Antibiotic Allergy Antibiotics in Beef Chicken

Northward. Franklin Adkinson, Jr.ⁱ

This paper addresses the outcome of whether antibiotic residues consumed in edible animal tissues sensitize and/or elicit allergic reactions in humans. Although many antibiotics are potentially sensitizing in susceptible individuals, the focus of this paper is upon the penicillins and tetracyclines. Of these, the penicillins have far greater allergenic potential.

The allergenicity of penicillins has been studied extensively (Levine, 1966; Stewart, 1973). Because the penicillin group of drugs is considered the prototype for allergic reactions to drugs (Parker, 1975), much of the post-obit commentary is derived from cognition of hypersensitivity to penicillin. The principles involved, however, should apply to less allergenic antibiotics including the tetracyclines and aminoglycosides.

At that place are three basic questions apropos this issue:

one.: Is there a potential for allergic reactions in humans either direct or indirectly owing to antibiotics in foodstuffs?
ii.: Are there documented cases of such allergic reactions to antibiotic residues, and, if so, what is the magnitude of the problem?
3.: What studies could exist conducted to document further the extent of the trouble, both actual and potential?

Prevalence of Allergic Sensitivity to Penicillins and Tetracyclines

Penicillins display remarkably fiddling toxicity fifty-fifty in loftier doses. About adverse reactions are attributed to ''allergy.'' Allergic reactions to penicillin range from anaphylactic shock, which tin can be life-threatening and even fatal, to mild evanescent skin rashes of little clinical outcome. These allergic reactions have differing immunological mechanisms (Table 1). When penicillins are given in therapeutic doses, the incidence of astringent life-threatening reactions is small-scale, probably less than i in 50,000 courses of handling (Idsoe et al., 1968). However, because of the huge quantities of penicillin drugs administered yearly in the United States, there are an estimated 300 to 500 deaths from anaphylactic reactions to therapeutic penicillin each yr (Feinberg, 1961). On the other manus, mild reactions to penicillin, principally peel eruptions resembling those of measles, are common, and, at least for one semisynthetic penicillin (ampicillin), may afflict ten% to 12% of treated patients (Almeyda and Levantine, 1972).

Table 1

Immunopathological Reactions to Penicillin .

Between 1% and 10% of the full general population volition relate a history of some agin feel associated with penicillin therapy. The lower prevalence figure (ane%) is probably more applicable to children and immature healthy adults, while the higher prevalence effigy (10%) reflects the frequency with which medical charts are likely to be marked "allergic to penicillin" among older patients hospitalized for serious medical problems. More than recent studies of the most serious forms of allergy to penicillin (type I in Table one: IgE-mediated, or reaginic, allergy) have shown that some patients spontaneously lose allergic sensitivity with time (Adkinson et al., 1971; Green et al., 1977; Levine and Zolov, 1969). This spontaneous loss of allergic sensitivity is likely to occur for other less serious types of allergic reactions too, judging from the fact that it is often possible to treat previously allergic individuals safely (Bierman et a1., 1972; Levine, 1972).

Tetracyclines are infrequently implicated in allergic reactions. Allergic reactions of the type I diverseness (anaphylactic shock and urticaria) have occasionally been documented in the literature (Schindel, 1965) but are extraordinarily rare. Tetracycline-induced skin rashes, including phototoxic dermatitis, are the nigh mutual adverse reactions that are by and large considered "allergic," although there is no clear evidence of an immunological ground for these reactions (Dewdney, 1977).

Conditions for Sensitization

Some of the factors that influence the development of allergic hypersensitivity to penicillin are: chemic construction and reactivity of the drug; cross-reactivity with other sensitizers; dosage, elapsing of therapy, number of courses of therapy; fashion of administration of the drug; use of additives and solvents; and patient factors, including history of drug sensitivity, atopy^one age, genetic factors controlling drug metabolism or immune response, and underlying illness affecting metabolism of excretion of the drug.

Three factors deserve mention in the present context: poly peptide reactivity, private susceptibility, and dose requirements.

