Minor Determinant Mixture Research Articles

The role of major and minor determinants in penicillin allergy testing: Time to revisit an old friend?

Skin testing is an important step in evaluation of penicillin allergic reactions. It includes testing to the following: amoxicillin, benzyl penicillin, and products generated invivo after penicillin administration, the major determinant hapten penicilloyl-polylysine (PPL) and the minor determinant mixture (MDM). Although PPL and MDM are available as a commercial kit, their supply and cost remain problematic. We aimed to evaluate the performance and utility of PPL and MDM in penicillin allergy testing. A retrospective audit over a 5-year period was undertaken for those with penicillin testing in a tertiary immunology unit. In all, 214 patients were identified. Of those patients, 151 (70.6%) were female and the average age was 58 years. Unspecified penicillin was the most common index drug (n=127 [59.3%]), followed by amoxicillin (n=3 [24.8%]) and amoxicillin-clavulanic acid (n= 21 [9.7%]). The result of skin testing was positive in 23 patients (10.7%); skin prick testing was positive in 10 patients (4.7%), and intradermal testing (IDT) was positive in 13 patients (6.1%), the majority of whom had identified amoxicillin or amoxicillin-clavulanic acid as the index drug (n= 22 [95.7%]). The result of testing to PPL and/or MDM was positive with IDT only (n=5 [23.8%]). PPL and MDM positivity coexisted with a positive reaction to amoxicillin IDT in 2 patients, 1 of whom passed an amoxicillin challenge. Additionally, 2 positive tests to PPL were present with a negative result for MDM; of these 2 positive results, 1 was positive to amoxicillin IDT. In only 1 case were the results of testing for MDM and PPL both positive, with negative results to all native β-lactams tested; the patient tolerated an amoxicillin challenge. Overall, the negative predictive value for both skin prick testing and IDT was 89.5%. Benzyl penicillin and amoxicillin alone may be sufficient for invivo testing in suspected individuals with penicillin allergy.

Results of penicillin skin testing in patients with suspected penicillin allergy - the Qatar experience.

Background: Unverified penicillin allergy has been linked to adverse patient events and increased healthcare expenditure owing to the usage of broad-spectrum, expensive antibiotics. Penicillin allergy test is the gold standard to diagnose penicillin allergy; and in this study, we present data from Qatar which have not been published before.Methods: Patients with a history of penicillin allergy who underwent penicillin allergy testing between January 2015 and December 2020 at the Allergy Division of the Hamad General Hospital were retrospectively reviewed from the division registry. Benzylpenicilloyl-polylysine (PPL) and minor determinant mixture (MDM) kit DAP-penicillin (0.04 mg +0.5 mg)/vial) (penicillin G, amoxicillin (20 mg/vial), and lately clavulanic acid (20 mg/vial) (DAP, Diater, Madrid, Spain) were used for skin and intradermal testing according to published guidelines. Patients with negative skin tests were administered direct oral challenge with amoxicillin/clavulanate (500/125 mg) and observed for 2 hours.Results: Of the 189 charts reviewed, 183 patients had a complete data set for analysis. Patients were predominantly women (n = 132, 72%) with an average age of 42 years. Of these patients, 149 (81.4%) had a history of an immediate allergic reaction to penicillin, 10 had a history of delayed reactions, and 24 had other or undefined reactions. A total of 39 (21.3%) patients were diagnosed with penicillin allergy (30 patients with positive skin test results and 9 using a direct oral challenge).Of the 30 patients with positive skin testing, 5 reacted to PPL, 8 to MDM, 13 to amoxicillin, and 4 to clavulanic acid.Conclusion: Previous studies indicate that 90% patients with a history of penicillin allergy were able to tolerate the drug (10% were truly allergic). Our data showed that 21% were truly allergic to penicillin. This high positive rate can be attributed to the high pretest probability based on the detailed history obtained before the test, which led to the exclusion of patients with symptoms incompatible with penicillin allergy from the test.

Allergological Study of 565 Elderly Patients Previously Labeled as Allergic to Penicillins.

