Beta-lactam Antibiotic Allergy

Authors: Brad McClimon, PharmD, M.D., Miguel A. Park, M.D.

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History

Adverse drug reactions are a significant cause of morbidity and mortality in the inpatient and outpatient setting. Beta-lactam antibiotic allergy continues to be a common form of adverse drug reactions. Drug allergy is often classified by the Gell and Coombs classification of hypersensitivity which consists of four types of reaction. This is described in greater detail in Table 1. The focus of this chapter will be on type I adverse drug reactions (IgE mediated) which is the only type of adverse drug reaction we can evaluate and treat. Commercially available reagents for penicillin skin testing are unavailable in the United States at the time of writing this chapter, however, a commercially available product is expected to be available soon.

PENICILLIN ALLERGY

Epidemiology

The prevalence of penicillin allergy in the general population is not known. The incidence of self-reported penicillin allergy range from 1 to 10% (1, 18) with the frequency of life-threatening anaphylaxis estimated at 0.01% to 0.05% (4).

Pathogenesis

The penicillin antibiotics consist of a beta-lactam ring and a variety of side chains. The beta-lactam ring or the side chains may participate in hypersensitivity reactions (19, 29). The specific haptens have not been identified (17).

Risk Factors

A history of an adverse drug reaction to penicillin or cephalosporin is the most important risk factor (17). A history of atopy does not appear to be a risk factor for allergy to beta-lactam antibiotics (17). Female gender may confer an increased risk of penicillin allergy evidenced by a positive penicillin skin test in patients with a distant history of penicillin allergy (23).

Clinical Manifestations

From a clinical standpoint, the most practical method of classifying penicillin allergy is to divide the adverse drug reactions into IgE mediated (immediate-type hypersensitivity reaction) versus non-IgE mediated hypersensitivity reactions (Table 1). For example, IgE mediated or immediate-type reactions include anaphylaxis, angioedema, urticaria, and bronchospasm. These IgE mediated reactions occur within minutes after drug administration but can also be delayed up to 72 hours. The non-IgE mediated hypersensitivity reactions include hemolytic anemia, interstitial nephritis, thrombocytopenia, serum sickness, drug fever, morbilliform eruptions, erythema multiforme minor (EM), Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN), and others. These adverse reactions occur most commonly after 72 hours (14). Describing the signs and symptoms experienced by the patient is an important part of documenting adverse drug reactions.

Diagnosis

Utility of the Patient’s History in the Evaluation of Penicillin Allergy

The patient’s history plays an integral part in the evaluation of a penicillin allergic patient. For example, if the patient describes a history consistent with EM, Stevens-Johnson syndrome, or TEN, then penicillin skin testing would not be indicated because the skin test only tests for IgE mediated adverse reactions. However, the history plays a very limited role in predicting the outcome of the penicillin skin test. For example, the severity of adverse reaction from penicillin is a poor predictor of a positive penicillin skin test. Gadde et al.(12) and Green et al.(13) reported that 17-46% of patients with a prior history of anaphylaxis to penicillin had a positive penicillin skin test. In those who experienced urticaria to penicillin, 12% had positive penicillin skin test, and those with exanthems, only 4% had a positive penicillin skin test. In this same study, 1.7% of patients with no history of penicillin allergy had positive skin test. Patients with maculopapular rashes do not have significantly higher incidence of positive skin tests than those with a negative history (13). Solensky et al. (31) showed that 33% (347/1063) of patients with a history of penicillin allergy and positive penicillin skin tests had a “vague” history of prior reaction to penicillin. A "vague" history was defined as one unlikely to be IgE-mediated (such as maculopapular rash, GI symptoms, or an unknown reaction). The authors conclude that patients with a vague history should still undergo penicillin skin testing because a large number of penicillin allergic patients (those with evidence of IgE to penicillin on penicillin skin test) would be missed.

In contrast, Salkind et al. (28) reported that a history consistent with a penicillin allergy had an increased likelihood of having a penicillin allergy (positive likelihood ratio of 1.9: 95% CI, 1.5-2.5). A negative history of penicillin allergy lowers the likelihood of a penicillin allergy as assessed by penicillin skin testing (negative likelihood ratio of 0.5: 95% CI 0.4-0.6). However, both the positive and negative likelihood ratios have small impact on the pre-test probability as assessed by JAMA Users Guides to the Medical Literature for Diagnosis Articles (15, 16). Hence, although the patient’s history is an important element in the evaluation of penicillin allergy, the clinical utility is limited.

