drug allergy and cross-reactivity

quick recognition

• correlation ≠ causation — always consider non-drug causes of rash (infection, primary dermatologic conditions, other medical illness)
• drug allergy is not hereditary — family history is irrelevant (exception: HLA-associated reactions in specific ethnic groups, e.g. HLA-B5801 and allopurinol, HLA-B1502 and carbamazepine)
• common pitfall: anchoring on drug allergy when the rash has another cause

easy wins — not allergic

• patient has never taken the drug
• avoiding based on family history only (non-HLA-related)
• tolerated the same drug since the initial reaction
• history consistent with side effect (sleepiness with opioids, headache, nausea) — not immune-mediated

classification

immediate reactions

• occur within 1–2 hours of first administered dose
• IgE-mediated → anaphylaxis, urticaria, angioedema, bronchospasm
• pseudoallergic (non-IgE) immediate reactions — opioids, vancomycin, fluoroquinolones, radiocontrast → direct mast cell degranulation, not true allergy

delayed reactions

• onset hours to weeks after exposure
• critical question: dangerous or not?

Dangerous delayed reactions	Non-dangerous
SJS/TEN — skin sloughing	drug exanthem / morbilliform rash
AGEP — generalised pustules	mild exfoliation during resolution
DRESS — organ damage + eosinophilia
drug-induced nephritis/hepatitis
drug-induced cytopenia
serum sickness–like reaction

pseudoallergic reactions

Non-IgE-mediated immediate reactions via direct mast cell/basophil activation — typically cutaneous, dose-dependent. If multisystem involvement → treat as anaphylaxis, give epinephrine.

Drug class	Management
opioids	decrease dose, rotate agent, premedicate with antihistamines
radiocontrast	hydration, use non-ionic iso-osmolar agent — switch agent if prior reaction (steroid premedication not recommended per CAR/CSACI)
infusions (e.g. rituximab, vancomycin)	antihistamines ± steroids, resume at slower rate
N-acetylcysteine	limited cutaneous symptoms → treat with antihistamine; any respiratory symptoms, angioedema, or hypotension → stop infusion ± epinephrine; restart 1 h after symptom resolution if needed (switch to PO NAC if hypotensive)

---

management framework

immediate reactions

1. treat as anaphylaxis → stop the drug
2. wait 4–6 weeks before any skin testing
3. skin testing does not exist for many drugs (e.g. TMP/SMX) and is imperfect
4. if alternatives exist → use alternative
5. if no alternatives → desensitisation
   • temporary induction of tolerance
   • resource-intensive (usually ICU or monitored setting)
   • risk of reaction exists but is generally low
   • tolerance is lost once drug is stopped

delayed reactions — dangerous (SCAR)

• do not use drug or related drugs — cross-reactivity patterns less clear for delayed reactions
• no reliable allergy clinic testing exists
• clinical pharmacology may have access to in vitro testing (outpatient)

delayed reactions — non-dangerous

• if alternatives available → use alternative
• if no alternatives → may use and treat through symptoms (e.g. antihistamines for morbilliform rash)
• desensitisation is not available for delayed reactions

drug challenge protocols

Protocol	Step 1	Step 2	Observation
1-step	full dose PO/IV/IM/SC	—	30–60 min
2-step	1/4 tab PO or 1/10 IV dose	full dose	30–60 min per step

Outcome	Features
positive	urticaria, angioedema, exanthem, wheeze, hypoxia, hypotension, anaphylaxis
possible	flushing, vomiting, cough, abdominal cramping, persistent pruritus without rash, fever, mouth/eye soreness
doubtful	dizziness, tachycardia, subjective lip/tongue swelling, subjective throat tightness, lump in throat, dyspnoea, transient pruritus without rash, headache

Consider placebo-controlled challenges for possible/doubtful reactions.

