Drug Allergy

Penicillin, Aspirin and Sulfa DrugsDiagnosis and Treatment

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 hyperacuity

(2) Idiosyncratic drug reactions (3) Immunologic drug reactions (AKA drug

allergy)

Adverse Drug Reactions

Type ExampleDrug intolerance Tinnitus after a single

ASA tabletIdiosyncrasy Glucose 6-phosphate

deficiency: anemiaafter antioxidant drugs

Immunologic drugreactions

Anaphylaxis frombetalactam 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 dependentcytolysis (IgG/IgM)

Hemolytic anemias,thrombocytopenias,interstitial nephritis

III Immune complex damage Serum sickness, drugfever, some cutaneouseruptions, vasculitis

IV “Delayed” or CellularHypersensitivity

Contact dermatitis,?morbilliform dermatitis

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

Drug Desensitization

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

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

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.

I Kiss you!!

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.

Signs and symptoms

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 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.

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.

Sogn et al

Skin testpositive

Skin testnegative

Allergicreactions

Patients with ahistory ofpenicillin allergy

139 566 7/566 (1.2%)

Patients withouta history ofpenicillin allergy

25 568 0/568 (0.0%)

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

Hennessy et al

A 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)

<80 50 1.00 (ref)

81-160 41 0.74 (0.30-0.77)

161-250 54 0.26 (0.09-0.74)

>250 54 0.76 (0.35-1.64)

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 and TEN with sulfa drugs

Non-urticarial drug eruptions (Stevens-Johnson syndrome, TEN) 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

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 Metabolism

Sulfamethoxazole 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 acetylation

The 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 patients

Lee et al investigated the prevalence of slow acetylation in AIDS patients

Group Prevalence of SlowAcetylation

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 patients

The 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 patients

The accumulated metabolites can then cause cellular injury which may be expressed clinically as an adverse reaction.

Skin Testing

Some 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.

Desensitization

The 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.

Desensitization

Kalanadhabhatta et al39

A prospective study with 13 patients with AIDS (CD4<200) with PCP and allergy to sulfonamides who failed alternative therapy (dapsone, pentamidine). The allergic reactions noted were a generalized, pruritic maculopapular rash, urticaria, angioedema, and pruritis. All patients had tolerated oral desensitization to cotrimazole without any adverse reaction including three patients who were critically ill and on mechanical ventilation. Total follow up ranged from 4 to 84 weeks.

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NSAIDS

In 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%.

Mechanisms

The 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.

Mechanisms

In 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 NSAID’s in vitro inhibition of COX. This has been consistently reaffirmed over the years.

Mechanisms

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

Mechanisms

Three hypothesis have been proposed to explain AIA:– (1) cyclooxygenase inhibition– (2) overproduction of leukotrienes– (3) chronic inflammation of the airways

COX Inhibition

5-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 Inhibition

When 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 airways

Eosinophil 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 NSAIDS

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

Signs and Symptoms

Urticaria, 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.

Testing Numerous 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 Challenge

A standard 3 day protocol is described below.

Time Day 1 Day 2 Day 3 8 AM Placebo ASA, 30 mg ASA, 150 mg11 AM Placebo ASA, 60 mg ASA, 325 mg

2 AM Placebo ASA, 100 mg ASA, 650 mg

Oral ASA Challenge Patients 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 Treatment Patients should avoid ASA and other analgesics that inhibit

COX. NSAIDS that cross react with ASA in respiratory and

cutaneous reactions:– piroxicam mefenamic acid flurbiprofen– ketoprofen meclofenemate diclofenac– ketorolac etodolac nabutemone– indomethacin oxaprozin sulindac– tolmetin zomepirac ibuprofen– naproxen naproxen sodium fenoprofen– diflunisal

Prevention and Treatment

Acetaminophen 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 Treatment

Patients 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 Inhibitors

Selective 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.

Desensitization

NSAID 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.

Desensitization The 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 al Between 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

Conclusion

Patients 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.

Conclusion

Up 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.

Conclusion There 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.

Conclusion NSAID 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.

Thanks

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