• The estimated true incidence of penicillin hypersensitivity worldwide is low; up to 90% of patients who reported penicillins allergy could be delabeled safely after formal testing.

• Cross-reactivity between truly penicillin allergic patients with third and fourth generation cephalosporins and/or carbapenem is very low (Figures 1 and 2 and, Table 1). It is mainly determined by the R side chain.

• Alterations in antibiotic prescribing due to reported penicillins allergy has been shown to result in poorer clinical outcomes, increased incidence of serious antibiotic-resistant infections, prolonged hospitalisation, and increased healthcare burden.

• Careful drug allergy history paired with the PEN-FAST risk assessment (Table 2) should be performed, to decide if formal testing is needed; delabeling of allergy will result in more judicious use of narrow spectrum beta-lactam (BL) antibiotics when clinically indicated and improve patient safety.

Figure 2: Comparison of R1 & R2 structural similarities between B-lactams drugs. 

Drugs that have identical R1 or R2 are listed as R1 (red cell) or R2 (gold cell). If ONLY the ring or branch chain moiety of the R1 structure is identical, it is listed as R1’ or R’’, respectively. Drugs that have similar R1 or R2 structures are listed as r1 or r2. If ONLY the ring or branch chain moiety of R1 structure is similar, it is listed as r1’ or r1’’, respectively. Blank cells imply NO R1 or R2 structural similarities. (Zagursky & Pichichero, 20183)

• Obtain a detailed history of the drug allergic reaction (Refer Section 2.1).

• Conduct risk assessment of the patient using the PEN-FAST Clinical Decision Tool; proceed with either test-dose challenge (score <3) or refer if score more than 3.

• Send bloods for in vitro tests; refer for skin and provocation testing to centers specialized in drug allergy testing for moderate and high-risk patients.

• Refer to Table 3 for list of medications needed on-site when performing the test dose challenge for low-risk patients at the point-of-care.

1. When did the reaction occur?

2. Which medication was prescribed, and what was the route of administration?

3. What was the indication for the medication?

4. How many courses of this medication or a related medication have been administered?

5. How many doses were received prior to onset of reaction?

6. How soon after the most recent dose did the reaction occur?

7. Were there any concurrent medications administered?

8. What was the nature of the reaction? Specifically ask about:

• Raised, erythematous, pruritic rash with each lesion typically lasting <24 h? (hives/urticaria)

• Swelling of the tongue, mouth, lips, or eyes (angioedema)

• Respiratory or haemodynamic changes with skin manifestations (anaphylaxis)

• Lesions or ulcers involving the mouth, lips, or eyes; skin desquamation (SJS, TEN, and other severe type IV reactions)

• Organ involvement such as haematologic, renal, or hepatic (cytopenias, Acute Interstitial Nephritis (AIN), transaminitis)

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, and other severe type IV reactions

• Joint pain (serum-sickness like reaction)

• Rashes that were not hives, were mild, or delayed in onset (mild type IV reaction or morbilliform rash)

• Nausea, vomiting, diarrhea, minor laboratory abnormalities or local injection reactions

9. Was the medication stopped?

10.  Was medical attention sought in an emergency room or from a community physician?

11. How was the reaction managed?

12. Were there symptoms of unexplained fever, arthritis/arthralgia, lymphadenopathy, skin exfoliation or mucous membrane involvement?

13. How long did symptoms last?

14. Were any symptoms consistent with severe cutaneous adverse reaction (SCAR – SJS/TEN, DRESS, AGEP, Exfoliative dermatitis)?

15. Has the same medication been taken subsequently? If yes, was there a reaction?

16. Has any recurrent signs and symptoms occurred with subsequent same drug exposure?

17. Are there other tolerated antimicrobial agents? 

*Adapted from Jeimy S et al. Practical guide for evaluation and management of beta-lactam allergy: position statement from the Canadian Society of allergy and clinical immunology. 2020.Allergy Asthma Clin Immunol;1695.

Risk assessment before referring for testing, using the PEN-FAST Clinical Decision Tool for possible point-of-care testing:

Risk assessment should be performed using the recently published and validated PEN-FAST clinical decision tool - a predictive screening tool for true penicillin allergy to identify low risk penicillin allergy patients that do not require referral for formal allergy testing.

PEN-FAST is a validated clinical decision-making tool with a high negative predictive value for patients >12 years old. It is a point-of-care screening tool that identifies adult patients with low risk of penicillins allergy and therefore, do not require formal allergy testing when the total score is <3 (Table 2)13; therefore, a drug provocation test (DPT) by the treating physician is recommended.

All routes of administration are possible for a DPT (oral, subcutaneous, intramuscular or intravenous). Nevertheless, the oral route is preferred as the risk of a severe reaction with the oral route is low. The cumulative dose should be documented and may be 10-20% more than the therapeutic dose. For patients with a PEN-FAST score of <3 (interpreted as very low risk and low risk), a test dose challenge is recommended.

Test dose challenge:

• Giving 1/10 of the normal concentration intravenous medication or ¼ of the oral dosage being given followed by a 20-minute observation. If no objective symptom(s) is/are observed, a full dose x 1 (or the remaining 9/10) is given followed by a 2-hour observation period (Table 3).

*There is NO MERIT in drug skin testing referrals for SCREENING purposes (i.e. testing without prior history of exposure and subsequent reaction to the drug)

Table 3: Test dose challenge and medications to have on-site 

• Bloods should be sent for mast cell tryptase level during (up to 4 hours) a suspected acute anaphylaxis.

• This should be repeated 24 hours later for baseline measurements. For normal acute tryptase level, the equation 1.2 x baseline tryptase + 2 should be used to interpret results.

• In vitro quantification may be sent for specific IgE to penicilloyl G and penicilloyl V to the Allergy lab, Institute for Medical Research (IMR). The specific IgE:total IgE of > 0.002 has been shown to have high predictability of true penicillin allergy.

Figure 3: Penicillin allergy risk stratification, and relative contraindication to re-administration. 

1. Type 1 or IgE-mediated reaction:symptoms within 2 hours after first dose, duration < 24 hours. 2. Type II, III, IV: symptoms  >2 hours after drug  administration. [Adapted and modified from Jeimy S et al. Practical guide for evaluation and management of beta-lactam allergy: position statement from the Canadian Society of allergy and clinical immunology. 2020.Allergy Asthma Clin Immunol;1695]. 

• If provocation is not tolerated, document the BL(s) intolerance in the patient records

• If provocation is tolerated, delabel and/or document the BL(s) tolerance in the patient records

• An allergy card/passport/medic alert should be issued for future avoidance of the allergic BL(s)