20 Questions on Penicillin Allergies
Dr. Nishant Patel
Introduction
On average, 60% of patients admitted to the hospital receive an antibiotic, and in approximately 50% of those cases, antibiotic use is inappropriate (eg no indication, wrong antibiotic, incorrect dosing/duration, etc.).¹ This can result in direct harm to patients due to inadequate treatment of infection, toxic side effects, and superinfection with resistant bacteria. Combine this information with the fact that penicillins, one of the most prescribed classes of antibiotics, are often labeled as allergies in patients’ charts, prompting use of other classes of antibiotics which can lead to harm. Thus, antibiotics are unlike any other class of medications because of the potential public health consequences due to their selection of resistant bacteria, which may become dominant in the hospital and community.
One way clinicians can mitigate this risk of societal harm is by accurately de-labeling patients as penicillin-allergic. In this blog post, I will go over key pearls about penicillin allergies and debunk common myths, in a question-and-answer format.
1) What is a penicillin?
Penicillins (PCNs) are a group of antibiotics ending in the suffix -cillin that are widely used to treat various bacterial infections. They were one of the first medications to be effective against infections caused by staphylococci or streptococci. They are part of the β-lactam class of antibiotics. Commonly used PCNs include penicillin V (oral), penicillin G (IV/IM), amoxicillin, ampicillin, nafcillin, and piperacillin.
2) How common is a PCN allergy?
In the United States, about 5-10% of patients have a PCN allergy documented on their chart. However, 90-95% of those patients are not actually allergic.² Thus, less than 1% of patients have a true PCN allergy, and serious allergies only occur in 0.03% of the population.³
3) Why are so many patients inaccurately labeled as being PCN-allergic?
There are many reasons for this. In childhood, many viral exanthems get confused with a PCN allergy,⁴ and this “allergy” remains in the patient’s chart through adulthood. Additionally, there is a misconception that PCN allergies are hereditary. There has been no identified genetic basis to PCN allergies, so even if individuals in your family are truly PCN-allergic, that does not mean you should avoid taking PCNs. Finally, common side effects such as headache, vomiting, and diarrhea get mistakenly listed under the allergy label, but these are adverse effects, not allergies.
4) Do PCN allergies fade over time?
Yes! Approximately 80% of patients that were previously allergic to PCN lose the allergy in 10 years.⁵ Thus, there is a good chance that your patients who do not know any details about their PCN allergy but “just remember having it as a kid” can safely tolerate PCNs now.
5) Why is over-labeling of PCN allergies harmful?
Other classes of antibiotics that are unnecessarily used in place of PCNs come with more side effects and risks than PCN-based antibiotic regimens (see next question). Additionally, those antibiotics may not be as efficacious in treating the infection at hand.
6) What are common side effects and risks of antibiotics that are used in place of PCNs?
Fluoroquinolones can cause QTc prolongation, tendonitis, confusion, increase the risk of aortic aneurysms, and increase the risk of MRSA colonization.⁶ They are also becoming increasingly resistant in communities, so be sure to check your local antibiogram.
Clindamycin requires frequent dosing, which can lead to nonadherence, and comes with many GI side effects, including an increased risk of C. diff. There is also rising streptococcus and MRSA resistance to clindamycin.
Vancomycin has the potential to be nephrotoxic, ototoxic, and cause bone marrow suppression (i.e. leukopenia). Although it is the gold standard for treating MRSA infections, it is not very effective for treating MSSA infections such as bacteremia, and has been shown to lead to worse outcomes than preferred PCN-based regimens such as nafcillin or cefazolin. Additionally, vancomycin prophylaxis in the OR can lead to more surgical site infections if used in place of cefazolin.⁷
Aztreonam is frequently thought of as the go-to antibiotic for patients with PCN allergies, but it does not have a broad spectrum of activity. Its gram-negative coverage is inferior when compared to beta-lactams, and it provides no gram-positive or anaerobic coverage.
7) What should we be asking when taking an allergy history?
Taking a good history can help you determine what type of hypersensitivity reaction your patient had in the past. Here are some good questions to include in your history-taking:
How soon after taking a PCN did the reaction occur? What were the symptoms?
Did you have a rash? If so, was there significant desquamation, mucocutaneous involvement, or organ involvement?
Did you have to be hospitalized or treated for the allergic reaction with medications?
Have you tolerated antibiotics such as amoxicillin, Augmentin, or Keflex since the reaction?
8) What are the types of hypersensitivity reactions that are common with PCN allergies?
The most common hypersensitivity reactions are Type 1 (IgE mediated) and Type 4 (T cell mediated).
9) What are the characteristics of a Type 1 hypersensitivity reaction?
This is the most common type of allergic reaction. The reaction generally occurs fast, usually within 6 hours but often within 1 hour of exposure. Additionally, two or more organ systems will be affected. Common manifestations include diarrhea, vomiting, urticaria, angioedema, and anaphylaxis.
