The Pre-brief
Beta-lactam intolerance is often misconstrued as an “allergy” and subsequently documented in the patient chart, forever committing the patient to inferior or unnecessarily broad-spectrum antibiotics.
Although they are the most common cause of drug-induced delayed rashes, beta-lactam antibiotics infrequently cause a true IgE mediated reaction. This means we have an opportunity to challenge the allergy labels in the patient chart and be better antibiotic stewards. This is especially true in the emergency department setting where many patients are first started on therapy.
Introduction
Beta-lactam antibiotics, which include penicillins, cephalosporins, carbapenems, and monobactams, are the most common antibiotic class implicated in hypersensitivity reactions. Beta-lactam adverse drug reactions are documented in up to 15% of patient charts, and these reactions often go unverified, resulting in avoidance of the drug class.
Misclassified allergies
It is common to encounter patients in the ED with an indicator on their profile for penicillin allergy and much of the time the reaction type is undocumented. This is concerning because it could be an unverified allergy that is recorded in the patient’s chart incorrectly after a non-immunologic reaction such as nausea, headache, or fatigue. These adverse drug reactions are not true allergies and may prevent a patient from receiving a beta-lactam antibiotic.
Children may have had an observed allergic reaction to a beta-lactam; however, it is likely the observed reaction was related to a viral exanthem rather than the medication itself. It is expected that the incidence of true beta-lactam allergies in children is low. Several studies suggest that 75% of penicillin allergy labels are obtained by the age of three and are either not truly allergic in nature, low risk for immediate hypersensitivity, or are a potential antibody-mediated reaction that may have waned over time. This is important not just because of misclassification but because IgE-mediated reactions to beta–lactams may self-resolve over time. 80% of patients who tested positive for a penicillin allergy via penicillin skin test and 60% who tested positive for a cephalosporin allergy via cephalosporin skin test are no longer positive after 10 and 5 years, respectively. Additionally, mild reactions that are T cell-mediated do not necessarily re-occur with re-challenge.
Patients may also have an allergy label due to a family history of penicillin allergy which has no relation to the risk of a true allergic reaction.
Sacco and colleagues completed a study looking to identify if inpatient penicillin allergy testing changed clinical outcomes during hospitalization. Patients were admitted to the hospital with a documented penicillin allergy and were subsequently skin tested and challenged; 95% of these patients were not truly penicillin-allergic and their allergy labels were able to be removed from their charts.
How are true allergies classified?
If a true allergy exists, the body reacts to the allergen by producing antibodies called immunoglobulins (IgE) which release chemicals causing a reaction. The reaction causes symptoms in the throat, lungs, nose and skin. The Gell and Coombs classification system describes the reactions and categorizes them into four subtypes:
Type I IgE Mediated
Onset: immediately after exposure, within one hour up to six hours
Examples of a hypersensitivity reaction: angioedema, bronchospasm, anaphylaxis, extensive urticaria, airway compromise
Note: Anaphylaxis is rare for penicillin: 0.001% for the parenteral route of administration and 0.0005% for oral route of administration.
Type II IgE Mediated (Cytotoxic)
Onset: Usually less than 72 hours but could occur in up to 15 days
Examples of a hypersensitivity reaction: hemolytic anemia, thrombocytopenia
Type III IgE Mediated (immune complex)
Onset: 1-3 weeks after the start of therapy
Examples of a hypersensitivity reaction: serum sickness, arthralgia, lymphadenopathy, vasculitis
Type IV T-Cell Mediated (not IgE mediated)
Onset: days to weeks after the start of therapy
Examples of a hypersensitivity reaction: DRESS, maculopapular rash, fixed drug eruption, Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis
Note: The most common beta-lactam reaction is a maculopapular rash
What are the ramifications of mislabeled allergies?
The allergy section in the patient chart, although intended to act as a safety barrier in preventing patient harm, has inadvertently become a catch-all of vague, unreconciled adverse drug events. These events could be a true antibody-mediated reaction that warrants a hard stop for future ordering of beta-lactams, or could be a potentially manageable side effect that has resulted in any or all of the following:
- Increased risk of adverse effects:
- Avoidance of penicillins and cephalosporins in patients with unverified penicillin allergy is associated with increased rates of clostridium difficile; Clostridium difficile is considered a public health threat by the CDC and prevalence has increased by 23% in US patients admitted to hospitals with a penicillin allergy documentation compared to those without a penicillin allergy documentation.
- Increased use of inferior antibiotics:
- Patients are subsequently provided alternative antibiotics which could be broader spectrum, have lower efficacy, and increased side effects. Alternative agents include vancomycin, clindamycin, gentamicin, and fluoroquinolones.
- Increased antibiotic resistance:
- Use of broader coverage may increase risk of multidrug resistant organisms
- One study has shown that patients with documented penicillin allergy had a 14% increased prevalence of methicillin resistant staphylococcus aureus (MRSA) and 30% increased prevalence of vancomycin resistant enterococcus (VRE) compared to patients without documentation.
