Guideline/Protocol Title:

Inpatient Beta-lactam Allergy Guideline

Original Author(s):

Iris M. Otani MD

Collaborator(s):

Antimicrobial Stewardship Programs

Approving committee(s):

P&T

P&T Approval Date:

Feb 14 2018

Last revision Date:

12/09/2018, 01/10/2020, 03/15/2024

PURPOSE/SCOPE:

To guide clinicians in prescribing antibiotics for pediatric and adult inpatients with known or suspected history of allergic reactions to penicillin or cephalosporin antibiotics.

EXECUTIVE SUMMARY

Patient Population: The information in this document provides recommendations for testing and safe antibiotic administration practices in patients with documented penicillin OR cephalosporin allergy. For patients with documented allergies to penicillin AND cephalosporin antibiotics, please Voalte on-call Allergy for assistance with beta-lactam antibiotic administration.

Location: This guideline is for use on inpatient units. It is not for routine use in emergency departments, perioperative units (pre-operative holding areas, operating rooms, post-anesthesia care units), neonatal units, or obstetrics units. Please Voalte on-call Allergy if assistance is needed with beta-lactam antibiotic allergy evaluation in these settings.

Test Dose: The test dose procedure that is described in this guideline is a safe procedure that can be performed by primary teams on inpatient units. Allergy consultation is not needed when the Test Dose is used as part of the Inpatient Beta-Lactam Allergy Guideline. Allergy approval is needed for the Test Dose to be performed for medications other than beta-lactam antibiotics. With Allergy approval, the Test Dose can be performed by primary teams on acute and transitional care units for medications other than beta-lactam antibiotics outside of the Inpatient Beta-Lactam Allergy Guideline.

1. Step 1. Review medication administration history in APeX to see if patient tolerated beta-lactam antibiotic(s) in the past.
2. Step 2. Review the history of the adverse reaction for ALL agents in the pharmaceutical class of beta-lactam antibiotics listed in APeX with the patient to determine the type of reaction and recommended management (Appendix 1). Updated the documented adverse reaction in APeX with the patient-reported history.
3. Step 3. If appropriate, follow the Penicillin Allergy Pathway (Appendix 2A or 2B) or Cephalosporin Allergy Pathway (Appendix 3A or 3B). If a test dose procedure is recommended, follow directions for the Test Dose Procedure (Appendix 4). Please Voalte on-call Allergy if you have questions.

On-Call Allergy Voalte: Consult Adult Allergy 1^st Call and Consult Peds Allergy 1^st Call

BACKGROUND / INTRODUCTION

Most patients with documented penicillin allergy do not have an active allergy [1]. Additionally, cross-reactivity rates between different beta-lactam antibiotics are low, and patients with testing-verified penicillin allergy can still safely receive many cephalosporins and all carbapenems [1].

Over-cautious avoidance of first-line beta-lactam antibiotics in patients with a documented penicillin has significant negative clinical impact. Inpatients with reported penicillin allergy have longer hospital stays, receive more alternative antibiotics, and have more drug-resistant infections [2].

A beta-lactam allergy guideline with recommendations for which antibiotics are safe to prescribe in patients with beta-lactam allergy can improve patient care by allowing these patients to receive more effective, less toxic, and/or less costly antibiotics [3]. The UCSF guideline has been approved since Feb 2018, and has had a significant positive impact on antibiotic prescribing practices [4].

Note: Although beta-lactam antibiotic allergy evaluations are recommended, use of this guideline should not delay care of an active infection. An alternative antibiotic per the primary team or Infectious Disease should be administered to treat active infection even if beta-lactam allergies have not been addressed.

SUPPORTING EVIDENCE

Penicillin Allergy (PA) Pathway – Appendix 2. Please see 2A for adult patients and 2B for pediatric patients.

1. Penicillin skin testing is a validated tool for evaluating PA, with a high negative predictive value [1]. Currently, it is recommended that a negative penicillin skin test is followed by a test dose procedure, because minor determinants (breakdown products of penicillin) are not available for skin testing [5].
2. Patients with PA can still safely receive many cephalosporins and all carbapenems as cross-reactivity between beta-lactam antibiotics are mediated by structural similarities between side chains [1].
3. Patients confirmed to be selectively allergic to aminopenicillins (amoxicillin or ampicillin) but who tolerate Penicillin G should avoid cephalosporins with identical side chains. Cephalexin (Keflex) is the only cephalosporin on UCSF formulary with identical R group side chains to aminopenicillins.

Cephalosporin Allergy (CA) Pathway – Appendix 3. Please see 3A for adult patients and 3B for pediatric patients.

