Curr Allergy Asthma Rep (2014) 14:459 DOI 10.1007/s11882-014-0459-z

ANAPHYLAXIS AND DRUG ALLERGY (DA KHAN AND M CASTELLS, SECTION EDITORS)

Evaluation of Antibiotic Allergy: the Role of Skin Tests and Drug Challenges Roland Solensky & David A. Khan

Published online: 21 August 2014 # Springer Science+Business Media New York 2014

Abstract Antibiotic allergies are frequently reported in both adult and pediatric populations. While a detailed drug history is essential in the evaluation of antibiotic allergy, the history is typically insufficient to determine the presence of a drug allergy. The most readily available diagnostic testing for evaluating antibiotic allergies are drug skin testing and drug challenges. This review will focus on updates in the evaluation of antibiotic allergy utilizing immediate skin tests, delayed intradermal testing, drug patch tests, and drug challenges for both adults and children with histories of antibiotic allergies.

on an elective basis, when patients are not in immediate need of treatment, because validated testing is available. The vast majority of patients with a history of penicillin allergy are found to not be allergic, and this has been shown to decrease utilization of broad-spectrum antibiotics and decrease costs [2–4]. For allergies to non-penicillin antibiotics, evaluation is typically pursued if treatment is anticipated or when patients report multiple antibiotic allergies and are running out of treatment choices. This review will address recent advances in the evaluation of antibiotic allergies via skin testing and drug challenges.

Keywords Antibiotic allergy . Penicillin allergy . Drug challenge . Drug patch tests . Drug skin tests . Pediatric Classification Introduction Clinicians commonly encounter patients who report allergies to antibiotics. A recent review of a large electronic medical record database revealed that 9 % of patients had a listed allergy to penicillins, 5.4 % to sulfonamide antibiotics, 1.3 % to macrolides, 1.3 % to cephalosporins, 0.9 % to tetracyclines, and 0.6 % to quinolones [1]. Formal evaluation of allergy to antibiotics may be warranted, depending on the implicated antibiotic and the type of reaction that occurred. Diagnostic testing for penicillin allergy is commonly pursued This article is part of the Topical Collection on Anaphylaxis and Drug Allergy R. Solensky The Corvallis Clinic, Corvallis, OR, USA D. A. Khan (*) Division of Allergy and Immunology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8859, USA e-mail: [email protected]

Adverse drug reactions (ADRs) are broadly classified into type A (predictable) reactions and type B (unpredictable) reactions [5]. Type A reactions are usually dose dependent, related to the pharmacologic action of the drug, and occur in otherwise normal individuals. Examples of type A reactions include drug overdose, side effects, and drug–drug interactions. In contrast, unpredictable reactions are usually dose independent (or less dose dependent) and not related to the pharmacologic actions of the drug, and they occur only in susceptible individuals. Examples of type B reactions include aspirin-induced tinnitus while on conventional dosages (intolerance), hemolytic anemia resulting from dapsone given to G6PD-deficient individuals (idiosyncratic reaction), and penicillin-induced anaphylaxis (allergic reaction). Allergic reactions differ from other type B reactions in that they are (or assumed to be) mediated by an immunologic mechanism. Gell and Coombs is the most commonly used classification scheme for allergic drug reactions [6]. In this system, there are four types of hypersensitivity reactions: immediate reactions mediated by antigen-specific IgE antibodies leading to mast cell/basophil activation (type I),

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antibody (IgG or IgM) cytotoxic mediated reactions against a cell surface (type II), immune complex deposition reactions (type III), and delayed T cell-mediated reactions (type IV). Type IV can be further divided into four subtypes according to the predominant effector cells: macrophages (type IVa), eosinophils (type IVb), T cells (type IVc), and neutrophils (type IVd) [7].

