Clinical Allergy, 1988, Volume 18, pages 515-540

REVIEW

Immediate hypersensitivity reactions topenicillin and related antibiotics

M. E. WEISS and N. F. ADKINSON

Johns Hopkins University, Sehool of Medicine, The Good Samaritan Hospital.Baltimore. Maryland, U.S.A.

IntroductionThe discovery of penicillin by Fleming led to tremendous benefits in clinical medicine.Penicillin quickly became one of the most commonly prescribed drugs in the world.Despite a wide therapeutic index, it soon became clear that the penicillins could producea vast array of immunological responses that could cause severe and fatal allergicreactions in some patients. The first reported case of anaphylaxis due to penicillin wasin 1946 [I], and the first reported death was in 1949 [2]. Subsequently, a broad spectrumof allergic reactions to penicillin have been recognized. Available data do not permitexact conclusions as to the true frequency of allergic reactions to penicillin but they arereported to occur from 0-7 to S% of treatment courses in different studies [3],Allergenicity of penicillins is the major clinical problem that precludes the use of thisclass of antibiotics in a significant portion of the general population who are believed tobe sensitive. In this article we will discuss allergic reactions to ^-lactam antibiotics, withspecial emphasis on IgE-dependent reactions in man.

Allergic reactions

Types and prevalenceGell and Coombs classified four types of immunopathologic reactions [4], all of whichhave been seen with penicillin {Table I).

Type I reactions—immediate hypersensitivity. These reactions result from theinteraction of preformed penicillin-specific IgE antibodies that are bound to tissuemast cells and/or circulating basophils via high affinity IgE receptors; the result isurticaria, laryngeal oedema, bronchospasm with or without hypovolaemic shock.Anaphylactic reactions occur inO O15'/o to 0 004% of penicillin treatment courses [5].Fatality from a course of penicillin occurs with an incidence of 0 0015 to 0 OO2'>'>, orone death per 50 000-100 000 treatment courses. The use of /i-adrenergic antagonistsby a patient may increase the risk of death if anaphylaxis occurs, as treatment of an

Correspondence: N. Eranklin Adkinson. Jr. MD. Division of Clinical Immunology. The Good SamaritanHospital. 5601 Loch Raven Blvd, Bahimore. MD 21239. U.S.A.

515

516 M. E. Weiss and N. F. Adkinson

Table 1. Classification of Immunopathological reactions to penicillin

Type ofreactions*

I

II

QI

IV

V

Description

Anaphylactic(reaginic)hypersensitivityCytotoxic orcytolytic damageImmune complexdisease

"Delayed" orcell-mediatedhyf>ersensitivityldiopathic

Primary effecior meehanism(s)

Antibody

IgE

IgGIgMSolubleimmunecomplexes(Ag Ah)None known

IgM(?)777

Cells

Basophils.mast cells

Any cell withisoantigenNone directly

Sensitized Tlymphocytes

7777

Other

C . RES

C

7?7?

Clinical reactions

Anaphylaxis. urticaria

Coombs 4-haemoiytic anaemia;drug-induced nephritisSerum sickness:drug fever

Contact dermatitis,

Maculopapular eruptionsEosinophiliaStevens-Johnson syndromeExfolialive dermatitis

* According to the scheme of Gell and Coombs [4J.C . Complement; RES, reticuloendothelial system; Ag-Ab. antigen-antibody; (?) indicates that theimmunopathological mechanism is unknown.

anaphylactic reaction is made more difficult [6-8]. Type I reactions are the mostimportant clinically because of the fear of anaphylaxis with its potential for mortality.Because of this concern much research has been directed toward a better understand-ing and prevention of these reactions.

Type II reaetion.s—cytotoxic antibody. Penicillin determinants can become chemi-cally bound to circulating blood ceils leading to their accelerated destruction via IgG orIgM antibodies and complement. Clinically the result is a haemolytie anaemia orthrombocytopenia.

Type III reactions—immune eomplexes. Penicillin-specific IgG or IgM antibodiesform circulating complexes with penicillin haptenized to serum proteins, largelyalbumin. These circulating complexes can fix complement and then lodge in tissue sites,causing tissue injury.

Type IV reactions—delayed hypersensitivity. Contact dermatitis from penicillininvolves thymus-derived lymphocytes. The high rate of contact dermatitis frompenicillin (5-10%) used in mouthwashes and toothpaste in the 1940s led todiscontinuation of its use as a topical antibiotic in patient remedies. Contact dermatitisis still occasionally seen in individuals who are occupationally exposed to penicillins,such as nurses and pharmacists, but most cases are currently restricted to thoseinvolved in antibiotic manufacturing and packaging [5.6].

ldiopathic reactionsThe precise immunological mechanisms for these reactions are not known; indeed, ithas been difficult to establish unequivocally that a drug-specific immune mechanism is

Hypersensitivity reactions to penicillin and antibiotics 517

Table 2. Classification of allergic reactions lo penicillin!

Spectrum ofReaction type Onset clinical reactions

Immediate 0- I hr AnaphylaxisHypotensionLaryngeal oedemaUrticarial/angioedemaWheezing

Accelerated I 72hr Urticaria/angioedemaLaryngeal oedemaWheezing

Late >72hr Morbilliform rashInterstitial nephritisHaemolytic anaemiaNeutropeniaThromboeytopeniaSerum sicknessDrug feverStevens Johnson syndromeE.xfoliative dermatitis

t According to Levine [14j.

casually related. The tnaculopapular rash associated with penicillin is an example ofone such idiopathic reaction. The frequency of measles-like rashes in patients treatedwith penicillin is about 2%. Ampicillin-induced rashes occur with greater frequencyand occur in 5-2-9-5% of treatment courses [10-12]. Patients given ampicillin duringinfections with Epstein-Barr virus, cytomegalovirus. or with acute lymphocyticleukaemia, have a much higher incidence of rash (69-100%) [13]. The reason for thisincreased incidence is unknown.

Interestingly, about 25"/. of patients with diffuse erythematous exanthems havebeen found to have very high levels of penicilloyl-specific IgM antibodies [14]. Theimmunological mechanism for exfoliative dermatitis and Stevens-Johnson syndromeis presently unknown. A non-immunoiogical reaction to penicillin is the pseudo-anaphylactic reaction observed after intramuscular or inadvertent intravenousinjection of procaine penicillin [ 15]. This reaction is most likely due to a combination ofa toxic and embolic phenomena from procaine. and is not an IgE-mediated reaction[15].

Levine proposed classifying adverse reactions to penicillin according to their timeof onset [14] (Table 2). Immediate reactions occur within the firsl hour after penicillinadministration and are manifested clinically by diffuse urticaria, rhinitis, wheezing,laryngeal oedema, hypotension or shock. Accelerated reactions occur I 72 hr after theadministration of penicillin and are almost always manifested by urticaria, bu:occasionally laryngeal oedema is seen. Late reactions begin more than 72 hr after theonset of penicillin therapy and include maculopapular exanthems. drug fever,haemolytic anaemia, nephritis, leukopenia. exfoliative dermatitis. Stevens-Johnsonsyndrome and serum sickness, which can include fever, arthralgia. diffuse adenopathy,rash and renal involvement.

