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IMMUNOCHEMICAL MECHANISMS INVOLVED INPENICILLIN HYPERSENSITIVITY INEXPERIMENTAL ANIMALS AND IN

HUMAN BEINGSBERNARD B. LEVINE

Assistant Professor of Medicine, New York University School of Medicine, New York, N.Y.

IN addition to its importance in clinical medi-cine, the human penicillin allergy systemprovides a comparatively well defined haptenicsystem for the study of fundamental immunemechanisms involved in human allergicdiseases. Also, the understanding of themechanisms involved in clinical allergicreactions to penicillin would in turn allow formore rational approaches to the prediction,diagnosis, prevention and management of thesediseases. Penicillin allergies are, of course,immune diseases, i.e., they follow antibody/antigen reactions taking place in relation totissue. Accordingly, the following kinds ofinformation are important in elucidating theirimmune mechanisms: (1) the chemical mechan-ism of antigenicity of penicillin; (2) theantigenic specificities of immune responses topenicillin; (3) the kinds and quantities of anti-bodies synthesized in response to the admini-stration of penicillin and, (4) the relationshipof the nature of the immune responses to theoccurrence of clinical allergic reactions. Studiesin experimental animals provided a basis forlater studies in human beings, and broadenthe biological significance of the resultsobtained. This paper will deal with the chemi-cal mechanisms of antigenicity of penicillin,the antigenic specificities of the immune res-ponses of guinea pigs, rabbits and humanbeings to administration of penicillin, our earlyviews on the possible immune mechanismsinvolved in clinical allergic reactions to peni-cillin, and the clinical implications of theseviews.

Antigenicity of Benzyl PenicillinIn order for low molecular weight chemicals

to induce immune responses, they must firstcombine irreversibly with tissue macromolecules(most probably, proteins) to form the hapten-protein conjugates which induce the synthesisof specific antibodies. This view is widelyaccepted among immunologists, and is basedon much data which show that of aIarge anumber of simple chemicals, only

those whiclh combine, through covallentlinkages, with proteins or with protein-model compounds are capable of induc-ing immune responses (Landsteiner, 1945;Gell, Harrington and Pitt-Rivers, 1946; Eisen,1959). With regard to many drugs which cancause allergic reactions, but would appear fromtheir structural formule to be incapable ofreacting irreversibly with proteins, it is reason-able to postulate that either a trace contami-nant, a degradation product, or an interme-diate metabolite of the drug may be the actualprotein-reactive material (Landsteiner, 1945).With regard to the antigenicity of benzyl peni-cillin (penicillin G, PG), the available evidenceindicates that PG first rearranges to form anisomer, D-benzyl-penicillenic acid (BPE) (Fig.1), which is a highly reactive compound, andwhich is the protein-reactive compound res-ponsible for the induction of immune res-ponses to PG (Levine, 1960a, 1960b, 1961).This rearrangement appears not to be depen-dent upon in vivo enzymatic catalyses. Itoccurs in vitro as well as in vivo, and its rate isincreased by low pH and by the presence ofcations such as Cu+ +, Zn+ +, Fe+ +(Florey et al., 1949; Clarke, Johnson andRobinson, 1949). BPE reacts irreversiblymainly with lysine e-amino groups of proteinsto form benzylpenicilloyl-amine haptenic groups(Levine, 1961; Levine and Ovary, 1961). (Fig. 1).Other haptenic groups are formed to a lesserextent, as will be taken up below. Alterna-tively, it may be considered that PG mightreact to form benzylpenicilloyl haptenicgroups by a direct addition reaction of thepl-lactam carbonyl to lysine amine residues ofproteins. This view of the antigenicity of PGappears less likely from the following lines ofevidence: (1) although this latter reaction doesproceed at pH 11.5 with a half life in the orderof minutes (Levine, unpublished data), itwould proceed very much slower at pH 7.5,probably in the order of I /10,000th as rapidlyas at pH 11.5; (2) PG does rearrange to BPEunder physiological conditions in vitro (Levine,

