Infections from drug-resistant microbes continue to rise, but the development of new antibiotics has declined since the golden age of antibiotic discovery in the mid-20th century.1,2 To slow the growth of drug-resistant organisms, governments, healthcare organizations, and medical facilities across the globe are adopting antimicrobial stewardship programs. One goal of such programs is to conserve the effectiveness of current antibiotics through optimal use of antimicrobial drugs.3 β-lactam antibiotics are some of the most effective agents against antimicrobial infection, yet they are commonly withheld from patients who are allergic to penicillin.4 In the United States, approximately 8% of the general population claims to have a penicillin allergy.5 Evidence shows, however, that most people who believe they have a penicillin allergy can tolerate the antibiotic and only 1% of people are truly allergic.6 As a result of the high rate of false penicillin allergies, infectious disease experts suggest that antimicrobial stewardship programs implement protocols for verifying patient-reported penicillin allergies before antibiotics are administered.
False Penicillin Allergy: A Multifactorial Problem
Kimberly Blumenthal, MD, MSc, is an allergist/immunologist at Massachusetts General Hospital in Boston. She has extensively researched how patient-reported penicillin allergies influence antibiotic selection and patient outcomes and attributes the high prevalence of false penicillin allergies to a combination of factors. “Many people incorrectly believe they are allergic to penicillin because either they were never allergic or their allergy went away,” Dr Blumenthal said. She also noted that penicillin intolerance or symptoms of an underlying viral infection are frequently mistaken for a penicillin allergy, especially in children. For example, Vyles and colleagues surveyed 600 parents of children admitted to the emergency department with a reported history of penicillin allergy and found most allergy diagnoses were based on low-risk symptoms such as rash and itching.7 The investigators tested 100 children with low-risk symptoms and found none had a true penicillin allergy.
According to George Sakoulas, MD, an infectious disease clinician at Sharp Memorial Hospital in San Diego, California, and a researcher with the division of host-microbe systems and therapeutics at the University of California, San Diego School of Medicine, the broad use of penicillin to treat viral febrile illnesses in the 1950s and 1960s may explain why many adults today believe they have a penicillin allergy. “β-lactam use in the setting of mononucleosis can cause a rash that is not an allergy. Also, older preparations may have had impurities that could have caused rashes and other reactions,” he said.4
Dr Blumenthal explained that a penicillin allergy is technically termed hypersensitivity and involves the development of immunoglobulin E (IgE) antibodies in response to “a part of penicillin or its breakdown products.” Anaphylaxis or anaphylactic shock are the most severe IgE-mediated reactions.5,6 Delayed T-cell mediated reactions, which are occasionally life-threatening, are also possible.5 “Of those [patients] who are truly allergic, studies have documented that the allergy wanes over time,” she said. At 5 and 10 years after an IgE-mediated reaction to penicillin, approximately 50% and 80% of people, respectively, are no longer hypersensitive.8 Without testing or additional penicillin use, however, patients have no way of knowing that they no longer have an adverse reaction to penicillin.
Risk for Cross-Reactivity vs Risk for β-lactam Avoidance
All β-lactam antibiotics, which includes penicillins, cephalosporins, carbapenems, and monobactams, are so named for the β-lactam ring in their molecular structure.5 Dr Blumenthal noted that 97% of patients with a confirmed penicillin allergy are able to tolerate cephalosporins and 99% can tolerate carbapenems. “Although these are favorable percentages, there is cross-reactivity among β-lactams due to structural similarities in their side chains, and caution should be taken when prescribing [them] to patients with confirmed penicillin allergies,” she said. Because of the potential risks, Dr Blumenthal said, “Healthcare providers are hesitant and unlikely to prescribe a β-lactam to a patient with an unverified penicillin allergy, especially in patients who are acutely ill.”
Unverified penicillin allergies have serious consequences for patients and for society. “Penicillin-related drugs are the optimal drug class for treating many infections, as they are specific and targeted,” according to Dr Blumenthal. The harms associated with using alternatives to β-lactam agents in patients with unverified penicillin allergies include “more treatment failures, more adverse events, more healthcare-associated infections, and more antibiotic resistance,” she said. In a recently published retrospective study, Dr Blumenthal and colleagues compared surgical site infection rates in patients with and without a reported penicillin allergy whose surgical procedure required perioperative antibiotics.9 Patients who reported a penicillin allergy were 50% more likely to develop a surgical site infection (adjusted odds ratio [aOR], 1.51; 95% CI, 1.02-2.22).9 The investigators attributed the excess risk solely to the use of an antibiotic other than a β-lactam.
