- 02:49 Penicillin Myths
- 07:20 Penicillin Allergy
- 11:21 Allergic Reactions
- 19:01 Managing allergic reactions
- 26:53 Alternative medications
- 33:28 Recap
Pearl 1: Penicillin myths
Myths: While 5-10% of the population thinks that they are allergic, 90-95% of patients labeled as penicillin allergic can take penicillins. This is because:
- Penicillin allergy fades with time
- Viral exanthems often mislabeled as penicillin allergy
- Adverse effects are mistakenly labeled as allergies
- There is a misconception that there is a strong genetic basis of penicillin allergy
Pearl 2: Harms of over labeling of the penicillin allergy
- Harms: Patients with penicillin allergy receive more:
- Fluoroquinolones – QTC prolongation, tendonitis, inferior empiric coverage compared to higher gen cephalosporins, increased MRSA colonization
- Clindamycin – C. difficile risk, increasing resistance
- Vancomycin- more surgical site infections, increased risk of VRE
- Aztreonam – inferior coverage compared to higher generation cephalosporins
- Higher rates of MRSA, VRE, C. diff, and more time in the hospital
Pearl 3: Types of allergic reactions and how to take a good allergy history
A good allergy history should include:
- How soon after taking the penicillin did the reaction occur? Within an hour?
- What were the symptoms (if the patient remembers)?
- If there was a rash, was there significant desquamation, mucocutaneous involvement, blistering, or organ involvement?
- Were medications or hospitalization required?
- Have you ever tolerated amoxicillin (or another penicillin) since the initial reaction without issues?
- Type 1 hypersensitivity reaction- IgE mediated
- Most common type of allergic reaction
- Fast – Usually within an hour, should occur <6 hours
- More than two organ systems- commonly involves- urticaria, angioedema, emesis/diarrhea, anaphylaxis
- Type 4 hypersensitivity reaction which is T cell mediated
- Second most common
- Slow- occurs at least 48h after exposure (often delayed by days to weeks)
- Caveat – Can occur in <24 hours in the setting of rechallenge
- Mild -Drug rash -Most common type 4 reaction
- Maculopapular eruption- may have mild desquamation but should not have significant desquamation
- No organ involvement
- Bothersome, but not life threatening, can treat through if other options are not available Severe rashes- also called severe cutaneous adverse reaction (SCAR)
- Severe- Steven Johnson Syndrome/Toxic epidermal necrolysis, DRESS/DIHS
- SJS-Ask about mucosal involvement, hospitalization, time in the burn center
- DRESS/DIHS-Ask about hospitalization, organ involvement, systemic steroid use
- There are several scoring systems for DRESS/DIHS
- Severe- Steven Johnson Syndrome/Toxic epidermal necrolysis, DRESS/DIHS
Pearl 4: Management
- Start with a direct oral challenge in very low risk situations such as unknown reaction >10 years ago, pruritus without rash
- Direct challenge: Give 250-500mg of amoxicillin and observe
- Tools such as the Pen-fast rule can help identify those with low risk of allergy
- In patients with a history of IgE-mediated reaction in the past (hives, itching, anaphylaxis), skin testing with intradermal/subcutaneous injection of penicillin metabolite can be performed, followed by oral challenge if skin testing is negative
- A negative skin test has a high negative predictive value for penicillin allergy and gets you “95%” of the way there
- If both of these tests are negative, the patient should be de-labeled
- Testing for penicillin allergy cost effective and covered by most insurance
- However, less than 50% of hospitals currently have access to inpatient skin testing
- In these cases, a graded challenge of a cephalosporin can be performed where a small dose (10%) is given followed by a larger dose if small dose is tolerated
- Patients with positive penicillin skin test or history of anaphylaxis who absolutely need a penicillin should undergo penicillin desensitization
- 6-13 steps where sequentially greater doses of a penicillin are given to “trick” the body into tolerating the medication
- Only effective as long as the body has constant exposure to the medication
Pearl 5: When is it safe to use cephalosporins or carbapenems in a penicillin allergic patient?
- While cross-reactivity rate of penicillins and cephalosporins is commonly cited as 10% (rounded up from 8%), this is based on older studies with more early generation cephalosporin and with small study numbers. Cross reactivity more likely around 2-3% in those with confirmed allergy
- Most cross reactivity is mediated through R side chains rather than the beta lactam rings.
- Higher rates of cross-reactivity if the R1 side chain looks similar such as cephalexin/cefadroxil and amoxicillin/ampicillin, ceftriaxone and cefepime, ceftazidime and aztreonam.
- Cefazolin is unique as it does not share R1 side chains with any beta-lactams
- Generally it is safe to give a higher generation cephalosporin (3rd or above) to a patient with a type 1 reaction in an observed setting with a graded challenge (test dose procedure)
- Patients with mild type IV reaction can be given full dose cephalosporin without a test dose
- Carbapenems are generally safe to give in patients with a Type 1 or mild Type 4 reaction
KB: I think that the most common myths and misconceptions that I hear include that penicillin allergy lasts forever and that once you’re diagnosed with a penicillin allergy, it is yours from that day and carries forward forever and always holds true.