Protein Reactivity

Drugs, like all small molecular weight chemicals, cannot stimulate an immune response in animals or humans unless they possess the chapters to "haptenize," i.eastward., interact irreversibly with larger molecules, usually proteins, thereby' forming an immunogenic multivalent drug-protein complex. The immunochemistry of such interactions between penicillin and native proteins has been studied in detail (Stewart, 1967). The principal pathways involved are schematized in Figure 1.

Figure one.

Major pathways of penicillin-protein interactions.

The major antigenic determinant for penicillin is the penicilloyl moiety of the complex, formed by covalent linkage of the beta lactam band of penicillin to epsilon amino groups of lysine residues in native proteins. This antigenic complex is formed naturally and spontaneously under physiological conditions without known participation of enzymes or catalysts. This penicilloyl-protein complex stimulates the host immune organisation to produce antibodies and immunoreactive cells that are capable of inflicting immunopathological harm. It is at present well established that preformed penicilloyl-poly peptide complexes are much more efficient than the unconjugated penicillin molecule at both stimulating an immune response and eliciting an allergic reaction in a previously sensitized individual (Siegel, 1959; Stewart, 1967). Immunologically, the antibiotic "residue" of prime importance is the penicilloyl-protein complex rather than the free penicillin molecules. As is discussed further beneath, no analyses of penicilloyl residues in foodstuffs obtained from penicillin-treated animals have ever been undertaken.

There have been no detailed immunochemical studies of interactions of tetracycline with host proteins (Dewdney, 1977). The poly peptide reactivity of tetracyclines is generally considered to be quite pocket-size. This fact alone is thought to account for the rarity of hypersensitivity reactions to this course of antibiotics.

Individual Susceptibility

Recent studies by my laboratory have indicated that non all individuals possess the chapters to answer immunologically to therapeutically administered penicillin, even if treated with prolonged high dose therapy (Adkinson, 1977). This suggests that there may be genetic and/or metabolic restrictions on the ability to develop hypersensitivity reactions to penicillin. The proportion of the general population that may exist susceptible to the development of allergy to penicillin remains to be determined.

Dosage Requirements for Sensitization

From immunological studies of laboratory animals and humans, it is clear that the dose of any immunogenic substance required for initiating an immune response is appreciably greater than that required to elicit an allergic reaction of the blazon I variety. The optimal immunizing dose and the minimal dose for eliciting an acute allergic reaction may differ by several orders of magnitude. Furthermore, evidence from studies of both laboratory animals and humans suggests that low-dose immunization favors the production of IgE-antibody over IgE-antibody in animals that are genetically capable of mounting an IgE-antibody response (Marsh, 1975). Thus, in that location is reason to suspect that there may be a potential for the development of IgE-mediated hypersensitivity by chronic low dose antigenic exposure. However, for ingested antigens (as opposed to inhaled, airborne antigens) this potential take chances has not been explored by studies in either laboratory animals or humans. Thus, there are no data to point whether penicillin administered to humans chromically at residue-level doses tin elicit a penicillin specific immune response in a susceptible individual. Too, information concerning the threshold sensitizing dose for orally administered penicilloyl-protein complexes are not available either for laboratory animals or humans

Atmospheric condition for Provocation of Allergy Symptoms

In an individual who has been rendered allergic to penicillin past prior therapeutic administration, what is the risk of provoking allergic symptoms by penicillin residues in ingested foodstuffs? As discussed above, the dose required to elicit an allergic reaction would exist expected to exist considerably below that required to initiate an immune response. The threshold dose for provoking an allergic reaction depends upon the degree of allergic sensitivity of the private ingesting the antibiotic residues.

Clinical observations were made by Walzer and Siegel in 1956 (Siegel, 1959). They passively sensitized peel sites on normal subjects with serum drawn from patients with high reagin (IgE) titers to penicillin. All serum donors had previously experienced immediate allergic reactions following treatment with penicillin. Seventy-two hours after the recipient subjects were fed measured amounts of crystalline penicillin Thou, and the sensitized sites were observed for the appearance of wheal and flare signs, which are indicative of IgE-mediated peel reactions. In those studies, which were positive, the oral threshold dose of penicillin required to produce a positive skin test was forty to l units. Administered intravenously, doses of 12.five to 25 units were sufficient to produce a positive skin response.