Utility of the Penicillin Skin Test in the Evaluation of Penicillin Allergy

Penicillin skin testing is performed with prick and intradermal tests. This includes both the major and minor determinants (Penicillin G and/or minor determinant mix (MDM)). Benzyl penicilloyl is the major determinant. Several different MDM, not commercially available, have been used in the large penicillin trials. These include benzyl penicilloate, benzyl penilloate, benzyl penicillin, and/or benzyl-n-propylamine. After a positive histamine control, the prick test is performed. This is followed by the intradermal test if the prick test is negative. A wheal of 3 mm or greater with erythema greater than the control on either the prick or intradermal tests is considered a positive test (6).

Penicillin skin testing with both major and minor determinants is the most reliable tool in the diagnosis of a penicillin allergy mediated by IgE. A patient with a history of an immediate-type hypersensitivity reaction to penicillin and negative skin test to both the major and minor determinants is at a low risk of an immediate-type hypersensitivity reaction to penicillin. Gadde et al. (12) and in a multicenter study (30) reported a reaction rate of 2.9% and 1.2%, respectively, in patients who received penicillin with a positive history penicillin allergy and a negative penicillin skin test to both the major determinant and MDM. Thus, patients with a history of penicillin allergy and negative skin test to the major determinant and MDM will have a low occurrence of immediate-type adverse reaction on administration of penicillin.

A positive penicillin skin test reflects the presence of specific IgE antibodies to penicillin. Patients with a positive skin test to penicillin are at an increased risk of an immediate-type hypersensitivity reaction to penicillin. Limited data is available on the true positive predictive value of a positive penicillin skin test (6, 28, 33).

Utility of the In-Vitro Penicillin Testing in the Evaluation of Penicillin Allergy

In vitro assays (Radioallergosorbent test (RAST) or enzyme-linked immunosorbent (ELISA)) for IgE antibodies the major determinants of penicillin G, penicillin V, amoxicillin, and ampicillin (32) is another approach in the diagnosis of IgE mediated penicillin allergy (34). A history of an immediate-type hypersensitivity reaction to penicillin with a positive in vitro test would suggest an IgE mediated penicillin allergy. However, a negative test would not exclude a penicillin allergy because these tests are relatively insensitive and do not test for minor determinants (6) Hence, the most reliable means of diagnosing an IgE mediated penicillin allergy is by penicillin skin testing.

Management

At the time of this writing, the major determinant (benzyl penicilloyl) for penicillin skin testing is no longer available commercially. Some medical centers are able to produce their own major and minor determinants. Hence, we recommend in patients with a history of penicillin allergy needing penicillin, one should contact their local allergist or a medical center to inquire their capability to evaluate these patients with penicillin skin testing.

If penicillin skin testing is not available or penicillin skin test is positive, then a non-beta-lactam antibiotic is recommended or penicillin desensitization. If penicillin desensitization is chosen, the patient must undergo desensitization prior to each subsequent course of penicillin. If the patient has a history consistent with a non-IgE mediated adverse drug reaction, then re-challenge or desensitization with penicillin is contraindicated.

Several penicillin desensitization protocols are available in the literature. Table 2 provides an example of a penicillin desensitization protocol.

CEPHALOSPORIN ALLERGY

Epidemiology

The overall incidence of reaction to cephalosporins appears to be approximately 0.1-2%(4, 21, 22). The adverse drug reaction rate may be higher in patients allergic to penicillins. Adverse drug reaction rates in patients with penicillin allergy range from 0.17%-15% (9, 10, 19).

Pathogenesis

The cephalosporin antibiotics consist of a beta-lactam ring and a variety of side chains. The beta-lactam ring or the side chains may participate in hypersensitivity reactions (19, 29). The specific haptens have not been clearly identified (17).

Risk Factors

History of reaction to penicillin or cephalosporin is the most important risk factor for adverse reactions. Patients with a history of reaction to penicillin and positive penicillin skin tests may be at higher risk for a reaction to cephalosporin than those who only have a history of allergy to penicillin (17). A history of atopy does not appear to be a risk factor for allergy to beta-lactam antibiotics (17).

