Continuing Education Activity

Penicillin (PCN) was discovered by Alexander Flemming in 1928 and became widely used in 1942 to treat various staphylococcal and streptococcal bacterial infections. Today, penicillin is still one of the most widely prescribed antibiotics. Penicillin is also one of the most frequently reported medication allergies. The penicillin family of antibiotics includes penicillin derivatives of ampicillin and amoxicillin as well as cephalosporins, monobactams, carbapenems, and beta-lactamase inhibitors. All penicillins share the same core beta-lactam and thiazolidine ring structures but differ in their side chains. Identification of true penicillin allergy is critical as 80% to 90% of people once considered allergic are ultimately able to tolerate penicillins resulting in the decreased need for broad-spectrum antibiotics and development of multi-drug resistant organisms. This activity reviews the pathophysiology of penicillin allergy and highlights the role of the interprofessional team in the management of these patients.

Objectives:

• Identify the cause of penicillin allergy.
• Review the pathophysiology of penicillin allergy.
• Summarize the treatment of patients with penicillin allergy.
• Describe interprofessional team strategies for improving care and outcomes in patients with penicillin allergy.

Introduction

Penicillin (PCN) was discovered by Alexander Flemming in 1928 and became widely used in 1942 to treat various staphylococcal and streptococcal bacterial infections. Today, penicillin is still one of the most widely prescribed antibiotics. Penicillin is also one of the most frequently reported medication allergies. The penicillin family of antibiotics includes penicillin derivatives of ampicillin and amoxicillin as well as cephalosporins, monobactams, carbapenems, and beta-lactamase inhibitors. All penicillins share the same core beta-lactam and thiazolidine ring structures but differ in their side chains. Identification of true penicillin allergy is critical as 80% to 90% of people once considered allergic are ultimately able to tolerate penicillins resulting in the decreased need for broad-spectrum antibiotics and development of multi-drug resistant organisms.[1][2][3][4]

Etiology

Penicillin is a beta-lactam antibiotic. Included in the penicillin family of antibiotics are penicillin G, penicillin V, procaine penicillin, benzathine penicillin as well as over 15 related compounds with broader antibacterial effects. Type 1 and type 4 hypersensitivity reactions mediate the most common allergies to penicillin. Serious allergic reactions to penicillin are Type 1 and mediated by IgE. Risk factors for IgE mediated reactions include high-dose parenteral administration and repetitive or frequent dosing of penicillins. Most severe reactions occur between the ages of 20 to 49 years. Previously, PCN related antibiotics such as cephalosporins were avoided given concern for cross-reactivity. Current research suggests that similarities between the chemical structures of the R-side chains are what determines cross-reactivity between classes of penicillin-related compounds, enabling greater use of antibiotics previously avoided. Of note, amoxicillin is the most common of the penicillins associated with cross-reactivity.[5][6]

Epidemiology

Approximately 10% of patients report an allergy to penicillin however up to 90% of these patients do not have a true allergy. The incidence of anaphylaxis to penicillin is 0.02% to 0.04% and is mediated by a type 1 hypersensitivity reaction. Overall, cutaneous eruptions are the most commonly reported reaction. IgE antibodies decrease over time. In patients who have previously tested positive for penicillin allergy, there is an expected 10% decrease/year of a subsequent positive reaction. Therefore, with the avoidance of PCN, 80% to 100% of patients will ultimately test negative for penicillin allergy 10 years after the initial positive test. The presence of an underlying bacterial or viral infection with penicillin administration also often resulted in false reporting of penicillin allergies such as the exanthem seen with EBV.

Cross-reactivity with other penicillin-related compounds, specifically cephalosporins, has resulted in the avoidance of drug use. Early studies may have also over-estimated cross-reactivity between penicillin and cephalosporins as the production of early generation cephalosporins may have been contaminated with small amounts of penicillin. Penicillin has a single R side chain whereas cephalosporins have two. If the penicillin side chain is similar to either cephalosporin side chain, there is a greater risk of cross-reactivity. This more commonly occurs with first and second generation cephalosporins than with third or fourth generation cephalosporins making the latter more attractive treatment choices when a patient has a proven penicillin allergy. Overall, cross-reactivity with aminopenicillins is less than 2%, carbapenems less than 1% and cephalosporins less than 3%. There is no significant reported cross-reactivity with monobactams.

Pathophysiology

All penicillins share the same core beta-lactam and thiazolidine ring structures but differ in their side chains. The ring structure is metabolized into major (penicilloyl) and minor (penicillin, penicilloate, and penilloate) antigenic determinates. Immediate reactions are the result of IgE that cross-like on mast cells when exposed to the antigenic component. The result is degranulation and release of histamine as well as other vasoactive substances. It is the minor antigenic determinates that generate IgE specific responses that are associated with true penicillin allergy. These minor determinates result in immediate reactions, within minutes to 1 hour, and characterized by signs and symptoms of acute anaphylaxis such as urticaria, flushing, dyspnea, bronchospasm with wheezing, angioedema, hypotension, tachycardia, mental status change or gastrointestinal (GI) upset. The major antigenic determinates more commonly are associated with less severe urticarial reactions.

Delayed reactions are mediated by IgM and IgG which activates the complement system resulting in inflammatory reactions that include Type 2 to 4 hypersensitivity reactions. Serious hypersensitivity reactions include hemolytic anemia, toxic epidermal necrolysis (TEN), Steven's Johnson Syndrome (SJS), vasculitis, interstitial nephritis, serum sickness, thrombocytopenia, and neutropenia.

