CROSS-SENSITIZATION BETWEEN NEOMYCIN AND STREPTOMYCIN*

EDWIN SIDI, M.D., MARC HINCKY, M.D., ANDROBERTLONGUEVILLE, M.D.

The importance and long-term consequencesreactions of irritation showed up, but skin testing of skin sensitization due to topical therapeuticwas negative on these patients. It was only after agents has been stressed for some time. Inre-applying neomycin in patients treated with it particular, the high frequency of intolerance toseveral months previously that a number of cases the "para group" has been described followingof sensitization appeared. These reactions seemed sensitization to sulfa preparations. Lately, theto us to be of limited general importance due to problem of sensitization to the thiazine nucleustheir small number. However, they had to be has arisen because of the many cases of sensitiza-kept in mind because of the numerous forms tion to Phenergan cream and the numerous newunder which neomycin was being used and products belonging to this chemical group whichmarketed (such as eye drops, ear drops, intestinal are now being marketed. However, among anti-medication and more recently for pulmonary biotics up to now there has been little in the wayinsufflation); in addition, a closely related anti- of precise evidence for cross-sensitization. Be-biotic, framycetin sulfate, was being put on the cause of the dangers inherent to sensitization wemarket. Patients sensitized to neomycin had to had always sought to use for topical therapybe cautioned against the use of all these prepa- antimicrobial substances which would not be alsorations. administered parenterally. Neomycin has there- During the study of a case of eczema due to fore gained considerable importance in derma-contact with neomycin it was found that this tological therapy, being a potent antibiotic apatient had become extremely sensitive to rare sensitizer and seldom used internally. streptomycin. A detailed history of this case

TABLE I Summary of Patients Tested Patch Tests Patient Histoly Reaction to Treatment Neomycin Streptomycin

F. C. Neomycin compressesAcute spread of eczema +++ ++++ (retreatment) H. M. Neomycin compressesAcute spread of eczema ++ +++ (retreatment) B. G. Neomycin compressesAcute spread of eczema ++ +++ (retreatment) J. Y. Neomycin unguent andAnaphylactoid and ec-Not tested Not tested streptomycin i.m zema F. T. Sensitivity to antibiotics +++ +++* V. M. Sensitivity to antibiotics ++ +++* F. A.(Nurse) Handles streptomycin Hand eczema ++' +++ H. S.(Nurse) Handles streptomycin Face and hand eczema ++e +++ * Noknown previous contact

During the first year of use of neomycin in ourrevealed no previous contact to streptomycin and service no sensitizations were found. A fewit was therefore decided to test all further cases sensitized to neomycin or streptomycin with *Fromthe Service of Dermato-Allergy at the Fondation Ophthalmologique Adoiphe de Roths-both of these compounds. It was found that child, Paris (Dr. Edwin Sidi, Chief). patients sensitized to either one of them are Presented at the Eighteenth Annual Meetingregularly sensitive to the other. of The Society for Investigative Dermatology, Inc., New York, N. Y., June 2, 1957. Up to the present time we have only a limited 225 226 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY series of eight such cases. However, due to the In a number of instances, ordinary patch importance of cross-sensitization of this nature,testing was insufficient to elicit a reaction. How- we are presenting these findings. A summary ofever, light scarification of the area prior to testing the data pertaining to these eight cases is given inregularly yielded positive results in sensitized Table I. Of these eight patients with positivepatients. This is in accord with a recent article by patch tests to both antibiotics five had never hadEpstein (1) who found intradermal testing neces- contact with streptomycin as far as could besary to elicit positive reactions to neomycin. ascertained by careful history taking. TwoIntradermal tests were not performed by us patients had no known contact with neomycinbecause of the previous occurrence of a severe but had been handling streptomycin. Oneaccident in a streptomycin sensitive patient patient had contact with both antibiotics andbeing tested intradermally (2). reacted with an anaphylactoid response to an DISCUSSION intramuscular injection of streptomycin, followed Neomycin, obtained from &reptomyce8 fradiae, by eczematization of the neomycin treated area.is a mixture of nearnine and two glucosides of this In every case the reaction to streptomycin wassubstance. Framycetin, obtained from Strepto- markedly more positive than that to neomycin.myces lavendulae, is another neamine glucoside. The common neamine moiety is a cyclohexane Neomycin: bearing two amino groups (Fig. 1). H H The glucide fractions of neonlycin B, C, and H H framycetin are