The Penicillin Allergy Conundrum


Author: Andrew Moore, MD (EM Resident Physician, PGY-3, NUEM) // Edited by: Teddi Rusinak, MD // Expert Commentary: Katie Allen, PharmD

Citation: [Peer-Reviewed, Web Publication] Moore A, Rusinak T (2016, September 13). The Penicillin Allergy Conundrum [NUEM Blog. Expert Commentary By Allen K]. Retrieved from 

The Case



A 50-year-old woman presents to your emergency department with a chief complaint of pain and swelling in her left leg.  You diagnose a non-purulent cellulitis and place an order for cefazolin.  However, your electronic medical record (EMR) immediately shows a “pop-up” indicating this patient has a penicillin allergy. Right now you are thinking, “Are you really allergic to penicillin?” and “What’s the worst that could happen if you do get a penicillin?”

Prevalence of Penicillin Allergy

Penicillin allergy is the most commonly reported allergy in the United States with a prevalence of up to 12.8% of the population [1-4]. While this may seem inconsequential, recent data suggest patients with reported penicillin allergies have increased hospital length of stay and increased risks of clostridium difficile, vancomycin resistant enterococcus, and MRSA infections [5-7]. This leads back to our original question, “Are you really allergic to penicillin?”

We know that of patients who report a penicillin allergy, 90% are able to tolerate penicillin [8]. Using these numbers we can extrapolate that only 1/100 patients have a true allergy to penicillin. Furthermore, cross-allergenicity rates are much less common than originally thought. More recent studies demonstrate cephalosporin-penicillin cross-allergenicity rates between 0.1% and 2%, carbapenem-penicillin cross-allergenicity rates less than 1% and aztreonam-penicillin cross-allergenicity rates 0% [19].

Emergency Department Approach to Patients with a Self-Reported Penicillin Allergy

In most settings a good clinical history of allergy symptoms can appropriately guide antibiotic choice [9,10]. When obtaining a history, it is important to ask about a patient’s previous reaction to penicillin. A rash is usually IgG mediated and not concerning while hives, angioedema or anaphylaxis are consistent with a true IgE mediated allergy. It is also useful to know if the patient had to previously seek emergency department care for an allergy as this indicates a more serious reaction. Lastly, asking the patient what antibiotics they tolerated in the past (i.e amoxicillin or other beta-lactams) may help you assess for true penicillin allergy. If it is deemed that a patient has an allergy description that is not consistent with an IgE mediated allergy, it is likely safe to attempt use of another beta-lactam such as a cephalosporin [13-16]. For patients deemed unsafe to attempt alternative beta-lactam treatment, start a non-beta-lactam and refer for allergy testing. In one prevalence study, only 6% of patients reporting penicillin allergy were referred for allergy testing [3]. If the patient is being admitted to the hospital, consider inpatient testing for IgE mediated hypersensitivity as this has been shown to decrease both inpatient complications and cost of care [17,18].

Expert Commentary


Thank you for bringing attention to this important topic. Self-reported penicillin allergies have become a huge problem in light of the looming antibiotic crisis stemming from our increasing rates of antibiotic resistance and lack of new antibiotics in the pipeline. Penicillins, despite being some of our oldest antibiotics, remain some of our most effective, bactericidal options. When we eliminate all beta-lactams from our arsenal we are left with sub-optimal drugs with larger side effect profiles and broader antimicrobial spectrums. As you described, this will inevitably lead to worse patient outcomes and potential colonization with resistant organisms.

The actual cross-sensitivity between penicillins and cephalosporins is considered much lower than originally proposed when cephalosporins were first marketed in the 1960s. Early reports of cross-reaction (up to 41.7%) have been attributed to contamination of early cephalosporins with trace penicillin derivatives [20,21]. Recent studies have failed to reproduce this incidence and have concluded that cross-reactivity between penicillins and cephalosporins is more likely between 0% and 10%, with first generation cephalosporins (e.g. cefazolin, cephalexin) carrying a higher risk of cross-reaction than those of later generations (e.g. ceftriaxone, cefepime) [21]. It is also worth noting that it has been shown that patients with a penicillin allergy are more likely to react to any drug (including structurally unrelated compounds) as compared with those who do not report a penicillin allergy.  Further complicating this issue is the fact that some beta-lactams (namely amino-penicillins like amoxicillin) cause an idiopathic, non-IgE-mediated rash in up to 10% of patients [20].  For these reasons I agree with your proposed approach.  At our institution we routinely feel comfortable administering a cephalosporin to patients who report non-life threatening reactions to penicillins (i.e. rash) without allergy testing.

