The incidence and features of systemic reactions to skin prick tests.

BACKGROUND: Skin prick testing (SPT) has been regarded as a safe procedure with few systemic reactions. OBJECTIVE: To evaluate the rate of systemic reactions and their associations after SPT in the largest population to date. METHODS: In this study reactions were recorded prospectively in a specialist UK allergy clinic for 6 years (2007-2013). An estimated 31,000 patients underwent SPT. RESULTS: Twenty-four patients (age range 7 months to 56 years, mean 23.5 years, 17 female patients, 12 with asthma) had systemic reactions. The rate of systemic reactions to SPT was 0.077%. The likely allergens causing the reaction were foods (18; peanut, 7; walnut, 1; Brazil nut, 2; pistachio, 1; lupin, 1; cow's milk, 2; shrimp, 1; spinach, 1; legume, 1; soy, 1), aeroallergens (4; rabbit, 1; rat, 1; ragwort, 1; grass pollen, 1), wasp venom (1), and Tazocin (1). The causative SPT wheal was larger than 8 mm in 75%. The reaction to Tazocin was severe, with anaphylaxis occurring minutes after SPT. Reactions were treated immediately in the clinic and did not require further medical care. CONCLUSION: In this largest single-center study, the rate of systemic reactions after SPT was 77 per 100,000 patients. It is the first study to identify foods as a common and important cause (75%), with nuts posing the highest risk. This study reports the first systemic reaction to venom SPT and the first anaphylactic reaction after drug SPT. There was an association with a history of severe reactions and large skin test reaction. There are risks, albeit small, when undertaking SPT.

Serological studies of piperacillin antibodies.

BACKGROUND: Penicillin-induced immune hemolytic anemia (IHA) is associated with immunoglobulin G antipenicillin detected by testing penicillin-coated red blood cells (RBCs). Antibodies to piperacillin, a semisynthetic penicillin, would be expected to react similarly; however, antipiperacillin can be detected by testing in the presence of the drug. Piperacillin is commonly used in combination with tazobactam, which causes nonimmunologic protein adsorption onto RBCs. In six cases of piperacillin-induced IHA, reactivity with piperacillin-coated RBCs was not similar to reactivity of antipenicillin with penicillin-coated RBCs. STUDY DESIGN AND METHODS: Antipiperacillin was tested against piperacillin-coated RBCs prepared using different pH buffers. Plasma from blood donors and sera/plasma from patients were tested with piperacillin-coated, penicillin-coated, and uncoated RBCs. Hapten inhibition studies were performed using different concentrations of piperacillin. Donors' plasma were tested in the presence of piperacillin; sera from patients with IHA were tested in the presence of tazobactam. RESULTS: Piperacillin required high pH for binding to RBCs. Agglutination of piperacillin-coated RBCs was observed in 91 percent of donors' and 49 percent of patients' plasma and was inhibited by piperacillin. In contrast to patients with IHA due to piperacillin, donors' plasma tested in the presence of piperacillin did not react. Tazobactam antibodies were not detected. CONCLUSION: A high percentage of donors' and patients' plasma contain an antibody to piperacillin or a chemically related structure detected by testing with piperacillin-coated RBCs. A diagnosis of piperacillin-induced IHA should not be made solely on the reactivity of a patient's plasma/serum with piperacillin- or piperacillin/tazobactam-coated RBCs; testing in the presence of piperacillin is more reliable.

Cephalosporin induced toxic epidermal necrolysis and subsequent penicillin drug exanthem.