probable biases bearing an amino group. At the present time in France the com- mercially available form of neomycin is prac- 112N NH2 H H tically pure neomycin B. The formula for strepto- mycin is shown in Fig. 2, and also consists of a substituted cyclohexane (streptidine) linked to an HO 0(H) amino-substituted biose (streptobiosamine). H OH".. The chemical configuration causing cross- Neamine Bio8ainine sensitization between neomycin and streptomycin FIG. 1 is likely to be found in the aglycone moieties, but Sire piomycin:H OH H H HN / NH C—HN NH—C / H H H,N NH, HOH OH\0(11) Sire plidine /C—OH CII / HC-I/H—NR—CH, 0 1/ 0 I C H\ CHOH \\ CH\ CH I Oj CII, CH,OH Sire piobiosamine FIG. 2 CROSS-SENSITIZATION BETWEEN NEOMYCIN AND STREPTOMYCIN 227 the exact chemical group responsible for thispast ten years, it was found that between 1947 phenomenon has not been ascertained. Both orand 1949 the sulfa compounds caused 41% of either of the amino-cyclohexane and biosaminethese eruptions; by 1953, the antihistamine fractions may be implicated. creams were causing 50% of the reactions. A word now about the clinical aspects of thisRecently the antibiotics have come to the fore to work. The type of reaction seen after topicalconstitute the main cause of contact dermatitis sensitization to antibiotics seems to be somewhatdue to therapeutic agents during 1956. different than that expected in the usual allergic The importance of these sensitizations is contact dermatitis. Instead of an acute vesicular obvious considering the many important uses of oozing process at the site of contact the reaction these substances. The number of cases of cross- is more often of the dry desquamative spreading type which may at times involve covered areassensitization between neomycin and streptomycin more suggestive of atopic dermatitis. reported here is small. Investigation of similar In addition, the necessity for scratching thecases by other workers should yield important skin area to be patch tested in order to obtaindata. reproducible results seems to indicate a deeper REFERENCES site of reaction than in the usual contact derma-1. EPSTEIN, S.: Contact dermatitis from neomycin titis. Both of these facts have also been pointed due to dermal delayed (tuberculin type) sensitivity. Dermatologica, 113: 200, 1956. out by Epstein (1). 2. Sw:, E. AND LONGUEVILLE, R.: Shock and In examining the figures on dermatitis due to urticaria after intradermal test with strepto- therapeutic agents observed in our clinic over the mycin. Scm. Hop., 14: 579, 1954.

DISCUSSION DR. CLARENCE S. LIVIN000D (Detroit, Michi-and neomycin. Unfortunately due to a mis- gan): I am very much interested in this paperunderstanding, only intradermal tests were done because for some time now we have been ac-in the case of streptomycin whereas both cumulating a series of patients who haveintradermal tests and patch tests were done with evidently been sensitized to neomycin by theneomycin. In a small series of 15 patients with prolonged topical application of the antibiotic,positive patch and intradermal tests to 1:100 particularly in patients with eczematizedaqueous solution of neomycin, 4 were found to dermatitis. We have been impressed by the facthave a positive intradermal test to 1:100 aqueous that often it is not easy to recognize these re-solution of streptomycin; all of these patients actions. Dr. Stephan Epstein is of the samewere also tested intradermally to dihydro- opinion (Epstein, Stephan: "Contact Derma-streptomycin and in each case the reaction was titis from Neomycin Due to Dermal Delayednegative. We are not able to interpret the pos- (Tuberculin-Type) Sensitivity," Dermatologicasible significance of this observation and ob- 113: 191, 1956). We have been disturbed by theviously this whole subject requires further study. fact that these reactions seem to persist for a In our daily practice, we find it rewarding to more prolonged period than is usual for contactreview carefully the previous medication of sensitivity reactions due to many other medica-patients with chronic eczematous dermatitis ments. In performing patch tests on many ofwith particular reference to the previous use of these patients, there has been a tendency in acombinations of hydrocortisone and neomycin. few cases for positive reactions to appear as longIn some of these patients we have found that the as 4 or 5 days after application rather thandiscontinuation of such therapy followed by the within a period of 24 to 48 hours, and in someappropriate use of plain hydrocortisone topical instances, the positive patch tests have per-application results in improvement and control sisted for as long as several months. of the eczematous process despite the fact that When I saw this paper listed on the programthe previous combined hydrocortisone-nea-- several months ago I asked two of my colleaguesmycin ointment or lotion