Cross-reactivity Between Penicillins And Cephalosporins And Specific Antibodies In Serum

With the abused using of cephalosporins in clinical therapy during these years, the incidence of allergic reactions showed upward trend. Rencent studys concluded that cross-reactivity amongβ-lactams could be mostly attributed to same or similar side chain structures. So we conducted a group of subjects who had positive skin test or had allergic reaction toβ-lactams to elucidate the underlying mechanism of cross-reactivity between penicillins and cephalosporins and evaluate character of side chain in cross-reactivity for further step.MethodsRAST was used to examine 8 kinds of penicillin specific IgE antibodies of different antigenic determinants (BPO, APO, PVO, AXO, BPA, APA, PVA, AXA) and 11 kinds of cephalosporin specific IgE antibodies of different antigenic determinants (CEXO, CLO, CEZO, CPZO, CTO, CZO, CXO, CEXA, CLA, CEZA, CPZA) among 420 penicillin allergic patients and 80 healthy subjects, as well as 34 cephalosporin allergic patients and 88 healthy subjects, respectively; RAST inhibition was used to examine the inhibition rate of 4 penicillins (BP, PV, AP, AX), 7 cephalosporins (CEX, CL, CEZ, CPZ, CT, CZ, CX), 2 nuclear structures (6-APA, 7-ACA)and 4 side chain structures(PHA, PHOA, NPG, PHPG)among 4 typically allergic patients.Results1. Specific IgE antibodies in serum of allergic patients1.1 The relationship between allergic reaction and specific IgE antibodiesExcept for CPZO-IgE, the values of other 18 kinds of specific IgE antibodies were significant higher than control (P<0.05). Among specific IgE antibodies to penicillins, the positive rate of BPO-IgE was the highest (28.63%), and that of APA-IgE was the lowest (8.81%); among specific IgE antibodies to cephalosporins, the positive rate of CPZA-IgE was the highest (8.15%), and that of CPZO-IgE was the lowest (2.64%). Among 420 penicillin allergic patients, 291 patients (69.29%) showed at least oneβ-lactam specific IgE antibodies positive; 269 patients (64.05%) showed at least one penicillin specific IgE antibodies positive; 95 patients (22.62%) showed at least one cephalosporin specific IgE antibodies positive; Among 34 cephalosporin allergic patients, 33 patients (97.06%) showed at least oneβ-lactam specific IgE antibodies positive; 19 patients (55.88%) showed at least one penicillin specific IgE antibodies positive; 32 patients (94.12%) showed at least one cephalosporin specific IgE antibodies positive. The results indicated that the positive rate ofβ-lactam specific IgE antibodies and cephalosporin specific IgE antibodies in cephalosporin allergic group are significant higher than that in penicillin allergic group (P<0.01), but there was no significant difference in the positive rate of penicillin specific IgE antibodies between the two group (P>0.05).1.2 The relationship between skin test,allergic symptom,allergic reaction type,sex and IgE antibodiesAccording to different skin test results, there was no significant difference between positive skin test group and negative skin test group; In terms of allergic symptoms, there was no difference among anaphylactic shock group, urticaria group, and other symptoms group either. The same was true in the positive rate of these three kinds IgE antibodies to the male and female, as well as patients with immediate hypersensitivity reaction (IHR) and those with delayed hypersensitivity reaction (DHR)(P>0.05). 1.3 The relationship between antigenic determinants and the positive rate of specific IgE antibodiesWhen tested only one kind ofβ-lactam specific IgE antibody, the positive rate was 23.79%; When tested 19 kinds ofβ-lactam specific IgE antibodies, the positive rate come up to 71.37%.The results indicated that the more determinants we examined (under 7 kinds), the higher positive rate it showed (P<0.05) and the positive rate became saturate with the increasing of tested determinants.2. Cross-reactivity between penicillins and cephalosporins2.1 The general information of cross-reactivityAmong 454 allergic patients, 90 patients (19.82%) showed cross-reactivity between penicillins and cephalosporins. The analysis of specific IgE antibodies to the same or similar side chain drug's minor antigenic determinants showed that APA-IgE and AXA-IgE, APA-IgE and CEXA-IgE, AXA-IgE and CEXA-IgE, BPA-IgE and CLA-IgE levels all straight related, and the positive rate of CEX specific antibodies in AP,AX positive group was higher than in negative group(P<0.05), but there was no significant difference in positive rate of CL specific antibodies between PG positive group and negative group.2.2 Cross-reactivity between penicillins and cephalosporins in penicillin allergic patientsAmong 420 penicillin allergic patients, 73 patients (17.38%) showed cross-reactivity between penicillins and cephalosporins; 95 patients (22.62%) at least one cephalosporin specific IgE antibodies be positive. Among these penicillin allergic patients, APA had the highest cross-reactivity with CLA, CPZA, which was up to 25.64%, and