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Drug Allergy

Written Prof. P Potter


Page 1   A. Incidence
  B. Type of Drug Reactions
  C. Risk Factors
  D. Important Features of Allergic Drug Reactions
  E. Immunological Basis for Drug Reactions
  F. Drugs associated with Anaphylactic Reactions
  G. Diagnosis of Anaphylactic Drug Allergy
  H. Approach to the Patient with an Anaphylactic Drug Reaction
  I. Allergy to Penicillin
  J. References

A. Incidence


About 15% of all hospitalized patients will experience an adverse reaction to drug therapy, and it is estimated that truly allergic reactions occur in about 5% of all treatments (Ref.1). The prevalence varies from one drug to another (e.g. reactions to radiocontrast agents and penicillin are common, but very uncommon for glucocorticoids).



B. Type of Drug Reactions


These have been classified as follows (Ref.2):


Non-Drug Related

  1. Psychogenic
  2. Coincidental


Drug Related

  1. In susceptible subjects
    1. Intolerance
    2. Idiosyncratic
    3. Allergic or hypersensitive

  2. In non-susceptible subjects
    1. Overdosage
    2. Side effects due to pharmacological actions (e.g. Tachycardia).
    3. Secondary to therapeutic effects (e.g. Herxheimer)
    4. Drug interactions



C. Risk Factors


Anaphylactic reactions to drugs are uncommon in children but increase with age. Atopy is a risk factor for anaphylaxis to drugs such as chymopapain (Ref.2). A familial tendency for anaphylactoid reactions to drugs has been clearly identified in certain families although the mode of inheritance is unclear. Intravenous administration increases the risk of anaphylaxis and a previous history of any reaction to a drug is an important risk factor. Allergy to muscle relaxants, latex and chymopapain is more common in females, and patients with AIDS and cystic fibrosis are at greater risk of anaphylactic reactions to most drugs, but particularly to sulphonamides. There are certain patients who present with multiple drug allergies and these patients are at the greatest risk for further reactions.



D. Important Features of Allergic Drug Reactions


  1. Allergic drug reactions typically occur at low concentrations of the drug.
  2. There is often a history of no previous reaction following exposure to the drug.
  3. The allergic reaction to the drug does not resemble pharmacological actions of the drug.
  4. Symptoms occur rapidly on re-administration of the drug and subside within 3-5 days of discontinuance of the drug. The drugs most commonly associated with allergic reactions are penicillins, sulphonamides, sulphonylurea hypoglycaemics, ACE inhibitors, thiazide diuretics.
  5. The clinical manifestations may be immediate or delayed.



E. Immunological Basis for Drug Reactions


Clinical reactions to drugs are conveniently classified by the underlying Gel and Coombs immune mechanism.


  1. Type I Immediate Reactions
  2. These reactions may result in anaphylaxis, urticaria, bronchospasm and angioedema and occur within 30 minutes of drug administration. Penicillin is the most common cause of a true Type I IgE mediated drug allergy.


    Immediate reactions may also occur via non-IgE mechanisms following exposure to radiocontrast media, aspirin, local anaesthetics and opiates such as morphine and codeine. These agents cause direct histamine release from mast cells. Activated complement components C3a and C5a may also activate mast cells directly.


  3. Type II Reactions
  4. These reactions are due to cytotoxic antibodies binding to drug-hapten-tissue proteins and occur with the drug induced Coombs-positivehaemolytic anaemias and thrombocytopenias. Interstitial nephritis may be induced by methicillin and phenytoin sodium due to the induction of anti-tubular basement membrane antibodies.


  5. Type III Reactions
  6. Penicillin is the most common cause of a serum sickness-like syndrome which results from immune complex deposition particularly after prolonged administration of penicillin and manifests as maculopapular skin reactions, fever, joint pain and lymphadenopathy. Sulphonamides may induce a hypersensitivity angiitis or vasculitis. Fever may be the sole manifestion of Type III drug reaction.


  7. Type IV Reactions

These usually result from delayed hypersensitivity to topical drug applications. The preservatives such as the parabens may also cause sensitivity. Interstitial pneumonitis associated with gold therapy is another example.



F. Drugs associated with Anaphylactic Reactions


Drugs which are most commonly associated with anaphylaxis are the penicillins and sulphonamides. Patients who react to penicillins have a 20% risk of reactions to cephalosporins as well. Although cross reactivity among the penicillins is common, cross reactivity among sulphonamides such as sulphamethoxazole, sulphisoxazole and sulphadiazine is extremely variable and may not occur at all. Recently anaphylactic reactions have been increasingly observed following exposure to ACE inhibitors, muscle relaxants and local anaesthetics.


