About one in ten Americans carries a penicillin allergy in their chart (1). When those people are actually tested, the large majority are not allergic.
That gap is one of the most consequential unforced errors in medicine, and almost nobody goes back and checks.
Where the label usually comes from
Most penicillin allergy labels were applied in childhood, by someone who is no longer involved, based on something that happened once.
The classic story is a rash during a course of amoxicillin at age four. Here is the problem with that story. Viral illnesses cause rashes. Children with viral illnesses get prescribed antibiotics. When a rash appears on day three, the antibiotic is the thing everyone is looking at, so the antibiotic gets the blame and the label goes in the chart. It never comes out.
The other common origins are a family member’s allergy transferred onto the patient, and side effects filed as allergy. Nausea is not an allergy. Diarrhea is not an allergy. A yeast infection is not an allergy. They are all reasons to dislike a drug and none of them are reasons to avoid it for life.
Even genuine allergy fades. IgE-mediated penicillin sensitivity wanes over time, and a substantial proportion of people who really were allergic at twenty are not allergic at fifty.
The label is not free
This is the part I want to land, because people assume that avoiding penicillin is the cautious choice and therefore the safe one.
It is not. Blumenthal and colleagues followed 64,141 adults carrying a penicillin allergy label against 237,258 matched comparators for a mean of six years (2). The people with the label had an adjusted hazard ratio of 1.69 for MRSA and 1.26 for Clostridioides difficile.
The mechanism is not mysterious, and the authors show it. Those patients received far more of the alternatives: macrolides at over four times the rate, clindamycin at nearly four times, fluoroquinolones at twice (2). Those drugs do more collateral damage to the gut and select harder for resistance. The excess MRSA and C. difficile were mediated by that substitution.
So the label does not sit there harmlessly. It quietly buys worse antibiotics for the rest of a person’s life.
There is a score for this, and it runs on history alone
The thing that changed my thinking here is that you do not need a skin test to identify most of the people who are low risk. You need four questions.
PEN-FAST was derived and validated by Trubiano and colleagues (3). It scores like this:
Five years or fewer since the reaction: 2 points. Anaphylaxis or angioedema, or a severe cutaneous adverse reaction: 2 points. Treatment required for the episode: 1 point.
A score under 3 means low risk. In the derivation cohort, only 17 of 460 low-risk patients tested positive, giving a negative predictive value of 96.3 percent (3).
Read the criteria again and notice what is not in them. No skin prick. No specific IgE. No blood work at all. Every input is something the patient tells you.
That is why this belongs in a conversation rather than a laboratory, and it is why I think most clinicians could be doing more of this than they are.
What I actually do with this on a video visit
I ask everyone about allergies before I prescribe anything. That part is unremarkable. What is worth describing is what happens next, because it is where most of these labels give themselves away.
When somebody tells me they are allergic to amoxicillin, I ask what the reaction was.
Two answers come back more than any others. The first is that they do not really remember, because they were a baby and their parents told them. The second is some version of “I think I am allergic because my mom is.”
Neither of those is an allergy history. The second one is not even about the patient.
Here is where I part company with the enthusiastic version of this argument. A person who is sick today and needs an antibiotic today is not in a good position to test a theory about their own immune system. If there is any real concern about anaphylaxis in what I am hearing, I do not push it. I pick something else and move on, and I am comfortable with that.
I also do not send people off for an oral challenge as a matter of course. That is a real procedure with a real indication, and routing every vague childhood label into an allergy clinic is not a good use of anyone’s afternoon.
What I do instead is tell them the label is worth reopening properly, and that the time to do it is when they are well rather than in the middle of an infection. It belongs with whoever manages their ongoing care, in a visit where nobody is waiting on a prescription.
The distinction matters. The label deserves to be examined. The examination should not happen while someone is sick and I am trying to treat them.
What a real reaction looks like, and what has changed about treating it
None of the above applies to someone who has had a genuine severe reaction. Anaphylaxis, angioedema, or a severe cutaneous adverse reaction such as Stevens-Johnson syndrome or DRESS means the label stays. Those people are not candidates for de-labeling and should not be challenged.
