Penicillin Allergy: Evaluation and Testing
17
September

By Adem Lewis / in , , , , , , , , , , , , , , , , , , /


Apparently when I was little, I was
given penicillin and had terrible hives, and the pediatricians told my parents that
if I was ever given it again, I would die. So my entire life I was told that if I
ever took penicillin, it would kill me. Over 95% of people labelled as
penicillin allergic are not. Despite the fears expressed by this patient
and those like her, for most people, penicillin antibiotics are safe and effective. They are also the optimal
treatment for many infections. It’s important for individual patients,
as well as the healthcare system as a whole, that these inappropriate diagnoses be
removed from patients medical records. So all patients with a penicillin
allergy diagnosis should be evaluated. The over-diagnosis of penicillin allergy
is the subject of a new JAMA clinical review. This video covers five toolkits from that review
that are a resource for clinicians interested in performing penicillin allergy
testing in their practice. This video will explain risk stratification of
patients undergoing penicillin allergy testing, patient preparation for testing, testing low
risk patients and management of reactions to oral penicillin challenge
including anaphylaxis, testing moderate risk patients,
and follow-up management. Before testing, you must first determine your
patient’s penicillin allergy risk level through a thorough history. Since there are three parts to penicillin
allergy testing– skin prick, intradermal, and oral challenge– identifying
a patient as low, moderate, or high-risk for having a true penicillin
allergy will determine what types of testing they’ll need. The history should include details of the past
reaction, if the patient knows any, including timing relative to the penicillin dose, and what treatment the patient
received at the time of the reaction. Some examples of low risk patients include
the patient who says theyÕre allergic to penicillin but also reports tolerating
a course of Augmentin prescribed to them at urgent care last year. Patients like this can be reassured
they are not allergic to penicillin. Patients who report reactions to penicillin
that are consistent with intolerance rather than a true allergy– such as nausea,
vomiting, diarrhea, or headache– can also be reassured, though a direct
amoxicillin challenge may be needed to provide maximal reassurance to the patient. On the other hand, patients who have
experienced severe reactions to penicillin in the past, including blistering rash,
hemolytic anemia, thrombocytopenia, nephritis, hepatitis, fever, joint pain, or
anaphylaxis, are considered high-risk and should not be tested, but can be
considered for specialist referral. Patients with unstable or compromised
hemodynamic or respiratory status or pregnancy are always considered
to be at least moderate risk for having a true penicillin allergy. Anyone else with a history of
a reaction temporally associated with penicillin should undergo some
form of penicillin allergy testing. Once you’ve determined your patientÕs
risk level, you can move on to testing. Review what medications your patient is
currently taking before beginning any part of penicillin allergy testing. For higher risk patients, beta-blockers
should be held for two days before testing because beta-blockade can inhibit the
action of epinephrine during anaphylaxis. If challenges are routinely performed
in patients on beta-blockers, your anaphylaxis kit should include glucagon
to overcome beta-blockade if necessary. For skin testing, the patient
should not have taken an antihistamine in the last five days. Tricyclic antidepressants and antipsychotics
can have strong antihistamine activity that can last a week or longer
after stopping the medication. High doses of immunosuppressants, including
steroids, are most likely to interfere with a delayed response, but may
also interfere with skin testing to rule out IgE-mediated reactions. However, you can do a skin test as long
as there is a positive histamine response, so you can check a histamine prick
test before canceling the test. After medication review, perform
a physical exam, including vitals, inspection of the oropharynx
and uvula, and, if available, establishing a baseline peak flow meter reading. Confirm that the patient is in
their usual state of health. Contraindications to testing include
acute illness, new medications, increased rescue inhaler use, increased
oxygen requirement, or new chest tightness. Toolkit E provides a sample
anaphylaxis kit checklist. Prior to any testing, you must have an
anaphylaxis kit in the clinical area that has medications needed to rescue someone
in the event of an anaphylactic reaction. It should also include IV
fluids and an IV start kit. Check the kit before each test to
make sure nothing is missing or expired. Any drug used should be immediately replaced. Although all sites should
have access to a similar kit, keep in mind that anaphylaxis resulting from oral amoxicillin challenge
testing is an extremely rare event. If your patient is low-risk,
then they can proceed to the direct oral amoxicillin challenge. Toolkit B covers the oral amoxicillin challenge
for low risk patients, which is a single 250 mg or 500 mg dose of amoxicillin followed
by observation for a minimum of an hour, with vital sign checks every 30 minutes. Going directly to the
oral challenge is appropriate for patients who report these symptoms. Toolkit C outlines oral challenges
for moderate risk patients in clinics without the resources for skin testing. Following an oral challenge, the most