BPO had the lowest cross-reactivity with CTO, which was only 2.46%; The positive rate of CPZA-IgE was the highest, which come up to 7.38%, the positive rate of CTO-IgE was the lowest, just 2.62%. There was significant difference between penicillin positive group and penicillin negative group in positive rate of cephalosporin specific IgE antibodies (P<0.01). But there was no difference between penicillin major and minor determinants IgE positive group in positive rate of cephalosporin specific IgE antibodies, that of cephalosporin major determinant IgE, as well as that of cephalosporin minor determinant IgE (P>0.05).According to allergic symptoms, 126 patients who had allergic history were separated into anaphylactic shock group,urticaria group and other symptoms group. Of these three group, positive rate of cephalosporin specific IgE antibodies in urticaria group was significant higher than that in other symptoms group (P<0.01666), but there was no significant difference between skin test positive group and skin test negative group, immediate hypersensitivity reaction (IHR) group and delayed hypersensitivity reaction (DHR) group, male group and female group. The analysis of specific IgE antibodies to the same or similar side chain drugs' minor antigenic determinants showed that APA-IgE and AXA-IgE, APA-IgE and CEXA-IgE, AXA-IgE and CEXA-IgE, BPA-IgE and CLA-IgE levels all straight related, and the positive rate of CEX specific antibody in AP,AX positive group was higher than in that negative group(P<0.05), but there was no significant difference in positive rate of CL specific antibodies between PG positive group and negative group.2.3 Cross-reactivity between penicillins and cephalosporins in cephalosporin allergic patientsAmong 34 cephalosporin allergic patients, the positive rate was35.29% when tested only one kind of cephalosporin specific IgE antibody while the positive rate came up to 94.12% when tested 11 kinds of cephalosporin specific IgE antibodies. The results indicated that the more diterminants we examined (under 4 kinds), the higher positive rate it showed (P<0.05) and the positive rate became saturate with the increasing of tested determinants. Among 34 cephalosporin allergic patients, 18 patients (52.94%) showed cross-reactivity between penicillins and cephalosporins; 32 patients (94.12%) showed at least one kind of cephalosporin specific IgE antibody positive; 19 patients (55.88%) showed at least one penicillin specific IgE antibody positive. Among these cephalosporin allergic patients, the positive rate of BPO-IgE,AXO-IgE was the highest, which was up to 23.53%, but the positive rate of PVA-IgE was as low as 0%. The levels of 9 kinds of cephalosporin specific IgE antibodies in cephalosporin allergic patients were significant higher than in control (P<0.05). But there was no significant difference between cephalosporin antibody positive group and negative group, skin test positive group and negative group, immediate hypersensitivity reaction (IHR) group and delayed hypersensitivity reaction (DHR) group, male group and female group (P>0.05).3. The mechanism of cross-reactivity between pencillins and cephalosprinsThe typical case 646 showed frequently high inhibition rate when used penicillins and cephalosporins, as well as individual side chain structures and nuclear structures as inhibitors. We suspected that case 646 may develop comprehensive cross-reactivity when useβ-lactams.The typical case H11 showed high inhibition rate of PG,PV,AP,CEX,CZ,CX and 7-ACA,6-APA when the concentration of inhibitor was 100mmmol/L, but the inhibition rate of several side chain structures were relatively low. We suspected that case 646 may develop cross-reactivity when useβ-lactams and this correlates to nuclear structures tightly.The typical case 1112 showed highest inhibition rate of CEX, which was up to 76.58%, followed by AX, but the inhibition rate of NPG,PHPG was much higher than that of 6-APA,7-ACA and PHA,PHOA. We suspected that case 646 may develop cross-reactivity when use AX and CEX, and this because specific IgE in this patient can recognize the side chain structure of these two drug.The inhibition rate of CL was much high in case H166, especially when the inhibitor concentration came up to 100mmol/L.The inhibition rate of the other 10 antibiotics as well as side chain structures and nuclear structures were low. We suspected that case H166 may not develop allergic reaction when useβ-lactams except for CL, and CLO-IgE positive related to specific IgE antibodies recognizing the whole CL molecule.Conclusion1. RAST that has high hypersensitivity and specificity is an excellent method as a complement to in vivo tests in the evaluation of subjects allergic to cephalosporins;2. There definitely exists cross-reactivity between penicillins and cephalosporins, and the rate of cross-reactivity come up to 19.82%;3. Cephalosporin specific antibodies recognizing antibiotics have widely structural specificity, and side chain structures play an important role in cross-reactivity.