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Drug Reactions

ANTIBIOTIC ALLERGIES

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Evaluation of Suspected Antibiotic Allergies 39259567​

  • Drug challenges, when indicated, should be performed to remove incorrect drug allergies from a patient’s medical record, especially for penicillin or sulfonamide allergies (strong recommendation; moderate certainty of evidence [COE]).

  • For individuals at low risk of an antibiotic drug allergy, a supervised drug challenge may rule out a true allergy (conditional recommendation; low COE).

  • Children with prior benign cutaneous symptoms (eg, morbilliform drug eruption, urticaria) from use of aminopenicillins do not require skin testing before monitored direct amoxicillin challenge (strong recommendation; moderate COE).

  • For adults with remote history (>5 years) of mild nonanaphylactic reactions, such as benign cutaneous symptoms, monitored drug challenges without prior skin testing may be considered to rule out allergies to β-lactam, sulfonamide, fluoroquinolone, and macrolide antibiotics (conditional recommendation; low COE).

  • For individuals with prior nonanaphylactic penicillin allergy, a cephalosporin can be administered without testing or additional precautions. In patients with prior anaphylaxis to penicillin, a structurally dissimilar cephalosporin (eg, cefazolin, cefpodoxime, ceftriaxone, ceftazidime, cefepime) can be administered without prior testing (conditional recommendation; moderate COE).

  • For individuals with a history compatible with penicillin or cephalosporin allergy, a carbapenem, such as ertapenem, may be given without special precautions (conditional recommendation; moderate COE); aztreonam may also be considered but should not be used among individuals with ceftazidime allergy due to ceftazidime-aztreonam cross-reactivity (conditional recommendation; moderate COE).​

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DRESS

Background/Overview                                                                                                                                                                                  

  • Recent review articles incorporated here include:

Wei BM, Fox LP, Kaffenberger BH, Korman AM, Micheletti RG, Mostaghimi A, Noe MH, Rosenbach M, Shinkai K, Kwah JH, Phillips EJ, Bolognia JL, Damsky W, Nelson CA. Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. Part I. Epidemiology, pathogenesis, clinicopathological features, and prognosis. J Am Acad Dermatol. 2024. PMID: 37516359.​

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Wei BM, Fox LP, Kaffenberger BH, Korman AM, Micheletti RG, Mostaghimi A, Noe MH, Rosenbach M, Shinkai K, Kwah JH, Phillips EJ, Bolognia JL, Damsky W, Nelson CA. Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. Part II diagnosis and management. J Am Acad Dermatol. 2024. PMID: 37516356.

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Clinical Presentation                                                                                                                                                                                     

Variation with causative drug​

  • The clinical presentation (timing, pattern of systemic involvement, etc) is something many have looked at to try an correlate with the causative drug.  This table and chart is informative along those lines.

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Culprit Drugs 39002560                                                                                                                                                                                

High Risk

Allopurinol, Carbamazepine, Phenytoin, Vancomycin, Sulfasalazine, Amoxicillin, Dapsone, Lamotrigine, Trimethoprim-sulfamethoxazole, Phenobarbital, Clozapine, Piperacillin-tazobactam, Minocycline, Strontium ranelate.

Intermediate Risk

Cefotaxime, Valproic acid, Ceftriaxone, Isoniazid, Amoxicillin-clavulanic acid, Nevirapine, Telaprevir, Rifampin, Ethambutol, Meropenem, Mexiletine, Raltegravir, Iodinated contrast media, Ibuprofen, Vemurafenib, Captopril, Hydroxychloroquine, Imatinib, Oxcarbazepine, Azithromycin, Imipenem, Olanzapine, Trimethoprim, Zonisamide, Atovaquone, Cefepime, Celecoxib, Enoxaparin, Furosemide, Amlodipine.

Low Risk

Abacavir, Acetazolamide, Acyclovir, Alectinib, Alpelisib, Alverine citrate, Amikacin, Amiodarone, Amphotericin, Ampicillin, Apremilast, Apalutamide, Apixaban, Aripiprazole, Aspirin, Azathioprine, Benznidazole, Benzylpenicillin, Bortezomib, Canakinumab, Carvedilol, Cefdinir, Cefixime, Cefotetan, Ceftazidime, Certolizumab, Chloral hydrate, Cisplatin, Citalopram, Clarithromycin, Clotiapine, Cocaine, Codeine phosphate, Dasatinib, Denosumab, Desloratadine, Dicloxacillin, Dinndolylmethane, Dolutegravir, Efavirenz, Epoetin alfa, Erlotinib, Ethosuximide, Etodolac, Etoricoxib, Everolimus, Fenofibrate, Flavoxate, Flucloxacillin, Gabapentin, Glimepiride, Griseofulvin, Hydantoin, Icotinib.