PurposeElderly people thought to have an allergy to beta-lactams (BLs) may tolerate the drugs in subsequent exposures due to initial false labeling of allergies, the spontaneous loss of sensitivity to BLs over time or age-related decline in sensitization. As a result, they may be treated with less appropriate antibiotics, causing more side effects and entailing increased costs for health systems. The aim of this investigation was to assess whether patients in the third and fourth age with previously confirmed allergies to BLs had lost sensitization and could tolerate these antibiotics.Patients and methodsPatients allergic to BLs were divided into group A (aged 60–79 years) and B (aged ≥80 years). Clinical history, skin testing, drug challenge tests (DCT) and evaluation of resensitization were used to classify participants as showing immediate reactions, non-immediate reactions, or tolerance. We compared clinical entities, drugs involved, and final outcome by age group.ResultsOf 1362 cases evaluated, 565 underwent an allergological study. The skin was the most common organ involved. Anaphylaxis and side chain reactions were more frequent in group A (p<0.01), as were positive DCT. Classical benzylpenicillin determinants (benzylpenicilloyl and/or minor determinant mixture) were more frequent triggers in group B (p< 0.01). Resensitization after challenge occurred in very few participants.ConclusionThe risk for allergy to BLs decreases with age and a history of anaphylaxis by BLs is a predictor of positive results in skin tests (ST). Both immunoglobin E (IgE) and T-cell–mediated responses can disappear in elderly people, who can develop tolerance to these antibiotics. These results are of clinical relevance to patients who need to be treated with antibiotics from this family.

Mild to moderate hypersensitivity reactions to beta-lactams in children: a single-centre retrospective review

ObjectiveBeta-lactam (BL) antibiotics are the most reported drugs in hypersensitivity reactions in children. More than 90% of these children tolerate the suspected drug after diagnostic work-up. Skin tests (STs) show...

Penicillin Allergy Evaluation: A Prospective, Multicenter, Open-Label Evaluation of a Comprehensive Penicillin Skin Test Kit

Ten percent of the population claims an allergy to penicillin, but 90% of these individuals are not allergic. Patients labeled as penicillin-allergic have higher medical costs, longer hospital stays, are more likely to be treated with broad-spectrum antibiotics, and develop drug-resistant bacterial infections. Most penicillin skin test reagents are not approved by the Food and drug Administration or readily available to evaluate patients labeled penicillin-allergic. To determine the negative predictive value (NPV) of the Penicillin Skin Test Kit containing the major allergenic determinant (penicilloyl polylysine), a minor determinant mixture (penicillin G, penicilloate, penilloate), and amoxicillin, produced according to Food and Drug Administration standards. This was a prospective, multicenter, open-label investigation of penicillin skin testing using the Penicillin Skin Test Kit. Skin test-negative subjects were challenged with 250 mg amoxicillin, whereas skin test-positive patients were not challenged. The primary end point was NPV of the Penicillin Skin Test Kit, defined as the percentage of subjects with negative skin test results who did not experience an IgE-dependent reaction within 72 hours of amoxicillin challenge. In total, 455 patients with a history of penicillin allergy underwent skin testing and 63 (13.8%) had 1 or more positive test results; 65% of the positive test results were to the minor determinant mixture and/or amoxicillin alone. In the per protocol group of 373 skin test-negative subjects, 8 developed potential IgE-dependent reactions following oral amoxicillin challenge, translating to an NPV of 97.9% (95% CI, 95.8-99.1; P < .0001). All but 1 of the reactions was mild or moderate, and most subjects who required treatment received only antihistamines. The Penicillin Skin Test Kit, containing all relevant penicillin allergenic determinants, demonstrated very high NPV. Removal of a penicillin allergy label in a large majority of currently mislabeled patients has substantial personal and public health implications.

Penicillin skin testing in the management of penicillin allergy in an outpatient pediatric population

Eight to ten percent of patients believe that they are allergic to penicillin, yet only 10% of those patients have evidence of an immunoglobulin E (IgE) mediated allergy upon penicillin skin testing (PST). In the adult population, a negative PST result is associated with a low risk of immediate reaction on oral challenge, but further studies are needed in the pediatric population. To calculate the negative predictive value (NPV) of the current skin testing regimen of penicillin, benzylpenicilloyl-polylysine (the major determinant), and ampicillin in a pediatric outpatient population to assess the utility of adding the minor determinant mixture to the skin testing regimen. A retrospective chart review was conducted of all pediatric patients seen in a single-center pediatric allergy/immunology outpatient clinic between January 1, 2010, and March 1, 2016, who underwent PST for presumed penicillin drug allergy. Only 38% of patients who underwent PST had a drug reaction history consistent with an IgE-mediated reaction. 28.8% of the patients had a positive PST result. The addition of ampicillin to the standard PST regimen of penicillin and benzylpenicilloyl-polylysine identified an additional 4.1% of patients. Two patients (3.2%) reacted on oral challenge with a minor rash. The NPV of the PST regimen was 98%. No significant predictive variables for a positive PST result were identified. Given the high NPV of the current PST regimen, we do not recommend additional testing with the minor determinant mixture. Despite this high NPV, the utility of PST in the low-risk, low-pretest probability outpatient pediatric population was limited, and select patients may be able to proceed directly to oral challenge.