Anaphylactic reactions may also follow exposure to:

  • fentanyl,
  • Pethidine,
  • dextrans,
  • anti-inflammatory drugs (diclofena, aspirin, pyrazoles),
  • antibiotics (neomycin, streptomycin, bacitracin, clindamycin, dapsone, cephalosporins, vancomycin),
  • chemotherapeutic agents (asparaginase, cyclophosphamide, bleomycin, cytarabine, methotrexate),
  • antiseptics (mercurochrome, chlorhexidine gluconate),
  • solvents (cremophor),
  • dyes (erythrosine and tatrazine),
  • preservatives (parabens and sulphites),
  • diagnostic agents (fluoroscein, iodine contrast reagents),
  • enzymes (aprotinin, chymopapain, streptokinase),
  • hormones (ACTH, calcitonin, glucocorticoids, insulin protamine),
  • antivenoms,
  • human serum albumin,
  • tetanus,
  • toxoid,
  • acetyl cysteine,
  • cimetidine,
  • desferoxamine,
  • latex and allergy immunotherapy vaccines (Ref. 3).



G. Diagnosis of Anaphylactic Drug Allergy


  1. Skin Tests

    Anaphylactic symptoms usually follow rapidly after exposure to the drug. Some reactions are slower in onset and may occur between 30 min � 2 hours. Because of the potential morbidity and mortality, direct challenge testing with the drug is never justified. Rarely, incremental skin testing may be performed by experienced clinicians, under controlled conditions in an I.C.U. setting in hospital when the drug is considered essential and alternatives are not available (Ref. 2). Written informed consent of the patient must always be obtained. This procedure may be considered, for example, in patients with a history of penicillin allergy, after more than two years has lapsed since the previous reaction, provided penicillin is required for a life-threatening disease (such as subacute bacterial endocarditis). Penicillin allergy is a variable state and many patients will lose their anaphylactic sensitivity with time. Skin testing is particularly useful for penicillin sensitivity and is extremely reliable. The negative predictive value for anaphylaxis is good (Ref. 4).


    Skin tests are also useful for identifying the drug responsible for anaphylaxis when the patient has received a combination of drugs. Skin prick testing may usefully be performed for penicillin, toxoids, insulin, chymopapain, streptokinase, ACTH, egg protein vaccines, latex, muscle relaxants, thiopentone. Skin tests are less reliable in the diagnosis of allergy to sulphonamides and other antibiotics, dextrans, furosemide, chlorhexidine, ethylene oxoid, protamine and cimetidine.


    Skin tests may be falsely positive with the quinolones. Skin tests are completely unreliable or hazardous for aspirin, chemotherapeutic agents, prazosin, sulphites, fluorescein, iodinated contrast media, glucocorticoids, gammaglobulins, desferoxamine and most other drugs.


  3. Laboratory Tests

Laboratory tests are safe and are useful for confirming sensitivity to a small range of drugs. They may, however, be falsely negative since the sensitivity of the in vitro tests is lower than skin testing. Specific IgE to the drugs may be measured using the RAST system. RAST's are available for peniclloyl G, penicilloyl V, porcine and human Insulin, Alcuronium, suxamethonium, ampicillin, amoxycillin, theopentone, ACTH, protamine, procaine, pyrazinamide, sulphamethoxazole, cephalosporin and trimethoprim. Interpretation of the results should be made by an allergy specialist with due regard to clinical data. The maculopapular rash following ampicillin administration, following infectious mononucleosis is not IgE-mediated and probably toxic.


Recently, a new test measuring mast cell tryptase in serum has become available. Serum tryptase levels rise rapidly during anaphylaxis. This test has been found to be useful particularly when an anaphylactoid reaction occurs during anaesthesia, as a reliable index of mast cell activation.



H. Approach to the Patient with an Anaphylactic Drug Reaction


  1. Discontinue the drug immediately.
  2. Treat the symptoms and signs of anaphylaxis, urticaria or asthma using adrenaline, antihistamines, bronchodilators, intravenous fluids, steroids or vasopressors where necessary. It is useful to take blood samples for measurement of serum tryptase within 2-3 hours of the event.
  3. Advise the patient to wear a Medic Alert disc and provide him with a list of safe alternative drugs.
  4. Advise the patient to avoid similar or cross-reacting drugs in the future (e.g. cephalosporins in the case of penicillin allergy).
  5. If in doubt about the drug concerned, perform laboratory tests. If these are positive, further skin testing is unnecessary. Regard the patient as sensitive to that drug.
  6. Only embark upon further skin testing for certain drugs (mentioned above) in a controlled environment if the patient requires the drug for a life-threatening condition. Always perform prick testing prior to intraderma testing with high dilutions of drugs (always less than 3 mg/ml).
  7. Rarely patients may be desensitized in I.C.U. using incremental doses of the drugs. This is considered for drugs like penicillin or insulin where use of the drug could be absolutely life-saving.
  8. Remember that drug allergy is a variable state in most patients and that in the case of penicillin, 85% of patients who give a history of a previous reaction to penicillin will tolerate a course of penicillin at a later stage. If more than 2 years have lapsed since a previous reaction, laboratory or skin testing may be performed to confirm ongoing sensitivity.
  9. Pre-treatment with corticosteroids and antihistamines has permitted safe administration of iodinated radiocontrast media and has also protected against latex exposure during surgery.
  10. Where patients appear to react to widely differing drugs the possibility that reactions are occurring to the additives, preservatives and dyes should always be considered.
  11. Remember that avoidance of the drug and the use of a safe substitute is the most appropriate plan of action in patients who have had genuine drug anaphylactic reactions.



