Navigating β-Lactam Allergies: Importance of Patient History and Documentation

Antibiotics are one of the most frequently prescribed medications in both the inpatient and outpatient settings.1,2 The Centers for Disease Control and Prevention (CDC) provides data citing millions of antibiotic prescriptions written by providers each year.1,2 According to its 2023 Antimicrobial Use Option Data Report, approximately 56% of ICU patients in the United States receive broad-spectrum antibiotics for hospital-onset infections.1 β-Lactam antibiotics, such as penicillins and cephalosporins, are first-line therapy options for many common infections.1,2 Unfortunately, β-lactam allergies are the most commonly listed drug allergies in the electronic health record.3 Approximately 10% of patients in the United States report some type of β-lactam allergy, but only 10% of those patients are found to be truly allergic.3,4 In a meta-analysis of 1391 patients, 95% of “penicillin allergic” inpatients were negative upon testing, and 96% of pediatric patients with listed “penicillin allergies” had negative skin testing followed by negative oral challenges.5Many patients may not understand the differences between an intolerance and an allergy and incorrectly report an allergy to their health care provider.3 When allergies are documented incorrectly or incompletely, patients may be unnecessarily exposed to broad-spectrum antibiotics, which can potentiate negative individual and public health effects like adverse drug reactions, antimicrobial resistance, longer hospital stays, higher hospital costs, and treatment failures.3,6,7 Not only is the type and severity of allergy important to note, but the timing of the reaction may influence treatment decisions. Approximately 50% of patients with immunoglobin E (IgE)–mediated allergic reactions lose sensitivity within 5 years, and 80% within 10 years.8Understanding the different types of adverse drug reactions is essential for effective diagnosis and management. An adverse drug reaction is an undesirable or harmful effect caused by a medication when taken correctly and includes both drug hypersensitivities and intolerances (see Figure9). A drug hypersensitivity is a type of adverse drug reaction that encompasses allergic reactions and other exaggerated immune responses to medications.3,9 It involves mechanisms such as the production of antibodies or activation of T cells against the drug, leading to a variety of symptoms.3,9 A drug allergy is a subset of hypersensitivity and is an immune-mediated reaction where the immune system mistakenly identifies a drug as harmful and mounts a defense against it.3,9 This defense can result in symptoms ranging from mild rashes to severe anaphylaxis and pose significant health risks.3,9 A drug intolerance refers to an inability to tolerate certain side effects of a medication at normal doses, often due to genetic variations affecting drug metabolism.9 Unlike allergic reactions, intolerances do not involve the immune system but can still cause discomfort and impact treatment efficacy.9Hypersensitivity reactions are exaggerated immune responses that can be classified into immediate and delayed types, as noted in Table 1.3,9 Immediate hypersensitivity, classified as type I, occurs within minutes of exposure to an antigen and is mediated by IgE antibodies.3,9 These antibodies bind to mast cells and basophils, triggering the release of histamine and other inflammatory mediators.3,9 Types II and III hypersensitivity reactions are considered nonimmediate and involve immunoglobin G and M (IgG and IgM) antibodies, resulting in cytotoxic and immune complex–mediated damage, respectively.3,9Delayed hypersensitivity is classified as type IV, typically takes days to develop, and is mediated by T cells rather than antibodies.3,9 These T cells release cytokines that recruit and activate other immune cells, causing local tissue inflammation and damage.3,9Hypersensitivities to β-lactams primarily involve IgE-mediated mechanisms, or type I hypersensitivity.10 This mechanism involves the binding of IgE antibodies to the β-lactam, resulting in symptoms such as urticaria, angioedema, bronchospasm, and anaphylaxis.3,9 β-Lactams can also be responsible for types II through IV hypersensitivity, although at a lower incidence.10 Type II hypersensitivity occurs when cells bound to β-lactams are targeted by IgG or IgM antibodies, resulting in cytotoxicity and cell destruction.3,9 This manifests in conditions such as hemolytic anemia, thrombocytopenia, and granulocytopenia.3,9 A type III hypersensitivity occurs when a β-lactam forms an immune complex with antibodies and deposits into tissues.10 This causes complement activation and results in inflammatory reactions such as serum sickness, where patients may experience fever, rash, and joint pain.3,9 Type IV hypersensitivity involves the activation of T cells by β-lactam antigens, resulting in a range of symptoms from mild to severe that include dermatitis, maculopapular rashes, and Stevens-Johnson syndrome.3,9Understanding the type of reaction can help prescribers understand the likelihood of being able to safely use a similar antibiotic or whether they would need to consider a structurally unrelated option. Cross-reactivity is when a patient allergic to one β-lactam antibiotic experiences a reaction to another β-lactam with a similar chemical structure.11 It was historically believed that the β-lactam ring itself was responsible for cross-reactivity, but more recent research has shown that the R1 side chain is the most likely culprit.11,12When evaluating β-lactam allergies, distinguishing if the allergic reaction occurred to a penicillin or a cephalosporin is important in assessing future antibiotic safety. Cross-reactivity with penicillin is highest with first-generation cephalosporins, however the risk is still relatively low and estimated at less than 10%.11,12 The risk further decreases with later generations of cephalosporins and is estimated at less than 1% for third- and fourth-generation cephalosporins.11,12 Some cephalosporins have unique side