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APPENDIX F ZOONOTIC ASPECTS OF SUBTHERAPEUTIC ANTIMICROBIALS IN FEET) John F. Timoney1 BACTERIAL COLONIZATION OF HUMANS The pathogenic bacteria found in animals and humans can be arranged into two groups based on their host specificity (Table 1~. The first, and by far the largest, group contains host-adapted bac- teria, most of which are uniquely adapted to specific hosts and rarely infect or colonize other hosts. This specificity may be an attribute of genus, species, serotype, phage-type, etc. The second, and much smaller, group of bacteria have limited or no host speci- ficity and may colonize or infect a variety of hosts. Transfer of these bacteria between host species may occur at a perceptible rate, but this rate is difficult to quantitate because of overlapping reservoirs. Only salmonellae in the second group, some serotypes of non- pathogenic Escherichia colt, and possibly some strains of Staphy- lococcus aureus may be involved in the transfer of antibiotic resistance genes between animals and human beings. THE TRANSFER OF BACTERIA FROM ANIMALS TO HUMANS To what extent do bacteria from poultry, pigs, or calves trans- fer to humans? Is the transfer greater in farm workers, rural in- habitants, and meat handlers than in others? Is food contamination the primary route of transfer? These questions are addressed in the following paragraphs. E. cold and Salmonella are used as models since these organisms appear to have the greatest potential as vehicles for plasmid transfer between the reservoirs in animals and humans. E. ooZi There remains substantial doubt as to whether strains of E. cold from farm animals (poultry, pigs, calves) contribute to the composition of flora in the human gut (Garrod, 1976; Siegel, 1976; Siegel _ al., 1974~. Tools used for studying this issue have included serotyping (Bettelheim et al., 1974; Howe and Linton, 1976), phage-typing (Siegel et al., 1974), and a combination of Department of Microbiology, New York State College of Veterinary Medicine, Cornell University, Ithaca, N.Y. 182
183 TABLE 1 Representative Common Pathogenic Bacteria of Humans and Animals Grouped According to Presence or Absence of Host Adaptationa Adapted to Host Act inobacillus lignieres ii Bordetella pertussis Brucella abortus Brucella cants Brucella ovis Campylobacter fetus (venerealis) Clostridium perfringens Type A Clostridium perfringens Type B Clostridium perfr~ngens Type D Corynebacterium diphtherial (humans) Enteropathogenic E. colt: Specific serotypes for lambs, calves, infants, humans, piglets, and older pigs Erysipelothrix rhusio- pathiae Haemophilus influenzas Haemophilus suds Moraxella bovis Mycobacterium avium Neisseria gonorrhoeae Neisseria meningitidis Salmonella cholerae-suis Salmonella pullorum . Salmonella typhi Shigella spp. Staphylococcus aureus-- Most strains are adapted to specific hosts (Davidson, 1972; Gibbs et al., 1978; Shimizu, 1977; Wang, 1978) Streptococcus equi Streptococcus pneumonias Streptococcus pyogenes Treponema hyodysenteriae Treponema pallidum Not Adapted to Host . (cattle) (humans) (cattle) (dog) (sheep) (cattle) (humans) Bacillus anthracis Some se rot ypes of nonpathogenic E. cold Listeria monocytogenes Pasteurella pseudotuberculosis Salmonella typhimurium and many other serotypes Staphylococcus aureus--A few strains may not be adapted (sheep) to hosts (Live, 1972) Klebsiella pne''moniaeb (sheep) Proteus spp.b Pseudomonas aeruginosa Serratia marcescens~ Yersinia enterocolitica (swine, turkeys) (humans) (pigs) (cattle) (birds) (humans) (pigs) (poultry) (humans) (horse) (humans) (humans) (swine) (humans) From Bruner and Gillespie, 1973, and Dubos and Hirsch, 1965. No evidence exists that animals are a source of these organisms for humans.
