Cephalosporin Allergy Elizabeth Phillips, MD, FIDSA, FAAAAI - PowerPoint Presentation

Slide1

Cephalosporin Allergy

Elizabeth Phillips, MD, FIDSA, FAAAAIProfessor of Medicine, Pharmacology, Microbiology, Immunology & PathologyJohn A. Oates Chair in Clinical ResearchVanderbilt University Medical Centre

2018 Annual Meeting of the Tennessee Society of AnesthesiologistsFebruary 23, 2018 

Why is this an important topic?

General classification/understanding of drug allergyIgE versus Non-IgE mediated reactions in the peri-operative settingMany patients labeled as penicillin allergic are excluded from cephalosporins peri-operatively however low risk of cross-reactivity with penicillinsCephalosporins (cefazolin) is the most common cause of peri-operative anaphylaxis in many countriesUnderstanding cross-reactivity between cephalosporins and other cephalosporins

What is an Allergy vs. a Side-Effect vs non-Allergic Off-target effect

Peter J, JACI Practice 2017;5(3):547-63

Most Patients Labeled as Penicillin Allergic are Not truly Allergic

Majority not truly allergic to begin with

IgE mediated reactions are not life long10% of patients per year lose reactivity to penicillin80% over five years to amoxicillin and other aminopenicillins

Probably a higher percentage for cephalosporinsMany T-cell mediated HLA restricted reactions appears to be life long

Assume this for DRESS and SJS/TENTesting can help differentiate these reactionsSkin/prick/oral challenge – immediateDelayed intradermal/patch/ex vivo - delayed

Penicillin Skin Testing

Prick & intradermal (0.02 ml)

Penicillin skin testing with validated major and minor determinants has negative predictive value of 97-99%

Additional 1-3% picked up on oral challenge with penicillin VKIn combination with oral challenge takes about 3-4 hoursApproximately 10% per year will lose skin test reactivity (unstable phenotype)Percent skin test positive higher when reaction within last year<5% of more remote reactions skin test positive

JAMA 1993; 270:2456-63

Why Bother?

Individual HealthMost are not allergicSecond and third line drugs are less effective and often have more toxicitiesEasier to appropriately label patients when they are well rather than sick (when they actually need antibiotics)Constricted choices from over-labeling (domino effect)Longer time to appropriate antibioticsMost labeled by age 3 (75%)

Public Health/Stewardship

Facilitate antibiotic appropriateness on a population levelAntibiotic resistanceClostridium difficileCost (both of the drugs and treating the adverse drug reactions)

Very difficult to tell difference between IgE vs. Non-IgE mediated reactions on clinical features alone

Timing is very important:90% reactions within minutes of inductionNMBA, antibiotic, induction agent

Maintenance of anesthesiaLatex, volume expanders, dyes, contrast

IgE vs. Non-IgE

11

Non-IgE mediated reactions to NMBA occur with similar frequency as IgE mediated

We now know how these activate mast cells (through MRGPRX2)Generally less severeNMBAs vary in terms of propensity for histamine release

D-tubocurarine, atracurium, mivacuriumRapacuronium (withdrawn from US)

24

NMBAs are a Cause of Non-IgE Mediated Mast Cell Activation

15 Minutes

45 minutes

Vancomycin Non-IgE mediated histamine release in the skin

Case

57 year old man admitted for knee replacement surgery.20-30 minutes after receiving lidocaine, propofol, rocuronium and fentanyl and 5 minutes after cefazolin developed hypotension, erythema/flushing, hives on chestSerum tryptase 11.2 (<10.9) 2 hours after reactionIntradermal skin testing positive to cefazolin 1 mg/ml

Cef

azolin Most Common Cause of Peri-operative Anaphylaxis in the United States

From 1992 to 2010, identified 38 patients with perioperative anaphylaxis

18 patients had likely IgE-mediated reactionsAntibiotics most common identified agent (50%)7/9 cases due to cefazolinInduction agents (16.7%)Latex (16.7%)NMBA (11%) – now recognized to cause non-IgE mediated mast cell activation

Others

Chlorhexidine, isosulfan blue, protamine, flumazenil

Gurrieri C et al. Anesth Analg 2011;113:1202–12 (Mayo Clinic Experience)

Kuhlen JL J Allergy Clin Immunol Pract. 2016 Jul-Aug;4(4):697-704

Lee YS, Sun WZ. Asian J Anesthesiol. 2017 Mar;55(1):9-12.

Pipet A, Clin Exp Allergy. 2011 Nov;41(11):1602-8.

Cefazolin is Overlooked as a Cause of Peri-operative Anaphylaxis

Penicillin and Cephalosporin Cross-reactivity

Beta-lactam allergies

Imipenem, meropenem, ertapenem

carbapenems

cephalosporins

Penicillins

Monobactams “aztreonam

”

<2%

<5%

0

0

0

Trubiano et al. JACI In Practice 2017 Nov - Dec;5(6):1532-1542

MOST CEPHALOSPORIN CROSS-REACTIVITY AT THE LEVEL OF THE R1 SIDE-CHAIN

Case – Cefazolin Anaphylaxis

Positive skin test to cefazolinNegative skin testing to penicillins (major/minor determinant + ceftriaxone) + rocuronium, propofol + lidocaineNegative challenge to lidocaineNegative challenges to amoxicillin + cephalexinSAFE TO TAKE ALL PENICILINS AND CEPHALOSPORINS EXCEPT CEFAZOLIN

Intradermal skin testing positive to cefazolin 1 mg/ml

Most Common Cross-reactivity Patterns

Aminopenicillins (amoxicillin, ampicillin)Aminocephalosporins (cefalexin, cefadroxil, cefprozil, cefaclor)

Shared R1 Ceftriaxone and Cefepime

Prick test Positive to ceftriaxone

Intradermal test positive to cefepime (share R1 with ceftriaxone) Negative to other cephalosporins

-negative oral challenges to amoxicillin-negative oral challenges to cephalexin and cefuroximeADVICE: selective avoid ceftriaxone, cefotaxime and cefepime (shared R1)Safe to take all other penicillins and cephalosporins

Cephalosporin Allergy – Key Points

Penicillin allergy label is common and a common cause for avoidance of cephalosporins but >95% can be removed by testing and <2% cross-reactivity overallNon-IgE mediated mast cell activation is common in peri-operative setting (NMBA, opioids, vancomycin, contrast, fluoroquinolones)

Cefazolin most common cause of true IgE mediated peri-operative anaphylaxis in USCefazolin anaphylaxis is typically selective for this drug (distinct side chains) – testing should occur but patients typically tolerant other cephalosporins and penicillinsKey cross reactivity patterns exist between cephalosporins typically because of a shared R1 side-chain

QUESTIONS?