According to the CDC, in 2020 there were over 200 million outpatient antibiotic prescriptions in the US.1 This is a substantial number and confirms that antibiotics are one of the most frequently prescribed classes of medications. Reported antibiotic allergies are just as common, particularly antibiotics from the penicillin class. Past data have shown that around 10% of the US population reports an allergy to penicillin; however, less than 1% of the population has true immunoglobulin E (IgE)-mediated allergic reactions.2 Furthermore, the CDC states that around 80% of individuals with IgE-mediated penicillin allergy lose their sensitivity after around 10 years.2 Antibiotics from other beta-lactam classes are often linked with penicillin allergies leading to an overall decreased utilization of beta-lactam antibiotics in patients with penicillin allergy.3 These reported allergies are of concern because more broad-spectrum antibiotics are often used in the place of beta-lactams and can lead to several untoward outcomes including inadequate treatment, adverse drug reactions, and increased healthcare costs.4 The intent of this review is to educate NPs on the consequences of reported penicillin allergies as well as different approaches to delabeling erroneous allergies that can be utilized in clinical practice.

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Background

Penicillins and other beta-lactams

The discovery of penicillin in 1928 was a turning point in modern medicine. It would be a little over a decade later that the first systemic dose of penicillin was administered.5 The first trials of systemic penicillin ushered in a "golden age" of antibiotic research which eventually resulted in the discovery of several modern classes of antibiotics.5 Penicillins are a subgroup of the beta-lactam class of antibiotics, which also includes cephalosporins, carbapenems, monobactams, and beta-lactamase inhibitors.6 They are classified together because of a biochemically similar 3-carbon and 1-nitrogen (beta-lactam) ring.6 This beta-lactam ring is often a source of concern with drug allergies, particularly for cross-reactivity between beta-lactam drug groups. Previous literature overestimated the penicillin-cephalosporin cross-reactivity rate to be around 10%; however, more modern studies have found that this is more dependent on each antibiotic's unique chemical side chain and immunologically mediated cross-reactivity rates may be as low as less than 1%.3,4 Full side-chain comparison charts should be utilized when the question of cross-reactivity arises.3 Much of historically high rates of cross-reactivity between cephalosporins and penicillins may have been related to early cephalosporin formulations being contaminated with penicillin.7 Beta-lactam antibiotics are advantageous as they offer varying degrees of antimicrobial coverage, are generally well-tolerated with minimal adverse drug reactions, and often are less cost-prohibitive than other antibiotic classes.6

Types of adverse drug reactions

Allergic reactions to medications are classified as hypersensitivity reactions (HSRs), which are a subset of adverse drug reactions (ADRs).7 ADRs are any unexpected medication effect occurring at normal, therapeutic doses, while HSRs are ADRs that are immunologically mediated.7 The Gell-Coombs classification system is commonly utilized to describe HSRs (see Hypersensitivity reactions by Gell-Coombs classification). This system classifies drug reactions into four categories based on the type of immune response and the onset of reaction.8 Type I reactions are immediate-onset IgE-mediated drug reactions, whereas type IV reactions are delayed-onset cell-mediated reactions.8 One subtype of delayed cell-mediated reactions that are important to note are severe cutaneous adverse reactions (SCARs). SCARs include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TENS), and drug rash with eosinophilia and systemic symptoms (DRESS). These are severe reactions, and patients with prior history of them should avoid future exposure to the offending drug.8 Cytotoxic and immunocomplex reactions such as serum sickness, acute interstitial nephritis, and hemolytic anemia are also indications to forgo future penicillin exposure.9

Consequences of penicillin allergies

Lack of adequate treatment

Beta-lactam antibiotics are often first-line therapy for several common infections. Treating a patient with listed beta-lactam allergies can be challenging and often leads to inadequate treatment. Invasive infections with methicillin-sensitive Staphylococcus aureus (MSSA) are a major area of concern for patients with penicillin allergy. Appropriate treatment with antistaphylococcal penicillins is often forgone in favor of vancomycin in these patients. Vancomycin has consistently been proven to be inferior to beta-lactams for MSSA management.4 Reported penicillin allergies lead to increases in improper therapy utilization, which has demonstrated increased mortality in patients with MSSA infections.10,11 In acute sepsis management, patients with penicillin allergy have both increased time to first antibiotic dose and delays in receipt of effective therapy based on culture data.12,13 Surgical prophylaxis is another area of treatment impacted by reported beta-lactam allergies. Cefazolin, a first-generation cephalosporin, is the most utilized antibiotic for surgical prophylaxis. Patients with beta-lactam allergy are 8 to 16 times more likely to receive alternative therapy for surgical prophylaxis, and this has demonstrated an up to 50% increase in odds of a surgical site infection.14 Thankfully, studies where educational tools about beta-lactam allergies have been introduced in the perioperative setting have successfully increased beta-lactam utilization and improved perioperative prophylaxis timing without significant increase in documented allergic reactions.15,16

Adverse reactions of alternative therapies

Patients who have a listed allergy to penicillin are more likely to receive alternative therapies. This often leads to the use of more broad-spectrum agents such as fluoroquinolones, clindamycin, tetracyclines, and macrolides. In general, it has been appreciated that these patients are at increased risk for hospital readmissions, increased length of stay, and early cessation of antibiotic treatment secondary to adverse outcomes.17 Both fluoroquinolones and macrolides are known to cause QTc interval prolongation which can lead to life-threatening arrythmias.18,19 Fluoroquinolones also carry other unique adverse reactions including tendinopathies, glycemic control issues, and aortic dissection.18 Patients with penicillin allergies and severe infections requiring long-term I.V. antibiotics are often given vancomycin which is known to be nephrotoxic and requires drug-level monitoring.20Clostridioides difficile infection is an established adverse reaction to antibiotics. Alternative agents like fluroquinolones and clindamycin are both well-known to cause C. difficile infections.21 Increased utilization of broad-spectrum antibiotics in patients with penicillin allergy is associated with higher risk for acute C. difficile infections.22

