This document discusses the importance of drug allergy testing, specifically for penicillin allergy. It reviews the steps for taking a medication allergy history and testing, including skin testing for penicillin. Avoiding antibiotics due to reported allergy can increase costs, treatment failure, infections, and resistance. Testing is important as up to 95% of patients reporting penicillin allergy may actually be able to tolerate it. The document reviews indications for challenge or desensitization, including using challenge for low-risk histories and desensitization when no alternative treatments exist. It provides an example case of a boy who has penicillin skin testing to safely receive treatment for an infection.

1. Drug Allergy
Testing How
and is it
important?
Brian Schroer MD
Director of Allergy and
immunology
Shankar Upadhyayula MD
MRCPCH
Director of Antimicrobial
Stewardship

2. Objectives- By the end of the meeting
participants will:
• Review why drug allergy testing is necessary.
• Review and discuss the steps of medication allergy history
and subsequent testing.
• Discuss implementation of routine allergy testing

3. Case: Calvin 7 Years old with recurrent AOM

4. Case: Calvin 7 years old
• Calvin is a 7 y/o with recurrent AOM.
• CC: Evaluation of a reaction to Amoxicillin.
• HPI: 2 months ago he had systemic “Rash” and swelling of his
lips.
• Resolved in ED with “steroids and Benadryl”
• No prior reactions

5. How? History
• History is the number 1 test.
• Are they allergic to the drug?
- Was the reaction due to a drug? Or a virus?
- Was it an immune response to the drug? Side effect?
Idiosyncratic?
- If it was a drug allergy, what is likely mechanism?

6. How? Calvin’s History
• What drug? Some pink liquid.
• What dose? I don’t know- 10ml?
• Why were they on it? Ear infection
• How many times had they had it before? Too many
• Since?- Heck no.
• How long were they on it before the reaction? I dunno- 2-3 days?
• How soon after taking a dose did something happen? About 30
minutes

7. How? Calvin’s History
• What symptoms/signs happened? Rash and swelling
• Describe the rash. I dunno- welts?
• Show me:
• Googles picture of hives:- yes, like that but all over.

8. How? Calvin’s History
• What Didn’t happen?-
• Fever, Joint pain, blistering rash, desquamation- No
• What was used for treatment? Or self resolved?
• The ED gave him diphenhydramine: told him to take it 4 times per
day for a week, and gave him five days of steroids.
• How long did the symptoms last for? One day.
• Have these symptoms occurred before? Never.
• My doctor told me he can never take penicillin again!

9. How? History Taking Tools
• There are few validated tools.
• New screening tool for Penicillin recommended by AAAAI,
Infectious Disease society of America (ISDA), Society for
Healthcare Epidemiology of America (SHEA).
• Shenoy. JAMA 2019 321;2:188-199.1
Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of a penicillin allergy. A Review. JAMA 2019 321;2:188-199.

10. How? Supplement part A: Low Risk History

11. How? Moderate Risk

12. How? Moderate Risk
x
x
Urticaria!
CALVIN!
X
X

13. How? High Risk

14. How? Details of Reaction

15. Why NOT Just Avoid It? What could go wrong!
• 10% or 32million in US have ”Allergy” to PCN1-4
• 95% of those without a history of a severe reaction would
be able to tolerate PCN5
• Akron Children’s Has:
• 10,848 Patients with antibiotic allergy
• 8,273 Patients with penicillin allergy
• 992 Patients with cephalosporin allergy
• 506 Both penicillin and cephalosporin allergy
1. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of a penicillin allergy. A Review. JAMA 2019 321;2:188-199.
2. Zhou L, et al. Drug allergies documented in electronic health records of a large healthcare system. Allergy. 2016;71(9):1305-1313.
3. Macy E, Ho NJ. Multiple drug intolerance syndrome: prevalence, clinical characteristics, and management. Ann Allergy Asthma Immunol. 2012;108(2):88-93.
4. Trubiano JA, Adkinson NF, Phillips EJ. Penicillin allergy is not necessarily forever. JAMA. 2017;318(1):82-83
5. BigbyM, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions. a report from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975 to 1982. JAMA.
1986;256(24):3358-3363.