BACKGROUND: Drug hypersensitivity is classically divided into IgE mediated and non-IgE mediated disease. We report a rare case of consequent IgE mediated and non-IgE mediated reactions within the beta lactam class of antibiotics. CASE SUMMARY: An 84-year-old man developed toxic epidermal necrolysis (TEN) due to ceftriaxone, a third generation cephalosporin, involving 72% of the body surface area. The patient recovered but within weeks subsequently developed an acute IgE mediated allergic reaction to piperacillin/tazobactam, an extended spectrum penicillin. Further IgE RAST revealed positive results to penicillin major determinant. DISCUSSION: This case demonstrates the complexity of drug hypersensitivity reactions. While it is accepted that IgE mediated penicillin allergy is a predisposition to cephalosporin allergy, this case displays an unusual correlation between drug hypersensitivity and drug class. There have been few studies that evaluate the cross reactivity with penicillin or other beta-lactams in subjects with primary hypersensitivity to cephalosporins. This clinical scenario emphasizes the need of more studies on cephalosporin allergy in particular as shown by this case of sequential non-IgE mediated cephalosporin induced TEN reaction pursuant by an IgE mediated penicillin allergy.

"In vivo" and "in vitro" tests in the diagnosis of Beta-lactams allergy.

The results of "in vivo" and "in vitro" diagnostic tests in 114 patients reporting an allergic reaction to Beta-lactams are presented. Skin test gave an overall positivity of 85% and determination of specific IgE of 42%. Skin tests have a greater sensitivity but "in vitro" tests are an useful associated diagnostic method.

Female sex as a risk factor for penicillin allergy.

BACKGROUND: Identification of risk factors is an integral part of a physician's evaluation of a patient. OBJECTIVE: To determine whether female sex is an independent risk factor for penicillin allergy. METHODS: Rates of positive penicillin skin test (PST) results, according to sex, were determined in patients with a history of penicillin allergy undergoing penicillin allergy evaluation with major and minor determinants of penicillin between June 1, 2002, and June 30, 2004. Univariate and multivariate logistic regression analyses were used to calculate unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for sex differences in the rates of positive PST results. RESULTS: Of the 1,921 patients, 1,759 underwent PST and 157 did not; 5 medical records were not available for review. The mean patient age was 60 years. Sixty-four patients (4%) had a positive PST reaction; of these, 53 (83%) were females and 11 (17%) were males (OR, 3.6; 95% CI, 1.9-7.2; P < .001). In a multivariate logistic regression analysis adjusted for age, history of multiple drug allergies, and elapsed time from the initial penicillin adverse drug reaction to PST, female sex again had a significant risk of a positive PST reaction (OR, 3.2; 95% CI, 1.6-6.7; P = .001). CONCLUSION: A greater risk of penicillin allergy exists in association with female sex in patients with a history of penicillin allergy.

Flare up to betalactams.

BACKGROUND: The flare up phenomenon has most frequently been described with nickel. Not many cases of flare up to drugs have reported in the literature, however we have reported it with different medications. METHODS AND RESULTS: A 31-year-old woman developed an adverse reaction with an antibiotic during her childhood. Prick test with penicillin (100,000 IU/ml), penicilloyl polylysine (PPL), minor determinant mixture (MDM), amoxicillin (200 mg/ml), ampicillin (200 mg/ml) and cephalotin (200 mg/ml), and intradermal test to the same substances diluted in saline were all negative immediately. We performed an oral challenge test with 500 mg of amoxicillin. Twelve hours later, the intradermal test to PPL and MDM became positive (PPL 10 x 10 mm, MDM 8 x 7 mm). All patch tests were positive after 72 hours with erythema, vesicles and infiltration and the patient also had exanthema with pruritus on her entire body. CONCLUSIONS: We present one patient with delayed allergic reaction caused by amoxicillin and penicillin, that we all know as Flare up. We suggest that this phenomenon of Flare up occurs by a Type IV mechanism mediated by T-cells without participation of IgE antibodies. The betalactam hypersensitivity mechanism which has usually been described is an IgE mediated reaction, but there are other not very well known mechanisms that are responsible for the delayed reactions.

In vitro reactivity of penicilloyl and penicillanyl albumin and polylysine conjugates with IgE-antibody.