Clinical Manifestations

Adverse drug reactions to cephalosporins include both IgE mediated and non-IgE mediated adverse reactions. IgE mediated (Gell Coombs type I hypersensitivity reactions) include urticaria, angioedema, bronchospasm, and/or anaphylaxis. Anaphylactic reactions to cephalosporins seems to be relatively rare (0.001-0.1%) (7, 20), however, deaths have been reported (26). All types of adverse drug skin reactions have been reported to occur in 1-3% of patients receiving cephalosporins (21). Severe skin reactions seem to be less common compared to penicillins but cases of Stevens-Johnson Syndrome and exfoliative dermatitis have been reported (17). Other types of non-IgE mediated adverse reactions include serum sickness like reaction, fever, anaphylaxis, and positive Coomb’s test.

Diagnosis

Unlike penicillin allergy, a validated skin testing for cephalosporin antibiotics is not currently available. Thus, the medical history is essential to the diagnosis of cephalosporin allergy. A complete history should include description of the reaction, time course of the reaction, and complete medication history.

Cephalosporin in Patients With a History of Penicillin Allergy

Patients with penicillin allergy may be more likely to have an adverse drug reaction to cephalosporin antibiotics. It is controversial whether this is due to the shared beta-lactam ring or similar side chains or increased tendency for multiple drug hypersensitivity reactions in penicillin allergic patients. As a result, clinicians often face the dilemma of whether to prescribe a cephalosporin antibiotic to patients with a history of penicillin allergy.

In a review by Kelkar et al (17), an adverse reaction rate of 4.4% (6/135) was noted in patients with a history of penicillin allergy and a positive penicillin skin test challenged with a cephalosporin. In the same review when patients with a history of penicillin allergy and a negative penicillin skin test were administered a cephalosporin, only 0.6% (2/351) had an adverse reaction. Another large review found a reaction rate to cephalosporins of 8.1% in penicillin allergic patients compared to 1.9% in patients without a history of penicillin reaction (19). These studies indicate there may be an increased rate of adverse drug reaction in penicillin allergic patients and penicillin skin test positive patients.

Alternatively, the American Academy of Pediatrics endorse using selected second and third generation cephalosporins (cefdinir, cefuroxime, or cefpodoxime) in patients who experienced a non-type I hypersensitivity reaction to penicillins (2, 3). The recommendations are based on reports of minimal cross reactivity between penicillins and second or third generation cephalosporins with side chains different than the penicillin antibiotics (5, 24, 25). The studies found increased rates of cross reactivity between penicillins and first generation cephalosporins and minimal cross reactivity with second or third generation cephalosporins or among cephalosporins with differing side chains (22, 24, 25). The cross reactivity with first generation cephalosporins is thought to be due to similar side chain structure. This perceived lack of cross reactivity when the side chains differ has prompted some to recommend proceeding with administration of cephalosporins with differing side chains in patients with history of type I hypersensitivity to penicillins (25).

However, in a retrospective study of 350,000 reports of adverse drug reaction identified 12 fatal anaphylactic reactions to antibiotics over a five year period. Six of the 12 patient deaths were attributed to cephalosporin antibiotic and four of the six were known to be penicillin allergic(26). Hence, some caution is still advised if a cephalosporin is to be given in patients with a history of penicillin allergy.

Cephalosporin in Patients with a History of Cephalosporin Allergy

No validated skin test or in-vitro testing for cephalosporins exists. The risk of receiving a different cephalosporin than the original cephalosporin causing the adverse drug reaction is not known(17).

Management

Cephalosporin Use in Patients with a History of Penicillin Allergy

The Joint Task Force on Practice Parameters (6) recommends that if a substitute with a non-β-lactam antimicrobial agent is not available for patients needing a cephalosporin, patients with a history of an immediate-type hypersensitivity reaction to penicillin should undergo penicillin skin tests. If penicillin skin tests are negative, cephalosporin can be administered with a less than 1% risk of immediate adverse reaction. However, if penicillin skin tests are positive, then the patient should either avoid ß-lactam antimicrobials, or be considered for cephalosporin desensitization. Patients with a history of penicillin allergy who subsequently have tolerated a cephalosporin agent generally do not need to undergo penicillin skin testing prior to re-administration of the same cephalosporin drug.

