Adverse Reactions to Drugs • Can be categorized as follows: • (1) Drug intolerance --- predictable side effect at low to therapeutic doses due to altered drug metabolism or end organ hyperactivity • (2) Idiosyncratic drug reactions • (3) Immunologic drug reactions (drug allergy)
Types of Allergic Reactions • Type I (immediate) • Type II (cytolytic) • Type III (immune-complex associated) • Type IV (delayed)
Symptoms of allergic drug reactions • Skin reactions (80%) • Anaphylaxis (9 - 15%) • Respiratory symptoms (6 - 9%) • Drug fever (2 - 6%)
Anaphylaxis versus Anaphylactoid Reactions • Anaphylaxis refers to a systemic, immediate hypersensitivity reaction due to the IgE-mediated release of mediators from mast cells and basophils. • Anaphylactoid reactions refer to clinically similar events as anaphylaxis but are not mediated by IgE. They cause, via an unknown mechanism, the degranulation of mast cells and/or basophils.
Multivalency • Generally, an antigen must be presented to the immune system in a multivalent form to elicit a specific immune response. • Valency refers to the number of binding sites available to bind antibody. • Multivalency is necessary to ensure cross-linking of receptors on the surface of cells, which then causes transduction of the signal within the cell and the initiation of an immune response.
Multivalency • Drugs alone are poor stimulators of immune responses due to their simple structure and low molecular weight. • Drugs can fulfill the requirement for multivalency and elicit an immune response in two ways: (1) form hapten-carrier complexes and (2) be converted into reactive intermediates.
Haptenization • A hapten in this case would be a particular drug, which would be immunogenic in protein-conjugated but not free form. • An example would be penicillins and other betalactams that bind covalently to proteins.
Conversion into reactive intermediates • This may occur via drug metabolism in the liver or elsewhere. • This is the case with sulfonamides, which are acetylated and oxidated to yield the predominant N4-sulfonamidoyl hapten.
Factors that Increase the Risk of Allergic Reactions • Chronic diseases that require continuous or frequent courses of therapy with the same or cross-reactive drugs • Some allergic reactions are more likely to occur with certain infections • e.g. Aminopenicillins with EBV infection, • Sulfonamides with AIDS patients • Atopy, a genetically determined state of hypersensitivity, manifested as asthma, hay fever, and atopic dermatitis • History of other drug allergy • Family history of allergic drug reactions
Evaluation of Drug Allergy • First, obtain a complete drug reaction history, atopic history, complete medication list, and chronology of all symptoms and signs. • Second, narrow the list of medications suspected based on the temporal association between starts and stops and changes in dose.
Evaluation of Drug Allergy • Third, stop and/or substitute all drugs with known allergic potential begun on the day of or several days prior to the reaction. If the suspected drug cannot be substituted, skin testing can be used to assess IgE response. Currently skin testing is accepted to test only for penicillin allergy. Radioallergosorbent testing can also be used to evaluate for drug allergy.
RAST Testing • In RAST testing, a given allergen is bound to polydextran bead. Serum is then added and antigen-specific IgE will bind to the immobilized antigen. Radiolabeled anti IgE is then added. The amount of bead-bound radioactivity is proportional to the concentration of antigen-specific IgE in the serum.
Disadvantages of RAST testing • Skin testing is preferred since it correlates better with clinical symptoms. A positive RAST test may occur in asymptomatic individuals. • Expensive • Limited range of antigens available
Evaluation of drug allergy • Finally, in skin test negative patients, readminister the suspected drug if necessary with gradual escalation of the dose or desensitize. Another option, of course, would be choose another drug. • Rechallenge should generally begin at 1% of the desired therapeutic dose and increased incrementally (3-fold) at intervals determined by the half life of the drug and the patient’s prior experiences with it • No rechallenge of drug should be done in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or with any mucous membrane involvement.
Drug Desensitization • Effective in the treatment of type I allergic reactions and may be effective for other reactions that are delayed in onset but are not IgE-mediated • Antigen-specific mast cell desensitization appears to be responsible for the tolerant state • Specific mast cell desensitization is poorly understood
Successful antibiotic desensitizations Penicillins Sulfonamides Aminoglycosides Clindamycin Cephalosporins Vancomycin Pentamidine Anti-tubercular agents Successful desensitizations to other agents Chemotherapeutics Antivenoms Heterologous sera Insulin Deferoxamine LHRH Measles vaccine Heparin Tetanus toxoid D-penicillamine Corticotropin Carbamazepine Drug Desensitization
Desensitization • The starting dose for the drug can be determined by performing intradermal skin tests with the native drug at a dose that does not cause a non-specific irritant reaction. • For example, if a 0.02 ml intradermal injection of a drug at 1 mg/ml concentration does not cause a local or systemic reaction, oral desensitization may be started at the dose injected (i.e. the tolerated dose, 20 µg).