518 M.E. Weiss and N, F, Adkinson

Penicillins Cepholnsporms

COOH

Monoboctoms

0II

R-C-NH

Corbopenems

S-R

Fig. 1. Structure of the four classes of /f-lactam antibiotics in use today. Ali contain the four-rriembered^-lactam ring. ,

Immunochemistry

Haptenic antigens and their detectionPenicillin (MW 356) is a low molecular weight chemical so must first covalentlycombine with tissue macromolecules (presumably proteins) to produce mullivalenthapten-protein complexes, which are required for the induction of an immuneresponse [16]. Approximately 5% ofthe molecules administered to humans becomecovalently bound to proteins [17]. Reactions are usually with amino acids, which arecapable of assuming a charge on their side-chains such as lysine or histidine [18].Initially, many of the allergic reactions observed with penicillin were attributed toimpurities consisting of high molecular weight proteins and polymers in the re ativelycrude early preparations of penicillin [19]. However, subsequent studies have shownthat samples of penicillin free from detectable amounts of contaminating proteins andpolymers can elicit hypersensitivity reactions. It thus became clear that allergicreactions could be elicited by the penicillin molecule itself [20,2!]. Penicillins consist ofa 6-aminopenicillanic acid nucleus, which includes a /Mactam ring on whichantimicrobial activity depends, and a five-membered thiazolidinc ring (Fig. 1).Pioneering studies by Levine and Parker showed that the /f-lactam ring spontaneouslyopens under physiological conditions so that its carbonyl moiety can form an amidelinkage, largely with epsilon amino groups of adjacent proteins, forming the penicilloylgroup (22, 23). This penicilloyl group has been designated the major determinantbecause about 95% ofthe penicillin molecules that irreversibly combine with proteinform penicilloyl groups [14]. The major pathway from penicillin to penicilloyl involvesthe formation ofthe highly reactive penicillenic acid intermediate, although it has beenshown that some penicilloyl determinants can be formed directly from penicillin(Fig. 2) [14]. This reaction occurs with the prototype benzylpenicillin and virtually allsemi-synthetic penicillins. Although the side-chain does influence the rate of pencilloyiformation, it does not appear to affect significantly the relative immunogenicity ofvarious semi-synthetic penicillins.

Penicillin

Hypersensitivity reactions to penicillin and antibiotics 519

Penicillenic acid

O H H HII i I \ y \

R - C - N - C - C CI I IC - N CH - COOHO

Isomenzation

H SHI I

C = C

C C^ N - COOH

IProtein

Penicilloyl-Protein

O H H H

CC

,C N1 '

Protein Protein

CH-COOH

amidelinkage

• NH — CH — C - *IIO

Majorantigenic

determinani

Minorantigenic

determinants

Fig. 2. Principal pathways for the formation of penicillin antigens under physiological conditions in vivo.From Adkinson [451; reproduced with pertnission of American Society of Microbiology.

After the identification of the major antigenic determinant. Parker coupledpenicilloy! determinants to a weakly immunogenic polylysine carrier molecule to formpenicilloyl-polylysine (PPL). This preformed 'complete antigen" has been successfullyused as a test allergen for the detection of penicillin hypersensitivity in experimentalanimals and man [18]. The use of this synthetic antigen tor skin testing bypasses theinefficiency of/rt-r/ro conjugation of penicillin to tissue proteins and leads to a three tofour-fold enhancement of diagnostic sensitivity [23,24]. Penicilloylated proteins havesubsequently been used to detect serum IgE antibodies against the major determinantin a RAST assay [25].

Not all IgE-mediated penicillin sensitivity can be identified by skin testing withPPL. Levine and Redmond found that benzylpenicillin can also be degraded by othermetabolic pathways to form additional antigenic determinants [26]. These derivativesare formed in small quantities and stimulate a variable immune response, and hencehave been termed the 'minor determinants*. Because some of the determinants arelabile and cannot readily be synthesized in multivalent form, skin testing for minordeterminant specificity has employed a mixture of benzylpenicillin and one or more ofits hydrolysis products. The original minor determinant mixture (MDM) evaluated byLevine et al. [26] consisted of benzylpenicillin itself, its alkaline hydrolysis product(benzylpenicilloate) and its acid hydrolysis product (benzylpenilloate). The signifi-cance of positive skin tests to 'minor determinants' will be discussed below. It is

520 M. E. Weiss and N. F. Adkinson

assumed that the minor determinants produce weal-and-flare reactions by firstreacting chemically with proteins in the skin-test site to form the appropriatemultivalent conjugates, but this view is unproved and the exact chemical natu.'e oftheconjugates are presently unknown. Specific absorption experiments have indicatedthat the PPL-reactive. the penicillin-reactive., and the penicil!oate-penilloate-reactiveantibodies are distinct and non-cross-reactive [26]. Nevertheless, the synthesis ofpenieilloyl-IgE antibody and IgE antibody to minor determinants appear linked. Asubject who synthesizes antibody to one determinant is five to ten times more likely tosynthesize antibody to other determinants than control subjects [27].

Humoral immune response to penicillin antigensPenicillin is capable of eliciting a drug-specific immune response involving all majorclasses ofantibodies and immunocytes. There is marked heterogeneity in an individualpatient's immune response to penicillin, as manifested by difl'erences in haptenspecificity, differences in isotypes and quantity ofantibodies formed, as well as inantibody affinity.

Using a highly sensitive passive haemagglutination assay, antibodies to benzylpe-nicilloyl (BPO) were detected in almost 100'>i. of normal subjects, including some whodenied previously receiving penicillin therapy. Most, however, had low titres of BPO-specific IgM antibodies [14.27]. The synthesis of BPO-reactive IgM antibodies inindividuals who have never received penicillin may be due to environmental contactwith minute quantities of penicillin; or. more likely, to sensitization by naturallyoccurring cross-reacting moieties. About 40% of subjects receiving >2 g of penicillindaily, for at least 10 days, made a BPO-specific IgG antibody response to penicillin [28].The ability to mount an IgG or IgE response may partially be under genetic tontrol.

Levine has shown that immediate hypersensitivity reactions to penicillin areusually mediated by IgE antibodies directed against minor determinants, althoughsome immediate reactions are due to IgE antibodies against the major determinant[14,26,27]. This is despite the fact that BPO-specilic IgE antibodies occur about fivetimes more frequently than MDM-specific IgE antibodies in patients recently treatedwith penicillin. Levine [!4] postulated that the rarity of BPO-specific IgE-mediated,immediate hypersensitivity reactions may be explained by the fact that virtually allpatients who make BPO-specific IgE antibodies also produce BPO-specific IgGantibodies, which could act as'blocking antibodies'. These IgG antibodies compete forantigens with cell-bound IgE antibodies and thus diminish or prevent mediator releasefrom mast cells. No IgG antibodies directed against the minordeterminants have beenfound [26]. This inability to produce IgG antibodies against minor determinants maybe related to the smaller quantities of minor determinants produced upon penicillinadministration, which may not be sufficient to stimulate an IgG responi^e. Analternative explanation for the association of minor determinant-specific IgE anti-bodies with immediate anaphylactic reactions is that the binding afifmity of minordeterminants-specific IgE antibodies may be very high, due to low-dose induction,compared with that of BPO-specific IgE antibody.

Accelerated and late urticarial reactions are generally mediated by BPO-specificIgE antibody, and rises in BPO-specific IgG antibody have been correlated temporallywith the spontaneous disappearance of the urticarial reaction despite continuous

Hypersensitivity reactions to penicillin and antibiotics 521

penicillin treatment [14]. The difference between accelerated and late urticarial reactorsis that the former have BPO-specific IgE antibodies before treatment whereas in thelatter these antibodies develop during the course of therapy [14,26].

Risk factors for IgE-dependent penicillin reactions

AgeYoung and middle-aged adults between the ages of 20 and 49 seem to have the greatestrisk for acute allergic reactions to penicillin [5]. It is generally agreed, despite sparseevidence, thai, while penicillin reactions do occur in both children and the elderly, thefrequency of these reactions is less than in adults [29]. Athough the frequency ofanaphylactic reactions may be less in the elderly, they are more at risk for fataloutcomes due to their compromised cardio-pulmonary reserve. The reduced risk ofreactions in children may be due to the fact that a child's cumulative penicillin exposureis likely to be much less than that of an adult, although in one study over half theparents reported thai iheir child had received a /Mactam antibiotic by 2 years of age[30]. There is also evidence from studies of hymenoptera sensitivity that children's IgEantibody responses dissipate more rapidly than those of adults [31 ]. In one study. 42children with positive skin tests to penicillin reagents were skin tested 1 year later and14 (33%) had lost their skin-test reactivity [32].