I'd also like to highlight the importance of documenting not only the drug the patient is allergic to, but also the reported reaction. When prompted patients often state they personally have never had a penicillin, yet one of their family members is allergic. I've also had patients self-report penicillin allergies because they have an allergy to mold (FYI modern penicillin is synthetically derived and has not been produced using mold since the 1940s, consequently an “allergy” of this nature would be unfounded).  All of these factors lead to the immense over-reporting of penicillin allergies and documenting reactions becomes vital in helping us choose the most appropriate antibiotic for each patient.

Katie Allen, PharmD

Clinical Pharmacist of Emergency Medicine; Department of Pharmacy; Northwestern Memorial Hospital

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  1. Solensky R. Hypersensitivity reactions to beta-lactam antibiotics. Clinical reviews in allergy & immunology 2003;24:201-20.
  2. Macy E. The clinical evaluation of penicillin allergy: what is necessary, sufficient and safe given the materials currently available? Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 2011;41:1498-501.
  3. Albin S, Agarwal S. Prevalence and characteristics of reported penicillin allergy in an urban outpatient adult population. Allergy and asthma proceedings : the official journal of regional and state allergy societies 2014;35:489-94.
  4. Zhou L, Dhopeshwarkar N, Blumenthal KG, et al. Drug Allergies Documented in Electronic Health Records of a Large Healthcare System. Allergy 2016.
  5. Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin "allergy" in hospitalized patients: A cohort study. The Journal of allergy and clinical immunology 2014;133:790-6.
  6. Jeffres MN, Narayanan PP, Shuster JE, Schramm GE. Consequences of avoiding beta-lactams in patients with beta-lactam allergies. The Journal of allergy and clinical immunology 2016;137:1148-53.
  7. van Dijk SM, Gardarsdottir H, Wassenberg MW, Oosterheert JJ, de Groot MC, Rockmann H. The High Impact of Penicillin Allergy Registration in Hospitalized Patients. The journal of allergy and clinical immunology In practice 2016.
  8. Gonzalez-Estrada A, Radojicic C. Penicillin allergy: A practical guide for clinicians. Cleveland Clinic journal of medicine 2015;82:295-300.
  9. Li M, Krishna MT, Razaq S, Pillay D. A real-time prospective evaluation of clinical pharmaco-economic impact of diagnostic label of 'penicillin allergy' in a UK teaching hospital. Journal of clinical pathology 2014;67:1088-92.
  10. Khasawneh FA, Slaton MA, Katzen SL, et al. The prevalence and reliability of self-reported penicillin allergy in a community hospital. International journal of general medicine 2013;6:905-9.
  11. Shah NS, Ridgway JP, Pettit N, Fahrenbach J, Robicsek A. Documenting Penicillin Allergy: The Impact of Inconsistency. PloS one 2016;11:e0150514.
  12. Gerace KS, Phillips E. Penicillin allergy label persists despite negative testing. The journal of allergy and clinical immunology In practice 2015;3:815-6.
  13. Martinez Tadeo JA, Perez Rodriguez E, Almeida Sanchez Z, Callero Viera A, Garcia Robaina JC. No Cross-Reactivity With Cephalosporins in Patients With Penicillin Allergy. Journal of investigational allergology & clinical immunology 2015;25:216-7.
  14. Buonomo A, Nucera E, Pecora V, et al. Cross-reactivity and tolerability of cephalosporins in patients with cell-mediated allergy to penicillins. Journal of investigational allergology & clinical immunology 2014;24:331-7.
  15. Callero A, Berroa F, Infante S, Fuentes-Aparicio V, Alonso-Lebrero E, Zapatero L. Tolerance to cephalosporins in nonimmediate hypersensitivity to penicillins in pediatric patients. Journal of investigational allergology & clinical immunology 2014;24:134-6.
  16. Crotty DJ, Chen XJ, Scipione MR, et al. Allergic Reactions in Hospitalized Patients With a Self-Reported Penicillin Allergy Who Receive a Cephalosporin or Meropenem. Journal of pharmacy practice 2015.
  17. Rimawi RH, Cook PP, Gooch M, et al. The impact of penicillin skin testing on clinical practice and antimicrobial stewardship. Journal of hospital medicine 2013;8:341-5.
  18. Arroliga ME, Vazquez-Sandoval A, Dvoracek J, Arroliga AC. Penicillin skin testing is a safe method to guide beta-lactam administration in the intensive care unit. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 2016;116:86-7.
  19. Frumin J, Gallagher JC. Allergic cross-sensitivity between penicillin, carbapenem, and monobactam antibiotics: what are the chances? Ann Pharmacother. 2009 Feb;43(2):304-15. doi: 10.1345/aph.1L486. Epub 2009 Feb 3.
  20. Terico AT, Gallahjer JC.  Beta-lactam hypersensitivity and cross-reactivity.  J Pharm Pract. 2014 Dec;27(6):530-44.
  21. Romano A et al. Cross-reactivity among beta-lactams. Curr Allergy Asthma Rep. 2016 Mar;16(3):24. 
Posted on September 12, 2016 and filed under Pharmacology.