Understanding Beta-Lactam

& Antibiotic Allergies:

Principles and
Management Strategies
Jennifer McCarthy, PharmD, MS
PGY-1 Pharmacy Resident
Parkview Health
About Me
Objectives

1 2 3 4 5
Understand the Explain the Identify allergy Describe the Apply the principles
principles of mechanism for characteristics of implications for of allergy risk
hypersensitivity antibiotic cross- patients with low- allergy skin testing screening to
reactions with allergies risk allergies and penicillin optimize patient
respect to patient desensitization care within a patient
care case
Overview of Beta-Lactam
Allergies1,2
•Estimated that approximately 10% of all US patients
report an allergic reaction to a beta-lactam antibiotic
▪ Approximately over 80% of these patients lose their sensitivity after
10 years.
▪ <1% have a true IgE mediated reaction
•Secondary to documented beta-lactam allergies
within the EMR
▪ Increased use of broad-spectrum, alternative agents
Types of
Hypersensitivity
Reactions3
What type of hypersensitivity do
beta-lactam allergies fall under?
Type I
Hypersensitivity
Reactions3
Beta-Lactam Side Chain Role in Drug Allergies2,4
Previously was thought to be related to the core beta-lactam ring structure
o However, this would mean that patients would be allergic to all beta-lactam
antibiotics
o Beta-lactams are too small to bind to IgE
IgE-mediated allergies occur to the R1-side chains
o Development of IgE antibodies to the R1 specific side chain structure
▪ Via the binding of proteins
Penicillin & Cephalosporin Cross Reactivity
Rates1,2
Reported cross-reactivity rates between
penicillin's and cephalosporins range from about
16% to 40% with identical side chains

Cross reactivity stems from identical R1

side chains
o Not how a specific antibiotic is classified
▪ i.e. aztreonam & Ceftazidime
▪Antibiotics that have unique side chains are
not cross allergic with other drugs
o Cefazolin & ceftaroline
Why The Term "Penicillin Allergy" Is
Misleading
•"Penicillin's" refers to four general groups of antibiotics:
o Natural penicillin's
o Anti-staph penicillin's
o Aminopenicillins
o Anti-pseudomonal penicillin's
•When people say "penicillin allergy" they are commonly referring to
o An aminopenicillin (ampicillin ± clavulanic acid)
o Penicillin G or penicillin VK
•Excessively broad term as most agents may not be cross-allergic
o Leading to an inappropriate antibiotic class allergy
Consequences of
Inappropriate Drug Allergies
Suboptimal Antibiotic Therapy
o Most patients generally receive broad spectrum antibiotics
i.e. carbapenems
•Contributes towards emerging antibiotic resistance
•Delays in patient care
•Increased outpatient mortality
•Increased healthcare costs associated with
o Skin test ordering
o Increased hospital length of stay
o Hospital readmissions secondary to treatment failure
o Costs of utilizing alternative agents
Patient Case #1
•MW is a 32 YOF admitted to your medicine team with complaints of suprapubic
abdominal pain. She has a history of recurrent UTI's, reporting 3 UTI's over the last 5
months. Her abdominal pain is dull and located in the bilateral lower quadrants. She
denies fever, sweat, or chills.
•CT of Abdomen & Pelvis: No evidence of acute abnormality or urinary
tract obstruction
Previous Antibiotic Dispensing History
02/12/2024 Nitrofurantoin 100 mg PO BID x 10 days

12/05/2023 Nitrofurantoin 100 mg PO BID x 10 days

11/20/2023 Bactrim 800/160 mg PO BID x 7 days

Patient Case #1
Urine Culture (03/15/2024)
Escherichia coli (Non-ESBL Producer)
>100K CFUs (Abundant growth)

Urine Culture Susceptibilities Report (03/15/2024)

Meropenem MIC ≤1 Susceptible
Nitrofurantoin MIC ≥4 Resistant
Piperacillin/Tazobactam MIC ≤1 Susceptible
Sulfamethoxazole/Trimethoprim MIC ≥5 Resistant
Patient Case #1
The team decides to discharge the patient on Augmentin
875 mg-125 mg PO BID x 10 days

