Drug allergy. Dean Tey. Monday 17 May Paediatric Allergist & Immunologist

Transcription

1 Drug allergy Dean Tey Paediatric Allergist & Immunologist Monday 17 May 2010

2 Drug challenge Gold standard for determining if a patient is tolerant or allergic to a particular drug Patient is admitted to hospital for 4 hours Graded doses of the index drug is administered, starting typically at 1/100 th of the final treatment dose Patient then completes the medication course at thome Contraindications: SJS, TEN, DRESS Khan DA and Solensky R. Drug allergy. JACI 2010;125:s

3 Drug Allergy: Talk Outline 1. Background: adverse drug reactions 2. Epidemiology 3. Mechanism of action 4. Assessment on history 5. Investigations 6. Drug desensitisation 7. Specific drugs

4 Drug desensitisation New term is drug tolerance induction, as procedure is used for both IgE and non-ige mediated drug allergies Indicated where there is an absolute need for a particular drug and no suitable alternative exists it Aim is to allow the patient to temporarily tolerate the drug in a safe manner (through immunologic or other non-immunologic mechanisms) Khan et al. JACI 2010;125:S

5 Drug desensitisation General principles The amount of drug tolerated by patient during the skin test determines a safe initial dose (usually 1/10,000 th of the final treatment dose) Double dose every 15 minutes until final dose Mild reactions occur in about 1/3 of patients, but no fatal reactions have been reported In order for patient t to remain desensitised, d it is necessary to continually administer medication Solensky R. Drug Hypersensitivity. Med Clin N Am 2006;90:

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7 Drug Allergy: Talk Outline 1. Background: adverse drug reactions 2. Epidemiology 3. Mechanism of action 4. Assessment on history 5. Investigations 6. Drug desensitisation 7. Specific drugs

8 Specific drugs 1. Beta-lactams Penicillins Cephalopsorins 2. Sulfonamides 3. Local anaesthestics 4. Radiocontrast media 5. Aspirin & NSAIDs

9 Specific drugs 1. Beta-lactams Penicillins Cephalopsorins 2. Sulfonamides 3. Local anaesthestics 4. Radiocontrast media 5. Aspirin & NSAIDs

10 How do we approach allergy testing for a child with suspected penicillin allergy?

11 Beta-lactams: Penicillins Beta-lactam ring 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6):

12 Beta-lactams: Penicillins Thiazolidine ring 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6):

13 Beta-lactams: Penicillins R1 side chain 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6):

14 Structural similarities and differences of penicillin side- chains Baldo BA. Penicillins and cephalosporins as allergens structural aspects of recognition and cross-reactions. Clinical and Experimental Allergy 199;29:

15 Beta-lactams: Penicillins ~ 95 % 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6): Khan et al. (2010). Journal of Allergy and Clinical Immunology 125:S

16 Testing for penicillin allergy 1. A panel of reagents are suggested: 1. A panel of reagents are suggested: Classical penicillin reagents: PPL, MDM and benzylpenicillin Semi-synthetic penicillins: Amoxycillin and ampicillin 2. Start with SPT if negative proceed to IDT 3. If IDT negative proceed to drug challenge

17 NPV of penicillin IDTs? Generally considered to be very high Large scale studies show that only 1-3% of skin test-negative patients develop a mild, self-limiting reaction when challenged to the drug Gadde et al. JAMA 1993; 270: (n = 775) Sogn et al. Arch Intern Med 1992; 152: (n = 726) Mendelson et al. JACI 1984; 73: (n = 240) Sullivan et al. JACI 1981; 68: (n = 740) Solensky, R. (2006). Medical Clinics of North America 90(1):

18 NPV of penicillin IDTs? 330 adults (mean age 38 yo) referred with a history of an immediate reaction to penicillin 27% (89/330) CAP-FEIA and skin test negative to BPO, MDM, amoxycillin and ampicillin 73% (241/330) positive to penicillin CAP-FEIA or skin test 45% (40/89) were tolerant to both benzylpenicillin and amoxycillin 55% (49/89) had immediate allergic reactions to penicillin on drug challenge 45% (22/49) reacted to benzylpen 55% (27/49) reacted selectively to amoxycillin Torres et al. Clin Exp All 2002; 32: 270 6

