Review of the use of cephalosporins in children with anaphylactic reactions from penicillins

Department of Pediatrics, University of Alberta, Edmonton, Alberta Correspondence: Dr Joan L Robinson, 2C3 Walter Mackenzie Centre, University of Alberta Hospital, Edmonton, Alberta T6G 2B6. Telephone 780-407-1680, fax 780-407-7136, e-mail jr3@ualberta.ca Received for publication June 15, 2001. Accepted February 21, 2002 TK Hameed, JL Robinson. Review of the use of cephalosporins in children with anaphylactic reactions from penicillins. Can J Infect Dis 2002;13(4):253-258.

A common problem in paediatrics is determining whether a cephalosporin can be used in a child with a history of a serious reaction from a penicillin, and whether a penicillin can be administered to a child with a history of a serious reaction from a cephalosporin.In many cases, such patients are prescribed antibiotics that are less effective, more toxic, have a broader spectrum or are more expensive than the drug of choice for their condition.
Diagnostic tests for antibiotic allergies are limited and are standardized only for penicillin.
When penicillin is metabolized, the beta-lactam ring opens to form a penicilloyl derivative that, when bound to serum and tissue proteins, accounts for more than 90% of immunologically active penicillin metabolites (the major determinants).However, about 16% of allergic reactions to penicillin involve multiple, different antigens that result from further penicillin metabolism.These antigens are referred to as minor determinants (1).In patients who have a history of penicillin allergy but negative skin test results using major and minor determinants, studies have shown that the chance of a serious allergic reaction to penicillin is negligible (1).Skin testing for cephalosporin allergy is sometimes performed, but is not standardized because the antigenic determinants of a serious allergic reaction have not been established.
Standard teaching is that patients who have had possible anaphylaxis from penicillin should be given cephalosporins only with extreme caution, because their risk of developing anaphylaxis from cephalosporins is increased (2).Penicillins have a beta-lactam ring attached to a thialazolidine ring with one side chain, while cephalosporins have a beta-lactam ring attached to a dihydrothiazine ring with two side chains ( 1) (Figure 1).Because of the similar struc-tures, there is a theoretical risk of cross-reactivity between penicillins and cephalosporins.
Soon after cephalosporins were introduced, there were reports of anaphylaxis in patients who were given cephalosporins and who had also experienced anaphylaxis from penicillin.Furthermore, during the initial clinical trials with first-generation cephalosporins and cefamandole, 8.1% of patients with a history of allergy to a penicillin had a possible allergy to a cephalosporin, compared with 4.5% of patients with no such history (3).However, in those initial trials, no attempt was made to ensure that the reaction to the penicillin or to the cephalosporin was truly allergic.The purpose of the present study was to determine whether there is further evidence in the literature to support the avoidance of cephalosporins in children with suspected penicillin allergies.If the risk of cross-reactivity between penicillins and cephalosporins is low in the adult population, the same is probably true for the paediatric population.Therefore, the incidence of case reports of anaphylaxis from cephalosporins in adults or children with anaphylaxis from penicillin or a positive penicillin skin test was studied.The results of cephalosporin challenge in patients with pos- itive penicillin skin tests were also reviewed.If it is exceedingly rare for children to develop anaphylaxis from cephalosporins, it may not be necessary to avoid their use in children who are allergic to penicillins.Therefore, the total number of published case reports of anaphylaxis from cephalosporins in all children was also researched.

DATA AND METHODS
The literature was reviewed for results of cephalosporin challenge in adults or children with anaphylactic reactions from penicillin or with positive penicillin skin tests.Case reports of anaphylaxis from cephalosporins in paediatric patients (up to 16 years of age) were also researched.MED-LINE, EMBASE, Toxline, International Pharmaceutical Abstracts and PubMed were used to search the literature published from 1966 to 2001, using 'anaphylaxis', 'penicillin', 'cephalosporin', 'beta-lactams', 'cross-reactivity', 'cross-sensitivity', 'drug allergy' and 'drug hypersensitivity' as keywords, and by referencing the bibliographies of related papers.Cases with urticaria or life-threatening symptoms (apnea, bronchospasm or hypotension) were considered to be anaphylaxis.We also contacted Health Canada, the Canadian Medical Protective Association (CMPA) and the Boston Collaborative Drug Surveillance Program to determine whether they were aware of any unpublished cases of cross-reactivity between penicillins and cephalosporins, and anaphylaxis from cephalosporins in children.

RESULTS
A review of case reports of anaphylaxis from cephalosporins in adults or children with a history of penicillin allergy or a positive penicillin skin test is presented in Table 1.In five cases (4-8), patients with a history of anaphylaxis from penicillin developed anaphylaxis from a cephalosporin.Three of the cases involved anaphylaxis from the older, first-generation cephalosporins, cephalothin and cephaloridine, while two cases involved anaphylaxis from the second-generation cephalosporins, cefaclor and cefamandole.There were 12 other published reports of anaphylaxis from cephalosporins in adults with a history of penicillin allergy or a positive penicillin skin test but with no history of anaphylaxis from penicillin.In nine of these cases, the class of cephalosporin was known (six were cephalothin, one was both cephalothin and cephalexin, one was cephalexin and one was cefamandole).The CMPA was not aware of any legal action in Canada that resulted from the administration of a cephalosporin to a patient with an allergy to penicillin.Health Canada's Adverse Drug Reaction Monitoring Program and the Boston Collaborative Drug Surveillance Program had no additional unpublished reports of anaphylaxis from cephalosporins in patients who were allergic to penicillin.
Table 2 summarizes the studies of cephalosporin challenge in children and adults with positive penicillin skin tests.Only one study (9) focused on paediatric patients.Of a total of 158 patients, there were seven positive challenges with cephalosporins.Four of the seven suspected immunoglobulin E (IgE)-mediated reactions were mild (one reaction to cephaloridine and three reactions in which the cephalosporin was not specified), while three were serious reactions that consisted of anaphylaxis from cephaloridine or cefamandole.

