Drug AllergyPenicillin, Aspirin and Sulfa DrugsDiagnosis and Treatment

Adverse Reactions to DrugsCan be categorized as follows:(1) Drug intolerance --- predictable side effect at low to therapeutic doses due to altered drug metabolism or end organ hyperacuity(2) Idiosyncratic drug reactions(3) Immunologic drug reactions (AKA drug allergy)

Adverse Drug Reactions

Type

Example

Drug intolerance

Tinnitus after a single ASA tablet

Idiosyncrasy

Glucose 6-phosphate deficiency: anemia after antioxidant drugs

Immunologic drug reactions

Anaphylaxis from betalactam antibiotics

Types of Allergic Reactions

Type I (immediate)Type II (cytolytic)Type III (immune-complex associated)Type IV (delayed)

Types of Allergic Reactions

Type

Mechanism

Examples

I

Anaphylactic (IgE-mediated)

Acute anaphylaxis, urticaria

II

Complement dependent

cytolysis (IgG/IgM)

Hemolytic anemias, thrombocytopenias, interstitial nephritis

III

Immune complex damage

Serum sickness, drug fever, some cutaneous eruptions, vasculitis

IV

Delayed or Cellular Hypersensitivity

Contact dermatitis, ?morbilliform dermatitis

Symptoms of allergic drug reactionsSkin reactions (80%)Anaphylaxis (9 - 15%)Respiratory symptoms (6 - 9%)Drug fever (2 - 6%)

Anaphylaxis versus Anaphylactoid ReactionsAnaphylaxis 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.

MultivalencyGenerally, 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.

HaptenizationA 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 intermediatesThis 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 ReactionsChronic diseases that require continuous or frequent courses of therapy with the same or cross-reactive drugsSome allergic reactions are more likely to occur with certain infections

e.g. Aminopenicillins with EBV infection, Sulfonamides with AIDS patientsAtopy, a genetically determined state of hypersensitivity, manifested as asthma, hay fever, and atopic dermatitisHistory of other drug allergyFamily history of allergic drug reactions

Evaluation of Drug AllergyFirst, 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 AllergyThird, 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 TestingIn 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 testingSkin testing is preferred since it correlates better with clinical symptoms. A positive RAST test may occur in asymptomatic individuals.ExpensiveLimited range of antigens available

Evaluation of drug allergyFinally, 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 patients prior experiences with itNo rechallenge of drug should be done in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or with any mucous membrane involvement.

Drug DesensitizationEffective in the treatment of type I allergic reactions and may be effective for other reactions that are delayed in onset but are not IgE-mediatedAntigen-specific mast cell desensitization appears to be responsible for the tolerant stateSpecific mast cell desensitization is poorly understood

Drug DesensitizationSuccessful antibiotic desensitizationsPenicillinsSulfonamidesAminoglycosidesClindamycinCephalosporinsVancomycinPentamidineAnti-tubercular agents

Successful desensitizations to other agentsChemotherapeutics AntivenomsHeterologous seraInsulinDeferoxamineLHRHMeasles vaccineHeparinTetanus toxoidD-penicillamineCorticotropinCarbamazepine

DesensitizationThe 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 g).

DesensitizationParenteral 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.

DesensitizationSullivan et al4830 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.

I Kiss you!!

PenicillinsThe 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 determinantsThe 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 DeterminantsBeta 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.

Signs and symptoms Allergic symptoms commonly include:an erythematous, maculopapular and usually pruritic rashurticaria

Less common symptoms include angioedema, serum sickness, arthralgias, bronchospasm, laryngeal edema, and anaphylaxis

Signs and SymptomsAn 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.

Skin testingMore 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 alA 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.

Sogn et al

Skin test positive

Skin test negative

Allergic reactions

Patients with a history of penicillin allergy

139

566

7/566 (1.2%)

Patients without a history of penicillin allergy

25

568

0/568 (0.0%)

Skin testingUp 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 TestingSince recurrent rather than continuous therapy can resensitize patients to penicillin, skin tests should be repeated before subsequent courses of therapy.