16. Why NOT Just Avoid It? What could go wrong!
• The baseline risk for any reaction to β-lactam antibiotics is
approximately 2.0%.5
• 80-90% of true penicillin allergic patients (Anaphylaxis)
are tolerant in 10 years.4
• There is never no risk. The risk can be minimized.
5. BigbyM, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions. a report from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975 to 1982.
JAMA. 1986;256(24):3358-3363.
4. Trubiano JA, Adkinson NF, Phillips EJ. Penicillin allergy is not necessarily forever. JAMA. 2017;318(1):82-83

17. Why NOT Just Avoid It? What could go wrong!
• Use of alternatives increases:
• Cost
• Treatment failure
• Side effects.
• Surgical site infections.
• Microbial resistance?

18. Why NOT Just Avoid It? What could go wrong!
• Use of alternatives increases:
• Cost6
• Higher Direct Drug costs from inpatient admission: $0-$609/patient
• Higher total inpatient costs for inpatient: $1145-$4525/patient
• Higher Outpatient prescription costs: $14-$193/patient.
6. Mattingly TJ II, Fulton A, Lumish RA, et al. The cost of self-reported penicillin allergy: a systematic review. J Allergy Clin Immunol Pract. 2018;6(5): 1649-1654.

19. Why NOT Just Avoid It? What could go wrong!
• Use of alternatives increases Treatment Failure
• Treatment failure7
• Retrospective review of 456 adults with MSSA bacteremia
• Patients with PCN allergy were 13% less likely to receive optimal therapy
• PCN allergy was largest predictor for not receiving optimal therapy.
• Infectious disease consult was largest predictor of receiving optimal
therapy!
7. Blumenthal KG, Shenoy ES, HuangM, et al. The impact of reporting a prior penicillin allergy on the treatment of methicillin-sensitive Staphylococcus aureus bacteremia. PLoS One.

20. Why NOT Just Avoid It? What could go wrong!
• Use of alternatives increases infections
• In 300,000 adults in UK: PCN allergic vs case matched controls.8
• MRSA infection: PCN allergy associated with increased risk of MRSA
(Hazzard ratio 1.69)
• Penicillin alternatives accounted for 55% of increased risk for MRSA
• C. difficile: PCN allergy associated with increased risk of C. difficile
(Hazzard ratio 1.26)
• Penicillin alternatives accounted for 35% of increased risk for C. diff
• US study of 50,000 inpatients Case Control:9
• Significantly more fluoroquinolones, clindamycin, vancomycin.
• 14.1% more MRSA, 30% more VRE, ↑0.59 days of hospitalization
8. Blumenthal KG, Lu N, Zhang Y, Li Y, Walensky RP, Choi HK. Risk of methicillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy:
population based matched cohort study. BMJ 2018; 361, k2400
9. 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; 133: 790e6

21. Why NOT Just Avoid It? What could go wrong!
• Use of alternatives increases:
• Surgical site infections.10
• SSI- 8385 patients, 9094 surgical procedures
• 11% had PCN allergy
• PCN allergy patients – 50% higher odds of SSI attributable to using
second-line antibiotics.
1. Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The impact of a reported penicillin allergy on surgical site infection risk. Clin Infect Dis 2017; 66:
329e362016;11(7):e0159406.

22. Why NOT Just Avoid It?
• Use of alternatives increases:
• Microbial resistance?1
• Theoretically using narrow spectrum antibiotics should decrease
development of antimicrobial resistance.
• However, it is not yet proven that penicillin allergy label increases this.
1. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of a penicillin allergy. A Review. JAMA 2019 321;2:188-199.

23. Why not do any testing?
When the drug cannot/should not be used.10
• Blistering Rash
• Hemolytic Anemia
• Hepatitis/Nephritis/-itis.
• Fever
• Joint pain
• Serum sickness like reactions
• DRESS/AGEP
• Severe cutaneous adverse reactions (SCAR)
1. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of a penicillin allergy. A Review. JAMA 2019 321;2:188-199.

24. Who should help resolve PCN allergy?
• Not just for allergists.
• There are not enough specialists available.
• Need to develop antibiotic stewardship programs and teach
others how to test:1
• Infectious disease
• RNs
• Pharmacists
• Emergency room, Internal Medicine, Pediatrics
Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of a penicillin allergy. A Review. JAMA 2019 321;2:188-199.