History The evaluation of antibiotic allergy must begin with a complete history. The decision to pursue diagnostic testing and/or consider readministration of the antibiotic is largely based on the reaction history. If possible, the original medical record describing the reaction should be obtained and reviewed. The following are the most important components of an antibiotic allergy history: name of the antibiotic; time elapsed since the reaction; reaction characteristics; timing of reaction in relation to drug exposure; indication for antibiotic, concurrent medications, and therapeutic management of the reaction; treatment with same or similar antibiotic since the reaction; similar symptoms in the absence of antibiotic treatment; and presence of an underlying condition that favors reactions to certain antibiotics.

Immediate-Type Skin Testing Immediate-type skin testing detects the presence or absence of drug-specific IgE antibodies. Therefore, only patients whose reaction histories are compatible with possibly being IgE mediated are candidates for this type of skin testing, such as pruritic rashes, urticaria, angioedema, or anaphylaxis. Patients with clearly non-IgE-mediated reactions (such as Stevens–Johnson syndrome, interstitial nephritis, vasculitis, etc.) should not undergo skin testing. For penicillins, validated testing allows evaluation to be performed electively, in advance of need, and this has been shown to decrease utilization of broad-spectrum antibiotics and decrease costs [2–4]. For allergies to non-penicillin antibiotics, evaluation is typically pursued if treatment is anticipated or when patients report multiple antibiotic allergies and are running out of treatment choices. Prick–puncture skin testing should be performed first, along with positive and negative controls. If prick–puncture tests are negative, they are followed by intradermal skin testing. Skin test results are recorded 15 min after placement on the skin. An increase in the wheal of 3 mm or more, compared with the negative control, is considered positive [8]. Antibiotic skin testing should only be performed by trained personnel, in a controlled setting, with preparedness to treat potential reactions such as anaphylaxis. When

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performed in standard fashion (prick–puncture before intradermal testing), the safety of antibiotic skin testing (primarily based on penicillin testing) is comparable to testing with venoms, foods, or aeroallergens.

Penicillins Penicillin spontaneously degrades to reactive intermediates that act as haptens and covalently bind to self-proteins, which may elicit an immune response—such as production of specific IgE antibodies. The most important intermediates to induce allergenic responses are penicilloyl (called the major antigenic determinant because about 95 % of penicillin degrades to this), penicilloate, and penilloate. The latter two compounds, along with penicillin itself, are collectively known as the minor antigenic determinants. The R-group side chains (which distinguish different penicillins) can also serve as allergenic determinants. Since 2009, after several years of being off the market, the major penicillin determinant is commercially available in the USA as penicilloyl–polylysine (PPL, Pre-Pen). Of the minor determinants, only penicillin G is available, while some medical centers synthesize penicilloate for local use. Ampicillin diluted from an IV formulation can be used for skin testing, but IV amoxicillin is not available in the USA. There are ongoing efforts to obtain FDA approval for a complete penicillin skin testing kit containing all the determinants. The rate of positive penicillin skin tests is declining. Macy et al. found that the penicillin skin test-positive rate at Kaiser San Diego declined from 15.4 % in 1995 to 3.4 % in 2007 (average change per year p=0.0032) [9]. Jost et al. reported an even more precipitous decline in positive penicillin skin tests in children referred to an outpatient academic allergy clinic [10]. From 1980 to 1993, the positive skin test rate was 27.7 %, compared to only 0.4 % during 1994–2003. The reasons for this observation are not clear but may have to do with decreased use of parenteral penicillin in favor of oral aminopenicillins. The use of only Pre-Pen and penicillin G for skin testing is a common practice among allergists, due to commercial unavailability of the other minor determinants (penicilloate and penilloate). In contrast, most large-scale published penicillin skin test studies used the full set of major and minor determinants [11, 12]. Recently, Macy et al. evaluated 500 patients with a history of penicillin allergy with skin testing using only Pre-Pen and penicillin G and oral amoxicillin challenges (in skin test-negative patients) [13•]. Overall, only eight patients (1.6 %) were found to be allergic, four via positive skin tests and four via positive amoxicillin challenges. The observed reactions were mild and easily treated with antihistamines. The calculated negative predictive value (NPV) of penicillin skin testing was 99 % (492/496). The NPV depends on the

