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13 o Therapeutic and prophylactic doses o f antimicrobials in humans increase the preval ence of antimicrobial -res istant microorganisms in their bacterial flora and in the flora of the ir close contacts . o Data that would a l l ow measurement of the frequency o f trans fer o f R factors ( res istance factors ) from the bacterial flora of anima l s to the fl ora of humans were not ava i l abl e ; nor were quantitative data on the frequency of R- factor trans fer among components of the human microbial fl ora . o Avai l able data were insufficient to determine any relationship in the general human population between ingestion of meat from animal s fed subtherapeutic amounts of antimicrobials and the prevalence of drug-resistant ï¿½. QQli . The l imited ava i l able data suggested that ant imicrobial Â res istant ï¿½. QQli were as preval ent in vegetarians as in meat-eaters . The purpose of the present study , initiated 7 years later by the Institute of Medicine at the request of the Food a nd Dru g Administra tion (FDA), was to deve l op a forma l quantit a tive a s s e s sment of huma n hea l th r isk a s s o c iated with the subth e ra peutic u s e o f pen i c i l l in and the tetra c yc l i n e s in a nima l feed . HISTORICAL BACKGRQUND It is helpful to review briefly the history of federal pol icies regarding the use of penicil l in and the tetracycl ines in animal feeds . 6 , 7 FDA approved the use of penici l l in and chl ortetracycl ine as feed additives in 1 9 5 1 and the use of oxytetracycl ine i n 1 9 5 3 . In 1 9 7 2 , FDA issued a pol icy statement regarding the use of antimicrobial drugs in feeds . 6 , 7 In 1 9 7 7 , the agency issued a Notice o f Opportunity for Hearing ( NOOH ) o n penic i l l in- and tetracycl ine-conta ining premixes to help to determine whether the previously approved New Drug Appl ications for the drugs should be withdrawn because of poss ible adverse effects on human health . 4 , 5 In 1 9 7 8 , before any action on these NOOHs , Congress stipulated that the FDA should seek rigorous evaluation of the ava ilable scienti fic evidence of human health ha zards associated with the use of the drugs in subtherapeutic concentrat ions in animal feed . That stipulat ion led to FDA ' s request that resulted in the 1 9 8 0 Nati onal Research Counci l report . Congress , i n its fiscal 198 1 appropriations hearings , requested that FDA hold any proposed withdrawal proceedings on the New Drug Appl ications in abeyance until the research recommended in the report could be done and evaluated .
14 Between the congress ional request and the study reported here , the National Resources Defense Counci l ( NRDC ) in December 1 9 8 4 submitted a petition asking the Secretary o f Health and Human Services t o suspend approval of the drug appl ications for subtherapeutic use of penici l l in and the tetracycl ines in animal feeds . s NRDC alleged that the use of the drugs presented an " imminent hazard" to the publ ic health . A decision to invoke the imminent-hazard provis ion would have resulted in immediate withdrawal of the drugs from the market . FDA reviewed the petition and the sc ienti fic evidence submitted in support of the claim of imminent haz ard . In s umma ry , the FDA stated that it bel ieved that NRDC has not estab l i shed that antibiotic-resistant Salmonella , whose res istance results from subtherapeutic uses o f penici l l in and the tetracycl ines in animal feed , have a s igni ficant impact on the outcome of human salmonel losis . Moreover , the figures used by NRDC to cal culate mortal ity and morb idity rates were derived , in part , from a study that was not des igned for that purpose and , therefore , could be biased . The FDA recommended that the Secretary deny NRDC ' s petition on the grounds that an " imminent hazard" has not been demonstrated . COMMITTEE APPRQACH The present Committee on Human Health Risk Assessment of Us ing Subtherapeutic Antibiotics in Animal Feeds has sought data that could be used in making a quant itative assessment of ha zards and risk to human health . It has sought the results of peer-reviewed scientific studies on several pathogenic organisms that infect both humans and anima l s , that cause disease and death in humans , and for which ant imicrobial susceptibil ity testing is commonly performed . The need for data on mortal ity ( reports of human infectious disease reported to state and federal agencies ) further l imited the bacterial infections that might be included in this study . Few data on morbidity were ava i l abl e . The committee needed a definitive end point ( survival or death ) that was not a fforded in any publ ished evaluations of the effects o f salmonel lae in caus ing morbidity in humans . Several other diseases were cons idered , and these are discussed in Chapter VI , but morbidity and mortal ity data on the l isted diseases other than salmonellos is were unava ilable or insufficient in quant ity and qual ity for risk assessment . (Morbidity was not assessed in the present model , because o f the lack of data o n the cases studied , and the current model has no provis ions for morb idity . ) Infection with Salmonella spec ies ( other than s. typhi ) was selected for several reasons : salmonel lae are o ften isolated from farm anima l s and foodstuffs derived from them ; salmonel lae are pathogens for
