Adverse Reactions to Drugs

Drug Metabolism and Adverse Reactions

Most drugs and their metabolites are not immunologically detectable until they have become covalently attached to a macromolecule. This multivalent hapten–protein complex forms a new immunogenic epitope that can elicit T- and B-lymphocyte responses. The penicillins and related β-lactam antibiotics are highly reactive with proteins and can directly haptenate protein carriers, possibly accounting for the frequency of immune-mediated hypersensitivity reactions with this class of antibiotics.

Incomplete or delayed metabolism of some drugs can give rise to toxic metabolites. Hydroxylamine, a reactive metabolite produced by cytochrome P450 oxidative metabolism, may mediate adverse reactions to sulfonamides. Patients who are slow acetylators appear to be at increased risk (see Chapter 59). In addition, cutaneous reactions in patients with AIDS treated with trimethoprim-sulfamethoxazole, rifampin, or other drugs may be a result of glutathione deficiency resulting in toxic metabolites. Serum sickness–like reactions in which immune complexes have not been documented, which occur most commonly with cefaclor, may result from an inherited propensity for hepatic biotransformation of drugs into toxic or immunogenic metabolites.

Risk Factors for Hypersensitivity Reactions

Risk factors for adverse drug reactions include prior exposure, previous reactions, age (20-49 yr), route of administration (parenteral or topical), dose (high), and dosing schedule (intermittent), as well as genetic predisposition (slow acetylators). Atopy does not appear to predispose patients to allergic reactions to low-molecular-weight compounds, but atopic patients in whom an allergic reaction develops have a significantly increased risk of serious reaction. Atopic patients also appear to be at greater risk for pseudoallergic reactions induced by radiocontrast media. Pharmacogenomics has an important role in identifying individuals at risk for certain drug reactions (see Chapter 59).

β-Lactam Hypersensitivity

Penicillin is a frequent cause of anaphylaxis and is responsible for the majority of all drug-mediated anaphylactic deaths in the United States. Although IgE-mediated reactions may occur after administration of penicillin by any route, parenteral administration is more likely to cause anaphylaxis. If a patient requires penicillin and has a previous history suggestive of penicillin allergy, it is necessary to perform skin tests on the patient for the presence of penicillin-specific IgE, ideally with both the major and minor determinants of penicillin. Skin tests for minor determinants of penicillin are important because approximately 20% of patients with documented anaphylaxis do not demonstrate skin reactivity to the major determinant. The major determinant is commercially available (Pre-Pen). The minor determinant mixture is currently not licensed and is synthesized as a nonstandardized testing reagent at select academic centers. Penicillin G is often used as a substitute for the minor determinant mixture, and may have negative predictive value similar to testing with major and minor determinants. Patients should be referred to an allergist capable of performing appropriate testing. If the skin test response is positive to either major or minor determinants of penicillin, the patient should receive an alternative non–cross-reacting antibiotic. If administration of penicillin is deemed necessary, desensitization can be performed by an allergist in an appropriate medical setting. Skin testing for penicillin-specific IgE is not predictive for delayed-onset cutaneous, bullous, or immune complex reactions. In addition, penicillin skin testing does not appear to resensitize the patient.

Other β-lactam antibiotics, including semisynthetic penicillins, cephalosporins, carbacephems, and carbapenems, share the β-lactam ring structure. Patients with late-onset morbilliform rashes with amoxicillin are not considered to be at risk for IgE-mediated reactions to penicillin and do not require skin testing before penicillin administration. Many patients with Epstein-Barr virus infections treated with ampicillin or amoxicillin can experience a nonpruritic rash. Similar reactions occur in patients who receive allopurinol as treatment for elevated uric acid or have chronic lymphocytic leukemia. If the rash to ampicillin or amoxicillin is urticarial or systemic or the history is unclear, the patient should undergo penicillin skin testing if a penicillin is needed. There have been reports of antibodies specific for semisynthetic penicillin side chains in the absence of β-lactam ring–specific antibodies, although the clinical significance of such side chain–specific antibodies is unclear.