Drug-resistant infections

There are more than 2.8 million drug-resistant infections annually in the US.23 Common drug-resistant infections include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci, and drug-resistant Neisseria gonorrhoeae. Patients with reported penicillin allergies have been shown to have increased rates of MRSA.22 Increased fluoroquinolone use in the setting of listed penicillin allergy may also be driving rises in drug-resistant strains of Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.24 The CDC recognizes reported drug allergies as a potential cause for increased antibiotic-resistance rates and includes accurate allergy assessments as a recommended antimicrobial stewardship intervention.25

Financial cost

The financial burden of penicillin allergies on the healthcare system should also be taken into consideration. A meta-analysis from 2018 concluded that patients with penicillin allergy had up to $609 more in inpatient drug costs, and patients without penicillin allergies had total inpatient cost savings of up to $4,000.26 The same analysis also showed outpatient antibiotic prescription costs for patients with penicillin allergy were between $14 and $193 more than those without penicillin allergy.26

Delabeling reported penicillin allergies

Delabeling reported penicillin allergies often starts by simply taking a detailed history of the reported allergy. This can be confidently carried out by general practitioners. No standardized practice exists for the collection of a penicillin allergy history. However, several useful variations have shown promise in previous studies.15,24,27-29 Allergy assessment does not need to be reserved for patients who actively need antibiotics; it may be best to do at routine office visits as it may prevent future delays in antibiotic treatment. The most important points to establish in an allergy history are as follows: (1) what medication caused the reaction, (2) what reaction or symptoms occurred, (3) how soon after taking the medication did the reaction occur, (4) how many years ago did this reaction happen, and (5) subsequent tolerance of similar antibiotics.4,20,27

Risk stratification

Once a full history of the reaction is obtained, the reported allergy can be properly risk-stratified. This places the patient in four unique categories of risk including low, medium, and high-risk, along with a select category of patients who should avoid penicillin exposure and future challenge.20,27 Low-risk patients have mild reactions that are often not true allergy symptoms, such as nausea or headaches.20,27 Patients with reported "family history" of penicillin allergies or unknown reactions that occurred more than 10 years ago and did not have IgE-mediated symptoms should also be considered low-risk.27 In these cases, a direct challenge can be performed. Direct challenges involve giving the patient a single dose of amoxicillin 250 mg P.O. and observing them for reaction over 1 hour.20,27 Amoxicillin is utilized as amoxicillin tolerance demonstrates tolerance to all penicillins.27 Direct challenges have established safety in multiple prior studies.30-32 When an allergy challenge is performed one should have emergency medications on standby in the event of a severe allergic reaction, which makes the use of drug challenges in primary care or community settings difficult. For drug safety reasons, it may be best to defer drug challenges to the inpatient setting and refer outpatients to allergists. Additionally, either verbal or written consent from the patient to perform any type of penicillin challenge should always be received. As with any procedure, risks and benefits should be clearly explained to the patient prior to starting.

Moderate-risk patients include those with minor skin rashes and true allergic symptoms (isolated urticaria or angioedema without systemic or anaphylactic reaction).20,27 Patients in this class can undergo an oral challenge, but it must be done after penicillin skin testing is performed. Skin testing for penicillin allergy can be done by any properly trained medical professional. It has proven to be both efficacious and cost-effective in the clinical setting.20,33 Furthermore, penicillin skin testing has been successfully utilized in multiple clinical settings.20 If the patient has a negative skin test, they can complete an oral amoxicillin challenge. For these moderate-risk patients, one may choose to administer a test-dose or graded challenge.9 This involves giving the patient 10% of the usual dose first, observing them for 1 hour, and then giving the full dose followed by another hour of observation. In the primary care setting, one should consider referring moderate-risk patients to an allergist. Of note, both pregnant and critically ill patients should automatically be considered moderate-risk or higher regardless of type of prior reaction.27

Levels of risk of patients with penicillin allergy and recommended interventions

Any patient with reported anaphylaxis, multiple/recurrent antibiotic allergies, or prior positive penicillin skin tests should be considered high-risk and referred to an allergist for evaluation.20 Patients who have a reported history of SCARs, drug fever, serum sickness, hemolytic anemia, or end-organ dysfunction from antibiotics should forgo allergy testing and drug challenges and be prescribed an alternative therapy (see Levels of risk of patients with penicillin allergy and recommended interventions).27

Desensitization

In certain situations, high-risk patients with severe IgE-mediated reactions may need to receive penicillin as it may be their only treatment option. These patients can be desensitized to penicillin by receiving increasing doses in rapid succession.34 This procedure requires adherence to strict protocols and should only be performed in the inpatient setting, ideally under direct supervision of an allergist.

Conclusion

While some patients with listed penicillin allergies may have had prior severe reactions to penicillin, most have not and could safely receive penicillin without complication. The benefit of fully evaluating a questionable allergy often outweighs risks of alternative therapies. Overutilization of broad-spectrum antibiotics has both individual patient and global consequences. NPs can be on the forefront of delabeling penicillin allergies by taking a proper drug allergy history, risk-stratifying patients, and utilizing appropriate interventions based on patient risk.

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