CephalosporinsIt 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.

CephalosporinsThe 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 CephalosporinsCurrently 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 DrugsCo-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 DrugsUp 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 HIVA recent retrospective case-control study found an association between the number of opportunistic infections and the occurrence of TMP/SMX hypersensitivity reactionsHennessy et al, however, found no correlation between low CD4 counts and an increased risk of hypersensitivity reactions to sulfa

Hennessy et alA retrospective cohort study involving patients in an outpatient HIV clinic and university-affiliated IM and ID practices receiving cotrimazole for primary PCP 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

CD4 Count

Number of Subjects

Relative Rate (95% Confidence Interval)

250

54

0.76 (0.35-1.64)

Signs and SymptomsThe 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 RechallengeA 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 ReactionMultiorgan, 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 1/1000skin reactions occur in 1.5 - 3% given sulfa drugs

Sulfonamide Hypersensitivity ReactionMaculopapular 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 and TEN with sulfa drugsNon-urticarial drug eruptions (Stevens-Johnson syndrome, TEN) typically occur 7-14 days after initiation of treatmentIncidence is between 1/1000 and 1/3000Any patients with either disease should be removed from the drug and rechallenge avoided

MechanismThe 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

Sulfa Drug Metabolism

Sulfa drugs are metabolized in the liver by two pathways: oxidative metabolism by the cytochrome p450 system and acetylation by N-acetyltransferase.

Sulfa drug MetabolismSulfamethoxazole is predominantly cleared by acetylation and excreted by active tubular excretion. The alternative pathway yields a reactive metabolite, sulfamethoxazole hydroxylamine, which can generate an immune response.

Generally, slow acetylators develop more adverse reactions, whereas rapid acetylators are more prone to show an inadequate response to a standard dose.

Slow acetylationThe ratio of rapid versus slow acetylators varies widely among ethnic groups throughout the world.

For example, approximately 50% of Caucasians and African-Americans are slow acetylators while this is rare among Asians.

Slow Acetylation in AIDS patientsLee et al investigated the prevalence of slow acetylation in AIDS patients

Group

Prevalence of Slow Acetylation

AIDS-ill

27/29 (93%)

AIDS-stable

19/29 (66%)

HIV positive

10/18 (56%)

Control (HIV negative)

18/29 (62%)

Slow acetylation in AIDS patientsThe cause of the increased prevalence of slow acetylation in acutely ill AIDS patients is not known.Due to slow acetylation, more of the drug is shunted to alternative oxidative pathways.

These pathways form toxic metabolites which are normally detoxified by scavengers, such as glutathione. A few studies have reported decreased levels of GSH in HIV patients but this has not been confirmed in other studies.

Slow acetylation in AIDS patientsThe accumulated metabolites can then cause cellular injury which may be expressed clinically as an adverse reaction.

Skin TestingSome investigators have reported positive skin tests in approximately 25% of patients with immediate hypersensitivity reactions to SMX, but others have not found it useful in predicting the recurrence of SMX related adverse events.Currently, skin testing cannot be recommended.

DesensitizationThe earlier reports of desensitization to sulfonamides had limited success rates, ranging from 45 to 82%. The success rates of desensitization have improved significantly over the years.

DesensitizationKalanadhabhatta et al39A prospective study with 13 patients with AIDS (CD4

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NSAIDSIn 1922, the association of ASA sensitivity, asthma, and nasal polyposis was described by Widal et al and was subsequently coined as the aspirin triad.Aspirin-induced asthma (AIA) affects 10% of adults with asthma.

After ingestion of ASA or an NSAID, an acute asthma attack occurs within 3 hrs, usually accompanied by profuse rhinorrhea, conjunctival injection, and periorbital edema.

NSAID Intolerance (NI)NI prevalence in asthma and nasal polyposis or rhinosinusitis is 30-40%.In chronic urticaria, the prevalence of NSAID intolerance is 20-30%.

