383 + 1.28 1.73 2.03 1.66 360 16 to 13 to 10 1.26 1.67 2.02 1.63 372 + 1.34 1.83 1.8.0 1.67 355 14 to 11 to 8 1.23 1.64 1.54 1.50 374 + 1.26 1.84 1 88 1.66 359 *The protoin loves of the dists were lowered when tho play reached a walalt of 75 b and again when the wolghts roochod 150 b 162 Sbartoon plos por group Initial weight 299 to 37.5 lb per cent when the pige reached 75 lb and again at 150 b In the absence of chlortetracycling, the rate of gala for the entre feeding period varied signifcantly among tho several groups of protein Levels, and the results indicated that to the presence of the antibiotic the protein requirement was lowered 40 that tho pigs receiving succesve lovels of 14, 11, and 8 per cent of protetor to the presence of the antibiotic gained as well as those receiving higher lovels of protein fo tho absenco of the antibiotic. The asperiments were carried out with Daroc pigs on a diet conslatog predominantly of corn and soybean meal. Jensen and associatelo fed protein lovels of 10 12, 14, 16, 18, and 20 per cept, with and without 8 mg of chlortotracycline or orytetracycline per lb. of diet, to pigs weightag 31 to 36 l, until tho pigs reached a weight of 200 Lb. The 52 ) ANTIDOTICS MONOGLAPHS ·Table XIII Increased Growth Roto In Rots Fod Chlortetracyclino with Soybean Dlob Avorogo dolly gain (Gm.) Row soybean Heatod soyboan moal moal Malos Fomalos Malos Femalos Supplement/100 Gm. diet None 0.42 0.78 2-36 1.85 1.50 1.29 2.60 233 Chlortotracycline 20 mg DL-methionine 0.5 Gm. Chlostetracyclino plus mothlonka 2.33 17 3.36 2.58 3.02 2.01 4.02 2.40 averago daily gatos of the pigs appeared to reach a maximum at betworn 18 and 18 ра cent protein without antibiotics and at 14 per cent protein with antibotics, but the effect was not statistically dgnificant Effects on Nitrogen Motabolism Streptomycin was found to have no effect on the utilization of food protein In rata by Black and Bratzler 1 An al-vegetablo diot supplemented with vitamin B12 was used. In another studyle supplament of antibiotics was used at a lower level. 10 per coat, of dietary proteln, and again no effect was found on the nutrogen retention of paired fed rats duo to the supplement. The utiliza Hon of energy was improved by the antibiotics. Carroll and co-workerslm. 107 fnvestigated the effects of chlortetncyclino and methionine on the utilization of nitrogen in diets containing either raw or heated soybeans when fed to rats. The amount of nitrogen absorbed from the diet during passage through the small intestino was increased by chlortetra cyclmo but not by methionino The Antbloto also improved the absorption of lysine leucine, methionine and cystine. A marked increase in grouth rate accompanied the feeding of chlortetracycline us shown in tablo VIII107 The lower availability of methionine in raw us compared with heated soybeans is well established. The authors concluded that a sparing action of chlortetracy clino for dietary methionino was suggested by these results, either due to an ANTIBIOTICS IN NUTRITION | 53

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·CHAPTER IV Antibiotics in Animal Production The theoretical and experimental etaminations of the mode of action of antibiotics give way to practical considerations when the effect of these substances in the dict is measured in terms of animal production, and it is in this field that antibiotics have made ono of thetr greatest contributions Tho steady Increase of the human population makes it incumbent on chemical technology to furaish means of increasing the supply of food. The use of antblotics has bocreased the supply of meat by lowering the death losses of young farm and mals and by improving the elidency of conversion of feed into meat. Las sdteri* stated that the feeding of entblotics to farm animals has brought about & new era in livestoch production. The following appraisal of the effects of antibiotics on swino production is summarized from an article by Catron. 107 The practical effective feeding lovel of suitable antibiotics for swine is apprordmately 5 mg/lb of food and therapeutic lovels commonly used in treating disease uro 30 to 100 times us high. Antblotias aro effective in either dry lot of pasture feeding Their uso increases growth rate by 10 to 20 per cent from weaning to 200 lb mder average feod lot conditions with an increase in feed consimption of 5 to 10 per cent and a saving of about 5 per cent of feed required per unit of gain in growing and fattening pigs Antibiotic produce tho marmum growth response when fed to young pigs and the increaso in Gulos in plgı weighing from 100 to 200 lb is less When antiblotlo feeding is discontinued after pigs reach 75 to 125 Tb cessation of accelerated growth rato occurs and the growth rate tends to follow that of the control anlmnls however tho plg previously fed antibiotics maintain their early growth advantage The number of runts is reduced and the uniformity of pigs receiving antibiotics is Boveral times greater than that of unsupplemented controls. The response to antibiotic feeding appears to bo in proportion to the disease level the practice controls a high percentage of nonspedfic enterits (scours) in swine but coro- ANTIBIOTICS SN NUTRITION | 57 ·Tablo XV Effect of Chlortetracycline in the Presence of Chronic Respiratory Disease in Chica Plouropneumonla-like Inoculum applied Ay wt., Gmy at 4 wk when chlortetracydino added, Gm./ton 50 100 327 349 338 Nono (control) Inoculum applied 283 324 348 Tho roduction wou evident in the weights at 4 weeks except on the higher lovel of chlortetracycline (tablo XVI In an experiment under commerdal conditions where chronla respiratory disease was endemio in which 5000 birds were used in each to two groups, the results at 10 weeks uo shown in tablo VI. Various treatment u shown below were usod in a flock of chickens to which signs of chronic respiratory disease appeared at the ago of 6 proeba while the birds were on a diot containing 4 Gr./ton of procaine penfalm. Tho floch was divided into five groups each with about 4000 birds (tablo XVII) The results are of great interest in that the efficiency of feed conversion * much lower in group 1 (unsupplemented) than in group 4 which grow at the Tablo XV Effect of Foeding Antolotics on Chlebo with Chronic Gospiratory Disease AY Wt Por cont mortality Gmfood/ Git gain Supplomantton of dot 10 68 1.30 111 4 Gm. procaine pentettiin 4 Gm. procalne ponke in plus 100 Gm chlortetracycline 2.82 1.40 2.81 Thoro won 5000 chicos used in each group. 60 ANTIBIOTICS MONOGRAPHS ·Table XVI Results with various Lovels of Chlortetracycline on Chica with Chronk Respiratory Disease Gm, of chlortetracyclino addod/ ton of det Ay final wty kg Mortality Gm food/ Gm gain 6 to 8 w 8 to 12 wk Nono Nono 1.49 109 475 100 1.63 6.1 2.90 200 200 1.57 51 3.57 100 5.7 3.69 100 70 mg /liter in drinking water None 1.56 7.8 3.86 Ame rate, indicating that the effect of the antibiotio was to improve the utiliza tion of outrients, rather than to increase the appetite In other experiments, tho food to tako per unit of body wolght per day was about 20 per cent lower to groups receiving high levels of chlortetracycline than to controls. The findings by White-Stevens and his collaborators indicato the effect of a subacuto diseaso to depressing the rato of growth and the utilization of nutrients by chids and the action of chlortetracyclino in reversing these nutritional sequcbuo of the disease Antiblotla In Swino Production Migs under farm conditions have been shown to be outstandmg among domestic animals in growing moro rapidly and officiently when small amounts of antibiotics, especially chlortetracycliac, aro added to the dict A comparison of various antibiotics, summarizing work published in 1950 to 1953 was made by Braude and co-workerses and tablo XVIII, which has been published elsewhere," was condensed from their roviow It may be seen from tablo VIII that chlortetracycline, orytetracycling pencilin, and streptomycin have given the best results in promoting the growth of swine Erythromycin was reported to produce no response 10 ANTIBIOTICS IN NUTRITION | 61 ·Table XVIII Growth and Effidency of food Utilization of Pigs Rocotring Various Antibiotics Fond required per unit of water (Ursupplementod= 100) Growth bodex (unsupplemented=100) Antibiotic 1359 90.2 (146) (44) 110.6 943 115.2 (187)* ( 53) (50) (23) (12) 94.4 123.7 Chlostotracydino Ponicillin Stroptomycin Oxytetracydino Bactradin Chloramphenicol Noortydn Polymyan Subton 93.9 (17) (10) 1090 103.0 105.5 98.7 93.3 87.6 96 100 (1) (1) 89 13.0 (1) * Figures in parentheses Indicato number of comparisons. Dried wholo cultures and fermentation rondues containing chlortetracy clino and vitamin Bua wero supplied by our laboratory early in 1919 to investie gntors who were engaged in studying the nutrition of swine. Markod growth rospouses, associated with the provention of diarrhos, were soon observed and woro communicated to w in the runner of 1949 by Catron, Cunha, and Kolder The effectiveness of the chlortetracyclino fermentation realdue was contrusted with the lack of activity of a vitamin Bza concentrato from the streptomycfo fermentation in a publication by Cunha and co-workers" Further publications appeared in 1950.76, 97 4 10 BT The effects of the applement lo abolishlog scowing, and in producing its most markod effects whoro bloody dlarrhea was rampant, promptly lod to the establishment of the disease lovol concept es an Interpretation of tho antiblotte growth response in pigs. This concopt has been reloforced by the observation that the response to pigs has progressively di minished in many laboratories where antibiotics vo fed, while tho growth of unsupplemented pigs has improved and the incidence of diarrhea has lesened. 62 | ANTIBIOTICS MONOGRAPHS ·Many of the diets used in tho cxperiments with pigs vero defident vitamin B1. and consisted predominantly of corn and soybean mcal so that the growth responses obtained to the crude chlortetracyclino fermentation materals was due to both vitamin B12 And tho antibiotic. Experiments with crystal line antibiotics and vitamin B12 soon established that both supplements were needed for optimum growth of pigs. The use of antibiotics in diets for baby pigs, such as creep feeds and artificial milk, was found to be cspecially benefical In preventing mortality and producing rapid early growth. Carpenters found that baby pigs receiving a creep feed containing chlortetracycline grew 43 per cent moro rapidly than controls and Wahlstrom and co-workers found that chlortetracyclino la creared the growth of baby pigs on a purified diet by 31 per cent. No effect was obtained with penicillin. Similar results wero formd by Noland and coworkers and by Williams and co-workers.530 Rutiness or unthrifttnets in young plgs may often be successfully treated or prevented by adding antibiotics to the diet. *1 *In ono Investigation 4 unthrifty pigs that were fed a diet containing 11 mg/Kg. of chlortetracyclino gained three times as much wedght to a fivo work perlod es did tho unsupple- Idented controls. The effect of the type of protein concentrate on modifying the growth response to antibiotics in pigs has been studied by soveral favestigators. In the first published investigations with pigs, Bumsido and co-workomst found that the crudo fermentation containing chlortetracyclino and vitamin B12 produced a markedly greater responso lo pigs when peanut meal was used as compared with either soybean meal or fishmeal Barber and co-workerslo fowd that the response to antibiotics was much less on a diot containing fishmeal than ou en all vegetable diet and stmílar findings were described by Robinson et al. *** These findings may be related to sparing effects of the anubloties on the roquirement for amino acids. Becker and co-workers found in contrast to tho work by Barber and Robinson that the growth response of pigs to chlortetra cycline or to a mixture of antibiotics was greater with menhaden fishmeal than with soybean meal as the supplementary protein. In the absence of antblotic, tho pigs showed a growth response to tryptophane when added to the cornfishmaal diet thus raising the question of a possible sparing effect of the anti biotic supplement In other investigations, the response to antibloties varied with different sources of protein but no consistent trend can be perceived and Do doubt the results depend to some crtent on variations la tho nutritional quality of the various amples of meal that were used. *34 The effect of implanting pellets of antiblotes on the growth of pigs was ANTIBIOTICS IN NUTRITION | 63 ·w r Tablo XVIII Growth and Emdensy of Food Utilization of Pigs Receiving Various Antibiotics Food required Antblotic Growth Index (unsupplomonted = 100) por unit of pain (unsupplommented = 1 1359 90.2 (146) 110.6 94.3 115.2 (187) (53) ( 50) (23) (12) 94,4 Chlortetracydine Ponledon Streptomych Oxytotracycline Bacitracin Chloramphenicol Noomycin Polymyxh Subtiin 123.7 93.9 103.0 (41) (17) (10) 109.0 105.5 98.2 93.3 87.6 (3) (1) 96 100 (1) (1) 89 130 *Roures In parentheses Indicato number of comparisont Dried wholo cultures and fermentation reziduos containing chlortet clino and vitamlo Byg werd applied by our laboratory early in 1849 to toy gators who were engaged in studying the nutrition of swine. Marked gr responses snodated with the prevention of diarrhce, were soon observed pero communicated to us in the summer of 1919 by Catron, Cunha, and Er Tho offectiveness of the chlortetracyclioo fermentation residuo was contra with the lack of activity of a vitamin Bng concentrato from the streptoc fermentation in a publication by Comba and co-workers ** Further publica appeared in 1850 , 17 th $0 31 The effects of the supploment fo abolis scaring and to producing its most markod effects whicro bloody diarrhes rampant, promptly led to the establishment of the disease lovel concept Interpretation of tho sotiblotlo growth response to piga. This concept has relnforced by the observation that the respondo in pigs has progrestrel minished in many laboratories where antibiotios are fed, while the growi supplemented pigs has improved and the incidence of diarrhea bus lesse ·Alany of the dicts used in the experiments with pigs were deficient in vitamin B17 and consisted predominantly