Desensitization • Parenteral desensitization should be using 1/10 or 1/100 of the dose that was administered intradermally. • Desensitization is a REVERSIBLE process that is dependent on the continued presence of the drug. • It is also drug-dose dependent in that a substantial dose increase may result in breakthrough allergic symptoms.
Desensitization-example • Sullivan et al48 • 30 patients with histories of allergic reactions to PCN, positive skin tests, and life threatening infections (bacterial endocarditis, Pseudomonas sepsis or pneumonia) were desensitized. Skin test reactions disappeared or diminished in all 23 subjects who were retested after desensitization. Full courses of antibiotic therapy and cure of the infections were accomplished in 30 of 30 patients.No deaths, anaphylaxis, or severe acute allergic reactions occurred. Pruritic cutaneous eruptions appeared in 9 patients (30%) 6 to 48 hrs after the onset of therapy. One patient developed reversible nephritis 3 weeks into therapy with PCN G.
Penicillins • The reported history of penicillin allergy ranges from 0.7% to 10%. • There are four classes of betalactam antibiotics: penicillins, cephalosporins, carbapenems, and monobactams. • The first three all have bicyclic nuclei in contrast to monobactams (aztreonam), which lacks a second ring adjacent to the betalactam nucleus.
Major and minor determinants • The betalactam ring is unstable and readily acylates lysine residues in proteins. The penicilloyl epitope is produced, which is called the “major determinant” since over 75% of all IgE mediated reactions are directed against this epitope.
Minor Determinants • Beta lactams can also haptenize covalently through carboxyl and thiol groups, which results in a variety of less dominant or “minor” determinants. • Minor determinant IgE responses have been associated with anaphylaxis, while penicilloyl IgE responses are usually associated with urticarial reactions.
Allergic symptoms commonly include: an erythematous, maculopapular and usually pruritic rash urticaria Less common symptoms include angioedema, serum sickness, arthralgias, bronchospasm, laryngeal edema, and anaphylaxis Signs and symptoms
Signs and Symptoms • An example of a delayed reaction would be maculopapular or morbilliform rashes associated with treatment with aminopenicillins, particularly ampicillin. • The incidence of rash associated with ampicillin has been estimated at 9.5%. • Since the rash typically appears 2-3 days or more after drug administration, it is thought to represent type IV (delayed) hypersensitivity.
Allergic Reactions to Penicillins • Allergization often occult (food containing pen. or the pen. mould itself) • Anti-pen abs are detectable in almost everyone • Patients reports of previous ‘allergy’ are frequently inaccurate • A class problem manifesting as - • Rash (MP > urticarial) • Fever • Bronchospasm • Vasculitis • Serum sickness/Stevens-Johnson • Anaphylaxis • Rashes most frequent with ampicillin (10%); essentially 100% in IM infection. • Rashes more likely if allopurinol co-administered • Cross-sensitisation with cephalosporins now thought to be <1% and reactions usually mild • If pen drug-of-choice consider either ‘controlled’ challenge or desensitisation • * VERY uncommon <1/10,000 prescriptions; 2/3 have previously received it and of these only 1/3 report previous reaction. Frequency
Skin testing • More than 80% of history-positive patients will have negative skin tests. • Allergic reactions observed in the retreatment of history-positive, skin test-negative patients have virtually all been mild and self-limited; no life-threatening false-negative reactions have been reported.
Sogn et al • A prospective study using patients with infectious diseases for which penicillin or related compounds was the drug of choice. Patients were skin tested with major and minor determinant antigens. Only if skin tests were negative, patients were given penicillin or a semisynthetic penicillin. 9 skin test positive patients were accidentally given penicillin and 2 had allergic reactions. The allergic reactions noted in the table that follows were urticaria, generalized erythema, and pruritis.
Skin testing • Up to 67% of patients with positive skin tests have experienced clinical allergic reactions when given therapeutic doses of penicillin. • For patients with a history of rash with the aminopenicillins, skin testing with extended observation for late reactions and also patch testing is recommended.
