Clinical Experience With Penicillin SkinTesting in a Large Inner-City STD ClinicJyothi Gadde, MD; Michael Spence, MD, MPH; Barbara Wheeler, RN; N. Franklin Adkinson, Jr, MD

Objective.\p=m-\Toestablish (1) the prevalence of positive penicillin skin testsamong outpatients with well-defined but variable history of penicillin allergy and (2)the reproducibility, safety, and negative predictive value of skin testing with benzyl-penicilloyl polylysine (PPL) and a minor-determinant mixture (MDM).

Design.\p=m-\Serialconsenting outpatients with current indications for penicillintherapy were skin-tested in duplicate with PPL and MDM. Subjects with negativeskin tests (93% of those positive by history and 95% of those negative by history)received therapeutic courses of benzylpenicillin (81%) or ampicillin (19%). Nega-tive predictive value of skin testing was established by 72-hour follow-up for adversereactions to drug.

Setting/Patients.\p=m-\Atotal of 5063 consecutive, qualifying outpatients in a Bal-timore, Md, sexually transmitted disease (STD) clinic. The study group was young(73% between 20 and 40 years old), 66% male, and 90% black; 25% had historyof atopy. Follow-up was 94% complete.

Results.\p=m-\Positiveskin tests were observed in 7.1% of 776 individuals with pre-vious history of penicillin allergy and in 1.7% of 4287 subjects negative by history(P<<.001). Previous history of anaphylaxis or urticaria was associated withsignificantly higher rates of positive skin tests of 17.3% and 12.4%, respectively(P<<.001). Only 4% with history of exanthem had positive skin tests (P=.03). Thecoefficient of variation for duplicate skin tests was 11%. Time intervals since lastpenicillin treatment did not influence the rate of positive skin tests. Adverse reac-tions to skin tests occurred in 13 (1.2% of patients positive by history; 9.4% of thosewith positive skin tests). A mild anaphylactic reaction occurred in one individualwhose preliminary scratch testing was inadvertently omitted; systemic pruritus orurticaria occurred in 11 subjects; one had a large local reaction. After penicillin ad-ministration to individuals with negative skin tests, acute allergic reactions occurredin 0.5% of subjects negative by history compared with 2.9% of subjects positive byhistory (\g=x\2=33.3; P=.0001). Reactions were generally mild and self-limited; only twocases of mild anaphylactic reaction occurred, both in patients with history of severeIgE-mediated reaction.

Conclusions.\p=m-\Skintesting with both major and minor penicillin determinants issafe using current recommendations, and both reagents are necessary for maxi-mizing the identification of sensitized subjects. Routine penicillin skin testing canfacilitate the safe use of penicillin in 90% of individuals with a previous history ofpenicillin allergy.

(JAMA. 1993;270:2456-2463)

From the Division of Allergy and Clinical Immunol-ogy, Department of Medicine, The Johns Hopkins Uni-versity School of Medicine, Baltimore, Md. At the timeof the study, Dr Spence was affiliated with the BaltimoreCity (Md) Eastern Health District Clinic for SexuallyTransmitted Disease. He is now with the Depart-ment of Obstetrics and Gynecology, Hahnemann Hos-pital, Philadelphia, Pa.

Reprint requests to The Johns Hopkins Asthma andAllergy Center, 5501 Hopkins Bayview Cir, Baltimore,MD 21224 (Dr Adkinson).

A HISTORY ofpenicillin allergy can beelicited in up to 10% of various medicalpopulations.1 A previous history of hy-persensitivity to penicillin has been theprincipal limiting factor in the use ofthis efficacious, and otherwise relativelysafe, group ofdrugs. If the patients withcontinuing risk of acute allergic reac-

tions could be identified, penicillin couldbe used in many patients who are cur¬

rently deprived of its benefits. For thispurpose, skin testing with two reagents,benzylpenicilloyl polylysine (PPL) anda minor-determinant mixture (MDM),has been widely used. Sensitivity to oneor both reagents has been noted in 8.8%to 91% of subjects with prior penicillinallergy in various studies2; such indi¬viduals are at substantial risk of IgE-mediated hypersensitivity reactions,which can be life threatening.2"10 Con¬versely, those patients with negativepenicillin skin tests are at acceptablylow risk for acute reactions, despite priorpenicillin reactivity.1·35·1118

Between 1979 and 1984, we estab¬lished a surveillance program for peni¬cillin allergies in a large public sexuallytransmitted disease clinic facility in Bal¬timore, Md. We report herein our ex¬

perience with penicillin skin testing in5063 subjects, including 776 who had a

previous history ofpenicillin allergy. Wedetermined the reproducibility andsafety of a reliable skin-test method, theprevalence of positive skin tests in pa¬tients with previous history of prior re¬

activity, the frequency ofequivocal tests,the pattern ofskin-test reactivity to ma¬

jor and minor determinants, and the re¬

lationship of time interval since last peni¬cillin treatment to current skin reactiv¬ity. We found that penicillin skin testingcan be safely performed and reliably in¬terpreted in a high-volume outpatientsetting. Penicillin was administered tosubjects with negative skin tests. Al¬though a higher rate of adverse reac¬tions was observed in subjects positiveby history, the majority of these reac¬tions were mild and self-limited.