184 serotyping and fermentation reactions (Guinee, 1963). Investiga- tors have found a wide variety of E. cold strains in feces of humans and animals. Serotypes and phage types in samples from humans and animals were substantially different. Only a small proportion of strains from animals and humans had the same serotype (Bettleheim et al., 1974, 1976; Fein et al., 1974) or phage-type (rein et al., 1974; Siegel _ al., 1974~. In the surveys cited above, a major proportion of the strains from animals could not be typed. In contrast, most of the strains from humans reacted in the typing system, thereby providing further evidence that the _ cold flora of humans and animals are essentially separate and discrete. Even when similar serotypes are found in humans and animals, there is substantial doubt as to their common identity since a large number of subtypes can be found within one serologic O group (Guinee, 1963~. Varying results were obtained from experiments in which volun- teers were dosed with cultures of E. cold of animal origin. Smith (1969) dosed himself with a series of up to 1 billion E. cold strains of animal origin, but found that these strains persisted only briefly in his alimentary tract. Recently, Linton et al. (1977b) reported that one out of five volunteers who handled raw chicken meat subse- quently exhibited intestinal colonization by E. cold strains from the meat. These strains persisted in the intestine for approximately 10 days. Cooke et al. (1972) observed that an antibiotic-sensitive _ cold of animal origin persisted for 120 days in a volunteer who received a large dose of organisms. Hirsh and Wiger (1978) reported a crossover of resistant E. cold from calves to their handlers. There is also circumstantial evidence of brief colonization of the human intestine by E. cold of animal origin. Dorn et al. (1975) have shown that antibiotic resistance patterns of E. cold from farm families who killed and consumed their own animals for meat resembled those of their livestock. No such relationship was evident for families who did not process their own cattle or swine for meat. Wells and James (1973) found that resistance to more than three antibiotics was twice as common in E. cold from farm people who had direct contact with swine fed antibiotics than it was in their relatives who had only indirect contact with pigs. Both studies imply that the bacteria from the livestock had colonized the in- testines of the humans long enough to pass on their resistance factors to the indigenous E. colt. However, Wiedemann and Knothe (1971) and Moorhouse (1971) were unable to prove that contact with
185 livestock was related to the occurrence of antibiotic resistance in indigenous strains of E. cold in humans. The conflicting nature of these results indicates that brief colonization of the intestines of humans by bacteria from animals and transfer of resistance to indigenous E. cold in humans occur only sporadically and that further study is required to elucidate the factors that facilitate this process. The opportunity for resistant E. cold to transfer from meat or other animal products to humans, either by ingestion or in- directly by contact, is certainly available since many investiga- tors, e.g., Kim and Stephens (1972), Lakhotia and Stephens (1973a, b), Linton et al. (1977a, c), and Walton and Lewis (1971), have shown that eggs and the carcasses of poultry, swine, and calves may be contaminated with antibiotic-resistant E. colt. Furthermore, there is evidence that meat handling is an ~mpor- tant factor in the transfer of resistant bacteria from animals to humans (Dorn _ al., 1975; Linton et al., 1977b). Siegel (1976) observed that slaughterhouse personnel shared E. cold phage types more often than would normally be expected. He postulated that this was due to common exposure of these workers to contaminated meat. In the United States and in Britain, meats and other foods of animal origin are usually cooked sufficiently to inactivate E. colt. Consequently, in those countries, colonization of humans by animal strains probably occurs mainly through contact with the contaminated product before cooking or via secondary contamination of other cooked items in the kitchen. The possible importance of handling in the transfer of E. cold is indicated by the findings of Linton et al. (1977b) and Dorn et al. (1975~. However, since their observations are very limited, much more study of this subject is required. Cooking routines vary greatly among different regions of the world. For example, in the Netherlands, many potentially contaminated meat items are eaten in a relatively uncooked condi- tion. Such variations are seldom considered when comparing data on human salmonellosis in different countries. Factors that are not related to the consumption of meat are also involved in the prevalence of antibiotic-resistant E. cold in the human intestine, but their mechanisms are not understood. The well-known study of Guinee _ al. (1970), showing that vege- tarians and babies were somewhat more likely to carry resistant _ cold than were meat-eaters, has not yet been explained. Other