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* ~CH3 ~!2OHCC (H)* CH2 CO NH HC-CH C' 3 14H2 O'CH2-CO-NH-HC-CH C(CH3)2

*1 CH3 1

C-N - CHCOOH (CM2)4 O= C NH-CH COOH

G HNHPenicillin G + N,HCCI2)4

Isomerization 0°H tsine * -Amino Group

HS NH CN-C - CH C(CH3)2 of Protin 0I *I

* CH2 C ,C NH-CH COOH DE-Lysyl-C0-AmIde ofO O \D-Benzy[pen;c;iloic ACJd ReSidUeD-Benzypenicilenic Acid + (Mixture of Diastereomers)

H20 /Cy S y / S )S

? + BSOS Cysteine Disulfide Linkage C C

* CH2 CO0NH HC-CiH C(CH3)2 of Protin N-CCH (CH3)22 ) fPoenIIC NH-CH-COOH *CH2C C, NOi-Cl COON0 OH 400

D-Benzylpeniclloic Acid D-Benzylpenicillenic Acid- CYNCysteine Mlxed Disuifide Residue Cy-SH

Isomerization H3C-C-CH3

HS NH2-CH COOHO*CH2 CO NHHC-CH 'C(C113)2

I I I \Penacill_mne-CysteineC N-CH COOH + Cy Mixed Disulfide Residue

0 \011 / Cy

D-Benzylpenamoldic Acid CY-SH + Bezylpenillooldehyde*'CH2 CO NH HC- CH \C(CH3)2 CO2I

COOH NH-CH COOH® D-Benzylpr.cmaldic Acid -Cysteine MixelI Disulfide Residue

FIG. 1.-Postulated chemical pathways leading to the formation of "penicillin antigen6".

1960b; Clarke et al., 1949) and undoubt-edly also in vivo. The rate of rearrangementin vivo is unknown. Based on the data ofEagle (1947) and on arguments given previously(Levine, 1960a), it may be as much as 10%per hour; (3) BPE is an exceedingly chemic-ally reactive compound. In aqueous solution,pH 7.5 at 370C. it is hydrolyzed at the rate of11% per minute (Levine, 1961) at least 550times more rapidly than is PG under identicalconditions (Benedict, Schmidt and Coghill,1946); (4) sensitization of guinea pigs (forallergic contact dermatitis, Levine, 1960a),rabbits (for serum antibodies, Levine, 1961b;1964a) and human beings (for skin sensitizingantibodies, Levine and Price, 1964) and prob-ably also for serum 7S and 19S antibodies(Levine, unpublished data) induces the forma-tion of antibodies specific for a mixture ofdiastereoisomers of the benzylpenicilloyl hap-tenic group rather than for the a-diastereoisomeralone. If the "complete penicillin antigens"

which induce antibody formation, wereformed by the direct addition of the pl-lactamcarbonyl of penicillin to amine residues ofprotein, the resulting benzylpenicilloyl haptenicgroups would be formed as a diastereoisomer(Levine, 1962). If the reaction proceededthrough the intermediate formation ofbenzylpenicillenic acid, the benzylpenicilloylgroups would be formed as a diasteroisomericmixture (Levine, 1961a). The finding that anti-PG antibodies are specific for a diastereoisomericmixture of benzylpenicilloyl groups is thusconsistent with the view that PG combineswith tissue proteins through the intermediateBPE. An unequivocal proof of this view,however, requires precise measurements of therate of rearrangement of PG to BPE underconditions which simulate physiological condi-tions in vitro, e.g. the reaction solution shouldcontain traces of Cu++, etc. These argumentsgiven above, although indicating -that PGreacts with tissue proteins primarily through

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the reactive intermediate BPE, do not excludethe possibility that PG may also react directlywith proteins to some extent.