Siegel (1959) and Bierlein (1956) have provided evidence that the oral dose of penicillin required to activate a passively sensitized peel site in a normal recipient is from 100 to 10,000 times larger than that needed to induce a clinical reaction in the allergic patient from whom the reaginic serum was drawn. If ane assumes a conservative ratio of 100:1, then the oral assistants of as piffling as 0.4 units of penicillin would be sufficient to elicit allergic reactions in patients with severe IgE-mediated penicillin allergy.

A number of reports certificate systemic reactions in sensitive individuals who were skin-tested with less than 1 unit of penicillin Thou, including i patient who adult systemic symptoms post-obit an intradermal test with 3 x 10-vii units of penicillin (Bierlein, 1956). It is therefore clear that very modest doses of penicillin, administered orally or through the skin, are capable of eliciting allergic reactions in some exquisitely sensitive patients. It is doubtful that such small doses could elicit clinical symptoms in a majority of penicillin-allergic patients. Whether chronic ingestion of subthreshold doses can somewhen result in symptoms is likewise unknown.

Evidence of Allergic Reactions to Antibody Residues

Milk

The literature yields just a few documented cases of allergic symptoms that are clearly related to the presence of antibody residues in beast foodstuffs. Almost all of these reports deal with penicillin-contaminated milk. In 1959 Siegel carefully reviewed the information on allergic reactions to penicillin in milk. He noted that in a 1956 Nutrient and Drug Administration (FDA) nationwide survey of penicillin contamination of milk, v.ix% of the samples were constitute to exist contaminated with penicillin. The caste of contagion ranged from 0.003 to 0.55 units/ml of milk, averaging 0.032 units/ml (D.C. Grove, personal communication; Welch, 1957). Zimmerman (1957-1958) reported that urticaria post-obit ingestion of milk was a mutual occurrence amongst 52 penicillin-sensitive patients. Unfortunately, these patients were not studied immunologically, nor were the implicated milk samples analyzed for penicillin content.

The best studied case of allergic reaction from penicillin in milk was reported by Borrie and Barrett (1961) in Swell Britain. A 25-year-old woman suffered a moderately severe subacute eczematous eruption, which was traceable to penicillin-contaminated milk. Assay revealed that some milk samples that did non contain penicillin were however capable of provoking allergic symptoms. The patient'due south symptoms were relieved, all the same, by addition of penicillinase to the milk she consumed at dwelling house. Attempts at desensitization by the oral route were undertaken starting at 1 unit of penicillin per day. Desensitization had to exist abandoned because of recurrent symptoms of allergy. For this patient, who possessed an intense IgE-mediated allergy to penicillin, less than 1 unit (<0.6 g) of penicillin per day was sufficient to provoke allergic symptoms. The elimination of her symptoms by the addition of penicillinase to her milk may exist taken as show that preformed penicilloyl-milk protein complexes were not a major contributor to the elicitation of her allergic reactions.

Stricter governmental enforcement of FDA regulations concerning penicillin-contaminated milk has reduced considerably the occult intake of penicillin by the full general population over the by 2 decades. By the mid-1960's the prevalence of penicillin-adulterated milk in the United States had dropped to 0.5% (Huber, 1971b), Every bit recently as 1969, Wicher et al. reported an acute allergic reaction in a highly penicillin-sensitive patient who had ingested commercially available milk containing penicillin at approximately 10 units/ml.

Current FDA regulations prohibit measurable penicillin residues in milk offered for sale in the United States. Virtually all penicillin contamination of milk products can be traced to the therapeutic utilise of antibiotics in livestock and non to the use of animate being feeds containing subtherapeutic doses of penicillin. Thus, the being of allergies in humans that are attributable to penicillin-contaminated milk can be considered irrelevant to the substantive issue before the commission, namely, the health hazards of subtherapeutic doses of antibiotics. Still, these cases of allergy induced by penicillin-contaminated milk provide useful in germination regarding minimal threshold doses required for provoking allergic symptoms in highly sensitive patients.