1. Considering the similarity and dissimilarity of side chains is essential for determining cross-reactivity between penicillin and cephalosporin antibiotics and within cephalosporin antibiotics because cross-reactivity is mediated by structural similarities between side chains [1]. Although validated specifically for penicillin allergy, PEN-FAST is included in CA pathway as it outlines features consistent with low-risk allergy [6]. Potential for cross-reactivity between penicillin and cephalosporin antibiotics is shown in Appendix 5 [7].

Definitions

Beta-lactam antibiotics: antibiotics who chemical structure consists of a core beta-lactam ring with side chains – penicillin, cephalosporin, monobactam, carbapenem antibiotics

Side chains: component of chemical structure of beta-lactam antibiotics that can be identical/similar or unique between certain beta-lactam antibiotics

Adverse drug reaction: any adverse event due to pharmacologic effects of the drug

Allergic reaction: adverse drug reaction mediated by IgE activation of allergy cells (mast cells, basophils)

Type II-IV reaction: adverse drug reaction mediated by cells and proteins of the immune system but not involving IgE activation of allergy cells

PEN-FAST: validated scoring system that identifies low-risk penicillin allergies that do not require formal allergy testing [6]

APPENDIX

Appendix 1: Determining the Type of Reaction and Recommended Management

Appendix 2A: Penicillin Allergy (PA) Pathway – Adult

Appendix 2B: Penicillin Allergy (PA) Pathway – Pediatric

Appendix 3A: Cephalosporin Allergy (CA) Pathway – Adult

Appendix 3B: Cephalosporin Allergy (CA) Pathway - Pediatric

Appendix 4: Test Dose Procedure

Appendix 5: Cross-Reactivity of Penicillin and Cephalosporin Antibiotics on Formulary at UCSF

Reference #

Citation

1

Khan DA, Banerji A, Blumenthal KG, et al. Drug allergy: A 2022 practice parameter update. J Allergy Clin Immunol. 2022 Dec;150(6):1333-1393. PMID: 36122788.

2

Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: A cohort study. J Allergy Clin Immunol. 2014 Mar;133(3):790-6. PMID: 24188976.

3

Blumenthal KG, Shenoy ES, Varughese CA, et al. Impact of a clinical guideline for prescribing antibiotics to inpatients reporting penicillin or cephalosporin allergy. Ann Allergy Asthma Immunol. 2015 Oct;115(4):294-300.e2. PMID: 26070805

4

Otani IM, Tang M, Wang L, …, Doernberg SB. Impact of an Inpatient Allergy Guideline on β-Lactam and Alternative Antibiotic Use. J Allergy Clin Immunol Pract. 2023 Aug;11(8):2557-2567.e6. PMID: 37182569.

5

Solensky R, Macy E. Minor determinants are essential for optimal penicillin allergy testing: a pro/con debate. J Allergy Clin Immunol Pract. 2015 Nov-Dec;3(6):883-7. PMID: 26164809.

6

Trubiano JA, Vogrin S, Chua KYL, et al. Development and Validation of a Penicillin Allergy Clinical Decision Rule. JAMA Intern Med. 2020 May 1;180(5):745-752. PMID: 32176248

7

Blumenthal KG, Shenoy ES, Wolfson AR, et al. Addressing Inpatient Beta-Lactam Allergies: A Multihospital Implementation. J Allergy Clin Immunol Pract. 2017 May-Jun;5(3):616-625.e7. PMID: 28483315

Revision History

Revision Date

Update(s)

12/09/2018

• Updated the allergy pager numbers.

01/10/2020

• Added precaution that the guideline is intended for patients with documented penicillin OR cephalosporin mono-allergy, and not for patients with multiple beta-lactam antibiotic allergies.
• Updated pediatric-specific test dose procedure guidance.

04/05/2024

• Updated testing and administration recommendations per the 2022 Drug Allergy Practice Parameter in Appendix 2A and Appendix 3A. Appendix 2A - Guidelines now advise that (1) it is safe to administer cefazolin, 3^rd-5^th generation cephalosporin, and carbapenem antibiotics in patients at high-risk for persistent penicillin allergy (2) it is safe to administer 1^st-2^nd generation cephalosporin antibiotics in patients at low-risk for persistent penicillin allergy. Appendix 3A – Guidelines now advise determining safety of beta-lactam antibiotic administration based on side chain similarity/dissimilarity rather than generation.
• Included validated PEN-FAST score to help differentiate between high-risk and low-risk allergic reaction in Appendix 2A and Appendix 3A.
• Appendix 2B and Appendix 3B maintain prior content for risk stratification in pediatric patients due to differences in risk stratification approach (clinical prediction rule not validated in pediatric patients).
• Updated Allergy contact information to Voalte.