19 New vs old penicillin reagent kit? Previously Pre-Pen (Hollister-Steer and Allergopharma) Available commercially from Recently New kit from Diater Laboratories became available Consists of PPL vial = Benzylpenicilloyl yp y poly-l-lysine y (and mannitol) MDM vial = Sodium benzylpenicillin, benzylpenicilloic acid, sodium benzylpenicilloate (and mannitol) Concordance Recent studies have indicated excellent concordance with the old kit for both benzylpenicilloyl major determinant (97.4%) and the minor determinants (100%) 1. Romano et al. Allergy 2007; 62: 53-58

20 What about cross-reactivity with cephalosporins? Beta-lactam ring 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6):

21 What about cross-reactivity with cephalosporins? Thiazolidine ring Dihydrothiazine ring 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6):

22 What about cross-reactivity with cephalosporins? R1 side chain: implicated in cross-reactivityreactivity 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6):

23 What about cross-reactivity with cephalosporins? R2 side chain: disappears after beta- lactam ring opens 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6):

24 What about cross-reactivity with cephalosporins? Historical 10% cross-reactivity : reactivity a myth? 1 st gen cephalosporins were introduced in 1960 s (cephaloridine, cephalothin) Soon after, several retrospective studies reported increased frequency of cephalosporin-allergy in penicillin-allergic subjects (8%), compared to those without (1-2%). 1,2 1. Dash CH. J Antimicrob Chemother 1975;1(Suppl 3): Petz LD. J Infect Dis 1978;137(Suppl):S74-9.

25 What about cross-reactivity with cephalosporins? These reviews likely overestimated true rate of cross reactivity Until 1982, compounds related to penicillin had been produced by using a cephalosporium mould and the cephalosporins included in the analyses were contaminated with penicillin 1 Patients t were not proven to be penicillin-allergic illi i (either through diagnostic testing or drug challenge) 4 Most 1 st gen cephalosporins p have similar R-group side chains to benzylpenicillin, and this factor (rather than beta-lactam ring) may have led to crossreactivity 2 1. Preger S and Healy B. BMJ 2007;335: Solensky R. Med Clin N Am ;90:

26 What about cross-reactivity with cephalosporins? In a recent meta-analysis 6 studies of 2387 patients with penicillin allergy and 44,897 without Cross-reactivity was found to be related to cephalosporin generation 1 st generation OR 4.79 (95%CI ) 2 nd generation OR 1.13 (95%CI ) 3 rd generation OR045(95%CI ) 13) Implications For life-threatening conditions where it is optimal to use a cephalosporin antibiotic in a penicillin-allergic patient Consider use of a 2 nd or 3 rd generation cephalosporin with a different side chain under suspicion 1. Preger S and Healy B. BMJ 2007;335:991.

27 What about cross-reactivity with cephalosporins? 128 adults with immediate reaction to penicillin and +ve skin test. All skin tested to cephalothin (1st gen), cefamandole (2nd gen), cefuroxime (2nd gen), ceftriaxone (3rd gen), cefotaxime (3rd gen), ceftazidime (3rd gen). 96% (123/128) patients had negative skin tests to cefuroxime (2 nd gen), ceftazidime (3 rd gen), ceftriaxone (3 rd gen) and cefotaxime (3 rd gen) 22 declined challenge 100% (101/101) who accepted challenge tolerated single dose cefuroxime axetil and ceftriaxone (single IM dose) 3.9% had positive skin tests to cefuroxime (2 nd gen), ceftazidime (3 rd gen), ceftriaxone (3 rd gen) or cefotaxime (3 rd gen) NOT ELIGIBLE FOR CHALLENGE Romano et al. Ann Intern Med 2004; 141: 16 22

28 Pichichero ME. Journal of Family Practice 2006; 55 (2):

29 Pichichero ME. Journal of Family Practice 2006; 55 (2):

30 Specific drugs 1. Beta-lactams Penicillins Cephalopsorins 2. Sulfonamides 3. Local anaesthestics 4. Radiocontrast media 5. Aspirin & NSAIDs

31 Sulfonamides Pathogenesis Likely T-cell-mediated mechanism (rather than specific IgE or IgG antibodies) 1 Increased risk in HIV-positive patients, due to: altered drug metabolism (slow acetylation), relative glutathione deficiency and viral stimulation of cytochrome p450 and gammainterferon 2 Clinical 2 Mostly causes delayed generalised maculopapular eruptions, associated with fever and pruritus 1. Choquet-Kastylevsky et al. Curr Alelrgy Asthma Rep 2002;2: Solensky R. Med Clin N Am 2006;90:

