Common drugs that cause allergic reactions

Allergies to drugs aren’t all that common—only about 5% to 10% of adverse reactions to drugs are allergic, according to the American Academy of Allergy, Asthma & Immunology (AAAAI). However, when allergic reactions to drugs do happen, they can sometimes be sudden and severe. 

But, before we delve into common drugs that lead to allergy, it’s important to clarify the terminology used to describe the untoward effects of drugs. By nature, allergies are immunological whereas adverse effects are predictable symptoms or signs related to the mechanism of a drug. Furthermore, intolerance is defined as a low threshold to adverse reactions that don’t involve the immune system. For example, if nausea, vomiting, or diarrhea are defined as adverse reactions, then a person with drug intolerance would be more likely than others to experience these symptoms.

Now that we’re copacetic with the terminology, let’s look at allergy a little further and at the 5 common pharmacological culprits of allergy.

Allergy defined

An allergy is an IgE-mediated hypersensitivity in which the body overreacts to an allergen in a reproducible fashion; it can be elicited by structurally similar compounds, including medications. Allergies may or may not abate over the course of a lifetime.

Immediate, type I hypersensitivity reactions have rapid-onset symptoms (within 1 or 2 hours of exposure) including angioedema, urticaria, bronchospasm, and anaphylaxis. 

Delayed immune reactions, or type IV hypersensitivity, can take several days to manifest and include macular, papular, or morbilliform rash. Take note that such rashes can be due to the drug itself or exacerbated by an infection. For instance, rash perceived to be caused by amoxicillin allergy could manifest due to concurrent infection with Epstein-Barr virus or HIV. 

More serious delayed immune reactions include:

• Aseptic meningitis

• Serum sickness-like reactions typified by vasculitic rash, flu-like symptomatology, arthralgia and, less commonly, proteinuria

• Stevens-Johnson syndrome, which is an iteration of toxic epidermal necrolysis marked by a red-purple rash and blistering of the mucous membranes/skin

Antibiotics

The most common antibiotic that elicits an allergic reaction is penicillin (think penicillin G)—with 8% of Americans reporting this allergy—followed by sulfonamides and tetracyclines. Of note, most people who report penicillin allergy don’t have a true allergy, as only 1 of 20 experience a clinically meaningful IgE-mediated reaction following oral re-challenge. Anaphylaxis is relatively rare and occurs in 1–4 patients per 10,000 penicillin exposures, with an estimated 10% of these reactions turning deadly.

As detailed in a small case-control study published in the Journal of Allergy and Clinical Immunology, researchers found, on multivariable analysis, that only family history of penicillin allergy remained contributory to penicillin allergy, as well as the IL4 single nucleotide polymorphisms (SNPs) rs11740584 (P = 0.012), rs10062446 (P = 0.021), and rs2070874 (P = 0.035). Despite these results, it remains to be elucidated whether a history of atopy or a family history of antibiotic allergy increases the allergic risk of antibiotics.

Regarding more serious delayed-hypersensitivity reactions, cephalosporins (particularly cefaclor) and sulfonamides can result in serum sickness. Sulfonamides can precipitate Stevens-Johnson syndrome, and trimethoprim or co-trimoxazole can lead to aseptic meningitis.

Antibiotic allergy most commonly occurs in adults between age 20 and 49 years, with beta-lactam antibiotic allergy twice as likely in women. Parenteral administration is linked to higher odds of allergic reactions than oral administration. 

If previous medical history of antibiotic allergy is assured, then no testing is necessary. If uncertain, antibiotic allergy could be tested via serum specific IgE to penicillin. Of note, most people who are allergic to penicillin are not allergic to the whole molecule. Rather, they’re allergic to degradation products of penicillin attached to self-carrier molecules. Moreover, serum-specific IgE testing covers major antigens but not minor determinants, thus a negative result does not exclude allergy with the sensitivity of the test as low as 45%. Cephalosporin allergy can be tested with skin-prick or intradermal testing. 

Now time for the $64,000 question: Can people with an antibiotic allergy take the antibiotic if necessary? It depends. With acute IgE-mediated hypersensitivity, the reaction will likely recur, and the drug should be administered only if the benefits outweigh the risks. Of note, desensitization can be instituted, as with penicillin treatment for neurosyphilis. Patients with severe delayed reactions should not receive antibiotics that they’re allergic to, although minor reactions, such as rash, do not preclude their use, as is commonly the case with amoxicillin and other beta-lactams. 

NSAIDs

Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen or naproxen, can lead to allergic reactions. Symptoms include hives, itching, swelling, nasal congestion, wheezing, shortness of breath, and feeling faint/passing out. Most patients who are allergic to aspirin are also allergic to other NSAIDs. On a related note, acetaminophen allergy is also possible.