New Section


I. Allergy to Penicillin


  1. Incidence:
  2. 2% of all treatments will have systemic reactions. 4% will have urticaria. 0.2% will have anaphylactic shock with a 0.02% mortality. Atopy is not a risk factor and mean age is 20-49 years (Ref.4).


  3. Types of Reactions:
  4. Reactions may be immediate (within 1 hour) and these manifest mainly as anaphylaxis, urticaria, angioedema or bronchospasm.


    Accelerated reactions (1-72 hours) manifest mainly as urticaria, but may manifest as erythema multiforme, a maculopapular rash or serum sickness.


    Late reactions (after 72 hours) usually manifest as morbilliform rashes or fever, but also serum sickness, recurrent urticaria and arthralgia.


  5. Mechanisms:

Penicillin is a low molecular weight substance which needs to combine with protein to become immunogenic. Major degradation products of penicillin are the BPO (Benzyl penicilloyl) haptenic groups (the major antigenic determinant). One can bind benzyl penicillin to polysine synthetically to form penicilloyl polylysine which is non-immunogenic but can be used to identify penicilloyl specific IgE by skin test (marketed as Pre-Pen but not yet freely available in South Africa). The minor determinants are other degradation products of penicillin which are important causes of anaphylaxis, (MDM is available in Europe). Minor determinants (MDM) may be prepared by diluting fresh and 2 week old Penicillin G, 10 000 units/ml for skin testing purposes.


NB: Testing with only major determinants will fail to detect up to 10% of

penicillin sensitive subjects.



(d) Testing:


    1. Skin tests with major and minor determinants are predictive of immediate and accelerated reactions to penicillin.
    2. Skin prick tests are the first line tests and are followed by intradermal tests.
    3. Begin with the polylysine penicilloyl prick tests, followed by an intradermal test.
    4. Follow up if negative with a MDM test at diluted concentrations: 1:1000, 1:100, 1:10.
    5. A wheal of: 0-3mm = negative
    6. 3-5mm = equivocal

      5-10mm = positive

      >10mm = strongly positive

    7. False positives occur in 27% and false negatives less than 1%. Only perform intradermal tests if prick tests are negative.
    8. The risk of anaphylactic reaction to penicillin is extremely low if skin tests to MDM & PPL are negative.
    9. For drugs other than Penicillin G, skin testing can also be performed using diluted drugs (less than 3mg/ml).
    10. RAST testing may be done to confirm suspected sensitivity, but false negatives do occur.


  1. Management:

  1. Avoid b -lactams and cephalosporins in patients with a history of allergic reactions to penicillin.
  2. Choose macrolides or cyclines.
  3. Remember that penicillin allergy is a variable state and 85% of patients will tolerate penicillin at a later state. Specific skin testing should be performed if clinical indications indicate that Penicillin therapy is absolutely essential. RAST testing will confirm sensitivity.
  4. Rarely (e.g. in Subacute Bacterial Endocarditis), it may be necessary to desensitize a patient to penicillin. This can be carefully done within a few hours in ICU according to defined protocols (Ref.2) but should only be performed by a specialist familiar with the technique.



New Section




  1. Sullivan T J. Drug Allergy. In Allergy, Principles and Practice, 3rd Ed, Vol 2. Eds. Middleton E, Reed C, Ellis E, Adkinson N F and Yunginger JW. C Mosby, St Louis, Chapter 65, pp 1523-1533, 1988.
  2. Mellon MH, Schatz M, Paterson. Drug Allergy in Manual of Allergy and Immunology. Ed. Lawlor GJ, Fischer TJ. Little Brown and Company, Boston. Chapter 12, pp 742-271, 1988.
  3. Vervloet D, Pradal M. Drug Allergy. SM Ewert Ab, Sunbyberg, Sweden. Chapter 13, pp 222-224, 1991.
  4. Sullivan TJ. Diagnosis and Management of Drug Allergy. In Current Views in Allergy and Immunology. School of Medicine, Medical College of Georgia, Atlanta, pp 1-15, 1993.
  5. Potter P.C. Anaphylactoid and anaphylactic drug reactions. Mims Prescribing Power, 8-11, August 1994.



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