Varying degrees of in vitro cross-reactivity have been documented between cephalosporins and penicillins. Although the risk of allergic reactions to cephalosporins in patients with positive skin test responses to penicillin appears to be low (<2%), anaphylactic reactions have occurred after administration of cephalosporins in patients with a history of penicillin anaphylaxis. If a patient has a history of penicillin allergy and requires a cephalosporin, skin testing for major and minor determinants of penicillin should preferably be performed to determine whether the patient has penicillin-specific IgE antibodies. If skin test results are negative, the patient can receive a cephalosporin with no greater risk than found in the general population. If skin test results are positive for penicillin, recommendations may include: administration of an alternative antibiotic; cautious graded challenge with appropriate monitoring, with the recognition that there is a 2% chance of inducing an anaphylactic reaction; and desensitization to the required cephalosporin. Cross-reactivity is most likely when the cephalosporin shares the same side chain as the penicillin (Table 152-3).

Conversely, patients who require penicillin and have a history of an IgE-mediated reaction to a cephalosporin should also undergo penicillin skin testing. Patients with a negative result can receive penicillin. Patients with a positive result should either receive an alternative medication or undergo desensitization to penicillin. In patients with a history of allergic reaction to one cephalosporin who require another cephalosporin, skin testing with the required cephalosporin can be performed, with the recognition that the negative predictive value of such testing is unknown. If the skin test response to the cephalosporin is positive, the significance of the test should be checked further in control subjects to determine whether the positive response is IgE mediated or an irritant response. The drug can then be administered by graded challenge or desensitization.

Carbapenems (imipenem, meropenem) represent another class of β-lactam antibiotics with a bicyclic nucleus that demonstrate a high degree of cross-reactivity with penicillins, although prospective studies suggest incidence of cross-reactivity on skin testing of approximately 1%. In contrast to β-lactam antibiotics, monobactams (aztreonam) have a monocyclic ring structure. Aztreonam-specific antibodies have been shown to be predominantly side chain–specific; data suggest that aztreonam can be safely administered to most penicillin-allergic subjects. On the other hand, administration of aztreonam to a patient with ceftazidime allergy may be associated with increased risk of allergic reaction owing to similarity of side chains.

Sulfonamides

The most common type of reaction to sulfonamides is a maculopapular eruption often associated with fever that occurs after 7-12 days of therapy. Immediate reactions, including anaphylaxis, as well as other immunologic reactions, have also been suggested. Hypersensitivity reactions to sulfonamides occur with much greater frequency in HIV-infected individuals. For patients in whom maculopapular rashes develop after sulfonamide administration, both graded challenge and desensitization protocols have been shown to be effective. These regimens should not be used in individuals with a history of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). Hypersensitivity reactions to sulfasalazine used for treatment of inflammatory bowel disease appear to result from the sulfapyridine moiety. Slow desensitization over ≈1 mo permits tolerance of the drug in many patients. In addition, oral and enema forms of 5-aminosalicylic acid, thought to be the pharmacologically active agent in sulfasalazine, are effective alternative therapies.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Blistering mucocutaneous disorders induced by drugs encompass a spectrum of reactions, including SJS and TEN (see Chapters 654.2 and 654.3). Epidermal detachment of <10% is suggestive of SJS, 30% detachment suggests TEN, and 10-30% detachment suggests overlap of the 2 syndromes. The features of SJS include confluent purpuric macules on face and trunk and severe, explosive mucosal erosions, usually at more than 1 mucosal surface, accompanied by fever and constitutional symptoms. Ocular involvement may be particularly severe, and the liver, kidneys, and lungs may also be involved. TEN, which appears to be related to keratinocyte apoptosis, manifests as widespread areas of confluent erythema followed by epidermal necrosis and detachment with severe mucosal involvement. The risk of infection and mortality are high. Skin biopsy differentiates subepidermal cleavage characteristic of TEN from intraepidermal cleavage characteristic of the scalded-skin syndrome induced by staphylococcal toxins. TEN must be treated in a burn unit. Corticosteroids are contraindicated because they can significantly increase the risk of infection. High intravenous doses of immunoglobulin have been shown to be beneficial in patients with TEN, likely because of inhibition of Fas-mediated keratinocyte cell death by naturally occurring Fas-blocking antibodies in the intravenous immunoglobulin preparation.