Nonmilk Foodstuffs

A single instance report from the Federal Republic of Germany (Tscheuschner, 1972) documents acute angloedema and pruritus in a penicillin-allergic patient who ingested freshly processed meat from a sus scrofa that had been given a therapeutic injection of penicillin iii days prior to slaughter. Analysis of the ground pork revealed a penicillin content of betwixt 0.three and 0.45 units/m of meat. Since the patient noted symptoms after the beginning bite of the footing pork, the minimum allergenic dose for this patient was likely to take been less than 10 units of penicillin.

In French republic, Cany (1977) reported five cases of urticarial reactions patently induced by ingestion of food contaminated with antibiotics. Unfortunately, the antibody residuum contained in the foodstuffs was not determined nor was the antibiotic sensitivity of the patients confirmed immunologically. All the same, taken together, these descriptive example summaries raise the possibility that antibody-contaminated foodstuffs may exist responsible for triggering allergic reactions more frequently than is generally appreciated. Additional report of antibody residues in meat pro ducts produced in France would be helpful in further evaluations.

The literature contains no other documented cases of allergic reactions owing to remainder antibiotics in animal tissues other than milk.

Level of Antibiotic Residues in Nonmilk Foodstuffs

Penicillins have a relatively curt one-half-life and are rapidly eliminated from mammalian tissues subsequently discontinuation of therapy.

Tetracyclines are excreted adequately rapidly in urine but may crave 4 to 5 days to disappear from soft tissues. Moreover, they have a high affinity for bones and teeth. Messersmith et al. (1967) demonstrated that pigs fed up to five times the usual recommended concentration of penicillin in their feed (fifty yard of penicillin/ ton) continuously for xiv weeks had undetectable (<0.025 units penicillin/g) penicillin residues in edible tissues within 0, 5, and vii days afterwards withdrawal. In the same study, residues in pigs fed up to 500 1000 of chlortetracycline/ton continuously for 14 weeks were less than 1 ppm in all tissues in all sampling periods.

In 1970 Huber (1971b) studied the prevalence of antibacterial drug residues in more than v,000 animals at the time of slaughter. Tissues, urine, and/or feces were nerveless from swine, sheep, cattle, and poultry. Antibody residues ranged from a low of ix% in beef cattle to a loftier of 27% in swine. Tetracycline residues were found more frequently than were penicillin residues. This and like surveys (Dean et al., 1964) indicate that exposure to antibody residues in foodstuffs past the general public has been appreciable.

In view of the elimination studies by Messersmith et al. (1967) and others (Huber, 1971a), the widespread antibiotic residues in edible meats as tardily equally 1970 advise that antibiotics were used frequently in therapeutic doses and/or that required periods for withdrawal from antibiotic-enriched feeds were being widely ignored. More than contempo surveys accept reported that penicillin residues were found infrequently in edible meats except when the animals had received injections of penicillins (Nutrient and Drug Assistants, 1978). No tetracycline residues were detected amidst thousands of meat samples analyzed in 1976 (Food and Drug Administration, 1978).

In the United States the impact of these tissue residues on homo allergy may be mitigated somewhat past the fact that about edible meats are cooked prior to consumption. Chlortetracycline is inverse by cooking into isochlortetracycline, a compound without known biological activity (Shirk et al., 1956-1957). Similarly, the antibacterial activeness of penicillin (and presumably its allergenic potential) is significantly reduced by heating (Shahani et al., 1956).

Risk Cess

In view of the paucity of clinical, experimental, and epidemiological data, precise estimates of the gamble of acquiring or manifesting allergic illness every bit a outcome of antibiotic residues in human foodstuffs are impossible to derive. Nevertheless, several observations can be made in an endeavor to set the potential human being health risks in perspective.

Offset, it seems highly unlikely that a sizable proportion of those individuals ingesting foodstuffs containing trace quantities of antibiotic residues will become sensitized to a clinically significant degree. This exclamation is based on 3 facts:

There is no show that such primary sensitization occurred, fifty-fifty afterward ingestion of penicillin-contaminated milk. Of course this does not evidence that sensitization does not or cannot occur, but simply that clinically apparent cases are very rare or nonexistent.
In this age of antibiotics, exposure to penicillin (and other antibiotics) in therapeutic doses is very mutual, and the prevalence of prior therapeutic exposure to antibiotics among the adult population is observable. Thus, an private is at many orders of magnitude greater risk of becoming sensitized to penicillin later on treatment with a prescribed course of antibiotic than later ingestion of antibiotic residues in food. This supposition reflects the frequency of antibiotic prescription.
Moreover, a greater rate of sensitization is to exist expected from high (therapeutic) doses of antibiotics than from the depression-level exposures from foodstuffs. All the same, we know virtually nothing about the immunogenicity of chronic low-dose assistants of penicillins and tetracyclines in human being populations. Conspicuously, such studies would be useful in defining further the risk potential for antibiotic sensitization past depression level exposure.