MATERIALS AND METHODSSubjects

A total of 9313 consecutive qualifyingsubjects from the Baltimore City East¬ern Health District Clinic for Sexually

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Transmitted Disease were evaluated be¬tween 1979 and 1984. All had a currentindication for penicillin therapy. Previ¬ous penicillin use and type of adversereactions, if any, time elapsed since lastpenicillin dosage, and personal and fam¬ily history ofatopy (early-onset asthma,seasonal rhinitis, atopic dermatitis) weredocumented for all subjects. Historiesof prior adverse reactions to penicillinwere categorized into five groups basedon clinical description: (1) anaphylaxis,(2) generalized urticaria, (3) exanthema-tous rashes, (4) other, and (5) those whowere uncertain. All subjects positive byhistory were skin-tested. Subjects nega¬tive by history were invited to partici¬pate in a randomized controlled study ofthe value of routine penicillin skin test¬ing (results to be reported elsewhere).All individuals with negative skin testsin both groups were treated with peni¬cillin. The protocol was approved by theJohns Hopkins Committee on ClinicalInvestigation, and written informed con¬sent was obtained from all subjects.Reagents

Benzylpenicilloyl polylysine (Pre-Pen,Schwarz Pharma, Milwaukee, Wis) is a

conjugate of benzylpenicillin with poly-L-lysine at a concentration of 6X10"5mEq penicilloyl moieties in a sterilephosphate-buffered saline solution. Theindividual constituents of the penicillinMDM (crystalline benzylpenicillin, ben-zylpenicilloate, and benzylpenilloate)were prepared and standardized bySchwarz Pharma. The MDM was con¬stituted monthly from lyophilized ma¬terials to consist of 10 mmol/L of each ofthe three constituents in sterile phos¬phate-buffered solution, pH 7.4, andstored frozen at -20°C until the day ofuse. The MDM was prepared and usedunder physician-sponsored Investiga-tional New Drug number 1358.

Skin-Testing ProcedureIntradermal skin testing was used for

the definitive evaluation of all subjects.All skin tests were performed in dupli¬cate except for diluent control. Suffi¬cient volume of each reagent was in¬jected intradermally, using a 25- to 27-gauge needle and tuberculin syringe toraise a 2- to 3-mm wheal (approximately0.02 to 0.03 mL). The wheal sizes weremarked with a fine-tip ballpoint pen im¬mediately after injection and 20 min¬utes later, and a permanent record ofthe wheals was obtained by transfer¬ring the outline with transparent tape.Wheal sizes of 5 mm or greater at 20minutes were considered positive.Erythema was difficult to read in mostof the dark-skinned subjects (90% were

black), so this parameter was not mea-

Table 1.—Results of Penicillin Skin Testing in an STD* Clinic PopulationSkin-Test Results!

History ofPenicillin Allergy!

Negative,No.

Equivocal,No. (%)

Positive,No.§

%Positive!!

Positive (n=776) 700 21 (2.7) 7.1

Negative (n=4287) 4201 13(0.3) 73Total 4901 34 (0.7) 128

*STD indicates sexually transmitted disease.tSkin tests judged by criteria specified in the text.¿History was taken at face value in all subjects who had been told or believed that they should not take penicillin

again because of prior adverse events. Patients negative by history denied any prior adverse experience withpenicillin or related ß-lactam antibiotics.

§Frequency of positive skin tests differed between groups: xa=68; P<<.001.Positive to benzylpenlcilloyl polylysine and/or minor-determinant mixture.

sured. Preliminary scratch tests withPPL and MDM were performed in pa¬tients with previous histories of peni¬cillin allergy. If a large wheal-and-flareresponse or systemic reaction to ascratch test was observed, subsequentintradermal tests were performed withthe corresponding reagent diluted 102-fold to 104-fold. Subjects who were posi¬tive to the MDM were also skin-testedwith individual constituents (data to bereported elsewhere). Tests were con¬sidered equivocal if only one of the du¬plicate tests was positive, erythema oc¬curred without wheal formation, thescratch test was positive but intrader¬mal tests were negative, or the subjectdid not react to at least one of theconstituents when the MDM was posi¬tive.

Treatment With Penicillinand Follow-up

Skin-test-negative subjects receivedtreatment with penicillin. Subjects withequivocal skin-test results were nottreated with ß-lactam antibiotics. Sinceall of these subjects required treatmentfor sexually transmitted diseases, ap¬propriate penicillin dosages were given.The majority received high-doseparenteral penicillin (penicillin G pro-caine, 73%; penicillin G benzathine, 8%)with probenecid. Oral therapy consist¬ing of 3.5 g of ampicillin and probenecidwas given to 19%. All patients werefollowed up by telephone or postcard72 hours after receiving penicillin. Sub¬jects with previous histories of adversereactions to penicillin were followed upagain at 10 days. Often postcards frompatients detailed adverse reactions butdid not include any treatment taken.Adverse reactions were classified as

clinically similar to IgE-mediated re¬actions (anaphylaxis, urticaria, and an-

gioedema); cutaneous (nonurticarial rashand/or systemic pruritus); atypical (tem¬porally related but with atypical or un-described side effects); other possiblyimmunologie reactions such as fever,chills, and joint swelling; and procainerelated (dizziness, light-headedness, nau¬

sea, or apprehension occurring within

10 minutes of administration of penicil¬lin G procaine without any other asso¬ciated symptoms).Statistical Methods

Categorical frequency data were com¬

pared by the 2 test (d/=l except wherenoted) or by Fisher's Exact Test. Dif¬ferences between means were evaluatedby Student's t tests, using paired analy¬sis when appropriate. Pearson's product-moment coefficient was calculated to es¬timate association between continuousvariables. All reported values repre¬sent two-tailed tests of the null hypoth¬esis, with values of .05 or less consid¬ered statistically significant.