However, being the diligent resident you are, you decide to

double check their allergies first and you notice their allergy
documentation is listed as...
What Would Be Some Questions You
Would Have For This Patient?
 1. How long ago was your reaction?
Questions to o Five years ago or LESS indicates low risk
Ask Your 2. Was the reaction anaphylaxis or
Patient to angioedema?
Assess Their 3. Was the reaction a severe cutaneous
adverse reaction?
Allergy o i.e. Steven Johnsons Syndrome (SJS)/TENs
Severity 4. Did your reaction require treatment?
 Key Components of Allergy History
Collected
Timeframe since reaction

Type of reaction experienced

If reaction was severe enough that it required

treatment

Remember: Most patients will remember if reaction was

severe enough to warrant treatment or hospitalization
Additional
Methods to
Assess Severity
of A Penicillin
Allergy
Antibiotic Allergy Skin Testing
Benefits
o Sensitive – NPV of 97-99% indicating that a penicillin can be tolerated

Gold Standard to Remove A Penicillin Allergy - Specialized 2-Step Process

o Intradermal Skin testing, if negative, then followed by
o Oral challenge with a penicillin

Limitations
o Costly
o Specificity is unclear as most tests lack a penicillin challenge
o A negative penicillin allergy doesn't exclude allergies to structurally unrelated beta-
lactams
▪ Cefazolin or ceftriaxone
Examples of Allergy Skin Testing Results6,7
Penicillin Desensitization
What is desensitization?
• Patients with a known or highly suspected allergy are gradually exposed to escalating doses of a
drug
• Intentionally provoking an allergic reaction
• Rigorous, validated protocols must be followed carefully

After controlling the reaction, more drug is given

• Over time, IgE antibiotics against the drug are depleted
• As a result, the reaction subsides & patient can tolerate the drug

The drug must be continually administered to work

• If patient stops being exposed for a long period of time, re-exposure may cause anaphylaxis

Rigorous, validated protocols must be followed carefully

 •For situations where a specific antibiotic is uniquely
useful
o Must be performed in an ICU or ED with the capacity
to treat anaphylaxis or angioedema immediately
Role of •As there is increasing understanding about lack of
Desensitization cross-sensitivity
o Rarely required
•ID will always be present to assist in these situations
where it is indicated!
 Is It a Common Drug Side Effect or
Hypersensitivity Reaction?
Adverse Drug Effect Hypersensitivity Reaction
• Nausea/Diarrhea • SJS/TEN
• Abdominal pain/cramping • Anaphylaxis
• Dizziness
• Angioedema
• Drug fever
• Dyspepsia (Doxycycline) • Rash/hives
• Crystalluria (Sulfonamides/Macrobid) • Drug-induced lupus
• Brown discoloration of urine erythmematous (DILE)
(Macrobid) • Hemolytic anemia
Support From
Primary
Literature
 Components of
the PEN-FAST
Allergy Screening
Assessment
Su C, et al. (JAMA 2023)8
Evaluating the PEN-FAST Clinical Decision-making Tool to Enhance Penicillin Allergy De-labeling.
A retrospective medical record review of 120 patients to validate PEN-FAST in risk stratification of
Study Design
reported penicillin allergies
PEN-FAST scores were compared with positive skin test results: sensitivity, specificity, NPV, and
Objective
positive likelihood ratio
PEN-FAST scores of 2 or less had
sensitivity, specificity, NPV, and a positive 73% of patients had PEN-Fast scores of 2 or less.
likelihood ratio of 100%, 75.9%, 100%, and 4.14, All had negative test results.
Results respectively.
3.4% of patients had positive test results:
• 2 had positive skin test results & a PEN-FAST score of 3
• 2 had negative skin test results but failed DOPC (PEN-FAST scores: 3 & 5
Further validates the accuracy behind the PEN- Confirms that low risk patients would be the
Key Points
FAST tool ideal candidates to trial DOPC
PALACE Trial (July 2023)9
Copaescu AM, et al. Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The
PALACE Randomized Clinical Trial
Randomly assigned to direct oral penicillin challenge [DOPC] (intervention arm) or Penicillin Skin Testing (control
Study Design arm)
• Inclusion Criteria: PEN-FAST Score < 3