of corn and soybean mcal so that the growth responses obtained to the crudo chlortetracycline fermentation matorials was due to both vitamin Bus and the antibiotic. Experiments with crystal Ime antiblotics and vitamin B12 soon established that both supplements wero needed for optimum growth of piges The use of antibiotics in dlots for baby pigs such as creep feeds and arti fidal milk, was found to bo especially benefical in proventing mortality and producing rapid carly growth Carpenter found that baby pigs receiving a cTtep feed containing chlortetracyclino grow 43 per cent more rapidly than controls and Wahlstrom and co-worken found that chlortetracycline in creased the growth of baby pigs on a purified diet by 31 per cent. No effect was obtained with penidlkn. Similar results were found by Noland and coworkers and by Willems and co-workers. Runtiness or unthriſtiness in young pigs may often be successfully treated or prevented by adding antibiotics to the diet. 91 934 In one fnvestigation #1 unthrifty pigs that were fed a diet containing 11 mg/kg of chlortetracycline gained three times as much weight in a five week period as did the unsupplomented controls. The effect of the type of protoln concentrate on modifying the growth response to antibiotica in pigs has been studied by several tovestigators In tho first published Investigations with pigs, Burnsido and co-workery's found that the crudo fermentation containing chlortetracyclino and vitamin Buy produced a markedly greater response in pigs when peanut moal was used as compared with either soybean meal ar fishmoal Barber and co-workerslo found that the response to anubiotics wu much less on a diet containing flahmeal than on en all-vegetablo diet and stmllar findings were described by Roblason et alt These findings may be related to sparing effects of tho antibiotics on the roquirement for amino acids. Becker and co-workers found in contrast to the work by Barber and Robinson that the growth response of pigs to chlortetra cycline or to a mixture of antibiotics was greater with menhaden fishmeal than with soybean meal as the supplementary protein. In the absence of antibiotic, the plgs showed a growth response to tryptophane when added to the com fishmeal diet thus malsing the question of a possiblo sparing effect of the anti blotic supplement. In other investigations, the response to antblotias varied with different sources of protein but no consistent trend can be perceived and no doubt tho results depend to some extent on variations in the nutritional quality of tho various samples of meal that were used. 0134 The effect of implanting pellets of antibiotics on the growth of pigs was ANTIBIOTICS IN NUTRITION 1 63 ·lambs appeared in 1851 when Jordan and Bell found that chlortetracycline promoted the growth of lambs and decreased onterotoremla. Many investigaton of antibiotics in the foeding of ruminants, conducted for the most part with chlortetracycling, wero published to the years between 1951 and 1955. Reviews have been written by Knodt and Lapter 11 Chlar tetracyclino has been reported to increase the growth rate, feed consumption, and effidency of foed utilization of young calves and lambs and to reduce the inddence of certain diseases including scoun, pneumonia, and lfver abscesa In calves, and enterotoxemia in lambs. With older riminants, digestivo upsets have sometimes been encountered, but it is often possible to forestall these by rogulating tho composition of tho ration and the dosage of the entblotic. The most marked effects have been found with unthrifty animals, Chlartetracycling and other antibiotics have boon found to dopress the digestion of cellulose fa vitro by mired cultures of rumca microorganisms, but such effects do not seem to be evident in the intact animal. Effects on Dairy Caloos Marked focreases in the rate of growth of dairy calves during the first 5 or 6 months of Hfo have been observed by various investigators when chlortetracyclino was added to the nation. Tho most marked effocts wero observed in calves which were housed in comtaminated quarters where the incidence of scount was highbut responses were also obtained by Bartley and co-workers when the msupplemented animals were gutning at a normal rate. Two levels of chlortetracyclino were compared, 15 mg. 45 mg/day and the highor lovel was found moro effectivo la promoting growth and to reducmg tho incidence of various types of infections. In further studies, to lovols of 45 and 80 mg of chlortetracycline vero compared and wero found to be oqually effoctivo in reducing the fncidenco of infections. Much Lerger doses, 200 to 800 mg of chlortetracyclino per 100 lb of calf weight, wero fed to calves without produciog aportda or weight loss or any other violblo detrimental offects and ono calf not provlously supplemented, was given 25 Gm. of chlortetracycline dally botween 16 and 20 woels of ago without deleterlous offocte Many investigations with chlortetracyclino in the dlots of dafry calves have been carried out by Rusoff and co-workers. ith 4. EH IM The antblotte was found to increase tho rato of gate of both Jersey and Holstein calves by 20 per cent over that of the control animals through 10 weeks of age Comparisons woro made between aral supplementation and Intramuscular Injection and the tajected animals were found to grow more rapidly than those receiving tho antibiotic arally These observations led the anthors to consolado that the mode of action of chlortetracycline in producing the antibiotic growth response was not due to an effoct in the rumen because od 66 | ANTIBIOTICS MONOGRAPHS ·the injected antibiotio was shown to be present in tho bile and not in the rumen contents. At autopsy the animals receiving chlortetracycline showed larger skeletal size and more meat than did the controls This was thought to lodtcate that the antibiotic was producing an effect on the pituitary gland. The authors wero unable to detect any chlortetracycline to the pituitary pleen thymus, and muxalar tissues so that it is difficult to implicate tho pltuitary gland on the basis of these studies No effects on tho yield and composition of the milk were produced by feeding supplements of 130 mg of chlortetra cycline dally to datry courtoi por were physiologic effects produced when chlortetracycline was fed to bulls at a rate of 300 mg dally ** A decreaso to thickness of duodenal and fejunal sections of the Intestinal wall and an to crease in the leal section were found in calves receiving chlortetracycline ** Richardson and co-workerst found do growth-promoting effect of chlor tetracycline when given by intramuscular injection to datry calves. Tbo gains in 4 weeks werd &2 b for un supplemented calves, 120 lb for calves receiving two levels of oral chlortetracycline, 90 lb for calves Implantod subcutaneously with chlortetracycline, and 82 b for calves tojected intramuscularly with chlortetracycline It was noted by Roy and co-workers that the beneficial effect of colostrum on calves appeared to be related to tho provention of scouring. Accordingly the effects of chlortetracycline and colostrum were compared in experiments in which 40 cakes were used, and was found that tho calves receiving chlortetracyclmo without colostrum wero protected against scours in a man ne that resembled the effect of colostrum when fod without chlortetracycline The authors made the interesting suggestion that colostrum might bo impor tant for its antibacterial effect. The feeding of chlortetracycline to colostrum. deprived calver Increased live-weight gain significantly and reduced the inci dence of scouring and the occurrence of abnormally high rectal temperatures. Colostrum fed alves behaved similarly to tho chlortetracyclino-fod calves when compared with unsupplemented controls. No effect op milk production and feed consumption was found when chlor tetracyclino was led to mature lactating dalry cows which received 130 mg dally for 30 days, 300 to 500 mg daily ** or 700 mg, dally for 10 dayx Tho untblotic was not detected in the mill in the latter lovestigation. Antibiotics In Beef Cattle Feeding The addition of chlortetracycline or penicillin at high levels ranging up to 600 mg dally to the nations of beef cattlo was found in earlier lavestigations ANTIBIOTICS IN NUTRITION | 67 ·to be followed by various effects tocluding a loss of appetite, a depression the apparent digestiblity of crudo Aber and a decrease in nitrogen te tiol. 11,31 * Such apparent digestive disturbances were noted to dkope when the feeding period was prolonged 10+ In later tovestigations it was for that chlortetracyclino was tolerated better when fed at lover lovels and the diet was high la roughego, thus Toyrea ** found the following averaged gains in an esperiment lasting 90 days with 20 beef cattle par groep in E the inital weight of tho animals was about 080 lbs, when chlortetracyano given in doses of Q, 72, 90 and 108 mg per animal per day the averago gain was 276 3.19 3.11, 300 lb, respectively In a secood experiment, an supplemented group gained 261 lb. dally per head, a group receiving 80 of arytetracyclino dally 265 lb and a groop receiving 80 mg, of chlorte cyclino daily 281 Ib. Matsushima and co-workerr** found that calves which were fed 15 mg chlortetracyclino dally grow more rapidly than control calves and wore from scouring which occurred frequently in the controle. Tho calves slaughtered at 75 to 10 months and 80 per cent of tho supplemented cal had normal livers a compared with 10 per cent of tho controls, 70 perc of which had abscessed livers, presumably from Infections which mate through the portal circulation. Perry and comprar kert*** observed a mark decrease in the incidenco of cours when chlortetracycline was fed at mg/100 lb of body weight dally to beef calves. The dally gain wus 1.78 In the supplemented group as compared with 1.59 b for the controle dar the 80 day experimental period. In tho samo investigation, the effect of chl totracycline on older boof animals wus enminod. The addition of chlortet cyclino to a concentrato type of ration for yourling halfers and stoers, starte at 91 mg/lb of grain and increasing stepwiso to 27.2 mg resulted in de gains of 1.64 lb as compared to 1.52 for control. In other expertmonts, mark improvements in rato of growth and celluloso digestion were observed the chlortetracyclino was added to high roaghage rations (tablo W contatat supplement A, which consists of 85.1 per cont soybean meal, 14 per of molasses, 14 per cent alfalfa meal, 5.2 per cent bonancal, 17 per cent with cobalt, and a concontrato supplying 2270 units of vitamin A and 2 umíts of vitamin D per pound of supplement. Duitoman and Boulerth at compared bacitredn and chlortetracycloo F 122 day periods in two experiments, each of which involved 10 animals p group fed 122 days on a ratio of slags, milo and cottooxced meal with t result that in the first erperiment those animals fed no mopplevnent had average dally gatn of 1.34 those with 45 mg daily of bacitracin added, la 1 68 | ANTIBIOTICS MONOGIAPHS ·those with 45 mg daily of chlortetracyclino added, 172. In the second caperi ment the average daily gains were 1.45 for those fed no antibiotic supplement 134 for those fed 45 mg daily of bacitracin, and 1.52 when 45 mg daily of chlortetracycline was added The experimental woth with beef cattlo in which favorablo results were reported and carried out principally with chlortetracycline A level of about 10 mg/100 lb of body weight was maltablo and the best responses woro on rations high in roughago. Sotbacks may occur when antibiotics are given at high levels, especially to animals that are receiving high-concentrate diets. Antibiotia In Lamb Foods The oral administration of fairly high doses of antibiotics to lumbs was found to produce digestive disturbances by Colby and co-workers, *** who noted that Lambs receiving daily 100 mg of chlortetracyclino or pealcillin lost welght and developed diarrhea whllo Turner and Hodget:noted that a singlo dose of 780 mg, of chlortetracycline to Merino sheep was followed by loss of appetito and weight Lower supplementary lovels are better tolerated. Jordan" and Jordan and BcIP found that lambs on fattening ratioos tolontod low dosage with chlortetracyclino and there was some roduction of enterotoxemia. In further expostments, 300 chlortetracyclino was fod to lambs at levels of 43 to 108 mg. dally and slight improvements in growth were seen in three of four trials. In another report, lambs recefying chlortetracycline in a pelleted ration roquired 10 per cent less feed per unit of gain than controls. * Hatfield and Garrigushot studiod the effects of chlortetracyclino when 10mg/lb was added to a concentrated feed which was offered freo choico with alfalfo hay The supplemented lambs grow about 10 per cent faster then the controls und produced alightly botter carcasses. These mvestigators summarized tho results of three experiments involv ing 190 lambs. Ratioms rupplemented with chlortetracyclino at levels of 5.5 to 78 mg/lb gavo mall but consistently higher average daily gain and produced daily gatos which wero 055 +014 lb higher than those of the controls, Tho feed eiiciendes and carcass grades of the supplemented lambs were higher than those of tho controls. The average performance of lambs receiving diets containing orytetracycline and penicillin was approadmately the samo or slightly better than that of controls but the differences were not significant Chlortetracycline did not eliminate caterotoxemla but the authors concluded at improvement in gain and efficiency wus sufficient to show that chlor tetracycline has a practical place to lamb nations." ANTIBIOTICS IN NUTRITION | 69 ·Dag/ta Badges et al** fed chlortetracycline to lambs at lovels of L1 to 15 of diet. Increases in the rate of gain resulting from fooding the antibiotic were small and were not statistically significant. Slight improvements in efficiency of feed utlization and in carcers grado and dressing percentago vero noted in tho antbiotic-fed lambs Effects of the composition of the ratio co the response to chlortetracycline were recorded by Elliott and Ellsworth who found an effect of tho antibiotic on growth with 80 per cent of rooghage and 20 per cent of grain but not with higher lovels of grain while