S: That was our expert discussant, Dr. Blumenthal. We’ll let her introduce herself.
KB: I’m Kim Blumenthal. I’m an allergist and researcher at Mass General Hospital and assistant professor at Harvard Medical School.
S: Today we are discussing penicillin allergy- that pesky label that ruins the best planned antibiotic regimens. I am Dr. Shreya Trivedi, an internist at BIDMC. And today I’m joined by very two passionate souls
D: Hi, I’m Dan Taupin, an infectious disease attending at BIDMC.
AM: Hi, I’m Ann Marie Kumfer. I am a hospitalist at the University of North Carolina.
S: So before we get started, lets just make sure we are on the same page… Dan breakdown for us, what is a penicillin?
D: Absolutely! So people usually just think about penicillin G… but there’s so much more… it’s those antibiotics that we use all the time that end in -cillin. Its aminopenicillins like ampicillin and amoxicillin, the one’s we use to treat staph like (AM) like nafcillin, oxacillin and methicillin, and we cannot forget about Piperacillin and its trusty sidekick tazobactam.
S:And the thing to know for this episode that Penicillins fall in the larger family of antibiotics called beta lactams and so you’ll hear us say the word b-lactams often. Some of the other antibiotics to know that fall in that b-lactam family are cephalosporins, carbapenems, and the poor lonely monobactam aztreonam.
D: Let’s get started with the questions we’ll be covering today. Make sure to test yourself by pausing after each of the five questions.
S: Remember, the more you test yourself, the deeper your learning gains.
D: Pearl 1: Over-labeling
S: Why is there so much over-labeling of penicillin allergies?
D: Pearl 2: Alternative antibiotics
S: What are the alternative antibiotics often used in PCN allergic patients and what are their potential harms?
D: Pearl 3: Allergy history and types of allergic reaction
S: What are the four types of allergic reactions and what are the important questions to ask to differentiate between those?
D: Pearl 4: Management
S: Which patients should undergo direct oral challenge, skin testing, or desensitization? How are these performed?
D: Pearl 5: Cross-Reactivity
S: When is it safe to use a cephalosporin or carbapenem in a patient who is allergic to penicillin?
Pearl 1 – Penicillin myth busting- What percentage of patients with a label of penicillin labeling are actually allergic.
S: Lets start with a very common scenario – say I am seeing a patient in clinic who is coming in for screening for a STI. And I see penicillin listed as an allergy.
D: How about this situation from the inpatient side? A patient is admitted from the ED with sepsis from pyelonephritis. You look back at her old urine cultures, and you notice some pretty resistant bugs. You decide cefepime is a good choice for her. So you go order cefepime in the EMR when… suddenly… big red pop-up screen comes out of nowhere. It says: ALERT! PENICILLIN ALLERGY.
AM: And then you scream and run from the room. This scenario is the hospitalist worst nightmare, because there is nothing worse than finding the perfect antibiotic regimen only to encounter my nemesis, the penicillin allergy.
S: It’s kind of bizarre how often I see penicillin allergy listed in a chart – it makes me curious why is it that so many patients have that penicillin allergy listed?
KB: So right now in the United States, we have from five to 10% of all Americans who have a penicillin allergy label on their record. So they think that they’re allergic to penicillin, or it is documented somewhere that they were allergic to penicillin. And of all of those patients, when we evaluate them, whether we’re evaluating them in the clinic or in the hospital, somewhere around 90 to 95% of them are not allergic. So they don’t have an immediate penicillin allergy at all.
S: Wow that label is wrong 90-95% of the time. So we dug into this, we found 4 big reasons why many patients are unnecessarily labeled as that. The one that was the most eye-opening was learning that penicillin allergies actually fades over time
KB: I tell patients that in a 10 year period, 80% of them are no longer allergic. So that way they realize that they’re penicillin allergy history, which was likely more than 10 years ago, that there’s more an 8 in 10 chance that they’re not actually allergic.
S: And so the take away for me is when I hear a patient who says “Oh, I had hives allergy years ago,” I’ll feel pretty reassured that their immune system probably has an 80% chance or so that it’s chilled out a bit by now
AM: Not only do allergies fade with time but the 2nd big reason is that a lot of allergies weren’t actually allergies to begin with.
D: That actually happened to me when I was a kid. I had this viral infection and unfortunately I was given amoxicillin and got a rash. And of course I was told I had a PCN allergy.
S: That’s crazy! For you Dan is it that you had this rash because of the viral infection you had like a viral exantham or was it the penicillin and you had a PCN allergy? It kind of reminds me of that old egg and chicken scenario – what came first? What actually caused it?