RESULTSPopulation Demographics

A total of 9313 subjects were included.The mean age of subjects was 25 years(range, 20 to 80 years); 73% were be¬tween 20 and 40 years of age. Womenconstituted 34% ofthe population. A per¬sonal history of atopy was elicited in24.9%. Ninety percent of the subjectswere black, 9% were white, and the re¬mainder were in other racial groups. Ofthe study population, 776 (8.3%) reporteda previous adverse reaction to penicillinor another ß-lactam antibiotic. Of these,52 had history of anaphylaxis, 274 hadexperienced urticaria, 166 had exan-thematous rashes, and 227 reported otheratypical adverse reactions. Fifty-sevensubjects were uncertain about their his¬tory or could not recall the particularsymptoms experienced. The remaining8537 (91.7%) denied previous difficultieswith penicillin; of these, only 4287 sub¬jects were skin-tested as part of ran¬domized controlled study ofroutine peni¬cillin skin testing among subjects nega¬tive by history (data to be reportedelsewhere). A significantly higher per¬centage of women than men reportedprevious adverse reactions to penicillin(11.1% vs 6.9%, respectively; 2=47.6;P<<.001). A history of atopy (rhinitis,eczema, or asthma) was obtained signifi¬cantly more frequently among individu¬als with previous adverse reactions than

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in those without adverse reactions (34%vs 23%, respectively; 2=27.6; P«.001).Of the 326 patients with histories of ana-

phylaxis and/or urticaria, 34.4% were

atopic by history. A history of rhinitisoccurred in 27.4% of subjects positive byhistory, with 11.9% having asthma and6.8% demonstrating eczema. In the sub¬jects negative by history, the incidencewas lower, with 15.5% having rhinitis,while 8.6% exhibited asthma symptomsand only 2.6% had eczema.

Rates of Positive Skin Tests AmongGroups Positive and Negativeby History

A total of 776 individuals with priorhistories of adverse reactions to peni¬cillin or other ß-lactam drugs were evalu¬ated by skin testing (Table 1). Of these,55 subjects (7.1%) reacted to either MDMor PPL or both. Another 21 subjects(2.7%) had equivocal skin responses toone or both reagents. Of the 4287 sub¬jects with no previous history of peni¬cillin sensitivity, 73 (1.7%) had positiveskin tests. An additional 13 (0.3%) dem¬onstrated equivocal tests. The rate ofpositive skin tests was significantlyhigher ( 2=68.0; P<<.001) in the grouppositive by history than in the groupnegative by history (7.1% vs 1.7%, re¬

spectively). The rate of equivocal testswas also significantly higher in the grouppositive by history (2.7% vs 0.3%)( 2=57.0; P<<.001). The frequency ofatopic background was similar in groupswith positive (25%) and negative (25%)skin tests (P=.96), unlike the case withhistory of prior reactions. Likewise, theprevalence ofatopy was not significantlydifferent in skin-test-positive (21%) andskin-test-negative (36%) groups ( 2=3.3;P=.06) among those with previous his¬tories of anaphylaxis and/or urticaria.

Skin-Test PatternsOf subjects with positive skin tests,

75% reacted to PPL alone, 10.2% to theMDM alone, and 14.8% to both PPL andMDM (Table 2). There was no differ¬ence in the distribution of skin-test pat¬terns between groups that were posi¬tive and negative by history.Prevalence of Positive PenicillinSkin Tests With Various Historiesof Penicillin Reactions

Types of previous reactions and ob¬served skin-sensitivity patterns to thereagents are summarized in Table 3. Ahistory of penicillin anaphylaxis was

given by 52 subjects, of whom nine(17.3%) had a positive skin test. Of the274 subjects with urticarial reactions inthe past, 12.4% demonstrated currentskin reactivity. Only 4% of those withhistory of exanthematous rash had a

Table 2.—Reactivity Patterns to PPL and MDM Among Patients With Positive Skin Tests*

History ofPenicillin Allergyf

Skin Test Pattern, No. (%)IPPL Only Both MDM Only Total

Positive 38 (69) 12(22) 5(9) 55

Negative 58 (79.5) 7 (9.5) 1(11) 73Total 96 (75) 19(14.8) 13(10.2) 128

*PPL indicates benzylpenicilloyl polylysine; and MDM, minor-determinant mixture.tx2 analysis revealed no significant difference in frequency of reaction patterns between patients positive and

negative by history ( 2=3.7; P=.15).

Table 3.—Previous Allergic History and Current Skin Test

Type ofPrevious Reaction*

Skin-Test Reactivity.tNo. of Patients

No. PPL Both

Prevalenceof Positive

Skin Tests, %

Prevalence of PositiveSkin Tests Relative to

Patients Negativeby History^

Anaphylaxis 52 9/52(17.3)§ 10.2Urticaria 274 24 34/274(12.4)11Exanthema 166 7/166 (4.0)11 2.4

Other 227 4/227 (1.8)#Uncertain 1/57(1.7)# 1.0None 4287 58 73/4287 (1.7)

*See text for definitions.fPPL indicates benzylpenicilloyl polylysine; and MDM, minor-determinant mixture.tRatio of skin-test prevalence for reaction type to prevalence rate for patients negative by history.§ 2=158; P<<.001 for comparison with rate of patients negative by history.|! 2=124; P<<.001 for comparison with rate of patients negative by history.Hx2=4.3; P=.03.#Fisher's Exact Test, Pa.8 for comparison with rate of patients negative by history.

positive skin test. A history of adverseeffects other than these three catego¬ries was given by 227 individuals, ofwhom only 1.8% were positive whenskin-tested. Among 57 subjects whowere uncertain about previous type ofreaction, 1.7% demonstrated sensitiv¬ity. A previous history of urticaria and/or anaphylaxis is associated with a sig¬nificantly increased rate ofskin-test sen¬

sitivity compared with subjects nega¬tive by history ( 2=30.0; P«.001).Subjects reporting only exanthematousreactions also had a significantly higherrate of reactivity compared with sub¬jects negative by history ( 2=4.3; P=.03).Other rates of adverse reactions were

indistinguishable from those of subjectsnegative by history (Pa.5, by Fisher'sExact Test). When compared with sub¬jects negative by history, those withanaphylaxis and urticaria had a 10 andseven times greater probability of hav¬ing positive skin tests, respectively. His¬tory of exanthem was associated with arelative risk of 2.4. Subjects whose re¬actions were categorized as other or un¬certain were indistinguishable from thesubjects who were negative by history.Distribution of Intensityof Skin-Test Responses

Intensity of skin-test responses wasmeasured as mean orthogonal diametersof the wheals. Duplicate skin tests werein good agreement with a mean coeffi¬cient of variation of 9.9% for diametersin the 5- to 9-mm range and 11% forthose with 10- to 15-mm diameters.