Immune responsivenessAbundant experimental evidence has indicated a genetic basis for an animal's ability torespond immunologically to a variety of low molecular weight chemicals [33]. Westudied 60 patients who received at least 2 g of penicillin daily for at least 10 days, andfound that 38% made peniciiloyl-specific IgG antibodies, 18% made penicilloyl-specific IgE antibodies, and about 5O'Vi) made neither [28]. Patients who do not readilyamount a penicillin-specific immune response will have little or no risk of atlergicreactions lo penicillin. Whether immune responsiveness to penicillin is geneticallybased remains to be determined.

Persistence of penicillin-specific IgEWe prospectively studied the skin reactivity to PPL and a minor determinant mixture(MDM), as well as serum BPO-specific IgE and IgG antibodies in a group of 60patients [28]. The half-life of BPO-specific IgE antibody ranged from only 10 days to anindeterminantly long interval ( > 1000 days). This variable rate of decline in penicillinantibodies was not found to correlate with any clinical or immunological parameters,including the recentness of penicillin therapy, antibody titre at entry, or the patient'shistory of prior penicillin reaction. In addition there was no correlation between thehalf-life of tetanus-toxoid IgE and BPO-specific IgE. suggesting that the disappearanceof penicilloyl antibodies is not just a function of net IgE catabolism [28]. Additionalstudies will be needed to determine which factors control the metabolism of penicillin-specific IgE antibodies and the role, if any, that occult exposure to penicillin or cross-reacting antigens in the environment plays. Obviously an individual whose penicillin-specific IgE antibody response persists is at greater cumulative risk for allergicreactions to penicillin than one whose IgE antibody quickly disappears.

522 M. E. Weiss and N. F. Adkinson

History of atopy or other allergyInitial studies suggested that patients with a history of atopy had a higher frequency ofpositive skin tests to penicillin reagents than controls [14]. However, a later, larger-scale study demonstrated no differences in skin-test reactivity to penicillin reagents inatopic and non-atopic individuals [28]. Conversely, other studies found no difference inthe frequency of atopy by history in skin-test positive as opposed to skin-test negativesubjects [29,34]. Although published information concerning the allergic backgroundof patients who suffered fatal penicillin reactions is incomplete, an atopic backgroundwas found with a higher than expected frequency in these individuals [5j. Therefore,although an atopic background does not predispose an individual to a higherfrequency of IgE antibody production towards penicillin determinants, an atopicdiathesis may put sensitized individuals at increased risk for severe anaphylacticreactions if IgE antibodies are produced.

Route and dose of administrationParenteral administration of penicillin has been shown to produce more allergicreactions than orally administered penicillin. Sullivan et al. reviewed the worldliterature and found that a total of only nine anaphylactic deaths have been reportedafter oral administration of /Mactam drugs [35]. This is in stark contrast to thehundreds of reported deaths each year after parenteral administration. Whether therelative safety of the oral route depends on the lower dose usually administered, orrelates to route-specific differences in handling and absorption ofpencillin antigens, isnot clear. We recently examined this issue in patients attending a sexually tran;smitteddisease (STD) clinic. The observed rate of probable immunologie reactions within thefirst 72 hr of procaine penicillin (30 g i.m.) was 14%, which was no greater than forcomparable doses of oral ampicillin {3 5 g p.o.) (P>005) . In contrast there was anexcess incidence of reactions {2 24%) to benzathine penicillin (I 5 g i.m.), in keepingwith the known propensity of repository penicillins to elicit a higher rate ofallergicreactions [36].

Previous exposure to penicillinSince anaphylactic reactions to penicillin require previous exposure for the develop-ment of penicillin-specific IgE antibodies, one would expect that all individuals withhypersensitivity reactions to penicillin would have had a history of a previous,uneventful treatment with penicillin. This is not always the case. Rarely a patient maybecome sensitized and express a clinical allergic reaction during an extended firstcourse of penicillin. In addition, occult environmental exposures to penicillin occur.These sources include milk [37] or meat from cows treated with penicillin, andpenicillin found in other foods such as a frozen dinner [2], and even a soft drink [38].The sale of meat or milk from cows treated with penicillin has been widely prohibitedfor some time, but a study done in I960 showed that 6% of the milk sampled in theUnited States, and 5-45% of milk samples from England and Wales, containedpenicillin [5]. Recent evidence suggests that contaminated food products may sail be asource of sensitization and reactions in certain individuals. In 1985 4-4% of milkscreened in Scotland was found to contain detectable penicillin residues [39]. In 1986,Ormerod et al. found that 15 out of 50 patients with chronic idiopathic urticaria hadpositive penicilloyi RASTs and skin tests to penicillin determinants. Out of these 15,13had provocative challenges with 250 ml of milk containing 25 U of benzylpenicillin

Hypersensitivity reactions to penicillin and antibiotics 523

Tabk 3. The Influence of prior reaction lype on igE-depcndcnt reactions among palients with negative jicnicillinskin tests

History of prior reaction

AnaphylaxisUrticariaExanthcmOther/unceriainNone

Rate of IgE-dependentreactions aftertreatment (%)•

15-4 (2/13)+7-8 (25/192)t+2-4 (3/126)tt+0-5 (1/202)0 45 (18/3996)

* During lirst 72 hr of treatment. Of the 21 reactions amonj!hislory-positive patients, 16 involved transient uriicarialreactions, three cases included angioedema, and ihree casesmanifested mild dyspnoea and/or dysphagia. There were nocardiovascular alterations in any case. Dala from Adkinson[28].

t / ' = 0-002 compared with history negative subjects.t t / ' = <0 (XIOI compared with history negative subjects.t t t P = 0-049 compared with history negative subjects.

(01 U/ml) with four positive, three equivocal and six negative reactions [40]. Otherpotential hidden exposures include hreast-milk exposure for an infant whose mother istreated with penicillin [34], occupational exposure for medical and drug manufacturingpersonnel [9], and reagents used in skin testing [41].

History of. and interval sitwe. previous penicillin reactionsIndividuals with a history of a prior penicillin reaction have a four to six-fold increasedrisk of subsequent reactions to penicillin, compared to those without previous histories[29]. Whereas those with a negative history of a prior penicillin allergy have a 2-3%allergic reaction rate, those with a positive history have rates of 9- lO'/'.i [34]. However,the type of prior penicillin reaction dramatically affects the risk of reaction, even inskin-tesl negative patients. In a recent study, we found that patients with histories ofanaphylaxis and urticaria had significantly higher reaction rates Ihan those with vagueor unknown histories of penicillin reactions (Table 3). Therefore, patients with a priorhistory of IgE-dependent reactions to penicillin remain at some risk for the recurrenceof such reactions if they are retreated with penicillin, even when IgE antibodies topenicillin have declined to levels undetectable by skin testing [28]. However, since mostserious and fatal allergic reactions to /Mactam antibiotics occur in individuals whohave never had a prior allergic reaction, a negative history of penicillin allergy shouldnot leave one with a false sense of security.

As noted above, the serum half-life of anti-BPO-specific IgE antibodies in humansis quite variable, but for a group of penicillin-allergic patients, the time lapsed sinceprevious reactions is inversely related to the risk of an IgE-mediated reaction. Sullivanet al, reported that skin tests done within the first 1-2 months after an acute allergicreaction were positive 80-90% of the time. Thereafter, there is a time-dependentdecline in the rate of positive skin tests in both adults and children, to less than 20% by

524 A/. E. Weiss and N. F. Adkin.son

10 years [41]. Others have shown a similar decrease in skin reactivity with increasingtime from the last allergic reaction, but with a much lower skin-test reaction rate thanSullivan [32]. Nevertheless, some patients persist with a penicillin-specific IgE antibodyindefinitely. We have found positive skin tests in patients whose last known exposure topenicillin occurred more than 40 years ago. Patients who have had penicillin serumsickness reactions often persist with intense IgE antibody formation and may remain athigh risk for allergic reactions for many years [14].