Frequency of selective immediate responders to aminopenicillins and cephalosporins in Turkish children.

Beta-lactam antibiotics (BLA) are the most commonly prescribed antibiotics and are responsible for the majority of immediate hypersensitivity reactions to drugs in children. Cross-reactivity is important in hypersensitivity to BLAs because these drugs all share a common beta-lactam structure and some share similar side chains. The aim of this study was to evaluate the clinical characteristics of patients who are diagnosed with immediate-type BLA hypersensitivity and frequency of patients with side chain hypersensitivity, "selective responders." The study included patients who were diagnosed with immediate-type BLA hypersensitivity between January 2011 and May 2016 in a pediatric allergy outpatient clinic. The patients who had negative penicillin test (minor determinant mixture, benzylpenicilloylpoly-L-lysine, penicillin G) results and could tolerate penicillin V and/or BLAs with dissimilar side chains but had positive skin and/or provocation test results with the suspected drug were diagnosed as selective responders. During the study period, 357 patients (55.2% girls) were admitted to our clinic with suspected immediate-type BLA hypersensitivity. Parents of 11 patients did not give consent for an allergy workup with the suspected drug. Forty-five of the patients were diagnosed (45/346 [13%]) based on skin test or drug provocation test results. The most common susceptible agent was amoxicillin-clavulanate. Of the patients, 71.4% with a reaction to sulbactam-ampicillin /or amoxicillin-clavulanate and 93.7% with a reaction to cephalosporin were classified as selective responders. Among children with immediate BLA hypersensitivity, selective responders constituted an important group. Most of the patients with reactions to aminopenicillin and cephalosporins safely tolerated penicillin V and BLAs with dissimilar side chains after negative allergy workup results.

Utility of basophil activation testing to assess perioperative anaphylactic reactions in real-world practice.

IntroductionPerioperative anaphylactic reactions due to drugs and substances associated with general anesthesia can potentially be life‐threatening. The objective of this study was to investigate the significance of the basophil activation test (BAT) for allergy diagnosis work up.MethodsA total of 14 patients (5 men, 9 women; mean age: 57.8 years) with clinical records of anaphylactic reactions under general anesthesia were studied by means of anesthesia records, skin and serological tests. Eleven healthy subjects without any history of allergic sensitization to anaesthetic drugs served as controls. BATs based on stimulation of whole blood cells measuring CD63 activation of basophils and using CCR3 as basophil marker by flow cytometry (Flow CAST®, BÜHLMANN Laboratories AG, Schönenbuch, Switzerland) were performed with the following substances (in dependence on the history and the skin tests of the patient): analgesics (acetylsalicylic acid, celecoxib, diclofenac, ibuprofen, indometacin, metamizole, paracetamol, propyphenazone, tramadol), antibiotics (PPL (benzylpenicilloyl polylysine), MDM (minor determinant mixture), amoxicillin, cefuroxime, ciprofloxacin, doxycycline, erythromycin, roxithromycin, sulfamethoxazole, trimethoprim), local anesthetics (articaine, bupivacaine, lidocaine, prilocaine, procaine, methyl‐4‐hydroxybenzoate), narcotics and NMBA (atracurium, cisatracurium, etomidate, neostigmine, midazolam, mivacurium, pancuronium, propofol, pyridostigmine, succinylcholine, sufentanil, thiopental, vecuronium), and other individual substances.ResultsThree patients showed positive results in the BAT: One to metamizole, one to PPL, and one to pancuronium. BATs with these substances were negative in controls.ConclusionsThe BAT should be used complementary to skin tests, especially if IgE‐mediated mechanisms are presumed and skin tests are inconclusive. A positive reaction in BAT identifies the culprit agent with high probability.