no relation between roughage level and responso was found by Botkins and Pauleyha morbo reported that the average daily gain was 0.287 lb for the controls and 0.304 for the lambs receiving 10 mg of chlortetracyclino per lo of nation. In a earlier Investigation, Bothing and Peolestos found no response to chlortett Tabla Xox Effed of Chlortetracyeline on Growth of Boof Cottlo Rocotring vorlous ration Day of oxport mant No. anbrals por group Additions to supplement A Chlortetraydino addition mg/day Averog. Initial wt., lb. Daily gary b. 56 5 0 662 1.69 56 5 Ground carn cobs Ground com cobs Ground com cobs 75 680 2.18 56 5 678 1.83 167 9 0 1.26 713 Ground com cobs Ground corn cobs 161 9 75 1.03 713 168 9 0 711 216 169 9 Ground cobs plus ground yollow com Ground cobs plus ground yollow corn Groon chopped corn Groen chopped com 75 715 216 49 12 2.28 0 1021 49 12 2.71 75 1032 First wook 25 mg, second wook 50 mg, then 75 mg. dally 70 | ANTIBIOTICS MONOGRAPHS ·- cycline 30 mg per lamb per day during a U17 day feeding period. Reductions in scouring and enterotoxemia were found to be associated with feeding chlor tetracycline by Kunkel and co-workers:10, 31 as follows in 118 without ant blotic 8.5 per cent died of enterotoremla and 93 per cent died of all causes in 232 Lambs fed 5 to 15 mg of chlortetracyclino per b of diet, 17 diod of all cuses with no deaths from antorotoxemia. Entcrotoxemia in lambs is com monly accompanied by Clostridial infection of the digestive tract. No effects of antibiotics, chlortetracycline, orytetracycline and penldllin, wero obtafned in an experiment with lambs by Kinsman and Riddell.913 Bohman and coworkers.nl: fed graded levels of chlortetracycline, 5 to 20 mg/lb of grain mix, to 140 lambs from 2 to 4 wecks of age to market welght, with or without added B vitamin No detrimental or beneficial effects wero noted on mto of gain dressing percentage or carcou grade. The experimental work with lambs indicates that e vartablo but prodomi nantly favorable effect is obtained when lambs aro fed a low lovel of chlortet recycling, about 10 mg/lb of diet. Many of the observed effects appear to bo related to the suppression of harmful bacteria. High dosage with antblotics may cause digestive disturbances. Good results have been found when antibloties were fed to cull ac scrub lambs. The Elted of Dietary Antlblotlas on Reproduelon In Animals A pumber of investigators bavo studied tho results of adding antibiotics to the diet on reproduction in chickens, pigs, and, in a few cases, laboratory animal. Most of the measurable effects have been beneficial. In a number of cuses, no effects were found. The interpretation of such results may be complicated if tho maternal diet is inadequate with respect to certain vitamins which are spared by an antbiotic. Antibloties do not readily pass through the placental barrier into the fetus as fodged from studies with pigs dor do antibiotics tend to become concentrated in the egg yolk. Carpenter and Larsop"! fed i Gm, of chlortetracycline threo tlmes dally to soves, starting two days beforo the expected farrowing date. The baby pigs were bled within the first few hours after birth and before they had nursed, but no antibiotic was found in their blood serum, although It was present at levels of 003 to 1.3 mg/ml in the serum of all 5 of tho sows. Various investigators have studied the birth weight and survival rate of young pigs us affected by adding antibiotics, in most cases chlortetracycline, to the materne diet in son of the culier experiments, mudo supplements ANTIBIOTICS IN NUTRITION | 71 ·Table XX Effod of Chlortetracydino on Roproduction in Pigs Lerrol of chlortet rocydino Gm/ton No of soms and guts Startod Farramod AY no. pigs/ Attor Invostlgators Ay birthe Pig bona wt, da deod, 16 15 70 2.95 Carpenter and Larson14 23 17 83 2.98 0 (a) 20 (a) 0 (b) 20 (6) 0 14 14 10.6 2.9 10.9 14 14 8.6 31 5.8 Catron 20 18 8.9 2.89 9 40 20 19 9.7 284 16 0 10 7 69 2.90 10 20 11 10 61 2.88 $ 0 25 20 10.0 2.90 10 40 25 19 10.3 2.86 8 0 24 20 10.3 29 10 24 2 100 3.0 11 0 30 25 8.8 5 2.1 10 30 26 10.6 6 3.0 10 Davey Green and Slovenson 16 5.0 20 wa 100 72 67 6 3 2.68 3.06 3.08 100 10 8 38 3 70 2.66 8 9.5 213 8.4 100 34 8 7 8.7 251 Vatapis 62 0 13 225 TI 8.8 20 26 25 9,4 2.50 Derson 0 0.9 T3 12 9.B 2.51 10 28 13 12 2.36 91 20 7.4 13 10 9.A 2.60 30 13 12 94 72 | ANTIBIOTICS MONOORAPHS ·were used which contained vitamin Biz as well us an antibiotic so that the effects could not be definitely attributed to the latter Carpenters fed a supplement containing chlortetracycline and vitamin Bug for 48 to 90 days prior to parturition without observing any effect on tho size of the litter tho averago birth weight, or the number of pigs born dead. Further studies 14 in which the supplement was fed through two gestation periods led to similar results, al though slight differencos were observed in favor of the supplement (table EXI) Vestal and co-workers'lused a simllar supplement and found that tho control pigs bad an average birth weight of 2.45 lb as compared with 2.58 lb for the pigs from tho says that received the supplement at a level supplying 8 Gm. of chlortetracycline and 9 mg /ton of vitamfo Bs. No effects of each a supplo ment on the birth weights vero foumd in studies by Dyar 116 Becson and co-workeryt17 fed various lovels of crystallino chlortetracycline to sott's durmg gestation (tablo XI) They found that heavies and stronger plgs wero produced at birth when tho lovel of chlortetracyalino to tho material diet was 20 ar 30 Gm./ton than when the lovel was 0 or 10 Gm. The antiblotio had no effect on the number of pigs per litter Tho authors summarized their work as follows "Gets fod Aurcomycin at levels of 20 to 30 Gm. per ton of feed farrowed beaver and stronger pigs at birth than tho gilts receiving no mattbloties or a lovel of 10 Gm. of Aurcanycto. Aurcomycta hed no sgnificant effect on the number of pigs farrowed or tho weaning welght of tho piga Pigs from the sows receiving the high level of antibiotic (80 Gm. per ton) during pregnancy wero stronger and more tiform la appearinco at weaning Tho percentage of the pigs weaned was not signficantly influenced by antibiotlo feeding but was slightly higher for the high Aureomycin group." The effect of chlortetracyclino on reproduction in swino through successivo reprodactive cycles and generations was exhaustively studied by Davey and co-workers. ** Diets containing relatively high lovels of the antiblotis 50 and 100 mg/lb. of feed, werd included together with a lower lovel in order to Accelerato or intensify the effects of continuous antibiotic feeding Tho high la cls produced no adverse effects in number of pigs born per litter birth wedghts, or weaning weights as compared with a low lovel. The results by Davoy and co-workers in tablo XXI represent experiments to consecutivo years. Tho results in the second year were obtained with the daughters of tho females used in the first year so that the effects of chlortetracyclino were measured through two generatloss. The lower average weights of the second year pigs was stated to bo probably due to the use of younger sows in the scoand ytar The effects of antibiotics la the diet of the row on the growth of baby pigs ANTIBIOTICS IN NUTRITION | 73 ·are usually complicated by the fact that the young animals consume part of the mothers food, and tho osperimental results are difficult to ovaluato. Meddock and associates' found that chlortetracycline was not detectable fn the blood and milk of sows rocefvtog the antibiotic at lovels up to 20 mg/Th. of diot. However when single oral doses of chlortetracycline up to 4 Cm. vor given by capsule, a maximum level of 0.74 xg./ml was found in the blood sorum and 221 pg/ml in the milk whey The effect of dietary antibiotics on the compoatlon of hens egg hum important bearing on any affects on hetchability or embryonio doveloparent When any of sovural antibiotics wero Injected into eges, tho lafectloos were well tolerated by tho developing embryo (tablo III) at lovels that far ascooded those that have been found in eggs following the administration of high levet of antiotics to layłng hens. Broquist and Kohleral found that po antibioti potency was detectablo in oggs laid by hans receiving a diet containing 20 a 200 Gtr./too of chlortotracycline, and only small amounts, ranglng from 0.15 to 3.1 pg. per egg were found when the antibiotic level was 2000 Gm./ton of diot. Wong and co-workers to werd unable to detect tho presenco of oxytotis cyclino and penicilio in eggs oven when the bens wero fed tho antbloties at lovels of 1000 Gm./ton of diet. Clearly any effects of tho entblotias on batchability whon fod at the usual levels are probably cartod indirectly nother than through their presence in the ogg. This view is supported by publications which indicate that the content of certain vitamins in the egg may be the croused following the feeding of antibiotics to heaus. Walbel and co-workerslas found increases in the blotin and follo acid content of ogg yolla when pearcolin was fed to laying hens at lovels of other 5 ar 200 mg/Kg. of diot. Theso itthon ruggested that the increases wero dao to changes in the intestinal for brought about by the antibiotia. The besa) dlot was not deficient in blotin ar folio add The effoct of certain antibiotics in increasing the hatchebility of by hond om diet dofdent to vitamin Du presonts some umsolved probleme. Soveral investigators hevo repartod that this improvement lo hatchabflity was not accompanied by an crane in the vitamin B1, content of the ogg ar that the fncrease in vitamin Bia was insufficient to account for the improvement for hetchability * Stronore and co-workers to reported to addition that the foedtog of a supplement containing chlortetracycline to pullets dortog the growlog podod medo them resistant to vitamin Big defidency of the breeder dlet, meanied by a doprendon in hetchability which could be corrected vitamtn Bus and that this resistanco persisted after the cessation of antiblotte fooding for a period of several months. This was further empbesteed by thets hald 74 | ANTIBIOTICS MONOGRAPHS ·later observations in which the resistanco continued into the second year aft withdrawal of the supplement. Laying house mortality cos production, and fertility were not influenced by the growing or the breeder diets However the presence of a vitamin Bırantibiotic supplement in the growlag diet resulted in focreased batchability during the two year period in all four comparisons (table (XII) and the addition of chlortetracycline to the breeder diet also resulted to increased hatchabllity Embryonic mortality showed dmilar trends. The effect of the antibiotic during the laying perlod was beneficial and the addition of a supplement containing vitamin Big and chlortetracyclino to the rearing dlet was followed by improvements in the subsequent reproductive performance. The authors ruggested that the prolonged feeding of the anti biotic may influence the intestinal flora or may mako available e nutrient to Tablo XXII Rolation of Dlots during Roaring Porlod and Laying Perlod to Mortality of Hond, Eog Production and Hatchability of Fortthon Eggs In Rhodo Island Rod Homs Diet during rearing period Hatchability Mortality during 2 yr Egg production during 2 yr Serlos 2d yT 1st & 2d yr A 1 550 470 46.4 53.9 594 А 1 + AFST 550 479 33.2 А 2 400 426 38.3 43.8 A 600 45.6 73.6 79.2 2 + AFS Average 52.5 458 479 59 1 D 1 30 B 42 1 61.3 68.8 B ITAFS 439 419 74.3 74.4 2 62.5 438 67.5 63.8 B 47.5 45.0 71.6 73.3 2 + AFS Average 46.2 43.2 68.6 69.6 Sories A recived no antblotte during the two yoor loying porlod ond sarles B rocelred a supplement of crystalline chlortotrocyclined TAFS= Antibiotic vitamin Big upploment in roaring diet. ANTIBIOTICS IN NUTRITION ·lucrease hatchability It was not possiblo to explain th of the apparent vitamin Bu content of tho ogg yolls for when the birds received chlortetracyclino even though 1 eggs was higher The presence of an imidentified "hatchabi of hers recerving an antibiotic as a supplement to a die Buy was also noted by Elam and co-workers" Further known vitamin liko factor in the eggs of hons which had supplements was provided by Slinger and co-workerst & Hershberger & Slinger and co-workers found that tho prog und received penicillin wero 3 per cent heavier at 10 works from bens without the antibiotic supplement. The chicks w a commercial dict that was supplemented with pentellina Bentley and Harshberger fod an all vegetablo diet to laying h the effect of vitamin Bu and antibiotics in the diet of hens a the progeny Tho addition of chlortetracyclino or bacitrachu to hens lucreased tho growth of tho progeay on vitamin Bus defid though tho ogg yolks, livers of the bens and tho livers of tho c showed no difference in vitamin Bus content as determined with . leichmannli. Furthermore, foedlog procalao penicillin to the horis frease the growth of thefr progeny when both the hens and rereived diots containing additional amounts of vitamin B. The Huu açala raiso the possibility that e growth promotlag factor Vitamin Beg may be stored in the egg as a result of foeding antiblol Amplis feless yolks to rats which received a basal corn soybean dieto Alul vitamin Bus and lodinated casoin. Egg yolks from heas recetvá Hutetracycline, badtrecto, or penaldilla produced more rapid grom Thule from supplemented beds. Egg Produdlon la Poultry 14 autritional requirements of chickens and turkeys for ogg produ than ** Hann erspects less critical than tho requirements for batchability tida yil frems this may be expressed in the statement that on certain defic thith Both will mntinuo to lay oggs at a fabrly goo the batchabu ohikte falls to extremely low lovels, or in ents o eggs m hth at #16* To essential naturo of certain vit ding to Nyurt, the acid, and ittamin B or hatchablity lished thiules unitary conditiat CTO boas ir high n het mid mually been fo e no affect nya 78 ) ANTIBIOTICS MONOG of e ·daction Increases have been observed to accompany the feeding of antbiotics when the rato is depressed by certain unfavorablo cnvironmental conditions. Several investigators havo poted improvements in hatchability when ant biotics were fed, and in somno cases a marhed increaso was noted when the diet was deficient in