Skin testing for penicillin allergy

Clinical experienceWithholding indicated penicillin therapy in the 5-20% of patients who by history, statethat they are allergic to the drug, can have significant adverse clinical consequences,including treatnient failures and increased toxicity and cost of alternative antibiotics.Since withholding of penicillin therapy is otherwise the most effective means ofpreventing allergic reactions to penicillin, it became clinically important to develop ameans of predicting which patients are at risk for acute IgE-mediated reactions.

Immediate weai-and-flare skin tests with penicillin reagents have proven veryuseful for detecting such patients. Skin tests have no predictive value in non-IgE-mediated reactions, such as serum sickness, haemolytic anaemia, drug fever, interstitialnephritis, contact dermatitis, exfoliative dermatitis, or maculopapular exanthems.Accelerated or late IgE-mediated reactions may even occur despite negative pre-treatment skin tests because of fluxes in IgE synthesis during treatment.

Clinical trials evaluating skin testing for penicillin allergy initially used penicilloy!-polylysine (PPL) alone. When it became clear that not all important IgE-mediatedreactions were predictable with this solitary reagent, future studies included skin testswith benzylpenicillin and finally with other minor determinants such as penicilloate.penilloate and the putative hapten penicilloyl-amine.

It can be seen in Table 4 that 7-63% of patients who give positive histories ofpenicillin allergy have positive skin tests to either PPL or minor determinants. Themuch higher rate of positive skin tests in Sullivan's large study [41] is difficult toexplain, but may be related to the high proportion of individuals having stronghistories of IgE-dependent reactions or to a high proportion of patients who were skintested soon after clinical reactions. With negative histories of penicillin allergy, the rateof positive skin tests is between 2"/li and 7% (Table 4).

When patients are given therapeutic doses of penicillin after negative ski n tests toPPL and MDM. IgE-mediated reactions occur very rarely (Table 5) and are almostalways mild and self-limited. About 1 "A, of patients with histories of penicillin allergybut with negative skin tests will develop accelerated urticarial reactions, andapproximately 3% will develop other mild reactions. Penicillin anaphylaxis has notbeen reported in skin-test negative patients. When properly done, negative skin testsindicate that the risk of a life-threatening reaction is almost negligible and any ^-lactamantibiotic may be safely given.

A limited number of skin-test positive patients have been treated with therapeuticdoses of penicillin (Table 5). The risk of an acute allergic reaction ranges from aboutWVo in history-negative subjects to 50 70"/̂ in history-positive subjects, a risk similarto that seen in patients with positive histories and skin tests for hymenoptera

Hyper.sensitivity reactions to penicillin and antibiotics 525

Table 4. Rates of positive penicillin skin lesls

ReferenceSkin tests Subjectsreagents cvuluated

"A,positive Comments

Hisiory-posiiive suhjec UPaerker c/o/. (1962) [89]

Rylelc/o/ (1963) [90]

Brown VI ul. (1964) [91]

Buddcf «/. (I964)[92]

Levine and Zolov (l%9l [42]

Lentz and Nicholas (1970) [93]Adkinson e/«/. (19711 [94]

Gretnc; ul. (1977) [95]

Wiirnngion ff «/. (!97R)[47]

Chundni<-/o/. (I9KO)[32]

Sullivan end. (I9S1)[4I[

Adkinson (I9K1) (pers. comm.)

Solley fiul. (19X2) [46]

Saxon (iyS3) [MI!

Sogncf o/. (1983) [96]

Mendelson el ul. (I9K4) [97]

Hisiory-ncgiiiiie suhjevis

Ryieii-I III. (1963) [90]

Brown ffii/. (1949) [91]Budd dill. (1964) [92[

Lentz and Nii:holas (1970) [9.1]AdkinMin ,'i ,il. (1971) [94]

Greene;.;/. (1977) [95|

Adkinson (1981) (pers. comm.)

Sogn <'/.;/. (I9S3I [96]

PPL

PPL

PPL

59

43

1003

39"n

40"..,

PPLPenG

PPL

Pen G

PPL

M D M

PPL

PPL

M D MPPL

Pen G

PPL

M D M

PPL

M D M

PPL

M D M

PPLM D M

PPL

M D M

PPLM D M

PPL

M D M

PPL

M D M

PPL

PPL

PPL

PPL

Pen G

PPL

PPI

M D M

PPL

PenG

PPLM D MPPL

M D M

22

27

2IS

124

Kl

171B

255

300

740

776

778

300

606

240

1191

950

12 559

40

5337

163

1229

42N6

567

91"/.,

26"..

15"-..

33"'n

35'^,,

19"-,.

115

16"/:,

63"'i>

7.|

14",,

10'!-,,

14%

8'8

4'Vr>

6-5

6"/,,

5%

71

6%

7%

l'7

4"/,,

Patients from a STD clinicLarger volume (0 07 ml) than normally used nowinjected intradermallvI2"i. were slrongly posiiivcLarger volume (0 07 ml) ihan normally used nowinjected mtradermallyLarger volume (0 07 0 05 ml) than normally usednow mjccled mtradermally. Patienis largely fromSTD clinicsAll 22 subjects had documented immediate oraccelerated reactions 3 months prior lo skintestingHistory of reaction in past. Concentration ofPPL high (5 >; 10- 'M)Compared wiih 3% positive skin tests in wardpatients randomly testedSTD clinicMedical inpatietits

46 V,, -)- for prior history of anaphyiaxis

Children and adults

Children

95'"n had positive history of penicillin allergy (Seebody of text for further cotnment)Out-p;itients m a STD ciinic

Also skin tested with ampicillin and mcthiciilin

In-patients

Children and adolescents

See comments from hisiiiry-positivi; suhjectsSee comments from history-positive suhjectsSee comments from history-positive subjectsConcentration PPL high (5 x 10 ** Ml

STDclinif patientsMedical in-patients

Out-piiticnis in a STD clmic

In-piitients

526 M. E. Weis.s and N. F. Adkin.son

Table S. Incidence of allergic reactions to penicillin among patients who were skin tcsled

Skin-testReference

Stjbjectsevaluated

"r, Wilh Comments (unless otherwise stated all subjectsreactions had positive histories of penicillin allergy)

Negative skin lesisParker ef a/. (1962) [89]Rytelffaf (I963)[9O]Browne/a/. (1964) [91]Levine f/«/. (1969) [42)

Lcntz and Nicholas (1970) |93]Leni/ and Nicholas (1970) [94]Greener «/. (1977) [95)

Adkinson ff d/. (1971) [94|

Warnngton ci ul. (1978) [47]

Chandra f( n/. (1980) [32]

Sulhvan ('/.j/ (I981)|4i[

Adkinson (1981) (pers. L'omm.)

Adkinstin (1981) (pers. comm.)

/ / j / . |I982)[46]

Sognc/u/. (I9S3)[96|

Sogn flat. (l9S.l)i96]

Mendelson cf

Posilive .skin ic.u.sParker p/a/-(l962)(K9|

a/. (I963)[9O]

Browne/a/. (1964) (9I|Brown e/o/. (1964) [91)Levcne and Zolo\ (1969) [42]

Adkinson e/u/ (1971)194)

Green .'fi//. (1977) [95]

Chandra era/. (1980)[32]

SoUey^fu/. (I982)[461

PPLPPLPPLPPL

MDMPPLPPLPPL

PenGPPL

MDMPPL

MDMPPL

MDMPPL

MDMPPL

MDMPPL

MDM

PPLMDMPPL

MDMPPL

MDMPPt.