Skin Testing • Since recurrent rather than continuous therapy can resensitize patients to penicillin, skin tests should be repeated before subsequent courses of therapy.
Cephalosporins • It has been reported that there is an 8.1% incidence of allergic reactions to various cephalosporins in patients with histories of penicillin allergy compared to a reaction rate of 1.9% in patients without such histories.
Cephalosporins • The overall incidence of cephalosporin allergy in the general population is about 4%, so the 8% incidence of reactions in the PCN-allergic group is only a 2-fold increase. • When PCN-allergic patients receive ANY drug, the incidence of adverse drug reactions is 3 times higher compared to those with no history of PCN allergy.
Skin testing with Cephalosporins • Currently there are no reliable cephalosporin allergens available for skin testing. • Allergic reactions to cephalosporins do not appear to correlate with positive penicillin test reactions.
Summary of Studies of Cephalosporin to Patients with Histories of Penicillin Allergy and Penicillin Skin Test Evaluations
Sulfa Drugs • Co-trimazole, or sulfamethoxazole-trimethoprim, is used extensively in the HIV population as prophylaxis against Pneumocystis carinii pneumonia. • It is estimated that the overall prevalence of sulfa hypersensitivity in the general population is approximately 3.3%, while in the HIV population it is in the range of 17-20%.
Sulfa Drugs • Up to 80% of these reactions has been reported in HIV-positive patients compared to less than 5% in HIV-negative patients. • The incidence of adverse events to cotrimazole is greater than 50% in patients receiving the medication for treatment for active PCP.
Sulfa Drugs and HIV • A recent retrospective case-control study found an association between the number of opportunistic infections and the occurrence of TMP/SMX hypersensitivity reactions • Hennessy et al, however, found no correlation between low CD4 counts and an increased risk of hypersensitivity reactions to sulfa
A retrospective cohort study involving patients in an outpatient HIV clinic and university-affiliated IM and ID practices receiving cotrimazole for primary prophylaxis. The outcome measured was the occurrence of a cutaneous hypersensitivity reaction (rash, fever, or pruritis) per chart review that resulted in discontinuation of cotrimazole. Hennessy et al
Signs and Symptoms • The most common adverse reactions to sulfa drugs in AIDS patients include rash, nausea and vomiting. • The rash is usually a generalized exanthema, which may or may not be pruritic and often is accompanied by fever. • The majority of patients can be treated with antihistamines and the rash in over 65% of cases will resolve without further sequelae despite continuation of cotrimazole.
History of Rash and Rechallenge • A history of rash is not necessarily a contraindication to retreatment as less than 20% may have a recurrence on rechallenge. • Shafer et al • 34 homosexual men given IV cotrimazole for PCP with development of hypersensitivity reactions in 21 of these patients (erythematous macular or maculopapular rashes, fever). All 31 survivors were started on oral cotrimazole for PCP prophylaxis but only 4 developed reactions which necessitated discontinuation of the drug (desquamative rash, fever, etc..)
Sulfonamide Hypersensitivity Reaction • Multiorgan, systemic disease characterized by fever, skin rash, and toxicity in one or more internal organs starting 7 to 14 days after initiation of therapy. • Incidence of life-threatening reactions is less than 1/1000 • skin reactions occur in 1.5 - 3% given sulfa drugs
Sulfonamide Hypersensitivity Reaction • Maculopapular eruptions and urticarial rash occur most frequently within the first 1-3 days after administration, are usually not accompanied by fever, and resolve spontaneously on withdrawal. • Other disease states associated with the hypersensitivity reaction include: hepatotoxicity, eosinophilic pneumonitis, aseptic meningitis, AIN, serum sickness,polyarthritis, and blood dyscrasias.
Stevens Johnson syndrome with sulfa drugs • Non-urticarial drug eruptions (Stevens-Johnson syndrome) typically occur 7-14 days after initiation of treatment • Incidence is between 1/1000 and 1/3000 • Any patients with either disease should be removed from the drug and rechallenge avoided
Mechanism • The mechanism of hypersensitivity to cotrimazole is poorly understood. Several hypotheses have been put forward to explain the predominance of reactions in HIV patients: • (1) slow acetylation in HIV patients • (2) polypharmacy with drugs such as INH and rifampin that compete for metabolism in the liver • (3) reduced availability of cellular glutathione