MechanismsThe search for an underlying antigen - antibody mechanism has not been successful.Skin tests with ASA-lysine have been negative, and numerous attempts to demonstrate specific antibodies against ASA or its derivatives have been unsuccessful.

MechanismsIn patients with AIA, asthmatic attacks can be caused by ASA and other NSAIDS. After desensitization, cross desensitization to other NSAIDS that inhibit cyclooxygenase (COX) also occurs.

Szczeklik et al reported in 1975 that drug cross-reactivity could be predicted on the basis of each NSAIDs in vitro inhibition of COX. This has been consistently reaffirmed over the years.

MechanismsDuring inflammatory respiratory disease, leukotrienes, histamine, and eosinophilic cationic protein are formed and released with subsequent increase in vascular permeability, mucus secretion, and bronchial hyperreactivity.

MechanismsThree hypothesis have been proposed to explain AIA:

(1) cyclooxygenase inhibition(2) overproduction of leukotrienes(3) chronic inflammation of the airways

COX Inhibition5-lipoxygenase and COX catalyze the production of leukotrienes and prostaglandins, respectively.Prostaglandin E2 has several immunoregulatory effects, including inhibition of 5-lipoxygenase and preventing the release of mediators from mast cells.

COX InhibitionWhen ASA is given, COX-1 and COX-2 are disabled, PGE2 synthesis stops and its modulating effects on mast cells and 5-LO are removed, and mediators are released or synthesized.Leukotrienes are continuously and aggressively synthesized in patients with AIA before any exposure to NSAIDS/ASA, and during ASA-induced reactions, marked acceleration of synthesis occurs.It is not known why interruption of PGE2 synthesis does not induce respiratory reactions in all humans.

Chronic inflammation of the airwaysEosinophil infiltration of the airways appears to be a central feature of AIA. The large numbers of eosinophils, loaded with leukotriene enzymes, may be responsible for the overproduction of leukotrienes.

Delayed reactions to NSAIDSAppear to have an immunologic basis since they recur on re-exposure with a shorter latency after re-exposure.

Signs and SymptomsUrticaria, angioedema, rhinoconjunctivitis, bronchial asthma, and occasionally anaphylactoid reactions.Stevens Johnson syndrome and TEN have been associated with NSAIDS in 14% and 19% of cases, respectively.The most frequent delayed cutaneous reaction is a morbilliform exanthem, which usually occurs 1 week after therapy is begun and can last 2 weeks.

TestingNumerous attempts to demonstrate specific antibodies against ASA or its derivatives have been unsuccessful. Skin test responses with ASA-lysine have been negative.Currently, the only way to test for NSAID intolerance is with provocation tests.

There are three types of provocation tests: oral (most common), inhaled, and nasal.Only oral ASA challenges are available in the US.

Oral ASA ChallengeA standard 3 day protocol is described below.

Time

Day 1

Day 2

Day 3

8 AM

Placebo

ASA, 30 mg

ASA, 150 mg

11 AM

Placebo

ASA, 60 mg

ASA, 325 mg

2 AM

Placebo

ASA, 100 mg

ASA, 650 mg

Oral ASA ChallengePatients with a history of severe or very rapid ASA or NSAID-induced reactions may be started with a dose lower than 30 mg.As soon as signs and symptoms of reactions occur (20% decrease in FEV1, rhinorrhea, ocular injection, periorbital edema, stridor, and rarely flushing, urticaria, cramps, or explosive diarrhea), the ASA challenge is stopped.Oral challenges to detect anaphylaxis should not be done; history of anaphylaxis should be relied upon instead.