vitamin B1 No increase in hatchability and no consistent Increase in ogg production wero noted when antibiotics vero fed by Sunde et al, although the highest egg production was in a group receiving a supplament containing chlortetre cycline. Berg and co-workers's famd no effects on egg production or hatch ability when orytetracycline of chlortetracyclino were fed at levels rang ing from 4 to 15 mg/kg of diet The reproductive performanco of all tho groups was eicellent Walbel and co-workers14 stated without presenting data that the addition of penicillin to a diet of natural foodstuffs resulted in no measurablo effect on egg production, egg wolght, or hatchability over a 10 month period. Tho blotin and folic acid contents of the egg yol were greater in the supplemented groups Lillie and Bindtos found no significent effects of a supplement containing chlortetracyclino on egg production or batchability and Brown and co-workers to reported no effects with penicillin in a similar experiment with Laying hens Other favestigators who hevo reported that anti biotics were without effect on egg production includo Petaren and Lampman who used penicillin streptomycin and oxytetracyclino Halbrook and co-workers'll who used chlortetracyclino with both chickens and turkoy, Sher wood and Milbys who used chlortetracycling, oxytetracycling, and pealcillin, Carpenter and Duckworth who used chlortetracycline, Marlakulandia and co-worherstel who used orytetracyclino and Johnsont who used pealclin. Elam and co-workers to reported increases in egg production when anti bloties were added to the diet of pullets 10 birds wero used in each group A decrease in egg production was noted in hot weather by Heywang! who found that the adalton of 50 or 100 Go of chlortetracyclino per ton of diet helped to prevent the decrease. Balloune noted that the addition of chlortetra cycline at a high level (100 Gm./ton of diet) improved egg production to pul lets which had gone into a laying slump Egg production increased from the January average of 294 per cent to 407 per cent in February in two groups whero chlortetracyclino was added to the diet at the rate of 100 Gr./ton. Tho improved nto of production was continued in March. No increase in pro duction occurred to unsupplemented controls during the same periods. Heywang' found that the addition of chlortetracyclino at levels of 50 or 100 Go/ton to the diet of laying pullets resulted in greater egg production during periods of hot weather than was observed in unsupplemented coatrols, ANTIBIOTICS IN NUTRITION | 77 ·This may Indicato a diminished resistance to chlortetracycline-sendtivo injurt ons microorganisms durlog hot weather (average mean temperature 88 F) White-Stevens and Zeibel studied the effects of chlortetracycline durtag various periods of the growing period on egg production by pullots. A dgnts cant and consistent month to-month difference in egg production was found betwoen bens receiving 50 Gm. of chlortetracycline per ton of diet througbout the growing and laying period as compared with control. Threo groups of hens wero used for each treatment Tho por cent production (oggs per 100 hens per day) for 12 month periods was as follows there was 659 per cent og production without anthiotic, 69.1 per cont when chlartetracyclino was fod befaro ogg-laying started, 67.3 per cent when chlortotracyclino was fed only aftor ogg-laying started, and 09.8 per cent when chlortetracyclino wa fed throughout the 12 month period. Carlson and Kohlmeyer 440 selected physically superior pullets and fed them a diet containing 50 to 100 Gm./ton of chlortetra cycling, following which theso birds produced more oggs than controls which had appeared to bo physically superlar Carlson and co-workers1 also noted that egg production in turkoys was improved slightly when chlortetracyclibro was added to a diet which containod supplomentary vitamin Buy Antibiotics and Ego Production in Hons with Chronic Rospiratory Diseaso Tho appearance of signs of chronio respiratory disease in laying bons is characteristically accompanied by a drop in ogg production. The effect of high lovels of chlortetracycline in the dlot in the control of chronic respiratory dis ease was studied by Whito-Stovens and co-workers." In mo capertroent chronic respiratory disease appeared to a breeder flock containing 298 bens that had been in production for 10 months. The flock was dividod into two equal groups and one group received an addition of chlortetracycline, 100 Gm./ton of feed. At the start of the experiment the hens in the supplemented group word laytag 74 per cent less than the controls but during the final week of tho 45 day experimental perfod the birds receiving the antibiotic produced 79 per cent more ogg per hen per day than the controls. A second esperiment was carried out using 630 bens per group. Lovels of l, 50, 100 and 200 Gm of chlortetracycline per ton of feed were used. The highest lovel was decreased to 100 Gm./ton after five months The cumulative egg production of the first two groups ww equal during e nine month period and egg production in groups 3 and 4 wero respoctively 83 and 3.3 per cent more than the control group. The hatchability for group I was 780 per cent, for group 2, 83.4 per 78 ANTIBIOTICS MONOGRAPHS ·cent for group 3, 83.3 per cent and for group 4 83 1 por cent, so that the combined effects of increased cgg production and hatchability were in favor of the supplemented groups. Carson and co-workers' found that egg producton in pullots with CRD was improved by Injectiog a suspension of 50 mg of oxytetracycline in mineral oil. The mean egg production of 143 treated birds for 81 days of the postinjection porlod was 44.7 eggs as compared with 38.8 eggs for the control birds. The effect of chlortetracyclino on the ogg production by turkeys In flocks wbere sinusitis and bluccomb wero occasionally observed was improved by chlortetracycline The average egg production in tivo unsupplemented groups totalig 599 birds was 45 and 55 per cent. The production of two correspond ing groups receiving 115 Gm./ton of chlortetracycline was 57 and 58 and for two groups with 230 Gm./ton of chlortetracycling, 59 and 61 per per cent cunt 145 ANTIBIOTICS IN NUTRITION | 79

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·CHAPTER V Physiologic and Other Effects Of Dietary Antibiotics Effects of Antibioties on the Endocrine System Chlortetracyclino and the Thyrold Gland. Ershof has reported:14, 14 that crude supplements derived from the fermentation of peniallin or chlortetra cycline prolonged tho survival of immaturo rats which received todc doses of desiccated thyroid gland. Ho noted that crystallino chlortetracycline hydrochlorido was ineffectivo thus perhaps indicating the existence of an unidenti fed noventibiotic factor in the residues However Mates and Ogloh' found that penicillin and neomycin wero effectivo in overcoming the growth-depressing effect of fodinated caseln for rets. No goitrogenic effects were observed for the antibiotics. Calemnich and co-workerskt reported that either peniallio or chlortetracycline at the low level of 1 mg/Kg of diet produced a soveralfold focrease to the weight of thyroid glands of Immature white mats with a threeto-fourfold decrease in [191 uptako by tho gland after 42 days of feeding They raggestod that chlortetracycline and peniallin had a godtrogenic action stmllar to the thioaradis. Inability to repeat theso observations was reported by Libby and Meter"" and by Grant.** In studies with rats, even though 20 to 50 times higher lovels of the antibiotio weto fed than were used by Calesich, Grant noted in contrast that thero was a small but definito increase in the uptako of Ilh by the thyrold when chlortetracyclino was fed to nuts. It was also pointed out by Grunt that rats receivtog 2 per cent propylthiouracil la tho diot as used by Calesnick and co-workers lived for less than tiro weeks in his experi ments us opposed to the rosults reported by Calesnick et al who indicated that their nats lived through the sky week period on the propylthlourd supplement No effect on the lodhe metabolism of thyroid slice la vitro was found in experiments with chlatetracycline by Taurog and Chaikoff.350 These Investi ANTIBIOTICS IN NUTRITION 81 ·t gators Incubated sheep thyrold tissue slices for Roger solution contalaing with or without 10 pg/ml. of chlortetracycline. After two hours of Incabe at 37 C the tienes were homogenuzed and hydrolyzed with penarcallo en hydrolysato was chromatographed for separation of the lodino-containing tians. The chromatograph indicated that both preparations contained app mately the same amounts of radloactivo dilodotyrostno, monotodotyrosine, roatne, and froo lodido so that chlortetracyclino had no effect upon the up of 112 or on organic ſi formation by sheep thyroid tissue slices. Thatr finca indicato that any affect of dietary antibiotics on the thyroid is indfrect, per mediated through the intestinal bacteria. Simlarly Telkka and Kuulstoi found no differences in the histo picture of the thyroid gland of antiblotic-supplemented rats as compared the controls. Both chlortetracycline and orytetracycline were used at lovel 10 mg./Kg. of diet. The relative weight of tho gland was practically thos in all three groups Maghrabi and Tumar noted a slight deproudon of thy size in young chicks that received 50 mg of chlortetracyclino per kg of A small increase in the weights of tho thyroid glands of chicks recet chlartetracycline was noted at eight weeks of age by Mellen ad Walle The thyroid weight was 67 mg/kg of body weight for the ansupplemer brds, 89 for the chlortetracycline-fed birds, and 78 mg for tho birds cofving bacitracta No such differences were found by Grante as shown table XXIII. Both chlortetracyclino and vitamin By wero reported by Meltes, e counteract tho delotalous effocts of cortisone on vitamin By defident r The effect of the antibiotic would seem to bo related to improvlog tho util mg Tablo XXIII Avorage Body Walghts, Thyroid Weights, and 1131 Uptoboa of 10 Wook Old Male Chickons 24 Hours ofter Introvenoun Injection of 1188 1151 uptako CPM per Chlortetracydino oddod per ton of ditet Body w Gm Thyrold wt. mg/kg body wt. mg trynold Nono 156 1259 90.7 156 100 Gm 1339 89.4 'Thore were 10 bodo por group.154 82 | ANTIBIOTICS MONOGRAPHS ·Tablo XXIV Partial Protection of Rats Against Alloxon Diabetes by Chlortatrocyclino Chlortetra cyclin por ka of diet Gm Ar gain in body w in 28 days Gm. Avoro e dally Diurosh, Urinary sugar Gma. Treatment None 0 28 None 28 Allaxan 0 9.6 73 3.85 Allaxan 0.2 19.0 89 5.0 tion of vitamin B12 or incrousing its intestinal synthesis Wahlstrom and Johnson? found that cortisono aggravated vitamin Bu deficiency in baby pigs but do lloviation was produced by chlortetracycline. An efect of chlortetracyclino on partially protecting rats against alloran diabetes was reported it and is summarized in table XXIV The experiment was carried out because it had been observed that patients with severo diabetes bad shown improvement during treatment with chlor tetracycline. Tho effects of chlortotracycline stogly and in combination with diethylstill bestrol and -thyrordne on the growth of pigs were studied by Barber and coworkers who found ovidence for an additive effect on growth and feed cfidency when the combination was fed. Effects Following Various "Strees Conditions Bacz et als found an 18 per cent greater survival after rotation to a drum in rats receiving oral chlortetra cycline than fu untreated controls These results prompted an examination of the liver slices of the experimental rats, and it was found that the liver preparations from rats receiving chlortetracyclino orally or via portal vein in jection did not release varoactivo ferritin (VDV1) into the incubation medium after 90 and 120 minutes of anoxla, in contrast to control liver slices. This fuggested , mechanism by which chlortetracycline may have partially protected the drummed rats against shock. Finete reported that penicillin and chlortetracycline were ineffective when administered parcaterally in prevent ANTIBIOTICS IN NUTRITION 1 83 ·- fog irroversiblo shock foduced by hemochege in dogs, but there antibiot together with nootaycin produced a resistance to shock when given by mou- Chlortetracycline and streptomycin at lovels of 50 mg/kg of diet we found to fncrease tho tolerance to emetino in rats w a low protetu diet. ** Radiation Intury Following exposure of the total body to roentgen - acute radiation sickness, accompanied by hemorhage and infection, may valop. A number of Investigations havo shown that protective effects muy Himos result if antibiotics aro administered to experimental animals poder Irrudiation. Such affects may bo important in the event of accidental caport to radioactivo materials. Penicillin, stroptomycin, chlortotracycline, and of totracycling have all been used in these experiments. Howland and co-workers found that chl@tetracyclbo ajoviated dient and prolonged the survival time for five to seven days beyond the comtr lo rats following an LD- dose of roentgen nay radiation Chloramphenie streptomyon, and penſailtin were less effective. Good results were also obtain with chlortetracycline in dogs Müller and associates has found that the De tality of Irradiatod mico was lowered by streptomyco and to a lesser deg by chlatetracycline but that tho protectim was less if tho mico dovelop certain tafections Gustafson and Kaletakyto reported that orytotracycli probably protected against radiation Infury by reducing bactaranta, in an periment la which orytetracycline was given 72 hours prior to radiation, E mean survival time was raised to 150 days from 10 8 days In further studies by Furth and his associates her not tho results with do and rats were fodafinito. In two aperiments, each fovolving 08 dogs, protective effects were obtafood from other chlortetracyclino or wholo blow transfusions The authors Dovertheless concludod that the prophylact administration of a broad spectrum antiblotlo is still advisablo desplto results of this study in the ovent of an atomio catastropho and the courague osposure to Infootion, Antiblothes and Liver Physiology Antibiotics and Deficiencies of Choline and Methionine. Deficiencies follo add and vitamin Bu are well Lnown to