AM: Would you say the decision to give antibiotics was a rash decision? This is interesting because I was reading a study about kids who had a delayed urticarial rash or maculopapular rash while on beta lactam antibiotics and then were rechallenged. I was surprised to find that 93% did not get a rash when given penicillins again- it was probably that pesky virus causing the rash all along.
D: Well, I guess I was part of that 93% then (A: always getting that A ). The third big reason for mislabeling, which I see all the time, are when side effects like headache or diarrhea are listed under the allergy label. And of course those things are really uncomfortable, but diarrhea is an adverse effect, not an allergy!
AM: Yeah completely agree. Lets continue with that myth-busting with our last myth about penicillin allergy that we often run into
KB: Another one is that it runs in families. I get patients telling me all the time that their whole family has penicillin allergy, and that’s why they avoided it. And I think that that’s problematic and just really not true. We just don’t really think that there’s a genetic basis that we’ve identified.
S: Preach! Let’s recap pearl. So it seems that 10% of the population or so thinks that they are “allergic to penicillin,” but less than 10% of people with a label of penicillin allergy are actually allergic. And the reason for over labeling includes 1) most people don’t know that penicillin allergies actually fade over time, 2) viral rashes often get confused with a drug allergy, 3) adverse effects often getting mistakenly labeled as an allergy, and 4) misconception that penicillin allergy is hereditary.
Pearl 2: Why is PCN allergy over-labeling a problem? And more specifically, why are alternative antibiotics problematic?
AM: Ok, ok Got it! Penicillin allergies are way over documented. And I actually see a lot of patients in the hospital with penicillin allergy who instead get vancomycin, clindamycin, fluoroquinolones, or even poor lonely aztreonam.
KB: If you need antibiotics on a lot, and you’re not given their beta lactam antibiotics, which the penicillins are part of, then you have a higher likelihood of developing MRSA and C. diff.
S: MRSA and C. diff- definitely things I try to avoid. Dan, let me pitch it to you – as the ID expert in the room, what do you think about these alternative antibiotics?
D: I have a lots thoughts.
A: Ok, let’s prepare for a little bit of antibiotic bashing.
D: Let’s start with fluoroquinolones. I have a love/hate relationship with quinolones. Their high bioavailability makes them really useful in certain situations, but the side effects! Oh man, so many side effects…
S: Lay it on us Dan!
D: You’ve probably heard about the tendonitis and QTc prolongation, but fluoroquinolones can also cause confusion, raise your risk of aortic aneurysms, and believe it or not increase the risk of MRSA colonization.
S: Quinolones actually increases your risk of MRSA! Ugh no buenos!
AM: On top of that, I’ve been burned by quinolone resistance- I remember a patient who had pyelonephritis who apparently had a penicillin allergy documented and so instead given fluoroquinolones. The patient ended up actually decompensating and turns out sensitivity came back and the E.coli was resistant to the fluoroquinolone.
S: I wonder what would have happened to your patient had they gotten that beta lactam up front.
D: And as a general rule of thumb, in patients with a history of resistant gram negative infections, reaching for a broad spectrum beta lactam like cefepime or pip-tazo will generally get you better coverage than a quinolone.
S: Thank you ID consult! What about Clinda? Clindamycin often gets thrown at patients who have a penicillin allergy.
D: … that’s also very C. diffogenic.
AM: And also gets a ding with resistance – there’s rising Strep and MRSA resistance to clindamycin
D: Clinda is not very patient friendly with the frequent dosing and GI side effects.
S: .. Ah I definitely know first hand the GI side effects of Clinda. So moving on to the next antibiotic on the chopping block, what about Canc? Dan, what are your thoughts on using Canc instead of beta-lactams?
D: Vancomycin has it’s downfalls too. When you are treating a patient with a MSSA bloodstream infection, Vancomycin has actually worse outcomes than anti-staph beta-lactams like nafcillin or cefazolin. And for you perioperative medicine fanatic’s, vancomycin prophylaxis in the OR can lead to more surgical site infections if used instead of cefazolin.
AM: Don’t forget about the risk of selecting for vancomycin resistant enterococcus (VRE)! And that potential for nephrotoxicity.
S: Alright moving onto our last but prolly not least antibiotic alternative we see often aztreonam- I can’t remember how many times I’ve been to a rapid response on a decompensating patient and they’d have a penicillin allergy and then go get vanc, metronidazole and aztreonam.
D: Shreya, I was probably at that rapid response with you… and this happens all the time. Patients with penicillin allergy are actually 18 times more likely to get Aztreonam. And that’s unfortunate because azotronam doesn’t provide nearly as good of gram negative coverage as other beta lactams. It also has no gram positive coverage. It’s not my favorite.
AM: Sorry, aztreonam, I don’t think you’re making it onto Dan’s fantasy antibiotic draft.
D: Absolutely not! To summarize our run down of antibiotic alternatives, and this is exactly what I tell my patients who have penicillin allergies – is that these alternative antibiotics often have more side effect and may not be as good at treating you infections
Pearl 3: Adverse drug reactions and taking an allergy history. Why is it important to take a good allergy history? What should we be asking about?
