CHILDREN – PENICILLIN ALLERGY DELABELING

At least 5 million children carry a penicillin allergy label (27).  A recent study reported the rate of oral penicillin anaphylaxis in the Kaiser Permanente Southern California system was only 0.00048% (28). Fatalities attributed to oral amoxicillin are rare. Among 100 million individuals exposed to oral amoxicillin in the United Kingdom between 1972 and 2007, only 1 death associated with anaphylaxis from oral amoxicillin was identified (1,29).  The majority of children who carry a penicillin allergy label have been over diagnosed as a result of a viral exanthem occurring within the course of treatment (27). However, less than 10% of patients with a penicillin allergy label will have a confirmed allergy by oral challenge (28).

Most children acquire a penicillin allergy label in early childhood. In a study of 605 patients presenting to a pediatric emergency department with parent-reported penicillin allergy (median age 6 years), 75% were diagnosed before their third birthday (30).

Oral Amoxicillin Provocation Challenge

Skin testing for penicillin allergies can be used to rule out IgE-mediated reactions. However, among low-risk patients who are unlikely to have an IgE-mediated allergy on the basis of a clinical history, skin testing can be safely deferred while proceeding directly to an oral provocation challenge with amoxicillin (31,32).  This has helped develop penicillin allergy delabeling clinical pathways that empower healthcare providers to identify low-risk patients for penicillin allergy delabeling without the need for skin testing or referral to a pediatric allergy and immunology specialist.

Proceeding to oral amoxicillin challenge in children with low-risk histories of both immediate and non-immediate reactions to amoxicillin appears safe.  Mill et al (33) evaluated 818 children, reporting that 94.1% tolerated direct oral challenge without risk stratification by skin testing.  Only 2.1% of patients developed mild immediate reactions (limited to the oral mucosa or skin), with 3.8% of patients reporting nonimmediate reactions. The supervised challenge had a specificity of 100%, negative predictive value (NPV)) of 89.1% and a positive predictive value (PPV) of 100%. While graded oral provocation challenge is often performed, the incremental margin of safety of a two-step challenge compared with a single-dose challenge is likely small, as immediate reactions are typically mild (33).

The usual single-dose oral amoxicillin challenge consists of amoxicillin (45 mg/kg per dose with a maximum 1000 mg) given orally followed by a 60 minute observation.

                                                            Urticarial Rash

Urticaria is the most common clinical symptom of a drug reaction, drug-viral interaction, and non-IgE-mediated mast cell activation (34). When it occurs within an hour of exposure to a drug, it can represent an immediate reaction potentially associated with anaphylaxis. Delayed urticaria that occurs several hours to days after drug exposure is often non-IgE-mediated. The underlying cause of cutaneous drug reactions during viral infections may involve a viral-induced polyclonal activation of lymphocytes, an enhancement of cellular immunity, or changes in drug metabolism.

Although published pathways have categorized patients with a history of an urticarial rash as moderate risk, existing pediatric evidence has revealed that a history of a delayed urticarial rash is not an increased risk factor for a true IgE-mediated penicillin allergy (33).

Therefore, a delayed onset of an urticarial rash alone can place a penicillin allergic patient In the low-risk group.

                                                         Cross Reactivity to Other Beta-lactams

Beta-lactams (penicillins, cephalosporins, carbapenems and monobactams) are a group of drugs that share a 4-membered beta-lactam ring.  There is a side chain that arises from the beta-lactam ring (R1).  Cephalosporins additionally have a 6-membered ring and another side chain (R2). The R1 side chain and, less frequently, the R2 side chain have been demonstrated to contribute significantly to cross-reactivity within the penicillin class itself and also between penicillins and cephalosporins.

Approximately 2% of patients with penicillin allergy cross react to a cephalosporin.

Cefazolin does not share R1 or R2 groups with other cephalosporins.

The rate of cross-reactivity between penicillins and both carbapenens (imipenem, meropenem and ertapenem) and aztreonam in children has been determined to be <1% so it is safe for a patient with penicillin allergy to receive these drugs (35,36).