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4/6/2016 1 Drug Allergy: Focus on Antibiotics 4/6/2016 Drug Allergy: Focus on Antibiotics Jonathan Grey, Pharm.D. Clinical Coordinator/Antibiotic Stewardship Specialist Morton Plant Mease Healthcare April 9th, 2016 Disclosure Information I have no actual or potential conflict of interest in relation to this presentation Objectives By the end of this presentation, you should be able to: Classify the different types of drug hypersensitivity and explain the various strategies for drug avoidance based on these classifications Describe the risk of cross sensitivity between the antibiotic classes, including the role of R1 side chains in determining β-lactam cross sensitivity Delineate between the different roles of antibiotic desensitization, direct/graded challenges, and antibiotic skin testing in response to a patient with a reported allergy Discuss the significance of some non- β-lactam drug allergies and their impact on patient care 1 4/6/2016 Predictable Drug Reactions Predictable Dose dependent Related to pharmacologic action Occur in otherwise healthy individuals i.e. Dizziness with BP meds, hypoglycemia with insulin Unpredictable Drug Reactions Drug • Undesirable effect intolerance • Low doses • Normal metabolism, excretion, bioavailability • i.e. ASA tinnitis Drug • Abnormal, unexpected idiosyncrasy • Underlying abnormality of metabolism, excretion bioavailability • i.e. Dapsone hemolytic anemia Drug allergy • Immune mediated • Drug specific antibodies, T cells, or both • i.e. penicillin rash Pseudoallergy • Mimic anaphylaxis • No sensitization period, can occur with first dose • Not immune mediated • Occur due to direct release of mediators • i.e. Redman with vancomycin, Morphine histamine release NEJM 2006;354:601-609 2 4/6/2016 Gell and Combs Classification Type Classification Onset Clinical Features I IgEmediated Immediate: 30-60 min Urticaria (Hives) immediate Angioedema Accelerated: 1-72 hrs Bronchospasm (T-cell mediated) Anaphylaxis II Cytotoxic 5-12h/>72h Hemolytic anemia, Neutropenia, Thrombocytopenia III Immune complex 3-8h/>72h Serum sickness IV T-Cell mediated or 24-48h/>72h Contact dermatitis delayed Maculopapular/ morbilliform rash Interstitial nephritis SJS, TEN Other Unknown Variable DRESS, eosinophilic pneumonia, drug- induced lupusn Treatment Alternatives for Allergies- Type II Avoid the offending agent Cross sensitivity have been noted within the same class for some agents Neutropenia with vancomycin and teicoplanin β-lactams Cephalosporin cross sensitivity- related to R1 and R2 side chain similarity Carbapenems an option in patients with piperacillin/tazobactam induced hemolytic anemia? Single case report of tolerance J Clin Pathol. 1987 Jun;40(6):700-1. J Allergy Clin Immunol Pract. 2015 May-Jun;3(3):452-3. Treatment Alternatives for Allergies- Type III Possibly agent specific (i.e. cefaclor) Alternate metabolism results in reactive intermediate compounds Limited data on cross sensitivity of other beta lactams If β-lactam used, use alternate class with different R1/R2 side chains http://www.aaaai.org/ask-the-expert/reactivity-β-lactams.aspx 3 4/6/2016 Treatment Alternatives for Allergies- Type IV/Delayed Contact dermatitis Avoid same beta lactam/antibiotic class Cephalosporin cross sensitivity with occupational contact dermatitis SJS/TEN Never take any remotely similar antibiotic i.e. lifelong avoidance of all β-lactams Dermatol Online J. 2011 May 15;17(5):13. Treatment Alternatives for Allergies- Type IV/Delayed (continued) Maculopapular rash May tolerate β-lactams with different side chains Aminopenicillins Childhood rash after exposure often linked to viral syndrome True delayed type reactions can still occur Can usually tolerate dissimilar cephalosporins, or even penicillin V Treatment Alternatives for Allergies- Type IV/Delayed (continued) Interstitial nephritis Only one documentd case of possible cross-reactivity Piperacillin/tazobactam and Meropenem Reasonable to try a different Beta-lactam class with different side chains J Antimicrob Chemother. 2007 Jul;60(1):107-11. 4 4/6/2016 Tolerability of Cefazolin after Non-IgE Hypersensitivity Reactions to Nafcillin Blumenthal KG, et al. Antimicrob Agents Chemother. 