Adverse drug reactions are broadly defined by the World Health Organization as “any noxious, unintended, and undesired effect of a drug that occurs at doses used for prevention, diagnosis, or treatment.”¹ These reactions can be classified into types A and B.

Type A reactions, which account for most adverse drug reactions, are predictable, dose dependent, and related to the pharmacologic mechanism of the drug. Examples include respiratory depression with the administration of increasing amounts of opiates or cushingoid features with chronic systemic steroid use. Type B reactions are unpredictable, dose independent, and not related to the drug’s pharmacologic actions. Allergic reactions to a medication are included in this type. Another example of a type B reaction is drug-induced lupus from minocycline.

Allergic reactions require prior sensitization and typically show signs consistent with an underlying allergic mechanism. They eventually resolve after the implicated drug is discontinued.² Nonimmune hypersensitivity reactions, also termed pseudoallergic reactions, are clinically similar to allergic reactions but cannot be proved to be immunologic owing to a lack of detectable drug-specific antibodies or drug-specific T lymphocytes. Many causes for these reactions have been proposed, and they are dependent on the implicated drug. For example, the “allergic reaction” caused by radiocontrast material could be from nonspecific histamine release and complement activation, while the chronic cough seen with angiotensin-converting enzyme inhibitors could be from the accumulation of bradykinin.³ This chapter focuses primarily on immune-mediated type B reactions.

PATHOPHYSIOLOGY

The immune-mediated reactions are organized according to the Gell and Coombs classification¹ as follows:

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  Type I: immediate hypersensitivity reactions (anaphylaxis)

  
  
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  Type II: cytotoxic antibody reactions

  
  
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  Type III: immune complex reactions

  
  
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  Type IV: delayed hypersensitivity reactions

Type I reactions develop when a drug or drug metabolite interacts with preformed specific immunoglobulin E (IgE) antibodies bound to mast cells and basophils. This results in cross-linking of IgE FcεRl receptors on mast cells and basophils, leading to cellular degranulation and the release of histamine and leukotrienes. These released chemicals propagate urticaria, bronchospasm, vasodilation, and other manifestations of anaphylaxis (see Chapter 47). Type II reactions involve binding of IgG or IgM antibodies to recognized cell membrane–bound drug antigen. The cells become coated with antibody and are then injured via the complement system. Drug-induced hemolytic anemia is an example of such a reaction. Type III reactions are due to soluble antigen–antibody complexes deposited in the walls of blood vessels, which then activate the complement cascade. This is seen in serum sickness, which consists of fever, urticaria, lymphadenopathy, arthralgias, and a characteristic serpiginous rash at the interfacing dorsal-ventral regions of the hands and feet. Type IV reactions involve antigen-specific T-lymphocyte–mediated reactions, such as those seen in allergic contact dermatitis. Classifying drug hypersensitivities into one of these four categories may not always be possible.

A hapten is a small antigenic determinant that can cause an immune response only when bound to a carrier molecule. Reactive drug metabolites, acting as haptens, may bind to proteins, resulting in the creation of immunogens that may then elicit an immune response. Penicillin, for example, is reactive because of its unstable β-lactam ring, which can open to bind with other proteins.^1,3,4 Penicillin is metabolized to penicilloyl, and, when combined with a protein, it is known as the major determinant. Penicillin can also be metabolized to penicilloate, penilloate, and benzyl-n-propylamine. When coupled with proteins, these are known as the minor determinants. Major and minor determinant-specific IgE responses detected on skin testing tend to be associated with urticaria and anaphylaxis, respectively.³

EPIDEMIOLOGY

A meta-analysis of 39 prospective studies of hospitalized patients found that serious drug reactions can affect up to 6.7% of hospitalized patients, and the incidence of fatal drug reactions is about 0.3%.⁵ Anesthetics, antibiotics, radiocontrast material, and allergen extracts are the medication categories involved most often in fatal reactions.³ Risk factors for drug allergy include drug type, degree of drug exposure, route of administration, intercurrent viral infection, and allergies to other medications (Table 48-1).³

Antibiotics are frequent causes of medication allergy. Penicillin is one of the most frequent causes of anaphylaxis and is still the only antibiotic with an FDA-approved skin test with useful predictive values on skin testing for IgE-mediated reactions. However it is still recommended that patients undergo a drug challenge if skin testing is not performed with the minor determinant, which is not yet commercially available. Anaphylaxis has never been reported in a patient with a negative penicillin skin test.⁶ Morbilliform rashes to penicillins alone are not considered life threatening, but caution is advised if the rash bears any similarity to urticaria. Different penicillins can be cross-reactive owing to the shared β-lactam ring structure as well as side chains.⁷ Although positive penicillin skin tests are not more frequent among atopic patients, an atopic history may be a risk factor for a more severe allergic reaction to penicillin. A family history of β-lactam allergy may also increase the risk of sensitization.⁸ The risk of an allergic reaction to a cephalosporin in a patient with a history of penicillin allergy may be as high as 2% in those with a positive penicillin skin test.⁸ The greatest degree of cross-reactivity is seen with first-generation cephalosporins. Many experts feel third-generation cephalosporins are very well tolerated in patients with penicillin allergy.⁹ In patients with a negative penicillin skin test with major and minor determinants, the risk of an adverse reaction to a cephalosporin is no greater than among the general population.¹⁰ Therefore in those who are skin-test positive to penicillin, an alternative to a first-generation cephalosporin with a similar side chain should be chosen. Patients allergic to amoxicillin should avoid cephalosporins with identical R-group side chains (cefadroxil, cefprozil, or cefatrizine). Patients allergic to ampicillin should avoid cephalosporins and carbacephems with identical R-group side chains (cephalexin, cefaclor, cephradine, cephaloglycin, loracarbef).⁸ Some practitioners will choose an appropriate third-generation cephalosporin and do an in-office challenge with the first dose with an hour of observation.

Cross-reactivity among cephalosporins, like penicillins, may be due to β-lactam ring structure or side-R1 side-chain similarities.¹ Penicillins, carbapenems, and first-generation cephalosporins also tend to have cross-reactivity owing to side-chain similarities. The monobactams (e.g. aztreonam) are generally well tolerated in most penicillin-allergic patients. Cross-reactivity has not been demonstrated between monobactams and cephalosporins, except between aztreonam and ceftazidime, which have shared side-chain characteristics.¹¹ In addition to anaphylaxis, numerous other adverse drug reactions have been described with β-lactam antibiotics.

Cephalosporin skin testing is less reliable, with many studies suggesting non-irritative concentrations of 2 mg/mL. However, the negative predictive value has not been established. Carbepenems and aztreonam are tolerated in over 95% of patients with cephalosporin allergy. Few studies have evaluated quinolone skin testing. Venturini performed a retrospective study of 71 patients with reactions to quinolones. They found a very high negative predictive value (94%). However, there were many false positive skin tests.

Erythema multiforme is thought to be lymphocyte mediated and is characterized by a rash starting distally and progressing proximally that consists of targetoid lesions with a dusky center and a red circumference. Up to 50% of cases are thought to be medication related, starting 1 to 2 weeks after drug exposure.¹² Common associated medications include sulfonamides, penicillins, nonsteroidal anti-inflammatory drugs (NSAIDs), and barbiturates (see Chapter 64).¹² Stevens-Johnson syndrome and toxic epidermal necrolysis can also be medication-induced phenomena that involve a spectrum of blistering mucocutaneous disorders (see Chapter 65).¹³