Somewhat higher coefficients of varia¬tion of 14.3% and 17.9% were observedin the ranges of 16 to 20 mm and 21 to24 mm, respectively. Figure 1 shows thefrequency distribution of mean diam¬eters for PPL and MDM skin testsobserved in 128 subjects. The PPLskin tests averaged 13.9 ±.4 mm

(mean±SEM), whereas mean diameterof MDM skin tests was 10.7±.5 mm

(P<.001; Table 4). Mean wheal diam¬eters for various skin-test patterns areshown in Table 4. The MDM wheal sizewas greater in those reacting to bothPPL and MDM (P=.008), but this wasnot observed for PPL skin tests (P=.5).For the 19 subj ects reacting to both PPLand MDM, no correlation was observedbetween the PPL and MDM diameters(r=.25; P>.5) (Fig 2).Equivocal Skin Tests

In 21 (2.7%) of 776 subjects positiveby history and 13 (0.3%) of4287 subjectsnegative by history, skin-testing resultswere questionable (Table 1). Tests wereconsidered equivocal if only one of theduplicate tests was positive (eight sub¬jects), erythema occurred without anywheal formation (five subjects), thescratch test was positive but intrader¬mal tests were negative (five subjects),and all minor-determinant constituentswere negative despite positive tests withthe mixture (16 subjects). Eighty-twopercent of these subjects were retestedlater (mean interval±SEM, 52±8 days),and all repeat tests were found to becompletely negative.

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Fig 1.—Mean wheal diameters of benzylpeni¬cilloyl polylysine (PPL) and minor-determinant mix¬ture (MDM) intradermal tests in 128 patients withpositive skin tests. Three subjects who were

strongly positive to the scratch test were skin-testedwith 1:10 or 1:100 dilutions of the reagent.

5 10 15 20 25PPL Skin Test Wheal

Diameter, mm

Fig 2.—Correlation of skin-test wheal diametersfor benzylpenicilloyl polylysine (PPL) and minor-determinant mixture (MDM) skin tests in 19 subjectsreacting to both (r=.25; Pa.5).

Adverse Reactions to Skin TestingAdverse reactions to skin testing oc¬

curred in 13 of 128 subjects with posi¬tive skin tests. Patients with a past his¬tory of allergic reactions had a higherrisk of an adverse reaction to skin test¬ing when compared with the group thatwas negative by history (10 of 55 vsthree of 73; 2=4.2; P=.04). The types ofreactions, previous history, and currentskin-test pattern are shown in Table 5.An anaphylactic reaction occurred in one

subject (case 1), in whom scratch test¬ing was inadvertently omitted. In thiscase, systemic urticaria developed im¬mediately after the intradermal skin testand the patient complained of general¬ized pruritus, nausea, and dizziness. Mildhypotension was observed and wheez¬ing was heard on auscultation. The pa¬tient was treated with epinephrine anddiphenhydramine hydrochloride and re¬

sponded immediately. This patient hadhad an urticarial reaction to penicillin 17years previously. She failed to react toPPL but was strongly positive to MDM.Unfortunately, we failed to measure the

Table 4.—Wheal Diameters and Reactivity Pattern*

Wheal Diameter, Mean -SEMI I

Reaction Pattern No. PPL MDM P\PPL+MDM* 19 14.4±.9 11.8±.53PPL only 96 13.8+.4MDM onlylj 12 9.0±.4All PPL-posltive 115 13.9±.4All MDM-positiveH 31 10.7±.5

*PPL indicates benzylpenicilloyl polylysine; and MDM, minor-determinant mixture.tStudent's r test.¿Paired Student's (test between PPL and MDM wheal diameters; P<.019.¿Comparison of PPL wheal diameter for PPL only vs PPL+MDM patterns.llComparlson of PPL vs MDM wheal diameters between reaction groups.11MDM diameter not recorded for one subject who had a systemic reaction after testing.

>.5§<.001||

<.001||

wheal size during the treatment of heracute reaction.

In three subjects, urticarial reactionsoccurred after skin tests. One was gen¬eralized, another was localized to theshoulders, face, and neck, and in the third,urticarial lesions were limited to the fore¬arm that was skin-tested. Generalizedpruritus without any skin lesions was ex¬

perienced by six subjects, while pruritusof the periorbital area occurred in oneand itching limited to the face, arms, andneck was seen in another. All reactionsoccurred 5 to 25 minutes after skin test¬ing. Diphenhydramine was administeredintramuscularly to four patients and oraldiphenhydramine was given to five pa¬tients. All reactions subsided promptly,and except for case 1, none required emer¬

gency attention (noted above).The distribution of intervals since last

penicillin exposure (Table 6) was the samefor subjects with adverse reactions toskin tests (all of whom were skin-testpositive) as for skin-test-positive sub¬jects who had no reactions to the skintesting. Mean intervals since last peni¬cillin treatment also did not differ (39 ±29months vs 48±5.1 months; P>.2).Interval Since Last PenicillinTreatment and CurrentSkin-Test Reactivity

Of the 776 individuals positive by his¬tory, 748 (96.3%) were able to estimate aninterval since last penicillin treatment.This interval was similar in subjects withpositive and negative skin tests (65±10months vs 81 ±3.2 months; P>1). Of the4287 subjects negative by history, 3383(78.9%) recalled an approximate intervalsince last penicillin treatment, and thisinterval was similar in skin-test-positiveand skin-test-negative subjects (25±7.3months vs 31 ±.7 months; P>.2).