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prevalence, and since the prevalence of penicillin allergy in this population was low, this limits the generalization of the results. The initial description of penicilloate by Levine and Zolov reported several patients who were skin test positive to only penicilloate (negative to penicilloyl and penicillin G) yet reacted on challenge with penicillin [14]. It is not clear what the prevalence of such patients is, because it is considered unethical to challenge skin test-positive patients. Large-scale studies (including previous ones from Macy and colleagues) have shown that about 10 % of patients with positive penicillin skin tests are positive only to penicilloate and/ or penilloate [10, 15, 16]. However, the positive predictive value (PPV) of an isolated positive penicilloate/ penilloate skin test is unknown. The NPVof penicillin skin testing is 95 % or greater. This is true when skin testing with only Pre-Pen and penicillin G [2, 13•] or with Pre-Pen and the full panel of minor determinants (penicillin G, penicilloate, and penilloate) [11, 12]. However, it is not appropriate to directly compare the NPV of these studies, due to differences in patient populations. The studies are descriptive and took place in real-life clinical setting; hence, the investigators were not obligated to evaluate all comers with penicillin allergy. In other words, the subjects were not consecutively encountered patients with a history of penicillin allergy. Instead, subjects were chosen for skin testing and challenge at the authors’ discretion. Therefore, investigators with access to only Pre-Pen and penicillin G may

hesitate to skin test patients with a history of severe anaphylaxis. A selection bias of excluding persons with more severe or recent reaction histories may overlook patients who may have reacted to only penicilloate/penilloate. The consequence of these potential biases is a higher NPV than would otherwise be observed. The role of skin testing with amoxicillin and ampicillin is not well defined. Inclusion of native aminopenicillins for skin testing is intended to detect IgE directed at the R-group side chain rather than the core portion of penicillins (major and minor determinants). Therefore, patients selectively allergic to amoxicillin, for example, tolerate penicillin and are skin test negative to Pre-Pen, penicillin G, penicilloate, and penilloate. In North America, very few patients are skin test positive to only aminopenicillins [15–18], compared to Southern Europe, where up to 50 % are positive to only amoxicillin [19–22] (Table 1). The reason for these differences is unknown. Additionally, the ideal concentration of aminopenicillins for skin testing is unclear and controversial.

Macrolides The relevant allergic determinants of macrolide antibiotics are not known; therefore, skin testing is limited to using nonirritating concentrations of native IV antibiotics. Empedrad et al. studied 25 non-allergic control subjects to determine the highest intradermal non-irritating concentration of 15

Table 1 Differences in selective aminopenicillin allergy between U.S. and Europe Reference

Number of penicillin history-positive patients

Number of skin test-positive patients

Number of skin tests positive to only amoxicillin/ ampicillin

Percentage of patients positive to only amoxicillin/ ampicillin

1,429

161

5

Mendelson LM (personal communication) Park et al. [16]

5,006

257

7

1,759

64

2

Lin et al. [17]

1,068

243

14

5/161=3.1a 5/1,429=0.35b 7/257=2.7a 7/5,006=0.14b 2/64=3.1a 2/1,759=0.11b 14/243=5.8a 14/1,068=1.3b

?

203

92

88

44

Matheu et al. [20]

824 (includes cephalosporin reactors) ?

69

17

Romano et al. [21]

?