chains that do not share similarities with penicillin, essentially making cross-reactivity unlikely.11,12 In fact, many of the injectable β-lactams used in the inpatient setting are dissimilar to penicillin and would not be expected to cross-react.11–13 These injectable β-lactams include Given the potential effect on patient safety and treatment efficacy, a thorough allergy assessment is a crucial component of care.5 Identifying allergies ensures that health care practitioners can avoid administering medications or substances that could trigger adverse reactions. Appropriate allergy identification also reduces mislabeling of intolerances or side effects as immune-mediated hypersensitivities, a practice that can result in inappropriate avoidance of medications that may be preferred treatment options.The patient interview is essential for clarifying allergies and ensuring accuracy of documentation.8 The health care practitioner should ask detailed questions to differentiate between true allergic reactions and other adverse effects.8 Example questions are provided in Table 2. Simply asking the patient “What happened when you took the drug?” can help identify symptoms indicative of an allergy, such as angioedema or urticaria, versus nonallergic symptoms like nausea or headache.8 In the event of a true allergic reaction, understanding whether the reaction occurred after the first dose or later doses helps distinguish between immediate (IgE-mediated) or delayed onset (non–IgE-mediated) reactions.3,8,9 Asking how the reaction was managed may provide insights into the severity and type of reaction.8 For example, a reaction that was managed with epinephrine and antihistamines may clue you into an IgE-mediated hypersensitivity.8The time elapsed since the reaction and the patient’s tolerance of similar medications can further clarify the allergy status.8,10 The length of time since the allergic reaction can provide insights into the likelihood of the allergy persisting.10 Research has demonstrated that allergies can diminish over time, especially if the initial reaction was mild or if the patient has not been re-exposed to the allergen.10,14 For instance, a patient who experienced a mild rash several years ago may no longer react to the same medication, whereas a recent severe reaction might indicate a higher risk of recurrence.3,9 Asking about the tolerance of similar antibiotics helps determine cross-reactivity and the accuracy of the allergy label.8 If a patient has safely used other β-lactam antibiotics, it suggests that the initial reaction may have been specific to a particular drug rather than the entire class.11A clinical decision tool, PEN-FAST, was designed to assess the risk of penicillin allergies.14,15 Using the information obtained from the patient interview, this tool can help health care practitioners determine whether a reported penicillin allergy is likely to be genuine or if it can be safely delabeled.15,16 The tool uses these criteria to evaluate the allergy15,16: A PEN-FAST score of less than 3 is associated with a high negative predictive value, meaning there is a low likelihood of a true penicillin allergy.If a patient is unable to provide clarification of their allergy history, a quick medical record review may help provide additional insight.8 Medical record review involves examining a patient’s medical history to identify any documented allergic reactions or previous exposure to allergens, such as β-lactams. The medical record can potentially help you determine if a patient has tolerated a similar medication since the allergy was documented. The record may also provide further details of the allergic reaction if it occurred within your health system.If it is determined that the reaction was experienced within your health system, the date the reaction occurred can help to establish a timeline and contextualize the reported allergy, since allergies that occurred more than 10 years ago may no longer be relevant.9 Progress notes from the admission where the allergy occurred may contain key terms such as urticaria, hives, anaphylaxis, or dyspnea, which indicate the nature and severity of the reaction.3,9Lastly, the patient’s inpatient and outpatient medication history may reveal β-lactam prescriptions that the patient has tolerated since the occurrence of the reaction.15,16 If the patient has tolerated β-lactams without adverse reactions, it may suggest that the initial allergy label was incorrect or that the patient has outgrown the allergy.8Penicillin skin testing is a diagnostic tool used to determine if a patient has a true penicillin allergy.17 This involves pricking the skin and applying a small amount of penicillin or its derivatives to observe for an allergic reaction, typically a wheal and flare response.17 Skin testing is particularly necessary for patients with a history of type I hypersensitivities or those with unclear histories who require penicillin or related antibiotics for treatment.17 This test is highly effective at ruling out IgE-mediated allergies.17Direct oral challenge involves administering a therapeutic dose of penicillin or a related antibiotic to a patient under controlled conditions to refute or confirm a reported allergy.18 This method is considered for patients with a low-risk penicillin allergy, often identified using tools like the PEN-FAST.18 Direct oral challenge is a quicker and less resource-intensive alternative to skin testing, making it suitable for outpatient settings.18 It is particularly useful for patients with vague or historical allergy reports, helping to delabel inaccurate allergy records and allowing safe use of penicillin.18Immediate type I hypersensitivity reactions are generally considered more severe due to potentially life-threatening symptoms.3,9 However, the CDC classifies nonurticarial rash, localized rash, and delayed onset rash (> 24 h) as low-risk allergies, meaning other β-lactams can likely be prescribed safely.19 In those with more severe reactions where no other safe and effective alternative medication is available, desensitization protocols may be