As seen in Table 6, 52% of subjectsnegative by history had received peni¬cillin within the past year compared with25% of the subjects positive by history.Skin-test positivity was independent ofthe interval since last penicillin dose inthe subjects negative by history ( 2=0.02,df=7; P=.9). A higher rate of positive

skin tests occurred in individuals posi¬tive by history at all intervals when com¬

pared with subjects negative by history.In the group positive by history, sensi¬tivity appeared to decline with time, butdifferences in interval rates did not reachstatistical significance. Subjects withprevious history of anaphylaxis had sig¬nificantly higher rates of positive skintests at all intervals than subjects withother histories.

Treatment With Penicillin in PatientsWith Negative Skin Tests

Only 649 (92.7%) of the subjects whowere positive by history and skin-testnegative elected to receive penicillintreatment (Table 7). Of these, 91.8%were followed up for 72 hours; and 54(9.1%) reported adverse reactions, in 34of whom these reactions were probablyimmunologie in origin. However, prob¬able IgE-mediated reactions occurredin only 17 (2.9%). Of these, nine (1.4%)had immediate reactions (within 1 hour),while eight (1.2%) had accelerated re¬actions (between 1 and 72 hours) (Table8). Delayed reactions (after 72 hours) inonly eight of 649 treated patients whowere positive by history generally con¬sisted ofcutaneous nonurticarial rash or

pruritus (Table 9).Anaphylaxis occurred in two subjects.

Urticaria, angioedema, and difficultybreathing occurred in both, but no car¬diovascular compromise was observed.Both patients responded to epinephrinepromptly. Both had received parenteralpenicillin G procaine. One of these sub¬jects remained skin-test negative 42 and132 days later, while the other was posi¬tive to MDM on day 18 and to both skintests at day 128. Twelve of the 15 otherswere retested (Table 8), and three dem¬onstrated positive skin tests.

All of the skin-test-negative subjectswho were negative by history receivedpenicillin (Table 7). A complete 72-hourfollow-up was obtained in 95.1%. Adversereactions within 72 hours of treatmentoccurred in 74 patients (1.9%), in 40 (1%)of whom these reactions were judgedprobably immunopathological in origin

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Table 5.—Adverse Reactions to Penicillin Skin Testing*

CaseNo.

Type ofSkin-Test Reaction

PreliminaryScratch Test

PPL MDMPrevious History ofPenicillin Reaction

Time Since LastPenicillin Dose, y

Skin-Test Results(Mean Wheal

Diameter, mm)PPL MDM

Anaphylaxis ND ND Urticaria +tUrticaria Urticaria 1.5 +(11)Pruritus Anaphylaxis +(18) +(18)

Anaphylaxis 14 +(13)Pruritus Urticaria +(14) +(11)Pruritus Urticaria 0.6 +(11) +(16)Pruritus Urticaria 2.0 +(6.3) +(6.8)Pruritus Anaphylaxis +(6.0) +(7.8)Pruritus Exanthem 20 +(17)

10 Urticaria ND ND None 4.0 +(14)Urticaria ND ND None 0.003 +(10)Pruritus ND ND None +(16) +(15)

13 Local swelling Urticaria 23 +(14) +(8.8)'Number of patients tested, 5063; number of patients with positive tests, 128, number of patients with equivocal tests, 33; and number of adverse reactions, 13 (systemic,

12; and local [lasting longer than 24 hours], one). Systemic reactions occurred in 0.24% of all skin-tested subjects and 9.37% of those with positive skin tests. See text for severityof reaction and treatment given. PPL indicates benzylpenicilloyl polylysine; MDM, minor-determinant mixture; and ND, not done.t/Wheal size not recorded.

Table 6.—Rate of Positive Penicillin Skin Tests as a Function of Time Interval Since Last Penicillin Dose

Time Since Last Penicillin Dose, mo

Rate* <6 6-12 13-60 >60 UnknownAll patients positive by history

(n=776)t 7/84(8.3) 12/110(10.9) 17/249(6.8) 18/306(5.9) 1/27(3.7)Past history of anaphylaxis and

urticaria (n=326)t 6/29(20.7) 9/50(18.0) 12/90(13.3) 16/157(10.2)Past history of exanthem (n=166)t 1/18(5.6) 1/21 (4.8) 4/57 (7.0) 1/62(1.6) 0/8Patients negative by history

(n=4287)t 22/728(3.0) 20/1030(1.9) 25/1189(2.1) 4/436(0.9) 2/902(0.2)Systemic reactions to

skin testing (n=13)§ 2/30 (6.7) 3/30(10.0) 4/37(10.8) 4/31(12.9)*Rates do not differ significantly over time (P>.05; see text).tNumber of positive test results/number of patients tested (% positive).¿Ellipses indicate not applicable.¿Number of reactions/number of positive tests (% positive).

(types 1,2, and 4; Table 7). Possible IgE-mediated reactions occurred in only 0.5%,or 18 subjects. Ofthese, only three (0.08%)had immediate reactions, while 15 othershad accelerated reactions. None had an

anaphylactic reaction. Most reactions sub¬sided within 48 hours, with only four sub¬jects havingpersistent urticaria for longerperiods. Eepeat skin tests were done innine of the 18 subjects. Only one of threesubjects with an immediate reaction hada skin test that was positive to PPL whenrepeated on days 33 and 125, but this sub¬ject continued to be negative to MDM.

