Clinical implications of ß-lactam allergies

May 2004

“I’m allergic to penicillin.” How many times have you had your patient tell you they were allergic to penicillin? Or how many times has a pharmacist called you and said a patient has a reported penicillin allergy and there could be cross-sensitivity with the cephalosporin or carbapenem you have just prescribed?

Beta-lactam agents are used as first-line treatment for many infections. Patients with a reported allergy to ß-lactam agents present a challenge to health care professionals and are often denied these highly effective and safe agents. Many health care providers will avoid all ß-lactam agents when a patient reports a penicillin allergy because of the risk of cross-sensitivity and the fear of anaphylaxis. The fear of anaphylaxis is not unfounded, since penicillin is the most frequent cause of anaphylaxis and may account for as many as 75% of all anaphylactic deaths in the United States (J Allergy Clin Immunol. 1998;101[6 Pt 2]:S465-528).

There are numerous alternatives for health care professionals to choose from to avoid ß-lactam agents. However, many of these alternatives are more toxic and more costly for the patient. The avoidance of ß-lactam agents in penicillin-allergic patients has been shown to increase overall health care costs and potentially lead to the development of resistant bacteria.

The true incidence of penicillin allergy in the general population is unknown, but has been reported to range from 1% to 10% and as high as 20% in the hospitalized population. Most reported drug allergies are poorly documented, with patients giving vague or incomplete histories of reactions. A patient-reported history of penicillin allergy is often unreliable for the following reasons: minor rashes in childhood are frequently misdiagnosed as penicillin allergy; morbilliform rash associated with ampicillin or amoxicillin is not immunoglobulin (Ig) E immune-mediated; and most patients with documented hypersensitivity to penicillin will lose their antibodies over time (JAMA. 2001;285:2498-2505). More than 80% of patients with a history of penicillin allergy do not have penicillin-specific IgE antibodies detected by skin test (J Allergy Clin Immunol. 1998;101[6 Pt 2]:S465-528). The presence of IgE antibodies indicates the patient is at risk for an immediate, anaphylactic-like reaction if penicillin or a related medication is administered. Although anaphylactic reactions are the most concerning, health care professionals should remember that ß-lactam agents have been associated with all four types of hypersensitivity reactions.

Types of reactions

Type 1 hypersensitivity, also known as anaphylaxis or immediate reaction, is the most serious. Type 1 reactions are mediated by IgE and have been associated with all classes of ß-lactam agents (Curr Pharm Des. 2003;9:983-988). Individuals at risk for a type 1 hypersensitivity reaction are those between the ages of 20 and 49 years who have had previous exposure to a ß-lactam agent and who are receiving the ß-lactam agent through the parenteral route (Drug Saf. 1995;13:273-280).

Type 2 hypersensitivity reactions are also known as cytotoxic reactions. These are mediated by IgG or IgM (Curr Pharm Des. 2003;9:983-988). Penicillin-specific antibodies may be found after several days of high-dose penicillin therapy. Interstitial nephritis is an example of a type 2 reaction. Interstitial nephritis is usually associated with the anti-staphylococcal penicillins but can be seen with any ß-lactam agent.

Type 3 hypersensitivity reactions are caused by antigen-antibody complexes involving IgG or IgM. This is the cause of serum sickness, which is most frequently associated with cefaclor (Ceclor, Eli Lilly). Drug fever is a subcategory of Type 3 hypersensitivity reactions.

Type 4 hypersensitivity reactions are cell-mediated and associated with contact dermatitis (Curr Pharm Des. 2003;9:983-988). Currently, this reaction is only of historical concern for the ß-lactam agents, which had previously been used in topical preparations. The topical use of penicillin was discontinued because of the high rate of contact rashes.

Beta-lactam agents also cause a number of nonallergic adverse effects, with macular rashes being the most important (Curr Pharm Des. 2003;9:983-988). The mechanism for nonallergic macular rash is unknown; it does not clearly involve immune components found in hypersensitivity reactions, such as antibodies or complement or cytotoxic cells. The rash usually manifests at least four to five days after therapy is initiated. The patient will not always experience a rash upon rechallenge with the offending agent and usually does not have cross-sensitivity to other ß-lactam agents.

Beta-lactam agents are too small in themselves to act as antigens (Clin Rev Allergy Immunol. 2003;24:201-219). They must first bind to a carrier molecule to form a covalent antigen capable of stimulating an immune reaction. Beta-lactam agents spontaneously degrade under physiologic conditions to reactive intermediaries capable of binding to proteins to form a hapten.