Cephalosporin Use in Patients With a History of Cephalosporin Allergy

A patient who has had an allergic reaction to a specific cephalosporin should avoid that cephalosporin. If an alternative cephalosporin is desired, the Joint Task Force on Practice Parameters (6) recommends one of the following: 1) perform a graded dose challenge with an alternative cephalosporin with a different side chain determinate or 2) consider skin testing with desired cephalosporin.

Desensitization consists of initially administering a minute dosage of the desired cephalosporin and gradually increasing the dosage with numerous steps. Table 3 provides an example of a cephalosporin desensitization protocol with a goal dosage of one gram intravenously (35).

CARBAPENEMS

Carbapenems share structural features with penicillins and potentially could cross react in penicillin allergic patients. A reaction rate of 9-11% has been cited among inpatients with history of penicillin allergy challenged with carbapenems (11). However, a recent Italian study challenged 103 patients with positive penicillin skin tests with meropenem after negative meropenem skin testing without incident (27). The authors currently recommend penicillin skin testing in penicillin allergic patients prior to administration of carbapenems. If the skin testing is negative, the patient may be administered a carbapenem. If the penicillin skin testing is positive, the authors recommend carbapenem desensitization or graded dose challenge.

CONCLUSION

Beta-lactam antibiotic allergy is relatively common and potentially fatal. If penicillin skin testing reagents are available, penicillin skin testing provides an excellent tool for risk stratification. Patients with a history of penicillin reaction with negative penicillin skin tests have a low rate of reaction when challenged with penicillin. Patients with positive penicillin skin tests should avoid beta-lactam antibiotics if possible or undergo desensitization with the desired agent. The cross reactivity between penicillins, cephalosporins and carbapenems remains controversial and needs further studies.

REFERENCES

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Tables

Table 1: Drug Allergy Classifications

Classification	Mediators	Mechanism of tissue injury	Clinical Presentation
Type I: Immediate Hypersensitivity	Mast cells, IgE, Mast cell derived mediators	Cross linking IgE receptors on mast cells results in release of mast cell mediators. Mast cell mediators such as histamine result in vasodilation, increased vascular permeability, and smooth muscle contraction.	Anaphylaxis, urticaria, angioedema, asthma, rhinitis
Type II: Antibody mediated	IgG, IgM, complement, phagocytes	IgM and IgG antibodies bind cellular surfaces. Bound antibodies results in opsonization and phagocytosis or activation of the complement cascade.	Hemolytic anemia, thrombocytopenia, intersitial nephritis
Type III: Immune-complex mediated	IgG, IgM, complement	Circulating complexes of antibody and soluble antigen deposit in vascular basement membranes. Immune complex deposition results in complement and antibody mediated recruitment of leukocytes.	Serum sickness, vasculitis, drug fever, cutaneous eruptions
Type IV: Delayed or cellular	CD4+ (helper) T-lymphocytes, macrophages, cytokines	Macrophage activation via cytokines released from helper T Cells	Contact dermatitis, exanthems

Table 2: Several Penicillin Desensitization Protocols are Available in the Literature.

Step	Conc (mg/ml)	amount (ml)	cumulative dose (mg)
1	0.1	0.1	0.01
2	0.1	0.2	0.03
3	0.1	0.4	0.07
4	0.1	0.8	0.15
5	0.1	1.6	0.31
6	1.0	0.32	0.63
7	1.0	0.64	1.27
8	1.0	1.2	2.47
9	10.0	0.24	4.87
10	10.0	0.48	10.0
11	10.0	1.0	20.0
12	10.0	2.0	40.0
13	100.0	0.4	80.0
14	100.0	0.8	160.0
15	100.0	1.6	320.0
16	1000.0	0.32	640.0
17	1000.0	0.64	1280.0

Interval between doses is 15 minutes. Vitals and peak flows are measured between each dose and the medicine is given by the IV route. Observe patient for 30 minutes, then give full therapeutic dose.

Reference: Borish L J Allergy Clin Immunol 1987; 80: 314-19 (8).