300

113

USA Macy and colleagues [18, 15]

Europe Torres et al. [22] Bousquet et al. [19]

a

ST-positive patients

b

All patients

92/203=45a N/Ab 44/88=50a 44/824=5.3b 17/69=25a N/Ab 113/300=38a N/Ab

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commonly used antibiotics [23]. They found erythromycin and azithromycin to be non-irritating at 0.05 mg/ml (1:1,000 dilution of the commercially available 50-mg/ml IV formulation) and 0.01 mg/ml (1:10,000 dilution of the commercially available 100-mg/ml IV formulation), respectively. In a separate study, the highest non-irritating concentration of clarithromycin in 18 control subjects was 0.05 mg/ml (1:1,000 dilution of the 50-mg/ml formulation—which is not commercially available in the USA) [24•]. The usefulness of macrolide skin testing was assessed in two recent publications. Mori et al. studied 73 consecutive children with history of allergic reactions to clarithromycin (62 % urticaria, 18 % angioedema, 19 % maculopapular rash) [24•]. All the children were skin tested (prick–puncture and intradermal) using 0.05 mg/ml IV clarithromycin, which was found to be non-irritating in 18 control subjects. Sixty four out the 73 patients underwent blinded 5-day challenges, regardless of the skin test results (9 patients refused). Overall, 9/64 (14 %) of the challenged patients had positive intradermal skin tests. Four patients reacted on challenge; two were immediate (urticaria) and two were delayed (days 3 and 4) reactions (maculopapular rashes). Additionally, 3/9 skin test positive patients and 1/55 skin test negative patients reacted on challenge. Thus, the skin testing had a PPVof 33 %, NPVof 98 %, sensitivity of 75 %, and specificity of 90 %. Seitz et al. studied 53 consecutive patients with history of immediate allergic reactions (defined as less than 1 h) to macrolides (79 % urticaria/angioedema, 21 % anaphylaxis) [25]. All patients underwent prick and intradermal skin testing with the culprit macrolide (such as erythromycin, azithromycin, or clarithromycin) using a 0.01-mg/ml concentration. Of these, 47/53 patients underwent graded challenges, regardless of the skin test results, with the same macrolide that caused the previous reaction (3 subjects refused and in 3 challenge was contraindicated due to underlying malignancy or cardiovascular disease.) None of the 53 patients had a positive skin test, and none of the 47 challenged patients experienced a reaction. Two other studies evaluating smaller groups of patients with history of macrolide allergy showed similar results [26, 27]. Taken together, it appears that skin testing with nonirritating concentrations of macrolide antibiotics may be useful and should be considered in the evaluation of macrolide allergy. Skin test-positive patients are much more likely to react on challenge than skin test-negative patients. Therefore, skin testing may be used as one factor to distinguish patients who are candidates for graded challenge with macrolides. Interestingly, despite the convincing history of macrolide allergy, the cumulative reaction rate on challenge in these four studies [24•, 25–27] was only 5 %, and most reactions were mild. This suggests that macrolide allergy, like penicillin allergy, may wane over time and may be outgrown.

