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type B drug reaction; drug-induced hypersensitivity syndrome; drug rash with eosinophilia & systemic symptoms (DIHS, DRESS)

Unpredictable from the known pharmacology of the drug with no apparent dose-response relationship Etiology: 1) pharmaceutical agents causing drug reactions a) beta-lactam antibiotics (most common) - penicillins - cephalosporins - cephalosporin allergy uncommon [12] - penicillin allergy not a risk factor for cefazolin hypersensitivity [31] - not mentioned among most common agents as cause of drug hypersensitivity in ref [1] b) sulfonamides allopurinol, anticonvulsants, minocycline most common [1] c) late onset (> 72 hours) - allopurinol, phenytoin, & dapsone most common [7] - carbamazepine [1] d) peri-operative agents - consider latex allergy - paralyzing agents - succinylcholine - tubocurarine e) insulin (human insulin is NOT free from hypersensitivity reactions) f) ACE inhibitors - maculopapular rash - cough - angioedema g) ziprasidone 2) hypersensitivity reactions a) type 1 hypersensitivity - immediate-type, immunologic, IgE-mediated - urticaria (2nd most common) - angioedema - anaphylaxis - mastocytosis [33] - more commonly via IV admnistration b) type 2 hypersensitivity - cytotoxic reactions, > 72 hours after administration - penicillin, cephalosporins, sulfonamides, rifampin, quinidine, quinine, salicylamide, isoniazid, chlorpromazine, sulfonylurea c) type 3 hypersensitivity - serum sickness, drug-induced vasculitis - exanthematous reactions (?) - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis - vasculitis - fixed drug eruption (?) d) type 4 hypersensitivity - morbilliform exanthematous drug eruption (most common) - bullous eruptions (?) - Stevens-Johnson syndrome ? - lichenoid eruptions (?) - photoallergic reactions e) unknown - erythema nodosum - exanthematous pustulosis - red man syndrome Epidemiology: 1) most true drug allergies are type-1 hypersensitivity, IgE-mediated 2) may occur at any age, but most common age 20-49 years 3) 80-90% of patients labeled as penicillin allergic do not have specific IgE to pencillin determinants & if indicated may be safely given - testing fails to confirm penicillin allergy in children with parent-reported penicillin allergy & low-risk symptoms (100% of 100 children) [17] 4) 4% of patients undergoing skin testing for pencillin allergy without prior history of allergy will be skin test (IgE) positive 5) most patients labeled penicillin-allergic are not penicillin intolerant [29] - 70% of patients with penicillin allergy will lose that allergy within 10 years [6] 6) allergy to cephalosporin in patient allergic to penicillin a) 1.1% absolute risk, 10-fold increase in relative risk [4,6] b) lack of cross-reactivity between cefazolin & penicillin [32] - cefazolin has no cross reactivity with any cephalosporin available in the U.S. [32] b) relative risk of allergy to sulfonamide same as cephalosporin [4] 7) more frequent in fall & winter [5] 8) more frequent in patients with dark-skin [5] 9) no sex bias [5] Pathology: 1) cutaneous disease, eosinophilia, fever & lymphadenopathy leading to multi-organ failure occurring within 8 weeks after introduction of a drug [5] 2) beta lactams a) haptenization of protein complexes b) major determinant results from reaction of beta-lactam ring with protein complex resulting in the penicilloyl moiety c) minor determinant result include penicilloate & penilloate moieties d) antibodies to 2nd & 3rd generation cephalosporins are more likely to be directed at side chains History: - hypotension, tachycardia, dyspnea Clinical manifestations: 1) immediate reactions: a) develop within 1st hour of therapy b) signs/symptoms - urticaria (74%) - rhinitis - wheezing - anaphylaxis c) parenteral administration associated with early onset 2) accelerated reactions: a) develop over 1-72 hours after onset of therapy b) may include urticaria 3) late reactions: a) begin > 72 hours after onset of therapy b) average onset 21 days after starting medication [7] - generally 2-8 weeks after starting medication - onset < 2 weeks unlikely [1] c) signs/symptoms - maculopapular eruptions - burning skin pain, morbilliform exanthem - drug fever - hemolytic anemia - serum sickness - nephritis - arthralgia (not a feature) [4] - leukopenias - erythematous exfoliative dermatitis - facial swelling [17] - erythema multiforme, Stevens-Johnson syndrome (SJS) - mucosal involvement can occur in DRESS, but is less severe than with SJS - lymphadenopathy [17] - pulmonary crackles (see chest X-ray) * images [13] Laboratory: 1) complete blood count (CBC) - may show eosinophilia* - may show atypical lymphocytosis* 2) may show elevated liver function tests* 3) specific IgE antibodies 4) serum tryptase (released from mast cells,mastocytosis) a) elevation occurs within 2 hours & is useful for confirming diagnosis of anaphylaxis b) baseline serum tryptase can identify patients at high risk for anaphylaxis 5) pulse oximetry: SaO2 may be low * may also be seen with Stevens-Johnson syndrome (SJS) [17] or