MDM

PPLPPL

PPLPPLPPL

M D M

PPL

M D M

PPL

PenG

PPL

M D M

PPL

M D M

1147760

13 530

185

4102

36

379

54

169

56

81

3996

596

290

478

523

219

2355

33

2(J6

I I

1

9

8

8

< 0 1% Only those with a negative history treated0'9% Only ihese with a negative history treated0'5"-, Most with a negative history of penicillin allergy3% One mild urticaria, the rest exanthems

012% Negative history of penicillin allergy2-8% Positive history of penicillin allergy

3% Only 1"^ telt to be IgE mediated

[•9% Only reaction was urticaria in patier.t with SLE

1'2"'': Two mild urticarial reactions

3'6"., Both reactions were mild: non-pruritic. ery-thematous rash

2'4"-.. Both reactions wore mild, late reactions

1 9'h, Patients with negative history of penicillinallergy

9-1% Positive history of penicillin alleigy. of thereactions 5 9",. fell to be possibly immunologicalreaction and 2 9',, Igli-mediated (none serious)

7"/r. Positive history of penicillin allergy 3-3"., feltrelated to penicillin administration

l"'i. Negative history of penicillin allergy 0",, reac-tions felt related to penicillin administration

\-4";. All three with late exanthems

39% All with negative histories of penicillin allergy5-2% Only these with negative hi^tones Ircatcd. See

comments from Table 427-i"n. Positive history of penicillin allergyIO'2'!-,, Negative history nf penicillin allergy73% .̂ 11 mimediate or accelerated reactions

100';..

100%

50%

Accelerated urticarial reaction

Some reacted to intradermal dose during de-sensiti7ation (many with immediate type reac-tions)All with accelerated reactions

Hypersensitivity reactions to penicillin and antibiotics 527

hypersensitivily. The risk appears, with limited experience, to be somewhat higherwhen patients have positive skin tests to minor determinant reagents [42].

Most recent studies in which history-positive, skin-test negative subjects havereceived penicilHn employed both major and minor determinant reagents for skintesting. Currently only PPL(PRE-PEN, Kremers-Urban, Milwaukee) at a concentra-tion of 6x 10"^ M (re: penicilloyl) is commercially available for use as a skin-testreagent in the United States. A variety of reagents are available in Europe. Use of PPLalone would miss between 10% and 25% of all potential positive reactions [34,41]. Ifone uses fresh benzylpenicillin G (aged penicillin offers no advantage) [43], diluted to aconcentration of 10 000 U/ml [10"-M], as the sole minor determinant, about 5 10% ofskin-test reactive patients will be missed [41.24]. However, those missed may be at riskfor serious., anaphylactic reactions [44]. The laek of access to a commercially available,minor determinant reagent has hindered the general application of penicillin skintesting for risk assessment. This is indeed unfortunate since about 80% of history-positive patients will be skin-test negative and can safely receive penicillin after properskin testing. Since semi-synthetic penicillins contain the same nucleus as penicillin G,and the nuclear confirmation determines the major antigenic specificity, skin testingwith reagents derived from semi-synthetic penicillins has not been necessary. Patientswith negative benzylpenicillin skin tests can, with rare exception, safely receive anysemi-synthetic penicillin. Conversely, semi-synthetic penicillin administration iscontra-indicated in patients with positive skin tests to PPL and MDM.

Technique and safetyThe technique of penicillin skin testing has been well described previously [45] and willnot be discussed in detail here. In order to provide a margin of safety, epicutaneoustests should precede intradermal tests. Positive (histamine or opiate) and negative(diluent) controls should be used. When properly performed with due consideration topreliminary scratch tests and appropriate dilutions, skin testing with penicillinreagents can almost always be safely accomplished. Systemic reactions occur about 1 %ofthe time [17]; these are usually mild but can be serious. Therefore, skin tests shouldbe done in the presence of a physician capable of managing anaphylaxis. and withimmediate access to medications and equipment needed to treat anaphylaxis. For aperiod of days to weeks after a systemic allergic reaction to penicillin, patients may bedesensitized and display negative skin-test results. Skin tests should therefore berepeated 3 6 weeks after acute reactions, if post-reaction tests initially are negative[17]. The preferred skin-test reagents are FPL and MDM. The addition of semi-synthetic penicillins as skin-test reagents is not generally required, but may be useful inselected cases. Solley et al. [46] suggested that skin testing with derivatives of semi-synthetic penicillins, in addition to the above mentioned reagents, increased the yieldfor detecting skin-test positive patients. Warrington et al. [47] and others found noadditional individuals who were skin-test positive when semi-synthetic penicillinreagents were added to PPL and MDM. Moss et al. found that patients with cysticfibrosis had positive skin tests to ticarcillin and piperacillin when skin tests to PPL orpenicillin were negative [48]. However. Moss et al. used concentrations of ticarcillinand piperaciliin for skin testing that Galant et al, showed caused non-specific irritativereactions in normal, non-penicillin-alicrgic subjects [49].

528 M, E, Weiss and N. E. Adkinson

Indications for ,<ikin testing and interpretation ofrcstdtsThe above data show that 2 7% of patients with no history ofallergic reactions topenicillin have positive skin tests (Table 4). Most penicillin-related anaphylacticfatalities occur in patients who give no history of a prior penicillin reaction. Ideally, allpatients should be skin tested before receiving ^-lactam drugs. A systematic study ofroutine skin tesling in history-negative STD clinic patients has indicated that suchtesting is probably not cost-effective (N. F. Adkinson, J Allergy Clin Immunol 1984;73: 163). At present we recommend that skin testing be done in all patients with ahistory of prior penicillin allergy, for whom a /f-lactam antibiotic is presently theindicated drug of choice. If skin-test posilive, an equally effective, non-cross-reactingantibiotic should be substituted when available. Skin testing to penicillin shouldgenerally be done immediately before its intended use, and repeated before each courseof ^-lactam therapy in patients with a history of an IgE-dependent reaction. Patientswith a history of exfoliative dermatitis, Stevens-Johnson or LyelTs syndrome, or otherreactions that constitute absolute contra-indications for penicillin adminijitration,should not be evaluated by skin testing.

Other tests to detect IgE antibodies to penicillinSolid-phase immunoassays such as the RAST have been developed to dexct IgEantibodies directs against the penicilloyl determinant. At present there is no in-vitroRAST for minor determinant antigens [45]. The BPO-specific RAST is positive in 6095% ofthe patients with a positive skin test to PPL. Because it is more time-consuming,more expensive, less sensitive for detection of the major determinant, and unavailablefor minor determinant detection, the RAST and other in-vitro analogues have limitedclinical utility. They have inferential value, only when positive. Although patients withnegative penicilloyl RAST are probably at low risk for clinical penicillin reactions, thistest alone does not exclude the possibility of anaphylactic reactions since as discussedabove, many such reactions are minor determinant mediated [25].

Penicillin desensitization

IndicatiottsEffective, non-cross-reacting alternative antibiotics to penicillin are usually availablefor patients with positive penicillin skin tests. If alternative drugs fail, induceunacceptable side-effects, or are clearly less efTective. then the administration ofpenicillin should be considered using a desensitization protocol. Infections in whichthis most commonly arises are subacute bacterial endocarditis due to enterococci, brainabscess, bacterial meningitis, overwhelming infections with Staphyloccoci or Pseudo-monas organisms such as osteomyelitis or sepsis, listeria infections, neurosyphilis, orsyphilis during pregnancy. Use of a desensitization protocol for penicillin skin-test-positive patients markedly reduces the risk of anaphylaxis. Desensitization does notprevent non-IgE mediated reactions from occurring. Patients with a prior history ofexfoliative dermatitis or Stevens-Johnson syndrome present an almost absolutecontra-indication to the re-administration of any /Mactam drug since an acceleratedlife-threatening reaction may occur.

Hypersensitivity reactiotjs to penicillin and antibiotics 529

Table 6. Oral desensitization protoi:i)l'

Slept

t2345

67

89

1011121314

Phenoxymethyl

penicillin

(U/m!)

