An Approach to Penicillin Allergy

Around 10% of subjects report that they are allergic to penicillin. More than 90% of them are found not to be allergic to penicillin on skin testing. It is estimated that only 0.02%-0.04% of the population has severe (anaphylactic) penicillin allergy.

Strictly speaking, the term "allergy" connotes an IgE mediated process, but in practice, intolerance, idiosyncracy and pseudo-allergy are all lumped under the sobriquet of "allergy." This is unhelpful for a lifesaving medication such as penicillin.

It would be useful to recall the Gel-Coombs classification of hypersensitivity reactions and recollect specific examples.

Gel-Coombs Classification

Type I- IgE mediated, e.g. urticaria, angioedema, bronchoconstriction, hypotension, syncope. i.e. anaphylaxis. Occurs within minutes to an hour (sometimes up to 2 hours, if only oral exposure)
Type II- Antibody mediated cytotoxicity. e.g. Haemolytic anaemia. Occurs within hours to days.
Type III- Immune Complex reaction, e.g. serum sickness- maculopapular rash, fever, joint pains, low C3, C4, low CH50. Occurs from 7-21 days after exposure
Type IV- Delayed hypersensitivity. e.g. maculopapular rash without pruritus, SJS, TEN, DRESS, occurs after days to weeks

It is important to differentiate between these various processes as it is only the Type I (IgE mediated) reaction that lends itself to skin testing, graded dose challenge and desensitisation. These procedures should not be attempted in subjects with non-IgE medited reactions, that is Types II, III or IV hypersensitivity.

Further, it is important to remember that hypersensitivity to skin testing declines with time @ 10% per year. Therefore, 10 years after an index episode of penicillin allergy, 80-100% of subjects would have lost IgE mediated hypersensitivity to penicillin.

The likelihood of developing penicillin allergy is higher after intravenous dosing, frequent dosing, as opposed to oral or infrequent dosing. Atopy itself does not increase risk of penicillin allergy, but atopic subjects are likely to have more severe anaphylactic reactions if they do develop it.

Subjects with EBV developing a maculopapular rash with an aminopenicillin are not penicillin allergic. They can receive penicillin and beta lactams if indicated.

The cross reaction between penicillin and other beta lactam antibiotics is low. There is estimated to be <2% cross-reaction with amino-peicillins, 3% cross-reaction with cephalosporins (less with 3rd and 4th generation than with 1st and 2nd), 0% with monobactams such as aztreonam and <1% with carbapenems. Aztreonam and ceftazidime cross react with each other. There is 10-40% cross reaction between aminopenicillins such as amoxycillin or ampicillin and cephalosporins. Cross reaction occurs due to shared side chains and is non-IgE in character. It is best not to use one if there is a history of insensitivity to the other. It is important to quiz the patient regarding the type of reaction they had with penicillin. The most important arbiter is the speed with which the adverse reaction occurred. If the hypersensitivity was within minutes to an hour, it was likely to have been IgE mediated. Reactions occurring after days are non-IgE medated. For severe delayed reactions such as SJS, TEN, AIN, DRESS, haemolytic anaemia or serum sickness, repeat use of penicillin and other beta-lactams is best avoided. Penicillin is the only antibiotic for which skin prick testing is reliable. There are two antigens that are used to test for penicillin allergy- a major determinant- penicilloyl polylysine, also called Prepen, and a minor determinant- penicillin G itself. Both must be injected. Intradermal administration is necessary only if there is no reaction to skin prick testing. A negative control (normal saline) and positive control (histamine) is used simultaneously. Results are read at 15 minutes and a wheal 3mm or bigger compared with the negative control is considered to be evidence of Type I penicillin hypersensitivity. Other beta lactams are not used for skin testing. The results are read at 15 minutes. The PPV of skin prick test for penicillin allergy is 50% while the NPV is 97%. Thus, a subject with negative skin prick test is very unlikely to have penicillin allergy, but half of those who test positive may not have allergy. Skin prick testing is best delayed for 4-6 weeks after a severe allergic (anaphylactic) reaction.

If skin test is positive, it is best to use an alternative antibiotic. If penicillin or a related beta lactam must absolutely be used as there are no effective alternative, then densitisation may be attempted. This is attempted by giving progressively increasing doses of penicillin every 15-20 minutes S/C or IV or every 30 minutes, orally. It is customary to begin with 1/10,000 to 1/1000 of the therapeutic dose. Success rates are high. For example, between 75% to 100% of subjects with cystic fibrosis, who generally have high rates of drug intolerance, are rendered penicillin tolerant.

If the skin prick test is negative in a subject with a history of an adverse reaction to penicillin, a graded dose challenge is used as a precursor to giving the therapeutic dose. This is done using 1/100 to 1/10 of the therapeutic dose to start with, increasing the dose every 30 minutes.

It is important to mention again, that neither skin prick testing, nor graded dose challenge or desensitisation should be used for non-IgE mediated hypersensitivity reactions to penicillin. In such hypersensitivity reactions,if severe, penicillin is best avoided altogether.


Reference:

Gozalez-Estrada A, Radojicic C. Penicillin allergy: A practical guide for clinicians. CCJM 2015;82:295-300.