2014 Jun;58(6):3137-43. Observational study of 17 OPAT patients switched from nafcillin to cefazolin after non-IgE mediated allergies. Maculopapular rash (n=10), immune mediated nephritis (n=3), isolated eosinophilia (n=2), immune mediated hepatitis (n=1) 16/17 completed course without further reaction 3 patients with maculopapular rash were switched to alternate agent first (daptomycin or vancomycin) Observational washout period Authors conclude that cefazolin is well tolerated in patients with non-Ige mediated hypersensitivity to nafcillin. Question 1 Ivy Drugabusa is a 26 yo female admitted to Morton Plant Hospital with persistent fever, cough, and malaise. PMH: hypothyroid SH: IVDA, “None in last year”. Ht: 63” Wt 55.5 kg VS: T 38.5, BP 105/60 HR 91 RR 16 BUN/SCR 14/0.9 WBC 15.9 Blood cultures reveal MSSA in 2/2 sets on admission, and again on repeat TEE: Positive for vegetation in tricuspid valve Patient was started on vancomycin in ER, and received this for two days until culture results returned. At thiat time they were switched to nafcillin and received this for several days. WBC normalized, and blood cultures are now negative. On day 7 of admission, patient’s SCr increases to 2.4. Increased eosinophils in serum and urine She is diagnosed by nephrology as having AIN Question 1 Based on the risk of cross sensitivity of Non-IgE mediated reactions, which of the following is the best therapeutic plan? a) Change therapy to IV vancomycin, to complete a 6 week course. b) Change therapy to IV daptomycin, to complete a 6 week course. c) Continue IV nafcillin as it is the drug of choice. Refer to dialysis. d) Change therapy to IV cefazolin. Monitor carefully for persistent or worsening of renal function. Complete a 6 week course. 5 4/6/2016 IgE Type I Hypersensitivity Reactions Urticaria Anaphylaxis IgE Sensitivity Reaction Cutaneous Reactions Cutaneous drug eruptions of all types occur in 1-5% of population PCN compounds are the most common cause Highest incidence with ampicillin/amoxicillin Only small percentage are IgE mediated. urticaria versus morbilliform rash 6 4/6/2016 Urticaria versus Morbilliform Rash Urticaria Morbilliform eruptions IgE mediated T-cell mediated Immediate Delayed Anaphylaxis Acute systemic allergic reaction 1-4 episodes/10,000 admissions Affects multiple organs Skin, Resp, GI, CV Symptoms Urticaria Swelling Difficulty breathing Abdominal cramps Vomiting Diarrhea Circulatory collapse Coma and Death Penicillin Allergy 7 4/6/2016 PCN Allergy: Statistics 9% of the US population report a history of penicillin “allergy” Penicillins among most commonly reported “allergies” Narcotics 13.9 %, NSAIDS 7.7%, ACEIs 2.9%, radiocontrast 2.3% Most commonly reported antibiotic allergy Sulfas 5.4%, cephalosporins 1.3%, macrolides 1.3%, tetracyclines 0.9% Am J Med. 2009 Aug;122(8):778.e1-7. PCN Allergy: correlation with skin testing results Number of patients with reported penicillin allergy and positive penicillin skin tests Less than 5% Skin test positive patients have been declining steadily over time Previously ≥ 10% Perm J. 2009 Spring;13(2):12-8. Risk Factors for IgE Mediated PCN Allergy Age 20-49 Route: topical > IV > oral Frequency Multiple drug allergy syndrome Hereditary factors Asthma Risk of sensitivity not greater, but reactions more severe Special Cases HIV infection Cystic Fibrosis 8 4/6/2016 What are the Penicillin Allergens? β-lactam ring Antimicrobial metabolite/s Chemical side chain β-lactam Antibiotics Metabolites 75% of PCN allergic patients react to the Major determinant NEJM 2006;354:601-609 9 4/6/2016 Reaction to Side Chain More common in Southern Europe Penicillin Skin Testing Preferred method for the evaluation of possible IgE mediated PCN allergy Performed in setting prepared to treat a possible allergic reaction. Test for PCN major and minor determinants Useful if want to use penicillin drug, but there is a questionable IgE mediated allergy Not useful in ruling out allergies to other β- lactam classes Penicillin Skin Test Reagents Major determinant Penicilloyl-polylysine (Pre-Pen) US: Up to 75% of PCN skin test + patients react Minor determinants Penicillin G- Commercially available Penicilloate Penilloate Ampicillin/amoxicillin Pencilloyl-polylysine/Pen G skin testing Amoxicillin 250 mg oral challenge if negative 0.2% of patients will react, and not to Pencilloyl-polylysine/Pen G Safely identifies patients with penicillin allergies NPV > 95% 10 4/6/2016 Pencillin Skin Test Process at Morton Plant Mease Inclusion Criteria Documented infection where PCN agent is drug of choice Histamine antagonits held for 24 hours Amenable skin surface (usually right and left forearms) Exclusion Non IgE mediated reaction Adverse effect, not allergy Anaphylaxis in last four weeks Hemodynamic instability Age < 18 Current part of protocol, but not a true exclusion for PST Pregnancy Current part of protocol, but PST is option in these patients if risk outweighs benefits Pencillin Skin Test Process at Morton Plant Mease It’s a TEAM effort! Administration of Penicillin Skin Test Step 1: Scratch test Place one drop of solution onto patient arm and use lancet to make shallow puncture Histamine: positive control Saline: negative control Pre-Pen®: major determinant Penicillin G: minor determinant
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