Adverse Drug Reactions

GENERAL PRINCIPLES

Definition

• An adverse drug reaction (ADR) is an undesired pharmacological response that occurs when a drug is given for the appropriate purpose.

• The etiology of a drug reaction can be immunologic, toxic, or idiosyncratic in nature.

• Drug allergy is due to an immune response that is mediated by drug-specific antibody or T cells.

Classification

• Type A reactions are predictable, often dose dependent, and related to the pharmacokinetics of the drug. They comprise up to 80% of all ADRs (e.g., hepatic failure due to overdose of acetaminophen, sedative side effects of antihistamines, drug-drug interactions, and gastrointestinal bacterial alteration after antibiotics).

• Type B reactions are unpredictable and are not related to the dose or the drug's pharmacokinetics. They account for 10%-15% of all ADRs.

î Immune-mediated adverse reactions can be from a variety of mechanisms. They usually occur on reexposure to the offending drug.

î Nonimmunologic reactions (pseudoallergic or anaphylactoid) are caused by IgE-independent degranulation of mast cells.

Epidemiology

• ADRs are reported to account for 10%-15% of hospitalized patients.¹

• Mortality from ADRs is significant and ranges from 0.14% to 0.32%.²

• Lifetime prevalence of drug-induced anaphylaxis is 0.05%-2%.¹ The most common drugs causing IgE- mediated anaphylaxis are penicillins and anesthetic agents given during the perioperative period. Drug- induced anaphylaxis is seen predominantly in older age group.

Etiology

• β-Lactam antibiotics are the most common drug class allergy in United States, which includes penicillins, penicillin derivatives (ampicillin and amoxicillin), cephalosporins, monobactams, and carbapenems. Penicillin allergy is the most prevalent antibiotic allergy of this class.

About 90% patients with history of penicillin allergy will be able to tolerate penicillins, as most patients outgrow their allergy over time.⁴ Given the lower likelihood of having true penicillin allergy, antimicrobial stewardship programs have been developed to decrease use of β-lactam alternatives.

• Hospitalized patients with a history of penicillin allergy have been shown to have a longer hospital stay with increased incidence of vancomycin-resistant Enterococcus, methicillin-resistant Staphylococcus aureus, and Clostridioides difficile infections compared to patients without a reported penicillin allergy.⁵

• The chemical structure of penicillins results in their high immunogenicity with a reactive β-lactam ring that covalently binds with carrier proteins to form a hapten, which stimulates an immune response.

î The major determinant of immunogenicity of penicillin is the benzylpenicilloyl form seen in 93% of tissue-bound penicillin.

î The minor antigenic determinants are all remaining penicillin conjugates. They comprise benzylpenicillin, benzylpenicilloate, and benzylpenilloate.

• The cross-reactivity between β-lactam antibiotics is variable and largely determined by their side­chain structure attached to the β-lactam ring.

î Risk of a cross-reaction between a penicillin and cephalosporin that do not share the same side chain is a careful history of the reaction is helpful in defining the potential risk. Patients may lose their sensitivity to a drug over time, and determining the date of reaction is useful. Symptoms that occur with the start of a drug course are more likely to be IgE-mediated than symptoms that develop several days after the completion of a course.

• The types of symptoms are also important. Toxic reactions (e.g., nausea secondary to macrolide antibiotics or codeine) are not immunologic reactions and do not necessarily predict problems with other members in their respective class.

Referral

• If no alternative drug is available and the patient has a history of an IgE-mediated reaction, the patient should be referred to an allergist for further evaluation.

• The allergist may perform one of several procedures if indicated depending on the medication, type of reaction, and availability of testing reagents.

• Skin testing may be performed to assess for the presence of IgE to the medication.

î Although skin testing may be performed to nearly any medication, sensitivity and specificity of the skin test results have been best established with penicillin.

î Results of testing to drugs other than penicillin must be interpreted within the clinical context of the case.

• Graded dose challenge assesses how the patient tolerates progressively larger doses of medication (e.g., 1/1000, 1/10, and full dose given 20 minutes apart).

• Drug desensitization is defined as induction of temporary state of clinical unresponsiveness or tolerance to a suspected drug. It is performed when the patient has an identified IgE-mediated reaction but still requires the medication.

° The drug must be taken daily at a specified dose to maintain the “desensitized state.”

î If a dose of the drug is missed following a desensitization procedure, then the patient will often need to undergo a repeat desensitization as the desensitization state will wane based on half-life of the drug.

î Successful desensitization or graded challenge does not preclude the development of a non-IgE- mediated or delayed reaction (e.g., rash).