Prevention and TreatmentPatients should avoid ASA and other analgesics that inhibit COX.NSAIDS that cross react with ASA in respiratory and cutaneous reactions:

piroxicammefenamic acidflurbiprofenketoprofenmeclofenematediclofenacketorolacetodolacnabutemoneindomethacinoxaprozinsulindactolmetinzomepiracibuprofennaproxennaproxen sodiumfenoprofendiflunisal

Prevention and TreatmentAcetaminophen is usually safe for these patients to take. However, high dose acetaminophen (1000 mg followed by 1500 mg) has been shown to have a cross-reaction prevalence of 34%.

Animal models have demonstrated that acetaminophen may have COX inhibitory activity.

Prevention and TreatmentPatients can also take the following drugs, which are all without anti-COX activity or are weak anti-COX 2 inhibitors:

sodium salicylate, salicylamide, choline magnesium trisalicylate, benzydamine, chloroquine, azapropazone, and dextropropoxyphene

COX-2 InhibitorsSelective inhibitors of COX-2, in theory, should be safe in patients with AIA due to continued synthesis of the protective prostanoid, PGE2, by COX-1.However, COX-2 inhibitors have not yet been studied in patients with AIA and are currently contraindicated.

DesensitizationNSAID allergic patients can also be desensitized. Small incremental doses of ASA are taken over 2 to 3 days until 400 to 650 mg of ASA is tolerated. ASA should then be given daily, with doses ranging from 80 to 325 mg to maintain desensitization.After each dose of ASA, there is a refractory period of 2 to 5 days, during which ASA and other COX inhibitors can be given without any risk of an allergic reaction.

DesensitizationThe patient most likely to benefit from desensitization is one with AIA who has just had sinus/polyp surgery.

ASA desensitization has been shown to delay recurrence of nasal polyp formation by an average of 6 years.The mechanism behind desensitization is poorly understood but may be associated with downregulation of leukotriene receptors.

Stevenson et alBetween 1988 and 1994, 78 patients with asthma and documented ASA sensitivity per oral challenge (decrease of 20% or more in FEV1 and/or naso-ocular reactions within 3 hours of incremental oral challenges) were enrolled in a prospective study investigating ASA desensitization. 10 patients discontinued ASA desensitization treatment due to gastritis. 3 patients were lost to follow up. After desensitization, all patients began a treatment program of 650 mg of ASA twice daily, which was continued from 1 to 6 years (mean 3.1 years). Data was compared for 65 patients from the year prior to ASA desensitization and one year before re-evaluation (January to March 1995)

Stevenson et al

Stevenson et al

ConclusionPatients with a history of penicillin allergy should be skin tested. More than 80% of patients with a history of penicillin allergy will have negative skin tests. Allergic reactions observed in the re-treatment of history-positive, skin-test negative patients have virtually all been mild and self-limited; no life threatening false-negative reactions have been reported.

ConclusionUp to 67% of patients with positive skin tests have had allergic reactions when given therapeutic doses of penicillin. There are no skin tests available to evaluate for cephalosporins. Positive penicillin skin tests do not predict allergic reactions to cephalosporins. If no other alternatives are available, cephalosporins can be administered cautiously to patients with a history of penicillin allergy.

ConclusionThere is an increased frequency of adverse reactions to sulfa drugs in HIV patients; the reason for which is not known at this time. A history of rash is not necessarily a contraindication to retreatment since less than 20% may have a recurrence on rechallenge. Skin testing cannot be recommended to evaluate sulfa allergy. Desensitization to sulfa drugs has had variable success.

ConclusionNSAID intolerance prevalence in asthma and nasal polyposis or rhinosinusitis is 30-40%. Aspirin-induced asthma affects 10% of adults with asthma. The only way to test for NSAID intolerance in the US is with an oral provocation test. High dose acetaminophen has been shown to have a cross-reaction prevalence of 34%. After ASA desensitization, cross desensitization to other NSAIDS than inhibit cyclooxygenase also occurs. The patient most likely to benefit from desensitization is one with AIA who has just had sinus/polyp surgery.

ThanksI would like to thank Andrew Namen, Donnie Dunagan, Ryan Secan, Melissa Matulis, and Steve Cochran for their assistance.