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 GI 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.
    • Immune-mediated adverse reactions can be from a variety of mechanisms. They usually occur on re-exposure to the offending drug.
    • Pseudoallergic reactions, formerly called anaphylactoid reactions, 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%–0.32%.2
  • Lifetime prevalence of drug-induced anaphylaxis is 0.05%–2.0%.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 8% of patients in health-care report have a penicillin allergy.3
    • About 90% patients with history of penicillin allergy will be able to tolerate penicillins, as most patients outgrow their allergy overtime.4
    • Rate of penicillin-induced anaphylaxis after parenteral administration is approximately 1–2 per 10,000 treated patients.5
  • 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 Clostridium difficile infections compared to patients without a reported penicillin allergy.6
  • The chemical structure of penicillins results in their high immunogenicity. Being immunologically inert, it spontaneously breaks down to reactive intermediates.
    • The core structure is composed of a reactive β-lactam ring that covalently binds with carrier proteins to form a hapten, which stimulates an immune response. The major determinant of immunogenicity of penicillin is the benzylpenicilloyl form seen in 93% of tissue-bound penicillin.
    • The minor antigenic determinants are all remaining penicillin conjugates. They comprise benzylpenicillin, benzylpenicilloate, and benzylpenilloate.
    • Most immediate reactions to penicillins are related to the major determinant. In other penicillins such as ampicillin, the R side chain is the antigenic determinant.
    • Penicillin can cause any of the four types of Gell–Coombs classification of adverse immune reactions. Most common clinical features being urticaria, pruritus, fever, and bronchospasm.
  • The cross-reactivity between β-lactam antibiotics is variable and largely determined by their side-chain structure attached to the β-lactam ring.
  • Before the 1980s, early first-generation cephalosporins had a higher cross-reactivity to penicillin because they were contaminated with a small amount of penicillin.6 Based on recent studies, the treatment of cephalosporins without preceding penicillin skin testing in patients with a history of penicillin allergy showed a reaction rate of 0.1%.7 Risk of a cross-reaction is 5.0%–16.5% with first-generation cephalosporins, 4% with second-generation, and 1%–3% with third- or fourth-generation.6
    • Although many of the reactions to second- and third-generation cephalosporins are directed at the side chains, skin testing to penicillin in these patients can be helpful because most severe anaphylactic reactions are directed against the reactive bicyclic core.
    • Patients with a history of a severe reaction to penicillin should be considered sensitive to cephalosporin unless they are skin test negative. Although patients with a history of a nonanaphylactic reaction to penicillin can often be given a second- or third-generation cephalosporin safely, it is advisable to precede the dose with an oral provocation challenge.
  • Skin test cross-reactivity has been documented between carbapenems and penicillins. Patients undergoing a graded carbapenem challenge with a positive penicillin skin test and a negative carbapenem skin test did not have any hypersensitivity reactions.4
  • The monobactam aztreonam rarely cross-reacts with penicillins. Ceftazidime does share an identical R-group side chain to aztreonam and is highly cross-reactive.8
  • Sulfonamide allergy
    • There is an increase in allergy to sulfonamides in patients with HIV compared to the general population. Trimethoprim–sulfamethoxazole hypersensitivity occurs in 60% of HIV-positive patients compared to 5% of HIV-negative patients.9
    • Type I IgE-mediated reactions to sulfonamides are not common. The most frequently seen reaction is a maculopapular rash (T cell-mediated) that develops 7–12 days after initiating the drug. Other reactions include urticaria and, less commonly, anaphylaxis, Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Cross-reactivity between antibiotic and nonantibiotic sulfa-containing medications is low. Patients with sulfonamide antibiotic allergy were more likely to react to penicillin than a sulfonamide nonantibiotic.10
  • NSAIDs and aspirin can cause IgE-mediated urticaria, angioedema, and anaphylaxis. It can also exacerbate urticaria in patients who have chronic urticaria. Exacerbation of respiratory symptoms in patients with underlying asthma is referred to as aspirin-exacerbated respiratory disease (AERD). Samter’s triad is the combination of asthma, NSAID sensitivity, and nasal polyposis. COX2 inhibitors are generally safe to administer in these patients. Aspirin desensitization followed by daily aspirin therapy in AERD patients improves asthma exacerbations, oral steroid use, reduced nasal polyps, and sinus infections.

Pathophysiology

The immunologic mechanisms for drug hypersensitivity are demonstrated in the Gell and Coombs classification of hypersensitivity (Table 11-1).

Table 11-1: Immunologically Mediated Drug Reactions
Type of ReactionRepresentative ExamplesMechanism
Anaphylactic (type 1)Anaphylaxis
Urticaria
Angioedema
IgE-mediated degranulation of mast cells with resultant mediator release
Cytotoxic (type 2)Autoimmune hemolytic anemia
Interstitial nephritis
IgG or IgM antibodies against cell antigens and complement activation
Immune complex (type 3)Serum sickness
Vasculitis
Immune complex deposition and subsequent complement activation
Cell mediated (type 4)Contact dermatitis
Photosensitivity dermatitis
Activated T cells against cell surface–bound antigens

Risk Factors

Factors that increase a patient’s risk of an ADR include size and structure of drug, route of exposure (cutaneous most immunogenic), dose, duration, frequency, gender (women > men), genetic factors (HLA type, history of atopy), prior drug reaction, coexisting medical illnesses, and concurrent medical therapy.

