Avoid any rash decisions: the skinny on cephalosporin use in patients with reported penicillin allergies

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Nechama Rothberger Pharm.D. BCPS, Ankit Gohel Pharm.D.

No matter what role you play as a member of the ER team, there is probably no doubt that at some point in the past week you’ve been faced with the following scenario (allowing for some small variations, obviously): a patient has documentation of a penicillin allergy and there is now an order for ceftriaxone or cefepime. Hoping to avoid having to upgrade the patient to the resus area while being bagged for acute anaphylaxis from the comfy seats in the fast track area, you call your friendly local pharmacist to find out what to do next.

Let’s start with a little background: Penicillins (including amoxicillin, penicillin VK, and piperacillin) are a part of the beta-lactam family of antibiotics that also includes cephalosporins (cephalexin/Keflex, cefazolin/Ancef, ceftriaxone/Rocephin, cefdinir/Omnicef, and cefepime to name a few), carbapenems (meropenem, ertapenem) and monobactams (aztreonam). The OG penicillin was discovered by Alexander Fleming in 1928, and despite approaching its 90th anniversary of discovery, the 15+ penicillin antibiotics on the market are one of the most frequently recommended and utilized classes of antibiotics worldwide. It is reported that penicillin allergies are among the most common drug allergies cited during medication reconciliation with a reported incidence of 10% (1).

However, according to the CDC, less than 1% of patients are truly allergic to penicillins, and up to 80% of patients actually lose their sensitivity after 10 years (2)! Dangerous manifestations of a true allergy to penicillin include anaphylaxis, angioedema, wheezing/shortness of breath or urticaria (a dangerous rash of round, red welts on the skin), which usually occur within 1 hour of receiving the antibiotic. Penicillins and some cephalosporins should generally be avoided in patients with reports of the previously mentioned reactions until skin testing can be performed by an allergist to evaluate the allergy. Patients reporting “allergies” that involve minor skin rashes, stomach aches, nausea, vomiting or family history of a penicillin allergy generally receive certain penicillins safely. But what about another member of the penicillin family like a cephalosporin?

How do allergies to penicillin occur happen?: It is believed that allergies may arise from the box-like beta-lactam ring (arrow) or the side chains attached to the molecules which serve as the core backbone to penicillin antibiotics. However, not all penicillins and cephalosporins were created equal.

Cephalosporins made their big debut on the market in the 1960s and have been continually tweaked until present day. Due to a lack of the advanced technology that is available today, early cephalosporins were manufactured from penicillins and the final products were often contaminated with leftover penicillin particles. Therefore, the incidence of cross reactivity of penicillins and first and second generation cephalosporins was fairly high in the past (up to 20%), but due to improvements in the drug manufacturing process has since decreased to less than 10% and 3% respectively (3). In order to make antibiotics that kill different bugs, the pharmaceutical industry modified the dangling structures (side chains) attached to the beta-lactam ring on cephalosporins every decade. This lead to a generation based classification of cephalosporins (1st generation: 1960s, 2nd generation: 1970s, 3rd generation: 1980s, 4th generation: 1990s, 5th generation 2000s). The more recent generations (3rd, 4th, and 5th) have less than 1% to no allergic cross-reactivity potential with penicillin.

Penicillins and cephalosporins with similar side chains are more likely to cross react with one another. If someone has penicillin allergy history, the risk of cross reactivity can be predicted. If someone is history of cephalosporin allergies, the risk of cross reactivity with penicillins cannot be so easily predicted and should used cautiously. If a patient had a severe allergy to penicillins such as angioedema, difficulty breathing or anaphylaxis, cephalosporins should be used cautiously since the potential outcome is risker if the drug-allergy cross react.

You may be wondering what the liability implications of giving penicillins or cephalosporins to a patient that reports penicillin allergies are. The cases with published legal outcomes found limited professional liability and identify clear precedence for clinicians who prescribed cephalosporins or carbapenems to a patient with a known penicillin allergy. These results should decrease litigation fears of providers and risk managers within healthcare systems.

So what should you do if you notice an antibiotic order for a patient with a reported penicillin allergy? Start by trying to find out which drug specifically caused the reaction and what happened when they took the suspected offending antibiotic.

It’s also helpful to ask if the patient has ever tolerated a different penicillin drug before, particularly a cephalosporin, after they experienced their allergy. This information will be helpful in deciding what the best antibiotic that can safely be used to treat the patient’s infection is.

The bottom line:  For the most part, cephalosporins can be used safely in patients with mild-moderate penicillin allergies. Use them cautiously if patients have had a severe life-threatening allergy to penicillins.



  1. James CW, Gurk-turner C. Cross-reactivity of beta-lactam antibiotics. Proc (Bayl Univ Med Cent). 2001;14(1):106-7.
  2. Center of Disease Control and Prevention. Is it really a penicillin allergy? Evaluation and Diagnosis of Penicillin Allergy for Healthcare Professionals.

    https://www.cdc.gov/antibiotic-use/community/pdfs/penicillin-factsheet.pdf. Accessed 12/21/17.

  3. James CW, Gurk-turner C. Cross-reactivity of beta-lactam antibiotics. Proc (Bayl Univ Med Cent). 2001;14(1):106-7.
  4. Jeffres M, et al. Systematic Review of Professional Liability when Prescribing Β-Lactams for Patients with a Known Penicillin Allergy