1000

1000

1000

1000

1000

tooo

KKKI

10 000

10000

10000

80 000

80 000

80 00080 000

Observe patient for 30 min

Change lo Bcnzylpcnicillin

15161718

500 000 U/ml

SOOOOO

500 000

500 000

Amount

(ml)

0 10 2

0 4

0 816

.1-2

6 4

12

2 4

4-8

10

20

40

8 0

G I V

0-250 5 0

I'OO225

Dose(U)

100

200

400

800

1600

.1200

6400

12 000

24 000

48 000

KOOOO

160 000

320 000

640 000

125 000

250 000500 000

I 125 000

Ciimulnlive

dosage (U)

IOO300

700

15003100

6.^00

12 700

24 700

4K700

%700

176 700

336 700

656 700

I 296 700

• Adopted frum Sullivan [17]

t Interval between sleps- 15 min.

ProcedureAcute penicillin desensitization should only be performed in an intensive care setting.Any remedial risk factors should be corrected. Beta-adrenergic antagonist should bediscontinued or tapered. Asthmatic patients should be under optimal control. Anintravenous line should be established, baseline ECG and spirometry should beperformed and continuous ECG monitoring instituted. Blood pressure, pulse.respiratory rate and clinical status should be recorded prior to the next dose, and 10and 20 min after each dose. We do not recommend pre-medication with antihistamineor steroids, as these drugs have not proven effective in suppressing severe reactions butmay mask early signs of reactivity that would otherwise result in a modification oftheprotocol [50.51].

Protocols have been developed for penicillin desensitization using both the oral andparenteral route [35.52] (Table 6 and 7). Theoretical advantages of the oral method arethat the oral administration of penicillin may lead to the destruction or lack ofabsorption of preformed conjugates and polymers that may play a role in theeUcitation ofthe acute allergic reaction. There have also been many fewer reportedcases of anaphylactic reactions to oral penicillin treatment, but this could be dose-rather than route-dependent. Advantages ofthe parenteral technique include directvisualization ofthe challenge site and the ability to place a tourniquet proximal to theinjection site in the case of a systemic reaction. As for 1987 there have been 93 reportedcases of oral desensitization, 74 of which were done by Sullivan and his collaborators[53]. Of these 74 patients, 32% experienced a transient allergic reaction either duringdesensitization (1/3) or during penicillin treatment after desensitization (2/3). These

530 M, E, Wei,ss and N. F, Adkinson

Table 7. Parenieral desensilizaliontypical schedule

Injectionno.

I t2345t678t9

101112t1314I5t161718

19

Benz>'lpenici!linconcentralion

(uni Is/ml)

IOO100

IOO

100

100010001000

10 00010 00010 00010000

100 000100 000100000

1 000 000

1 000 000

1 000 000

1 000 000

Conlinuous i.v. infusion

(1 OOOOOOU/hr)

prolocol;

Vol.'Route

(ml)*

0-1 i.d.

0 2 S.C.

0'4 S.C.

OR S.C.

O i i.d.

0-3 S.C.

0-6 S.C.

01 i.d.

0^2 S.C.

0 4 S.C.

0-8 S.C.

01 i.d.

0-3 S.C.

0-6 S.C.

01 i.d.0-2 S.C.

0 2 im

0 4 im

* Administer progressive doses al intervals ofnot less than 20 min.+ Observe and record skin weal-and-flare re-sponse U) intradermal dose.Abhrevialions: i.d.. intruiiermal; s.e. subcuta-neous: i.m.. intramuscular: i.v. intravenous.

reactions were usually mild and self-limited in nature. One IgE-mediated reaction(vv-heezing and bronchospasm) required discontinuation of the procedure beforedesensitization could be completed [54]. IgG- and IgM-mediated complications (serumsickness, haemolytic anaemia and glomerulonephritis) were seen in 5% of thosedesensitized, which is higher than expected from observations of patients treated withpenicillin who are not allergic to the drug [53]. Wendel et al, [55] desensitized 15pregnant women with serious infections (mainly syphilis) successfully. AI! 15 womenwere cured of their infections, and reactions during desensitization and therapy wereconfined to the skin (33%) and were not serious. Review ofthe literature has suggestedthat parenteral desensitization results in a higher rate of acute allergic reactions [52].Nevertheless, most patients can also be safely desensitized by the parenteral route, asindicated by the experience of Graybill et al, [56]. Recently, successful intravenousdesensitization in 12 patients was reported [57]. In this study there was an unusuallyhigh rate of isolated minor determinant skin reactivity. Of interest, but not reported,was whether skin tests to penicillin reagents converted to negative during intravenousdesensitization. A concurrent randomized trial comparing oral and parenteraldesensitization is needed to resolve the issues of relative safety and efficacy of the twoprocedures.

Skin-test responses to penicillin reagents diminish and frequently become negativewith successful desensitization [35,58.59]. During desensitization any dose that causes

Hypersensitivity reactions to penicillin and antibiotics 531

mild systemic reactions such as pruritus, fleeting urticaria, rhinitis or mild wheezingshould be repeated until the patient tolerates the dose without systemic symptoms orsigns. More serious reactions such as hypotension, laryngeal oedema or asthma requireappropriate treatment and, if desensitization is continued, the dose should bedecreased by at least ten-fold and withheld until the patient is stable [52]. Severalpatients have been maintained on chronic low-dose penicillin therapy (usually bid-tid)to sustain a chronic state of desensitization. Such individuals usually require chronicdesensitization because of continuous occupational-related exposures to /Mactamdrugs [58.60].

Several mechanisms have been proposed to explain the state of clinical tolerancethat is induced by penicillin desensitization procedures. Since skin-test responses areattenuated or converted during desensitization it was originally suggested that,gradually administered, penicillin safely consumed or blocked IgE antibody. Thisappears doubtful as BPO-specific IgE antibody in serum does not change during acutedesensitization [58]. The induction of IgG-blocking antibody has also been suggestedas the mechanism of clinical tolerance, yet it has now been shown that BPO-specificIgG antibodies do not increase acutely [58,61]. Late formation of specific IgG antibodymay provide some protection in the later stages of long-term therapy. Other proposedmechanisms include hapten inhibition from monovalent penicilloyl-protein conju-gates, tachyphylaxis to mediators, and mediator depletion. A more likely mechanism isa progressive degree of cellular desensitization in mast cells and basophils, induced by agradual exposure to 'complete' (multivalent) antigen, leading to an increase in theantigen threshold needed for subsequent mediator release. Sulhvan has shown that thiscellular unresponsiveness is both antigen specific and dose dependent [62]. BothNaclerio et al. and Sullivan have shown that the state of desensitization is one of adynamic equilibrium. Skin tests frequently become negative during and shortly afteracute desensitization. but later during therapy with penicillin they may fluctuate[58,62]. In one patient, skin tests were uniformly negative 30 min after the last dose ofpenicillin, and positive immediately before the next dose [62]. Naclerio ct al. showedthat during chronic desensitization to penicillin both BPO-specific IgE and IgGantibody, as well as total IgE antibody levels, initially increased and peaked at around3 weeks and then steadily declined [58]. Recently, we showed that a patient who wassuccessfully desensitized to penicillin and whose initial positive skin test to PPLconverted to negative, had no diminution of his basophils" in-ritro histamine releasewhen exposed to penicilloyl-human albumin [63]. Why the patient's own basophils,which were responsive to BPO in vitro, failed to release histamine when exposed tosufficient piperaciltoyl antigens (after desensitization) in his own blood, which wereshown to induce basophil degranulation in a passively sensitized normal donor, ispresently unclear. Once desensitized, the patient's treatment with penicillin must notlapse or ihe risk of an allergic reaction increases. If the patient requires a ^-lactamantibiotic in the future and still remains skin-test positive to penicillin reagents,desensitization would be required again.

