Drug Allergy and Desensitisation — Viva

Long Case Viva Defence

Candidate's opening statement (model answer)

"Mrs Margaret Chen is a 68-year-old woman with a history of mitral valve endocarditis caused by Streptococcus bovis, admitted for intravenous ceftriaxone, who carries a lifelong penicillin allergy label from a rash in childhood. She also has type 2 diabetes, stage 3 chronic kidney disease and atrial fibrillation. [1]

Her problem list is: (1) streptococcal endocarditis requiring a six-week course of intravenous beta-lactam therapy, for which ceftriaxone is the drug of choice; (2) a penicillin allergy label of low certainty, requiring risk stratification and possible delabeling; (3) the antibiotic stewardship implications of the label — if I default to vancomycin I expose her to nephrotoxicity with her CKD and inferior efficacy against streptococci; (4) the risk of cross-reactivity if I choose a cephalosporin, which is side-chain-dependent; (5) the communication and documentation needs across cardiology, microbiology, pharmacy and her general practitioner. [1]

This is a patient in whom refining the allergy label is both diagnostic and therapeutic. My immediate plan is to risk-stratify the label on history, confirm with skin testing and an oral challenge if low-moderate risk, and proceed with ceftriaxone — which has a dissimilar R1 side chain to penicillin and a cross-reactivity of approximately 1 per cent. If the label cannot be refined and a beta-lactam is essential, I would desensitise." [1]

Examiner probing questions and model answers

"Why is ceftriaxone safe in a penicillin-allergic patient?" [1]

"Ceftriaxone has an R1 side chain that is dissimilar to penicillin. Beta-lactam cross-reactivity is determined by the R1 side chain, not the core beta-lactam ring. The historical 10 per cent figure came from early studies that included contaminated cephalosporins and did not account for side-chain specificity. The modern figure is 1 to 2 per cent overall and near zero for cephalosporins with dissimilar side chains like ceftriaxone and cefuroxime. The cephalosporins to avoid in a penicillin-allergic patient are those that share the aminopenicillin side chain — cefalexin, cefaclor, cefadroxil — because they can cross-react with amoxicillin. I would not use cefalexin here if the allergy were to amoxicillin, but ceftriaxone is a safe choice" [2].

"What is the risk-stratified delabeling strategy?" [1]

"The 2022 practice parameter divides patients by risk. Low-risk patients — remote, non-severe, vague childhood reactions — can be delabeled by a direct oral amoxicillin challenge, 250 mg with one hour observation, without prior skin testing; over 95 per cent tolerate it. Moderate-risk patients — a more recent or convincing immediate history — undergo penicillin skin testing with the major determinant penicilloyl-polylysine and the minor determinant mixture, followed by an oral amoxicillin challenge if the skin test is negative. High-risk patients — recent anaphylaxis, severe immediate features, or a history of SJS, TEN or DRESS — are not challenged; if a beta-lactam is essential I proceed to specialist skin testing or desensitisation. SJS, TEN and DRESS are absolute lifelong contraindications" [1].

"How would you desensitise, and what is the key pitfall?" [1]

"Desensitisation is the graded administration of escalating doses to induce temporary clinical unresponsiveness. The Brigham 12-step protocol uses three solutions of escalating concentration, each given in four doubling intravenous doses over approximately 15 minutes per step, reaching the target dose over about 6 hours. It is performed in a monitored setting with intravenous access and resuscitation equipment. In the Castells series of 413 cases, 94 per cent of reactions during the procedure were mild or absent. The key pitfall is the 48-hour rule — tolerance is lost if the drug is withheld for more than about 48 hours, so every subsequent course requires a repeat full desensitisation. For this patient on a six-week ceftriaxone course, if she were desensitised and then had the infusion interrupted for more than 48 hours, I would need to re-desensitise before resuming — resuming the full dose after a gap can precipitate anaphylaxis" [3].

"What is drug provocation testing, and when is it the gold standard?" [1]

"Drug provocation testing — a graded oral or parenteral challenge with the suspected drug under supervised monitoring — is the gold standard for diagnosing drug allergy. The 2022 practice parameter positions it as the preferred confirmatory test for most non-severe, non-immediate reactions, increasingly over skin testing. A negative challenge allows delabeling; a positive challenge confirms the diagnosis. It is contraindicated in patients with a history of SJS, TEN, DRESS or severe immediate anaphylaxis, where the history alone establishes the contraindication" [1].

"What are the absolute contraindications to desensitisation?" [1]

"Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS are absolute lifelong contraindications — re-exposure causes a more severe and rapid recurrence and may be fatal. Drug-induced immune haemolytic anaemia and severe serum sickness are also absolute contraindications. Desensitisation is only for immediate IgE-type reactions or non-life-threatening reactions to an essential drug with no alternative." [1]

"How does the penicillin allergy label itself cause harm?" [1]

"The label drives the use of broader-spectrum, more toxic and more expensive antibiotics — fluoroquinolones, clindamycin, aztreonam, vancomycin. Patients with the label have higher rates of MRSA colonisation, Clostridioides difficile infection, surgical site infections, longer hospital stays and higher mortality. Removing a false label is a direct patient-safety intervention — it restores access to first-line beta-lactams and reduces the collateral harm of broad-spectrum alternatives." [1]

Short Case Viva — Skin examination of a drug eruption

Candidate's approach

"I would examine the skin systematically, beginning with a general inspection for the pattern and distribution of the eruption, then characterising the morphology, then examining the mucosal surfaces, then assessing for systemic features. [1]

On morphology: a maculopapular exanthem appearing days 5 to 10 of a new drug suggests a delayed T-cell reaction. Urticaria within minutes to one hour suggests an IgE reaction. Targetoid lesions with mucosal involvement suggest Stevens-Johnson syndrome. Sterile non-follicular pustules on an erythematous base suggest acute generalised exanthematous pustulosis. A round, well-demarcated violaceous plaque with post-inflammatory hyperpigmentation suggests a fixed drug eruption. [1]

For the severe reactions, I would assess the body surface area of detachment — under 10 per cent is SJS, 10 to 30 per cent is the SJS-TEN overlap, over 30 per cent is TEN — and examine the mucosal surfaces (oral, conjunctival, genital) for erosion. I would look for a positive Nikolsky sign. I would calculate SCORTEN within 24 hours to predict mortality. [1]

For suspected DRESS, I would examine for fever, facial oedema, lymphadenopathy and organomegaly, and I would request eosinophil count, liver function, renal function and human herpesvirus 6 serology, applying the RegiSCAR scoring system. [1]

My presentation would lead with the morphology and timing, offer the likely drug culprit, and request the confirmatory investigations — tryptase for immediate reactions, full blood count with eosinophils and liver function for DRESS, skin biopsy for severe reactions, and SCORTEN calculation for SJS or TEN." [1]

Examiner probing questions

"Which reactions are absolute contraindications to re-exposure?" [1]

"Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS are absolute lifelong contraindications to the culprit drug and to structurally related drugs. Re-exposure causes a more rapid and severe recurrence and may be fatal. Desensitisation is never offered after these reactions. The patient must carry an alert card and every future prescriber must be informed." [1]