32 Solensky R. Med Clin N Am 2006;90: Strom et al. NEJM 2003;349:

33 Specific drugs 1. Beta-lactams Penicillins Cephalopsorins 2. Sulfonamides 3. Local anaesthestics 4. Radiocontrast media 5. Aspirin & NSAIDs

34 Local anaesthetics Benzoate esters Benzocaine Chloroprocaine Cocaine Procaine Proparacaine Tetracaine (amethocaine) Amides Bupivacaine Levobupivacaine Lidocaine (lignocaine) Mepivacaine Ropivacaine Prilocaine Cross-react with other esters Does not cross-react with amides. Does not cross-react with either other amides or esters. Khan DA and Solensky R. Drug allergy. Journal of Allergy and Clinical Immunology 2010;125:S

35 Specific drugs 1. Beta-lactams Penicillins Cephalopsorins 2. Sulfonamides 3. Local anaesthestics 4. Radiocontrast media 5. Aspirin & NSAIDs

36 Radiocontrast media (RCM) Prevalence Anaphylactoid reactions 1 1-3% of patients receiving ionic RCM <0.5% of patients receiving non-ionic RCM Severe life-threatening reactions % of patients receiving ionic RCM 0.04% of patients receiving non-ionic RCM Fatality rate is 1-2 per 100,000 procedures 3 1 Wolf et al Invest Radiol 1991;26: Wolf et al. Invest Radiol 1991;26: Katayama et al. Radiology 1990;175: Caro et al. AJR Am J Roentgenol 1991;156:825-32

37 Radiocontrast media (RCM) Anaphylactoid versus anaphylaxis Reaction not mediated by specific IgE antibodies RCM likely has direct effects on mast cells and basophils leads to direct degranulation and systemic mediator release Complement activation may also account for some reactions Solensky R. Med Clin N Am 2006;90:

38 Radiocontrast media (RCM) Management 1. Determine if the study is essential 2. Explain risks to patient 3. Ensure proper hydration 4. Use a non-ionic, iso-osmolar osmolar RCM 5. Pretreatment with corticosteroid and antihistamine Solensky R. Med Clin N Am 2006;90:

39 Specific drugs 1. Beta-lactams Penicillins Cephalopsorins 2. Sulfonamides 3. Local anaesthestics 4. Radiocontrast media 5. Aspirin & NSAIDs

40 Type of reaction Aspirinexacerbated respiratory Notes Occurs in up to 20% of adult asthmatic patients, more common in women, has an average onset of around 30 yo 1 disease (AERD) Usually starts with rhinitis, progressing to sinusitis and nasal polyposis 1 Pathogenesis: aspirin leads to inhibition of COX-1 decrease PGE2 levels reduced inhibition of 5- lipoxygenase increased cysteinyl leukotrienes 2 Management: avoid both aspirin and NSAIDs; aggressive management of asthma and rhinitis 2 Exacerbation of Ingestion of NSAIDs that inhibit COX-1 can chronic urticaria & exacerbate chronic urticaria & angioedema 2 angiodema Most patients tolerate COX-2 inhibitors 2 Anaphylaxis Typically drug-specific and able to tolerate other NSAIDs 3 1. Stevenson DD. JACI 2006;118: Khan et al. JACI 2010;125:S Quiralte et al. J Investig Allergol Clin Immunol 2007;17:182-8.

41 Summary points 1. Severe cutaneous drug reactions SJS, TEN, AGEP, HSS (DRESS) Can cause significant morbidity and mortality Important to exclude these conditions as they present as contraindications for IDT and drug challenge

42 Summary points 2. Penicillin allergy Majority (90%) of self-reported penicillin allergic patients are actually tolerant following evaluation and drug challenge IDT should be performed to Major determinant: t benzylpenicilloyl ill l Minor determinant Side chains: amoxycillin and ampicillin Side chains: amoxycillin and ampicillin NPV for intradermal skin testing is good (1-3%)

43 Summary points 3. Penicillin and cross-reactivity reactivity with cephalosporins Previous reports of 10% cross-reactivity reactivity are a likely overestimated Cross-reactivity with cephalosporins are most likely due to similarities of R1-side chains (rather than sensitisation to beta-lactam ring) If skin testing ti is negative, patients t have a high h likelihood of tolerating a 3 rd generation cephalosporin

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