Antigenic Specificities of lmmune Responses toPG in Experimental AnimalsGuinea pigs can be made allergic (contact

dermatitis type) to PG by repeated percutaneousapplication of solutions of PG in a solventcontaining the anionic detergent Tween 80(Levine, 1960a).The haptenic specificities of allergic contact

dermatitis reactions were inferred from thepatterns of allergic cross-reactivity among PGand its highly purified degradation products, aswell as from the chemical reactivities of PGand its degradation products. The observationthat groups of guinea pigs sensitized with PG orwith BPE both give identical allergic reactionsto patch tests with PG and with BPE (i.e., thetwo groups of guinea pigs are "allergicallyequivalent"-see Levine (1960a) for more de-tailed descriptions) indicates that the allergiccontact reactions are specific for the diastereo-isomeric benzylpenicilloyl groups. In addition,specific allergic cross reactivity among PG,sodium benzylpenicilloate and D-penicillamineis observed (Levine, 1960a). These data and thefinding that benzylpenicilloate reacts withcystine (through the intermediate formation ofbenzylpenamaldic acid-cysteine mixed disul-fide) to form D-penicillamine cysteine mixeddisulfide (Levine, 1960c) (Fig. 1), indicates thatthe D-benzylpenamaldic acid-cysteine mixeddisulfide and the D-penicitllamine-cysteine mixeddisulfide groups are also haptenic determi-nants. In addition, the benzylpenicillenic acid-disulfide group (Fig 1) is a possible fourthhaptenic determinant. In the few studies doneon human beings, two of three patients withallergic contact dermatitis to PG reacted alsoto patch tests with D-penicillamine (Levine andEisen, unpublished data), which suggests thata similar haptenic heterogeneity exists inhuman beings with allergic contact dermatitisto penicillin. The foregoing observationsindicate that the antigenic specificity of aller-gic contact dermatitis induced by the simplechemical compound, benzyl penicillin, is direc-ted toward at least three different haptenicdeterminants (Fig. 1). This heterogeneity ofhaptenic antigenic specificity has been foundalso for the skin sensitizing antibodies inducedin human beings made hypersensitive tobenzyl penicillin (see below). From considera-tions of the chemical reactivities of PG and

its degradation products with protein-modelcompounds (Levine, 1960a, 1960b; Florey,1949), it is likely that most of the penicillin thatcombines irreversibly with tissue proteins formbenzylpenicilloyl haptenic groups, whereasonly a comparatively small fraction of the PGthat reacts forms the penamaldic acid andpenicillamine mixed disulfide haptenic deter-minants. On this basis, the benzylpenicilloylgroup has been termed the major antigenicdeterminant, and the two mixed disulfidedeterminants (including other unidentified tracehaptenic determinants, see below) have beentermed the minor antigenic determinants ofpenicillin hypersensitivity Levine and Price,1964; Siegel and Levine, 1964).

Antigenic Specificity of Rabbit Anti-benzyl-peniciflin Antibodies

Rabbits can be immunized to PG by injec-tion of PG emulsified in complete Freund'sadjuvants followed by booster injections ofaqueous penicillin or aqueous suspensions ofprocaine e-penicillin. Under these conditions,sera containing as much as 400-500 ug./ml. ofantibody protein can be obtained (Levine andOvary, 1961). These antibodies are specificfor the benzylpenicilloyl haptenic group asshown by quantitative precipitin techniques(Levine and Ovary, 1961), by passive cutaneousanaphylaxis (PCA) in guinea pigs (Levine andOvary, 1961; Levine, 1964a), and by passivehemagglutination (De Weck, 1962). Benzyl-penicilloyl haptenic specificity of theseimmunological reactions was confirmed byquantitative hapten inhibition techniques(Levine and Ovary, 1961; Levine, 1964a; De-Weck, 1962) using benzylpenicilloyl-e-amino-caproate (Levine, 1962) as the univalent hapten.The anti-benzylpenicilloyl antibodies showspecificity also for the lysine side chain ofproteins through which benzyl-penicilloylgroups are predominantly bound to protein,(Levine and Ovary, 1961; Levine, 1962; 1963).Other studies have demonstrated that anti-benzyl-penicilloyl antibodies produced byimmunization of rabbits with benzylpenicilloyl-rabbit serum albumin conjugates are specificalso for structural areas of the carrier protein(carrier specificity) (Levine, 1963). Some evi-dence indicates that anti-benzylpenicilloylantibodies produced by immunization of rab-bits with PG also show carrier specificity toas yet unidentified carrier proteins (Levine,1964a). Thus, available evidence indicates thatthe bulk of antibodies produced by immuniza-