“Antibiotics are the only class of drugs where every prescription treats not just an individual patient but society through changes in the [shared] microbiological environment,” Dr Sakoulas said. He noted that in addition to being less potent, “alternative non–β-lactam agents like vancomycin, clindamycin, and quinolones have a higher likelihood of causing Clostridium difficile infection and selecting methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) infections.” A retrospective matched cohort study by Macyand Contreras compared outcomes in 52,000 patients with a reported penicillin allergy who were admitted to a Kaiser Foundation hospital (cases) with hospitalized patients without a penicillin allergy (controls).10 The cases were significantly more likely than controls to receive fluoroquinolones, clindamycin, and vancomycin (P <.0001 in female participants). The cases had 23.4% (95% CI, 15.6%-31.7%) more C difficile infections, 14% (95% CI, 7.1%-21.6%) more MRSA infections, and 30% (95% CI, 12.5%-50.4%) more VRE infections than controls.10 “These resistant organisms and C difficile have a risk of transmission to other people, especially in the hospital,” Dr Sakoulas said. The penicillin allergy label is also associated with longer hospital stays and greater expense, partly attributable to the higher cost of using alternative broad-spectrum antibiotics.10
Antibiotic Stewardship and Reported Penicillin Allergy
The Centers for Disease Control and Preventionand various professional medical societies concerned with antibiotic stewardship recommend evaluating reported penicillin allergies before prescribing a broad-spectrum antibiotic.11 Dr Blumenthal has worked with colleagues to develop tools for addressing penicillin allergies in the inpatient setting.11,12 “At Massachusetts General Hospital and other Partners HealthCare System hospitals, we use an electronic guideline that directs the history and treatment options,” she said. An analysis showed patients reporting penicillin allergy were approximately twice as likely to receive penicillin or cephalosporin when the mobile-friendly electronic intervention was used (aOR, 1.8; 95% CI, 1.1-2.9).12 Dr Blumenthal said hospitals must implement solutions specific to their resources but that an antimicrobial stewardship program should, at a minimum, require “a structured allergy history intervention…that enables intolerances to be distinguished from allergies.” She advised that, “[m]ore coordinated efforts might include penicillin skin testing and/or drug challenges in patients with an unverified penicillin allergy who need antibiotics.”
Dr Sakoulas stated that an allergy history is usually sufficient because it often becomes clear if a patient never experienced a true allergic reaction. “It is amazing how many times we hear a patient claim an allergy because ‘my mom and sibling were allergic, so I assumed I was allergic.’” When the allergy history more strongly supports a penicillin allergy, he recommended performing an allergy test to confirm this. Dr Blumenthal said a challenge dose of the desired β-lactam is another option in patients with evidence of a penicillin allergy.
As a practicing allergist with a special focus on medication allergies, Dr Blumenthal noted that she appreciates how drug evaluation tools for individuals with other types of allergies or with multiple drug allergies have improved their care. She recommended allergists “work with infectious diseases clinicians and other healthcare professionals to create and implement widespread programs for penicillin allergy verification in the United States.” She predicted that adopting such interventions would increase the appropriate use of first-line β-lactam antibiotics and “translate to improved patient outcomes, fewer adverse reactions, and fewer healthcare-associated infections.”
- Fernandes P, Martens E. Antibiotics in late clinical development. Biochem Pharmacol. 2017;133:152-163.
- Davies J. Where have all the antibiotics gone? Can J Infect Dis Med Microbiol. 2006;17(5):287-290.
- Doron S, Davidson LE. Antimicrobial stewardship. Mayo Clin Proc. 2011;86(11):1113-1123.
- Sakoulas G, Geriak M, Nizet V. Is a reported penicillin allergy sufficient grounds to forgo the multidimensional antimicrobial benefits of beta-lactam antibiotics? [published online Jul 9, 2018] Clin Infect Dis.. doi:10.1093/cid/ciy557
- Pongdee T, Li JT. Evaluation and management of penicillin allergy. Mayo Clin Proc. 2018;93(1):101-107.
- Trubiano JA, Adkinson NF, Phillips EJ. Penicillin allergy is not necessarily forever. JAMA. 2017;318(1):82-83.
- Vyles D, Adams J, Chiu A, Simpson P, Nimmer M, Brousseau DC. Allergy testing in children with low-risk penicillin allergy symptoms. Pediatrics. 2017;140(2).
- Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259-273.
- Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The impact of a reported penicillin allergy on surgical site infection risk. Clin Infect Dis. 2018;66(3):329-336.
- Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: a cohort study. J Allergy Clin Immunol. 2014;133(3):790-796.
- Blumenthal KG, Shenoy ES, Wolfson AR, et al. Addressing inpatient beta-lactam allergies: a multihospital implementation. J Allergy Clin Immunol Pract. 2017;5(3):616-625 e617.
- Blumenthal KG, Wickner PG, Hurwitz S, et al. Tackling inpatient penicillin allergies: assessing tools for antimicrobial stewardship. J Allergy Clin Immunol. 2017;140(1):154-161 e156.