C. Juarez

Natural evolution of skin test sensitivity in patients allergic to β-lactam antibiotics

BACKGROUND Subjects with immediate reactions to penicillins and positive skin test responses may lose sensitivity if penicillin is avoided. The longer the interval between the reaction and the skin test, the greater the likelihood of having a negative result. OBJECTIVE We sought to study prospectively the evolution of skin test sensitivity in a group of subjects allergic to penicillin with positive skin test responses to different penicillin determinants. METHODS Skin tests were performed with major and minor determinants of benzylpenicillin (BPO/MDM), amoxicillin (AX), and ampicillin at the initial evaluation and repeated 1, 3, and 5 years later if the responses were still positive. Subjects were divided into 2 groups. Group A consisted of patients with a positive skin test response to benzylpenicilloyl or minor determinant mixture, and group B consisted of those with a selective response to amoxicillin and good tolerance to benzylpenicillin. RESULTS In group A (n = 31) after 1 year, 25 patients continued to have positive responses and 6 began to have negative responses; after 3 years, 18 continued to have positive responses, 5 began to have negative responses, and 2 were lost to follow-up; and after 5 years, 12 continued to have positive responses, 5 began to have negative responses, and 1 was lost to follow-up. In group B (n = 24) 12 had positive responses, and 12 had negative responses after 1 year; 6 had positive responses, 5 had negative responses, and 1 was lost to follow-up after 3 years; and no patients had positive responses, 5 had negative responses, and 1 was lost to follow-up after 5 years. Survival analysis showed significant differences between groups (log-rank test = 12.8; P <. 0003). CONCLUSION Patients with a selective response to amoxicillin tended to lose sensitivity faster than those who responded to several penicillin determinants, supporting the existence of at least 2 distinct types of IgE response in patients allergic to beta-lactam.

Diagnostic evaluation of a large group of patients with immediate allergy to penicillins: the role of skin testing

Background: Penicillin is no longer the most commonly prescribed β‐lactam, and the pattern of reactions has changed. We studied the diagnostic value of skin testing in penicillin‐allergic subjects from a population where benzylpenicillin is not now the most frequently used β‐lactam.

Allergy to penicillin with good tolerance to other penicillins; study of the incidence in subjects allergic to betalactams

Two hundred and eighty‐eight subjects with a history of allergy to penicillin were studied for objective proof of their allergy. On the basis of skin tests, specific IgE antibody measurements and direct challenge tests, 64 patients (22%) were shown objectively to be allergic to one or more penicillins. The following tests were carried out: skin tests to benzyl‐penicilloyl poly‐L‐lysine (BPO‐PLL), minor determinant mixture (MDM), amoxycillin (AX) and ampicillin (AMP), in‐vitro IgE antibody measurement to benzyl‐penicilloyl (BPO) and AX and challenge with benzylpenicillin (BP), phenoxymethyl‐penicillin (PV) and amoxycillin. Forty‐four cases were found to respond to benzyl or phenoxymethyl‐penicillin, however, 20 were shown to be sensitive to amoxycillin and unresponsive to tests with other penicillins. The contribution that any individual test gave for establishing the diagnosis was 21·8% for skin testing with BPO‐PLL, 9·3% with MDM and 12·5% with AX, Nine point three per cent were RAST positive to BPO and 1·5% to AX; 7·8% developed a positive response after challenge to BP, 7·8% to PV and 14% to AX. In 16% of the 64 positive cases more than one test was found to be positive. The challenge tests suggested that not all the penicillin‐sensitive subjects had IgE‐mediated reactions implying other immunological mechanisms. These results clearly demonstrate the importance of side chain‐specific diagnostic reagents and challenge tests. Thirty‐one per cent of the positive group or 6·9% of the total group would have been missed in this study using benzyl or phenoxymethyl‐penicillin diagnostic reagents alone.

Clinical evaluation of Pharmacia CAP System™ RAST FEIA amoxicilloyl and benzylpenicilloyl in patients with penicillin allergy

Background: The diagnosis of IgE‐mediated immediate reactions to penicillins can be supported by in vivo or in vitro tests using classical benzylpenicillin determinants. The wide variety of β‐lactams and the description of new specificities requires a re‐evaluation of the different tests available. The objective was to evaluate the diagnostic capacity of Pharmacia CAP System™ RAST FEIA amoxicilloyl c6 (AXO) and benzylpenicilloyl c1 (BPO) in patients with a documented IgE‐mediated penicillin allergy.

In vitro T‐cell responses to β‐lactam drugs in immediate and nonimmediate allergic reactions

Background:β‐Lactam drugs may induce both cellular and humoral allergic reactions, and there is evidence that T cells play an important role in the pathogenesis of these reactions. The aim of this work was to assess the sensitivity and specificity of the lymphocyte transformation test (LTT) as an in vitro diagnostic tool, in patients with either an immediate or a nonimmediate reaction to penicillin G and/or amoxicillin.