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tion of rabbits with PG show immunologicalspecificity for a rather large antigenic unitcomprised of the entire benzylpenicilloyl hap-tenic group, the lysine side chain, and pos-sibly also for structural configurations of asyet undefined autologous protein carriers towhich benzylpenicilloyl groups are bound. Noantibodies specific for the benzylpenicillenicacid mixed disulfide or the D-penicillaminemixed disulfide haptenic groups were detectedin rabbit anti-PG sera by precipitation and byPCA (Levine and Ovary, 1961; Levine, 1964a),nor could indirect evidence of antibodiesspecific for the D-benzylpenamaldic acid-mixeddisulfide haptenic group be obtained (Levineand Ovary, 1961). DeWeck (1962) stated thathe has detected anti-benzylpenicillenic aciddisulfide antibodies in rabbit anti-PG sera, butno supporting data was given.Antigenic Specificities of HumanR Anti-Penicillin Antibodies.On an operational basis, two different

classes of anti-PG antibodies can be detectedin human beings, i.e. skin sensitizing antibodiesand serum antibodies detectible by passivehemagglutination. From studies in other anti-genic systems, skin sensitizing antibodies arebelieved to be ylA globulins (Heremans andVaerman, 1962; Fireman, Vannier and Good-man, 1963). Antigenic specificities of skinsensitizing antibodies can be studied by directskin test for wheal-and-flare reactions, and bypassive transfer of sera from patients withrecent allergic reactions to the skin of non-sensitive human recipients. Three kinds ofantigenic specificities of skin sensitizing anti-bodies have been found by these studies:

(1) Benzylpenicilloyl-specific antibodies weredetected by direct skin tests (Levine and Ovary,1961; Levine and Price, 1964; Parker, Shapiro,Kern and Eisen, 1962) and by passive transfertechniques (Siegal and Levine, 1964). Skin testreagents which can be used for detection ofbenzylpenicilloyl (BPO) specific antibodies aremultivalent BPO-haptens such as BPO-proteinconjugates and BPO-polylysine. SuccinylatedBPO-polylysine conjugates of poly-L-lysinepoly-D-lysine appear, at present, to be themost useful clinical reagents for the detectionof BPO-specific skin reactivity. They areeffective elicitors of BPO-specific wheal-and-flare reactions (Parker et al., 1962; Levineand Price, 1964), they are virtually non-irritat-ing, and they are incapable of inducingimmune responses in experimental animals(Levine, 1964b; Parker and Thiel, 1963), and

probably also in man. BPO-specificity of thesewheal-and-flare reactions (Levine and Ovary,1961; Levine and Price, 1964; Parker et al.,1962; Siegal and Levine, 1964) as wellas specificity for a diastereoisomeric mixture ofBPO groups (Levine and Price, 1964) was con-firmed by hapten inhibition experiments, usingbenzylpenicilloyl aminocaproate (Levine, 1962)as the univalent hapten. Other experimentsindicate that the anti-BPO skin-sensitizingantibodies show specificity also for structuralconfigurations of the autologous carrier pro-teins which induced the synthesis of antibody(carrier specificity) (Levine and Price, 1964).Carrier specificity toward human serum albu-min was indicated in one patient (Levine andPrice, 1964), towards human gamma globulin inanother (Levine and Ovary, 1961), and to asyet unidentified proteins in others (Levine andPrice, 1964). Since skin sensitizing antibodiesmay mediate some kinds of allergic reaction topenicillin, the indication that anti-BPO anti-bodies are specific also for structural con-figurations of homologous proteins wouldsuggest that some allergic reactions to peni-cillin are, in part, auto-immune diseases. Theexact clinical significance of carrier specificity isnot yet known.