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Quinolones Skin testing with quinolones is complicated by the fact that these drugs may cause non-IgE-mediated mast cell degranulation, in addition to IgE-mediated (truly allergic) reactions. The symptoms of both reactions are identical, but unlike IgEmediated allergic reactions, non-IgE-mediated reactions may occur with first exposure, since prior sensitization is not necessary. Consequently, quinolone skin testing is prone to causing non-specific histamine release, and finding a non-irritating concentration can be difficult, particularly for ciprofloxacin. In the aforementioned study by Empedrad et al. (25 nonallergic control subjects underwent skin testing with antibiotics to find the highest non-irritating concentration), at least one patient had a positive intradermal skin test with even a 10 million-fold dilution of IV ciprofloxacin [23]. In another analogous study, a concentration of 0.067 mg/ml was found to be non-irritating, although only 16 control subjects were tested, and evaluation of more patients may have revealed irritant reactions [28]. Levofloxacin was reported by Empedrad et al. to be non-irritating at 0.025 mg/ml (1:1,000 dilution of the commercially available 25-mg/ml IV formulation). There are no similar studies on moxifloxacin, but one of the authors (RS) has found 0.016 mg/ml (1:100 dilution of the commercially available 1.6-mg/ml IV formulation) to be non-irritating. Information regarding the utility of quinolone skin testing in patients with a history of allergy to these antibiotics is very limited. The largest study included 64 consecutive patients with a recent (less than 1 year) history of immediate allergic reactions (defined as less than 1 h) to quinolones (53 % urticaria/angioedema, 47 % anaphylaxis) [29]. All 64 patients underwent prick–puncture skin testing using concentrations higher than those listed above (levofloxacin 5 mg/ml, moxifloxacin 1.6 mg/ml, ciprofloxacin 2 mg/ml), and these were found to be non-irritating in control subjects. Intradermal skin testing was not performed since the investigators were unable to identify non-irritating concentrations for some of the drugs. All but 13 patients were challenged, irrespective of their skin test results (6 patients refused and in 7, challenge was felt to be contraindicated.) Overall, 12/64 patients were skin test positive. Among the 52 skin test-negative patients, 45 underwent graded challenge with the same quinolone that caused the previous reaction and 3 reacted. Of the 12 skin test-positive patients, 6 underwent graded challenge and 3 reacted. The observed reactions were mostly urticarial and none required treatment with epinephrine. Hence, skin testing yielded a PPVof 50 %, NPVof 93 %, sensitivity of 50 %, and specificity of 93 %. Delayed Intradermal Drug Tests (DIDT) DIDT with readings of 24 h or more after injection is a useful tool in some cases of non-immediate drug reactions. While the

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exact technique varies among centers, an injection of 0.02– 0.05 ml of the drug to cause a 3-mm wheal is typical [30]. For antibiotic testing, reading the DIDT is typically done at 24–48 h, with a positive test showing an infiltrated and erythematous reaction. Non-irritating concentrations of drugs available in parenteral forms are similar for immediate and delayed IDT. Romano et al. evaluated the utility of DIDT and patch tests in 259 patients with non-immediate hypersensitivity reactions to penicillins (over 90 % were aminopenicillins) [31]. Ninety-four (36 %) were positive on either patch or DIDT tests. Three of 125 (2.4 %) skin test-negative subjects had positive challenges, while 2 of 5 (40 %) patch testnegative but DIDT-positive subjects had reactions to oral penicillin challenges suggesting a reasonable NPV of DIDT and a modest PPV. More recently, Romano et al. has reported the largest study on non-immediate reactions (maculopapular or urticarial) to cephalosporins involving 105 subjects [32]. DIDT were read at 48–72 h and were considered positive with the presence of infiltrated erythema ≥5 mm. Drug patch tests were also performed. If skin tests were negative, oral challenge with the cephalosporin was performed. Three subjects were positive with both patch and DIDT, while two additional subjects were positive only with DIDT. Eight-six subjects with negative tests underwent drug challenges and all tolerated them. None of the subjects with positive skin tests were challenged to determine if these were false positives. This study suggests a good negative predictive value for DIDT for delayed mild cutaneous cephalosporin reactions. However, given the low rate of positive DIDT (5 %), the added value of doing a DIDT versus going straight to a drug challenge is unclear. A study by Padial et al. seems to confirm this [33]. They evaluated 146 patients with histories of non-immediate reactions to beta-lactams in the last 4 years and performed drug challenges and identified 22 patients who were positive on drug challenge (16 aminopenicillins, 1 cloxacillin, and 5 cephalosporins) and performed DIDT and patch tests and found only 2/22 subjects (9 %) with positive tests on both DIDT and patch testing. Given the overall poor sensitivity of DIDT for mild, non-immediate beta-lactam allergy, its value as a useful diagnostic tool seems low. Drug Patch Tests (DPTs) DPTs are another diagnostic tool in the evaluation of delayed drug reactions. In the USA, there are no commercial preparations for antimicrobial DPT available, and even in other countries, commercialized products are very limited. There is considerable variability in the performance of DPT with the European Society of Contact Dermatitis recommending testing of the commercial product diluted at 30 % (petrolatum or aqueous) [34], whereas the European Network on Drug Allergy/European Academy of Allergy and Clinical Immunology recommends patch testing concentrations between 5