Diagnosis

Clinical Presentation

  • A history is essential for making the diagnosis of an allergic drug reaction. Questions should be directed at establishing the following information: sign and symptoms, timing of the reaction, purpose of the drug, other medications the patient is receiving, prior exposure to drug or related drug, and history of other allergic drug reactions.
  • Urticaria, angioedema, wheezing, and anaphylaxis are all characteristics of IgE-mediated (type 1) reactions.
    • Symptoms do not typically occur on the first exposure to the medication unless the patient has been exposed to a structurally related medication. On re-exposure, however, symptoms tend to manifest acutely (often <1 hour).
    • IgE-mediated reactions tend to worsen with repeated exposure to the offending medication.
    • Pseudoallergic reactions (non–IgE-mediated) can be clinically indistinguishable from IgE-mediated reactions because the final common pathway for their reaction is mast cell degranulation.
  • Maculopapular exanthemas are the most common cutaneous manifestation of drug allergy.
    • These reactions are mediated by T cells and typically delayed in onset, first occurring between 2 and 14 days of exposure to culprit medications. It can occur sooner with subsequent exposures. Lesions typically begin on the trunk, especially in dependent areas, and spread to the extremities.
    • Rarely, these rashes can progress to a more serious drug reaction involving blistering of the skin and/or end-organ involvement.
  • DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) are a serious life-threatening ADR, often presenting as rash and fever with systemic involvement, can manifest as hepatitis, eosinophilia, pneumonitis, lymphadenopathy, and nephritis.
    • Symptoms tend to present 2–6 weeks after introduction of medication and resolve few weeks to months after stopping the offending agent. Certain viral infections such as EBV, HHV-6, HHV-7, and CMV are associated with increased risk of complications.
    • First described with antiepileptic (carbamazepine) agents but has also been reported to occur with allopurinol, NSAIDs, some antibiotics, and β-blockers.
  • Erythema multiforme (EM), SJS, and TEN are all serious drug reactions primarily involving the skin.
    • EM is characterized most typically by target lesions. SJS and TEN manifest with varying degrees of sloughing of the skin and mucous membranes (<10% in SJS and >30% in TEN). Risk factors being HIV, hematological malignancy, systemic lupus erythematosus, and bone marrow transplant.
    • Readministration or future skin testing with the offending drug is absolutely contraindicated.

Prevention and Treatment

  • Acute drug reactions such as anaphylaxis should be treated promptly and discontinuation of the suspected drug is the most important initial approach in managing an allergic drug reaction.
  • HLA testing may be indicated in susceptible populations for prevention of a severe ADR for some drugs such as abacavir and carbamazepine.
  • Future use of the drug in question should always be avoided unless there is no therapeutic alternative available.
  • If use of the drug must be considered, 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.
  • If the patient is taking the drug for a life-threatening illness (e.g., meningitis with penicillin allergy) and the reaction is a mild skin reaction, it may be reasonable to continue the medication and treat the reaction symptomatically. If the rash is progressive, however, the drug must be discontinued to avoid a desquamative process such as SJS.

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.
      • Although skin testing may be performed to nearly any medication, sensitivity and specificity of the skin test results have been best established with penicillin.
      • 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 exact mechanism by which desensitization prevents anaphylaxis is unclear.
      • The drug must be taken daily at a specified dose to maintain the “desensitized state.”
      • If a dose of drug is missed for a period >48 hours following a desensitization procedure, the patient will often need to undergo a repeat desensitization.
    • Successful desensitization or graded challenge does not preclude the development of a non–IgE-mediated, delayed reaction (e.g., rash).

References

  1. Thong B, Tan TC. Epidemiology and risk factors for drug allergy. Br J Clin Pharmacol. 2011;71(5):684-700.  [PMID:21480948]
  2. Gomes ER, Demoly P. Epidemiology of hypersensitivity drug reactions. Curr Opin Allergy Clin Immunol. 2005;5(4):309-316.  [PMID:15985812]
  3. Macy E. Penicillin and beta-lactam allergy: epidemiology and diagnosis. Curr Allergy Asthma Rep. 2014;14(11):476.  [PMID:25216741]
  4. Khan DA, Solensky R. Drug allergy. J Allergy Clin Immunol. 2010;125(2 suppl 2):126-138.  [PMID:20176256]
  5. Weiss ME, Bernstein DI, Blessing-Moore J, et al. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259-273.
  6. Greenberger PA. Drug allergy. J Allergy Clin Immunol. 2006;117(2 suppl 2):464-470.  [PMID:16455348]
  7. Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: a cohort study. J Allergy Clin Immunol. 2014;133(3):790-796.  [PMID:24188976]
  8. Frumin J, Gallagher JC. Monobactam antibiotics: what are the chances? Ann Pharmacother. 2009;43:304-315.  [PMID:19193579]
  9. Phillips E, Mallal S. Drug hypersensitivity in HIV. Curr Opin Allergy Clin Immunol. 2007;7(4):324-330.  [PMID:17620824]
  10. Strom BL, Schinnar R, Apter AJ, et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med. 2003;349(17):1628-1635.  [PMID:14573734]

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