Penicilloylated (BPO) and penicillanylated (BPA) poly-L-lysine (PLL) and human serum albumin (HSA) were prepared and characterized by penamaldate assay and proton NMR spectroscopy. The conjugates were coupled to nitrocellulose (NC) discs and cyanogen bromide activated paper discs and their in vitro reactivities with serum IgE antibodies were examined. Results showed that on paper discs, 55.3 and 83% of the sera reacted with PLL conjugates of BPO and BPA, respectively, while 41.5 and 58.1% reacted with HSA conjugates. On NC discs, HSA conjugates gave better results, 75.6 and 70.7%, respectively for BPO and BPA, compared with 38.6 and 50%, respectively for the PLL conjugates. Overall, the BPA-PLL conjugate on paper discs proved to be the most reactive preparation. Addition of the BPO-PLL paper disc preparation detected more positive sera (85.1%) and we believe that the combined use of these two specificities offers the best test for the detection of penicillin-reactive IgE antibodies.

Induction and characterization of multianalyte antibodies against penicillins in egg yolk.

Antibodies against penicillins were induced in eggs of laying hens after immunization with 6-aminopenicillanic acid (6-APA) coupled to key-hole limpet hemocyanin (KLH). Development of the antibody titer was monitored by an indirect enzyme-linked immunosorbent assay (ELISA), with 6-APA coupled to ovalbumin as antigen for coating microtiter plates. Different characteristics (time course, affinity) of the immune reaction were observed by testing eggs of individual hens. Titer values varied between 150 and 2000. Antibodies were isolated by polyethylene glycol precipitation and affinity chromatography, using a hapten sorbent with 6-APA as ligand. Glycine buffer, pH 3.0, was used to elute the immunoglobulins. Antibody specificity was determined in a competitive ELISA with 7 penicillins and the cephalosporin cephalexin as competitors. Cross reactivities for the penicillins were between 100 and 290% (6-APA = 100%). Cephalexin cross reacted only marginally (3%).

[Antigenicity tests of tazobactam/piperacillin, tazobactam and piperacillin].

The antigenicity tests of Tazobactam/piperacillin (TAZ/PIPC), tazobactam (TAZ:beta-lactamase inhibitor) and piperacillin (PIPC:penicillin antibiotic) were performed in mice and guinea pigs. The following results were obtained. 1. TAZ/PIPC, TAZ or PIPC had no immunogenicity and allergenicity in either passive cutaneous anaphylaxis (PCA) test using BALB/c and C3H/He mice or in PCA test using guinea pigs. 2. Guinea pigs sensitized with TAZ/PIPC, TAZ or PIPC showed no anaphylactic symptoms in active systemic anaphylaxis (ASA) test. 3. Guinea pig PCA tests using protein conjugates as sensitizing and challenging antigens showed positive reactions. Immunological cross-reactivity tests were performed by using these conjugates in guinea pig PCA reaction. Results showed that TAZ/PIPC and PIPC cross-reacted with penicillin G (PCG) and ampicillin (ABPC), but not with cephalothin (CET) and cephmetazol (CMZ). TAZ did not cross-react with PCG, ABPC, CET or CMZ. 4. From the results of the passive hemagglutination (PHA) test, no antibody against TAZ/PIPC, TAZ or PIPC was detected. 5. In direct Coombs' test using human blood, TAZ/PIPC, TAZ, PCG and CET showed positive reactions at 20-80, 5-20, 80 and 10-20 mg/ml, respectively. 6. The results of a test on in vitro covalent binding activity with human serum albumin indicated that the order of binding potency was CET > CMZ > ABPC > PCG = PIPC > TAZ under the physiological condition (pH 7.2-7.4), and was CMZ > CET > ABPC > PIPC > TAZ > PCG under the alkaline condition (pH 10.0-10.5), respectively.

Intravenous desensitization to beta-lactam antibiotics.

Patients allergic to penicillin (PCN) often require treatment with beta-lactam antibiotics for life-threatening bacterial infections. In this article, we review our experience with rapid intravenous desensitization for patients who gave a history of PCN allergy and who had hypersensitivity demonstrated by skin tests. Skin testing was performed with both prick and intradermal techniques and with the recommended antibiotic as well as PCN G, penicilloyl polylysine, and a minor determinant mixture. Patients were transferred to the intensive care unit, and desensitization was performed with a buret technique that required minimal preparation and was easily applied to any antibiotic. Fifteen desensitizations in 12 patients were associated with no immediate reactions. One patient developed a delayed reaction consisting of a pruritic rash and angioedema. A second patient developed a more serious delayed serum sickness-like illness with fever, rash, eosinophilia, abnormal liver function tests, and urinary abnormalities. These reactions did not necessitate stopping the antibiotic, although the latter patient required corticosteroids to suppress his symptoms. Rapid intravenous desensitization is a rapid, safe, and effective technique for patients demonstrating hypersensitivity to beta-lactam antibiotics who require therapy with these medications.