lead to focrease the disturberto arlstag from dietary deficiencies of cholino and methlanine in the diets of me and chicks Folic add has a coenzymatic rolo vie totrahydrofolic add (THFI und its derivatives in the synthesis of methionine from homocysteino and "singlo-carbon wolt," which may be derived from formaldebydg serine, farmato a follow JA, 14 84 | ANTIBIOTICS HONOGRAPHS ·Formaldehyde or world Homocyıtolag Nothionlos THFA -CH2OHTHFA" ATP Fortate "HOTHFA" dellyo mathtopla THFA Chollas, ate. Follc acid The role of vitamin B12 is not clear but it seems to be connected with the formation or utilization of CH OHTHFA, the hydroxymethylated axnzyme that is involved in one routo for the formation of methionine from homocy stefne. The second routo for this synthesis is through the combination of betaloo or dimethylthetin with homocysteine in the presence of transmethylase. If the utilization or intestinal synthesis of folic acid and vitamin B12 is foproved by adding antibiotics to deficient diets, the effects of defidencies of cholino or methione ruch as fatty livers, hemorrhaglo kidnoys, or necrotic livers, may be alloviated to and anti-anemia effects of tho antibiotic may also be show.. Hepatic necrosis, a dietary liver disease of rata, has been extensively studied by Gyorgy and co-workors who showed that it was possiblo to produce the disease on a diet high in yeast and to prevent it by adding vitamin E, cystne or methionine. Chlortetracyclino was also found to provent hepatic necrosis when added to tho diet of rats but in contrast to the other preventive agents the effect of chlortetracyclino was found to be only temporary The mechanism for this effect of the antibiotic was thought to bo an inhibition of todo-productog bacteria in the lower intestino because tho necrosis de veloped predominantly in the left lobo of tho liver which derives its portal blood from the largo Intestine and stomach in contrast to the relatively normal right lobo which receives portal blood from the small totestino Abell and Beveridge171 confirmed the results with chlortetmcycline and found that sulfa guanidino bad como protective action. A number of antimicroblal agents were tested and chlortetracyclino was found to give the longest protection, fol lowed by oxytetracycling and streptomycin, then by sulfaguanidine whilo chloramphenicol, palymyxn, and penicillin were ineffective Vitamin B1, had no effect. Tho temporary naturo of the protection given by chlortetracycline led to tho conclusion that its effect was not direct but was mediated through 1 transient change in the intestinal flora and that eventually the bacterial ANTIBIOTICS IN NUTRITION | 85 ·types that were postulated as producing hepatotonicosis reappeared in an att blotic-tolerant form. In later studies penldllio was found to be effective. " The intestinal flors of the experimental rets on penicillin and chlortetracycling supplements wus studied and the type of changes produced by the two and biotics differed, furthermore, resistant bacteria appeared in the first weet while tho antinccrogenic affect lasted for five or six months.976 Against the bacterial theory of hepatic necrogeneds were observations with germ-free ratsuts which developed the disease when on a restricted food Intake but not when on full feed. This makes it appear that some ingredient of the deficient dlet could prevent necrosis and that the ingredient, pertups mothionino or cystine, wus absorbed to sufficient amounts only when the animals were on full feed under tho germ-free or antblotic-rupplemented.com ditions both of which have been reported to be accompanied by certain changes in the intestinal wall." Tho addition of antibiotics produced a change in the pattern of the urinary excretion of other-solublo acids as compared with unsupplemented or vitamin E-treated animals. ** Two unidentified adds with R values of 0.45 and 0.80 in butanol actio add water mixtures appeared to the urines of the antblotic-upplemented rats, theso substances bad no op peront relation to necrogeneals but their presence may be of much blochemical interest. Tho urinary excretion of volatile phenallo compounds by human subjects was found to decrease markedly following the administration of antibiotics by mouth. This was thought to bo duo to a depression of tho bacterial formation of phenols from tyrostno in the intestinal tract. *7 In otha ape ats by Gyorgy and his collaboratori, rats were fed en entirely different diet, deficient in labile mothyl and containing sucrose, 89 per cent lard, and 8 per cent cusein, which produced ciochotio changes and kidney injury The changes were prevented by chlartetracycling 25 mg dally 972 These indings with rats may be compared with dinical fovestigations in which chlottetracyclino was used to the treatment of hepatitis, **k om bepate come, and cforhoods. 141, 149 A patient with chronic posthopattula cinnhosts and continuous faundico of four years duration showed string fmprovements, including histopathologic changes, following five months totensive treatment with chlortetracycline.#1 Three patients with acuto fulminating hepatitis re covered following treatment with chlortetracyclinc. However in a contraded study to no differenco fa tho course of acute viral hepatitis was found between chlortetracychno-treated and control patients when 87 anses wero studied in cach group Do la Huerga and co-workerslu reparte cycling oxytetracycline, and penicillin suppressed the urinary excretion of trimethylamine in dogs following the togestion of a test dose of choline. This 86 | ANTIBIOTICS HONOCIAPHS that dietary chlortetra ·effect was thought to bo duo to the lowering of trimethylamine formation by the intestinal bacteria. The effect disappeared after one of two weeks as if the bacteria had become adapted to the presenco of the antibiotic. However Kaplan and co-workers" wero unable to repeat these observations They found that chlortetracycline had a lipotroplc effect on dogs with ligated pancreatic docts when given in largo doses. Similar changes occurred when choline was administered. The afects produced by chlortetracycline reached a matmum in three to four wecks and then receded and loveled off at an intermediate level, in one animal a second response was producod by adding follo acid and vitamin B12 to the treatment with chlortetracycline Elther choline or chlortet racycline were found by Barter and Campbell to prevent renal lesions in abs on diets bigh in fat and low in cholino. Vitamin Bug had some activity but oxytetracycling chloramphenicol, and penicillin were ineffective. No chango in the liver Lepids of rats was produced by adding chlortetracycline to a low ргоteln, low fat diet in studies by Comatzer aod Gallout and after four weeks there was a decrease in phospholipid synthesis in the group fed chlortetracy dine. On the clinical side, 12 cases of chronio liver disease were treated with chlartetracycline, 7 of whom shorved an improvement while in the remainfog 5 cores there was little or no evidence of benefit These effects of antibiotics may be contrasted with the findings of Seto und Lepper who found that an increase in the liver fat of young female rats was produced by a single intravenous injection of chlortetracycline or orytet necyrime, 100 or 150 mg/kg of body weight as follows the per cent liver fat, 18 to 24 hours after injection of the chlortetracyclino wus 15.5 +5,4 and the control was 7.1 +16 the per cent livor fat, 18 to 24 hours after lojection of orytetracycline, was 13.5 +6.2, and the control was 80 =18 The liver fat values returned to notinal within three days following with drawal of the drugs. No chango in the effect was noted when mothimalno or verlous B vitamins were given simultaneously The arperlmental latravenous Touto of administration may have been the reason for the difference between these results and thoso previously described, 972 ** and it is Interesting to note that Zimmerman and Humoller found that oral chlortetracycline did not effect tho endogenous respiration and cholinc oxidase activity of rat liver tissues wbllo chlortetr.cycline given parenterally or added in vitro depressed theso systems However Sborov und Sutherland in found that treatment with chlor tetracycline, 2 Gm. dally by mouth in a group of 18 patients with chronio vinal hepatitis or hepatic dirhosis, was folloved by increased liver fat u indicated by biopsy Thiese patients received a diet which averaged 126 Gm. of fat dally so that the increases in liver fat were perhaps to be erpected, moreover ANTIBIOTICS IN NUTRITION | 87 ·toric properties. Bacitraan may produce renal tubular Decrosis, espectally mfce Nelther streptomycin nor bacitracin ero readily absorbed from thod gestivo tract when givon orally Massive doses of chlortetracycline wore given to pigs by Cameront wh found no todo effects when 250 mg/kg of body wolght was fod dally for days. The level of the antibiotic normally consumed by pigs receiving typia chlortetracycline-supplemented feeds would not exceed 1 mg/Kg. of bod waght dally The pigs were fn excellent condition at the end of the aspartner and the bone marrow was found to be yellow in color at autopsy but shower no histologic abnormality Effacts on Growth of Homan Sublocts An approach to the study of the effects of antiblotlas on the growth o children presents certain difficulties as compared with experiments with more mals, first, because overy effort must be made with children to carclude the bacterial contaminations that contribute so much to the antibiotic growth effect to animals and second, because of the slow rato of growth of human belogs. Tho most marked offects of antibiotics on the growth of children may be expected where they are poorly doveloped due to sobnormal diets or to subacuto intestinal diseases Soveral encouraging reports have appeared regarding prematuro ffants. Porrinio fed chlortetracycline, 25 mg/Kg. of body weight dally to 10 pro maturo mfants and found that thoy gained 8 per cent fa preight during 10 day period as compared with no peight Increase for a group of 23 controbe. Robinson also reported to creused growth with prematuro Infants rocedying chlortetracycline who gained 20.5 cm. daly as compared with controls wbo getoed 18 Gm. daily Five of the 15 controls died from intercurrent Infections whille all of the supplemented group lived. Lower mortality in a group of chlatetracyclino-treated prematuro infand together with increased growth was reported by Snelling and Johnson 013 there was one death in a group of 17 who received 50 mg of chlortetracycline daily us compared with 8 deaths to 48 controls In a study of 57 supplemented prematuro infants and 58 controls, Cooduo" foumd that orytetracycline, 25 mg delly failed to alter the rate of Holght gato The mortality rates wero not reported. No effects in increasing weight gains were found in 2 infrats studied by Kaye et al. 46 Growth increasing effects for antiblottes on infants were reported by Déchenolls and Wetzel and Hopwood 4 who found that arytetracycline, streptomycte, and penldllin, 10 to 50 mg dally by month, tmproved tho 90 | ANTIBIOTICS MONOGRAPHS ·growth of school children Scrimshaw et al'lt studied Mayan children 7 to 12 ven of age living ha tho Guatemalan highlands and subsisting on diets low in inimal protein. In ono cipalment, 14 chldren who recived 50 mg. of chlor tetracyclino daily for 15 months gained an average of 0 48 cin of height monthly as compared with 0.33 cm. for 43 control children In two successivo 12 month periods following withdrawal of the antibiotic, they had the same rate of beight increase as control groups. In other experiments tho increases to height are shown in tablo XXV The average monthly weight gains varied widely trrespective of the type of treatment. It ww concluded that the oral administration of chlortetracycline dolly stimulated growth lo stature in pri mary school children under the experimental conditions encountered but the response to penicillin was variable Carter'll carried out a prolonged investigation of a study of the effects of administering 75 mg of chlortetracycline twice daily to mentally defectivo children for periods up to three years at the Florida Farm Colony Tho chldren Treto mentally deficient spastic cases and were almost entirely helpless Tho average yearly gain in weight for tho supplemented group was 6.5 lb whilo the control group averaged 19 lb in yearly weight gain. The supplemented group had a lower locidence of gastrointestinal disorders than tho controls. The effect of chlortetracycline on weight gains of undernourished children m Leryn was studied by Macdougall.*1 Thirteon children in the Ago rango of 1 to 3 years received chlortetracycling, 50 mg dally for ono to soven weels and Tablo XXV Incroesos In Helght of Children with and without Antibiotia Monthly gains in height om.* 50 mg. Controls ponicillin chlortotracydino 50 mg Experiment Longth of Hono 1 15 months 0.48 (14) 2 18 months 0.33 (43) 043 (23) 0.35 (38) 3 5 months 5 months 041 (32) 0.36 (38) 0.51 (39) 0.44 (35) 0.50 (37) 0 43 (35) The number of children por group is given in parentheses ANTIBIOTICS IN NUTRITION | 91 ·Public Health Aspects of Feeding Antibiotics to Animals The prolonged feeding of comparatively high levels of the common mnt. biotics to animals has not raised problems in public health us rogurds the con sumption of animal products. Broquist and Kohler'l found no detectable amounts of chlortetracyclino in the Hver and muscle of chicks recetying chlor tetracycling, 200 mg./kg of diet. Barely detectable amounts were present to the blood serum. At unusually high dietary lovels, traces of the antibiotio were found in the liver and muscle. The values ranged from less than 0.05 to 0.165 ug/Gm. of muscle when tho diet contained 2 Gm/kg of chlortetracycline up to 0 18 to 0 39 pg/Kg of live with a Gm. of chlortetracyclino per Kg of diet. Similarly with pigs the lovel in the muscle tissuo was 0.80 mg /Gm with 2 Gm. of chlortetracyclino per kg, of diet and undetectablo in the muscle with 200 mg/kg of diet. In further studies, Kahler und co-workers found that chlortetracyclmo in poultry meat was readily destroyed by cooking and the destruction of chlortetracychno proceeded moro rapidly than that of oxytetra cyclino. Chicken breast masclo containing 3 mg./Gm. of chlorbetracyclino was found to be frco from tho antibiotic after boiling for 15 minutes or after roasting for 30 minutes at 230 C. Tho prolonged administration of chlortetracycline to human subjects bas not produced untoward effects. A group of 184 elderly patients woro dosed arally with 800 mg of chlortetracyclino dally for prolonged porlode to a by McVay and Sprunt and an equal number in a control group received placebos.'