A retrospective comparison of false negative skin test rates in penicillin allergy, using pencilloyl-poly-lysine and minor determinants or Penicillin G, followed by open challenge.

BackgroundA history of penicillin allergy in patients is common, but only 10–15 % are truly allergic. While the gold standard for diagnosing penicillin allergy is challenge, it is not recommended that this be done without first carrying out diagnostic skin testing. This is carried out with the major determinant benzylpenicilloyl (PPL) and the minor determinant mixture (MDM), consisting of penilloate, penicilloate and Penicillin G. However, since availability of the MDM is limited, Penicillin G alone has been used.MethodsA retrospective chart review was carried out on patients tested for penicillin allergy in the Clinical Immunology and Allergy Clinic at the Health Sciences Centre, Winnipeg, Canada between 2005 and 2013. A total of 521 patients charts were reviewed, of whom 240 had skin testing, ImmunoCap® for IgE to Penicillin G and V and had oral challenges with penicillin, amoxicillin or cloxacillin.Results17/240 (7.5 %) were skin test positive, 8 to PPL, 4 to MDM and 5 to Penicillin G. One was also positive on ImmunoCap® testing. Three patients had negative skin tests but weakly positive ImmunoCap®. 222 patients with negative skin tests and serological tests were challenged. Of these, 12 patients reacted to challenge. Three of the challenges were equivocal. Of the nine patients with definite positive challenges, three were tested with Penicillin G and six with MDM. Therefore the false negative rates for testing were 2.3 % with PPL and Penicillin G and 6.97 % for PPL and MDM. The difference was not significant (p = 0.0856).ConclusionsIn this group of patients with a history of penicillin allergy tested with the major determinant of benzyl penicillin and either MDM or Penicillin G, there was no difference in the rate of false negative testing, based on oral penicillin challenges. Therefore, Penicillin G can be safely used as an alternative to MDM in diagnosing penicillin allergy.

Diagnosing penicillin allergy in the absence of minor determinant mixture

Background Penicillin allergy is a common presentation in allergy clinic. The diagnosis of immediate hypersensitivity is made using clinical history, skin testing, specific IgE levels and oral challenge. Skin testing is done using benzyl penicilloyl-polylysine (PPL) and a minor determinant mixture (MDM) consisting of penicillin byproducts. Although using PPL and MDM is considered first line for diagnosis [1], our clinic is unable to consistently obtain MDM. We have undertaken a retrospective chart review to assess our current protocol in diagnosing penicillin allergy using Penicillin G (PG) alone instead of MDM.

Penicillin allergy evaluation: experience from a drug allergy clinic in an Arabian Gulf Country, Kuwait.

BackgroundHypersensitivity to penicillin has been studied worldwide, but data regarding patterns of sensitization in Arabian Gulf countries are scarce.ObjectiveTo describe the patterns of penicillin hypersensitivity during a 6-year study in Kuwait in terms of demographics, type of the culprit drug, in vivo and in vitro allergy testing.MethodsOne hundred and twenty-four patients referred to the drug allergy clinic for penicillin allergy were fully evaluated by skin prick and intradermal testing. Drug provocation test was done on patients with negative results.ResultsA total of 124 patients were evaluated for penicillin allergy. Mean age was 37.8 (standard deviation, 12.7) years, range from 8 to 74 years. Thirty-nine male (31.5%) and 85 female patients (68.5%) were included. Diagnosis of penicillin allergy was confirmed in 46 patients (37.1%). Among the 44 confirmed allergic patients by skin evaluation we had 15 (34.1%) positive skin prick test, and 29 (65.9%) positive intradermal testing. Among patients with positive skin testing, 47.7% were positive to major determinant benzylpenicilloyl poly-L-lysine, 20.4% to minor determinant mixture, 50.0% to penicillin G and 40.9% to ampicillin; 13.6% of patients were positive to amoxicillin by skin prick test. One patient had a positive radioallergosorbent test and one had a positive challenge test.ConclusionPenicillin allergy is a common problem with an incidence of about one third in our study subjects.

