Drug Allergy and Desensitisation — DCE Clinical Case

Long Case — Penicillin allergy label complicating streptococcal endocarditis

Patient scenario

Mrs Margaret Chen is a 68-year-old woman admitted with a two-week history of low-grade fever, malaise and a new murmur. Blood cultures grow Streptococcus gallolyticus (formerly S. bovis), and a transtoesophageal echocardiogram shows a 10 mm vegetation on the anterior mitral leaflet with mild mitral regurgitation. The diagnosis is native-valve streptococcal endocarditis, for which intravenous ceftriaxone 2 g daily for four weeks (or benzylpenicillin) is first-line. [1]

Her medical history includes type 2 diabetes (HbA1c 64 mmol per mol, on metformin and empagliflozin), stage 3b chronic kidney disease (eGFR 38 mL per min per 1.73 m squared), atrial fibrillation on apixaban, and hypertension. She carries a penicillin allergy label dating to a rash in childhood, described by her mother as a non-itchy rash with a fever at age 4, with no recall of the drug, the timing or the features of anaphylaxis. She has never received penicillin since. [1]

Candidate's opening statement (SASPOP)

"Mrs Margaret Chen is a 68-year-old retired teacher presenting with a two-week history of low-grade fever, malaise and a new mitral murmur, found to have streptococcal (Streptococcus gallolyticus) native-valve endocarditis with a 10 mm mitral vegetation, in the setting of a lifelong penicillin allergy label of low certainty from a childhood rash. [1]

Her problem list is: (1) streptococcal native-valve endocarditis requiring a four-week course of intravenous beta-lactam therapy, for which ceftriaxone is first-line; (2) a penicillin allergy label of low certainty, requiring risk stratification and delabeling; (3) the antibiotic stewardship implications — if I default to vancomycin I expose her to nephrotoxicity with her stage 3 CKD and inferior efficacy; (4) type 2 diabetes and CKD, which complicate antibiotic dosing and toxicity; (5) atrial fibrillation on apixaban, which I will need to manage around the admission; (6) 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 amoxicillin challenge, and proceed with ceftriaxone — which has a dissimilar R1 side chain to penicillin and a cross-reactivity of approximately 1 per cent." [1]

Structured problem list and integrated management plan

Problem 1 — Streptococcal native-valve endocarditis. Ceftriaxone 2 g intravenously daily for four weeks is first-line for penicillin-susceptible streptococcal endocarditis. Dose-adjust for eGFR 38. Monitor with serial inflammatory markers, repeat blood cultures at 48 to 72 hours to document clearance, and repeat echocardiography at the end of therapy. Arrange a colonoscopy on recovery, because S. gallolyticus is associated with colonic pathology and colorectal neoplasia. [1]

Problem 2 — Penicillin allergy label. The history (childhood rash with fever, decades ago, no features of anaphylaxis, no recall of the drug) places her at low to moderate risk. The approach per the 2022 practice parameter [1] is penicillin skin testing with the major determinant (penicilloyl-polylysine) and minor determinant mixture, followed by an oral amoxicillin challenge if the skin test is negative. If negative, delabel and proceed with ceftriaxone. If the history were more concerning, or skin testing positive, ceftriaxone can still be given because its R1 side chain is dissimilar to penicillin (cross-reactivity approximately 1 per cent), with a test dose if the team is cautious.

Problem 3 — Antibiotic stewardship and the harm of the label. Avoiding all beta-lactams would force vancomycin, which is nephrotoxic (dangerous with her CKD), requires therapeutic drug monitoring, and is inferior to ceftriaxone for streptococci. Refining the label and using ceftriaxone is the stewardship-correct and patient-correct choice. Document the delabeling prominently. [1]

Problem 4 — Type 2 diabetes and CKD. Dose-adjust ceftriaxone for eGFR 38 (the standard 2 g daily is acceptable at this eGFR, but review). Hold empagliflozin during acute illness (risk of euglycaemic diabetic ketoacidosis). Continue metformin if renal function is stable. Monitor blood glucose and renal function daily. [1]

Problem 5 — Atrial fibrillation on apixaban. Continue apixaban unless there is a bleeding indication to stop. There is no routine need for antibiotic-anticoagulant interaction dose adjustment with ceftriaxone. Assess bleeding risk. [1]

Problem 6 — Communication and documentation. Communicate the refined allergy status to the cardiology, microbiology, pharmacy and general practice teams. Update the electronic medication record. Provide the patient with a written summary of the delabeling for future encounters. [1]

Probing questions and model answers

"What if she had a history of Stevens-Johnson syndrome to penicillin?" [1]

