Dealing with drug allergy

Drug Allergy: An Updated Practice Parameter is an official document promulgated by a collaboration of three professional societies. Although it is a bit dated it is the latest such edition written by the collaboration. Moreover, for penicillin allergy an update was published in Mayo Clinic Proceedings only months ago. The Mayo update generally follows the recommendations of this document. Below are some key points.

The overall classification of drug induced disease encompasses all types of adverse reactions, not just allergic reactions.

From the document:

ADRs are broadly categorized into predictable (type A) and unpredictable (type B) reactions. Predictable reactions are usually dose dependent, are related to the known pharmacologic actions of the drug…

Unpredictable reactions are generally dose independent, are unrelated to the pharmacologic actions of the drug, and occur only in susceptible individuals. Unpredictable reactions are subdivided into drug intolerance, drug idiosyncrasy, drug allergy, and pseudoallergic reactions.

Allergic reactions are defined as immunologic reactions. Although the Gell-Coombs classification remains the framework for thinking about allergic reactions, the current classification has been extended beyond that.

Categories outside the C-G classification include these below. Form the paper:

Hypersensitivity vasculitis Cutaneous or visceral vasculitis Hydralazine, penicillamine, propylthiouracil

DRESS Cutaneous, fever, eosinophilia, hepatic dysfunction, lymphadenopathy Anticonvulsants, sulfonamides, minocycline, allopurinol

Pulmonary drug hypersensitivity Pneumonitis, fibrosis Nitrofurantoin, bleomycin, methotrexate

Systemic drug-induced lupus erythematosus Arthralgias, myalgias, fever, malaise Hydralazine, procainamide, isoniazid

Cutaneous drug-induced lupus erythematosus Erythematous/scaly plaques in photodistribution Hydrochlorothiazide, calcium channel blockers, ACE inhibitors

Drug-induced granulomatous disease Churg-Strauss syndrome, Wegener's granulomatosis Propylthiouracil, leukotriene modifiers

Immunologic hepatitis Hepatitis, cholestatic jaundice Para-aminosalicylic acid, sulfonamides, phenothiazines

Blistering disorders Erythema multiforme, SJS, TEN Sulfonamides, cephalosporins, imidazole anticonvulsants, NSAIDs

Serum sickness–like reactions Erythema multiforme, arthralgias Cefaclor, cefprozil

Immunologic nephropathy Interstitial nephritis, membranous glomerulonephritis Penicillin, sulfonamides, gold, penicillamine, allopurinol

It should be mentioned that some of the categories listed above are poorly understood and may not represent purely immunologic mechanisms.

What is “desensitization?”

More from the paper:

What has often been referred to as drug desensitization is more appropriately described in this parameter as a temporary induction of drug tolerance. Drug tolerance is defined as a state in which a patient with a drug allergy will tolerate a drug without an adverse reaction. Drug tolerance does not indicate either a permanent state of tolerance or that the mechanism involved was immunologic tolerance. Induction of drug tolerance procedures modify a patient's response to a drug to temporarily allow treatment with it safely. They are indicated only in situations where an alternate non–cross-reacting medication cannot be used. Induction of drug tolerance can involve IgE immune mechanisms, non-IgE immune mechanisms, pharmacologic mechanisms, and undefined mechanisms ( Table 2 ). All procedures to induce drug tolerance involve administration of incremental doses of the drug. Through various mechanisms, these procedures induce a temporary state of tolerance to the drug, which is maintained only as long as the patient continues to take the specific drug.

Remember that this technique is recommend only when there is no reasonable alternative, and it doesn’t induce permanent tolerance.

There is also the idea of graded challenge, which is different from tolerance induction (desensitization). Graded challenge is essentially the administration of a test dose.

Remember this, too, from the paper:

Graded challenge (or induction of drug tolerance) should almost never be performed if the reaction history is consistent with a severe non–IgE-mediated reaction, such as SJS, TEN, interstitial nephritis, hepatitis, or hemolytic anemia.

The recommendations for dealing with beta lactam type I allergy are complex

If the allergic history is that of an anaphylactoid reaction there is almost no avoiding the use of special techniques such as skin testing or tolerance induction, were one to strictly follow the document recommendations. Clinical rules cannot assure safe administration of an antibiotic. Consider assessment of side chain similarity for the assessment of safety of cephalosporin administration, for example. Although side chain assessment can be of help in the assessment of risk, in the document there is no recommendation for using it as an assurance of safety. On the other hand, in a couple of cases it can be used to mandate avoidance (such as the use of aztreonam in a patient with an anaphylactoid reaction to ceftazidime).

The application of the special techniques of skin testing, test dosing and tolerance induction is complex and has many contingencies noted in the document and therefore requires expertise.

Practical aspects for the clinician in dealing with type 1 beta lactam allergy

Despite the complexities noted above one can be informed by data on absolute risk. For example, according to the Mayo paper, cross-reactivity between PCN and carbapenems is likely less than 1%, with similar risk for aztreonam. What should one do, for example, when confronted with a patient in septic shock with concern for pseudomonas and ESBL producing bacteria? Considering a mortality increase of 5-10% per hour of non coverage, can you get an allergist on site and skin testing done in time or does the risk of delay exceed a less than 1% chance of a reaction from a carbapenem?