did not seem to cause (Dr. Robert Fosnaugh and Dr. Hugh Reynolds)an obvious contact dermatitis. to test a group of these patients with apparent It seems most important to extend these sensitivity to neomycin with both streptomycinstudies on cross-sensitization reactions to neo- 228 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY mycin and streptomycin because if a significant DR. ALEXANDER A. FISHER (Long Island, percentage of patients are sensitized to strepto-N. Y.) : At the Skin and Cancer Unit we have been mycin by the topical application of neomycin, italso finding increasing numbers of patients who is of obvious significance. have become sensitive to neomycin. In a series of 100 consecutive patients, three became sen- DR. SAMUEL M. PECK (New York, N. Y.):sitized to neomycin. In all of these patients we This thought-provoking paper I think willobtained a positive patch test without doing the again lead us to re-evaluate our interpretationpreliminary scratch procedure. Two of the of skin testing for antibiotic sensitivity. patients had the so-called "subtle type" of Now that the research on penicillin sensitivitycontact dermatitis which did resemble dry has fallen so far into the background, I amatopic eczema. The other patient had a frank afraid that we are forgetting some of the basictype of contact dermatitis. After I had read the data which was demonstrated at that time.protocol on the paper presented just now, we Many problems were left unanswered and I amtested these three patients with streptomycin glad to note that the authors have revived someand found that one patient also reacted to of puzzles which arose at that time. No. 1, whatstreptomycin. is the relationship between an intradermal test Incidentally in 300 consecutive patients who with penicillin in a patient sensitive to penicillinused aureomycin ointment, only one showed a to the patch test with the same material? Yearssensitivity to aureomycin. That patient did not go it was shown that in patients with eczematoidreact to aureomycin given internally. In 100 richophytids one could obtain a positive patchconsecutive patients who used terramycin, there test to trichophytin. In other types of "ids",were no sensitivity reactions. In view of the fact this was not the case. What is the status in skinthat neomycin may cause cross-reactions with streptomycin, and in view of the fact that we eruptions due to penicillin sensitivity? You get ahave the impression that neomycin is not as positive penicillin test whether the patient has anefficient as aureomycin and terramycin, we eczematous vesicular type of eruption on thewonder why neomycin should be used at all. hands and feet or whether they have an erythema multiforme type, or urticarial type of eruption. Dn. RUDOLF L. BARR (New York, N. Y.): A positive patch test to penicillin is rare and onlyDr. Sidi and his group previously have made when there is a high degree of sensitivity tonotable contributions in the field of cross- penicillin even in non-eczematous eruptions.sensitization and he and his group should be This data should be reviewed and the workcongratulated on this beautiful new piece of repeated. It is my feeling that even the so-calledwork. positive patch test to an antibotic or to tn- When Dr. Ludwig and I first published a case chophytin and even tuberculin gives histo-of allergic eczematous sensitivity to neomycin logic picture which differs from the true patch(Ann. of Allergy, 10: 136, 1952) there was test to simple chemicals in contact dermatitis.surprise because at that time neomycin was It has never been explained to my satisfactionthought to be either non-allergenic or to have an why a patient with T. purpureum infection mayexceedingly low degree of allergenicity. What we show only an immediate reaction to tricho-have heard today about sensitization to neo- phytin. Yet the same antigen is present to givemycin confirms what has been observed with the a typical delayed reaction in a patient withuse of many other new topical medicaments; substances which in the beginning appear to trichophytids. The point I wish to stress here is this, that wehave a very low sensitizing index later on when they are more widely used, prove to have a much have to reevaluate our results, of skin testing with higher sensitizing index than was expected. The antibiotics. They can be used to some extent notreasons for this are too obvious to necessitate only to indicate the degree of sensitivity butdetailing before this audience. what is more important perhaps is to predict the As far as the clinical features of neomycin type of allergic response and its severity in thedermatitis are concerned, I can confirm Dr. A. A. sensitive patient. Fisher's statement that some patients develop CR0SS-SNSIPXZATION BETWEENNEOMYCINANT) STREPTOMYCIN 229