Alkali-treated penicillin G solution is a better option than penicillin G as an alternative source of minor determinants for penicillin skin test

Both benzylpenicilloyl-polylysine (PPL) and minor determinant mixture (MDM) are the recommended standard reagents for penicillin skin testing. However, penicillin G is commonly suggested as an alternative source of minor determinants. This study evaluated the accuracy of penicillin G and alkali-treated penicillin G compared with the standardized MDM for skin testing. Sixty-eight patients with histories of allergies to penicillin or semisynthetic penicillins were skin tested with commercial Kit penicillin allergenic determinants (DAP) (PPL and DAP-MDM; Diater Laboratorios, Madrid, Spain). The in-house MDM (IH-MDM), prepared by alkali-treated aged penicillin, and fresh penicillin G sodium (PGs) were tested alongside DAP-MDM. Positive penicillin skin test results were identified in 22 patients (32.4%) using commercial reagents (PPL+ DAP-MDM) and 19 of them reacted to DAP-MDM alone or together with PPL. The accuracy of IH-MDM and PGs compared with DAP-MDM was 89.7 and 76.5%, respectively. Our study shows that alkali-treated penicillin G is a better option than penicillin G as an alternative source of MDM for skin testing in case the commercialized MDM is not available. Minor determinants play a significant role for penicillin allergy in Thailand and should be included in the penicillin skin test panel to verify suspected cases of penicillin allergy. (ClinicalTrials.gov number: NCT00789217).

Diagnosis of Immediate Hypersensitivity to β-Lactam Antibiotics Can Be Made Safely with Current Approaches

Background: Diagnosing immediate hypersensitivity to β-lactam antibiotics is still a significant problem. Recently, a new penicillin testing reagent was introduced to the market. In this study, the recommendations of the European Network of Drug Allergy (ENDA) for the diagnosis of immediate reactions to β-lactams were followed, and the negative predictive value of this approach with currently available reagents was assessed. Methods: Eighty patients (age range: 6–74 years) with a history of immediate reactions to β-lactams were included. All cases underwent skin testing with benzylpenicilloyl-polylysine (PPL) and minor determinant mixture (MDM), followed by the culprit drug if necessary. If this step was negative, a drug provocation test was offered. If this step also yielded a negative result, then the patients were recommended to use β-lactam antibiotics in future whenever their use was indicated. Results: Overall, 29 patients (36.2%) were diagnosed as β-lactam allergic. The majority of the cases (72.4%) were diagnosed by positive skin tests to either PPL or MDM, whereas 10.3% were diagnosed by skin testing with culprit drugs and 17.2% with drug provocation tests. Regarding the use of the tested drug in the long term, almost half of the contacted patients had had an indication to use the tested drug and the majority had taken the whole course without problems. Conclusions: Although currently available new penicillin tests provide sufficient allergy data, all the steps recommended by ENDA should be followed in the diagnosis of immediate reactions to β-lactams. If these steps are negative, the patients usually tolerate β-lactams and only a few develop mild, non-life-threatening reactions in the long term.