- Increased hospital length of stay:
- This is likely due to increased treatment failure from the use of inferior antibiotics
Beta-lactam cross-reactivity: it’s a side chain Issue
A common misunderstanding is that if a patient is allergic to penicillin they are also allergic to all cephalosporins, carbapenems, and monobactams. Although cross-reactivity is possible, the risk is dependent on the chemical structure. Penicillins and cephalosporins have a common core beta-lactam ring; however, cross-reactivity is dependent on the R1 side chain, which distinguishes the two classes. If penicillin and cephalosporin share an identical R1 side chain and a patient has an anaphylactic reaction to one of those medications, then the risk for cross-reactivity is likely with the other. The same holds true within the drug class. If two cephalosporins share the same side chain, then cross-reactivity is likely.
In general, cross reactivity risk between penicillins and cephalosporins is <2% and cross reactivity risk decreases as you move down the cephalosporin generations (ex. increased risk of cross reactivity with a penicillin and a 1st generation cephalosporin compared to penicillin and a 4th generation cephalosporin) because the first generation cephalosporins have more similar R1 side chains to penicillins compared to later generations. Cross reactivity between penicillins and carbapenems is <1% and between carbapenems and cephalosporins is also <1%. Monobactams have no cross reactivity between penicillins or carbapenems and generally serve as a good alternative agent. For the most part this is true for cross reactivity to cephalosporins except ceftazidime which has an identical R1 side chain to aztreonam. The below is an adaptation of the cross reactivity chart developed by Zagursky and colleagues depicting medications with identical side chains. Interestingly cefazolin has no shared side chains among penicillins or cephalosporins. Cross reactivity among side chains that are similar but not identical and R2 groups have been reported.
Treatment algorithm
Blumenthal and colleagues provide an excellent algorithm to assist with decision-making of using a beta-lactam in patients with documented beta-lactam allergies. Below is an adaptation:
One interesting approach that Maguire and colleagues took was to increase penicillin and cephalosporin use in patients documented with penicillin or cephalosporin hypersensitivity by creating a clinical pathway in the emergency department. The pathway assesses the type of reaction the patient experienced and provides clinical decision support to determine if a penicillin/cephalosporin can be used at full dose, tested using a test dose procedure, or avoided. 310 beta-lactam antibiotic test doses were administered (85% cephalosporin’s vs 12% penicillin’s vs 4% carbapenems). 10 patients (3.2%; 95% CI 1.6%-5.9%) had a hypersensitivity reaction of which five had beta-lactams administered that were not in line with the protocol. 47% of patients had their allergy records updated (p <0.001%). The investigators concluded that implementation of such a procedure is a feasible and standardized approach to beta-lactam allergy labels, likely improving patient safety and quality.
The Debrief
- The rate of true IgE-mediated reactions to beta-lactams is 0.001%- 0.0005%.
- The most common beta-lactam reaction is a maculopapular rash which is not a true IgE mediated reaction.
- Documented beta-lactam allergies should be reviewed to determine if a true allergy exists or if the allergy is a mislabel. Mislabeled allergies should be removed from the chart to prevent patients from being precluded from future beta-lactam therapy.
- Cross-reactivity between beta-lactams is dependent on the R1 side chain of the chemical structure.
- Identical R1 side chain: true cross-reactivity is likely and an alternative agent may be considered.
- Similar R1 side chain: use clinical judgment to determine if the reaction should be challenged.
- Different R1 side chain:, cross-reactivity is unlikely and beta-lactam use may be appropriate.
References
- Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ. Antibiotic allergy. Lancet. 2019;393(10167):183-198. doi:10.1016/S0140-6736(18)32218-9
- Stone CA Jr, Trubiano J, Coleman DT, Rukasin CRF, Phillips EJ. The challenge of de-labeling penicillin allergy. Allergy. 2020;75(2):273-288. doi:10.1111/all.13848
- Sacco KA, Bates A, Brigham TJ, Imam JS, Burton MC. Clinical outcomes following inpatient penicillin allergy testing: a systematic review and meta-analysis. Allergy 2017; 72: 1288–96.
- Riedl MA, Casillas AM. Adverse drug reactions: types and treatment options. Am Fam Physician. 2003;68(9):1781-1790.
- Macy E. Penicillin and beta-lactam allergy: epidemiology and diagnosis. Curr Allergy Asthma Rep. 2014;14(11):476. doi:10.1007/s11882-014-0476-y
- Zagursky RJ, Pichichero ME. Cross-reactivity in β-Lactam Allergy. J Allergy Clin Immunol Pract. 2018;6(1):72-81.e1. doi:10.1016/j.jaip.2017.08.027
- Maguire M, Hayes BD, Fuh L, et al. Beta-lactam antibiotic test doses in the emergency department. World Allergy Organ J. 2020;13(1):100093. Published 2020 Jan 7. doi:10.1016/j.waojou.2019.100093