common reactions will be subjective symptoms such as itching without a rash, a scratchy
throat, or vague gastrointestinal symptoms. These symptoms are often side effects,
or result from patient anxiety. If a patient complains of any of these,
check their vital signs and examine them, looking for objective signs
of allergic reaction, and observe for an additional 30 minutes. If at that point there are no objective
symptoms, the patient can be reassured that the symptoms were likely
not an allergic reaction. If there are doubts about symptoms
resulting from an oral challenge, then consider specialty referral. The next most common reactions are
mild cutaneous ones that can be treated with antihistamines like
cetirizine or fexofenadine. Diphenhydramine can be used
but will cause drowsiness. Epinephrine may be used for more
diffuse urticarial reactions and will work more rapidly than antihistamines. Again, increase the observation period by
30 minutes to make sure there are no signs of a systemic reaction and that
the cutaneous reaction subsides. These symptoms represent a potential
penicillin-allergic response, so the patient should remain
labeled as penicillin allergic and specialty referral may be considered. Anaphylaxis typically involves
more than two organ systems. Look for these cutaneous, respiratory,
cardiovascular, and gastrointestinal symptoms. Low blood pressure alone in the setting of a known allergen exposure
is also considered anaphylaxis. Again, epinephrine can be considered for
diffuse urticaria to abort a reaction quickly and avoid progression to anaphylaxis. If a patient is having an anaphylactic reaction,
get out the anaphylactic kit and open it up. Lay the patient supine and elevate their legs. Check the airway, breathing,
circulation, and vitals. Bring the AED if one is available. Give epinephrine, adjunctive
medications, and IV fluids. And call 911. For patients determined to be of moderate risk, skin testing is performed before
an oral amoxicillin challenge. For penicillin allergy skin
testing,Êthis is what youÕll need. These are usually provided in
commercially available kits. In the US, there is one such kit on the market. The optimal site for both prick and
intradermal skin testing is the volar surface of the forearm or extensor
surface of the upper arm. Note any rash, irritation, or tattoos. You want to avoid these during skin testing. Use an alcohol swab to clean the skin. Once that’s dried, use a permanent marker
to mark where each reagent will be placed. Because most negative skin tests are
going to be completely invisible, the markings help you remember
where you put the skin test. We use a plus to indicate the histamine control
and a minus to mark the saline negative control. We use “PP” to indicate PrePen,
or the major antigenic determinant. The placement doesn’t matter, though
itÕs best to place the histamine furthest from the major determinant because
the flare can bleed into the next test if a patient has a very strong
reaction to the histamine. Take the applicator from the reagent, then
place the applicator on clean, dry, intact skin. You need to apply a little bit of
pressure to break the epidermis. A small drop of the reagent is going to
sit on top of the skin and be absorbed through the small punctum you’ve created. Repeat with the other reagents. Set a timer for 15 to 20
minutes before interpreting the results. The test is interpreted by comparing
the reaction to the major determinant with the reactions to the
histamine and saline controls. Begin by blotting off
extra reagents from the skin. Using a reaction measurement guide,
measure the size of the wheal, and the flare across the
widest diameter at each site. There are different acceptable criteria
for determining a positive test. One is a wheal larger than 5 millimeters, as
long as the flare is larger than the wheal. Another is a wheal larger
than 3 millimeters, with a change in the baseline erythema
of the flare larger than 5 millimeters. This histamine
site is about 4 millimeters across the widest diameter of the wheal, and
about 42 millimeters across the widest diameter of the flare, so this is positive
as expected. This saline control
is negative as expected. And at the major determinant site, you see
a 5 millimeter wheal and a 31 millimeter flare, so this skin prick test is
positive, which is rarely seen. Application of topical diphenhydramine or
hydrocortisone to the positive histamine control and other positive tests is rarely needed but
can be used to relieve short-lived symptoms. The histamine test should
be clearly positive. Common reasons for a negative histamine test
include inappropriate placement of the test or inhibition by medications,
often antihistamines. And chronically ill patients
may not respond appropriately. The saline control should be clearly negative. Common reasons for a positive saline include
dermatographia and chronic urticaria. The next step after negative skin
testing is intradermal testing, before proceeding to the final step,
the oral amoxicillin challenge. Each step increases the negative predictive
value of penicillin allergy testing. The skin preparation and placement of the
markings are the same, except you don’t have to place an intradermal histamine control. For intradermal testing, only
sterile reagents in vials are used, drawn up into tuberculin syringes. The technique is similar to
that used for placing a PPD. Inject a tiny amount of reagent,
approximately 0.02 milliliters, just below the epidermis, to raise a tiny bleb. After placing the