Hypersensitivity to Antiretroviral Agents

A growing number of adverse drug reactions have been observed with antiretroviral agents, including reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. Hypersensitivity to abacavir is a well-recognized, multiorgan, potentially life-threatening reaction that occurs in HIV-infected children. The reaction is independent of dose, with onset generally within 9-11 days of initiation of drug therapy. Rechallenge can be accompanied by significant hypotension and potential mortality (rate of 0.03%), and thus hypersensitivity to abacavir is an absolute contraindication for any subsequent use. Prophylaxis with prednisolone does not appear to prevent hypersensitivity reactions to abacavir. Importantly, genetic susceptibility appears to be conferred by the HLA-B*5701 allele, with a positive predictive value of >70% and a negative predictive value of 95-98%. Genetic screening would be cost-effective in white populations but not in populations of African or Asian descent, in which HLA-B*5701 allele frequency is <1%.

Chemotherapeutic Agents

Hypersensitivity reactions to chemotherapeutic drugs have been described, including to monoclonal antibodies. Rapid desensitization to a variety of unrelated agents, including carboplatin, paclitaxel, and rituximab, can be safely achieved in a 12-step protocol. Of note, this approach appears to be successful in both IgE-mediated and non–IgE-mediated reactions.

Biologics

An increasing number of biologic agents have become available for the treatment of autoimmune, allergic, cardiovascular, infectious, and neoplastic diseases. Their use may be associated with a variety of adverse reactions, including hypersensitivity reactions. Given the occurrence of anaphylaxis, including cases with delayed onset and protracted progression in spontaneous postmarketing adverse event reports, the FDA issued a boxed warning regarding risk of anaphylaxis and need for patient monitoring with use of omalizumab (see Chapter 144).

Vaccines

Measles-mumps-rubella vaccine has been shown to be safe in egg-allergic patients (although rare reactions to gelatin or neomycin can occur). The ovalbumin content in influenza vaccine is generally low and the majority of egg-allergic patients tolerate the vaccine. Skin testing with the influenza vaccine is not recommended for egg-allergic patients, but may be helpful if allergy to the vaccine itself is suspected. Egg-allergic patients should be given the injectable, not the live intranasal vaccine and be observed for 30 min after vaccination, in a setting prepared to treat anaphylaxis. For those with egg-allergic reactions resulting in more than urticaria, administration by an allergist is recommended.

Perioperative Agents

Anaphylactoid (non–IgE-mediated anaphylaxis) reactions occurring during general anesthesia may be caused by induction agents (thiopental) or muscle-relaxing agents (succinylcholine, pancuronium). Quaternary ammonium muscle relaxants (succinylcholine) can act as bivalent antigens in IgE-mediated reactions. Negative skin test results do not necessarily predict that a drug will be tolerated. Latex allergy should always be considered in the differential diagnosis of a perioperative reaction.

Local Anesthetics

Adverse drug reactions associated with local anesthetic agents are primarily toxic reactions resulting from rapid drug absorption, inadvertent intravenous injection, or overdose. Local anesthetics are classified as esters of benzoic acid (group I) or amides (group II). Group I includes benzocaine and procaine; group II includes lidocaine, bupivacaine, and mepivacaine. In suspected local anesthetic allergy, skin testing followed by a graded challenge can be performed or an anesthetic agent from a different group can be used.