"Then penicillin, ceftriaxone and all beta-lactams would be absolutely contraindicated for life — SJS is a non-negotiable contraindication. I would use vancomycin (with careful monitoring for her CKD) or daptomycin for the streptococcal endocarditis, in consultation with microbiology. Desensitisation would never be offered after SJS." [1]

"How does the SCORTEN score work, and when do you use it?" [1]

"SCORTEN is the prognostic score for toxic epidermal necrolysis, calculated within 24 hours of admission. Each of seven factors scores one point: age over 40, malignancy, heart rate over 120, detached body surface area over 10 per cent, serum urea over 10 mmol per litre, serum bicarbonate under 20 mmol per litre, and serum glucose over 14 mmol per litre. Mortality rises from about 3 per cent at score 0 to 1, to over 90 per cent at score 5 or more. I would use it to prognosticate and to guide transfer to a burns unit for high scores" [2].

"What is the 48-hour rule in desensitisation?" [1]

"Tolerance induced by desensitisation is temporary and is lost if the drug is withheld for more than about 48 hours. For a patient on a multi-week infusion, if the infusion is interrupted for more than 48 hours — for example, a delay in chemotherapy cycle or a drug shortage — a repeat full desensitisation is required before resuming. Resuming the full dose after a gap can precipitate anaphylaxis. Every chemotherapy cycle after the first desensitisation requires a repeat full procedure" [4].

"How would you manage a reaction during desensitisation?" [1]

"Stop the infusion, treat the reaction — adrenaline intramuscularly if anaphylaxis, antihistamine and bronchodilator for milder reactions — and once symptoms resolve, resume the protocol at the last tolerated dose or one step lower. The procedure is rarely abandoned; the vast majority of reactions during desensitisation are mild. In the Castells series, 94 per cent of reactions were mild or absent" [4].

Short Case — Skin examination of a suspected drug eruption

Examination instruction

"Examine this patient's skin. She was started on a new medication three weeks ago and has developed a rash." [1]

Systematic examination routine

1. General inspection — pattern, distribution, confluence. Is it localised or generalised? Is it symmetric? Does it involve the palms, soles, mucosal surfaces or intertriginous areas?
2. Morphology — macular, maculopapular, urticarial, targetoid, vesiculobullous, pustular, purpuric. Is it blanching? Is there epidermal detachment?
3. Mucosal examination — oral cavity (lips, buccal mucosa, tongue, palate), conjunctivae, genitalia. Erosion or ulceration suggests SJS or TEN.
4. Body surface area of detachment — estimate the percentage of detached or easily detachable epidermis. Under 10 per cent is SJS, 10 to 30 per cent is the SJS-TEN overlap, over 30 per cent is TEN. Perform a Nikolsky sign (lateral pressure causes epidermal shearing).
5. Systemic features — fever, lymphadenopathy, hepatosplenomegaly, facial oedema (DRESS), hypotension (anaphylaxis or SJS with skin barrier loss).
6. Specific signs — fixed drug eruption (round violaceous plaque with hyperpigmentation), AGEP (sterile non-follicular pustules), linear immunoglobulin A bullous dermatosis (annular bullae). [1]

Presentation template

"This patient has a generalised maculopapular eruption involving the trunk and proximal limbs, sparing the palms, soles and mucosal surfaces, with no epidermal detachment and no Nikolsky sign. The onset was day 18 of a new medication, consistent with a delayed T-cell-mediated drug eruption. There is associated fever and cervical lymphadenopathy but no organomegaly. There are no features of Stevens-Johnson syndrome or toxic epidermal necrolysis at present. [1]

Given the timing, the morphology and the systemic features, my differential is a delayed drug eruption versus DRESS. I would request a full blood count with eosinophil count, liver function, renal function, and a review of the medication list to identify the culprit. If the eosinophil count is elevated and there is hepatitis, I would apply the RegiSCAR scoring system for DRESS and stop the culprit drug immediately" [3].

Discussion questions

"Which drugs are the classic culprits for DRESS?" [1]

"The aromatic anticonvulsants (carbamazepine, phenytoin, lamotrigine), sulfonamide antibiotics, allopurinol, minocycline, dapsone and vancomycin. The onset is typically 2 to 8 weeks after starting the drug, which is later than a simple maculopapular eruption and is a clue to the diagnosis." [1]

"What is the management of DRESS with organ involvement?" [1]

"Stop the culprit drug immediately. Start systemic glucocorticoids — prednisolone 1 mg per kg daily, or intravenous methylprednisolone in severe disease — for any organ involvement (hepatitis, interstitial nephritis, pneumonitis, myocarditis). Taper slowly over weeks to months because relapse is common with early taper. Ciclosporin is used for severe or steroid-refractory cases. Monitor for viral reactivation — human herpesvirus 6, cytomegalovirus and Epstein-Barr virus. Re-exposure to the culprit drug is an absolute lifelong contraindication." [1]