10) What are the characteristics of a Type 4 hypersensitivity reaction?
Question 12
This is the second most common type of allergic reaction. It has a delayed onset, usually occurring >48-72 hours after exposure, but can often occur several days to weeks later. The most common manifestation is a mild maculopapular rash. However, severe life-threatening reactions such as SJS or DRESS can also occur.
11) What is the mechanism of cross-reactivity of PCNs with other antibiotics?
Cross-reactivity is mediated through R side chains (specifically R1).⁸ It is NOT due to a class effect or hypersensitivity to the core beta-lactam ring.
12) How common is cross-reactivity of PCNs with cephalosporins and carbapenems?
Historically, cross-reactivity was thought to be about 8-10%, but the risk is actually closer to 2% (less with carbapenems).⁹
13) What antibiotics should be avoided in patients with a true PCN allergy?
There are higher rates of cross-reactivity if the antibiotics share a similar R1 side chain. These include the aminopenicillins amoxicillin and ampicillin, as well as early generation cephalosporins such as cephalexin, cefadroxil, and cefaclor.¹⁰ A notable exception is cefazolin (1st generation), which does not share a similar side chain with any other beta-lactam, and is therefore safer to use.¹¹
Questions 13-14
14) Which antibiotics are safe to use in patients with a true PCN allergy?
In addition to cefazolin as mentioned above, late generation cephalosporins are safer to use as they do not share similar R1 side chains.11 Additionally, there is minimal data supporting cross-reactivity between PCNs and carbapenems (likely <1%), so they are generally safe to use as well.¹²
15) What tests can we use to determine if someone is truly allergic to PCN?
Skin testing with a subcutaneous or intradermal injection of PCN metabolite can be performed in those with a history of Type 1 IgE-mediated hypersensitivity reaction (eg hives, anaphylaxis) or a mild Type 4 reaction (eg simple rash). Penicillin skin testing has a very high negative predictive value¹³, so patients with a negative skin test are unlikely to develop an immediate-type hypersensitivity reaction to PCNs or other beta-lactam antibiotics. Skin testing, if negative, can then be followed by an oral challenge.
Questions 15-17
16) When is it safe to give an oral PCN challenge to someone with a documented allergy?
You can start with a direct oral challenge in very low risk situations (eg itching without rash) or if the patient had an unknown reaction >10 years ago. For example, give 250mg of amoxicillin and observe. In patients who have had more severe reactions in the past, start with skin testing as stated above and proceed to an oral challenge if negative.
17) What do I do if my hospital does not have access to inpatient skin testing?
Ideally, oral PCN challenges and skin testing should be done in a PCP’s office or by an allergist, prior to the patient being admitted to the hospital in the first place. If your hospital does not perform skin testing, a graded cephalosporin challenge can be performed in patients needing antibiotics who have a history of an IgE-mediated PCN allergy.¹⁴ As mentioned previously, PCN cross-reactivity to late generation cephalosporins is low, so this manner of challenging is rather safe. For example, give 10mg of ceftriaxone over 30 minutes (1% total dose) and monitor for symptoms like rash or shortness of breath. If no symptoms, then give 100mg of ceftriaxone (10% total dose) and continue monitoring. If no symptoms, give the final 890mg (89% total dose) while continuing to observe the patient. Patients who tolerate this graded challenge can be given full doses upon subsequent administrations.
18) Who should undergo PCN desensitization?
Patients who have a positive skin test or a history of anaphylaxis and absolutely need a penicillin (eg neurosyphilis, multidrug resistant organism) should under PCN desensitization. It is important to note that desensitization will not work and should be avoided for certain reactions such as SJS, TEN, and erythroderma as well as immunologic reactions such as serum sickness or hemolytic anemia.
19) How does PCN desensitization work?
Desensitization should be performed by an allergy specialist in an outpatient setting under close supervision or in an ICU. The protocol is anywhere between 6-13 steps, and involves giving tiny amounts of PCN in gradually increasing doses so that your IgE antibodies do not notice.¹⁵ This allows the patient to tolerate the medication momentarily without an allergic reaction. Desensitization is temporary.¹⁶ If your patient needs PCN again in the future, they will have to undergo the protocol again.
20) What can I do to help curb misconceptions about PCN allergies and the harms associated with over-labeling of PCN allergies?
Take a thorough allergy history and be specific when documenting in the allergy section of the EMR, as this is carried forward forever on a patient’s record. Remove the PCN allergy if applicable! Not only are patients with falsely reported PCN allergies prone to receiving antibiotics with more adverse effects, but they are at higher risk of nosocomial infections, have increased hospital stays, and therefore increased healthcare costs. Let’s do our part in helping patients overcome this avertible barrier to care.
Nishant Patel, D.O.
University of Louisville | UL · Department of Medicine | Internal Medicine Residency Program
Dr. Nishant Patel is an Third Year member of the Internal Medicine Residency Program at the University of Louisville. Learn more here.
References:
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