Cross-reactivity between a penicillin and a cephalosporin with the same side chain ☆ ☆☆ ★ ★★

BACKGROUND The cross-reactivity between penicillins and cephalosporins can be influenced by different factors, which are not all well known. The chemical structure of the side chain may contribute to the cross-reactivity. OBJECTIVE The study was carried out in allergic subjects who are selectively responsive to amoxicillin to determine allergenic cross-reactivity with a cephalosporin containing a side chain identical to that of amoxicillin, cefadroxil, and one containing a different side chain, cefamandole. METHODS Allergic subjects with a selective response to amoxicillin were chosen according to the following criteria: history of an immediate allergic reaction to amoxicillin, negative skin test responses to benzylpenicilloyl and minor determinant mixture of benzylpenicillin, negative RAST response to benzylpenicilloyl, and good tolerance to benzylpenicillin and phenoxymethyl penicillin challenges. In addition, subjects had to have a positive skin test response to amoxicillin and/or positive RAST response to amoxicilloyl or, if these test results were negative, a positive challenge test response to amoxicillin. In vivo cross-reactivity to cefadroxil was assessed by giving oral cefadroxil at increasing doses from 5 to 500 mg. In vitro cross-reactivity was determined by RAST inhibition studies with amoxicilloyl RAST disks and the following monomeric conjugates in the fluid phase: amoxicillin-butylamine, cefadroxil-butylamine, and the side chain para-hydroxy-phenylglycine. Tolerance to cefamandole was determined by giving 100 mg and then 500 mg parenterally. RESULTS Twenty-one patients with a selective response to amoxicillin were included in the study. Eight subjects (38%) had a positive response to cefadroxil, and none reacted to cefamandole. In vitro RAST inhibition studies indicated that cefadroxil-butylamine monomers cross-reacted with amoxicillin butylamine and the side chain contributed relevantly to the inhibition. CONCLUSIONS These results indicate that the percentage of cross-reactivity between penicillins and cephalosporins with an identical side chain is high and that this critical part of the molecule seems to be an important contributor to these results. The value is higher than previously reported data from similar studies of non-side-chain-related cephalosporins.

New aspects of allergic reactions to betalactams: crossreactions and unique specificities

Allergic reactions to betalactams, although not common, constitute the most frequent cause of adverse drug reactions induced by a specific itnniunological mechanism. Both cellular and humoral responses are involved in eliciting the reactions [1,2]. Although the incidence has decreased in recent years, perhaps as a result of improved manufacturing processes [3,4], some patients still suffer allergic reactions from these beneficial antibiotics [5-8]. These days the betalactam family consists of two major classes, penicillins and cephalosporins. and four minor, monobactams, carbapenems., oxacephems and clavams (Fig. 1). The major clavam, clavulanic acid, is included in this survey, although it is a betalactamase inhibitor and not an antibiotic. A list of different antibiotics belonging to these groups is presented in Table 1. Early studies with benzyl penicillin in man and animals [9 11] demonstrated that it was immunogenic and most of the antibody induced was directed against a structure formed by a reaction between the betalactam carbonyl and amino groups from lysines in proteins. This grouping, known as benzyl penicilloyl, was termed the major determinant accordingly. Initially it was believed that the side chain of the penicillin (Fig. 1, R group) played a minor role in the specificity of the antibody produced [11,12] and that the nuclear portion (common to all penicillins, see Fig. I, A and B rings) was the most important part of the determinant structure. This led to the assutnption that all penicillins would crossreact and patients allergic to one would react to all [13,14-16]. Whilst crossreaction between penicillins may be extensive for some patients the situation is much more complex because of the increased number of new betalactam antibiotics available and their frequency of use. So on the one hand there arc studies which show that crossreactivity can be extended across classes of betalaetam antibiotics, for example, penicillins with cephalosporins [17-20]. penicillins with carbapenems [21]. and cephalosporins with monobactams [22], whilst other studies highlight that some patients are

Anticonvulsant-induced toxic epidermal necrolysis: Monitoring the immunologic response

BACKGROUND Toxic epidermal necrolysis is a severe reaction with skin involvement induced by different drugs and other agents. The mechanisms implicated in the induction of the reaction are poorly understood. OBJECTIVE Our purpose was to study the involvement of T lymphocytes and other immunocompetent cells in the peripheral blood, blister fluid, and affected skin of 3 patients who had a severe reaction after receiving anticonvulsant medication. METHODS Quantification of T lymphocytes expressing the skin-homing receptor (cutaneous lymphocyte-associated antigen ¿CLA) in peripheral blood, skin, and skin blister fluid and assessment of other adhesion molecules, activation markers, and inflammatory interleukins by flow cytometry, immunohistochemistry, and reverse transcription-PCR. RESULTS An increase in CD3(+)CLA(+) cells paralleling the severity of the disease was observed in both peripheral blood and skin, tending to normalize as soon as patients conditions improved. E-selectin was detected in endothelial vessels in parallel with CLA expression on lymphocytes. An overexpression of TNFalpha, IFN-gamma, and IL-2 was also observed in PBMCs. The expression of the different markers changed over the course of the disease. CONCLUSIONS These data show an increase in activated T cells expressing the skin-homing receptor in both tissue and peripheral blood accompanying clinical symptoms, with a recruitment of macrophages and an overexpression of cytokines. All these results suggest an important role for T cells in the production of toxic epidermal necrolysis.

Controlled administration of penicillin to patients with a positive history but negative skin and specific serum IgE tests

Background Although subjects with a positive history of immediate allergy to penicillin and negative skin test are traditionally considered to tolerate penicillin, current evidence indicates that they may develop an immediate reaction despite negative skin and serum specific IgE tests. It is thought that these patients require additional tests to confirm the diagnosis.

Expression of the skin-homing receptor in peripheral blood lymphocytes from subjects with nonimmediate cutaneous allergic drug reactions

Background: In nonimmediate cutaneous reactions to drugs, the skin is the organ most frequently involved, and T cells may play a relevant role. T cells related to skin immune responses express the cutaneous lymphocyte‐associated antigen (CLA), the skin‐homing receptor.