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and 30 % with 5 % recommended for penicillins and cephalosporins [35]. Patients with severe cutaneous adverse reactions (SCAR) are usually tested initially with lower concentrations. DPT are read and interpreted similarly to other patch tests, initially at 48 h then 96 h, and if negative, 1 week later has been recommended. DPT in non-IgE-mediated drug allergy has recently been reviewed [36]. The largest reported experience with DPT is from Finland by Lammintausta et al. [37]. They performed a retrospective review over a 12-year period of 947 patients evaluated with immediate skin tests of which 826 patients underwent DPT with concentrations primarily of 20–30 % in petrolatum or saline. The interval between DPTs and their reaction was not reported. Antimicrobials accounted for 80 % of DPTs. Only 89/826 (10.8 %) of patients had a positive DPT. Most (81/89) had histories of exanthems and eight had fixed drug eruptions and were tested at the reaction site. Positive reactions differed by antimicrobial with the highest being ceftriaxone in 4/10 (40 %), clindamycin in 12/63 (19 %), and cefuroxime in 4/29 (13.8 %). Amoxicillin, penicillin, and cephalosporins were positive in between 3.0 and 4.1 % of patients. Trimethoprim was positive in 10/163 (6.2 %) and sulfamethoxazole in only 1/215 (0.4 %). Macrolides, quinolones, and tetracyclines were tested in 130, 32, and 108 patients, respectively, with no positive DPT seen. Drug challenges were performed in 246 patients and revealed fairly good concordance with 14/17 (82.3 %) positive challenges in those with positive skin tests (13/14 were DPT+) and negative challenges in 207/229 (90.4 %) with negative skin tests. DPTs also vary in their usefulness based on the type of drug reaction. DPTs were positive in 94/173 maculopapular reactions to penicillins; however, DIDT detected an additional eight patients, suggesting that it has higher sensitivity [31]. As previously mentioned, in the study by Padial, only 2/22 patients with challenge-positive drug exanthems exhibited positive DPTs to beta-lactams. DPT has also been utilized for symmetric drug-related intertriginous and flexural exanthema (drugrelated baboon syndrome), which can be caused by antibiotics (especially amoxicillin) with variable results [38]. DPT for fixed drug eruptions due to antibiotics has yielded variable results. Most studies indicate that DPT at the residual hyperpigmented site of a fixed drug eruption (e.g., in situ DPT) will yield more positive reactions [36]. Andrade et al. found 0/15 positive patch tests for antibiotics when using lesional DPT but was positive in 40 % tested to nonsteroidal antiinflammatory drugs [39]. A 3-year multicenter French study noted 13/59 cases of fixed drug eruptions due to antibiotics, of which 3/6 had positive patch tests [40]. A meticulous study by Ozkaya-Bayazit et al. evaluated 27 patients with fixed drug eruptions proven by oral challenge with cotrimoxazole [41]. Patients with non-genital lesions underwent tape stripping followed by patch testing with sulfamethoxazole and trimethoprim in 10, 20, and 50 %