(2) Another group of patients showspecific wheal-and-flare skin reactivity bydirect skin test to crystalline potassium benzyl-penicillin (KPG) and to crystalline sodiumbenzylpenicilloate (free from PG impurity)(Levine and Price, 1964, and unpublisheddata). Two of these patients (out of eighttested) gave weak reactions also to a multi-valent D-penicillamine conjugate (Levine andPrice, 1964, and unpublished data). Two otherpatients were tested and failed to react +o D-penicillamine, penilloaldehyde and to benzyi-oxazolone (unpublished data). This pattern ofreactivity indicates specificity to the D-benzylpenamaldic-cysteine mixed disulfide andthe D-penicillamine-cysteine mixed disulfidegroups (Levine and Price, 1964). However, thisspecificity must be confirmed by more directexperiments. The postulated chemical pathwayleading to the formation of these haptenicgroups is shown in Fig. 1.

(3) The third kind of antigenic specificitywas observed by passive transfer technique(Siegal and Levine, 1964). Human skinsites passively sensitized with serum frompatients with recent immediate systemicaliergic reactions to penicillin, gave wheal-and-flare reactions to crystalline KPG, butnot to sodium benzylpenicilloate, nor to

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multivalent conjugates of the BPO, the D-benzylpenicillenic acid-disulfide or the D-penicillamine haptenic groups. The antigenicspecificities of these skin-sensitizing antibodieshave not been determined. Some possibilitiesare discussed in Siegel and Levine (1964). Inaddition to these three antigenic specificities,Parker et al. (1962) have reported skinsensitizing antibodies specific for the benzyl-penicillenic acid-mixed disulfide group, but thishas not as yet been confirmed (Levine, 1964).Accordingly, skin-sensitizing antibodies synthe-sized by human beings in response to theadministration of PG show considerable anti-genic heterogeneity. Similar antigenic hetero-geneity is seen in allergic contact dermatitis topenicillin (see above).

Hemagglutinating anti-penicillin antibodiesare detected by testing serum dillutions withhuman group 0 red blood cells (RBC) whichhad previously reacted with PG (Ley, Harris,Brinkley, Liles and Cahan, 1958; Watson, Jon-bert and Bennett, 1961; Van Arsdel, O'Rourke,Horan and Kamasaka, 1963, or with benzyl-penicillenic acid (Fellner and Levine, un-published data). Both methods of RBCsensitization result in BPO haptenic groupscovalently linked to the RBC mem-brane, probably through amide linkages withamino residues of membranous proteins. It isnot as yet known whether other of the pos-sible penicillis haptenic groups are alsocoupled to RBC by these methods of sensitiza-tion. Hemagglutinating human anti-PG anti-bodies are both 19S and 7S y-globulins, with19S -antibodies occurring considerably morefrequently '(Heremans and Vaerman, 1962;Schwartz and Vaughan, 1963; Fudenberg andGerman, 1960). Anti-BPO antibodies of theylA class may also give passive hemagglu-tination, but this has not yet been demon-strated. Tihe haptenic specificity of hemagglu-tination anti-PG antibodies is predominantlytowards the BPO group (Theil and Parker,1962; Fellner and Levine, unpublished data).Other haptenic specificities, although likely,have not as yet been demonstrated.

immulne Mechanisms of Allergic Reactions toPenicillinData pertinent to this problem can be

obtained from prospective and retrospectivecorrelations of the immune status of patientswith the occurrence of clinical allergicreactions. In these studies, it is important toconsider separately the different types of aller-

gic reactions, e.g., immediate systemic, laterurticarial, serum-sickness-like, etc., since eachkind of reaction may have distinctly differentimmune mechanisms. Ailso, it should be con-sidered that non-immune mechanisms (i.e., vas-cular sensitivity to histamine, or the activity ofthe reticuloendothelial system in clearing theplasma of antigen-antibody complexes) mayplay a rAle in determining whether a patient inwhom is present the immunological factorsnecessary to develop an allergic reaction, doesindeed develop an allergic reaction.