15 both f a rm anima l s and humans , some data are available on antimicrobial res istance among farm-animal and human isolates of salmonel lae : the Centers for Disease Control ( CDC ) conducts a nati onal survei l lance for salmonellae and receives numerous human salmonella isolates from a l l parts of the country for identi fication and serotyping , and CDC has conducted studies on the incidence of human salmonellosis in selected u . s . urban and rural counties . l , l Requis ite data related to salmonella infections as either the "underlying cause" or a " contributing cause " of human deaths were sought , and the relevant bacterial isolates were categori z ed as to antimicrob ial susceptibil ities . The drug-res istance profiles of the cl inical isolates have been examined with a view to determining the sources of drug resistance and whether drugÂ res istant isolates could be traced to farm origin or , even further , to subtherapeutic use of penicil l in or the tetracycl ines in animal feed . The task has been formidable , because o f the sparseness of data that l ink drug-res istant cl inical isolates to primary sources of infection , whether human or animal , and of data that identi fy the specific drugs used on the farm , their form of administrat ion ( for growth promotion or prevention of infection ) , and their dosages . The committee has recogni z ed several weaknesses in the data needed for risk assessment and its findings have highl ighted these weaknesses . Bacterial antimicrobial res istance can be natural or acquired , and the growth of bacteria with either type o f resi stance will b e selectively favored when antimicrobials are used in humans , in anima l s , or in other environments . Natural res istance to an individual antimicrobial perta ins to res istance of an entire species to that antimicrobial , e . g . , res istance of Pseudomona s aeruginosa to chloramphenicol . Such res istance usually arises from a lack of permeabi l ity to the drug or the lack of a susceptibl e target s ite for the drug . Acquired resistance occurs as a result of mutation or as a result of trans fer of res istance (R) plasmids . Exposure of large bacterial populations to various antimicrob ial agents results in selection of antimicrobial -res istant microorganisms , prov ided that the concentrations of the agents are above the minimal inhibitory concentrations (MICs ) for the exposed bacteria . That select ion occurs in bacterial cultures in vitro , in humans receiving ant ibiotics either prophylactica l ly or therapeutica l ly , and in animals whose feed conta ins antibacterial agents for growth enhancement , for treatment of estab l i shed infection , or for d isease prevention . One would l ike to know particularly the extent to which the human "pool " of drug-res istant enteric microorganisms is increased by the aggregate of diseaseÂ produc ing pathogenic stra ins , bowel flora , and gastrointest inal " trans ients " of animal origin that are
16 generated by subtherapeutic uses of penic i l l in and the tetracycl ines on the farm and in feedlots . General questions that might reasonably be ra ised concerning the importance of the subtherapeut ic use of penici l l in and the tetracycl ines in current problems of human infection with antimicrobial-resistant bacteria include the fol l owing : o What are the relative ( quantitative ) contributions to drug resistance , in bacterial species pathogenic for humans , of antimicrobial use in humans and in animals? o What are the relative contributions to bacterial drug res istance of subtherapeutic and therapeutic uses of antimicrobial agents? o Does bacterial res istance to penici l l in and the tetracycl ines foster res istance to other antimicrob ial agents used in the treatment of animal or human infections? More spec i f ical ly , what is the relationship of the subtherapeut ic use of these drugs in animals to res istance to other drugs? o If subtherapeut ic ( but not therapeutic ) use o f penici l l in and the tetracycl ines were el iminated , would the frequency of antimicrobial resistance among enteric pathogens be l ikely to increase , to decrease , or not to change? The committee hopes that newly developed molecular fingerprinting techniques that pinpoint the sources of infections with antibiotic-resistant pathogens and that trace routes of transmission ( animal to human or human to animal ) wi l l be used regularly in epidemiologic investigations and that a database wil l be estab l i shed for use in future assessment of risk . The pathways of infective bacteria from animals to humans or vice versa and the relationship of the devel opment of antimicrobial res istance in these bacteria to antibiotic use thus might be more clearly identi fied . The committee considered the ava i l able data on several bacterial organisms and selected nontyphoidal salmonel l a infections as the most appropriate infections t o cons ider in making the human health risk assessment , because rel evant human case reports , antibiotic resistance profiles in bacterial i sol ates , and other data needed were ava i l able . This report is organi z ed according to individual steps or issues of importance that the committee felt might directly