History and Physical

For patients presenting with an acute allergic reaction after administration of penicillin, it is important to determine when the medication was given, route of administration, as well as onset and type of symptoms including respiratory difficulty, GI symptoms, mental status changes, and cardiovascular collapse such as hypotension or skin findings. For those patients who report a history of penicillin allergy due to previous exposure, onset and timing are again important as is route and ability to tolerate other beta-lactams previously. Other important historical questions include how the penicillin allergy was managed. For example, if the patient was treated with antihistamines or epinephrine and had improvement/resolution of symptoms, this is supportive of an IgE reaction and a true penicillin allergy.

For patients presenting with an acute allergic reaction to penicillin, the initial exam should always focus on airway, breathing, and circulation. The patient should quickly and carefully be examined for edema of the lips, tongue or oropharynx and any difficulty swallowing or handling his/her secretions. Heart and lungs should be carefully auscultated as well for arrhythmia, and adventitious breath sounds such as wheezing or stridor. Confusion and abdominal pain are also findings of severe anaphylaxis. Cutaneous symptoms are often the first and most common finding of an allergic reaction, however, are absent in 10% to 20% of patients experiencing an allergic reaction. Common cutaneous symptoms are generalized urticaria, flushing, pruritis, and angioedema. 

Evaluation

To determine if a patient has an IgE mediated penicillin allergy, the only validated test currently available in the united states is penicillin skin testing. A board-certified allergist should perform the test. It involves a skin-prick with the application of the major and minor determinants as well as a control. The area of skin is examined 15 minutes later. If a wheel of at least 3 mm and concomitant erythema develop, the test is positive. The test should not be performed if the reaction to penicillin was a severe non-IgE mediated reaction.[7][8][9][10]

If skin testing is negative, intra-dermal testing can then also be performed using the same antigenic determinants. Just as with skin testing, a positive intradermal test is characterized by the development of a 3 mm or more wheal and erythema at the site of injection. Readings are taken at 15 min for a history of immediate reaction and at 48 and 72 hours with a history of delayed reaction.  Patients may need to wait up to 6 weeks after initial testing before undergoing intra-dermal testing.

A graded-dose challenge can also be performed when skin testing is negative. Here the patients receive anywhere from 1/100, if initial reaction was anaphylactic, to 1/10 of a dose with progressively increasing doses after that. After each dose administration, the patient has a 30 to 60 minute observation period. If no reaction occurs, the patients then receive a full dose, again followed by a period of observation. Testing must be performed by a board-certified allergist and should be performed at least 4 to 6 weeks after an acute reaction, use of steroids or anti-histamines or any signs of asthma or urticaria. The graded-dose challenge is also contraindicated if the initial reaction was a severe non-IgE mediated reaction such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).

Treatment / Management

Treatment for acute IgE mediated reaction to penicillin depends on severity. Patients presenting in acute anaphylaxis need to have immediate treatment with IM epinephrine (1 mg/ml) 0.3 mg to 0.5 mg every 5 to 15 minutes until resolution of symptoms. Adjunctive therapies include H1 and H2 antihistamines including diphenhydramine 25 mg to 50 mg intravenously (IV) and ranitidine 50 mg IV, respectively. Glucocorticoids should also be administered such as 125 mg methylprednisone. Patients with refractory symptoms should be treated with an infusion of epinephrine at 0.1 mcg/kg/minute. All patients presenting with acute anaphylaxis should be immediately placed on telemetry monitoring with large-bore IV for IVF resuscitation at 1 L to 2 L NS bolus. If patients are experiencing bronchospasm, albuterol 2.5 mg to 5 mg can also be considered. These patients require admission to the hospital. Patients with a resolution of symptoms after a period of observation are safe for discharge. [11][12][13]

For those patients presenting with mild reactions and have cutaneous findings only, treatment with an antihistamine such as diphenhydramine is adequate.

For patients with a true Type 1 IgE mediated penicillin allergy, another antibiotic should be used for treatment. If there is not another equally as efficacious antibiotic, patient's should undergo drug desensitization. The process of desensitization involves subcutaneous, intravenous, or oral administration of incrementally higher doses of the drug every 15 to 30 minutes until the patient tolerates the entire dose. For patients with histories of severe IgE mediated reactions, initial doses should be between 1/1,000,000 and 1/10,000 of the full therapeutic dose. Success rates for desensitization can reach up to 100%. Drug desensitization is again contraindicated in patients with severe non-IgE-mediated reactions such as SJS or TEN.

Differential Diagnosis

• Acute urticaria

• Allergic contact dermatitis

• Chronic urticaria

• Erythema multiforme

• Erythema nodosum

• Erythroderma

• Hypersensitivity vasculitis

• Irritant contact dermatitis

• Lichen planus 

• Sweet syndrome

Pearls and Other Issues

Identification of patients with a true, IgE mediated penicillin allergy is of vital importance to help improve antibiotic utilization with decrease usage of broad-spectrum antibiotics as well as slow the spread of multi-drug resistant bacteria. Other effects include overall decreased health care costs with decreased length of hospitalization as well as decreased readmission rate due to antibiotic failure.

Enhancing Healthcare Team Outcomes

All healthcare workers including the nurse practitioner and pharmacist who prescribe/dispense penicillin must ask the patient if he or she is allergic to the medication, as part of an interprofessional team approach to patient care. Penicillin allergy can be serious and result in a life-threatening anaphylactic reaction. Patients should be asked to wear an ID bracelet about their medical health problems, including allergies. The healthcare workers must ask for allergies at each and every admission because, in the complex world of medicine, some data are omitted or forgotten and lead to serious consequences. Pharmacists should check the patient medication record, checking for agents that may have crossover allergic reaction, and assess the safety of cephalosporins in conjunction with the prescriber. Nursing staff should be vigilant on the intake so that this mistake is never made, but also should have the patient clarify any prior allergic reaction to penicillin drugs. These interprofessional steps can prevent penicillin allergy and prevention is the optimal management strategy. [Level 5][8][14][15]