Penicillin Allergy Delabeling Can Decrease Antibiotic Resistance, Reduce Costs, and Optimize Patient Outcomes

Antibiotics are one of the most frequently prescribed medications in both inpatient and outpatient settings.^1,2 More than 266 million courses of antibiotics are prescribed annually in the outpatient setting; 49.9% of hospitalized patients were prescribed ≥ 1 antibiotic during their hospitalization.^1,2 Among all classes of antibiotics, penicillins are prescribed due to their clinical efficacy, cost-effectiveness, and general safety for all ages. Unfortunately, penicillins also are the most common drug allergy listed in medical records. Patients with this allergy are consistently treated with broad-spectrum antibiotics, have more antibiotic resistant infections, incur higher health care costs, and experience more adverse effects (AEs).^3,4

Drug allergies are distinguished by different immune mechanisms, including IgE-mediated reaction, T-lymphocyte-mediated mild skin reactions, and severe cutaneous adverse reactions (SCAR), or other systemic immune syndromes, such as hemolytic anemia, nephritis, and rash with eosinophilia.³ Although drug allergies should be a concern, compelling evidence shows that > 90% of patients labeled with a penicillin allergy are not allergic to penicillins (and associated β-lactams).^3,4 Although this evidence is growing, clinicians still hesitate to prescribe penicillin, and patients are similarly anxious to take them. This article reviews the health care consequences of penicillin allergy and the application of this information to military medicine and readiness.

Penicillin Allergy Prevalence

Since their approval for public use in 1945, penicillins have been one of the most often prescribed antibiotics due to their clinical efficacy for many types of infections.³ However, 8 to 10% of the US population and up to 15% of hospitalized patients have a documented penicillin allergy, which limits the ability to use these effective antibiotics.^3,4 Once a patient is labeled with a penicillin allergy, many clinicians avoid prescribing all β-lactam antibiotics to patients. Clinicians also avoid prescribing cephalosporins due to the concern for potential cross-reactivity (at a rate of about 2%, which is lower than previously reported).³ These reported allergies are often not clear and range from patients avoiding penicillins because their parents exhibited allergies, they had a symptom that was not likely allergic (ie, nausea, headache, itching with no rash), being told by their parents that they had a rash as a child, or experiencing severe anaphylaxis or other systemic reaction.^3,4 Despite the high rates of documented penicillin allergy, studies now show that most patients do not have a serious allergy; < 1% of the population has a true immune-mediated penicillin allergy.^3,4

Broad-Spectrum Antibiotic Risks

Even though penicillin allergies are often not confirmed, many patients are treated with alternative antibiotics. Unfortunately, most alternative antibiotics are not as effective or as safe as penicillin.^3,4 Twenty percent of hospitalized patients will experience an AE related to their antibiotic; 19.3% of emergency department visits for adverse drug reactions (ADRs) are from antibiotics.^5,6 Sulfonamides, clindamycin, and quinolones were the antibiotics most commonly associated with AEs.⁶

In a large database study over a 3-year period, > 400,000 hospitalizations were analyzed in patients matched for admission type, with and without a penicillin allergy in their medical record.⁷ Those with a documented penicillin allergy had longer hospitalizations; were treated with broad-spectrum antibiotics; and had increased rates of Clostridium difficile (C difficile), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE).^7,8 In addition to being first-line treatment for many common infections, penicillins often are used for dental, perinatal, and perioperative prophylaxis.^1,3 Nearly 25 million antibiotics are prescribed annually by dentists.¹ If a patient has a penicillin allergy listed in their medical record, they will inevitably receive a second- or third-line treatment that is less effective and has higher risks. Common alternative antibiotics include clindamycin, fluoroquinolones, macrolides, and vancomycin.^3,7,8

Clindamycin and fluoroquinolones are associated with C difficile infections.^9,10 Fluoroquinolones come with a boxed warning for known serious ADRs, including tendon rupture, peripheral neuropathy, central nervous system effects, and are known for causing cardiac reactions such as QT prolongation, life-threatening arrhythmias, and cardiovascular death.^11,12 Fluoroquinolones are associated with an increased risk for VRE and MRSA, in more than any other antibiotic classes.^3,7,12,13

Macrolides, such as azithromycin and clarithromycin, are another common class of antibiotics used as an alternative for penicillins. Both are used frequently for upper respiratory infections. Known ADRs to macrolides include gastrointestinal adverse effects (AEs) (ie, nausea, vomiting, diarrhea, and abdominal pain), liver toxicity (ie, abnormal liver function tests, hepatitis, and liver failure), and cardiac risks (ie, QT prolongation and sudden death). When compared with amoxicillin, there was an increased risk for cardiovascular mortality in those patients receiving macrolides.^14,15

Vancomycin is known for its potential to cause “red man syndrome,” an infusion-related reaction causing redness and itching as well as nephrotoxic and hematologic effects requiring close monitoring.³ Vancomycin is less effective than methicillin in clearing MRSA or other sensitive pathogens; however, vancomycin is used in patients with a penicillin allergy label.^16-18 Intrapartum antibiotic use of vancomycin for group B streptococcus infection was associated with clinically significant morbidity and ADRs.^19,20 Perioperatively, patients with penicillin allergies developed more surgical site infections due to the use of second-line antibiotics, such as vancomycin or others.²¹