an acute vesicular, allergic, eczematous contactand eczematoid sensitization. But the fact we type of dermatitis of the usual type. In manythink that it will produce a few cases of this type other eases, however, the eruption takes on theshould be kept in mind. appearame described by the presenters and several of the discussers. Da. R. L. MAYER (Summit, N. J.): Dr. It is most interesting to reflect upon the reasonsSidi's paper is very interesting and thought- which led to preferential use of neomycin over theprovoking indeed. The importance of the problem tetracycline group compounds as topical medica-of cross-sensitization lies not only in the practical, ments on the part of many dermatologists. As farbut also in the theoretical, aspects. Its practical as I know neomycin became so popular as aimportance is evidenced by its general medical topical medicament principally for 3 reasons:significance, as well as by the fact that the FDA 1) it has an excellent spectrum of antibacterialnow requires appropriate tests to eliminate activity; 2) it was thought to have a very lowstrong sensitizers, in particular among com- allergenicity and 3) it was not being used orpounds intended for topical use. Unfortunately, hardly was used systemically. On the other handwe do not yet possess an adequate test which topical application of the tetracycline groupwould permit the prediction of possible sensitizers compounds was considered to be perhaps some-of the immediate and anaphylactic type among what risky, because allergic sensitization afterdrugs. topical use might interfere with their systemic use Within this cross-reaction, mentioned in later on. Experience has shown that the tetra-Sidi's paper, neomycin seems to be considerably cycline group compounds have a very lowless sensitizing than streptomycin. I have de- eczematogenic sensitizing capacity indeed andscribed similar cases in the antigenic group of their topical use has not interfered to any sig-azo dyes, and the question arises why, within nificant extent with their systemic administra-groups of closely related and cross reacting sub- tion. Except for their yellowish staining proper-stances, certain compounds are strong, others ties I prefer these compounds to neomycin asonly weak sensitizers, and others only elicitors. topical medicaments. There may be many reasons for this, such as differences in exposure, differences in the mode of DR. IRA L. SCHAMBERO (Philadelphia, Pa.):application, differences in solubility, rapidity of I have under my care at present a nurse withelimination, chemical stability, etc. One of the contact dermatitis due to streptomycin. Amost important factors is the chemical nature of member of the Pennsylvania Occupationalthe carrier to which the sensitizing substances Disease Board who called me concerning thisbecome attached within the body. All cross- patient's request for compensation stated thatreacting compounds of low molecular weight are dermatitis due to common or frequent sen-haptens which acquire sensitizing properties sitizers is compensable whereas dermatitis causedonly after they have been attached to a suitable by a substance which only rarely sensitizes is not.carrier to form antigenic substances of high This seems to me a very curious legal concept.molecular weight. It is generally assumed that the carriers to which haptens become attached DR. JEAN HEwrrr (Paris, France): I wasdo not play any active role in the process of greatly interested in this paper. It is manysensitization. This seems to me not correct, and I years that I know I follow the works of Sidi andhave lately drawn attention to the fact that, on his colleagues. I believe we will see more andthe contrary, the type of sensitization seems very more cases of cross-sensitization of the typemuch dependent upon the chemical and physical nature of the carrier (globular or fibroid protein, because the chemical formulae of products which are used have sometimes a common part. Weground substance, lipopolysaccharides). Other factors explaining the differences in the ability to think too that it is generally said that neomycinsensitize may be differences in the way various is a very useful topical medicament because thissubstances, even chemically closely related, kind of cross-sensitization is above all theo-combine with the carrier. retically useful to know in practice. It will Dr. Peck's question why a compound in- certainly give a few cases of cross-sensitizationjected intradermally will produce another type of 230 THE JOuRNAL OF INVESTIGATIVE DERMATOLOGY sensitization than a compound applied upon thecharacter of the dye, and that the dye in the dress skin, may be answered as follows: The carrierswould not have harmed a normal person. The with which the hapten will combine uponseller of that dress was not liable under the Sales epidermal application and intradermal injectionAct relating to implied warranty of fitness. In are different. In the first case there