morbilliform drug eruption [1] * absence of eosinophilia does not rule out DRESS [1] Special laboratory: - skin testing a) rapid & sensitive testing to evaluate true penicillin allergy b) major determinant - penicilloyl polylysine moiety - type 2 hypersensitivity - cytotoxic reactions > 72 hours after administration c) penicillin G included for minor determinants - reactivity to minor determinants is more predictive of risk of anaphylaxis - responsible for type 1 hypersensitivity - ref [1] suggests skin testing not available d) repeat skin testing may be necessary - RAST & ELISA unable to identify all patients who have a positive skin test to major determinant - skin biopsy if SJS-TEN suspected [17] - point-of-care beta-lactam allergy skin testing (pocBLAST) - oral challenge consisting of 1/10 the standard drug dose followed by full dose 1 hour later with subsequent 2-hour observation safe for low-risk patients [19,24] - direct penicillin challenge is safe for penicillin allergy evaluation [36] Radiology: - chest X-ray - bilateral interstitial infiltrates - lower lobe atelectasis Complications: - labeling a patient with penicillin allergy is associated with - longer hospital stays - increased antibiotic use - use of less safe, less effective, more expensive antibiotics [27] - development of more infections with resistant organisms [11] - delabeling a patient with penicillin allergy associated with cost savings on antibiotics & reduced exposure to broad-spectrum antibiotics [21] - self-reported penicillin allergy associated with increased risk for surgical site infection [20] - less likely to receive cefazolin (12. vs 92%) - more likely to receive clindamycin (49 vs 3%), vancomycin (35 vs 3%), gentamicin (24 vs 3%), or fluoroquinolone (7 vs 1%) - patients whose medical records list a penicillin allergy are at increased risk for MRSA & C difficile colitis [22] - electronic alerts to avoid cephalosporin use in patients with history of penicillin allergy reduces use of cephalosporins [30] Differential diagnosis: - Mycoplasma pneumoniae - not associated with eosinophilia - erythema mutiforme - suddent appearance - sharply demarcated - predilection for dorsum of hands, palms & soles, feet, face, elbows, knees, penis (50%) & vulva Management: 1) drug hypersensitivity is a severe, life-threatening reaction a) stop offending agent b) systemic glucocorticoids [1] c) antihistamines for pruritus [1] 2) avoid offending agent if history suggests true allergy (see history) - < 10% of patients labeled penicillin-allergic are truly allergic to penicillin - cefazolin allergy was rare in those reporting penicillin allergy [28] 3) hemolytic anemia, thrombocytopenia, Stevens-Johnson syndrome & exfoliative dermatitis preclude re-administration of offending agent 4) administration of beta lactam antibiotic to skin-test negative patients will not preclude development of non-IgE reactions such as most non urticarial & maculopapular rashes (not life-threatening) 5) history penicillin allergy characterized by mild non-puritic rash is not a contraindication to use of cephalosporin or 3rd generation penicillin [34] 6) beta-lactam antibiotic may be safely continued with monitoring with most non urticarial & maculopapular rashes 7) history of allergy to 1 beta-lactam antibiotic is not a reason to avoid all beta-lactam antibiotics [15] - in patients with gram-negative sepsis, benefits of appropriate empirical antibacterial therapy outweigh risk for allergic reactions [15] 8) preferred beta-lactam therapy may reduce adverse outcomes in patients with reported beta-lactam allergy 9) inadvertant administration of penicillin to a skin-test positive individual results in allergic reactions in 67% 10) low risk pencillin allergy defined as benign, immediate, or delayed rash (without angioedema, mucosal ulceration, or systemic symptoms) > 1 year prior [26] 11) select alternative pharmaceutical agent a) avoid cephalosporin in patients with penicillin allergy [4] - cephalosporin reaction occurs in 50% of patients who are allergic to penicillin - skin testing for penicillin does not predict cephalosporin allergy b) cefazolin allergy is rare in those reporting penicillin allergy [28] c) avoid carbapenem in patients with penicillin allergy [34] d) caution with sulfonamide in patients with penicillin allergy [4] 12) skin testing if penicillin is necessary for life-threatening infection 13) oral provocation challenge to amoxicillin safe & more accurate than skin testing [14] 14) Pen-Fast tool predicts likelihood of significant allergic response [35] 15) drug desensitization (protocol for penicillin desensitization (ref [25])

Related

anaphylactoid reaction anaphylaxis antigen desensitization; allergen immunotherapy hypersensitivity PEN-FAST Penicillin Allergy decision tool penicilloate moiety (minor determinant) penicilloyl moiety (major determinant)

Specific

drug eruption with eosinophilia & systemic symptoms drug eruption; drug rash sulfa allergy

General

adverse drug reaction (ADR)

References

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