AM: This is great, but honestly when I am 45 minutes into an admission interview and my pager is going crazy I sometimes just quickly run through the allergy section like “the chart say you’re allergic to penicillin, correct?” Okay, moving on.
KB: When I was a med student and I was taught how to take an allergy history, it went something like, so you’re allergic to penicillin I see here in the chart… and the patient would say yes, and you would just write that down. And that the allergy history is so much more than that. It is like the history of present illness we do for everything else. It involves the timing and the symptoms and what happened and that the history can be used to help decide how to prescribe antibiotics to that patient in front of you.
S: So what I found helpful in taking “good allergy history” is understanding something that I haven’t thought about since medical school – the pathophys behind the four Gell and Coombs hypersensitivity reactions. I think what’s helpful is when we tailor the questions to hone in on which one of those 4 hypersensitivity reactions it could be, it really helps with our management, which we’ll talk about later in the episode
KB: So I guess I’ll start as an allergist with my favorite types of reactions, which are the type that are mediated by IgE, which is our allergy antibody. And those are reactions that are typically immediate in onset
D: …Often within one hour of the first dose of an antibiotic course. That IgE is already formed and is just hanging out on the surface of mast cells. Then the allergen comes along and BOOM histamine gets shot out like a cannon.
KB: Those are the ones that have symptoms like hives, urticaria, angioedema, wheezing, anaphylaxis, and those, are the reactions that we needed to treat with first, if it’s severe epinephrine epinephrine and epinephrine epinephrine!!
AM: And that fast on-set type 1 IgE mediated rxn is why it is so important to ask about the timing of the symptoms
KB: How many days into taking a course did the symptoms occur? Was it the first day, the second day, the third day, a week later, a month later? All of that is very important because it gives you a hint at maybe what kind of reaction might’ve occurred.
S: But what if they don’t remember how soon after the antibiotic their symptoms started? If it was within an hour or so or if was longer…
KB: Then asking about treatment might help you with what the patient looked like to a clinician. If the patient was just told, Oh, stop that antibiotic and you don’t need to see anybody and you don’t need to take any medicine medication to treat your yourself. And then that situation is a low-risk situation. If the patient was told, okay, you need to come to the emergency room or give yourself epinephrine or come to a PCP office because that rash needs to be checked out. You get a sense for a more severe history of penicillin allergy.
S: Okay then last bit of questioning gets at type 1 IgE mediated reactions is a throwback from Pearl 1… the teaching points that IgE allergies can fade overtime
KB: So when did this occur in your life? Was it two weeks ago? Was it a year ago? Was it a 10 years ago? Was it in childhood? Those, all of those clues about timing are really important.
AM: OK now that we have type I down, I think we should mix it up and talk about type 4 hypersensitivity reactions next because both these type of reactions are common and both cause rashes.
D: Unlike the speedy type 1 hypersensitivity reactions, type 4 reactions are delayed, usually starting at least 72 hours after the first dose, and sometimes weeks into the course of a drug.
S: Why do type 4 reactions take so darn long?
D: Well these reactions are mediated by T cells, and it takes those T cells a little while to activate and multiply before anyone notices symptoms.
AM: Yeah, those T-cells take time to age… like fine wine
D: Exactly, in comparison to Type 1, which is like a shot of cheap tequila. It’s quick, and the aftermath is never good.
S: And just like the countless number of fine wines out there… Type 4 hypersensitivity reactions come in all shapes and sizes and for allergies, different severities
KB: The problem with Type 4 is that there’s a huge spectrum. So the benign maculopapular rash that you see every day on the hospital ward from the patient that’s on four antibiotics and just developed a rash and you’re, you know, monitoring maybe a little bit… that rash is a type 4hypersensitivity reaction. But also Steven’s Johnson syndrome is considered a Type 4 hypersensitivity action.
D: The thing I always emphasize about taking allergy histories is that once we narrow it down to a Type 4 delayed reaction, we then have to figure out if its a mild or severe Type 4 reaction, because that has major implications for management.
KB: I think that some of these things we can really get at, even when we’re talking about things that happened years and years ago. So asking about skin peeling is important and we don’t mean that fine, like skin desquamation that might happen, you know, after a drug rash, that’s like very common. We mean like detachment, like did your skin significantly peel.. Mucosal involvement… Was there a potential problems with your eyes or mouth?
D: Dr. Blumenthal is trying to rule out a history of severe type four hypersensitivity like SJS, where we would never want to rechallenge the patient with a beta lactam.
AM: Which makes sense. What other questions should we be asking the patient?
KB: Were there potentially organ involvement. Did anybody say that you needed to get blood work and they were worried about your livers or your kidneys in the past?
D: And that last line of questioning on liver and kidney involvement gets at another famous severe Type 4 reaction, DRESS, also known as drug reaction with eosinophilia and systemic symptoms.