The immunochemistry of penicillin has been well characterized (Clin Rev Allergy Immunol. 2003;24:201-219). This differs from the cephalosporins and carbapenems, in which the reactive intermediaries have not yet been identified. The ß-lactam ring of penicillin spontaneously opens under physiologic conditions to form several compounds. Penicilloyl accounts for 95% of the antigenic compounds and is called the major determinant. Penicilloate and penilloate make up the remaining 5% of antigenic compounds and are called the minor determinants.

The immune determinants of the cephalosporins and carbapenems have not been well characterized. These compounds likely also undergo spontaneous degradation of the ß-lactam ring, but these intermediaries do not appear to be antigenic. It has been postulated that immune responses to the cephalosporins and carbapenems are directed toward the side chains of the compound and not to the core ring structure. This in part may explain why some individuals can safely take some ß-lactam agents when a true allergy has been documented to penicillin.

Cross-sensitivity of cephalosporins

The issue of cross-sensitivity of cephalosporins in patients with penicillin allergy is not easily resolved. The overall rate of cross-sensitivity is unknown (N Engl J Med. 2001;345:804-809). Early preparations of cephalosporins contained trace amounts of penicillin in solution, resulting in a high degree of allergic reactions. These impurities have since been removed from cephalosporin preparations, and the prevalence of allergic reactions has declined.

Allergic reactions to cephalosporins manifest in many forms, such as macular rash, serum sickness, drug fever and, rarely, anaphylaxis. The frequency of anaphylaxis to cephalosporins has been reported to be less than 1% (N Engl J Med. 2001;345:804-809). Patients with a history of penicillin allergy may be at increased risk of an allergic reaction. However, people with a penicillin allergy and negative skin test are not at an increased risk of allergic reaction.

Clinical Implications

When a patient reports a penicillin allergy, health care providers are faced with the dubious task of sorting through incomplete and vague histories and then tasked with making a sound treatment decision. There are many approaches to managing patients with ß-lactam allergies, but all start with taking a good history regarding the offending agent and the reaction. Some of the questions to ask a patient may include but are not limited to the following (JAMA. 2001;285:2498-2505):

• What drug caused the reaction?
• What was the patient’s age at the time of the reaction?
• Does the patient recall the reaction or did a relative tell them about the reaction?
• What were the characteristics of the reaction (ie, maculopapular rash vs. urticaria)?
• How long after beginning the offending drug did the reaction begin?
• Has the patient taken antibiotics similar to penicillin? Consider asking about commonly used agents and always use the trade names, such as Augmentin (amoxicillin-clavulanate, GlaxoSmithKline), Keflex (cephalexin, Lilly), Ceftin (cefuroxime axetil, GlaxoSmithKline).
• If one of these agents has been taken, was there a reaction?

If the patient relays strong evidence of an IgE-mediated reaction, health care providers should consider penicillin skin testing. However, the skin test only uses the major determinant, penicilloyl; the minor determinants, penicilloate and penilloate, are not commercially available for use in the United States. When penicilloyl and penicillin G are used together for the skin test, it is estimated that 1% to 2% of individuals who are truly allergic to penicillin will be missed (Clin Rev Allergy Immunol. 2003;24:201-219). If the skin test is positive, there is an increased risk of having an immediate reaction to a ß-lactam agent, and either alternative agents should be used or the patient can be desensitized. If the skin test is negative, this does not eliminate the chance of an allergic reaction. However, the reaction is usually mild and self-limiting.

If there is weak evidence of a serious allergy, the clinician may consider alternative ß-lactam agents, such as cephalosporins. Penicillin skin testing may also be completed.

Conclusion

Patient reported allergies to penicillin can be a challenge for health care practitioners. Many of these allergies have vague histories that need to be clarified so that ß-lactam agents are not needlessly withheld from the patient.

For more information:

• The diagnosis and management of anaphylaxis. Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology and the Joint Council of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 1998;101(6 Pt 2):S465-528.
• Salkind AR, Cuddy PG, Foxworth JW. Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy. JAMA. 2001;285:2498-2505.
• Leviton I. Separating fact from fiction: the data behind allergies and side effects caused by penicillins, cephalosporins, and carbapenem antibiotics. Curr Pharm Des. 2003;9:983-988.
• Boguniewicz M. Adverse reactions to antibiotics. Is the patient really allergic? Drug Saf. 1995;13:273-280.
• Solensky R. Hypersensitivity rections to ß-lactam antibiotic. Clin Rev Allergy Immunol. 2003;24:201-219.
• Kelkar PS, Li JT. Cephalosporin allergy. N Engl J Med. 2001;345:804-809.

• Marianne Billeter, PharmD, BCPS, Clinical Pharmacology Specialist, Infectious Diseases, Ochsner Clinic Foundation, New Orleans.