25. When?
• Anytime, everywhere.
• At every allergist appointment
• Before surgery
• Chemotherapy
• Transplant
• Cystic Fibrosis
• Immunosuppression.
• BEFORE ANTIBIOTICS ARE NEEDED

26. Case: Calvin 7 years old
• Skin testing-
• SPT negative.
• ID wheal/flare in mm
• Control- 3/0
• Pre Pen- 10/44
• PCN G 5/7
• Histamine- 7/25
• Told to not take penicillin again- but if he needs it we can still use it…

27. Case Follow up: Calvin 9 years old
• HPI: 2 weeks ago had broken arm riding bike.
• Required orthopedic surgery
• 1 week later
• Fever, pain, drainage from wound
• Cultures- MSSA Methicillin sensitive Staph aureus
• ID recommends penicillin as best drug for clearing
infection.
• Now what?

28. Desensitization? When?
No equally efficacious alternatives
• Proven Drug allergy- History, tests, or challenge
• NO acceptable alternative drugs that are equally efficacious and have
no worse side effects.
• NO suggestion of
• Blistering rashes: SJS/TEN
• Erythema Multiforme
• Desquamation
• DRESS
• AGEP
• Serum Sickness
• Itis- nephritis, hepatitis
• Benefits outweigh potential harm.

29. Desensitization? When?
No equally efficacious alternatives, still allergic!
• Proven Drug allergy- History, tests, or challenge
• NO acceptable alternative drugs that are equally efficacious and have
no worse side effects.
• NO suggestion of
• Blistering rashes: SJS/TEN
• Erythema Multiforme
• Desquamation
• DRESS
• AGEP
• Serum Sickness
• Itis- nephritis, hepatitis
• Benefits outweigh potential harm.

30. How? Test for Low risk group- Challenge only

31. How? Test for Low risk group- Challenge only
• Low risk group
• Direct oral amoxicillin challenge can be performed in any patient
with a history of the following symptoms associated with penicillin:
• Isolated reactions that are unlikely to be allergic (e.g., gastrointestinal
symptoms, headaches)
• Itching without a rash
• Remote (>10 years) unknown history without IgE features
• May be used for patients with a “family history” or benign somatic
symptoms.

32. How? Low risk?

33. PCN 1 dose challenge if low risk no IgE

34. How? Moderate Risk- No test available?
Two step Challenge

35. How? Moderate Risk if no testing available- 2 dose
challenge.

36. Case: 9 Year old Calvin- Skin test is available!
• Repeat history with screen
• Has not taken penicillin since- Moderate Risk Category
• Now what?
• Skin test
• If negative- Single dose challenge.
• If positive- Desensitize if available.

37. How? Penicillin skin testing.

38. How? Penicillin skin testing negative
• One dose challenge- 250 or
500mg.
• Observe for one hour.
• Record +/- delayed
reactions.

39. Case: 9 Year old Calvin- Skin test is available!
• Repeat history with screen
• Has not taken penicillin since- Moderate Risk Category
• Repeat skin testing
• SPT negative.
• ID wheal/flare in mm
• Control- 3/0
• Pre Pen- 4/0
• PCN G 3/0
• Histamine- 8/28
• Single Dose Challenge- Monitored for 1 hour- no reaction.
• Completed therapy – no problems.

40. Calvin 9 years old- Follow up

41. Thank you!

42. References
1. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of a penicillin allergy. A Review. JAMA 2019 321;2:188-199.
2. Zhou L, et al. Drug allergies documented in electronic health records of a large healthcare system. Allergy. 2016;71(9):1305-1313.
3. Macy E, Ho NJ. Multiple drug intolerance syndrome: prevalence, clinical characteristics, and management. Ann Allergy Asthma Immunol. 2012;108(2):88-93.
4. Trubiano JA, Adkinson NF, Phillips EJ. Penicillin allergy is not necessarily forever. JAMA. 2017;318(1):82-83
5. BigbyM, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions. a report from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975 to 1982. JAMA.
1986;256(24):3358-3363.
6. Mattingly TJ II, Fulton A, Lumish RA, et al. The cost of self-reported penicillin allergy: a systematic review. J Allergy Clin Immunol Pract. 2018;6(5): 1649-1654.
7. Blumenthal KG, Shenoy ES, HuangM, et al. The impact of reporting a prior penicillin allergy on the treatment of methicillin-sensitive Staphylococcus aureus bacteremia. PLoS One.
8. Blumenthal KG, Lu N, Zhang Y, Li Y, Walensky RP, Choi HK. Risk of methicillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based
matched cohort study. BMJ 2018; 361, k2400
9. 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; 133: 790e6
10. Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The impact of a reported penicillin allergy on surgical site infection risk. Clin Infect Dis 2017; 66: 329e362016;11(7):e0159406.