It appears probable, at the present time,that immediate systemic allergic reactions topenicillin are mediated by skin-sensitizing(ylA) anti-PG antibodies. This statement isbased on the following evidence: Siegel hasreported, that all of 18 patients with recentimmediate systemic reactions to penicillincontained in their sera, skin-sensitizing anti-PG antibodies demonstrable by passivetransfer (Siegal, 1962). In addition, sixother patients with this clinical historyall showed direct wheal-and-flare skinreactivity to penicillin skin-test reagents (Fell-ner and Levine, unpublished data). This closeassociation of anaphylaxis and the presence ofskin-sensitizing antibodies has been found inother antigenic systems in human beings(Connell, Sherman and Myers, 1962), and inother mammalian species (Ovary, Benacerrafand Block, 1963; Nussenzweig, Merryman andBennacerraf, 1964). Of interest are the findingsthat the antigenic specificities of skin sensi-tizing anti-PG antibodies from patients withimmediate systemic allergic reactions weremainly to the minor antigenic determinants(i.e. skin reactions were evoked by skin testwith KPG alone, or by KPG and sodiumbenzylpenicilloate, see above) and only com-paratively rarely to the benzylpenicilloyl hap-tenic group (Levine and Price, 1964; Siegal andLevine, 1964; Siegal, 1962). The presence ofBPO-specific skin sensitizing antibodies doesnot necessarily mean that a patient will developan immediate systemic reaction on adminstra-tion of penicillin. Rytel, Klion, Arlander andMiller (1963) reported that none of 26 patientswith strongly positive wheal-and-flare reactionsto penicilloyl-polylysine, and who were imme-diately thereafter injected with 1.2 millionunits of benzathine penicillin developed imme-diate systemic reactions, although two of the26 developed late urticarial reactions. It ispossible that these patients were protectedfrom immediate systemic reactions by thepresence of circulating "blocking" antibodies

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(7S and/or 19S) of the same haptenic specificity.No prospective studies are yet available cor-relating the presence of skin-sensitizing anti-bodies of minor antigenic determinant specificityto the occurrence of immediate systemicallergic reactions.The immune mechanisms involved in late

urticarial reactions, in serum-sickness-like andin other types of late allergic reactions havenot as yet been elucidated. Since only 50-80%of such patients have detectable skin sensitizingantibodies (Levine and Price, 1964), immunemechanisms other than, or in addition tothose involving the participation of skin-sensitizing antibodies may be involved.

Clinical ImplicationsAn important clinical application of these

studies is to detect those patients who willhave an allergic reaction upon the administra-tion of penicillin. From the considerationsdiscussed above, patients who are liable todevelop immediate systemic allergic reactionsshould show wheal-and-flare reactions ondirect skin testing with the proper antigenicreagents, providing that the patients arephysiologically capable of manifesting suchskin reactions. The available data on the anti-genic specificities of skin-sensitizing antibodiesfound in patients with recent immediate sys-temic allergic reaction to penicillin indicatesthat crystalline KPG may be a more effectivedetector of the potential immediate reactorthan is penicilloyl-polylysine (see above, andLevine and Price, 1964; Siegel and Levine,1964). However, in order to detect the poten-tial immediate systemic reactor, patientsshould be tested with both these reagents. Apositive wheal-and-flare reactiondoesnotneces-sarily mean that a patient will have an imme-diate system reaction on administration iofpenicillin, but it increases the probability of itsoccurrence. A negative skin reaction to bothtest materials appears, at present, to indicatethat the patient will be able to receive penicillinwithout the occurrence of an immediatesystemic reaction. However, this view is basedon theoretical considerations and on experi-ence with a relatively small number of patients.It is still possible that other skin test materialswill have to be added to those now availablein order to detect very rare cases of penicillinallergy. Before negative skin tests to thematerials now at hand can be accepted asabsolutely ruling out the possibility of animmediate systemic allergic reaction, many