Management of Rashes Associated With Beta-lactam Rx

Source: Caubet JC, Kaiser L, Lemaitre B, et al. The role of penicillin in benign skin rashes in childhood: a prospective study based on drug rechallenge. J Allergy Clin Immunol. 2011; 127(1): 218– 222; doi: 10.1016/j.jaci.2010.08.025Investigators from Switzerland assessed the role of infectious and allergic causes in delayed-onset urticarial and maculopapular rashes in children treated with beta-lactam antibiotics. This prospective observational study from 2006 to 2008 included children aged 0 to 16 years who presented to the pediatric emergency department (ED) with an urticarial or maculopapular rash during or within 72 hours of finishing beta-lactam therapy.Children presenting to the ED underwent a clinical evaluation which included history and physical examinations, pictures of skin lesions, antibody titers for viruses associated with childhood skin rashes, and throat swab polymerase chain reaction (PCR) screening for respiratory viruses. Subsequent follow-up two months later included a second set of viral serologies and work-up for beta-lactam allergy.Allergy work-up included intradermal skin tests (IST) performed with minor determinant mixture, penicilloyl-polylysine, amoxicillin, and cephalosporin as indicated. In vitro assays for beta-lactam antibiotic IgE were drawn. Patch testing was performed with incriminating drugs. Oral challenge testing (OCT) was performed in all children. Initiation dose depended on the results of beta-lactam testing. A final visit two days later included patch and late intradermal skin test reading.Eighty-eight children, with an average age of 3.5 years, completed the study. Of these, 48.9% were on amoxicillin, 38.6% on amoxicillin-clavulanic acid, and 12.5% on a cephalosporin at the time of the rash. ISTs were positive in 12.5% of patients. OCT produced six reactions: one with amoxicillin, three with amoxicillin-clavulanic acid, and two with cephalosporin. Only four of the six children who later had a positive OCT developed immediate positive ISTs. However, those with positive ISTs had a higher rate of positive OCTs than those without (P<.05, Fisher exact test). The overall sensitivity determined for IST was 66.7%, and the specificity was 91.5%. Patch testing and delayed intradermal testing were negative in all 88 patients.Viral screening was positive in 46 of 82 children with a negative OCT and 2 of 6 children with a positive OCT. The viruses most frequently identified were enteroviruses; three of the positive OCT patients had findings suggestive of acute Epstein-Barr virus infection.The authors conclude that children who present with a benign skin rash and no other symptoms of allergic reaction while treated with beta-lactam antibiotics rarely have beta-lactam allergy, and should receive a one-dose OCT under medical supervision followed by two days of antibiotic dosing at home to establish whether antibiotics are responsible for the rash.Dr Nimmagadda has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.The development of urticarial and maculopapular rashes in the child with viral illness remains a diagnostic dilemma for pediatricians. Many children treated with beta-lactam antibiotics have an intercurrent viral illness as well. Oftentimes children with cutaneous urticarial or maculopapular rashes will get labeled as penicillin-allergic. These children are rarely re-challenged or tested.1 Studies have determined true antibiotic allergy prevalence to be under 10% in suspected drug-allergic pediatric populations.2Penicillin is degraded to major (95%) and minor determinants (5%). Immediate IgE-mediated reactions causing anaphylaxis are associated with minor determinants in 95% of the cases.3 Hypersensitivity to these two products can be assessed using cutaneous tests performed with major and minor determinants, thus avoiding serious anaphylactic reactions in beta-lactam-allergic individuals. Challenge and/or desensitization in patients with positive skin tests should only take place in well-controlled settings where emergency equipment and medications are available.3The current article highlights the infectious and allergic causes of benign skin rashes in relation to penicillin exposure. This understanding provides support for more accurate diagnosis and management in cases of suspected beta-lactam allergy. Caution should always be exercised in children with more than just cutaneous manifestations of drug allergy. OCT in these individuals is not recommended without further evaluation or consultation with an allergy specialist.This provocative study raises the question whether all children with benign skin rashes during beta-lactam treatment deserve carefully supervised OCTs.

Tolerability of Aztreonam in Patients with Cell-Mediated Allergy to β-Lactams

Background: Cross-reactivity between aztreonam and β-lactams is poor, but tolerability of aztreonam has been assessed in a few groups of patients suffering from IgE-mediated allergy to β-lactams. The aim of this study was to assess the cross-reactivity of aztreonam with other β-lactams and its tolerability in patients with cell-mediated allergy to these drugs. Methods: We studied 78 patients with cell-mediated allergy to β-lactams who underwent skin prick, immediate and delayed-reading intradermal tests as well as patch tests with penicilloyl-polylysine, minor determinant mixture, semi-synthetic penicillins, cephalosporins, aztreonam and imipenem. Patients with negative allergy testing with aztreonam underwent an intramuscular test dosing and were observed for 3 h. Results: Our patients experienced 94 non-immediate reactions; delayed-onset urticaria (34 cases), maculopapular exanthema (13 cases), urticaria/angioedema (15 cases) and itching erythema (13 cases) were the most reported symptoms. Amoxicillin (35 cases), ampicillin (28 cases) and bacampicillin (18 cases) were the most involved drugs. All patients had a positive patch test and/or a positive delayed-reading intradermal test to at least 1 β-lactam antibiotic and none had a positive patch or delayed-reading intradermal test to aztreonam. Then, 65 patients underwent intramuscular test dosing with aztroenam, and none of them had a clinical reaction. Conclusions: Our data confirm the lack of cross-reactivity between β-lactams and aztreonam in patients with cell-mediated allergy to these drugs. Delayed-reading intradermal tests and patch tests with aztreonam represent a simple and rapid diagnostic tool to establish tolerability in β-lactam-allergic patients.