* In the groups with congestive heart fallure, thero mero 15 deaths In the chlortetracyclino group who were medicated for 20 months and de crease in the incidence of respiratory Infections in 30 patients et compared with 19 deaths fn the control group and a decreaso in respiratory Infections les 4 control patients. Hematocrit values were higher in the chlortetracyclino group Along simlar Ihnes 189 diabetics were observed for an average of 19.5 mooths, again with a decrease in respiratory infections in the chlortetracycline group. Comprehensive liver function studies showed some evidence of improvement in this group. Thero observations emphastzo the lack of toalety of charter cycline when administered for prolongod periods at high dosage nates. No toxic reactions are imaginable from the traces of chlortetracycline which might bo present in the meat of animals fed high lovels of the antibiotic. Indeed, these traces of antiblotic were only of the order of 50 g/lb. or loss of musco Hosve even when the chickens received 2000 m. of chlortetracycline per ton of diet and the antibiotic was destroyed by ordinary cooktog procedures. It study 94 | ANTIBIOTICS MONOGRAPHS ·is also worth noting that the antibiotic-tolerant strains of bacteria, which appar in the intestinal tracts of animals rccelving dietary antibiotas appear pot to be pathogenic tho report of Libby and Schaiblen Indicates a downward trend to the mortality of chickens during four years of feeding antblotics. Afarkham and co-worker' found that the feeding of high levels of chlortetra Cycline did not inbibit tho de clopment of a normal Immuno response to vac dnation for Newcastle disease and infectious bronchitis in chickr. Conclusions An apparent Improvement in the nutritional status of animals mry bo often produced by adding small quantities of certain antblotics to the diet. Tbo utilization of food is often increased to growing animals by this addition as measured by a consequent decrease in tho amount of food required to produce a unit of gain in body weight. The daily rato of gain to weight is increased and the percentage of unthrifty animals is reduced. These effects are of great economic and practical importance in agriculture. Many opperlmental investi gations of the nutrltional changes underlying these effects have been made and a sparing action of antibiotics on the requirement for certain nutrients hus often been noted. The mechanism by which the antblotic produce their offects on Dutrition appears to be secondary to thelr antibacterial action Variations in the extent of these effects are inevitablo in vlow of the tnherent variations in the bacterial population. Changes presumably take place in tho Intestinal bacteria and these changes aro responsiblo for the nutritional ellocts. Euminations of tho types of bacteria in the intestual contents of antibiotic-fod animals have led to variablo and inconclusivo Andings as regards any correlation between feed ing antibiotics and the establishment of specific bacterial types When ant! bloties are administered, the total numbers of bacteria In mmples of the in testinal contents chincteristically decrease for a few days and then lacteuro above the original levels. Perhaps antibiotics suppress certain bacterlal forms which are inhibítory not only to the growth of the host but also to the growth of some of tho other intestinal bacteria The prolonged and widespread feeding of antibiotics to farm animals has not led to deleterious results or to the establishment of resistant strains of pathogenic bacteria. There is much evidence which indicates that one of the results is that the premises may become cleaned up so that the growth of tho resident antmals is Improved even in the case of those animals on tho same premises which aro glven unsupplemented diets ANTIBIOTICS IN NUTRITION | 95 ·21 MANTY G. J. Aminobetroto wd and rulfonamides fn nt nutrition Proc. Soc. Exper Blol & Mod 51 86, 1042 22 MONTHOUD, NP, AND MATTILA, O J: The effect of some myl antonio moku a experimental coccidios tofecticon fa chicken, J Permatol. 39:20, 1846. 23. STOGTAO E L R, AMD Jura, T E. Further obramation on the mful peotel fuctor Proc. Soc. Exper Blol & Mod. 73 523, 1850 24. WEIHIL AR, OLTRON J J AND HUTCHINO B L: Sturtilatory afect of turcomycto on the growth of chicles, Proc. Soc. Exper Blad & dlod. 74:11 1050 25 Gromis, A. Cm 40 ETAM, R. J. Effect of aatblotla, synthetto vitamins, vitab Biz add APF Pupplement a chick growth, Poultry Sc. 99 816, 1850. 26 LUI, AW: McMiJPY W N, AND TORP P. 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STOWSTAD E L A, AND Jom T H Growth-promoting effect of aureomyco ou turkey poults, Poultry Sc. 29 811, 1850 199 MODO, J. Brna, LR STINK J M. Walcor, R A AXO BLANC, G E.: Tbo dfect of narcotryan and streptomycto a growth of chicks and turkey poalos, Poultry Sc 29 771 1950. 200. MICGronn, J, STOIX J R Wacon, R. A., AND CANVAR JS: The effect of different antibiotias on growth of turkty poults, Poultry Sc 30 192, 1951. 201 KMG, E A. AXO Froz, JC The response of chicks und poult to Low Lovels of mtibtoties, Poultry Sc 30 821 1851 202. WowA, O M1, AMD Hol, ) E: The effect of antibodia on the growth of two vrletla of turkoy poults, Poultry Sc 31 78 1852. 203. HOUTO, GF AXD Nomno, L C.: Sousa romult of fooding antiblodas to chickens, Poultry Sc. 31 857 1852 204 Low, R. W. AND SANTOR, PE Uso of equivalent level of antibiotic and vomin B13 supplements with cottonseed and soybets all meal to chick diets, Poultry Sa. 82.208, 1053 205 LLUL, R J AND BIRD, H R Embuation of antibiotic feed supplement and crystal Ho aptthlotia ln chick nations, Poultry Sc. 32 531, 1853 208. BRATION H D.: ANDALON G. W AND Foz, DC. Antibioda and the growth of dock, Poultry Sc. 32:335 1853 207 Rokus, TD RETHOLD, J W., wm Walser, E. F: Tho influence of vrlow levels of peoleilio and streptomycia o rate of growth and feed iicmcy in broller diets Poultry Sc. 30.929 1051, 208. Pomo, H J1 Osona, E. B.: BADOOT A. CAND LIETADLA The effect of feeding crudo połymyrin D on the intestinal bacteria of chichens, Poultry Sc. 29 5.20, 1850 209 Brunox, HD AND HOL, D C Tbo comparative effect of solblothes on the growth of poults, Poultry Sc. 30 783, 1951 210. STOO, J IL SUBURTIL, J MNAND MOCra, J: Lack of growth response of tarkey poults to cortalo natrodotio tod bacteriostate agents Poultry Sc 31:179 1852 211 Pean, H. T. AND ROOGEN, NE Effect of streptotherido oo chic growth, Poultry Sc 31:1104, 1052 ANTIBIOTICS IN NUTRITION 1 107 ·174. Slov, S. J; Benczy J E PIPA, W F; Sm, ES, AND ADH, D. Efect of antibiotia on tho protetn requirement of broiler, Poultry Sc. 31:"57 1842 178 SCOTT H. M Gomi E, A, AND GLIJE, W A.: The protein roqolament of the chiet u influenced by apreomycin, Poultry Sc 31 751, 1952 178. SADA, H. C.; Stan, M. E. BLATLOKI, LC, Carta, J S. ARD NCCDove, Li Efoct of dietary penicillin on the efficiency of protein utilization by chicks, Arch. Btcchem. 44 348, 10:58. 177 SQUA, H. C.; BUATLOCI, L G Carva, JS, AND MICGDOND, ) Festoo affecting the growth response of turkey poults to antiblottas, Poultry Sc. 39 788, 1853 178 SLINGA, SJ GARI EM, PAP, WF AND HUL, DC: The Arcoco of animal protein factor pupplements and antibioties on the incidence od severly of whito fathas in turkoys J Nutrition 43 845 1851. 179 BILLY J MARCH, B E AKO STE, D F: The effect of feeding antibiotikas on the arbobydrato mod proten requirement of the chick, Ponity Sc. 81 863, 1802 180. MATTERSON L D Sorror, E P Deco, L, AND Locot A: The toenco of protoo lovel, atreonycto uod vitamla Bu on the growth cod food afsloocy of chica, Poultry Sc. 31:040, 1852 18L WHITE-STEVINI, R, AND 200, H. G. Chlortetracycline to relation to protda kerel of diet on growth oflclency of whlto rock bralkers, Poultry Sa 33 BQ, 1954 182 CATION D V JOU A H., HOMITA, PG MADDOCI, HL. M., AXO AO TO, G C Ro-ovaluation of proteia requtrements of growlog fattening wine Infocuced by feeding an antibiotic, J Animal Sc. 11 221 1952 183. Joan, A. H.; Acke, DC; MADDOCI, E. MADETOX G. C. HOWER, P C. HLADY E O AXD CADON D V: Different protein lovebs with mod without watt blodica for growing intshing wino effect on growth nto and feed eictency J Antral Sc. I{ 60 1955 184. BLAC, A, AND BATZA, JW: The effect of a vitamin Bu Applement, vitamto Bu, od stroptomycin on the metabolism of the nat, J Nutdtoo 7: 180 1852 185 KW, L K AND BLAC, A, The Inffocace of vitamto Bus and antibiotikas on prototo und nagy utletion to low proteta diet. J Natrtton 18:477 1852 180. CAROLI, N W HDIIY GW, Stirn, CL WILCOX, EL, AD GHAFAX W Ai Aboorption of nitrogen mod untro adds from mybean meal u affected by heat trotovent or ripplementation with roomycto kod methodne, Arch. Bochen. 45 260, 1053 187 HPALIY G W., Carros, A W; WILCOI, EL, AND CA, W R. The effects of turconrycto end methootno supplement fod to mb recetving robomo preb, Arch. Blocbern. 45 270, 1054. 188. Bont ME AND Scruca, Car Tho ofoct of nurcootycin on growth and protob utilization in tho nt, J Natation 54 971, 1854 189 Faxon, R. M. Stadion on the Influence of antiblottas kod metbaloo oo oftrogno Otilization and benl metabolion of the growing mele albtoont J Nutrition 53.875 1854 100 HARTBOOK, E W, AND JOHOR B. C Efects of dietary terramycin and methioboo Ropplanoat o fat and protea gains to remakng rates, J Nutrition 511205, 1958 191 MEADS R J, AND Foran, A M. Tho bofluence of borcumydn and vitamoto Buy aboo and in combiontion on otrogen utilisation by growing swing J Animal Sa Io prom, 100% 106 | ANTIBIOTICS MONOGRAPHS ·192. JILADC, R. J: The Influence of proten content of the diet and of aureonydo md/or Hamin B12 supplersentation upon performance of growing fattandng plgy Animal Sc. In preu, 1033 183 Brow PB, BC, D E TO, S W., AND CAM, L E: The afect of 207ca mycin on the growth iod metabollo of the pig, Arch Blochem. 41:378, 1852 18. Robo J M Haxon, L E. AND JALA, I J Effects of amnllo mod sod aureomyeo on nitrogea balance in pigs, Scientifio Journal Series of tho Allocata Agri cultural Experiment Station, J Antmal Sc. In press, 1853 105. Cur, EF AND FOLD, J P Tho assimilation of emino acide by becterie: 15 Ac- Hon of unoblothes on nocleo acids and protein synthesis in Saw Blochon. J 53 493, 1953. 104 LAMID, C. W Antibiotas os growth stimolants for dafry cattle J Datry Sc In pren, 1955 197 CATDON DV Antibiotics in swine outrition, paper prevented at the Univoority of Woondi, Nutrition Conferenco, 1953. 188. STOOTAD, EL R, AND Jum, TT Growth-promoting effect of aureomycin on turkey poults, Poultry Sc 9 811 1850 199 McGo, J. Ben, L. R. STOTO J R WILCOI, R. A AND BEAM, GE Tho dfect of aureomycin and streptonrycin on growth of chicks and turkey ponlt., Poultry Sc. 20 771, 1850. 200 McG, J Ston J R., VILoos, A. A, AND CANVI, J S Tho effect of different katblotias on growth of torkoy poula, Poultry Sc 30-492, 1851 201. KADE, E H., AND FATI, JC Tho roparso of chicks and poults to low lovels of antibiotier, Poultry Sc. 30-921, 1951 202 WOLNO, O 11, AXD HAL JE The effect of antibiottes on the growth of two varieties of turkey pouls, Poultry Sc. 31 700 1952. 203. Iloon, CF, AND Norm, L C.1 Somo remull of feeding antiblottan to chickens, Poultry Sc. 31 857 1852. 204 Low, RW, AND SANTOR P E. Use of equivalent lovels of soubtoto and vlburdin B12 sopplandents with cottonseed and soybean all meals in chiet dets, Poultry Sc. 38:288, 1853. 205. LOLL, AJ AMO BI, IL R Evaluation of mublotc feed supplement tod ryttal Hve lotiblodas in chick nation, Poultry Sc 33 531 1855. 200. BRAXON HD AXDOSSOW GW AX FOL, DC: Antibloda od the growth of dock, Poultry Sc. 33:335 1853. B07 Roos, T D. RETXOLD, J W AND WEF, The Influence of various levels of pealetten and streptomycin on nato of growth and feed eficiency to broller diets, Poultry Sc. 30 929 1851. 208. Porno, IL J4 OREN, ED: BAKEDOT A G, AND LOODINI, LA: Tho effect of feedlog crode polymyalo D on the intestinal bactate of bider, Poultry Sc 29 50, 1850 200 BRANDON, HD AXD HIAL D C. Tbo compantivo edect of antibiotia on the growth of poults, Poultry Sc. 30.783 1851 210. STROJ R: SIBUNTIL, J LICN, AO WcGooxts, J. Lack of growth response of turkey pools to contala Roubioda od bacteriostatio agents, Poultry Sc. 31:179 1852. 211 Peaa, H. T, AND Ropcz, NE Effect of streptothekin on chikt growth, Poultry Sc. 31:1104, 1052 ANTIBIOTICS IN NUTRITION | 107 ·174. Suoran, S. J BENCET J E Ppp, W F; SO, E S, AND ACHT, D.: Elect of ontbloda on the protein requirement of brothers, Poultry Sc 31:757 18 176. SCOTT H. M Goms E. AAND GLDTA, W Ai The proteto requtrument of the du Influed by trenyin, Poultry x 31 751 1852. 176. SADA, A C: STAM, M E. BLATLOCI, L G., CANTD, ) S. AxD MP, Effect of dietary penkeilin on the efficiency of protein otilization by chicha, Arch Blo chem. 44 340, 18:59 177 SATA, H. C., BLAYLOC, LG CARYO, J AND MCGINNE, J Factors affecting the growth rospoore of turkey poults to enthlotion, Poultry Sc. 22 788, 1852 178. SLUNCI, S J: Gun K M., Perp, WF AND HIL DC: The Indence of animal protein factor popplement mod utbiotia on the toddence and sevedly of white feathed to turtoys, J Nuteltlon 43 845 1851. 179 BIELY J MARCH, B E, AND SHIH, D F The effect of foeding antibiotia on the carbohydrate mod proton roqufrement of the chick, Poultry Sc. 31 863, 1062 180. MATTEPRON LDSMOD, E P De LAND LOT A: The toddence of protoo lovel, aurcomyda and vitamin Bu on the growth and food edency of chiclo, Poultry Sc. 31:840, 1952 18L. WATE-STEVKA, R, AND ZOO, H. G. Chlortetncyclino ta relation to proteto level of diet on growth officiency of white rock brothers Poultry Sc. 33 50, 1054 182 CATHON D V Joan A. H. Hoona, PG Masdoc, IM AD ALCOTTOM, G C Roordation of proteo requtranents of growing fattening woo o tadorned by feeding an antibiotic, J Animal Sc. 11. 