---

beta-lactam allergy

• 10% of Canadians have a penicillin allergy label → <5% are truly allergic
• anaphylaxis: 0.001% parenteral, 0.0005% oral exposures (general population)
• 75–80% outgrow true allergy after 10 years
• 75% of patients with a penicillin allergy label acquired it by age 3

PEN-FAST score

PEN-FAST (2020) — validated clinical decision rule for penicillin allergy de-labelling:

• if score <2 → direct challenge (no skin testing needed)
• alternatively: if reaction >5 years ago and rash was benign → direct challenge

beta-lactam cross-reactivity

Cross-reactivity is driven by side chain similarity, not the beta-lactam ring itself:

If allergic to…	Safe to prescribe	Avoid (shared side chain)
amoxicillin	cefazolin, cefoxitin, cefuroxime, ceftazidime, carbapenems	ampicillin, cefadroxil, cephalexin, cefprozil, ceftriaxone
penicillin	most cephalosporins, carbapenems	ampicillin, amoxicillin
cephalosporin (any)	carbapenems	check specific side chain pairs

carbapenems and monobactams

• safe without special precautions if penicillin or cephalosporin allergy
• applies only to immediate reactions or benign delayed rashes
• aztreonam can be used unless ceftazidime allergy (shared side chain)

when to avoid ALL beta-lactams

---

TMP/SMX allergy

• no skin testing exists
• mild rash or hives >5 years ago (or unknown history) → 1-step drug challenge
• 2-step challenge (1 h then 2 h monitoring) if:
  • non-severe immediate reaction in last 5 years
  • anaphylaxis any time before
  • significant patient anxiety
• SCAR → do not use
• if not challenging but drug is needed → desensitise

other antibiotics

fluoroquinolones

• no testing exists other than challenge
• mild skin reaction >5 years → 1–2 step challenge
• more severe or recent reaction → 1–2 step challenge to a different fluoroquinolone
• or desensitise

macrolides

• uncommon allergy; ~1% mild delayed rash; anaphylaxis extremely rare
• no skin test exists
• mild skin reaction → 1–2 step challenge
• or desensitise

---

ASA and NSAIDs

• ASA does not cause anaphylaxis but can cause severe asthma exacerbation in susceptible patients (ASA-exacerbated respiratory disease / AERD)
• NSAID hypersensitivity patterns:
  • COX-1 dependent (cross-reactive) — urticaria/angioedema or bronchospasm with multiple NSAIDs
  • COX-1 independent (single-drug) — true IgE-mediated allergy to one specific NSAID

ASA in cardiovascular emergencies

• without AERD → 2-step ASA challenge:
  • 81 mg → observe 90 min → 325 mg → observe 90 min
• with AERD → requires desensitisation (not a simple challenge)

---

radiocontrast media

• LOCM = low-osmolarity contrast media; GBCA = gadolinium-based contrast agent
• often pseudoallergic (non-IgE-mediated) — not true allergy
• skin testing is not well validated
• zero relationship between iodinated contrast and shellfish or povidone-iodine

CAR/CSACI approach

Known specific agent — mild/moderate reaction:

• switch agent — premedication is not recommended

Known specific agent — severe reaction:

• consider alternative imaging modality
• consider allergy referral
• if imaging cannot wait → switch agent + monitor injection
• premedication with steroids is not recommended
• second-generation antihistamine premedication is optional (mild/moderate only)

Unknown agent (before 2000):

• give LOCM — premedication not recommended

Unknown agent (on or after 2000):

• mild/moderate → consider second-generation antihistamine premedication
• severe → consider alternative imaging or allergy referral
• steroid premedication not recommended

---

what NOT to do

• anchor on “drug allergy” without considering non-drug causes of rash
• label side effects (nausea, headache, drowsiness) as allergy
• avoid an entire drug class based on family history alone
• assume allergy is permanent — most penicillin allergy resolves within 10 years
• avoid all beta-lactams for benign delayed rash — check cross-reactivity by side chain
• use steroid premedication for contrast allergy — not recommended by current guidelines
• label “iodinated contrast allergy” without specifying the exact agent
• desensitise for delayed dangerous reactions (SCAR) — desensitisation is only for immediate reactions
• avoid cefazolin in penicillin-allergic patients — cefazolin has a unique side chain and is safe