Background

Kimberly Blumenthal and colleagues at the Massachusetts General Hospital have been performing groundbreaking work on beta-lactam allergies.  Their work forms the foundation for much of the IBCC chapter on beta-lactam allergies (you might want to read it before this post, but if you don't have time, a one-minute synopsis is below).

One fundamental technique when approaching patients with possible beta-lactam allergy is a “graded challenge” or “test dose.”  This may be used when there is some suspicion of a potential allergy.  A small dose is provided initially with close supervision, to determine if the patient will react.  If this is tolerated, larger doses are subsequently given. 

Historically, there has been little evidence to guide the safety and performance of this strategy.  A new publication by the Blumenthal group describes their experience with this.

Blumenthal et al:  Outcomes from an inpatient beta-lactam allergy guideline across a large US health system

This is a retrospective, multi-center cohort study describing 1,046 test doses administered at five hospitals for management of patients with possible beta-lactam allergy.^​1​  This occurred within the context of a new protocol for management of beta-lactam allergies (example shown above).^​2​  Test-dose administration was used in the following situations:

• History of mild reaction to the drug, with a low suspicion for allergy → give same drug using a test dose.
• History of severe reaction to one antibiotic → give a different beta-lactam with a non-cross-reactive R side-chain using a test dose. 

Most test doses were provided on a medicine or subspecialty ward (only 11% occurred in an intensive care and 13% in an emergency department). 91% of test doses were performed without consulting an allergist. A skin test was rarely used prior to the test dose (<4% of patients).

Antibiotics administered via test-dose were mostly cephalosporins (809 doses) along with some penicillins (148 doses) and carbapenems (89 doses).  Forty patients had hypersensitivity reactions, most of which required no treatment. Three patients were treated with epinephrine, which is described in the highlighted text below:

A close reading of the three patients treated with epinephrine raises a question of whether some (or all) of these might have represented a psychosomatic response.  A prior study showed that 10% of patients with a history of antibiotic allergy may develop a psychosomatic reaction when given placebo tablets.^​3​  The three patients treated with epinephrine didn’t exhibit objective signs of anaphylaxis (e.g. urticaria, angioedema, hypotension), so one or more may have had a psychosomatic reaction.  Regardless, all three patients responded promptly to therapy without sequelae. 

Overall, this is a pragmatic, real-world study demonstrating the safety of a test-dose strategy for patients with allergy to a beta-lactam antibiotic.  The test-dose protocol was performed across a range of units in five hospitals, mostly without the supervision of an allergist.  Most test-dose challenges were performed outside of a critical care arena.  Nonetheless, the strategy was safe and robust.

The safety of the protocol is probably due primarily to the following two factors:

• Among patients with an antibiotic “allergy,” only <10% are truly allergic.
• Beta-lactam antibiotics with dissimilar R side-chains aren’t cross-allergic. 

Based on these two factors, a protocol which promotes the use of beta-lactam antibiotics with non-cross-allergic side-chains is far safer than traditionally believed.  This raises the question of whether a test dose is needed at all (or whether it would be safe to simply proceed with a full dose of drug).

Clinical pearls from this paper

#1: How to perform a test dose

Previously, there has been relatively little literature regarding how to do this.  Some papers recommended graded challenge, which involves administration of several escalating doses.  Others utilized a single test dose, followed by a full dose of the antibiotic. 

This study provides a simple, validated protocol for accomplishing this.  There is no evidence this protocol is superior to any other strategy.  However, in the absence of a competitor, this seems to be the best-validated strategy.  Furthermore, using a single test-dose is easier and faster than performing a complex graded challenge. 

Their test-dose procedure involved IV administration of 10% of the total antibiotic dose as a slow push over 5 minutes.  The patient was subsequently observed for 30-60 minutes prior to administration of the full dose. It should be noted that some patients didn't respond to the test dose but did have an adverse reaction to the full dose – so careful attention should be paid to the patient throughout administration of both doses.