more patients must be evaluated. At thepresent time, it is not recommended that priorskin testing of patients about to be treatedwith penicillin be instituted as a routine clini-cal procedure. Before this can be doneadditional information must be obtained onthe sensitizing capabilities of the skin testreagents. It is to be noted that negative skintests to the reagents will not rule out the sub-sequent occurrence of a late urticarial orserum sickness-like allergic reaction followingthe administration of penicillin. At presentthere is no definite way to detect the patientwho is more liable to suffer allergic reactionsof these types.

SumSome current views of the immunochemical

mechanisms of penicillin hypersensitivity arepresented. The antigenicity of benzylpenicillinappears to depend in large part upon its abilityto rearrange in vivo to its highly reactiveisomer D-benzylpenicillenic acid. The postu-lated chemical pathways leading to the forma-tion of the complete "penicillin antigens," andthe identities of the haptenic determinants arepresented. The administration of the simplechemical compound, benzylpenicillin, to ex-perimental animals and to man leads to theproduction of antibodies of at least threedifferent haptenic specificities. Some early viewsare given on the immune response of humanbeings to penicillin, on the possi(ble immunemechanisms involved in allergic reactions topenicillin, and on the present clinical applica-tions of these studies.

FIG. 1 is reproduced from J. exp. Med. (1960), 112,113 by kind permission of the Editor.

REFERENCESBENEDICT, R. G., SCHMIDT, W. H., and COGHILL, R. D.

(1946): J. Bact., 51, 291.CLARKE, H. T., JOHNSON, J. R., and ROBINSON, R.,

editors. The Chemistry of Penicillin. PrincetonUniversity Press, 1949.

CONNELL, J. T., SHERMAN, W. B., and MYERS, P. A.(1962): J. Allergy, 33, 365.

DEWECK, A. L. (1962): Int. Arch. Allergy, 21, 23.EAGLE, H. (1947): J. exp. Med., 85, 141.EISEN, H. N., in Cellular and Humoral Aspects of the

Hypersensitive States, (H. S. Lawrence, Edit.).P. B. Hoeber, Inc., New York, New York, 1959.

FIREMAN, P., VANNIER, W. E., and GOODMAN, H. P.(1963): J. exp. Med., 117, 603.

FLOREY, H. W., CHAIN, E., HEATLEY, N. G., JENNINGS,W. A., SANDERS, H. G., ABRAHAM, E. P., andFLOREY, M. E., Antibiotics, London OxfordUniversity Press, 1949, Vol. 2.

FUDENBERG, H. H., and GERMAN, J. L. (1960): Blood,15, 683.

by copyright. on June 30, 2020 by guest. P

rotectedhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.40.Suppl.146 on 1 D

ecember 1964. D

ownloaded from

152

GELL, P. G. H., HARINGTON, C. R., and PiTr-RIVERS,R. (1946): Brit. J. exp. Path., 27, 267.

HEREMANS, J. F., and VAERMAN, J. P. (1962): Nature(Lond.), 193, 1091.

LANDSTEINER, K., The Specificity of Serological Re-actions, Harvard Univ. Press, Cambridge, Mass.,Rev. Edit., 1945.