Of greater potential concern for human wellness is the potential provocation of an allergic reaction in a previously sensitized individual by ingestion of antibiotic residues. Here again the literature contains just a thin number of references to allergic reactions that are traceable to antibody residues in foods. Almost all of the cases reported have to practice with penicillin-contaminated milk, a moot consequence from a regulatory point of view, although there is certainly reason to continue monitoring compliance to existing regulations.

The instance reports dealing with sensitivity reactions to penicillin-contaminated milk have led u.s. to appreciate that very minor quantities of antibiotics are required to elicit clinically significant allergic reactions in very sensitive individuals. Evidently, some exquisitely sensitive individuals can experience adverse reactions to levels of penicillin that are undetectable with standard assay methods. Judging from the rarity of such cases, all the same, it is not unreasonable to conclude that either near penicillin-allergic patients are not adversely affected past penicillin residues in contaminated milk and/or milk supplies are not ofttimes contaminated with penicillin residues. The second decision is demonstratably true. The beginning decision is also likely to exist correct since at that place has been niggling prove that widespread contamination has resulted in a flurry of allergic problems, even during the early 1950's when the prevalence of contamination of milk past penicillin was 7% to 15% in the United States.

Using the bourgeois estimate that the incidence of penicilloyl IgE antibody in the general population is 1 in 50,000 and the assumption that 1% of penicillin-sensitive patients may accept ingested penicillin-contaminated milk over 1 year in the early 1950'southward, ane could await an appreciable number of milk-induced allergic reactions if the contaminated milk supplies were capable of eliciting allergic reactions in an appreciable number of sensitive individuals.

This analytical approach leads 1 to the tentative conclusion that antibiotic-contaminated foodstuffs can provoke allergic reactions in highly sensitive individuals, only these reactions appear to occur but rarely.

Thus, the absolutely sparse information indicate that there appears to be no reason to implicate antibiotic residues in fauna foods as a significant source of allergic disease, either potential or actual, for the public at large.

Conclusions and Recommendations

Based upon the above analysis, the following conclusions announced warranted.

(i): There is little reason to believe that foodstuffs obtained from animals fattened with antibiotic-supplemented feeds impose a pregnant take chances to human health by contributing to antibiotic-induced allergic reactions.
(2): Data are currently defective with regard to the clinical consequences of oral administration of antibiotic residues to patients with various degrees of provable allergic sensitivity and the capacity of antibiotic residues to engender a specific immune response in a genetically susceptible private who ingests them chronically in low doses.

The post-obit investigations could be undertaken to provide more definitive information on this question:

A study of the content of penicilloyl-protein complex in edible tissues from animals who have been fed subtherapeutic amounts of penicillin in their feed. Since the penicilloyl-protein complex may have a much longer half-life than does the free penicillin molecule and since penicilloyl protein conjugates are much more than immunogenic than free penicillin, such a study would provide needed data on the presence or absence of a potentially important immunogenic residual, which until now has been ignored.
Epidemiological studies of the incidence of penicillin antibodies among populations frequently ingesting foods with penicillin residues versus similar populations not regularly consuming such antibiotic residues. Careful attending would have to exist given to matching the exposure to therapeutically administered penicillin in both groups. Ideally, this report might exist all-time conducted amid individuals who tin can provide documentation that they have never received penicillin therapeutically.

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i: Sectionalization of Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine at the Expert Samaritan Hospital, Baltimore, Physician.
1: The relationship of the atopic status to diverse types of reactions to penicillin is uncertain except for fatal anaphylactic reactions, which occur more oft among atopic persons.

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Source: https://www.ncbi.nlm.nih.gov/books/NBK216508/