GENERAL INFORMATION
• Adverse drug reactions can be divided into predictable and unpredictable reactions.
• Unpredictable reactions are dose independent. It is not usually associated with the pharmacological effects of the drug and occurs in predisposed patients.
Classification of adverse drug reactions
Type A Predictable
• Overdose
• Side effect
• Drug interactions
Type B Unpredictable
• Drug intolerance
• Idiosyncratic reactions
• Pseudoallergic
• allergic
epidemiology
• The frequency of adverse drug reactions in the general or pediatric populations is unknown.
• Cutaneous drug reactions are the most common forms of adverse drug reactions and ampicillin, amoxicillin, penicillin and trimethoprim sulfamethoxazole make up the majority of the drugs accused.
Pathogenesis and Clinical Findings
• Immunologically mediated drug reactions are classified according to the Gell and Coomb classification;
1. Type-I. Early type hypersensitivity (IgE-mediated):
a. anaphylaxis
b. Urticaria
c. angioedema
d. Morbiliform rash (early onset)
2. Type-il. Cytotoxic reactions (IgG and IgM mediated):
a. Cytopenias (hemolytic anemias, thrombocytopenias)
b. interstitial nephritis
3. Type-III. Immune complex reactions (IgG and IgM mediated):
a. Serum sickness (Cefaclor)
b. vasculitides
c. SLE induced by medication,
d. drug fever
4. Type-IV. Late type (T lymphocyte mediated):
a. contact dermatitis
b. Morbilliform eruptions (late onset)
c. AGEP (Acute Generalized Eczematous Pustulosis)
d. SJS/TEN (sulfonamides, Phenytoin, Lamotrigine)
e. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms): It may be associated with HHV type 6 reactivation.
• Findings in Type-I reactions occur within hours (early reaction)
• In Type-II-II-IV reactions, it takes an average of 7-10 days for the symptoms to appear (late reactions).
• In rapid hypersensitivity reactions, a drug or drug metabolite interacts with a preformed drug-specific IgE antibody bound to tissue mast cells and/or circulating basophils. Cross-linking of adjacent receptor-bound IgEs by antigen causes the release of previously formed and newly synthesized antibodies such as histamine and leukotrienes, which clinically contributes to the development of urticaria, bronchospasm, or anaphylaxis.
Risk factors for adverse drug reactions:
1. The drug has a large molecule size
2. Frequent, high-dose or long-term use of drugs
3. The risk in women is 2 times higher than in men
4. If there is a family history of drug allergy, the risk increases 15 times.
5. Presence of EBV or HIV infection during drug use increases the risk
6. Having a severe reaction to drugs before
7. Genetic predisposition; Drug allergies are more common in some HLA tissue groups
8. Age (higher risk in adults)
9. Route of administration (local administration>parenteral>oral administration)
ATOPI IS NOT A RISK FACTOR.
THE REACTION IS MORE STRONG IN ATOPIC PATIENTS.
Diagnosis
• A correct anamnesis is the first step. However, it is important to remember that the history may be unreliable and many patients are inappropriately labeled as being allergic to drugs. In addition, relying solely on history may lead to overuse of drugs reserved for specific indications, such as the use of vancomycin in patients with suspected penicillin allergy.
• In fact, about 80% of penicillin-allergic patients have no evidence of penicillin-specific IgE antibodies when tested.
Diagnosis of early-onset reactions
1. Skin prick test or intradermal test
2. Measurement of specific IgE in serum
3. Demonstration of basophil activation
a) FAST (Flowcytometric basophil stimulation test)
b) CAST (Cellular antigen stimulation test)
c) Measurement of Beta Tryptase levels
d) Histamine measurement
Diagnosis of late-onset reactions
1. Drug-specific IgG and IgM measurement
2. Measurement of complement activation
3. Demonstration of basophil activation
a) FAST (flowcytometric basophil stimulation test)
b) CAST (cellular antigen stimulation test)
c) Beta. Measurement of tryptase levels d) Measurement of histamine
4. Lymphocyte transformation test (L TT)
5. Measurement of leukotrienes in urine
6. Late reading of intradermal tests
7. Patch test
• In drug-induced hemolytic anemia, direct and indirect Coombs tests are usually positive.