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concentrations in petrolatum. All of these occluded patch tests in petrolatum were negative. However, repeated open topical testing (single for genitalia) with sulfamethoxazole and trimethoprim in dimethyl sulfoxide yielded positive results with erythema and itching in 25/27 cases with negative tests in 20 controls. Therefore, DPT for antibiotics in fixed drug eruptions is variable, and in some cases such as cotrimoxazole, repeated open application with vehicles other than petrolatum may yield better results. The reaction types that DPT may offer the most promise for are SCAR. Recent literature suggests that DPT can be helpful in identifying culprit drugs in acute generalized exanthematous pustulosis (AGEP), Stevens–Johnson syndrome (SJS)/ toxic epidermal necrolysis (TEN) as well as drug rash with eosinophilia and systemic symptoms (DRESS). The largest experience of DPT in SCAR has recently been published by a multicenter study of the French Society of Dermatology [42••]. A total of 134 patients were evaluated, and DPT positivity varied by the type of reaction with 64 % (46/72) for DRESS, 58 % (26/45) for AGEP, and 24 % (4/17) for SJS/ TEN. Of the 46 positive DPT for DRESS, 18 were with antibiotics; of the 26 positive DPT for AGEP, 17 were with antibiotics; and of the 4 positive DPT for SJS/TEN, only 1 was with antibiotics. DPT in SCAR were well tolerated with only 1/76 positive DPT leading to a systemic reaction, a relapse of AGEP requiring corticosteroids. Thus, DPT appears to be safe and may be helpful in both DRESS and AGEP but is infrequently positive in SJS/TEN. Given the limited diagnostic tools for SCAR, DPT may be the best currently available diagnostic tool. Drug Challenges Drug challenges are the gold-standard for determining tolerance to a drug with very good but not 100 % negative predictive value. These diagnostic procedures can be used for histories of immediate and delayed drug reactions. Multiple terms have been used to describe these procedures including test dose, graded challenge, and drug provocation. The term drug challenge is the most accurate as it encompasses multiple- or single-dose challenges and is preferable to drug provocation as the typical purpose of this test is to prove tolerance, not to provoke a drug reaction. The European Network for Drug Allergy (ENDA) has published guidelines for drug provocation more than 10 years ago [43]. Several articles have been published recently updating this information. The duration of drug challenge remains controversial with some groups using single therapeutic dose challenges and others extending the challenge for several days. Hjortlund et al. evaluated 405 adults with beta-lactam allergy (72 % from penicillin) with penicillin-specific IgE and skin testing followed by a graded intravenous challenge, then a single oral

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challenge, followed by 7 days of penicillin therapy at home [44]. Of the 340 patients who underwent challenge, 20 (6 %) reacted with immediate reactions to the oral (n=15) or intravenous (n=5) doses while another 13 (3.8 %) had delayed reactions with the 7 days at home course. Reactions were most commonly urticaria and angioedema with no severe reactions reported. Given the low rate of delayed reactions and nonsevere nature of these reactions, the value of this extended duration challenge seems limited. A multicenter, multinational European study has evaluated the negative predictive value of drug challenges [45]. There were 118 patients who reported that they had taken the same drug that they had been tested negative for, and 9 reported cutaneous reactions (urticaria or exanthems). Five patients refused repeat evaluation while four accepted with two out of four reacting on observed challenge and two tolerating the drug. Based on this data, the negative predictive value for tolerating a therapeutic course of a drug following negative drug challenge was 94.1 %, with none of the reactors having serious reactions. Drug Challenges in Adults Safety of drug challenges is of great concern to patients and allergists and many drug reactions are contraindicated [43]. One of the largest studies of drug provocations in 898 patients reported by Messaad et al. noted a reaction rate of 17.6 %, some of which were anaphylactic [46]. In this study, patients were included with histories suggestive of drug hypersensitivity. This is in contrast to the approach recommended by the Drug Allergy Practice Parameter, which recommends drug challenges for patients with low likelihoods of reactions [8]. A recent report by Kao et al. from a single US university utilizing this approach noted a reaction rate of 10 drug allergies, and historical drug reactions with subjective symptoms. Ramam et al. noted that 13/23 (56.5 %) patients with histories of multiple drug allergies who were afraid to take additional medications developed symptoms or signs judged not to be true reactions [48]. Placebo-controlled challenges should be strongly considered in patients who have risk factors for subjective symptoms. Drug Challenges in Children Several recent studies have evaluated the role of drug challenges in children with histories of antibiotic allergy. Caubet et al. prospectively enrolled 88 children who presented to emergency departments with urticarial or maculopapular eruptions during or up to 72 h after beta-lactam antibiotics [49]. Their evaluation included skin testing to penicillin and