17 or indirectly provide ins ights into current health risks ( or might be identi fied as targets for future invest igation ) . The report deal s with the biologic impact of res istance to antimicrobial agents first , because the mechanisms of ant imicrobial resistance , populat ion genetics and the overgrowth of resistant microorganisms in the presence of antimicrobial agents , and bacterial resistance trans fer are wel l - studied topics relevant to ant imicrobial drug effects . Furthermore , definition of specific antimicrobial -res istance genes and other genes of plasmids provides a potent ial means of estab l i shing the common clonal identity of isolates obta ined at geographically distant yet epidemiologica l ly related s ites . The next chapter describes antimicrobial product ion in the Unites States as a means of estimating total antimicrobial use , whether for humans or anima l s and whether for treatment , disease prevention , or growth enhancement ( in farm animals ) . Particular attention was paid to estimating the use o f penicil l in and the tetracycl ines in l ivestock and poultry production . To the extent poss ible , the committee has estimated that portion of the total use of antimicrobials on the farm and in feedl ots accounted for by penici l l in and the tetracycl ines . Such estimates have been analyzed to apportion the total amounts to therapeut ic and subtherapeutic use and to growth promotion and disease prevention . Central to any cons ideration of poss ible adverse e ffects on human heal th are the patterns and prevalence o f antimicrobial res istance i n salmonel l ae and E Â· ï¿½ isolates of anima l and human origin . Chapter V discusses pos s ible differences in prevalence and patterns of res istance between isolates from healthy anima l s and from meat and poultry products and isolates from veterinary institutions that treat i l l anima l s . studies of the effects of l ong-term administration of subtherapeutic ant ibiotics to farm anima l s ( and l ater discontinuation ) o n the preval ence of antimicrobial res istance in the ir ï¿½. Â£Qli stra ins are reviewed , and temporal trends in res istance among isolates o f human origin are surveyed . The poss ible transmiss ion of antimicrobial -resistant pathogens or intestinal commensa l s of farm origin to humans is examined in the next chapter . Data bearing on the issue have come from experimental field stud ies , from epidemiologic studies of outbreaks of salmonellosis in which molecular biologic techniques have been used to establ ish cl onal ity o f isolates al ong the food chain from production t o human consumption , and from investigations of the occurrence in farm and slaughterhouse workers of infections due to ant imicrobial -res istant microorganisms of farm origin . The principal focus of this report i s the devel opment o f a risk model and its use for estab l i shing a n est imate o f
18 risk . The model described in Chapter VI I i s based on human salmonella infection and incorporates data on the fol lowing : o The numbers of cases reported annually . o The fraction of cases due to organisms res istant to more than one antimicrobial or resistant to ampicil l in ( the penici l l in congener that is used in treatment of susceptible human salmonella infections ) or the tetracycl ines . o The fraction of cases that result in death . o The fraction o f cases of farm origin . o The fraction of cases that might be attributabl e to the subtherapeutic use of antimicrobials in animal feeds . o The role of recent ingestion of antimicrobial agents for unrelated reasons in predispos ing to infection by smal ler inocula of antimicrobial -res istant pathogens than would ordinarily be required to produce disease ( the so-ca l l ed etiol ogic fraction ) , i . e . , the excess of cases attributabl e t o the effects of previously administered antimicrobial agents . Several European countries have placed restrictions on the use of antimicrobial s in subtherapeutic quantities in animal feeds over the last 2 decades . Their experience regarding use of antimicrobial s , patterns of antimicrobial resistance in B Â· ï¿½ and salmonel lae , and incidence of disease due to enteric pathogens in l ivestock and humans has been reviewed for ins ights into the consequences of such restrictions . The final chapters of the report present the conclusions reached by the committee and its recommendations for future research . REFERENCES 1. MacDonald , K . L . , M . L . Cohen , J . G . Wel l s , N . D . Puhr , N . T . Hargrett-Bean , and P . A . Blake . Changes in antimicrobial res istance of Salmonel l a isolated from humans nat ionwide , 1 9 7 9 to 1 9 8 5 . Abstract 1 1 3 in Interscience Conference on Antimicrobial Agents and Chemotherapy , New Orleans , La . , Sept . 2 8 -0ct . 1 , 19 8 6 . Washington , D . C . : American Society for Microbiol ogy , 19 8 6 .