are onlyKroger v. Industrial Commission (Wis. Supreme keratinic and collagenic substances involved;Ct. decided 1/13/42) the appellant contended in the second case, ground substances andthat the law was not intended to cover every globular protein. allergic tendency of certain sensitized indi- viduals to certain substances. That is the reason Da. MABEL G. SILVERBERG (New York,for the decision. N. Y.): Except for special experimental purposes, as was the case in this work, it is very undesirable Dn. HERMANN PIE1us (Monroe, Michigan): to scarify the skin before a patch test sinceSince Dr. Stephan Epstein is not here, and since I scarifying the skin increases the danger ofhad the privilege of examining all his histological sensitizing the skin by the patch test itself. preparations, I would like to point out that the response to patch tests with neomycin, at least DR. ALBERT M. KLIoN (Philadelphia, Pa.):in those cases that Dr. Epstein biopsied is not I think this originally neomycinophilic audienceeczematous. One may find some small vesicles in is being rapidly converted into a neomycino-the epidermis. These are around the sweat ducts phobic one. As a neomycin lover I wish to defendwhich probably permit the drug to penetrate the assault on this compound. I think it is almostdeeper into the skin. Most of the reaction is of the inevitable that some instances of sensitizationdermal type of contact sensitivity about which will be encountered when the use of an agentDr. Epstein has written lately. becomes widespread enough. Tons of neomycin He confused me greatly several times with his ointment are being applied to skin annually. Forbiopsies when he did not give me the history. I years there was scarcely a whisper—now comes awas tempted to diagnose lymphoblastoma rather sudden clamor that neomycin may be a strongthan dermatitis. It looks like reaction of the sensitizer. We have been through this precisereticulo-endothelial system rather than the situation before with other agents. Neomycin isleukocytic, inflammatory reaction that we expect a splendid surface disinfectant and I hardly thinkto find in contact dermatitis. it sensible to forego its use just because a few The second point I would like to make is this. cases of sensitization have at last turned up.Even though the rate of sensitivity to neomycin is probably very low and may not have gone up DR. VINCENT J. DERBES (New Orleans, La.):as Dr. Kligman said, I think the practical I would like to comment about the remark thatimportant thing is the insidiousness of the clinical Dr. Schamberg made about compensability. Imanifestations which are not easily recognized as think his committee in his state of Pennsylvaniacontact sensitivity by the physician who is not is basing its decision on the law, not on whataware of this type of reaction. Neomycin allergy physicians would regard as logic. The law states,manifests itself often only as a prolongation of the and many cases come to trial before com-course of the disease that is being treated. This is missions, that a substance which causes nsi-particularly true with the present use of the drug tivity only rarely, cannot be charged to the manufacturer or seller of that commodity. Thustogether with hydrocortisone, because the hydro- in the case of Frankes v. Bennett (146, S.W. 2d.cortisone then blunts the inflammatory reaction. 163 Arkansas) it has been ruled that "it is com-One may see only that the patient does not get mon knowledge that many people are allergic towell and may not consider that the neomycin is particular foods and cannot eat them no matterkeeping his disease going, unless he is aware of how pure nor how well prepared." Again, inthis peculiar type of sensitivity. Barrett v. Kresge (19A. 2d. 502, 144 Pa. Super. 516) the ruling stated that the dermatitis which DR. CYRIL MARCH (in closing): I want to thank a buyer suffered after wearing a dress was due tothe discussers in Dr. Sidi's name for the many her individual allergic nature, instead of to thecomments and for the confirmation that they CROSS-SENSITIZATION BETWEEN NEOMYCIN AND STREPTOMYCIN 231 have offered for most of the points in this com-number of patients who were negative on patch munication. I am also very glad that Dr. Mayertesting would have given positive reactions with answered Dr. Peck's question in such a clearthe scarification procedure. Some of the patients way. His comments open the way to manyin Dr. Sidi's small series did react positively to avenues of research. patch tests but the others would have been Dr. Livingood and Dr. Fisher comment on themissed, had scarifying not been performed. fact that they were able to demonstrate sen- As to Dr. Silverberg's comment on the dangers sitivity to neomycin by conventional patchof scarifying the skin prior to patch testing, I testing in their series. It is probable that ahave no comment. I don't know about it.