Worth knowing what has changed on the treatment side. For decades the only option for anaphylaxis outside hospital was an intramuscular auto-injector. There is now an FDA-approved epinephrine nasal spray, neffy, the first intranasal adrenaline product to reach the market (4). Pharmacokinetic studies show plasma concentrations comparable to or exceeding intramuscular injection, and, counterintuitively, nasal congestion does not appear to impair absorption (5).
I mention it because needle avoidance is a real reason people leave their epinephrine at home, and a device you will actually carry beats a better device you will not. If someone genuinely needs to carry epinephrine and the needle is the barrier, that conversation is now worth having.
It does not change the rule that epinephrine is the treatment and antihistamines are not.
For patients
If your penicillin allergy dates from childhood and you cannot remember what happened, it is worth reopening. Ask specifically to be assessed rather than mentioning it in passing, because in passing it stays in the chart.
Before that conversation, work out three things: roughly when it happened, what you or your parents remember seeing, and whether anyone treated it. That is most of the assessment.
Raise it when you are well. A visit for an infection is the wrong moment, because whoever is treating you needs to choose an antibiotic today and will reasonably play it safe. Bring it to a routine appointment instead, when nobody is waiting on a prescription.
If you have taken amoxicillin, Augmentin or any similar antibiotic since the original reaction and were fine, say so early. It is the single most useful thing you can tell your clinician.
And if your reaction involved breathing trouble, swelling of the face or throat, or a blistering rash, the label is real and it stays.
For colleagues
PEN-FAST costs four questions and identifies low-risk labels at the point of care with a negative predictive value of 96.3 percent (3). We are not short of the tool. We are short of anyone taking ownership of the conversation.
Frame it as a safety intervention rather than a convenience one, because it is. The hazard ratios in the Blumenthal cohort are for MRSA and C. difficile, not for inconvenience (2).
And ask the question that costs nothing: has this person taken a penicillin since. A meaningful share of these labels fall over on that answer alone.
The Bottom Line
Roughly ten percent of people carry a penicillin allergy label and most of them are not allergic, usually because a childhood viral rash got blamed on an antibiotic. The label is not harmless. Carrying it is associated with a 69 percent higher risk of MRSA and a 26 percent higher risk of C. difficile, driven by the broader antibiotics used instead. Four questions, scored as PEN-FAST, identify most low-risk labels without any testing at all, which makes this one of the few things in medicine that is fixed by a conversation. If your reaction was anaphylaxis, angioedema or a blistering rash, the label stays and you keep your epinephrine, which now comes as a nasal spray as well as an injector.
Related Reading
Allergic Antibiotic Drug Reactions: Am I Truly Allergic?
Antibiotic Side Effects and Resistance: The Real Story
Superbugs CRKP, CRE and MRSA: Who Is Actually at Risk?
Help, I Have a Sore Throat! Is It Strep?
Abscesses: What to Do About MRSA
Scott Rennie, D.O.
Board Certified in Obesity Medicine and Family Medicine
This blog is for educational purposes only and does not constitute individual medical advice. Always consult your own physician before making changes to your health, medications, or treatment plan.
Sources
1. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and management of penicillin allergy: a review. JAMA. 2019;321(2):188-199. PMID 30644987. https://pubmed.ncbi.nlm.nih.gov/30644987/
2. Blumenthal KG, Lu N, Zhang Y, Li Y, Walensky RP, Choi HK. Risk of meticillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study. BMJ. 2018;361:k2400. PMID 29950489. https://pubmed.ncbi.nlm.nih.gov/29950489/
3. Trubiano JA, Vogrin S, Chua KYL, et al. Development and validation of a penicillin allergy clinical decision rule. JAMA Intern Med. 2020;180(5):745-752. PMID 32176248. https://pubmed.ncbi.nlm.nih.gov/32176248/
4. Hernandez-Trujillo V, Tachdjian R, et al. Successful administration of neffy (epinephrine nasal spray) by patients and caregivers. Ann Allergy Asthma Immunol. 2026. PMID 42476303. https://pubmed.ncbi.nlm.nih.gov/42476303/
5. Takahashi K, Yanagida N. Intranasal adrenaline: a new treatment for anaphylaxis. Pediatr Allergy Immunol. 2026;37(3):e70316. PMID 41796069. https://pubmed.ncbi.nlm.nih.gov/41796069/
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