AM: And if someone had DRESS, you definitely don’t want to rechallenge them with a beta-lactam… you don’t want DRESS twice, or even once
S: Okay so quick recap. There are two major types of hypersensitivity reactions that can cause rashes. Type 1 is IgE mediated and it happens quickly, and causes hives and anaphylaxis if you’re unlucky. Type 4 is T-cell mediated causes a delayed rash that can range from mild maculopapular rashes to severe, life threatening reaction. Dan why don’t you bring it home for us?
D: Yes! The final piece of game-changing history is to figure out what antibiotics they have tolerated since their initial reaction.
KB: The final thing is exposure since.. I joke, but I don’t joke, but as an allergist our favorite consults or are for history of penicillin allergy, but the patient takes them amoxicillin at the dentist. So consult done, we’re all set. You tolerate a penicillin. Yes, you tolerated an amino penicillin, which we could get to, which means you basically tolerate almost every penicillin.
AM: Yeah nothing is more satisfying than finding out that they tolerated a course of a penicillin, and hitting the delete button on that penicillin allergy label. So one of my favorite things to do is to use the chart search function to see if they have tolerated a penicillin.
S: That’s genius! I’ve gotta use the search function more often because so many people don’t remember the names of their prior antibiotics
AM: Yeah, it’s actually pretty amazing how many patients have tolerated penicillins without even knowing it.
D: Ann Marie, you are making your pharmacists proud by deleting it from the allergy list. And with that, lets summarize pearl 4: The key to taking an good allergy history is determining the timing and specific symptoms during their initial reaction. This will help you figure out what type of hypersensitivity reaction they had. Then my favorite thing to do is to check if they’ve safely tolerated penicillin since that initial reaction without realizing it.
Pearl 4: What tests and tools do we have to determine if someone is really allergic to penicillin? When is it safe to give a penicillin challenge to someone with a documented penicillin allergy?
S: Ok so we know that 10% of people have a penicillin allergy documented but 90% of those people actually don’t have an allergy. But then how can we figure out who has a true allergy?
KB: I wish that more people knew that there was a test for true IgE-mediated penicillin allergy.
AM: Okay, just to make things clear. From here on out when we’re talking about testing, which is challenging patients with a penicillin again. We are NOT talking about those patients who have had a serious skin reaction in the past like -SJS or DRESS. In those situations, you should stay away from beta lactams like their jalapeño juice near the eyes.
D: So we’re talking about patients with the Type 1 hypersensitivity reaction, a mild Type 4 reaction… or an unclear reaction
AM: First, let’s talk about those folks with a very low risk of penicillin allergy.
KB: Something like itching, something like GI upset, something like family history, something like remote, unknown allergy. Those are sort of four big categories that would chop a lot of penicillin allergy out.
AM: And of those, GI upset and “family history” are so low risk that you don’t even need the challenge. Just go ahead and delete that allergy.
S: Delete Delete Delete. You are an inspiration Ann Marie. What about those low risk people, those who had a mild rash or a distant reaction with some details they don’t remember?
KB: And honestly would, you could give a just dose of amoxicillin under observation, as long as you know how to treat anaphylaxis and have an anaphylaxis kit. And that sounds like a very good, beneficial thing to offer.
S: Aka that is what we call a direct oral challenge!
D: In a perfect world, that direct oral challenge can be done in the PCP’s office. In the real world, if you don’t have the infrastructure to give the dose and watch them for an hour, a referral to allergy is the next best move.
S: What about managing those patients who aren’t so low risk. Say they give a good history for an immediate Type 1 allergic reaction? Say they give a good story for legit hives or even anaphylaxis?
AM: You want to be a bit more careful in these patients. But then we also know that many Type 1 reactions with fade with time.
S: That’s a nice reassuring pearl to bring up for some spaced repetition. It’d be nice if there was a way to tell if people were still allergic.
KB: We can test for this and that it’s a safe test and we should be doing it so much more than we’re doing it now.
AM: Dr. Blumenthal is talking about penicillin skin testing. Just a quick run down – skin testing is basically where we use the major penicillin metabolite and it’s injected under the skin with histamine and saline controls. If there is no reaction, then you’re good to go onto an oral challenge with amoxicillin.
KB: I like to tell patients that the skin test gets us 95% way there. And so it’s done to increase safety and to standardize the evaluation, but that really, you can still react after a negative skin test. And so I’m going to give you a drink of amoxicillin and watch you for an hour to make sure that you’re okay. And so that gets you sort of a hundred percent the way there.
D: To hammer that point home, for patients who you are a little nervous about going straight to the oral challenge, the skin test is gonna help you feel more confident. If the skin test is negative, they are good to go for a dose of amoxicillin.
S: Yeah, and the two things that really won me over about skin testing is that 1. its safe even with a history of anaphylaxis and 2.it’s covered by most insurances.
D: And a just a plug – if your hospital has the capacity, inpatient skin testing has been associated with less vanc and quinolone use and actually decreases costs in the long run. That will delight your hospital administrators!