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cephalosporins, drug patch tests, drug challenges, throat swab for respiratory viruses by PCR, and acute and convalescent sera for viral serologies. Drug challenges were performed an average of 10.8 weeks after the reaction with 150 % of therapeutic dose of the culprit beta-lactam for skin testnegative subjects (77/88) and at 50 % followed by the remaining 50 % dose 30 min later in subjects with positive reactions (11/88) to beta-lactam skin tests. Only six children had positive drug challenges (four urticarial and two maculopapular exanthems); one was within 30 min and the rest were delayed reactions. Four of these six children had positive skin tests. Positive viral PCR occurred in 56 % of the challenge-negative subjects and 33 % of the challenge-positive subjects. The authors concluded that a physician-supervised oral challenge with a beta-lactam is a safe and efficient diagnostic test in children with benign skin rashes and that skin testing is not helpful in these cases. This study helps confirm the role of viral exanthems in mimicking drug reactions in children. Whether preliminary penicillin skin testing can be abandoned in the evaluation of such patients requires further study. Ponvert et al. have reported on the largest experience with evaluation of beta-lactam allergy in 1,431 children from France [50•]. Similar to other reports, beta-lactam allergy was confirmed by skin testing or challenge in only 15.9 % of cases. An interesting finding was that 12/23 patients with serum sickness-like reactions, 17/21 with erythema multiforme, and 2/6 with Stevens–Johnson syndrome tolerated a complete course of the suspected beta-lactam. Of the 130 positive drug challenges, 42 occurred with a hospital challenge and 88 occurred with a home challenge. All reactions were reported as “mild to moderately severe” including two cases of severe serum sickness-like reactions. This study suggests that even children with more severe reactions may be considered for drug challenges; however, extreme caution should be exercised in such patients due to the potential high risk for recurrence of severe reactions. Another large study from Spain has recently been reported by Zambonino et al. involving 783 children evaluated for beta-lactam allergy using in vitro-specific IgE tests, skin tests, and challenge [51]. Betalactam allergy was confirmed in only 7.9 %; however, drug challenges were the most commonly positive test among both immediate and non-immediate reactions accounting for 56 and 96 % of positive tests, respectively. Reactions to drug challenge were predominantly exanthems or urticaria and judged to be usually mild. These two large pediatric studies confirm the overall safety of drug challenges in children. Kamboj et al. reported their experience from a university in the USA in evaluating 96 children with reactions to antibiotics including antibiotic skin testing and, if negative, challenges to penicillins (n = 60), cephalosporins (n = 7), azithromycin (n=24), and clindamycin (n=5) [52]. Similar to other studies, 90.6 % of children had either negative skin tests and passed their challenges. Of the four reactions on drug challenge, all

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were considered mild. Of interest, all of the 24 children evaluated for azithromycin allergy tolerated drug challenge. Overall, these studies indicate that similar to adults, most children with histories of antibiotic allergy tolerate the culprit drug and reactions with drug challenges are usually mild. Summary Several recent studies have advanced our understanding and approach to patients with antibiotic hypersensitivity reactions. The NPV for penicillin skin tests without minor determinants is high, particularly for those with non-anaphylactic reactions. Macrolide skin testing can be considered an additional diagnostic tool; however, the role of quinolone skin testing remains unclear. Drug patch tests for SCAR hold promise as a practical tool to identify culprit drugs. Finally, the safety of drug challenges in appropriately selected adults and children is reassuring. While diagnostic testing in drug allergy is still limited, the available tools are adequate to manage the vast majority of patients with antibiotic hypersensitivity.

Compliance with Ethics Guidelines Conflict of Interest Roland Solensky declares that he does consulting for Optimer Pharmaceuticals and that he and his institution have received grant money from Allerquest and Merck. David A. Khan declares no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the authors.

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