In individuals with asthma and aspirin allergy, nasal polyps and chronic sinusitis can result, with severe shortness of breath, nasal congestion, and wheezing all on the table. This condition is referred to as aspirin-exacerbated respiratory disease.

In patients who already have chronic idiopathic urticaria, between 20% and 40% will experience worsening hives and angioedema with aspirin or NSAID exposure.

Something to watch out for is that aspirin/NSAID allergy may take years to manifest. In other words, someone could be taking aspirin regularly for years without incident, and then suddenly develop an allergic reaction.

Diagnosis of aspirin or other NSAID allergy is clinical, with no blood or skin testing available. However, in controlled settings, allergists sometimes administer an oral challenge when it is unclear whether the patient is allergic to all NSAIDs. Treatment is complete avoidance, with particular attention paid to labels of both prescription drugs and over-the-counter products for variations of aspirin or NSAIDs.

Sulfa drugs

Although poorly defined, sulfa drug allergy is commonly reported. Between 3% and 6% of patients report adverse reactions, but with only a small number that are immune-mediated. The issue with labeling a patient with sulfa allergy is that it complicates the prescription of a wide range of drugs—not only antibiotics but also other medications containing sulfur, such as captopril, sulfate salts/morphine, heparin, ferrous sulfate, and thiazide diuretics. Cosmetics, soaps, and preservatives in food can also contain sulfur. Thus, because plenty of things contain sulfur, an improper diagnosis of sulfa allergy can cause consternation for the patient.

Plus, people who have had an allergic reaction to an antibiotic are at increased risk of a reaction to sulfonamide antibiotics. 

Whenever feasible, the diagnosis of sulfa allergy should be re-evaluated. Things to keep in mind include non-immune mediated intolerance or adverse effects, as well as delayed immune reactions, which are T -cell-mediated. Furthermore, knowing which specific drug leads to a “sulfa” allergy can help clinicians choose the best prescription for that patient.

Neuromuscular-blocking agents

Neuromuscular blocking agents (NMBAs)—including atracurium, succinylcholine, or vecuronium—are frequently administered during surgery to prevent patient movement and injury, to make endotracheal intubation easier, or for any reason to induce muscle relaxation. NMBAs are also the leading cause of immediate, type I hypersensitivity reactions (including anaphylaxis) during surgery, contributing between 50% and 70% of allergic reactions during anesthesia. In contrast, an estimated 20% to 35% of such allergic reactions are non-IgE mediated.

According to the authors of a review article published in the International Journal of Immunopathology and Pharmacology: “Among all drugs used for general anaesthesia, NMBAs seem to play a predominant role in the incidence of severe adverse reactions. Since their introduction in modem anaesthesia practice, much progress has been made in the identification of adverse reactions and their potential mechanisms. However, despite the introduction of newer drugs in clinical practice, the incidence of serious, immediate hypersensitivity-type reactions has remained virtually unchanged,” the authors wrote.

The precise mechanisms of NMBA allergy remain to be elucidated, and there is no gold standard for the diagnosis of such an allergy. Instead, diagnosis is rooted in clinical history, positive skin tests, and, if available, specific IgE testing. 

“In view of the constantly evolving anesthesiologic practices, and of the complexity of allergy investigation, an active policy to identify patients at risk and to provide any necessary support to anaesthetists and allergologists should be promoted,” the authors concluded.

Monoclonal antibodies

Monoclonal antibodies (mAbs), such as cetuximab and rituximab, are the foundation of targeted therapies for cancer and inflammatory disease. The rise in the use of these biologics has coincided with a concomitant rise in hypersensitivity reactions, which preclude the deployment of first-line therapies. But, investigators have recently elucidated different subtypes of hypersensitivity reactions, thus allowing specialists to manage these reactions via patient-specific desensitization protocols. 

According to the results of a 2018 study published in The Journal of Allergy and Clinical Immunology, researchers compared phenotypes, endotypes, and biomarkers of hypersensitivity reactions to 16 mAbs for 104 patients with outcomes of 526 subcutaneous and intravenous desensitizations.

They classified hypersensitivity reactions into four patterns: type I-like reactions (63%), cytokine-release reactions (13%), mixed type I/cytokine-release reactions (21%), and delayed type IV reactions (3%). Biomarkers included skin test, tryptase, and IL-6 levels. 

“The new classification allows for personalized patient evaluation and permits more accurate assessment of hypersensitivity reactions to mAbs,” according to the AAAAI. “This approach provides precision management recommendations for desensitization. Desensitization provides a safe and effective re-treatment option allowing patients to remain on culprit mAbs as first line therapy.”