COMMENTThe present study reports our peni¬

cillin skin-testing experience in a groupof 5063 outpatients from a single centerevaluated in a prospective fashion bythe same three-person technical team.Since the subjects were recruited froma sexually transmitted disease clinic,they are likely to have received peni¬cillin more frequently and perhaps more

recently than an age- and sex-matchedsample of the general population. Thispredominantly young, healthy, male

study group may not, therefore, be typi¬cal of general outpatient populationswith regard to the frequency of sensi-tization or reactions to ß-lactam antibi¬otics. However, we would expect thedata on skin-testing patterns and theirrelation to history and time from lastexposure to be representative.

The rate of 7.1% for positive skin testsfound in our 776 subjects positive byhistory is lower than the 8% to 40%range of incidences noted in similar out¬patient studies.4·11·16 We also observedpositive skin tests in 1.7% of patientsnegative by history, which is somewhatlower than the rates of 4% to 7% re¬

ported in earlier outpatient studies.1·14"17Patient selection,4·11·16 differences in theskin-testing technique,1·1417 and criteriaused for considering a test positive14·16may account for some of the variation infrequency seen. Other possible expla¬nations of our lower prevalence of posi¬tive skin tests include a significant de¬cline in the incidence of IgE sensitiza-tion from the past decades because ofincreasing purity and declining use ofparenteral repository preparations. Re-

ported rates of positive skin tests havegenerally been higher among inpatientsthan outpatients,5,7·19 among subjectswith acute allergic reactions to penicil¬lin,4·17·20"22 and when skin tests are donewithin 6 months of a penicillin reac¬tion.4'11'20·21

Although a history of atopy was ob¬served more frequently in our study insubjects with previous histories of ad¬verse reactions, an atopic backgroundwas equally frequent among individualswith positive and negative skin tests.This confirms results in another largeoutpatient study19,23 and suggests thatatopy may affect the expression of al¬lergic disease but not the rate of drugsensitization.

While 90% of skin-test-positive sub¬jects demonstrated major-determinantsensitivity, a significant minority (10%)reacted to minor determinants alone.These results are in agreement with pre¬vious studies in which one ormore oftheminor penicillin determinants wereused.4'5'7'11·12·20,24 Since IgE antibodies forminor determinants are clinically asso¬ciated with acute systemic reactions in¬cluding anaphylaxis,5,810,25 the use of anMDM is crucial for maximizing the nega¬tive predictive value of penicillin skintesting. The association between minor-determinant IgE and anaphylaxis is fur¬ther demonstrated in the current studyby the single subject (case 1, Table 5)who experienced a mild anaphylactic re¬

sponse to skin testing; her skin test was

positive to MDM but negative to PPL.Therefore, both PPL and MDM skintests have to be performed to identifypatients at risk of anaphylaxis.

We report herein the distribution ofreactions (as manifested by wheal size)to penicillin skin tests for the first time.Mean wheal size for MDM was 18%

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Table 7.—Outcome of Treatment With Penicillin in Patients With Negative Skin Tests

Current Reaction Type, No. (%)

Group

TotalNo. ofSkinTests

No. of PatientsGiven Penicillin(No. With 72-h

Follow-upComplete)

Reactions Within72 h: Negative

Predictive Value,No. (%)

1IgE-

Mediated Cutaneous3

Atypical

4Other

PossiblyImmunologie

5Penicillin

GProcaine

6Unavailable

forFollow-up

ImmunologieReaction to

Penicillin, No.(%ofType1,

2, or 4)Negative by history

(n=4287) 4201 4201 (3997) 74(98.1) 18(0.5) 17 (.4) 24 (.6) 5 (.13) 6 (.15) 4(.1) 40(1.0)Positive by history

All (n=776) 700 649 (596) 54 (90.9) 17(2.9) 13 (2.2) [5]* 13 (2.2) [3]* 5 (.84) 5 (.84) 35 (5.7)Anaphylaxis (n=52) 28 (26) 4 (84.6) 1 1 2 (7.7)Urticaria (n=274) 240 211 (199) 21 (90.4) 10 15(7.5)Exanthem (n=166) 159 147(134) 11 (91.8) 10(7.5)Other (n=227) 223 210(193) 16(91.7) 7 (3.6)Uncertain (n=57) 56 53 (44) 2 (95.5) 1 (2.2)

'Delayed reactions are indicated in brackets; but systematic 10-day follow-up was obtained only in patients positive by history.

smaller than for PPL (P=.02). Thus, thepenicilloyl response was "major" both interms of frequency and intensity of re¬action. The lack of correlation betweenPPL and MDM wheal diameters sug¬gests that the minor-determinant re¬

sponse is predominantly to nonpenicil-loyl determinants.24,26 The somewhatweaker skin responses to the minor de¬terminants in part may be due to theunconjugated simple haptenic form cur¬

rently used in MDM testing.Duplicate skin tests allowed us to dem¬

onstrate that reproducibility of positiveskin tests is acceptable. The coefficientsofvariation ranged from 10% to 18%, andas expected, variation was higher forwheal sizes greater than 15 mm. Eight of5063 skin-tested subjects tested positiveto only one of the duplicate tests; whenimmediately retested in duplicate, all were

negative, indicating some potential forfalse-positive results. In addition, an in-determinant number of discordant dupli¬cate skin tests produced clearly positiveresults when repeated. Equivocal testsoccurred in others due to erythema with¬out any wheal formation (n=5), a positivescratch test with no reaction to the in¬tradermal test (n=5), and a positive re¬action to the MDM without sensitivity toany of its constituents (n=16). Thus, webelieve that duplicate skin testing is an

important routine for drug-allergy skintesting to minimize erroneous results.