Graded Chalange and Drug Tolerance Induction
• When there is a definite medical need for a particular drug,
• When there is no suitable alternative medicine,
• It is the best test for diagnosis when there is no test with a high negative predictive value.
Treatment
• Specific desensitization, which includes progressive administration of an allergen to render effector cells less reactive, is reserved for patients who have IgE antibodies to a particular drug and for whom an alternative drug is not available or suitable.
• Oral desensitization is less likely to induce anaphylaxis than parenteral administration.
• Pretreatment with antihistamines and/or corticosteroids is generally not recommended.
β-Lactam Hypersensitivity
• Penicillin is a common cause of anaphylaxis. While IgE-mediated reactions occur by all routes of administration of penicillin, parenteral administration is more likely to cause anaphylaxis.
• If a patient needs penicillin and there is a history suggestive of penicillin allergy, alternative medicine should be used first.
• If penicillin group drugs must be used in cases where no alternative drug is available, skin testing should be performed to determine the presence of penicillin-specific IgE using both major and minor penicillin markers to confirm the diagnosis of allergy. Because approximately 20% of patients with documented anaphylaxis do not show skin reactivity to the major determinant.
• If the skin test is positive for major or minor markers of penicillin, the patient should be given an alternative antibiotic that does not cross-react. If administration of penicillin appears necessary, desensitization may be undertaken in an appropriate medical setting.
• Patients with late-onset morbiliform eruptions with amoxicillin are not considered at risk for IgE-mediated reactions to penicillin, and skin testing is not required before penicillin is administered.
• Almost all patients with Epstein-Barr virus infections treated with ampicillin or amoxicillin develop a nonpruritic rash. Similar reactions occur in patients with elevated uric acid treated with allopurinol or in chronic lymphocytic leukemia.
Cephalosporin allergy
• Allergic reactions to cephalosporins usually develop against side chains.
• Varying degrees of in vitro cross-reactivity have been noted between cephalosporins and penicillins. Although the risk of allergic reactions to cephalosporins appears to be low in patients with positive penicillin skin tests (<10%), anaphylactic reactions have occurred with the administration of cephalosporins in patients with a positive history of penicillin anaphylaxis.
• If a patient has a history of penicillin allergy and requires a cephalosporin, skin testing against the major and minor markers of penicillin should be preferred to detect the patient's penicillin-specific IgE antibodies. If skin tests are negative, the patient can take cephalosporins without any greater risk than in the general population.
• If skin tests are positive for penicillin, recommendations should include; consideration of the use of an alternative antibiotic, gradual provocation with appropriate follow-up, recognizing the 2% chance of inducing an anaphylactic reaction, or desensitization with a cephalosporin as necessary.
• Conversely, patients who require penicillin and have a history of an IgE-mediated reaction to a cephalosporin should undergo penicillin skin testing. If the tests are negative, patients can be given penicillin. If positive, either an alternative drug should be given or desensitization with penicillin should be performed.
• In patients who have a history of allergic reaction to a cephalosporin and need another cephalosporin, a skin test with a cephalosporin with a different side chain should be performed first. If the skin test is positive for the cephalosporin, another cephalosporin should be chosen. If the skin test is negative, cephalosporins can be given with gradual dose escalation.
• The carbopenems (imipenem and meropenem) form another class of 13-lactam antibiotics with bicyclic nuclei that show high cross-reactivity with penicillins.
• Unlike other 13-lactam antibiotics, monobactams (aztreonam) have a monocyclic ring structure. Aztreonama-specific antibodies have been shown to be predominantly side-chain specific. The data suggest that aztreonam can be administered to most patients allergic to penicillin.
Aztreonam cannot be used in ceftazidime allergy.
Antibiotics for those with penicillin allergy
• Macrolides
• Monobactams
• Lycomycin-clindamycin
• Aminoglycosides
• Vancomycin
• Ciprofloxacin