Managing penicillin-allergic patients may come in many forms depending on the patient and institution but it should always begin with a comprehensive allergy reconciliation (comprehensive patient interview regarding penicillin/beta-lactam allergy) and patient assessment.

Management consists of the following options depending on the patient’s risk category:

• Penicillin skin test (PST)
• Oral amoxicillin challenge
• Desensitization
• Avoidance of the target beta-lactam antibiotic and administration of alternative antibiotic therapy

Penicillin skin test

Penicillin skin testing (PST) is a favorable option that rules out the risk of a positive IgE-mediated (immediate) reaction. Skin tests have a high negative predictive value (NPV) of greater than 95% but a poor positive predictive value (PPV)generally less than 50%.

Allergists have previously been the major physicians performing PST in the outpatient setting. However, there is evidence supporting implementation of PST by emergency clinicians, internists, intensivists, infectious disease specialists and pharmacists (16, 17).

The standard PST procedure is a multistep process utilizing both minor and major determinant antigens which takes approximately 45 – 60 min to complete. Penicillins break down to a protein derivative (i.e., penicilloyl), which is the major allergenic determinant for IgE-mediated reactions. Potentially life-threatening immediate reactions may occur in patients secondary to IgE response to minor determinants (i.e., Penicillin G). Therefore, both major and minor determinants (penicilloyl and Penicillin G) are used for PST.

The PST can be performed at the bedside in a two-step modality: (1) a prick test, typically on the forearm, followed by (2) an intradermal test, if the prick test is negative.

Prick test

The prick test involves four components: histamine (positive control), saline (negative control) benzyl penicilloyl polylysine – PRE-PEN (major determinant) and dilute penicillin G (minor determinant) (18). A negative test means the patient has a positive reaction to the histamine and a negative reaction to the other 3 components.

Intradermal test

The intradermal test should only be conducted following a negative skin prick test. The intradermal test utilizes the same components excluding histamine. The chance of a systemic reaction occurring from PST is exceedingly rare, reported as 0.16% among nearly 20,000 patients exposed to both major and minor determinants (18). In cases of a severe reaction to the test, on-call or bedside rescue medications should be readily available with procedures in place if the need for a rapid response occurs.

Per CDC recommendations, to rule out penicillin allergy skin-test negative patients, an oral amoxicillin challenge can be done after skin testing (19). The negative predictive value (NPV) of skin testing with the major and minor penicillin determinants is > 95% but approaches 100% when followed by an oral amoxicillin challenge. An oral challenge with amoxicillin also has the added benefit of ruling out patients who tolerate penicillin, yet may have amoxicillin-specific reactions.

The following are contraindications to PST (nonIgE-mediated) reactions (delayed-Type IV):

• SJS     Acute interstitial nephritis
• TEN     Neutropenia
• DRESS     Serum sickness
• AGEP     Hemolytic anemia

Oral amoxicillin graded challenge

Many PST results are false positive secondary to a low threshold to define a positive test, high concentrations of reagents, reagents other PRE-PEN are used or improper preparation/storage. Previously, the use of PST alone was the reference standard for penicillin allergy testing. The need for oral antibiotic challenges to confirm current penicillin tolerance has been known for > 16 yrs.

Skin testing followed by an oral amoxicillin challenge has been widely used (20). The current reference standard test to confirm penicillin tolerance remains an oral challenge with a therapeutic amoxicillin dose. Skin testing is only performed to reduce the risk of serious oral challenge reactions in patients with moderate or high-risk histories.

Oral amoxicillin challenge should only be given to penicillin allergic patients with low-risk histories including:

• patients who have had isolated non-allergic symptoms (eg., GI symptoms)
• patients solely with a family history of a penicillin allergy
• patients with pruritis without a rash
• remote (> 10 yrs) unknown reactions or reactions without features suggestive of IgE-mediated reaction

Two amoxicillin challenge protocols are utilized:

1. Single-step challenge :
   • administration of 250 mg or 500 mg amoxicillin with 1 hour medical observation demonstrates PCN tolerance.

   OR

2. Two-step challenge
   • administering 25mg or 50 mg amoxicillin with 30 – 60 min medical observation followed by administration of 250 mg or 500 mg with 60 min medical observation demonstrates PCN tolerance.

For patients with a history of only penicillin allergy, after amoxicillin challenge is tolerated without An adverse reaction, all beta-lactams can be administered as indicated.

Penicillin (beta-lactam) desensitization

What is often referred to as penicillin desensitization is more appropriately described as a temporary induction of penicillin tolerance (14). Penicillin tolerance is defined as a state in which a patient with a penicillin allergy will tolerate penicillin without an adverse reaction. Penicillin tolerance does not indicate a permanent state of tolerance. All procedures to induce penicillin tolerance involve administration of incremental doses of the penicillin. These procedures induce a temporary state of tolerance to penicillin that is maintained only as long as the patient continues to take the specific penicillin. The goal of induction of tolerance is to modify an individual’s immune response so that penicillin can be given safely. If more than 5 half-lives intervene between penicillin doses, the patient must be desensitized again.

Induction of penicillin tolerance (desensitization) should never be performed if the reaction history is consistent with a severe non-IgE-mediated reaction (delayed Type IV):

• SJS     Acute interstitial nephritis
• TEN
• DRESS     Serum sickness
• AGEP     Hemolytic anemia

During desensitization, patients receive progressively higher doses of penicillin every 15 to 20 minutes intravenously or every 20 to 30 minutes orally until a full therapeutic dose is tolerated. Most protocols begin with a dose ranging from 1/10,000 to 1/1,000 of the final dose depending on the severity of the reaction.