blebs, wait 15 to 20 minutes and interpret the results using the
same criteria as the skin prick test. After skin testing is completed,
wipe the area down with an alcohol swab. You can apply topical
diphenhydramine or hydrocortisone to relieve itching from a positive test. Here we have an example of a
negative skin prick test on the left arm, followed by a negative intradermal
test on the patient’s right arm; this is a far more common sight than
the positive test demonstrated earlier. If intradermal testing is negative, you can
proceed to the oral amoxicillin challenge, which is the same as the direct
oral amoxicillin challenge for low-risk patient outlined
earlier in this video. But if a patient reacts during either skin test, do not proceed to an oral challenge
and consider specialty referral. Most patients don’t complain of
pain from the skin prick test applicators or the small needles used
for intradermal testing– though almost everyone will have itching
at the site of the histamine test. Occasionally bruising is seen in patients
on antiplatelet drugs or anticoagulants, but this is easy to distinguish
from a positive test. Fewer than 5 in 100 people undergoing
penicillin allergy testing will have a reaction. These are usually the mild skin reactions that
can be managed with antihistamine medications as outlined earlier in this video. Again, anaphylaxis during penicillin
allergy testing is extremely rare. Once testing is complete, the
patient’s chart needs to be clearly and thoroughly updated. If testing is negative, removing a
label of penicillin allergy can be difficult. First, edit the penicillin allergy
entry in the allergy record, adding details of the thorough allergy
history you took prior to testing. Use the free text box most EMRs will have
to document the test date and the result. Then delete the allergy from the record. Some EMRs will require a
reason to delete an allergy. Something like “resolution
of allergy” is appropriate. Second, provide documentation for the patient
to share with other clinicians and pharmacists. Ideally, your clinic will take the time to communicate directly with
the patientÕs pharmacy. If you’re not the patient’s primary
care clinician, the results also need to be communicated directly
to the primary care clinician. Finally, communicate to the patient that they
should call you if they develop new symptoms like itch or rash in the next 24 hours or if
the site of a skin test turns hard and itchy. A negative test consisting of negative skin
testing and a minimum of one hour of observation after an oral challenge means
that the patient does not have a risk of an immediate reaction, but
the risk of a delayed reaction at the population level is between 2-5%. If a delayed reaction develops, either at
the site of skin testing, or as a rash, this should be clearly documented,
ideally including a photograph, and specialty referral considered. If testing is positive, again, you’ll need to first edit the penicillin
allergy record in the EMR, adding the details about the patient’s allergy history that
you’ve elicited, and adding the test date and results that demonstrate allergy,
whether it’s a positive skin test or a reaction to an oral challenge. Specify the subjective and
objective findings of the reaction. Second, provide the patient with documentation
for their outside clinicians and pharmacy. Again, ideally youÕll communicate directly with the patient’s pharmacy
and primary care clinician. Third, let the patient know that
positive tests can wane over time so that re-testing in 5 years
should be considered. Finally, instruct the patient to
avoid all penicillins, cephalosporins, and carbapenems until they undergo further
evaluation by specialists if deemed appropriate. The need for specialty care can be based
on the patient’s specific health needs. Some additional considerations: tolerance
of a cephalosporin or other beta-lactam in a patient labelled penicillin allergic
does not rule out penicillin allergy. Tolerance of a penicillin
in a patient with a history of a cephalosporin allergy does not
rule out a cephalosporin allergy. This is because cross-reactivity between different beta-lactams can
occur based on shared side chains. In the setting of positive penicillin skin
testing, consider specialty consultation for further testing to assess
for cross-reactivity between penicillin and other beta-lactams. Or, if a patient has a history
of a cephalosporin allergy and negative penicillin skin
testing and amoxicillin challenge, consider specialty referral for further
testing to address the cephalosporin allergy. Patients with a history of reaction
to Augmentin may have reacted to the clavulanate component rather than
amoxicillin, so negative penicillin skin testing and oral amoxicillin challenge does not
exclude Augmentin allergy in these patients. A specialist can test for
sensitivity to clavulanate. Finally, the information provided in this
video isÊapplicable toÊadult populations in the US. There are extra considerations when testing
kids, hospitalized patients, and pregnant women, so these patients should be
evaluated by specialists. Given the large burden of inaccurate
penicillin allergy diagnoses, a clinician who starts allergy testing in their practice will be
helping their own patients, should those patients need penicillin therapy
in the future, and also be contributing at the population level, reducing costs
and minimizing a major contributing factor in the antimicrobial resistance crisis. For more information, read the
full clinical review at JAMA.com.


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