Other immunological strategies have been attempted to allow safe administrationof penicillins to allergic subjects. Univalent hapten inhibitors such as BPO-N:-formyl-lysine initially showed promise for the treatment of hypersensitivity reactions topenicillin [64 66], but subsequent clinical studies revealed that up to 38% of subjectsskin tested had positive skin reactions with the putative hapten itself. Furthermore, thehapten did not always prevent anaphylactic reactions [67].

532 M. E. Weiss and N. E. Adkinson

Sensitivity to related antibiotics

CephalosporinsThe isolation of cephalosporin-C from the slime mold cephalosporium in the 1950s ledto the engineering of a class of antibiotics knows as the cephalosporins [68]. Likepenicillin, cephalosporins possess a ^-lactam ring, but the five-member thiazolidinering of the penicillin molecule is replaced by the six-membered dihydrothiazine ring inthe cephalosporin nucleus (Fig. 1). Shortly after the cephalosporins came into clinicaluse, allergic reactions including anaphylaxis were reported and the question of cross-reactivity between cephalosporins and penicillins was raised [69]. Complicatingmatters, the early cephalosporin antibiotics were contaminated with trace amounts ofpenicillin [70], potentially leading to overestimates of the degree of cross-reactivity.

The exact haptenic determinants of the cephatosporin molecule causing allergicreactions are not known, making questions about the incidence of immunologicalcross-reactivity with penicillins difficult to answer. It is unclear whether cephalosporinsform minor haptenic determinants homologous to the minor determinants ofpenicillins [71.72].

Studies in both animals and man have demonstrated cross-reactivity betweenpenicillins and the cephalosporins. using haemagglutination to evaluate IgG and IgMantibodies. Cross-inhibition and absorption of sera with red blood cells sensitized withpenicillin or cephalothin demonstrate extensive cross-reactivity in vitro [72]. Further-more, patients undergoing treatment with penicillin have an increase in theircephalosporin antibody titre. and increases in antibody titres to penicillin v/ere alsoseen during cephalosporin treatment [73-76]. Passive cutaneous anaphylaxis reactionsin animals and Prausnitz-Kustner reactions in humans have indicated cross-reactivitybetween IgE antibodies to penicillin and cephalothin [70]. In i 967. Pedersen-Bjergaardintracutaneously injected volunteers with sera from !3 patients who had experienced asystemic reaction to penicillin; the intravenous injection of cephalothin 24 hr latercaused a positive P K reaction in 8 of the 13sites[7O]. Assemand Vickers found that of24 patients with established allergy to penicillin. 80" n had positive leucocyte histaminerelease tests and 5O'Vi) had positive lymphocyte transformation to cephaloridine-gamma-globulin conjugates, whereas none of the 10 non-penicillin-ailergic controlshad positive tests [74].

Retrospective studies have demonstrated that patients with a history of penicillinallergy were four to eight times more likely to have an allergic reaction when given acephalosporin than those without a history of penicillin allergy [77.78]. Problems withthose studies include the fact that, as seen above, a positive history of a penicillinallergy is confirmed by skin tests in only about 25''I. of cases. Secondly, many of thecephalosporin reactions may not have been immunologically mediated. Finally. Smithet al. [79] showed that individuals with prior adverse reactions to a chemicallyunrelated drug had about a three-fold increased risk of penicillin reactions.

Several studies have used native cephalosporins as skin-test reagents since relevantdegradation products are largely unknown. Concentrations of cephalosporins greaterthan I mg ml tend to give false positive reactions when used as skin-test reagents [80].When patients with positive skin tests to penicillin reagents are skin tested with nativecephalosporins. approximately 5O'Vn are positive [41, 74]. Some of these studiesemployed mg/mt concentrations of cephalosporins. Few cephalosporin skin-testpositive individuals have been challenged with cephalosporins to allow estimation of

Hypersensitivity reactions to penicillin and antibiotics 533

the predictive value of a positive skin test. Conversely, two studies involving smallnumbers of penicillin skin-test positive patients treated with cephalosporins have beenreported. Solley et al, [46] treated 27 penicillin skin-test positive patients withcephalosporin antibiotics without an allergic reaction, and Saxon challenged 10 suchpatients without adverse consequence [81]. In both studies the histories of priorreactions to penicillin were not detailed and it was not reported if cephalosporintreatments were administered using incremental dosing. Primary cephalosporinallergy in non-penicillin-allergic patients has been reported, but the exact incidence isnot clear [82].

Since we do not know the spectrum of haptenic determinants causing cephalos-porin allergy, and because the predictive value of skin tests using native cephalosporinsis unknown, accurate prediction of cephalosporin allergy must await future studies.The incidence of clinically relevant cross-reactivity between the penicillins and thecephalosporins is probably small, but it cannot be discounted on statistical groundssince life-threatening anaphylactic cross-reactivity has occurred. Until better predic-tive tests become available for the diagnosis of cephalosporins hypersensitivity. we fee!that patients with positive skin tests to penicillin reagents should not receivecephalosporin antibiotics unless alternative drugs are clearly less desirable. Ifcephalosporin drugs are to be used, they should be administered using a modifieddesensitization protocol.

MonobactatnsThe monobactams are a new group of/Mactam antibiotics that contain a monocyclicring structure rather than the bicyclic structure ofthe penicillins and cephalosporins{Fig. 1). Monobactams have bactericidal activity against aerobic Gram-negativebacteria [83]. The prototype of this new class of antibiotic is aztreonam. We havestudied the question of cross-reactivity between aztreonam, the penicillins and thecephalosporins. Rabbits were immunized with protein conjugates of penicillin,cephalothin or aztreonam, and the antisera obtained were studied for cross-reactivityin a solid phase radioimmunosorbent assay. Aztreonyl-HSA showed negligible abilityto inhibit anti-penicilloyl and anti-cephalosporyl antibodies; conversely, penicilloyland cephaiospory! conjugates had very weak ability to inhibit anti-aztreonamantibodies [84] (Fig. 3). This finding is in contrast to a greater degree of in-vitro cross-reactivity seen between benzylpenicillin and cephalothin. Free aztreonam was equallyefiTective on a molar basis with aztreonyl conjugates in inhibiting anti-aztreonamantibody binding. This indicated that the aztreonam-specific antibodies were largely, ifnot exclusively, side-chain specific (Fig. 4) [84]. This side-chain-specific immuneresponse was confirmed by showing that ceftazidime. a third generation cephalosporinthat has the identical bulky aminothiazolyl side-chain as aztreonam. completelyinhibited anti-aztreonam antibodies, while other monobactams with differing sidechains were non-inhibitory.

Aztreonam determinants analogous to the major and minor determinants ofpenicillin were used to skin-test 41 patients with positive skin tests to penicillin. Theconcentrations employed were shown in controls to be non-reactive in the skin. Noneof the 41 penicillin allergic subjects had a reproducible positive skin test to theaztreonam reagents [83]. Twenty of 22 patients, with positive skin tests to penicillinreagents and negative skin tests to aztreonam reagents, were treated with therapeuticdoses of aztreonam and none had IgE-mediuted reactions [85]. All 20 also had

534 M. E. Weiss and N. E. Adkinson

ia)& BPO-HSA

BPO-HSA

AZ-HSA

100

80

50

40

AZ-HSA

10"^ lO"* 10"̂ 10 '̂ I 10 10̂Inhibitor added (/ig)

Fig, 3, Cross-reaeiiviiy of rahbii antibodies raised agninsl bovine thyroglobulin (BTG) conjugates of Ihree /(-iaclatncompounds, (a) benzylpenicilloyl (BPO). (b) cephHlosporyl (CEPH) and M ii/ireonyl lAZ). The inhibilori used werepoiyvaleni i:onjugates of henzylpeniciDoyI-human serum ulbumin |BPO HSA), cephalosporyl human serum albumin(CEPH-HSA), and aztreonyl-human serum albumin (AZ-HSA). In panel b. E|. E;. and Ei refer to daia from threeindiviiiualrabbils. Otherwise, points are mean values for groups of ihree rabbits and bars indicate s.e.ni. From AdkinsoncfIII. [M]: reproduced wilh permission nf Aniimkrohiul .igt-nts and Cliemoiheriipy.