S: We’re making everyone happy – pharmacists, hospital administrators, ID docs. I guess this is something where I’m gonna change practice – if I’m seeing a patient in clinic for something unrelated and has a penicillin allergy they’re carrying around, I’ll be proactive and refer them to the allergy clinic. Sadly at some point, they’ll need an antibiotic, and it’s good to have options.
AM: Options are good, especially in the hospital cafeteria on the weekend. But what happens in the situation when you’re in the hospital and we cant just refer or consult an allergist? Are we stuck using fluoroquinolones and aztreonam then?
D: Actually no. So in our hospital, if someone comes in with an infection, but has a IgE mediated penicillin allergy, we will often give a cephalosporin using something called a graded challenge.
S: Wait a minute, wait a minute! What is a graded challenge?!
D: Okay, so a graded challenge is when you give a small initial dose, like 10% of the medication… some people call this a test dose. Then you observe the patient for about an hour.
S: Oh nice, so why do we do the test dose?
D: The reason why give a test dose is if the patient does have a reaction, it should lead to a more mild than with a full dose. But if they tolerate the test dose well, we can give the rest of the full dose while still watching them closely.
S: ok and then why are we doing graded challenges with cephalosporins if they have an allergy to a penicillin?
D: Well, we will talk about the cross-reactivity between penicillins and cephalosporins in the next pearl, but, spoiler alert, there’s a lot less cross reactivity than you think.
S: Nice! What about those super high risk patients with a positive penicillin skin test or a recent anaphylaxis reaction and they really needs a penicillin?
AM: Yeah this comes up from time to time say when it is a patient with neurosyphilis or someone growing a resistant bacteria only responding to a few antibiotics.
KB: If you anaphylax today to penicillin, but you need penicillin today, that would be fine. I could actually just give it to you by desensitization protocol. Now, desensitization protocol is somewhere between six and 13 steps.
D: Desensitization is a really sneaky tactic where you give such a small amount of penicillin that those IgE antibodies don’t even notice. You slowly give more and more until a normal dose is tolerated. Like slowly sneaking more and more spinach into your kid’s food.
S:I love tricking my child and the immune system. But we should mention up front the desensitization is often done in the ICU under close monitoring — so it’s quite resource intensive.
AM: Another thing with desensitization is that if you don’t use it, you lose it. Which means tolerance only last as long as there is constant exposure to the med. So if someone needs a penicillin again in the future they will need to go through the desensitization process again.
S: Very resource intensive! So let’s summarize to make sure I have it all correct. When I have a patient who is a low risk for a reported allergy, like skin itching without rash, or some distant, unknown history that didn’t need for treatment- I think what I’m taking away that I should just give a dose of amoxicillin and observe for an hour.
D: If the allergy history is more concerning for a type I IgE-mediated reaction, if its available you can use skin testing followed by an oral challenge. If skin testing isn’t available or isn’t practical and you need an antibiotic right away, you can do a graded challenge of a cephalosporin. If they had a recent IgE reaction or a positive skin test and they absolutely need a penicillin right now and don’t have the option for a cephalosporin, that is when you would do desentization.
Pearl 5: When is it safe to use cephalosporins or carbapenems in a penicillin allergic patient? What is the true rate of cross reactivity?
AM: I’m so glad we covered that, that’s super high yield. But what about when you have that patient with pyelonephritis with some resistant bugs and you really want to use a cephalosporin but then boom… penicillin allergy.
D: There’s a lot to unpack here but before we get started, just as a reminder… penicillins and cephalosporins are like cousins that are a part of a bigger family called beta lactams. And that’s simply because both classes have the beta lactam ring.
S: So does an allergy to one beta-lactam ring antibiotic mean an allergy to all beta-lactam ring antibiotics?
KB: There’s never been a randomized controlled trial of penicillin documented, like proven penicillin allergic patients and their tolerance of every single cephalosporin. What we instead have, or a bunch of people who might’ve reported a penicillin allergy in the past, some patients who had confirmed penicillin allergy and we sort of document whether they have objective signs that are symptoms with another cephalosporin or carbapenem. And so with that caveat, I’d say we know that there’s probably some cross-reactivity between beta lactam antibiotics, because they all have beta lactam rings, but the cross-reactivity risk is maybe not as high as it was ever thought to be an in our textbooks that 8% FDA label was rounded, like colloquially to 10%. Really the risk is probably somewhere in the 2%-3% cross-reactivity and the cross-reactivity is likely penicillin to cephalosporins that look alike.
AM: 3%! I def feel lied too!
S: But wait a minute, what does Dr. Blumenthal mean that cross-reactivity is higher when penicillins and cephalosporins look alike? Don’t they all share the beta lactam ring? Is she saying that some cephalosporins look a little bit more similar to penicillins than others cephalosporins?
AM: I have bad news for you. The answer involves organic chemistry.
