New approach to Cefazolin Penicillin allergic patients and surgical prophylaxis New approach to Cefazolin

Is changing to “Cefazolin can be safely administered to patients with history of allergy to penicillins including anaphylaxis, EXCEPT in those with severe delayed skin reactions – e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS.” If cefazolin 2g IV is ordered for a patient <80kg, not a big deal! If CeFAZolin allergic:

Objectives Explain differences between beta-lactams Explain cross reactivity For specific types of beta-lactam Explain the new approach to surgical prophylaxis

Beta-lactam Ring

Four different Classes of Beta-lactam Penicillin Cephalosporin Four different Classes of Beta-lactam All Unique Central Structure Carbapenem (e.g. meropenem) Monobactam

Penicillin Cephalosporin Side Chains make the difference within the classes and are responsible for most allergic reactions Carbapenem (e.g. meropenem) Monobactam

So Reactions aren’t about Classes   Similar C-7 Position Side Chain – Cross Reactivity Possible Within Group Similar C-3 Position Side Chain – Cross Reactivity Possible Within Group Penicillins Group 1 Penicillin G Group 2 Amoxicillin Ampicillin Group 3 N/A Group 3 N/A Cephalosporins Cefoxitin Cephalothin Cefaclor Cefadroxil Cefprozil Cephalexin Cefotaxime Ceftizoxime Ceftriaxone Cefepime Cefuroxime Note that Cefazolin is not here: It has unique side chains that are not found in any other beta-lactams

Of 1000 people reporting a penicillin allergy General Population Of 1000 people reporting a penicillin allergy The real occurrence of allergy in children is lower at around 6% (or 60 in 1000 with a reported allergy). Most reactions are minor such as mild delayed rashes Only 100 will have their allergy confirmed Of the 100 people with a true allergy to penicillin there is a low likelihood of reaction to another beta-lactam Infographics taken from INESSS “Outil D’aide à la Décision en cas D’allergy aux pénicillines`, Juin 2017

Similar Cephalosporins 10-15 people might react if given a cephalosporin that shares structural similarity with the involved penicillin Different Cephalosporins 1-2 people might react if given a cephalosporin that does not shares structural similarity with the involved penicillin Carbapenems Less than 1 person is likely to react to a carbapenem Infographics taken from INESSS “Outil D’aide à la Décision en cas D’allergy aux pénicillines`, Juin 2017

What is the math? If my patient is labelled as penicillin allergic: 10% chance patient is actually allergic 1% chance of reaction if given cephalosporin with a similar side chain 0.1% chance (1/1000) of reaction if given cefazolin

Why so many wrong allergies on profile? After 10 years, 80% of people lose allergy Older drugs weren’t pure Many had contaminants Hard to know what is allergy and what isn’t if rash present Many drugs are often given together, unable to tell which drug caused reaction

Beta-Lactams are Better Use of alternatives antibiotics results in: Worse efficacy 2-7x more infections Increased toxicity 2x time the readmission rate 3x times the C. diff and kidney injury rate Slower OR flow-through E.g. Vancomycin takes longer to infuse ? Increased resistance Blumenthal KG. Plos One 2016; DOI:10.1371/journal.pone.0159406 Less likely to receive optimal antibiotic therapy for MSSA bacteremia (47% vs. 80%, p<0.001) MacFadden DR et al. Clin Infect Dis 2016; 63: 904-10 35% inpatients did not received preferred β-lactam therapy ↑ readmission, CDI and AKI (OR 3.53, 95% CI 1.48-7.96) Jeffres MN et al. J Allergy Clin Immunol 2016; 137: 1148-1152 22% inpatients did not receive a β-lactam for G- BSI Resulted in ↑clinical failure (38 vs. 27%, p=0.03), inadequate empiric therapy based on blood culture results (75 vs. 92%, p<0.001) Koliscak LP et al. Antimicrob Agents Chemother 2013; 12: 5918-5923 Use of monotherapy with non-β-lactam results in suboptimal treatment of G- infections >25% of time Combination therapy tends to result in more AE and resistance (e.g. to FQ) Murphy J et al. J Oral Maxillofac Surg 2017; 75: 2223-2229 Use of clindamycin alternative therapy vs. β-lactam therapy (e.g. cefazolin) resulted in ↑SSIs (OR 7.0, p<0.002) SSI clindamycin 50% vs. cefazolin 25% vs. amp-sulbactam 19% Blumenthal KG et al. Clin Infect Dis 2018; 66: 329-36 Prescribed less cefazolin (12 vs. 92%, p<0.001) and more clindamycin (49 vs. 3%, p<0.001), vancomycin (35 vs. 3%, P<0.001), gentamicin (24 vs. 3%, P<0.001) Use of alternative antibiotics resulted in more SSI (OR 1.51, 95% CI 1.02-1.22)- ↑50%

What About Severe Reactions? Anaphylaxis is the most predictable reaction Anaphylaxis to penicillin is NOT a contraindication to cefazolin Delayed mild rashes may occur (not a true allergy) The benefits of beta-lactams outweighs the risk Severe delayed reactions are poorly understood Stevens-Johnson, Toxic Epidermal Necrolysis

How do I know? Signs of severe delayed infection: Reaction was more than 72 hours after drug started There were systemic signs of reaction Fever, hypotension Skin sloughing Organs failed (e.g. kidneys, liver) Patient required hospitalization

How likely are severe reactions? SJS-TENS occurs in 5-10/million population Neutropenia is generally reversible and occurs after several weeks of therapy Serum sickness is very rare and usually occurs after multiple doses of medication

If this is such a great idea . . . Why isn’t everybody doing it?

They are: 6 Provinces have adopted guidelines

Summary CeFAZolin is safe with almost all penicillin allergies Severe delayed reactions excluded (for now) We are starting education in the OR because It’s where we use the most ceFAZolin It supports OR flow-through This reduces adverse events and surgical infections We are making sure this is safe moving forward