221, 1952 183. JQUOT A. H. ACE, D C.; MADOOCI, H. M. ANTON GC HOHIYA, PG, HLADT EO AND CATION D V: Different proteta Lovol with and without anth biotics for growling-Anhblog wwdot affcot on growth rato and focd didency I Animal Sa 14 00 1955 184. BLAC, A, AND BATAN, J W: The effect of vitamin Bu supplement, vitamba B13 od streptomycin on the metabolion of the nat, J Nutrition 17:150 1852 185 KROON, LK, AND BLAC, A: The influence of vitamin B and antibiotos on proten und cergy utilization in a low proten diot. J Nutrition 48:477 1052.. 188. CANNOLI, RW HOLLIY GW. SIITLE, C. L, VICOS, E LA GLALAK W A: Absorption of altrogans and audio acids from woybean meal u affected by hant treatment or supplementation with aurconnycto and methionina, Arch Bloche. 45 200 1033. 187 HOLAT GW., CAMOLL, R. W WALCOI, E.L., AXOD GRAHAM, W R The effects of suroomycin and mothlontae supplement fed to mb receiving woybean meal, Arch Blochem 45 TO 1853. 188 Bonny ME AND Szocx, C. The offect of atreonrych co growth and protea aulination in the nt, J Nutrition 54:271, 1854 189 FORIT, PLM Studios on the infidence of antibiotics and methoolpo co nitroge utilization and banal motabobum of the growing male albtoo nat, J Nutrition 53.STA 1854 180 HammoosE. W., AND JOONTOH B C Effects of Hetary termonyeto and methtonton rupplemento ao fat and protein gatos ta preudling nts, J Nutrition 51:205, 1858 191 MLADE, R J AND Fome, I 1.1 The bofucce of curtomycin and villamo Bugaboo od to comblonton on oltrogco utilitation by growing swins, J Antwal sa Lo priest 1855. 106 | ANTIBIOTICS MONOGRAPHS ·10_ ALADT, R. J. The influence of protein content of the diet and of eureomda and/or Hitamla Bj Pupplementation upoo performance of growlog fattening pigs Animal Sc. La pross, 1955 183 Bronx, P B. BODER DE TEARLS W., AXD CARD, L E.: Tho effect of more myen on tho growth and metabolison of the plg. Arch Blochere. 41 378 1852. 101 Rosto, J 11 HARDOX L E, AND J020, J J. Efects of unallio add and bureau mydlo co nitrogen balance to rigs, Scenilo Journal Series of the Winnesota Agri cukul Experiment Station, J Animal Sc In press, 1955 195. 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The effect of different antibiotia on growth of turkey poults, Poultry Sc. 30 192, 1951 201 KIT, E , AND PNTI JC Tho smsponse of chicks kod poult to low Loveb of antibiotics, Poultry Sc. 30 921, 1951 202 WwwA, O AL, AND HOL, JE The effect of antibodies on the growth of two vuoletion of turkey poulto, Poultry Sc 31 789 1852 203. Home, GP AKO Nomes, L C.: Some remlts of feeding antibodies to chicken, Poultry Sc 31 857 1852. 204 Lowo, RW AND SAXTORO, PE Uro of oqutvakat levels of antiblotto and vihamia Bu Applements with cottonseed and soybeen oll meals in chick diets, Poultry Sc. 32:268, 1953. 205 LILI, RJ AKD Bưu H R Enlation of antibioto feed Applements and crystal. llo otibiotics tn chick nations, Poultry Sc. 32 831, 1853. 200. BRANIDO HL. D; ANDERSON GW And Hal, DCi Antblothes and the growth of docks, Poultry Sc. 32 335, 1858 207 ROMKOST D. RETHOLDAJ W AND WALA, E. F: Tho informace of various Lovels of pendolo and streptomycin onto of growth and feed diciency in brola dieta, Poultry Sc. 30 929 1931 208. PITUD, H J One, E. B. BONDIT R. G., AD LDIDDO, L. A. The effect of foodlog cudo połymydo D on the Intestinal bacteria of chickens, Poultry Sc 29.520, 1850 209 BRAXION H. D AND HA, DC: The compartire dfect of antibodies on the growth of poult, Poultry Sc 30-703, 1851 210. Stox, J A., SULPUNTA, J BicN, AND MOC, J. Lack of growth respose of turkey poult to certata antibiotices and bacteriostate agents Poultry Sc 31 179 1952. 211. Praz, H.T AXD HOOCR, NE.: Effect of streptothrida oa chick growth, Poultry Sc, 8111104 1052 ANTIBIOTICS IN NUTRITION | 107 ·174. SLIGA, SLBALT I E; POTE, W F, SNYDD, E S, AND ARTisus, D: Efect of antibioties on the proteo requirement of brollen, Poultry Sc 31 757 1862 176. Scott HM; Gorn, E A AND GLUTA, VA Tho proteta rogatrapent of the chick u foluenced by moreomyen, Poultry Sc. 31:751, 1952. 176. SAIDA HC STAR, ME BLATLOC, LG Camm, JS, AND MOCOOCA, LA Effoot of dietary penicilin on the iciency of protots utilitation by chiote, Arch Blo chem * 340 1853 177 SAIRA, HC BLATLOCI, L G; CATVR, JS, AND MOC, J : Pacto offecting the growth raporto of turkey poults to notibdation, Poultry So. 33:788, 1851 178. Suza, SJ GAXTLI L. M. PEPE, WF, AXD HILL, D C.: Tbo in loco of wutmal proten factor supplements and antiblotes on the toddence and severity of white father in turkeys J Natria 49 345 1961. 170 Biar J MAKEL B. E, AND Suomi, D F Tho afect of feadhg antibiotice on the carbohydrate and proteto roqutrements of the chick, Poultry Sc 31 BR, 1992 180 MATTARON L D. Soroc E. P., DECODE, LAND KOut A Tho filoenco of protein lovel, cursomycin end vitamin But on the growth and feed sledy of chicke, Poultry Sa 311940 1852 18L WAQI-STEVIA A AND ZOR, G: Chlortetracycltoo lo relation to proteta lovel of diet on growth oilclency of wholto rock brollars, Poultry Sc 33:50, 1954, 182. CATHON D V., JAUDX A. H. Hovm, P G MADDOCI, H. M, AND AHTOK, GC Roovalnation of proten requirements of growtog fattening wou infoenced by foodtg an antibiotis J Animal Sc. 11:221, 1952. 188. JAKICK A H.; Acca, DC; MALDOCI, H. Mor ALETOM GCHOITA, PC HEADY E. O. AMD CATRON D Different protein lovebs with and without anth blothes for growing-finabing swino effect on growth rato and feed eficiency I Animal So. 14100 1865 184 BUCI, A AWD BLATZ, JW The sect of a vitamin B1 opplement, vitamita Big and streptomycin on tho metabolam of the nat. J Nutdthon 171150 1992 185 KODO, L. L AND BLAC, A. The Influence of vitamin Bus and antibiotta on proton and coagy utilitation to a low protein diot. J Nutrition 48:477 1852 188. CARROLL, R. W: HUR G. W., SITTLQ, CL Wacor, E L AND CHALAM, WA Abecerption of nitrogen and amino acids from soybean noel u affected by heat treatment or applementation with turcowycto od metlicaina, Arch Blocha 45.280, 1953 187 Hoan G W Camou, R. W Wacor, E. L, AND Crawa, W R. The effects of awroomyelo nod matblootno supplements fod to not recetving roybens meals, Arch Blochem. 270, 1953 188 BONY AI E AND SCHOCI, C. The effect of Rutcomyoto on growth and protebe utilisation in the mat, J Nutritham 54 271, 1854 189 Fox, I M. Studies on the folderco of antibiotics and methionino oa nitrogo utilization and basal metabolies of the growing mele albtoo nat, J Nutrition 53:57 1854. 190. Hamzor, E. W, AND JON B C Effects of dietary ceramycin and methodno ruppledoab oo fat and protea gains to meaning ras J Nutrition 51 2085, 1033 191 Mrads, R. J, AHD Fordon, A M. Tho tfluence of Lorcornyen and vibanda Buy about and in combination on oltraga otilitation by growlog stra J Animal Sa La presh 16. 106 | ANTIBIOTICS MONOGRAPHS ·102. DIEADT, R ) : The Influence of protein content of the diet and a surcornych and/or Hooh Bi suppleritation upon performance of growing fattoning ples Animal So. In preu 1855 183. Brown PB: BECIL, D E., TAN, S. W, AND CAMD, L E: The effoct of narco mycin on the growth ind metabolism of the pig. Arch Blochem. 41 378, 1852. 194. Russo, J M: HANNOY, LE, AND JOOG, J J. Efects of an albic acid and aurcamycto on nitrogen babaco la pigu, Scientific Journal Series of the Monerota Agr! cultural Expatment Station, J Animal Sc. LA pret, 1855 195. GALI, E. F, AND Foca J P: The similation of anino adds by bacteria. 18. Ac thou of entblotics co onddo adds and proteto synthesis lo Scurou Blochem. J 53 483, 1953. 100. Lam, C. W Antblotias o growth summulants for dairy attie, J Dary Sc. In Pren, 1955 107 Cathor D V Antblottas in wae nutrition paper presented at the Untversity of Visconto, Nutrition Conference, 1858 198. STOKTAD, E. L R AXD Jokes, T H Grorth-promoting effect of moreomycin on turkey poults, Poultry Sc 29 811 1850. 199 McGowo, J Bing, L R, STERN J R Wacox, R , AND BUM, GE Tho effect of aureomycin and streptomycto on growth of chicke od turkey pools, Poultry Sc. 2971 1950. 200. McGre, J STORY J L. WILCOI, R A AND CARVIN, J S The doct of different ontblothes ou growth of toukoy poults Poultry Sc. 30-498, 1831. 201. Emas, E. H., AND Farra J C. The response of chicks and pools to low levels of antiblottes, Poultry Sc 30 921, 1951. 202 Wawa, O AL, AND HILL, J E.: The effect of antibotlas on the growth of two muddetta of turkoy poults, Poultry Sa 31 760 1959 203. Hmm, GFAND NON, LC Some results of feeding antibloda to chickens, Poultry Sc. 31:857 1852 204 Low, A W AND SAXTOR, P E Use of oquivalent loveb of antibiotio and vloemia Bu opplements with cottonseed and soybean all meal ta chick diets, Poultry Sc. 39.248, 1953 205 LUL R J AXD BO HA Evaluation of antibiotie feed supplements and crystalline mtiblottas in chick autors, Poultry Sc. 52831, 1852 2:00. BOARDION H. D Am CW AND HOL, DC Anubtoties and the growth of docka, Poultry Sc. 32:33.5, 1853 207 ROM, TD RETHOLD, J W., Axd Waus, EF Tho influence of varlow levels of perlailla and stoptoryca on rate of growth and feed eiidocy la brother dieto Poultry Bc. 30-8-29 181 408 Porno, H J: ODDG, E. B BANDSCT A. GAND LADOIDID, L A: The effect of feeding crudo polymoyun Do the latestinal bacteria of chidos, Poultry Sc 29 820, 1950 200. Baxmox II D AND INI, DC: The comparative effect of antibodies on tho growth of poolts, Poultry Sc. 30:783 1851 210 STIO J R.; STRUKTI, J BNAND McCoons, J. Lack of growth ropose of turkey poults to certain nubloth ood bacteriostate agents Poultry Sc. 31:179 1852 u Pro H. T. AKD Roocan, N E. Effect of streptotbirkto on chikt growth, Poultry Sc. 31:1104, 1952 ANTIBIOTICS IN NUTRITION | 107 ·318. GRAM, WE READ DC AND PODACI J Hi Growth stimolation A compaunattro olunttoo of several othletics on chick and swtoo growth, J Agok. 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SHonor V M, AND SUTRALAM, Li Fatty Hver following to comych od ter myefo thanpy to chronio hepatic discors, Costroenterology 18:48, 105L. 116 | ANTIBIOTICS MONOGRAPHS N ·SL FALOOS, WW Nou, I W, AND Pron, J T: Nitrogo metaboliem od tror hbtoboxy during atmaydin adminstration to patients with hepatio dicons, J Lab & Cun Mel. 41:500, 1953. 392 SUTIELAND DA MANX J D. Gry B AND SEXRON D: Effoct of awroomycin a liver fat tod liver function, Proc. Soc. Erpet Blol & Mod. 77 458, 1951 383. Jroa T N : Antimetabolites and antibodia us tools for research on blood formation, Am. J Clin Nutrition 3158 185% 80L LITHUAN 11. CADENA, V, AXD WATroy )Theripatto effect of awrocuryanto panicow Lemlo, Proc. Soc. Espe Blol & lied 74:881, 1850. 383. For 11.: Korn, A AND ILANCHEAVA, A1 Response of megaloblastio momla of preg nancy to crystallio penkalin G, Brt. 21. J 111103 1851 398. For IL, AND honor, A.: Treatment of megaloblastlo anemies. 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Tho influenco of crystallide nurcomycta and vitamin Buy on the protalo otilization of growing fattening swing, J Animal Sc. 13:184, 1854. 104. MOCHIL RD., Dout, K L EATCO H. D, AND ELLIOTT F I: Effect of adding various loved of an arconydo rupplanat to starter on growth and blood constituants of Guernsey calves, Stoms Agric. Exper Sta. INF 488, 1853. 105 Voax, IL, AND JACOBSEN N L Effect of nurloos entblotia and a detageat od of frequency of milk replacement fooding on young datry calvesJ Dalry Sc. 30 502, 1953. 200 OWA, F G, AND ALO, A S. Growth and hematological report of calves to ontblotto ad arzenical oppleraentation J Datry Sc. 371854 1854. *07 Act, F AXO SCADILAK N S.: The afect of opplements of intral and rego table protein, vitaroita Big and streamycia on hematological values to Central Amert co school children, Am. J Chn Nutrition 3.225 1955 +08. MOLITOR, II. AND Grapas, O B.: Pharmacology and topicology of nattblotion J Purecol & Esper Theap 03:1 1050. 109 CUCCION II si The bectolddal action in otoo of arcanerycia lo u aurronyata fermentation reddae against Brucells tuis, Corell Vet 11 110 1851 tla Pony F Aurcomyco w a growth factor la prematuro infants, Ball Social. btol per 2711151 1851 111. ROSTBOK Pi Controlled trial of surcomycin to presosturo twlos nod toplett, Lancet 116, 1862 ANTIBIOTICS IN NUTRITION | 117 ·412 SMOLINO, CE, Jordetox A: The ntao of aureomodo to provention of com infoction to the horpital fa dat children, Camad MAJ 60:6, 185 cm 418 Coac FJ: Studies of tror mycin to prematuro infants, Pediatras 11 0512, 183, 414. Kan, A CAUCHY RH., Axo Moony WW: Effect of vitamin Bu mod coreomycin a otrogen retention for Infanto, Portlatda 13:489, 1854 415 Dichte, E., Influcoce do intibiotique por la cromance, Lml Med. 18-124, 1051 418 Worce, N D, AND HOST000, H. H. Antibiotic mupplawendt overcome growth future to school children ) Agik & Food Chem. 2 1148, 1954 417 ScZWALAY N S.; GUDIAN MA AND TAXDONT O B Effect of kroonryca od penicillin on growth of Guatemalan school children, Fedation Proc. 13:417 1854 418 CARA, C. H. Pokonal communication, 1933. 419 BLACDOUGALI, L: Personal communication, 1955 120. HACHT TH, Aro Pesc, W E. Incluence of small done of antibiotio on the weight behavior of young males J Lab. & Clin Mod. He 1954. UL. Garum, GJ, JACZECH G G, AO Cmor MEEffect of furocaryoto upan nitrogo buknco and urtoery Mboflavio concretion in modanourishod mee, J Cha Investigation 31,631 1952 4%. Tarla J HA CONDON W S, AND BUMI, P: The effect of supplococotting the dlot of thorooghbred foul with creamy to hytrochkodda, Vot Roa 03:744, 1854 23. MURTHY MR. V AND STORIVALYS, M.: Effect of antibodia on the growth of the dharm, Bombyx mor, Naturo 172:284, 1853 424 LAWACS, J M, AO MCGDORA, J. The effect of termuryono to growth of mub bits, Arch. 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·INDEX ·Name Index Inchuding authon cited by Dane tn tert Abol, M. R., 83, ref. 371 Abotulit, H. J., 48 ref. 21 Ambro, C., 63, rof 430 Anderson, GW, 35 refs. 81, 120-181 Antro, F., 65, ref. 271 Ballonn, 8. L. 78 ref. 837 Baer, A., 83, ref. 8.50 Barber RS 49 3,83, ref. 163, 358 Bartley E E. refl878, 274, 279 Baumann, CA 45. ref 107 Buter J H., 87 re£ 383 Bocker DE, 63 ref 2:27 Boston, W M., 73, ref 317 BOIL, M. Cm, 65 ref. 270 BeLT D., 00 00 refu. 175 299 300 Bentley O G. 78 ref 824 Borg, L. R. 59 77 roll. 214, 328 Rory M. E, K, ro. 188 Boveridge, J MR., 85, ref. 871 Bich I 44, 61, refu. 141, 170 Bird, H. R, 22, 77 refl 31, 205 Black, A., 53. rofl. 184, 185 Blylock, LG, 35 ref 194 Bogdaooff, P D. Jr, 50 ref. 109 Bohman, V R., 71, ref 318 Botkins, A1 P 70, ref. 808 309 Bowland, J P 64 ref 240 Bruntom, H. D 58,09 04, reft. 35, 208, 210 Pratha J W 63, ref 184 Brrudo, R., 81, ref 225 Heldgon, J H, 0 ref. 308 Broquet, H P 74, 84, ref. 4L 497 Brow, F 2,34 ro. 193 Brown, J A 77 re£. 