The very limited usefulness of skin testing with penicilloyl‐polylysine and the minor determinant mixture in evaluating nonimmediate reactions to penicillins

The contribution of skin testing with penicilloyl-polylysine (PPL) and the minor determinant mixture (MDM) to the diagnosis of hypersensitivity reactions to penicillins differs greatly according to the type of reaction: immediate (occurring within 1 h after the last drug administration) or nonimmediate (occurring more than 1 h after the last drug administration). To assess the contribution of skin testing with PPL and MDM to the diagnosis of nonimmediate reactions to penicillins. We evaluated 162 adults who had had 232 nonimmediate reactions to penicillins, mostly aminopenicillins, and presented positive skin and/or patch tests to one or more penicillin reagents: PPL, MDM, benzylpenicillin, ampicillin, and amoxicillin, as well as any responsible penicillins. A total of 157 subjects (96.9%) displayed patch-test and/or delayed-reading intradermal-test positivity to penicillin reagents, which indicates a cell-mediated hypersensitivity; six of them also presented immediate-reading skin-test positivities. All 157 patients with a cell-mediated hypersensitivity were positive to the responsible penicillins (parent drugs); 16 of them also displayed delayed-reading intradermal-test positivity to MDM. Five (3.1%) of the 162 patients displayed only immediate-reading skin-test positivity (four to PPL and one to amoxicillin). Overall, 158 subjects (97.5%) presented positive responses to the responsible penicillins, while only 9 (5.5%) and 17 (10.5%) were positive to PPL and MDM, respectively. The contribution of skin testing with PPL and MDM in diagnosing nonimmediate hypersensitivity reactions to penicillins, especially cell-mediated ones, is very limited. This finding could be useful at a time when PPL and MDM are not available in all countries.

Benzylpenicillin skin testing is still important in diagnosing immediate hypersensitivity reactions to penicillins

The fact that both Hollister-Stier and Allergopharma ceased the production of penicilloyl-polylysine (PPL) and minor determinant mixture (MDM) in 2004 is severely hampering the diagnosis of beta-lactam hypersensitivity and may produce negative consequences. To assess the contribution of skin testing with benzylpenicillin to the diagnosis of immunoglobulin E-mediated hypersensitivity to penicillins, in order to determine how much such testing could compensate for PPL and MDM unavailability. We selected patients with histories of immediate reactions to penicillins and positive results to skin tests for one or more penicillin reagents (PPL, MDM, or benzylpenicillin), one or more semi-synthetic penicillins (ampicillin, amoxicillin, or piperacillin), or both. A total of 300 patients were selected, 105 in the French center and 195 in the Italian centers. Amoxicillin and ampicillin were the main responsible drugs. The most common clinical manifestation was anaphylaxis. The reagents most frequently positive to skin tests were amoxicillin (188, 62.7%), ampicillin (151, 50.3%), and benzylpenicillin (111, 37.0%). Among the 300 subjects, 113 (37.7%) were positive only to semi-synthetic penicillins, 109 (36.3%) to both semi-synthetic penicillins and the classic penicillin reagents, and 78 (26.0%) only to the latter. In the last group, 64 (21.3% of the 300 subjects) were positive only to PPL and/or MDM and 14 (4.7%) to benzylpenicillin, of whom 8 (2.7%) were positive only to the latter. Skin testing with benzylpenicillin can partially compensate for PPL and MDM unavailability. Moreover, it can slightly increase the allergologic workup's sensitivity and therefore reduce the number of potentially dangerous challenges.

Tolerability of Aztreonam in Patients with IgE-Mediated Hypersensitivity to Beta-Lactams