Adverse reactions including anaphy¬laxis have occurred following penicillinskin testing.16,20,22,27,28 Among the 128 pa¬tients with positive skin tests, 12 (9.4%)experienced some systemic responses totesting. Nine of the 12 had previous his¬tories of IgE-mediated (type 1, Table 7)reactions. The interval since last penicil¬lin treatment was not significantly dif¬ferent among those who reacted to skintests than among those who did not reactto skin tests (Table 6). Two thirds ofthesereactions involved systemic pruritus with¬out other signs and symptoms. Three pa¬tients (2.3%) had urticaria, and one of

these received therapeutic interventionwith oral antihistamines. Only one pa¬tient had anaphylaxis. A 31-year-oldwoman with a history ofpenicillin-inducedurticaria was skin-tested intradermallywithout preliminary scratch tests. Thisaccidental deviation from our usual pro¬cedure reinforces our belief in the impor¬tance of preliminary scratch testing insubjects positive by history. Intradermaltesting may not be necessary afterstrongly positive scratch tests and mayevoke systemic reactions in highly sen¬sitive patients. However, because scratchtests are notorious for false-positive re¬sults (five cases in this series), we rec¬ommend that weakly positive scratch test¬ing be followed by intradermal testing,but beginning with a 1:100 dilution of thestandard reagent concentrations.

Subjects with histories suggesting IgE-mediated reactions such as anaphylaxisand urticaria clearly have a higher preva¬lence of positive skin tests (17.3% and12.4%, respectively) compared with thosewith histories suggesting non-IgE-me-diated reactions (1.7% to 4%).4·13·20"22 Ofinterest is that skin-test rates amongthose with histories of exanthem are sig¬nificantly higher than for subjects nega¬tive by history (4% vs 1.5%; 2=4.3; P=.03),suggesting that some of these reactionswere probably IgE-mediated, which in¬dicates the lack of precision of historicalinformation. The lower rates of positiveskin tests seen in our subjects with ana¬

phylaxis and/or urticaria compared withother studies (42% to 83%)4·13·20"22 may re¬flect longer intervals since last treatment(77% who had an adverse reaction to peni¬cillin had their last treatment more than1 year earlier).

Penicillin hypersensitivity declineswith time.4,11·20·21 The interval since lastpenicillin treatment did not significantlyinfluence the rate of current skin-testreactivity in individuals negative by his¬tory, although about half had receivedpenicillin within the past year. Amongthose with previous adverse reactions, a

trend of decreasing reactivity was notedover time, although this was not statis¬tically significant. Others have reporteda significant decline.4,11,20,21 The loweroverall reactivity rates in our study andthe fact that 77% with anaphylaxis and/or urticaria had last received penicillinover a year earlier might explain our

inability to demonstrate any significantloss ofsensitivity with time. Our findingssuggest that approximately 80% of indi¬viduals with IgE-mediated reactionscould safely be treated with penicillinwithin 1 year from their adverse reac¬tion with the aid of skin testing.

Adverse reactions to therapeutic dosesof penicillin in subjects with skin testsnegative to PPL and MDM have beenreported to occur in 0.1% to 7% oftreatedcases.1,3,4,11-18,29,30 We observed a similarlylow incidence of possibly IgE-mediatedreactions. Although 9.1% of subjects whowere positive by history experienced ad¬verse effects, less than one third of thesereactions, or 2.9% of those treated, were

probably IgE-mediated. This is compa¬rable with the 1.2% rate of immediatereactions reported by the National Insti¬tute of Allergy and Infectious Diseasescollaborative trial.30 Mild anaphylaxis oc¬curred in two ofour subjects, both ofwhomhad a previous history of severe IgE-me¬diated reactions, and both received peni¬cillin G procaine intramuscularly. All ofour subjects received a bolus ofparenteralor high-dose oral penicillin, which mightaccount for the increased rate of overalladverse reactions. Either subthresholdsensitivity to the skin-testing reagent con¬centrations used or misinterpretation ofthe original skin tests (unlikely, with du¬plication) could account for positive re¬sults when skin tests were repeated at alater date in some of the individuals re¬

acting to penicillin treatment.On the other hand, the vast majority

(over 97%) of patients with previouspenicillin allergy were able to toleratefull-dose therapy after negative peni¬cillin skin tests. This finding, coupled

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Table 8.—Immediate and Accelerated Reactions to Penicillin Treatment in Patients With Negative Skin Tests

Onset of DurationCurrent Reaction Reaction, h of Reaction,

Type ofh Penicillin* Treatment Given

Last Dose Repeatof Penicillin, History Skin Tests

Past History mo of Atopy (PPL and MDM+)

UrticariaPatients Positive by History

10 P/B Diphenhydramine Anaphylaxis 30hydrochlorldeby mouth

Eczema/rhinitis Negative, days 7, 44, and 101

Urticaria/handswelling

48 A/B Diphenhydraminehydrochloride by mouth

Exanthem 12 None Not done

Urticaria 24 336 P/B None Swelling atinjection site

Eczema Positive to PPL only, days 13and 43; negative, days 106and 260

Urticaria P/B None Swelling atinjection site

None Not done

Urticaria, localized 0.08 P/B Diphenhydraminehydrochlorideby mouth

Swelling at 60 None Negative to PPL and MDM:injection site negative to PPL, day 12;

positive to MDM, days 168,275, and 329, and toMDMx10,+"day329

Angioedema of face;difficulty breathing/swallowing

P/B Treated in emergencydepartment

Exanthem None Positive to MDM/negative toPPL, day 18; positive toboth, day 128; negative toboth, days 252 and 282