829 Hruwa, PB 89 ref. 183 Hurgo, R C., 47 48 49 r. 28 Boroside, J E, 63,80 refu. 285 403 Celotoick, B 81, d. 367 Carreton, H. S 80, ref. 400 Campbell, 41, 87 ref. 845 Campbell, I A, 49 re£. 102 Calm, CW, 78, ref. 340 Carpantes El 77 ref 333 Carpenter L En 21 03, 71, rela 37 228 814 Carrol, RW, roft 186, 187 Caron, R. 79 ref 343 Carter C. H. 91, rof 418 Catron, DY 21 47 31, 57 refs 47 50, 168, 162, 187 Chackoff L L., 81, ref 350 Chance, CM 83, ref. 109 110 Cbox B.F, 48, ref 155 Clark, H. E., 84, ref. 888 Cam Betref. 90 Coates, ME, 21, 22, 28, 45 48, 49 ref. 30, 51 82, 60, 67 149 Colby RW 05 reft. 267 289 Common, RL, 4, ref 140 Coodto, FJ DO, re£. 413 Carnetrer fy E., 87 ref 689 Cooch, J R. 35 ref. 120 Crryloto-Alopo 40, ref. 157 Cube, T ].21 ref. 48 Daft, F 8., 45 ref. 148 Deroy RJ 73, ref 818 Dóchane, E., 90 ref. 415 Do la Hoergi, ] 86 ref 683 Deshmukh, PL, 88, no. 9 Domen, P L,, ref 455 Deckroth, I 77 re£133 Dưgnan v w 6, rc 8, 297 Dyer LA, 79, ref 316 Elam, J F, D9 82, 86, 76, 77 ref. 76, 128, 935 Elbott, R, F., 70 rok. 307 Elsworth, Sm, 70 ref 307 Emorront, Gref 180 Enhoff B H, 81, ref. 944, 445 122 | ANTIBIOTICS MONOGRAPHS ·Filos, V W., 89, 591 FALRV, 37 e 129 Foto, EF 41 re£. 134 Floe, J 83, ref 300 Toites, P, 35 ref ros Forbes B 11,81 rd. 184, 191 Foy IL, &, ref. 385-397 French, CE 4_ref 13.9 Furth, F1,84 refs. 363-587 rabnten, A. R 50 ref 169 Gabarda, Igref 421 Gal EP 16,55 res o 103 Caillo, D G, 87 ref 398 Garrigus U S, 09 ref. 302-303 Cardon, IL A-5 ref 69 Gardon, IV S 57 re£. 150 Greek, O E89 ref 408 Great, WC, 81 82, re{ 49 354 Cortafron, G. E. 84 ref. 361 Gywy P 85 88, refs, 45 53 Ilak bł, T IL, ..., ref 10 Ilalbrook, E R. ref 331 Halery 8, 45 ref 150 Mentre, D M 83 ret. 429 Haakon, L E 41, ref. 131 Hrncd, B. , 17 ref. 3 Hartrook, E W., 49 84 refs. 161 180 Radield, EE, 60 ref 302 Ilemn, F +43 ref. 431 Hershberger TV , ref. 324 Heywm. B. W.77 78, reft 336 338 Hiba, 33 ref 105 ILL, EG 19 ref. 165 HB, CIL, 59 reft. 216 210 HEG 23, ref. &I Hillam J P., 59 ref 218 Hodgets, Atv og ret 208 Hogan, AG 83 ref 436 Hopwood, II IL00 ref 416 Hos LH Jr., 43, ref. 111 Slowland, J V 84, ref 382 Itape T C., 93, ref 425 Ilahtanen, C, 33, ref 115 Ilamolla F L, 87 ref 399 JCTORET, IL 52, 54 183 Jobanca, B., 40, refl 67 156 Jokeson, B C., 16, 17 54, 82, 83, reft 154 100, 190 Johnson, E. L, 77 ref. 834 Lomon, A., 00, d. 419 Jordan, i ! 66, 9 de 275 899-301 fola, T IL, 44, rdf 143 Laplan, 1, 87 ref 384 Kaja, odse 414 Laby J W 5.ref. 215 hala EM 2, 33, rd. 107 Kemlor F B 69 ref. 298 297 King I OL, 22, ref 58 Kommam, D 1 71 ref 319 Inodt, CB 32, 33 80 ref 107 276 Koble A R4,01, refl 41 437 Kohlmeyrt 1,78 ref 310 Loketsky S., 81 ref 384 Kopel 89 refu 205 397 Entre F Il., ng 34 refs 73, 88 Kricky J L., 21 ref 49 Kunkel, H O 74, rets. 310, 311 Kuratsto, A N 82 rof 331 Lampman, C. E, 77 ref $50 Larson, N 1, ref 314 Largon NL, 23 ref 01 Laulta CW 57 08, ret 190 Lawrence J ML D2, ref 134 Lepine, P 23 ref & Lopper M IL, 87 ref 388 Leeuwenborg, P, 83 ref. 427 Libby DA 39 81 05 refs. 133, 135 348 Lichtman, IL, 89, ref 394 Lih, H 45 ref 147 Lille, RJ 77 ref 203 Lindblados 50 ref. 170 Linkswiler H 45, ref 148 Lodes J B 83, rd. 114 Loort, f , 33, 65, refs. 105 272 Lucky T D 28, 29 refs. 44,71 AlcDaniel, BC 4 ref. 148 Macdougall, L., 91 ref. 119 McGirls, J 82, ref. 424 Machika, L L., 50, re 178 McVay LV Jr 94, ref. 438 Maddock, HM 74, ref. 319 Megbrabs, ML 6, 82, rof 852 March, B 44 ref. 141 Dlartakubandie, A 77 rell Martham FS 85 ref 439 Marttbutes, , 7 Martin, C ) 17 ref 91 Matsushima J 69 ref. 294 Matterson, LD 81 69 ref. 34 184 Laura $ 18, ref 29 Mayfield, O J 17 ref 22 Mado RJ 34 res. 191 19. Mates, I 81 82, ref. 340 345, 350 50 Mellen, W J 82, ref 553 Mlgkorky B. D 50 ref 167 Alllby TT 77 ref 32. Miller CP 81 ref 303 lloltar 11 89 rdf 409 blonsco, 1 F 7 ref 40 Moore PB 17 ref 3 Marehouse, NF, 17 ref. 22 1 12 ANTIBIOTICS IN NUTRITION | 123 ·Moodcom, A B. , ref 599 Durrry TL, 49 ref. 188 Llurthy IL V, 02, ref. 429 Nelson, T S., 15 ref. 150 Noumann, AL 8, rof. 106 Noland, P A, 63, 64, rofs. 98, 244 Ogla, RC, 81, ref. 846 Oloron, J., 44, ref. 149 Olsson, N., 89, ref. 402 Puoles, L, 70 ref. 808, 309 Popper W F, 20 49, 50 refe, 68, 197 171 Parol, F., 90, re£. 410 Perry T W., 04, 68, roto. 245 283, 295 Petente. CF, 77 ref. 830 Plerod, W E 02, ref. 490 Radioon, J J, 83, 34, ref. 118 Richardson, C. V., 67 rof. 258 Richardson, D, 41 ref. 135 Riddalt, W H, 71, ref. 819 Robertı, B. S., 85, ref. 123 Robtao, L. L, 63 ref. 236 Robinson, P., 90, ref. 411 Ratno, P., 83, ref. 450-434 Romotor II., 85 ref. 119 Ron, En 19 ref. 100 Roy H. B, 67 rof. 287 Rwrot, L L., 83 85, 89 roft. 88, 119, 205, 878, 280-288 Russo, J M., 54, ref. 194 Sarott, HP, 45 ref. 151 Sanbolich, H. E., 46, ref. 1.59 Surco, H. C., 51, 59 ref. 170 177 Sbarov V M., 87 ref. 890 Schalbla, P J 89 85 roka. 133, 185 Schad, LLE, 46, ref. 184 Schock, C., 34, ref. 188 Scott, H ML., 45 51 rofs, 159, 175 Scott, M. L, 35, ref. 125 Scorshaw N S. 01, rof 417 Seto, T., 87 ref. 388 Sheffinar CS60, ref. 168, 169 Spoly B.Em 17 ret. 180 Sherwood, DF, 77 raf 338 Sloborth, J MN 29 ref. 72, 75 Slogren, E P., 5. 84 Stredare, J R., 74, rofl 4, 399 Stinger S, 42, B1, 76, refs, 187 178, 825 Smith, D C., 44, ref. 139 Smyser C. F Jr, 8%, raf 103 Spellboy, CE, 90, red. 419 Speer VC, 23 rd 48 Sprint, D 8., 94, ref. 438 Sroentvway, M, 82, ref. 493 Stephenson, E L 87 ref. 149 Stolatad, ELR, 44, ref. 143 Sood, M. L., 77 ref. 897 Sutherland, D A 87 88 robe *90 822 Sherlog, M. J. 64, ro. 248 Tarra FR, IT, 84, ref. 261 Tauros, A 82, rał. 850 Taylor J H, 37 92, re£. 160, To, A, 81rot. 851 Tan, S. W., 91, ref. 49 Tovran, E, 68, ref. 293 Tube D E., 89 ref. 300 Turner, A W., 60, ref. 298 Turper CW. 82, ref. 858 Umbrott, W W, 18, rof 14 Ungley CC, 80 ref. 401 Vartal, CM, 84, 73, refs, s2, 815 du Viground, V, 50, rok 137 Vyunghans, P 1, 83, rok. 428 Waibel, P E. 88, 46, 45 74, 77 ref 182 144, 145 Wahlstrom, RC, 17 63, 82, 83, reft 100, Wallace, IL D 64, 05, reft 307 178 Wala, EF, 8%, re£. 353 Watan, C. 11, 80, ref. 400 Wakley CE,Jr 30, rof. 178 Wetzel, N D., 0, ref. 418 White, EG-2, ref. 58 White Storcos, A., 51, , 78, raf. 181, 4, 839 849 Wbituary, R., 43. raf. 427 Williams, W L 29 87 63, rete. 74, 131 WIbon I E 89 ref. 197 Wit, LJ 80 rof 400 Wong & C, 74, rof. 820 Y conft, , 19, ref. 108 Zebel, H. G, SI 50 78, rod. 181, 284, 339 Zimmerman, H. E, 87 raf. SO 124 ANTIBIOTICS MONOGRAPHS ·Subject Index Anela -treatment with antibioties, 88-50 Animals - See deo under some of ontmolt - roubtotic feeding in animal prodoction 57 79 - conclusions, 85.00 Stro-free: -effect of foeding etibotia 28-29 reprodoction - effout omubiotic foeding, 71 79 Andatothen - ofoct on bacterial metabolism, 15-16 - on blood formation, 89-89 -oo chodbe and Dethlonfpe deficiency 85 -aegs prodoction in hens, 74-9 -on Intertinal bacterie, 19-20 -ootatertimal flon, 20-32 -on liver phytology 81-88 -00 m.ing Dese metabolkm, 50 - otrogen metaboliem, X-5 -on betrlent reqatramenta, 44-50 - protein requirement, 50-83 - reproduction to animal, 71 70 - on tumen microorganisms, 82-34 -rooipants, 63-71 -on strons conditions, 83 - vitamin rogarements, 44-50 -vitamin A, 47-49 - lamin B comples, 44-57 - vttumn D 49-50 -feeling to mal production, 57 79 - conclusions, B5-96 grouth foct. tibiotic talent intestinal microor Gintong at parce of midanuilled growth factor, 8438 -elfect of clans and dirty cyfroatient 00, 12-24 - effect of prolongod nowo of antiblotto feodine 38-12 - in geson-free animab, 28-20 - to human mbjects, 90-92 - mechanism of 13 17 18 10-42 - on chick embryos, 24-22 moopbologlo change produced by in chick, 25-28 - pharmacology 89-90 - physiologie effects of antibiotio fooding, 81-89 - production of, 15 - therapeutio wo to Anemia, 88-99 Aureomycin - Svo Chlortetracycline Badtrocin growth offect - Dot activo when injected, 20 - structural formula of bectracta , 15 Bacteria - affect of apulotla og metabolism, 18-16 - effect of chloramphenicol, 18 - effect of chlortetracycline, 16 - affoct of penicillin, 10 - effect of streptownyota, 18 intentira - affects of entblotios om, 17 18, 19-20 Bib Bography 97 119 Blod -effect of antibiothes on blood formation, 88-89 Caldun -edfort on unubtot feeding on requlroments, 49 50 Calres -elfort of chlortetracycline feeding og growth, 60-57 Carokcse -effect of antibiotic feeding an atrotre Tourtosents, 47-49 ANTIBIOTICS IN NUTRITION ! 125 ·Catth. -ofoct of mobiotic feedlog to beef cattle, 67-00 -chlostotracollag 67-69 70 Chlek Embryos -offoct of antibiotics on growth, 24-3 Chickers - Se aloo Poultry effect of mubotto foeding a proteto roqurunents, 50-51 - afect of hydrolized penicillin oz growth 36-38 - effect of prolonged uro of antibiotic fooding, 88 -porphaloglo chenga produced by feed. Ing aatihlotka, 1-29 respiratory dispone - intlbtotio fooding th, 89-61 - chlortetracyoltre, 5001 Children -- growth afect of antibiotics an, 90.42 Chlorurophenload -effect on bacterial metabo Hom, 18 Chlortotinoschino - comparison with colortran in feodling alves, 67 effect on bacterial metabolka, 18 -on chickory with chrodo respiratory cupcak, 50-81 -on egg production in her 78-79 - guinea pig 3 -am intortidal bactada, 17 18 - nitrogen metabolion, 59-55 -on proton requirements, 51-59 -oo nabbits, 82 83 - a reproduction in piş, 72-74 - o rumen polcroorgan tros, 32-34 - on the thyroid gland, 81-82 - on vitamin A reguraments, 49 - an vitamin B coopler requirements, - vttunta BIL 46-47 formatation due -- tan foodtog pigs, 2-63 growth effect - actio when infected, 80 - affect of environment on 29-23, 24 - a bocf cattle, 68-10 70 - datry calves, 60-67 89 - og barna, 822 - ou lampbe, 09-70 - milco, 83 -oppig, 63 - oprematuro infants, 90 - kurs, 99 - in provention of a neurods, B8-88 - protoctive ngutest aloon dubeta nt,&3 - structul formula 14 thespeutic to - ta doua of the liver tamom, 85 farlotty --Doutodo o prolonged sdmhdstrabiom to human subject, 04-05 Chaline delstency in dict, 84*5 - effoct of ontblottas an, 63 Colostrum - compete with chlastorcydoo in feadtag aalves, 67 Com - Do efect of clater cycle on couture botating.com, 07 Dlabota Hallitus aportante chlortatracycline protecttro sgulast alkanun duabetos to n., 83 Eggs - affect of antibiotto foeding of the han, 74-78 -- focreading batobability T470 Endocrino Glede - olfact of antibiotio feoding, 81-84 Erytrocorticot - affect of clean and duty arvironment and antibiotic growth offoct, 232-84 Foroward, 7 11 Guinea Pig - chlortetracyclino not too far os - penicilio tanke foc, 93 Hao production Se de Ege -effect of antiblotto fondtag on, 74-78 raptratory distan - efect of ontblotic feeding op production by bens with obroalo respiratory drepte, 78-70 Hooral effect of chlortetracyclind on, 02 Induti prandort effect of chlortor cycttoo as, Latortina fors - Srdoo Bacteris intacto -- enth tonto-tolerant totestinal microor ganoon oportco of ontdentified growth factor 34-38 - offect of antibiotic feeding 09. 19-312 Lambs -efect of mbblodic foeding 89-70 - chlortetricytos, 60-70 126 | ANTIBIOTICS MONOGRAPHS ·Loret -effect of oublotos on, 81-88 donct - treatment with chlortetracycline la man, 86 fot - effect of untblotias on, 87-88 Home! -beoeficial facts of antibioties, 21 presention by chilortetracycline 83-88 Mmg det - dilect of moublotio feeding on marga Deso metabolism, 50 lett fect of nattblotte fredlog on quality of 616 91-85 Vethtonino - deficiency in det, 81-85 - effect of antibiotla on, 85 Ice - effect of chlortetracyclino on, 83 trogen Metabolisen -elect of antibiotic feeding on, 53-55 - chlortetracycline 83-55 - Qytetracychne, 51 \utrition -effect of feedmg mubtothes on thora quirement for nutrients, 43-55 Orytetracyclino - efect on otrogen metabolien, 54 -on rabbits, 02 83 growth of oct. - garo-free poultry 26-29 -- Structanl formul, 14 Pealthn - efect on bacterial metabolum, 16 on vitamin A requirements, 49 on vitamto B comples roqutreurents, - vitamin D requirements, 49-50 grouth afat. - active when injected, 20 -effect of erytroarent (, 23-24 - growth of animals recetvtog hydro- Irred pentolin, 36-38 - structural formala, 14 tosketty: - toode for gutna ples, 03 Phorpborus - afect of antibiotic feeding on roqutrebentu, 50 ho -efect of antibioto feeding a growth 57-59 61-04 -chilarten.cycline, 63 - effect of entblotic feeding on protein to quirements 51-53 - effoct of chlortetracycline on nitrogen metabolion, 54-55 - effect of hydrolized peolella on growth, 87 - effect of prolonged wo of antiblotte feeding40-48 reproduction - effect of antibiotic feedlog T2 74 - chlortetracycling, 72-74 Poultry - efect of antibiotic feeding on growth, 58-59 Sehin fror -effect of feeding kotibiotics, 26-29 Protein -offoct of antibiotic foodig oo require ment, 50-63 chlortetracycling, 81-53 Pubko Halth - offect of antihoto feeding of animal, 91-85 Pabbits - effect of chlortotnyclino and anytette cyclino on, 82-83 Roma microorgelmut -effect of ontblotic feading an, 32-84 Rumambo - effect of antibiotic feedig. 85-71 Skworous - effect of chkatetracycline ag, 92 Streptongoa aureofacimus fermentation producto - effect on animal growth, 18, 21 Streptomycto effect on bacterial metabolism, 16 - on intestinal bacteria, 17 - og nitrogen metabollam, %3 growth ofect - not active when tofectod, 20 - structural formula, 14 Stress - effect of antiblotxc feeding on stres con ditor, 83 Sulforumidos - tn animal feeding, 18-17 Tortumycin - Sec Orytetracyclino Thyroid gland -effect of chlortetracyclino CD, 81-83 Vitamin A antibiotics on requirements, 47-49 - lect ANTIBIOTICS IN NUTRITION | 127 ·-chlortetricyollos, 49 --pantalin, 40 Vitamin B Compla - affect of mabiotic fooding on require meat for 44-47 -ofect of chlortotracycling, 44-47 -offect of pealehin, 44-45 Vibumin Bus -offoct of chlortetracyclino co roqutro ments, 46-47 -rodo in cholion methods deficiency 85 Vitamin D -doctol sotiblotte fonction angel maat, 49-50 - penicillin, 0-50 Vitamins - deicteary produced by commodo 10-17 - fact of Antiblotta a rede

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·ANTIBIOTICS MONOGRAPHS | 4 tibiotics in nutrition by Thomas H Juhes PhD nch Division AMERICAN CYANAHID CONTANY New York weword by HENRY WELCIL, PILD. AND FELIX MARTI IBAÑEZ, 21.D. A Publication of CAL ENCYCLOPEDIA, INC 30 EAST 60th STREET NEW YORK 22 NY