Workup                                                                                                                                                                                                           

Organ Workup​

  • CBC with diff (including platelets)

  • Kidney function tests: BUN, creatinine, eGFR, urine sediment

  • Liver function tests

  • Electrocardiogram

  • For patients with specific organ specific disease, or severe disease, consider the following driven by specialist of respective discipline:

    • coagulation tests (PT, Factor V, etc)​

    • skin biopsy

    • for severe liver involvement, liver biopsy, evidence of hemophagocytosis

    • ProBNP/BNP, troponin T, transthoracic echo

    • pancreatic enzymes

    • Chest CT or Xray; in selected cases, PFTs, bronchoscopy

    • CT/MRI brain, lumbar puncture​

Viral workup

  • Serum PCR for HHV6, EBV, CMV.  If positive, can consider HHV7.  

  • If planning systemic therapy, consider hep B and C screening

Treatment                                                                                                                                                                                                       

Delphi-based international consensus recommendations 37966824​

Treatment

  • Base treatment on disease severity.  

  • Corticosteroids should be given to all patients with confirmed DRESS

    • Mild DRESS: very high potency topical steroids tapering 6wks - 3mo​

    • Moderate DRESS: very high potency topical steroids or systemic steroids tapered over 6wks - 3mo

    • Severe DRESS: systemic steroids tapered over 6wks - 3mo

  • For steroid-refractory DRESS: cyclosporine, IL-5 or IL-5r inhibitors, or IVIG​

  • For DRESS with high CMV viral loads, consider addition of ganciclovir or valganciclovir

Follow-up
  • Monthly follow up for 6 months to assess:
    • bloodwork determined by organ involvement at diagnosis​
    • autoantibody screening
    • thyroid dysfunction screening
    • side-effect of prolonged steroid screening and management
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IMMUNE CHECKPOINT INHIBITORS

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  • A systematic review and meta-analysis demonstrated that immune-related cutaneous adverse reactions occurring during immune checkpoint inhibitor treatment were associated with improved overall survival, HR 0.61. (37672255)

STEVENS-JOHNSON SYNDROME/TEN​​

 

Causes                                                                                                                                                                                                           

Lee EY, Knox C, Phillips EJ. Worldwide Prevalence of Antibiotic-Associated Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Systematic Review and Meta-analysis. JAMA Dermatol. 2023. PMID: 36790777.

  • Key statistics from this meta-analysis:

    • 86% of cases could be determined to be caused by a single drug (14% multiple potential drug triggers).​

    • Antibiotics cause 28% of cases of SJS/TEN.  Anticonvulsants, allopurinol, and NSAIDs were other common triggers.  Infection was uncommon.

    • 32% of antibiotic-associated cases were from sulfonamides, 22% penicillins, 11% cephalosporins, 4% fluoroquinolones, 2% macrolides.

  • MY CRITIQUE: authors use some confusing phrasing like "proportion of antibiotics associated with SJS/TEN" and "proportion of antibiotics triggering drug-associated SJS/TEN", when they likely mean the proportion of cases associated with or triggered by antibiotics.  The distinction between "associated with" and "triggering drug-associated" is unclear too. ​

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Predicting Mortality                                                                                                                                                                                       

  • There has been some back and forth between SCORTEN and ABCD-10 over the last few years attempting to demonstrate which is the more predictive scoring system. 

Koh HK, Fook-Chong S, Lee HY. Assessment and Comparison of Performance of ABCD-10 and SCORTEN in Prognostication of Epidermal Necrolysis. JAMA Dermatol. 2020. PMID: 33084873.

This study determined SCORTEN to be more superior to ABCD-10.

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Treatments                                                                                                                                                                                                     

Plasmapheresis

  • After ineffective systemic corticosteroids, plasmapheresis provides no benefit compared to IVIg and is associated with increased costs and longer hospital stays. 36884227

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