186 studies unrelated to the food of humans have shown that antibiotic- resistant bacteria may be very prevalent in ecosystems in which there is no obvious selection pressure from antibiotic usage (Cooke, 1976a, 1976b; Sizemore and Colwell, 1977; Timoney et al., 1978). SaZmoneZZa spp. It is an almost universally accepted dogma that human salmo- nellosis (with the exception of typhoid and paratyphoid) is a zoonosis (Christopher _ al., 1974; Hook, 1971) and that animals are the immediate reservoir of Salmonella infections in humans. A logical extension of this dogma is that much of the antibiotic resistance in salmonellae in humans also derives from this reser- voir in animals. There is extensive documentation that various food items derived from poultry, swine, and cattle have served as sources of Salmonella infection for man (National Academy of Sciences, 1969~. Moreover, there have been detailed reports de- scribing epidemics of specific clones of S. typhimurium that originated in calves and spread into the human population carry- ing with them R factors apparently acquired in the original host (Anderson, 1968; Threlfall et al., 1978a,b). There is, however, a substantial and convincing body of evi- dence indicating that the role of animals as a source of Salmonella infection and associated R factors for humans is greatly exaggerated and that humans themselves are a major part of the Salmonella reser- voir. This evidence is outlined in the succeeding paragraphs. A major epidemic of Salmonella wien has been progressing in North Africa and Europe since 1969 (McConnell et al., 1979~. Most of the strains involved are resistant to antibiotics and have not been found in animals. The largest epidemic of typhoid in history, which occurred in Mexico during the early 1970's, was also caused by a multiresistant strain (Gangarosa et al., 1972~. Since S. typhi is found only in humans, animals were not implicated in the emergence of this resistant strain either. Both of these epidemics indicate that salmonellosis caused by multiresistant strains can occur in humans without involving an animal reservoir. Salmonellosis in the United States is most common in infants less than 1 year old (Ryder _ al., 1976~. Because of the small proportion of meat in the diet consumed by these infants, there is a low probability that the infection was derived from animals via meats. Salmonellosis is also common among institutionalized chil
187 dren, where person-to-person transmission occurs (Aaron et al., 1971; Schroeder et al., 1968~. Interestingly, dramatic outbreaks of salmonellosis attributed to ingestion of contaminated foods of animal origin involve mostly young and middle-aged adults (Hook, 1971), and there is minimal secondary lateral spread. The impor- tance of lateral spread in the epidemiology of human salmonellosis is underscored by the proliferation of that disease among the urban poor (Cherubin et al., 1969), where personal hygiene would be ex- pected to be deficient. Comparison of the 10 most frequently isolated serotypes from human and nonhuman sources reveals that about half of the serotypes are common to human and nonhuman sources and half are not (Mallory and Gangarosa, 1970; Ryder et al., 1976~. This implies that approxi- mately half of the serotypes causing salmonellosis in humans during the surveys were probably not derived from nonhuman sources. In- terestingly, a 2-year survey of Salmonella serotypes in the Gulf of Aarhus, Denmark, provides additional evidence for this conclusion (Grunnet and Brest Nielsen, 1969~. These investigators found that many of the serotypes common in human sewage outfalls were different frog those commonly found in animals or their feeds. Recent observations in rural and metropolitan New York (Cherubin et al., 1979; Timoney, 1978) suggest that the human and animal reser- voirs of S. typhimurium (the most common serotype in humans and ani- mals in this area) are essentially separate. The evidence supporting this conclusion is twofold: resistance to ampicillin appeared in strains from humans before it did in strains from animals and its prevalence declined between 1975 and 1977 when ampicillin-resistant strains in animals continued to increase (Cherubin et al., in press). Many of the strains from animals found in New York were derived from veal calves, the retail market for which is New York City. Epidemiological studies of salmonellosis in New York City have also provided definite evidence of the lateral spread of S. typhimur- ium (Cherubin _ al., 1969~. This serotype was proportionately much more common in crowded and slum areas and in children than in other areas of the city or in older populations. Furthermore, S. typhimurium was isolated much less frequently from general, usually foodborne out- breaks of salmonellosis than from sporadic cases. The general out- breaks tended to be caused by other, less well known serotypes. There has been a similar finding on a national scale (Center for Disease Control, 1964-1967~. Thus, there is good evidence, in the New York metropolitan area at least, that humans are an important immediate reservoir of S. typhimurium for infection of humans.