KB: So back to organic chemistry, I never knew I’d have to think about organic chemistry again, but we have a beta lactam ring and then we have two important side chains. And one side chain might be more important than the other. And people say that the R one side chain is more important than the R two side chain. So it turns out the amino cephalosporins, these are things like Cephalexin and Cefaclor. They have the same R one side chain or similar to like amino penicillin via ampicillin and amoxicillin. So it’s possible that that cross-reactivity is just because they have that same fun side chain rather than the beta lactam ring.
S: Dan I’m curious, how do you apply this practically when you get consulted on patients with penicillin allergies?!
D: When I see someone with a known allergy to an amino penicillin, like ampicillin and amoxicillin I think twice about giving them an oral first generation cephalosporins, like cephalexin/cefadroxil because I know they have they have similar side chains.
S: To make things easier, can we just say that late generation cephalosporins like ceftriaxone and cefepime are safer in penicillin allergy and just try to avoid those early generation cephalosporins ?
D: So you are on the right track Shreya, but there is one 1st generation cephalosporin where cross-reactivity is wayyyyy less likely- and that’s my favorite cephalosporin, cefazolin. Its side chain doesn’t look anything like any penicillin or cephalosporin, so risk of cross-reactivity is much lower. It’s a really a unique and beautiful snowflake.
AM: Awww I hear all the orthopedic surgeons rejoicing! [S: You get cefazolin, You get cefazolin!] Okay but, even though the risk of cross-reactivity is lower, when you’re giving cephalosporins to someone with a penicillin allergy -especially with a history of a high risk allergy like anaphylaxis, this should be done in an observed setting- at least until more studies are done. This is a good time to use a graded challenge.
S: What about carbapenems – they are also beta-lactams family? Can those be safely given in those with penicillin allergy?
KB: I generally don’t worry about the carbapenems and penicillin allergy. Maybe if you had anaphylaxis today and you needed a carbapenem tomorrow, I would give it to you by like a graded challenge or a test dose where I could observe you. Um, but I’d still give it to you.
S: Yeah there is even less data supporting cross reactivity between PCNs and carbapenems – it seems like they’re like far far distant cousins
D: Alright sounds like its a good time from recap
S: Cross reactivity between penicillins and cephalosporins is a lot lower than the 10% we learned about in medical school. The cross reactivity is thought to be due to side chains rather than the beta-lactam ring. Medications with similar side chains like cephalexin and amoxicillin are more likely to have some cause reaction, even though that’s likely to be low. Late generation cephalosporins and carbapenems are usually safe when given in an observed environment
D: And that’s even in the setting of prior anaphylaxis.
AM: And before wrapping up, we have just have one last word from Dr. Blumethal
KB: I think my favorite thing to just my plea is that the allergy list or allergy module of the electronic health record is a communication tool. It’s just not a list of drugs. It’s a communication tool to future providers forever that lives with the patient from the time that you’re entering something and probably until their death. And so therefore everything that you can add, if you’re seeing a reaction or you’re making clinical judgements, anything you can add into that part of the allergy list is important for that patient’s future clinical care for life. No-one’s going to read the long progress note from day 13 of a 40 day hospitalization, but everyone is going to see that allergy list. And so, over document there be specific. You can say whatever you want. I think it’s within a 200 character limit. It’s like a tweet. You can see whatever you want and the electronic health record allergy list. And you should think of it as you’re communicating to future clinical providers.
AM: I am a little hurt that no one is reading my day 13 progress note, there’s some great stuff in there.
S: Ugh what a bummer day 13 note!
D: Don’t worry Ann Marie, as an ID doc I’m reading that day 13 progress note Ann Marie.
S: And with that, we will leave it to Neda Frayha.
NF: Name is Netta Frayha I am a primary care internist in Baltimore, Maryland. I’m on faculty at the University of Maryland School of Medicine. And I am the editor and host of the primary care reviews and perspectives podcast.
S: And Dr. Frayha will be doing the recap for the episode.
NF: Pearl one, there are many penicillin allergy myths. Most importantly, 90 to 95% of people who have a penicillin allergy label are not actually allergic to penicillin. And I think if we think for a moment about if there were any other diagnosis or label, where if we knew that every time we saw it on a patient’s record, we knew that 95% of the time it was false, it would really blow our minds. And we should have that same level of appreciation for this particular statistic. And there are a couple of reasons for it that are good to keep in mind. One is that in childhood, kids will have a rash at the drop of a hat and they may have a viral exanthem that gets mislabeled as a penicillin allergy. And then that label sticks around in their chart for decades to come. There is a misconception in a lot of our patients that if a family member had penicillin allergy, that means that they must to, and this also is inaccurate. And then third, and this particular little Pearl just blows my mind every time, even true penicillin allergy fades over the years. So up to 80% of people with a true IgE mediated penicillin allergy will actually lose this allergic response after 10 years. This is incredibly empowering as we think about how to delabel our patients. This 95% statistic can have real harm attached to it. There are harms associated with this over labeling of a penicillin allergy. Patients who have this reported allergy will receive more second line antibiotics, that can really deviate from standard of care, depending on the infection that we’re talking about, they receive more fluoroquinolones, more clindamycin, more vancomycin, more aztreonam, all of which have their own adverse effects. Patients who have a reported penicillin allergy have higher rates of nosocomial infections like MRSA, VRE, and C. diff. They have higher risk of surgical site infections. They have longer hospital stays and they incur increased healthcare costs.