Insulin

Insulin use has been associated with a spectrum of adverse drug reactions, including local and systemic IgE-mediated reactions, hemolytic anemia, serum sickness reactions, and delayed-type hypersensitivity. In general, human insulin is less allergenic than porcine insulin, which is less allergenic than bovine insulin, but for individual patients, porcine or bovine insulin may be the least allergenic. Patients treated with nonhuman insulin have had systemic reactions to recombinant human insulin even on the first exposure. More than 50% of patients who receive insulin develop antibodies against the insulin preparation, although there may not be any clinical manifestations. Local cutaneous reactions usually do not require treatment and resolve with continued insulin administration, possibly owing to IgG-blocking antibodies. More severe local reactions can be treated with antihistamines or by splitting the insulin dose between separate administration sites. Local reactions to the protamine component of neutral protamine Hagedorn insulin may be avoided by switching to Lente insulin. Immediate-type reactions to insulin, including urticaria and anaphylactic shock, are unusual and almost always occur after reinstitution of insulin therapy in sensitized patients. Insulin therapy should not be interrupted if a systemic reaction to insulin occurs and continued insulin therapy is essential. Skin testing may identify a less-antigenic insulin preparation. The dose following a systemic reaction is usually reduced to one-third, and successive doses are increased in 2-5 unit increments until the dose resulting in glucose control is attained. Insulin skin testing and desensitization are required if insulin treatment is subsequently interrupted for more than 24-48 hr. Immunologic resistance usually occurs when high titers of predominantly IgG antibodies to insulin develop. A rare form of insulin resistance caused by circulating antibodies to tissue insulin receptors is associated with acanthosis nigricans and lipodystrophy. Coexisting insulin allergy may be present in up to a third of patients with insulin resistance. Approximately half of affected patients benefit from substitution with a less-reactive insulin preparation, based on skin testing.

Drug-Induced Hypersensitivity Syndrome

Drug-induced hypersensitivity syndrome, also referred to as DRESS (drug rash with eosinophilia and systemic symptoms) syndrome, is a potentially life-threatening syndrome that has been described primarily with anticonvulsants, although many other medications have been implicated (see Tables 152-1 and 152-2). It is characterized by fever, maculopapular rash, facial edema, eosinophilia, generalized lymphadenopathy, and potentially life-threatening damage of 1 or more organs, usually renal or hepatic. Onset is delayed, usually weeks after initiation of the medication. It has been associated with reactivation of human herpesvirus 6. Treatment is withdrawal of the medication, systemic steroids, and supportive care, but symptoms can worsen or persist for weeks to months after the drug has been discontinued.

Red Man Syndrome

Red man syndrome is caused by nonspecific histamine release and is most commonly described with administration of intravenous vancomycin. It can be prevented by slowing the vancomycin infusion rate or by preadministration of H₁-blockers.

Radiocontrast Media

Anaphylactoid reactions to radiocontrast media or dye can occur after intravascular administration and during myelograms or retrograde pyelograms. No single pathogenic mechanism has been defined, but it is likely that mast cell activation accounts for the majority of these reactions. Complement activation has also been described. There is no evidence that sensitivity to seafood or iodine predisposes to radiocontrast media reactions. Predictive tests are not available. Patients who have atopic profiles, who are using β-blockers, and who have had prior anaphylactoid reactions are at increased risk. Other diagnostic alternatives should be considered, or patients can be given low-osmolality radiocontrast media with a pretreatment regimen including oral prednisone, diphenhydramine, and albuterol, with or without cimetidine or ranitidine.

Narcotic Analgesics

Opiates such as morphine and related narcotics can induce direct mast cell degranulation. Patients may experience generalized pruritus, urticaria, and occasionally, wheezing. If there is a suggestive history and analgesia is required, a nonnarcotic medication should be considered. If this intervention does not control pain, graded challenge with an alternative opiate is an option.

Aspirin and Nonsteroidal Antiinflammatory Drugs

Aspirin and NSAIDs can cause anaphylactoid reactions or urticaria and/or angioedema in children, and, rarely, asthma with or without rhinoconjunctivitis in adolescents. There is no skin or in vitro test to identify patients who may react to aspirin or other NSAIDs. Once aspirin or NSAID intolerance has been established, options include avoidance and pharmacologic desensitization and subsequent continued treatment with aspirin or NSAIDs, if indicated. A number of studies suggest that cyclooxygenase-2 inhibitors are tolerated by the majority of patients with NSAID-induced adverse reactions.