Cross-reactivity between aztreonam and penicillins is poor, but clinical tolerance of aztreonam has been assessed, by means of tolerance challenge tests, only in a few groups of penicillin-allergic patients. The aim of this study is to evaluate the tolerability of aztreonam in a large group of beta-lactam-allergic patients. We studied all patients (greater than 14 years of age), with a clinical history of immediate reactions to any beta-lactam and with positive immediate-type skin tests and/or positive specific IgE to any of the studied beta-lactam; they were studied by means of: skin prick and intradermal tests with penicilloyl polylysine, minor determinant mixture, semisynthetic penicillins, cephalosporins, aztreonam and imipenem; detection of specific IgE to penicillin G, penicillin V, ampicillin, amoxicillin, cefaclor and ceftriaxone. Patients with negative immediate-type skin tests with aztreonam then underwent a graded intramuscular challenge. Forty-five patients (mean age 46.1 +/- 15.2 years), 27 females and 18 males, had positive skin tests and/or specific IgE to at least one of the studied beta-lactams. The most involved drugs were amoxicillin (23 cases), ampicillin (9 cases), penicillin G (8 cases) and other beta-lactams in the remaining cases. The most frequent reactions were anaphylaxis (27 cases) and urticaria (15 cases). All patients had negative intradermal tests with aztreonam and all patients tolerated the intramuscular graded challenge. Our data confirm the lack of cross-reactivity between beta-lactams and aztreonam. Immediate-type skin tests with aztreonam represent a simple and rapid diagnostic tool to establish tolerability in beta-lactam-allergic patients who urgently need this drug.

Non‐immediate reactions to β‐lactams: diagnostic value of skin testing and drug provocation test

beta-Lactam (BL) antibiotics can induce non-immediate skin reactions, frequently manifested as exanthema or urticaria. The time between drug intake and the reaction appearance is generally 24-48 h. Because the mechanisms involved are not completely understood, diagnostic tests for these reactions have still to be fully validated. To evaluate the role of skin and drug provocation tests (DPTs) in the diagnosis of patients with non-immediate reactions to BL. We evaluated a group of 22 patients who developed maculopapular exanthema or urticarial exanthema after BL intake. Diagnosis was confirmed by DPT with BL. Intradermal/patch testing was performed with benzylpenicilloyl, minor determinant mixture, amoxicillin (AX), ampicillin (AMP) and the culprit drug in patients and in 22 negative controls. Immunohistochemical studies were done in the affected skin at the acute phase of the reaction and after a delayed positive skin test/DPT. IFN-gamma and IL-4 were quantified in peripheral mononuclear cells, obtained during the positive response to DPT and after resolution of the symptoms. From the total number of cases, 12 patients developed urticarial exanthema and 10 maculopapular exanthema after DPT. Only two of the 22 patients (9%) had a positive delayed intradermal skin test: one to AX/AMP and the other to cloxacillin. Biopsies showed a mononuclear CD4, CD8 infiltrate and activated and memory cells. The cytokine expression showed a Th1 pattern in patients, in contrast with the Th0 pattern in controls. In patients with non-immediate reactions to BLs (maculopapular exathema or urticarial exanthema), the sensitivity of skin testing is low and DPT may be required to establish the diagnosis. The reproducibility of the reactions and the cytokine pattern expressed during the acute episode support a T cell-induced non-immediate response.

A comparison of the performance of two penicillin reagent kits in the diagnosis ofβ‐lactam hypersensitivity

Skin testing with penicilloyl polylysine (PPL) and minor determinant mixture (MDM) represents the first-line method for diagnosing beta-lactam hypersensitivity. However, in 2004, Allergopharma and Hollister-Stier announced their decision to stop the production of penicillin reagents (Allergopen and PrePen, respectively) within 1 year. Therefore, we decided to compare PPL and MDM from Allergopharma (Allergopen) with those from Diater (DAP). We skin-tested 195 subjects with both Allergopen and DAP reagents, as well as with other beta-lactams; 74 (group A) had had immediate reactions to beta-lactams and 74 (group B) nonimmediate reactions, while 47 (group C) underwent prophylactic tests. One hundred two patients (52.3%) had positive skin tests; 29 (14.9%) were positive to PPL and/or MDM. Of the 102 skin-test-positive patients, 44 belonged to group A, 57 to B and 1 to C; the last was positive only to Allergopen PPL (PPL-A) and tolerated the benzylpenicillin challenge. Minor determinant mixture reagents produced identical results in the 148 patients of groups A and B, 22 (14.9%) of which were positive. Both PPL reagents produced negative results in 139 of these 148 patients and positive ones in 5; one subject was positive to DAP PPL (PPL-D) and negative to PPL-A, while three patients were positive to PPL-A and negative to PPL-D; two of the latter tolerated benzylpenicillin challenges. Minor determinant mixture reagents produced identical results in all 195 patients. Results of skin testing with PPL reagents were concordant in 190 (97.4%) of them. Therefore, DAP reagents are a reliable alternative to Allergopen ones.