Outcomes Physician verified positive immune mediated oral penicillin challenge within 1-hour

372 patients in analysis Primary outcome occurred in 1 patient in

• (Median [IQR] age, 51 [35-65] years; 247 [65.5%] female) intervention & control group
• RD of 0.0084 pp (90% CI, -1.22 to 1.24 pp)
Results
Immune-mediated ADR’s 5-days post DOPC: 9 vs 10 (Intervention, Control; Respectively)
• (RD, -0.45 pp; 95% CI –4.87 to 3.96 pp)
No serious ADRs were reported
The PEN-FAST score correlation with anticipated results from a skin test was validated within a larger sample size
Key Points Future studies should focus on direct challenges in low-risk Most patients had a PEN-FAST score of 1 or 2
patients
 A 58-year-old patient reports an allergy to
amoxicillin in childhood with a reaction of
hives where he was then switched to a
different antibiotic. If a skin test was
performed today, what risk category of a
Patient Case positive skin test result would this patient
fall into?
#2 A. Very low risk
B. Low risk
C. Moderate risk
D. High risk
Key Takeaways
Very small subset of the US population have a "true" IgE mediated allergy to a
beta-lactam antibiotic

Most patients lose this hypersensitivity after 10 years, so likely adult patients who
report a childhood reaction of hives can tolerate a beta-lactam

There is low cross-reactivity between penicillin's and cephalosporins

Each patient's allergy history should be thoroughly evaluated on a case-by-case

basis

It's always good to inquire more information about the patient's allergy
Questions?
References
1. Is it really a penicillin allergy? - centers for Disease Control and ... Is It Really a Penicillin Allergy? Accessed March 5th,
2024. https://www.cdc.gov/antibiotic-use/community/pdfs/penicillin-factsheet.pdf.
2. Farkas J. Approach to beta-lactam allergy in critical care. EMCrit Project. February 11, 2023. Accessed March 5th, 2024. https://emcrit.org/ibcc/penicillin/.
3. Hypersensitivity Reactions (Types I, II, III, IV).; 2009. https://njms.rutgers.edu/sgs/olc/mci/prot/2009/Hypersensitivities09.pdf. Accessed March 5th, 2024.
4. De Rosa M, Verdino A, Soriente A, Marabotti A. The Odd Couple(s): An Overview of Beta-Lactam Antibiotics Bearing More Than One Pharmacophoric
Group. International Journal of Molecular Sciences. 2021; 22(2):617. https://doi.org/10.3390/ijms22020617. Accessed March 5th, 2024.
5. Allergy Resources. ADSP. https://adsp.nm.org/allergy-resources.html. Accessed March 5th, 2024.
6. Gu J, Liu S, Zhi Y. Cefuroxime-induced anaphylaxis with prominent central nervous system manifestations: A case report. Journal of International Medical
Research. 2019;47(2):1010-1014. doi:10.1177/0300060518814118. Accessed March 5th, 2024.
7. Positive reaction to allergy test. Mayo Clinic. Accessed March 5th, 2024. https://www.mayoclinic.org/tests-procedures/allergy-tests/multimedia/positive-
reaction-to-allergy-test/img-20006787. Accessed March 5, 2024.
8. Su C, Belmont A, Liao J, Kuster JK, Trubiano JA, Kwah JH. Evaluating the PEN-FAST Clinical Decision-making Tool to Enhance Penicillin Allergy Delabeling.
JAMA Intern Med. 2023;183(8):883-885. doi:10.1001/jamainternmed.2023.1572 Accessed March 5th, 2024.
9. Copaescu AM, Vogrin S, James F, et al. Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low -Risk Penicillin Allergy: The
PALACE Randomized Clinical Trial [published online ahead of print, 2023 Jul 17]. JAMA Intern Med. 2023;e232986.
doi:10.1001/jamainternmed.2023.2986. Accessed March 5th, 2024.