DISCUSSION
There have been only 17 published case reports of anaphylaxis from cephalosporins in patients with a history of penicillin allergy or a positive penicillin skin test.All cases occurred in adults.In nine of the 14 cases in which the class of cephalosporin could be determined, anaphylaxis was from first-generation cephalosporins, while the other five cases were anaphylaxis from second-generation cephalosporins.However, one limitation of the present study was that the reporting of cases was sporadic.Therefore, the infrequency of case reports may have been due to the fact that physicians are very compliant about not prescribing cephalosporins to patients with suspected penicillin allergies, the cases of cross-reactivity between penicillins and cephalosporins that occur are often not reported, or that it is very rare for crossreactivity to occur.
There have been seven studies in which 158 patients with positive penicillin skin tests were administered cephalosporins; seven had IgE-mediated reactions when they were administered a cephalosporin.Four of the reactions were mild (one reaction was to cephaloridine and three were in reaction to a cephalosporin that was not specified).There was one serious reaction to cephaloridine and two serious reactions to cefamandole in patients with allergies to penicillin.A possible explanation for the three serious reactions is that of all the cephalosporins, cephaloridine and cefamandole have side chain structures that are most similar to penicillin and, thus, cross-reactivity may have occurred (2).
When the class of the cephalosporin was specified, none of the serious reactions to cephalosporins in patients with positive penicillin skin tests involved third-generation cephalosporins.The risk of serious allergic reactions from cephalosporins in the general population appears to be less than 0.02%, and the risk is lowest for third-generation cephalosporins (possibly because cephalosporins are thought to be only antigenic if the side chain is bound to a serum protein, and free side chains compete with bound side chains for binding to IgE antibodies) (17,18).
Anaphylaxis from cephalosporins appears to be incredibly rare in children, with only 13 case reports in the literature.However, it is likely that not all cases would have been reported or even recognized.It is interesting that eight of those case reports came from Romano (15,16).He also mentioned a six-year-old with an immediate reaction to a cephalosporin in another paper (19), but it is not clear if this was an additional case.A recent review article found only 54 published cases of anaphylaxis to cephalosporins in both adults and children, but did not include all of the paediatric cases found in the present study (12,15,16).
The reason why a high incidence of cross-reactivity between penicillins and cephalosporins was thought to be likely is that both have a beta-lactam ring.However, there is increasing evidence that, in most allergic reactions to cephalosporins, it is the side chain rather than the beta-lactam ring that is the antigen (2).It is only the older, firstand second-generation cephalosporins (cephalothin, cephaloridine and cefamandole) that have a side chain that is similar to that of penicillin, while cephalexin has a side chain that is identical to that of ampicillin.In addition, older, first-generation cephalosporins were sometimes contaminated with penicillin before 1980 (20).These two facts may account for some of the early reports of cross-reactivity between penicillins and cephalosporins.Furthermore, the results of penicillin skin testing are not predictive of cephalosporin allergy, which again suggests that there is limited cross-reactivity (3).
There is evidence that patients with a history of penicillin allergy have three times the rate of patients in control groups of having an allergic reaction to any other antibiotic (17).Therefore, even if the risk of patients with a history of penicillin allergy having a serious reaction to cephalosporins is double that of patients in control groups, this risk may be lower than the risk of them having a serious reaction to any alternative antibiotic (2).It has been suggested that the low incidence of serious allergic reactions to cephalosporins may relate to the lack of stability of immunogenic metabolites (16).

CONCLUSIONS
There is minimal evidence in the literature to support the avoidance of cephalosporins in children with anaphylaxis from penicillins.Despite published guidelines to the contrary (20), a child or adult with a previous mild reaction to a peni-cillin can probably safely be administered a cephalosporin.If a more serious reaction to a penicillin has occurred, yet the patient has a negative penicillin skin test, it is probably safe to administer a cephalosporin (21).However, if skin testing cannot be done or if a patient is known to have had a positive penicillin skin test, it is not advisable to administer a full dose of an intravenous cephalosporin in the face of standard recommendations against this practice (20).However, it would appear to be safe to administer a supervised, graded challenge with a nonfirst-generation cephalosporin other than cefamandole or to embark on desensitization (22).

Figure 1 )
Figure 1) Comparison of chemical structure of penicillins and cephalosporins.R Side chain

Cephalosporins if anaphylaxis from penicillin occurs
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TABLE 1 Summary of case reports of anaphylaxis to cephalosporins in patients with a history of penicillin allergy or a positive penicillin skin test
*No further details of the reactions were given; † Ages unknown.F Female; M Male

TABLE 2 Summary of studies of cephalosporin challenge in patients with positive skin tests for allergies to penicillin
*Although three patients had positive challenges with cephalosporins, only two patients had suspected IgE-mediated reactions; † No further details were provided; ‡ Three penicillin skin-test-negative patients were selected on the basis of positive penicillin challenge; § Treatment courses with cephalosporins.IgE Immunoglobulin E

Cephalosporins if anaphylaxis from penicillin occurs
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TABLE 3 Case reports of anaphylaxis from cephalosporins in children
*No further details were provided