Pearl three, by getting a good allergy history, we can figure out what type of allergic reaction the patient might have had and therefore risk stratify them so that we can manage them better. By asking a few simple questions we can get to what type of reaction they had. And these questions are things like, when did the reaction occur? What were the symptoms? If the patient even remembers, if there was a rash, was there desquamation, did it involve the mucosal membranes? Was there blistering? Did the person needs special medications like steroids or epinephrine did they need to be in the hospital and then really critically, have they been able to tolerate penicillin since and here I’ll get really specific. I will ask, have you had Amoxicillin in the past 10 years, have you had Augmentin in the past 10 years, I’ll use brand names because that may jog their memory. And they may tell me that they’ve actually been able to tolerate the medicine fine, but by asking these questions, we can get to what kind of reaction they might’ve had, which will help us with management.
Pearl four when it comes to management, practice improvement is easy and it is absolutely within reach for all of us if our patient is low risk. And so this is, for example, if they had an unknown reaction more than 10 years ago, or if they had pruritis, but without a rash. Then, it is safe to give these low risk patients a direct oral challenge. And this is giving them 250 to 500 milligrams of amoxicillin and observing them for an hour. And then if they don’t respond or react to that oral challenge, we’re done. We have been able to identify that they’re not allergic. In more medium or moderate risk scenarios, these are patients with a history of an IgE reaction in the past, maybe hives, maybe bronchospasm maybe distant anaphylaxis, then these are the right patients who should receive skin testing with a series of intradermal injections of penicillin metabolites. And then if that’s negative, we can follow that up with the same oral challenge. Together, these two tests have a negative predictive value of 95 to 98%. So if the person has a negative skin test and a negative oral challenge, we can delabel them. We want to communicate this result with the patient’s primary care clinician and any other clinicians that are really involved in their care. And so importantly, we want to celebrate this with the patient themselves. We want to tell them, congratulations, you are not allergic to penicillin. If anyone asks you in the future, are you allergic to penicillin? You will say no, because so often the patient doesn’t understand what we’ve just done. And then they perpetuate the myth themselves, which is just such a shame.
Pearl five. Is it safe to use cephalosporins or carbapenems and pen allergic patients? And the answer is very often, yes. We often learn that the cross-reactivity between penicillin allergy and cephalosporins is around 10% and that’s actually a myth. It’s another myth. It’s based on old studies with older cephalosporins and small study numbers. In reality, the cross-reactivity is really more like 2%-3% and it’s mediated by the R1 side chain of the particular drug. So if it’s similar to a penicillin, like in, for example, cephalexin, which is nearly identical in its side chain to amoxicillin, then we can be a little bit more cautious. But if it’s a unique side chain, like for example, in Cefazolin, then we can feel really empowered to use that cephalosporin and not to worry. And similarly carbapenems are safe to give and patients with either that Type 1 or a very mild Type 4 reaction.
S: And that’s a wrap for today’s episode. If you found this episode helpful, please share with your team and colleagues and give it a rating on Apple podcasts or whatever podcast app you use! It really does help people find us!
If you want to add any of your own tips or share challenges, tweet us and leave a comment on our website page, on Instagram or Facebook page. Thank you to our peer reviewer Dr. Qura Rashid. Thank you to Max Had for the audio editing and Cathy Cichon for the accompanying graphics. As always we love hearing feedback, email us at firstname.lastname@example.org. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.
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Tags: 5 Pearls, Clinical Practice, EMR, history taking, hypersensitivity, primary care, Rash, rheumatology, skin testing
4 comments on “5 Pearls on Penicillin Allergy”
I really ,really enjoyed the podcast, Very informative and explained well . I see this daily and will definitely be more knowledgeable.
This was a great episode, and you all made it so easy to put into practice. Any hope that there will be a way to get CME credit from listening in the future?
Our CME episodes are produced in partnership with ACP. Specific episodes are designated CME-eligible as the content has to be reviewed and approved in advance, with CME credit offered contingent on taking a CME/MOC quiz after listening. We unfortunately cannot retroactively make an episode eligible for CME. You can find the list of CME episodes here: https://www.coreimpodcast.com/category/podcast/cme/
Realistically, how does one actually facilitate a PO penicillin trial with one hour of supervision? In the outpatient setting, most of mine would not be willing to stay for another hour.
In the inpatient setting, they would be easy to follow up on- but how would this work into billing and liability? Any adverse events related or not to the penicillin challenge would be scrutinized and I am not sure of another way to make it happen. Any thoughts on this? How are other docs facilitating penicillin challenge?