Emergency medicine and infectious disease specialists have examined and debated the dangers of prescribing cephalosporin antibiotics to patients with penicillin allergies. Confusion continues despite some well performed studies and reviews on this subject.
Resources such as the Physicians Desk Reference clearly state that penicillin allergy is a contraindication to cephalosporin use because of cross-reactivity to the shared beta-lactam molecule. While it is true that 10 percent of penicillin-allergic patients adversely react to cephalosporins as a class of antibiotics, a number of authorities suggest cephalosporins may be safe in some patients with penicillin allergies.1,2 Is this contraindication an axiom or myth?
Cephalosporins and penicillins can cause hypersensitivity reactions. Adverse reactions to penicillins include skin rashes, oral lesions, eosinophilia, fever, anaphylactic shock, interstitial nephritis (an autoimmune reaction to a penicillin-protein complex), and vasculitis. These reactions occur in approximately one to four percent of treatments with penicillin. Anaphylaxis is rare (<0.02%).3
Allergic reactions to cephalosporins are similar to penicillins, and include hypersensitivity reactions, anaphylaxis, nephritis, skin rashes, granulocytopenia, and hemolytic anemia. If a patient has a history of such an allergic reaction to these drugs, then most physicians avoid prescribing them to avoid a reoccurrence of that reaction. However, there are not always substitutions for these antibiotics that are as clinically effective at the same cost or convenience. Thus, many patients who should get a cephalosporin do not because of a history of a penicillin allergy.
Not Truly Allergic
A careful analysis of the studies of patients with a history of penicillin allergy is revealing. Many patients who report penicillin allergies are not currently allergic to penicillin.4 In truth, skin testing with appropriate penicillin reagents provides the only way to determine whether a patient is currently allergic to penicillin. Only five percent to eight percent of patients who claim to have a history of penicillin allergy in the United States have a positive response to a skin patch test. There are many reasons for this. The virus or bacteria afflicting the patient, not the antibiotic, may have been responsible for the specific reaction, which was considered an allergy.
There are many viral exanthems that resemble or could be mistaken for a drug allergy rash. Furthermore, patients with past allergic reactions to penicillin may have lost this sensitivity. One particular report suggests that 80 percent of patients who state they are allergic to penicillin will have a negative skin test, and in spite of their history theoretically should be able to take penicillin without incident.5
If many patients can take penicillin in spite of a penicillin allergy, how did the reports of cross-reactivity result in the risk-aversive practice of avoiding cephalosporins? It may be because the first-generation cephalosporins have the highest rate of cross-reactivity. These cephalosporins were the first to be used clinically and have a common side chain with penicillin.6 Even for these penicillins, the rate of cross-reactivity is still quite low. For example, amoxicillin and cefadroxil (first generation) share a common side chain.
Even when 16 subjects with documented skin tested allergies to amoxicillin were given cefadroxil, only two (12.5%) developed an allergic reaction.7 In patients allergic by skin-testing to penicillin, 14 percent developed allergic reactions to cephalexin (a first-generation cephalosporin), while none of the patients experienced reactions to ceftazidime (third generation). However, some first-generation cephalosporins appear to have greater cross-reactivity than others.
For example, of 1,000 patients skin-tested, 0.9 percent were allergic to cefazolin and all but one were also allergic to penicillin.8 If a penicillin-allergic patient is challenged with a cephalosporin that does not share a common side chain with penicillin such as cefuroxime (second generation) or ceftriaxone (third generation), then reactions are not expected. In one study, none of 41 penicillin-allergic patients exhibited cross-reactivity.9,10
Second- and third-generation cephalosporins are a different matter. Only two percent of patients with a positive skin test allergy to penicillin react to second- and third-generation cephalosporins, with most of the adverse reactions resulting in minor rashes.11 Therefore, conservatively estimating that 20 percent of people claiming histories of penicillin allergies are currently skin test positive for penicillin allergy and only two percent of penicillin skin-test positive patients will react to generation cephalosporins, the chance of a patient with a verbal but untested history of penicillin allergy reacting to a these cephalosporins is less than one percent.
Studies support this theory. One small study found that one cephalosporin adverse reaction occurred in 98 patients (1%) with positive penicillin skin tests and six reactions occurred in 310 patients (2%) with negative penicillin tests.12 In another study of penicillin-allergic patients diagnosed by skin testing, none developed an allergic reaction to cefuroxime (second generation) or ceftriaxone (third generation).13
Finally, one literature review noted that adverse drug reactions are three times more common in people with a history of penicillin allergies.14 Therefore, the increased rate of adverse reactions to cephalosporins in patients with penicillin-allergies may be due to genetic predisposition to allergy, antibiotic cross-reactivity to side chains, or both.
Practitioners remain either confused or indecisive about this issue. Surveys show that for patients with an infectious indication for penicillin and a history of penicillin allergy, more physicians would choose a cephalosporin for mild or moderate disease than would choose a cephalosporin for serious disease. This behavior was still seen if the allergy was described as severe, although cephalosporins were prescribed less overall in the latter scenario.15 Most sources agree that cephalosporins should be avoided in patients with a history of severe hypersensitivity reactions (such as airway compromise or hypotension) to penicillin.16
A number of good strategies can guide cephalosporin therapy in a penicillin allergic patient.
▪ When the history of the allergy is severe, seek alternative antibiotics other than cephalosporins. This is a safe conservative strategy.
▪ If possible, avoid first-generation cephalosporins in penicillin-allergic patients, but use them if the risk-benefit ratio is favorable. For example, a patient seems to recall a minor non-pruritic penicillin allergy rash as a child and has cellulitis. Remember to keep the patient informed.
▪ Second- and third-generation cephalosporins have less incidence of cross-reactivity, and are indicated when the clinical advantage to the patient is clear, even if the penicillin allergy history was not trivial. An example of this is the use of ceftriaxone in a patient with meningitis that has a history of a diffuse pruritic rash after penicillin. In this case, the advantage to the patient is the prompt treatment of a deadly disease with the risk of allergic side effects being no greater than if the patient had no history of penicillin allergy.
It is true that cephalosporins and penicillins share cross-reactive allergenic properties in sensitive individuals. However, the axiomatic contraindication of their use is a myth. A careful analysis of the risks and benefits and an understanding of the issues specific to each generation of cephalosporin will permit safe use that benefits patients.
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