Penicillin in milk--its importance in urticaria.

Fifty patients with recurrent urticaria were tested by means of the RAST test for penicillin allergy. Fifteen patients had positive reactions and of these, thirteen received provocation tests with 0.1 U/ml of penicillin in milk. Four had definite positive reactions, three doubtful reactions and six had no reaction. Although there has been improvement in the purity of milk, penicillin residues remain a potential cause of urticaria even in very low amounts and could have contributed to the urticaria in at least 8% of our patients. Veterinary use of antibiotics and food quality should be strictly regulated to prevent contamination of our diet.

Antibodies against the benzylpenicilloyl moiety as a probe for penicillin-binding proteins.

Antibodies against the benzylpenicilloyl determinant were used to identify complexes of benzylpenicilloyl and penicillin binding protein (PBP) of several bacterial species on immunoblots. Since radioactive penicillin was not needed, this technique readily allowed in vivo labeling studies even in Escherichia coli, where the saturating concentration was around 0.6 mg/ml. The antibodies showed no substantial cross-reactivity to other beta-lactam-PBP complexes with the exception of 6-aminopenicillanic acid. Surprisingly, some penicilloyl-PBP were hardly recognized by the antiserum, whereas the others could be stained according to the amount of penicillin bound.

Investigation into the immunologic cross-reactivity of aztreonam with other beta-lactam antibiotics.

The cross-reactivity between the monobactam antibiotic aztreonam and the commonly used beta-lactam antibiotics, penicillins, and cephalosporins was investigated. Antibodies to aztreonam, penicillin, and cephalothin were raised in rabbits. The ability of the homologous or heterologous drug or drug conjugates to inhibit antibody binding was assessed in a solid-phase radioimmunoassay. Aztreonam demonstrated very little ability to interact with anti-penicillin or anti-cephalothin antibodies as it required 10,000-fold higher concentrations than other beta-lactams to achieve equivalent blocking. Similarly, penicillin and cephalothin conjugates did not cross-react, to any significant degree, with anti-aztreonam rabbit antiserums. Interestingly, free aztreonam was as effective as conjugated aztreonam in reacting with antibodies raised against conjugated aztreonam. This result suggested that, in contrast to the other beta-lactams, antibodies to aztreonam recognize the side chain rather than the nuclear structures. Studies with other beta-lactam analogs confirmed that the IgG rabbit anti-aztreonam binding was indeed side chain-specific. Thirty-six volunteers were given a seven-day course of therapeutic doses of aztreonam and in none did any detectable IgE anti-aztreonam antibodies develop. Four of these subjects had evidence of preexisting IgG antibodies cross-reactive with aztreonam, but the levels rose in only one patient following drug exposure. This human IgG anti-aztreonam was also directed to the side chain and did not cross-react with cephalothin or penicillin. The ability of aztreonam to cross-react with human IgE to various penicillin determinants was also investigated. Aztreonam determinants analogous to the penicillin determinants (penicillin, penicilloyl, and penicilloate) were constructed and the maximal concentration that did not evoke false-positive skin test results was determined to be 6 X 10(-3) mol/liter. None of 41 patients with documented IgE-reactive skin tests to various penicillin determinants concurrently demonstrated reproducible reactivity to any aztreonam reagents. IgE anti-penicilloyl antibodies from three persons were also tested in vitro for their ability to cross-react with conjugated or free aztreonam. Minimal, if any, reactivity was observed between the IgE anti-penicilloyl and any of the aztreonam materials. These results indicate that there is very little cross-reactivity between the monobactam aztreonam and other beta-lactam antibiotics.