Urticaria A/B None Urticaria 60 Rhinitis Negative, day 94Urticaria 48 P/B Diphenhydramine

hydrochloride by mouthUrticaria Asthma Negative, days 41 and 104

Urticaria P/B Diphenhydraminehydrochloride by mouth

Urticaria None Negative, days 51 and 398

Urticaria/angioedema P/B Treated in emergencydepartment

Urticaria None Negative, days 36 and 75

Urticaria/chesttightness

P/B Treated in emergencydepartment/epinephrine

Urticaria 36 None Negative, days 42 and 132

Urticaria 0.5 P/B None Urticaria Rhinitis Negative, day 17Urticaria 48 A/B Diphenhydramine

hydrochlorideby mouth

Urticaria 12 None Not done

Urticaria/angioedemaof eyes

P/B Diphenhydraminehydrochloride by mouth

Urticaria None Positive to PPL, days 28, 127,161,219, 299, and 343

Urticaria A/B None Urticaria None Negative, day 9Urticaria 48 24 P/B None Urticaria None Negative, day 14Urticaria 48 120 P/B Diphenhydramine

hydrochlorideby mouth/epinephrine

Urticaria 36 None Negative to MDMX10, day 47;negative to PPLX50,§ day 47

Urticaria P/B NonePatients Negative by History

None None Not done40 P/B Treated in emergency

departmentNone None Not done

Urticaria P/B None None 12 None Negative, day 12Urticaria 12 P/B None None Asthma/eczema Positive to PPL, day 33; nega¬

tive to MDM, day 125Urticaria 0.5 P/B None None None Not doneUrticaria 24 P/B None None 120 Rhinitis Not doneUrticaria BIC Treated in emergency

departmentNone 12 Asthma/rhinitis Not done

Urticaria P/B None None None Not doneUrticaria 24 P/B Treated in emergency

departmentNone None Negative, days 399 and 1001

Urticaria 168 A/B None None Not doneUrticaria P/B Treated in emergency

departmentNone None Not done

Urticaria 24 P/B Treated in emergencydepartment

None Asthma/rhinitis Negative, days 17 and 74;negative to MDMxl0,t day74; negative to PPLx50,§day 74

Urticaria 12 P/B None None 0.03 Asthma Negative, day 14Urticaria P/B None None None Negative, day 40Urticaria 48 168 P/B Diphenhydramine

hydrochlorideby mouth

None Negative, day 97

Urticaria P/B None None Asthma/eczema/Negative, day 16rhinitis

P/B Diphenhydraminehydrochloride by mouth

None None

Urticaria 0.5 P/B None None 10 None Negative, days 45 and 94

*P/B indicates 4.8 million U of penicillin G procaine intramuscularly plus 1 g of probenecid by mouth; BIC, 1.2 U of bicillin intramuscularly; and A/B, 3.5 g of ampicillin by mouthplus 1 g of probenecid by mouth.

fPPL indicates benzylpenicilloyl-polylysine; and MDM, minor-determinant mixture.+Ten times the usual concentration.§Fifty times the usual concentration.

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Table 9.—Types of Posttreatment Reactions of Possible Immunologie Origin in Patients With NegativeSkin Tests

Reaction Category Description

Patients PatientsPositive by Negative byHistory, No. History, No.

Probably IgE-mediated AnaphylaxisUrticaria/angioedema 15

Other cutaneous reactions Pruritus with nonurticarial rashPruritus without rash

Maculopapular rash without pruritusPersistent local reaction

I [2]*H2] [il

Other possible Immunologiereactions Fever, restlessness, llght-headedness

Fever, chillsMild fever

*Delayed reactions (onset after 72 h) are shown in brackets for patients positive by history for whom systematic10-day follow-up was obtained (92% of those treated).

with the high prevalence of negativeskin tests in subjects positive by his¬tory, suggests that penicillin skin test¬ing can be a valuable tool to permit ß-lac¬tam therapy to be used safely in mostpatients who are now stigmatized withthe label of penicillin allergy. This con¬clusion is supported by numerous stud¬ies with similar findings,1,3,4,5,11"18 but hasrecently been challenged. Redelmeierand Sox,31 using a decision-analysis ap¬proach with a meta-analysis ofpublisheddata, concluded that skin testing is un¬

necessary in patients with "convincinghistories of severe allergic reactions topenicillin." This study has been criti¬cized for its unvalidated assumptions anduncritical pooling of studies with and

without minor-determinant testing.32Their principal conclusion hinges on anestimate of a pretest probability of .5 forsevere allergic reactions among patientswith "very strong" histories ofpenicillinallergy. Clearly, this is a gross overes¬timate since in the current study only17% of patients with convincing histo¬ries of anaphylaxis had positive skintests, and the risk of treatment withpenicillin in skin-test-positive patientswho are positive by history has beenestimated at 0.5 to O.7.210

Whether these remaining results are

generalizable to patients whose mast-cell function may be impaired by inten¬sive chemotherapy or immunodeficiencyis currently unknown. However, over

the past 10 years, we have proceeded insuch patients with extra caution andhave not experienced difficulties. Weconclude that skin testing with majorand minor determinants of penicillin issafe when intradermal testing is pre¬ceded by puncture or scratch tests. Skintesting with the major-determinant PPLalone will identify the majority of sen¬sitized subjects. However, about 10% ofallergic individuals will be missed if mi¬nor-determinant reagents are not in¬cluded. Only 7.1% of subjects with a pre¬vious history of penicillin allergy haveIgE-mediated sensitivity as measuredby skin testing. A previous history ofanaphylaxis or urticaria is more likelyto be accompanied by positive skin teststhan a history of exanthem or other re¬action types. Sensitivity clearly declineswith time. Re-treatment with penicillinwas well tolerated by the vast majorityof skin-test-negative patients who were

positive by history. Therefore, skin test¬ing with both reagents should permitthe use of this otherwise safe and effi¬cacious group of antibiotics in over 90%of individuals with previous histories ofreactions.

This study was supported by grant AI 11936from the National Institutes of Health, Bethesda,Md.

We gratefully acknowledge the helpful assis¬tance of the Baltimore City Health Departmentand the staff of its Eastern Health Division Clinicfor Sexually Transmitted Disease, Baltimore, Md.

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