LEVINE, B. B. (1960a): J. exp. Med., 112, 113.LEVINE, -B. B. (1960b): Nature (Lond.), 187, 939.LEVINE, B. B. (1960c): Nature (Lond.), 187, 940.LEVINE, B. B., and OVARY, Z. (1961): J. exp. Med.,

114, 875.LEVINE, B. B. (196la): Arch. Biochem. Biophys., 93,

50.LEVINE, B. B. (1962): J. Med. Pharm. Chem., 5, 1025.LEVINE, B. B. (1963): J. exp. Med., 117, 161.LEVINE, B. B., and PRICE, V. H. (1964): Immunology,

7,542.LEVINE, B. B. (1964a): Immunology, 7,527.LEVINE, B. B. (1964b): Nature (Lond.), 202, 1008.LEY, A., HARRIS, M., BRINKLEY, B., LILES, J., and

CAHAN, A. (1958): Science, 127, 1118.NUSSENZWEIG, R. S., MERRYMAN, C., and BENACERRAF,

B. (1964): J. exp. Med., in Press.

OVARY, Z., BENACERRAF, B., and BLOCH, K. J. (1963):J. exp. Med., 117, 951.

PARKER, C. W., SHAPIRO, J., KERN, M., and EISEN,H. N. (1962): J. exp. Med., 115, 821.

PARKER, C. W., and THIEL, J. A. (1963): J. lab. Clin.Med. (Abstr.), 62, 988.

RYTEL, M. W., KLION, F. M., ARLANDER, T. R., andMILLER, L. F. (1963): J. Amer. med. Ass., 186,894.

ScHwARTz, R. H., and VAUGHAN, J. H. (1963):J. Amer. med. Ass., 186, 1151.

SIEGEL, B. B. (1962): in Allergology, Pergamon Press,New York, 1962, p. 125.

SIEGEL, B. B., and LEVINE, B. B. (1964): J. Allergy,in Press.

THIEL, J. A., and PARKER, C. W. (1963): Presentedat 19th Annual Meeting, American Academy ofAllergy, March 12, 1963.

VAN ARSDAL, P. P., O'ROURKE, T. K., HORAN, J. D.,and KAMASAKA, Y. (1963): J. Amer. med Ass.,186, 118.

WATSON, K. C., JOUBERT, S. M., and BENNETr,M. A. E. (1961): Immunology, 4, 193.

CUTANEOUS REACTIONS TO PENICILLIN

C. D. CALNANProfessor of Dermatology, University of London, The Institute of Dermatology,

St. Johns Hospital for Diseases of the Skin, Leicester Square, London, W.C.2.

THE purely cutaneous reactions to penicillinare nowadays infrequent and relatively un-important. They consist of varying degrees ofacute or chronic non-specific inflammation,with or without abscess formation. They weremore commonly encountered with less purepenicillins and depot preparations sometimesinjected intradermally or subcutaneously ratherthan intramuscularly.

All other reactions with manifestations inthe skin are part of a general hypersensitivitystate, although they may not necessarily bemediated by a specific antibody directedagainst the drug. In this regard penicillin issimilar to sulphonamides in the very diversetypes of adverse reaction which it is capable ofproducing. The factors determining the typeof hypersensitivity reaction in an individualpatient are mostly obscure, with the possibleexception of contact dermatitis. In the lattercase, the route of administration-applicationto the cutaneous or a muco-orificial surface-isof paramount importance.

In the United States, there are well over a

hundred preparations of penicillin available tobe fed, injected, spread, insufflated and sprayedinto every conceivable cavity and surface ofthe body (Welch, Lewis, Weinstein andBoeckman, 1957). Individuals who have neverreceived penicillin are a fast diminishinggroup, a result of mass production and theavailability of this cheapest of all antibiotics.

IncidenceIf one accepts any undesired or unexpected

sequela as a reaction to the drug, the incidenceof penicillin reactions can be very high, beingdependent partly on the criteria of the physi-cian. Moore's (1946) figure is 0.56%, whileCormia, Jacobsen and Smith (1946) registeredit as high as 60%. The variation is, of course,partly due to uncritical acceptance of anysymptoms and signs, and partly due to theabsence of satisfactory methods of proof.Well controlled drug trials have shown thatskin eruptions may be seen in patients receiv-ing placebos as frequently as an active agent.Saline injections can induce the rash, arthralgia,

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