This is a simple approach which shouldn’t delay administration of the full antibiotic dose substantially.  Notably, it doesn’t seem necessary to provide several doses of escalating size; a single test dose seems sufficient.

#2: Be wary of delayed, non-IgE-mediated reactions

Although no patients in this study were harmed by IgE-mediated (allergic) reactions, three patients did have severe delayed reactions (interstitial nephritis, acute generalized exanthematous pustulosis, and a severe cutaneous adverse reaction).  This should serve as a warning and a reminder that a test-dose procedure will not protect against delayed, T-cell mediated reactions (e.g. Stevens Johnson Syndrome).  In patients with a history of severe T-cell reactions, re-challenge with beta-lactam antibiotics should be avoided.

#3. Test-dose should be used within the context of a larger, coherent strategy

Like many interventions in medicine, the success of a test-dose strategy depends on using it within an organized and coherent approach to beta-lactam allergies. This study shouldn't be interpreted to mean that any patient can be given any drug via a test-dose strategy – that could certainly be dangerous (e.g. if a patient had a history of anaphylaxis to penicillin, then penicillin should be given only within the context of a desensitization protocol).

The strategy used by Blumenthal is shown above and described further in a previous publication.^​2​ A similar strategy (based largely on Blumenthal's work) is described in the Internet Book of Critical Care, with an example below.

#4. Allergy to a cephalosporin may be slightly more worrisome than allergy to a penicillin

Multivariable analysis found that cephalosporin allergy was one risk factor for having a hypersensitivity reaction (odds ratio 2.96; confidence interval 1.34-6.58). This makes sense for the following reasons:

• Allergy to beta-lactam antibiotics isn't caused by the antibiotic alone, but rather complexes formed between the antibiotic and various proteins (an antibiotic molecule alone is too small to bind to an antibody). Cephalosporins are more chemically stable than penicillins, so they tend to stick to proteins less and thereby induce fewer allergic reactions. For example, the rate of anaphylaxis involving cephalosporins is ten times lower than for penicillins.^​4​
• Patients with allergy to a cephalosporin could be more prome to allergy in general, placing them at a slightly higher risk of reactions to other antibiotics.

Overall, this study validates the concept that patients with an allergy to one cephalosporin can be treated with non-cross-allergic beta-lactams. So we don't need to run for the hills when we encounter a patient with cephalosporin allergy. However, we may wish to be a bit more cautious with allergy to a cephalosporin, in comparison to allergy to a penicillin.

#5. It's safe to use non-cross-allergic cephalosporins for patients with a history of penicillin anaphylaxis

Over the past several years, there has been increasing recognition that beta-lactams with dissimilar side-chains are not cross-allergic. Despite this, many sources continue to recommend avoidance of cephalosporins in patients with a history of anaphylaxis to penicillin. This study supports the safety of using non-cross-allergic cephalosporins in such patients.

#6. Electronic medical record documentation of allergies is often wrong.

Even following a successful test-dose administration, the electronic medical record was often not updated to reflect that the patient could tolerate a certain antibiotic. This is a reminder of two things:

• The electronic medical record data on allergies is frequently wrong, often being only slightly more reliable than pure gossip.
• The electronic medical record is better at recording drugs that the patient can't tolerate, compared to drugs which the patient can tolerate.

Thus, one essential component of any allergy history is always determination of which drugs the patient was able to successfully tolerate in the past.

• A test-dose strategy can be used in situations where an allergy is unlikely (yet possible), to help determine the safety of providing a full dose of antibiotic.
• This is the largest study to validate any specific protocol for challenging patients with possible antibiotic allergy.
• Within the context of a structured protocol, the test-dose strategy was safe and effective (even without the assistance of an allergist and outside of an ICU).
• Administration of an advanced-generation cephalosporin using a test dose seems to be safe, even in patients with anaphylaxis to a penicillin.

Related

• IBCC chapter on beta-lactam allergy

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Josh Farkas

Josh is the creator of PulmCrit.org. He is an associate professor of Pulmonary and Critical Care Medicine at the University of Vermont.

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