measurable peniciiloyl-specific IgE and IgG antibodies prior lo irealment withaztreonam. and there was no boost in penicilloyl-specitic antibody titres afteraztreonam treatment, further supporting a lack of immunological cross-reactivitybetween penicillin and aztreonam [86.87]. Graninger et al. treated 23 patients withaztreonam., who by history had hypersensitivity reactions to penicillin and/orcephalosporins. In 22 of the 23 patients there were no adverse reactions, but onepatient had urticarial lesionsafter 3 weeks of treatment [88]. Taken together these datasuggests weak cross-reactivity between aztreonam and other /f-lactam antibiotics, andindicate that aztreonam may be safely administered to most, it not all. penicillin-allergic subjects. The immunogenicity of aztreonam also appears quite low in that of 36humans given multiple doses of aztreonam, an aztreonam-specific IgE and IgG

Hypersensitivity reactions to penicillin and antibiotics 535

100

80

; 60i

20

0

- / 'AZ-EACA//

• 7 /

1 1

-^ ^ -• Free A Z

P CEPH-EACA

/

/ ^Free CEPH/ , ' ^ BPO-FLYS

1 '^ '^-'Free BP

10"^ 10"'-' 10"' I 10 lO-' 10^

Inhibitor oddeb (/ig)

Fig. 4. Cross-reactivity of rabbil antibody raised againsi a bovine ihyroglobulin (BTG) conjugate of uztreonyl {AZ). Thetnonovalent inhibitors used were free a/treonunn AZ). free cepbaloihm (CEPH). Tree benzylpenicillJn (BP(, cephalosporyl-epsiIon aminoaproic acid (CEPH-EACA). and ben/ylpenicilloyl conjugated to formylaied lysine(BPO-FLYS). The dalasuggesi thai ihc immtjne response to airlreonam is side-thain spetitic. a finding thai was bwme oul in other studies. FromAdkinson [•/ iil. [84|; represented with permission of .Anlimiirnbial .Agents mid Ciwnwtlu-rapy.

response was seen in 0"A, and 3'!'i), respectively [84]. This compares favorably with aresponse rate of 20% and 38% for IgE and IgG. respectively, seen with penicillin [28].However, prior exposure to penicillins may safely be presumed where prior therapeuticexposure to monobactams had not occurred. Relative immunogenicity of this newclass of ^-lactam antibiotics will require additional studies of patients undergoingmultiple courses of monobactam therapy.

CarbapenemsAnother new class of ^-lactam antibiotics are the carbapenems. of which imipenem isthe prototype. Like penicillin, this class of antibiotics has a bicyclic nucleus containinga /Mactam ring and an adjacent five-membered ring (Fig. I). Imipenem has a widespectrum of antimicrobial activity against both Gram-positive and aerobic Gram-negative bacteria [80]. Saxon et al. skin tested 40 patients with histories of penicillinallergy., using imipenem reagents analogous to the penicillin determinants in dosesshown not to cause non-specific positive reactions [80]. Of 40 subjects skin tested. 20were negative to all penicillin and imipenem reagents. Of the 20 remaining, 10 subjectshad positive skin tests to at least one of the penicillin reagents and were non-reactive toany of the imipenem reagents. One individual with a positive skin test to imipenemoatehad a borderline positive test to the analogous penicilloate. Nine ofthe 20 subjects withpositive skin tests to penicillin reagents also had positive skin reactions to analogousimipenem determinants. There was a high degree of cross-reactivity between thepenicillin minor determinants and the analogous imipenem reagents [80], suggestingthe need to withhold carbapenems from penicillin skin-test positive patients.

ConclusionsBeta-lactam antibiotics remain the single most useful class of antibiotics in general usetoday. Their principal toxicity is allergy, which occurs in 0-7-4'M. of penicillintreatment courses. Immediate hypersensitivity reactions due to preformed penicillin-specific IgE antibodies constitute the most dramatic and worrisome allergic reaction.

536 M, E, Wei,ssand N, F, Adkinson

For penicillin and other /i-lactams. IgE antibodies can be produced against a numberof haptenic derivatives labelled the major and minor determinants. Immediate,anaphylactic reactions are more commonly associated with IgE antibodies directedagainst minor determinants, although IgE antibodies toward the major determinantmay also be involved. Clinical parameters such as age of the patient, immuneresponsiveness, persistence of drug-specific IgE antibody, personal history of atopy,route and dose of administration, and history of. and interval since, previous penicillinreaction are factors contributing to a patient's risk of an igE-dependeni allergicreaction to /Mactam antibiotics.

The most useful single piece of information in assessing an individual's potentialfor an immediate IgE-mediated reaction is his skin-test results with "major" anti "minor'penicillin determinants. When properly done and interpreted, negative skin-tent resultsindicate that the risk of a life-threatening reaction to penicillin is negligible. Positiveskin tests indicate that the patient isat high risk for an immediate or accelerated allergicreaction. U penicillin or a cross-reacting /i-lactam antibiotic is required, administrationof the drug should be done using a desensitization protocol, which substantiallyreduces the risk of a serious adverse consequence.

The exact incidence of penicillin and cephalosporin cross-reactivity is unknownand unpredictable for individual patients. In vitro studies with IgG and IgM antibodieshave demonstrated substantial cross-reactivity, and Prausnitz-Kustner reactions haveindicated appreciable cross-reactivity for IgE antibodies. Therefore, patients withpositive skin tests to penicillin reagents should not receive cephalosporin antibioticsunless satisfactory alternatives are not available. At present, a major limiting factor forbetter understanding cephalosporin and penicillin cross-reactivity, and for predictingthose at risk for an allergic reaction to cephalosporins. is our inadequate understand-ing ofthe haptenic determinants important for allergic reactions to cephalosporins. Ofthe newer /^-lactam antibiotics, imipenem has been shown to exhibit significant skin-test cross-reactivity with penicillin minor determinants, and therefore should beavoided in patients with positive penicillin skin tests. The monobactams. of whichaztreonam is the prototype, have thus far demonstrated negligible cross-reactivity,both in vitro and in vivo, with other /i-lactam antibiotics, and therefore appear suitablefor use in penicillin-allergic subjects.

For the future, we may hope for better definition of the determinants ofcephalosporin allergy, which is emerging as a primary drug allergy in its own right,more readily available diagnostic reagents for al! /i-lactam allergies, and clearerguidelines on the optimal desensitization regimen.

References1 Gorevic PD. Drug allergy. In; Kaplan A, ed. Allergy. New York: Churchill Livingston. 1985:473-506.2 Schwartz HJ. Sher TH. Anaphylaxis to penicillin in a frozen dinner. Ann Allergy 1984: 52:342 3.3 Sullivan TJ. Palhogcnesis and management ofallergic reactions to penicillin and other tieta-lactam

antibiotics. Pediatr Infecl Dis 1982; 1:.144 50.4 Gell PGH, Coombs RRA. Classiticalion ofallergic reactions responsible for clinical hypersensitivity and

disease. In: Gell PGH. Coombs RRA. Hachmann PJ. eds. Clinical Aspects of Immunology. Oxford:Blackwell Scienlific Publications. 1975:761 81.

5 Idsoe O, Guthe T. Willcox RR. De Weck AL. Nature and e.xlent of penicillin side-reactions, with

Hypersensitivity reactions to penicillin and antibioties 537

particular reference to Talalities from anaphylactic shock. Buli WHO 1968; 38:159 88.6 Berkelman RL. Finton RJ. Elsen WR. Beta-adrenergic antagonists and fatal anaphylaclic reatjtions to

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