188 Comparisons of the frequency of antibiotic resistance of salmo- nellae from healthy poultry, swine, and bovines (Lakhotia and Stephens, 1973 b; McGarr_ al., 1977; Food and Drug Administration, 1973; Smith, 1970, Timoney, 1972) with that of isolates from humans (Bissett _ al., 1974; Neu et al., 1975) show that resistance to_ _ antibiotics is much more common in strains from humans. This must be interpreted as suggesting either that the clones causing ill- ness and disease in humans are different from the ones being carried in healthy livestock and/or that after transfer of strains from animals to humans, the therapeutic use of antibiotics in humans re- sults in a selection pressure for antibiotic-resistant strains. Thus, a considerable body of evidence indicates that, with the exception of large outbreaks of foodborne salmonellosis in adults, many Salmonella infections in humans are derived directly from humans. It should be a relatively easy task to measure on a national scale the extent of transfer of salmonellae from the reservoir of animals to the reservoir of humans using data already on file at the Center for Disease Control (CDC) in Atlanta. Unfortunately, the format of CDC's Salmonella Surveillance Reports prevents any overall quantitative estimate of this transfer. Occupation-Related Transfer The occupation-related transfer of salmonellae is reviewed in a report of the National Academy of Sciences (1969~. The Salmonella carrier rate Is higher among food handlers than it is in the general population in the United States (Gallon and Steele, 1961~. There is also evidence that workers in abattoirs may carry salmonellae to their homes and subsequently infect members of their families (Public Health Laboratory Service, 1964~. Reports of Salmonella isolates from humans in urban and rural areas indicate that rural inhabitants appear to have a lower inci- dence of infection (Center for Disease Control, 1964-1976~. This may partly reflect a difference in availability of laboratory ser- vices. However, close scrutiny of these reports reveals that there are annually from 4 to 5 times as many isolates from New York City as from upstate New York, a predominantly rural area served by ex- cellent laboratory facilities at Albany. Also, the numbers of Salmonella isolates from humans in such states as Iowa, Indiana, Nebraska, and Oklahoma, where great numbers of livestock are raised, are among the lowest in the United States (Ryder et al., 1976~.
189 Transfer Via Food Contamination Food contamination provides a major source of salmonellae that are transferred to humans (National Academy of Sciences, 1969~. Processed foods, such as egg or milk products, are much more impor- tant in this regard than are fresh, unprocessed items (Center for Disease Control, 1976; Sanders et al., 1963--an indication that secondary contamination during and after processing is significant in the epidemiology of foodborne salmonellosis. THE TRANSFER OF GENETIC DETERMINANTS FROM BACTERIA OF ANIMAL ORIGIN TO OTHER BACTERIA IN HUMANS This subject will be dealt with by addressing the following questions: Is there a pool of resistance plasmids common to bac- teria of human and animal origin? Are the genes for colonization and enterotoxin production the same in E. cold from animals and humans? Resistance Plasmids and Resistance Genes in Bacteria from Humans and Animals Similarity of resistance patterns is not an adequate criterion for establishing the identity of genes or plasmids from different sources because the same resistance pattern may be determined by different plasmids or combinations of different plasmids in the same host cell (Timoney, 1978~. The evidence for similarity of plasmids from different sources must be based on DNA homology, in- c ompatibili ty grouping s tudies, and endonuclease digestion studies. Evidence from incompatibility testing and DNA homology studies indicates that resistance plasmids from bacteria isolated from humans and animals cannot be distinguished. Incompatibility (Inc) groups F. I, and N resistance plasmids are the same in animals and humans (Anderson _ al., 1975; Silver and Mercer, 1978~. Inc H plasmids of Salmonella typhimurium from humans and animals are also similar (Anderson, 1977~. Furthermore, among resistance plasmids from the Enterobacteria- ceae, the genes for TEM F-lactamase reside upon a 3.0 Mdal sequence of TUNA that is transposable from one plasmid to another (Hedges and Jacob, 1974~. This transposon has also been found in Haemophilus ~n- fluenzae type b (De Graaff _ al. , 1976) and in Neisseria gonorrhocae
190 (Elwell _ al., 1977~. Thus, the some gene for resistance to ampi- cillin is widely distributed among the pathogenic bacteria. Genes for tetracycline, kanamycin, chloramphenicol, trimethoprim3 and streptomycin have also been found to be transposable (Silver and Mercer, 1978~. This suggests that resistance genes can move freely among different bacteria and, presumably, between the reservoirs of these bacteria in humans and animals. Although enteric resistance plasmids from bacteria isolated from humans and animals are identical, some evidence suggests that among the Enterobacteriaceae the host organism is an important determinant of the kinds of plasmids hosted. For instance, S. typhimurium and enteropathogenic E. cold strains from calves in the same geographic area can harbor substantially different populations of resistance plasmids (Sato and Terakado, 1977~. (See Table 2.) The data gathered in New York State from 1974 to 1978 indicate that Inc H plasmids carrying resistance to tetracycline, kanamycin, and some other antibiotics were present in 74% of resistant S. typhi- murium strains from diseased calves whereas only 1% of similarly re- sistent enteropathogenic _ cold from calves harbored these plasmids. Interestingly, Smith et al. (1978) have also found only a low fre- quency of Inc H plasmids in multiresistant coliforms from sewage and river water in Britain. Thus, although resistance plasmids may be similar in humans and animals, some unknown factors restrict the free flow of these plas- mids from one group of enterobacteria to another. Furthermore, it is unlikely that multiresistant E. cold from animals could be the source of the Inc H plasmids that are so common in strains of _. typhimurium and S. typhi from humans (Anderson, 1977; Taylor et al., 1978), not only because their occurrence in potential donor coliforms is so infrequent in comparison to plasmids of other incompatibility groups, but also because Inc H plasmids do not transfer at body temperatures THE GENETIC DETERMINANTS FOR ENTEROTOXIN PRODUCTION IN B. ooLi FROM HUMANS AND ANIMALS . Toxigenic strains of Ee cold synthesize two types of toxins. One is heat stable (ST); the other is heat labile (LT). The genetic determinants for these toxins can occur together on the same or on separate plasmids. Gyles et al. (1974) and Skerman
191 TABLE 2 The Occurrence of H Incompatibility Group Plasmids in altiresistant SahmoneZZa byph*mur*um and Enteropathogenic Esoher*chia Hopi from Calves in New York State, 1974-19i8a - Strain (Number of Strains Tested) _ typhimurium (134) 37 _ cold (115) 1 a 37 o Unpubli shed da ta fr am Timoney, 19 7 9. Plasm'ds of incompatibility groups other than H. Pe rcentage s of Strains Group Plasmid s . H only ~ and Non HE Containing Non H only 16 69 Percentage of strains that did not transfer resistances at either 28 °C or 37 °C. No Transf era 10 30
192 _ al. (1972) found that ST-LH plasmids from humans and swine were approximately the same size (55-60 Mdal) but that the molec- ular weight of ST Dlasmids was highly variable. Later, So et al. (laid) showed that ST plasmids in strains from swine had no hom- ology with~ST-LH plasmids from either swine or humans but that there was considerable homology between ST-LT plasmids from each of these sources. However ? they found that these plasmids belonged to different incompatibility groups--the porcine ST-LH plasmid in F I and the human plasmid in F II. This difference in incompati- bility group did not involve a substantial amount of DNA. So et _ . (1976) demonstrated by DNA hybridization studies that ST-LH plasmids have a majority of nucleotides in common regardless of origin. Thus, there is good evidence that a substantial part of the ST-LH plasmid is c ammo n to strains of enterotoxigenic E. cold from both swine and humans. The DNA fragment in this plasmid, which encodes for LT toxin, is no greater than 3.0 kilobases (So et al., 1978~. _ _ ~ _ The ST determinant from a plasmid containing ST alone has been cloned in a DNA fragment of 3.4 kilobases and has been shown to be a transposon flanked by inverted repeats of IS 1 (So et al., 1979~. This transposability probably accounts for the differing molecular weight of ST plasmids. _ _ _ . These findings suggest that the ST genes in E. cold from a variety of hosts could be the same since they have the property of being able to transfer from one plasmid to another. Further- more, there are indications that the genes for ST-LT are also located on a transposon. Inverted repeat sequences of bases are known to bound the area containing the genes on a plasmid with ST-LT function (Silva et al., 1978~. SIMILARITY OF PLASMID-BASED GENES FOR COLONIZATION IN E. aoti FROM ANIMALS AND HUMANS A number of pilus- and capsule-associated antigens are known to be important in the colonization of the small intestine of pigs, calves, lambs, and humans by enteropathogenic E. colt. Included in this category are the K88 and K99 antigens, the pilus antigen of porcine _ cold 978 (Nagy et al., 1978) and the colonization_ factor associated with the human E. cold strain H-10407 (Evans et al., 1975~. Only the genetic basis of the K88 antigen has been well studied. Shipley et al. (1978) have shown that the genes for the K88 antigen are located on 50- and 90-Mdal plasmids. The larger plasmid is self-transmissible, but the smaller one is not.
193 More recently, Moot et al. (1979) have shown that the genes for K88ab synthesis lie on a DNA sequence of 4.3 Mdal or less. Studies to compare DNA sequences for K88 synthesis with DNA sequences from E. cold strains that colonize humans have not yet been reported. Since the K88 antigens have been found only on E. cold strains that are specific for swine (Moon et al., 1977), it Is likely that the genes for factors with similar function in E. cold strains from humans will prove to be dif f Brent . 0rskov et al. (1975) found the K99 antigen on enteropathogenic E. cold from calves and lambs. Moon et al. (1977) reported finding the same antigen on porcine E. cold of O groups lot and 64. These authors stated that the K99 antigen had not yet been found on human enteropathogenic strains. No studies on the characteristics of the K99 genes have yet been reported.
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