19 2. National Research Council , Committee to Study the Human Health E ffects of Subtherapeutic Antibiotic Use in Animal Feeds . The E ffects on Human Health of Subtherapeutic Use of Antimicrobials in Animal Feeds . Washington , D . C . : National Academy Press , 19 8 0 . 3. Ri l ey , L . w . , M . L . Cohen , J . E . Seal s , M . J . Blaser , K . A . Birkness , N . T . Hargrett , s . M . Martin , and R . A . Feldman . Importance o f host factors i n human salmonellosis caused by multires istant strains of Salmonella . J . Infect . Dis . 1 4 9 : 8 7 8 -8 8 3 , 1 9 8 4 . 4. u. s . Food and Drug Administration . Notice of opportunity for hearing . Penic i l l in-conta ining premixes : Opportunity for hearing . Fed . Reg . 4 2 : 4 3 7 7 2 - 4 3 7 9 3 , 1977 . 5. u.s. Food and Drug Administration . Notice o f opportunity for hearing . Tetracycl ine ( chlortetracycl ine and oxytetracycl ine ) -conta ining premixes : Opportunity for hearing . Fed . Reg . 4 2 : 5 6 2 6 4 - 56289 , 1977 . 6. u. s . Food and Drug Administration . Proposed Statement of Pol icy . Antibiotics and sul fonamide drugs in animal feeds . Fed . Reg . 3 7 : 2 4 4 4 - 2 4 4 5 , 1 9 7 2 . 7. u.s. Food and Drug Administration . Statement of pol icy and interpretation regarding animal drugs and medicated feeds . Antibiotic and sul fonamide drugs in the feed o f animals . Fed . Reg . 3 8 : 9 8 1 1-9 8 14 , 1 9 7 3 . 8. u. s . Food and Drug Administration . The Nat ional Resources Defense council , Inc . submiss ion of a petition to the Secretary of Health and Human Services . Fed . Reg . 4 9 ( 2 4 7 ) : 4 9 6 4 5 - 4 9 64 7 , Friday , December 2 1 , 1984 .
III BIOLOGIC IMPACT O F RES ISTANCE TO ANTIMICROBIAL AGENTS BBIEF HISTQRY OF CLINICAL DEYELQPKENT OF DRUG BESISTAHCE The di scovery of sul fonamide& and antib iotics in the first hal f of the twentieth century led to at least two biologic " revolutions . .. The first was the abil ity to treat infectious diseases . The second was the use of ant ibiotics to gain ins ights into the genetics of bacteria . In 1 9 4 3 , Luria and Delbruck 7 0 first demonstrated that the emergence of bacterial res istance to a s ingle antibiotic a fter exposure to it was a result of chromosomal mutation ( independent of antib iotic exposure ) , rather than an adaptive change . I n the years that fol lowed , it became conventional to cons ider that the emergence of any drug resistance in any bacteria was due to a selected mutation . Convent ional bel ie fs concerning the importance of mutation in drug res istance were overturned by events in Japan in the years j ust a fter World War I I . There , phys icians treating patients in epidemics of shige l l a dysentery used sul fonamide& extens ively . A substantial proport ion of those bacteria soon became res istant to sul fonamides . The widespread sul fonamide res istance caused physicians to switch from sul fonamide& to new drugs-Â streptomycin , tetracycl ine , and chloramphenicol --to treat shigella dysentery . By the late 1 9 5 0 s , many of the isolates of shigel lae were drug-resi stant , not only to sul fonamides , but to a l l drugs . That finding led invest igators to question , on theoretical grounds , mutation as the explanat ion for drug res istance . Mutation had previously been shown to take place in about 1 in 1 0 7 cel l s , and it stra ined credul ity to assume that cel l s of a single stra in could spontaneously develop drug res istance to four antibiotics over a short period . Moreover , several serotypes of Shigella spp . were shown to have developed multiple-drug res istance virtually s imultaneously , and this multiple-drug-resi stance pattern was actua l ly more common than resistance to a single antimicrobial . Japanese investigators showed in the late 1 9 5 0 s that multiple-drug resistance could be trans ferred from one bacterial species to another . In l ight of discovery of bacterial conj ugation in the preceding decade , it was poss ible to demonstrate that multiple-drug res istance was 20