employed under strict medical supervision.20 Types II and III reactions also pose significant risks and are generally not rechallenged due to the risk of irreversible, systemic immune activation upon re-exposure and lack of validated desensitization protocols.3,9 Delayed hypersensitivity reactions (type IV) may be rechallenged depending on the circumstance and under controlled conditions.3,9 For example, contact dermatitis is a milder reaction and may be rechallenged safely and successfully, whereas Stevens-Johnson syndrome or toxic epidermal necrolysis should never be rechallenged due to potentially fatal outcomes.3,9 For drug intolerances, which do not involve the immune system, rechallenging with different dosages or drugs within the same class is feasible and often effective.8Desensitization is a process used for patients who need a specific medication but have a confirmed allergy to it.20 It is typically reserved for cases where the benefits of the medication outweigh the risks of the allergic reaction.20 Common indications for desensitization include syphilis infection during pregnancy and neurosyphilis where penicillin is the drug of choice.19The process involves administering gradually increasing doses of the allergen under strict medical supervision until the patient can tolerate the therapeutic dose without an allergic reaction.20 The drug is administered at a concentration and rate that causes an immune response but does not result in a systemic reaction.20Although protocols exist for desensitization in the outpatient setting using oral antibiotics, a patient’s first desensitization is typically performed in the inpatient setting under close monitoring.20 These patients are likely to be admitted to an intensive care unit, where they can be monitored more frequently and under the care of physicians with the ability to treat anaphylactic reactions.20 Desensitization protocols are generally very complex, which requires the patient to be in a setting where nurses have fewer patients to care for and can devote necessary time to drug titration and patient monitoring.20 An example protocol can be found in Table 3.Patients undergoing desensitization should be monitored very strictly for the first 15 minutes of the first dose and for at least the first 5 minutes of subsequent dose escalations.20 If a patient experiences a reaction while receiving the protocol, the infusion should be stopped, and treatment should be administered.20 The preferred treatment may differ by institution, but mild reactions (eg, itching, hives, rash) with hemodynamic stability typically respond to diphenhydramine, while moderate reactions (eg, mild dyspnea, angioedema with hemodynamic stability) may necessitate the addition of steroids and H2 blockers to diphenhydramine.20 In both cases, the infusion is typically paused.20 Once the reaction resolves, the protocol can be reinitiated by repeating the step at which the reaction occurred.20 Severe reactions with hypotension, throat swelling, and respiratory distress require immediate cessation of the infusion and administration of epinephrine.20 The risk of continued desensitization must be weighed carefully at this point to determine if the protocol should continue; this is a decision that should be made by the prescriber.20Once the protocol is completed, the patient’s immune system is desensitized to the allergen.20 Following successful desensitization, patients can be downgraded from more intensive monitoring to regular hospital units.20 If major interruptions in therapy occur (eg, missed dose), it may be necessary to repeat the protocol to ensure patient safety with continued administration.20 Lastly, desensitization is temporary, and patients must begin regularly scheduled doses of the antibiotic to maintain the effects.20Alternative antibiotic options are considered when a patient has a confirmed allergy to penicillin or other β-lactam antibiotics and cannot undergo desensitization.17 These alternatives include antibiotics from different classes, such as macrolides, fluoroquinolones, or tetracyclines, which do not share the β-lactam structure.17More distant β-lactam relatives include carbapenems and aztreonam, which are commonly prescribed in the inpatient setting in the context of penicillin allergies.21,22 Carbapenems are broad-spectrum β-lactams that should be reserved for multidrug-resistant organisms to preserve their efficacy.21 Although somewhat structurally related to penicillin, carbapenems have a cross-reactivity rate of less than 1% and are frequently used in patients with penicillin allergies.21 Aztreonam is a monobactam antibiotic with no cross-reactivity to penicillin that is frequently prescribed for patients with reported allergies.22 While aztreonam covers many gram-negative organisms, including Pseudomonas aeruginosa, it is often more costly and has reduced susceptibilities compared with antipseudomonal β-lactams.22Choosing an alternative antibiotic can ensure effective treatment while avoiding the risk of allergic reactions and treatment delays. This approach is particularly important for patients with severe or life-threatening allergies, ensuring patient safety and therapeutic efficacy.17Assessing and managing drug allergies is a critical component of patient care that ensures safety and efficacy in treatment. Proper allergy assessment allows health care practitioners to use the most effective medications for treating infections and other conditions and prevent unnecessary avoidance of first-line treatments. Methods like medical record reviews and patient interviews provide valuable insights into a patient’s allergy history, helping health care practitioners to make informed decisions. Tools like PEN-FAST aid in evaluating the likelihood of penicillin allergies, while penicillin skin testing and direct oral challenges help confirm or refute reported allergies. Desensitization protocols offer solutions for patients who require specific medications despite confirmed allergies, and alternative antibiotic options ensure effective treatment for those who cannot tolerate β-lactams.