Lecture 5: Penicillin and antibiotic allergies






Russell E. Lewis
Associate Professor of Infectious Diseases
Department of Molecular Medicine
University of Padua


russelledward.lewis@unipd.it
https://github.com/Russlewisbo

Objectives

  • Describe the different types of hypersensitivity reactions based on clinical presentation and immunological mechanisms 

  • Recognise a patient history that will differentiate between immediate and delayed-type hypersensitivity reactions 

  • Describe the risk of cross-reactions between various beta-lactam antibiotics 

  • Describe the principles and contraindications for desensitisation

  • Describe the clinical manifestations, diagnosis and management of common non-beta-lactam antibiotic allergies

On target vs. off-target drug effects

Variable cutaneous presentation of
allergic drug reactions


widespread macupapular

widespread macupapular

macupapular aspect

macupapular aspect

isolated follicular

isolated follicular

coalescing erythema

coalescing erythema

Urticaria and angioedema


urticaria

urticaria

angioedema

angioedema

Acute generalised exanthematous pustulosis (AGEP)



Fixed drug eruption


Erythema multiforme, Toxic epidermal necrolysis (TEN)


DRESS: Drug rash with eosinophilia
and systemic symptoms

  • Latency: 2-8 weeks

  • Non-specific symptoms:

    • Fever (75%), lymphadenopathy (55-65%)

  • Hematological abnormalities:

    • Eosinophilia > 700 micolL (85-95%)

    • Leukocytosis (95%)

    • Neutrophilia (78%)

    • Monocytosis (69%)

    • Atypical lymphocytosis (35-67%)

  • Visceral involvement:

    • Liver (53-90%)-cholestatic and/or hepatocellular

    • Pulmonary (30%)-shortness of breath, cough

    • Cardiac involvement (2-20%)- hypotension, tachycardia, dyspnea, LV dysfunction, myocarditis

DRESS: Pathophysiology
and systemic symptoms



  • Pathophysiology:

    • Type IV T-cell activation (CD4+/CD8+) producing TNF-α

    • Reactivation of viruses from the Herpesviridae family (eg, HHV-6, HHV-7, Epstein-Barr virus [EBV], cytomegalovirus [CMV]) occurs in up to 75 percent of patients-cause or consequence? 

    • Some patient human leukocyte antigens are associated with higher risk

Classic “high-risk” drugs for DRESS


  • Allopurinol

  • Aromatic antiepileptic agents (carbamazepine, phenytoin, lamotrigine, …)

  • Sulfonamides

  • Vancomycin

  • Minocycline

  • Nevirapine

  • Anti-tuberculosis drugs

  • Mexiletine

β-lactams are lower risk

Stevens-Johnson Syndrome



Modified Gell and Coombs Classification


Immunological mechanisms





Penicillin allergy

Penicillin allergy epidemiology


  • 10-20% of patients will report a history of an allergy to PCN therapy 

  • However, only 0.5%-2% of all PCN administrations actually result in hypersensitivity reactions, most often rash 

    • Of these 1% are IgE mediated 

  • The incidence IgE PCN allergies is decreasing, partially due to the reduced use of parenteral PCN, which degradation products in solution may be the primary culprit 

  • Statistics from the UK 1972-2007 oral amoxicillin:

    • 1 death after anaphylaxis with oral amoxicillin (35 years and 100 million treatment courses)

  • Most reports of penicillin allergy describe unknown or cutaneous reaction


Public health implications

So if a patient reports they have a
penicillin allergy…


5% need allergy evaluation

  • Recent history if true IgE type reaction

  • Blistering rash

  • Hemolytic anemia

  • Nephritis

  • Hepatitis

  • Fever and joint pain

  • Severe cutaneous adverse reaction (SCAR)

95% can tolerate penicillins

  • Delayed, benign rash (Type IV reaction) that often does not recur with rechallenge
  • True IgE reactions wane over time, with 80% becoming tolerant after 10 years 
  • Many patients were never allergic, but had other symptoms they though represented a PCN allergy (concurrent viral infection, GI distress)

Top 4 patient penicillin allergy myths


  • Once you have an penicillin allergy, you have it for life

    • Allergy wanes over time, 80% of patients with type I (IgE-mediated reactions) will not have an allergy after a 10 year period

  • Viral rashes mistaken for antibiotic therapy

    • E.g., child with a viral exanthematous rash treated with a course of penicillin

    • Pediatric studies have reported >90% of children who developed rashes on antibiotic therapy do not develop a rash when rechallenged with penicillin again

  • Adverse effects mistaken by the patient as drug allergy

    • E.g. diarrhea, stomach cramps

  • “I have a family history of penicillin allergy”

    • No genetic basis has been identified for penicillin allergies

Penicillin allergy history



Timing and clinical presentation of reaction is key


How to assess patient risk


PENFAST score

PENFAST performance


Direct oral amoxicillin challenge

Palace study

Two step oral amoxicillin challenge


Anaphylaxis medications

How to assess patient risk


Skin testing

Allergic determinates

Penicillin skin test asssessment

Penicillin skin test assessment-Medium risk history

How do these test impact “medium risk” patients?


  • A negative skin test is associated with a 95% NPV for PCN allergy
  • A negative skin test plus negative amoxicillin challenge approaches 100% NPV for PCN allergy
  • If skin test is positive, amoxicillin challenge is not considered
  • Patient should be referred to an allergy/immunologist or desensitisation considered

Desensitization


  • Progressive, graded degranulation of mast cells (histamine release) by administering graded doses of antibiotic
  • Desensitization is contraindicated in patients with a history of a penicillin-induced exfoliative dermatitis, Stevens-Johnson syndrome, or toxic epidermal necrolysis
  • Desensitization has no effect on the incidence of non-IgE mediated reactions such as serum sickness, hemolytic anemia, maculopapular rashes, drug fever, hepatitis, or interstitial nephritis
  • If the patient does not receive a dose for a period of more than 24 hours, the risk for an immediate IgE-mediated reaction can be restored and repeat desensitization is required if the same drug is to be used again

Sample desensitization protocol

Other desensitization protocols

Cross-reactivity: Infectious diseases dogma

  • Common teaching: If a patient has a documented PCN allergy, the risk of cross reactions with cephalosporins is 10%
  • THIS IS FALSE, the actual cross reactivity is more likely 2%-3%
    • A subset of patients with history of anaphylaxis may have cross-reactivity determined by the R1 sidechain of the molecule
    • Cefazolin as a unique side chain and and very low risk for cross-reactivity


What is the cross-reactivity with carbapenems?


  • Cross reactivity with penicillin allergy and carbapenems is less than 1%
  • No cross reactivity between penicillins and monobactams (aztreonam)
  • A graded challenge or test dose can be considered:
    • i.e. Infuse 5-10% of dose and observe patient, then progress to full dose if not reaction
    • Skin testing (if available) could also rule out allergies

Special populations that should be
considered for testing


  • Peri-procedure before elective surgery
    • Importance of antibiotic timing/tissue levels at time of incision-less optimal with vancomycin that requires longer infusion
  • Pregnancy
    • PCN allergy associated with increased risk of cesarean delivery, post-cesarean wound complications, and longer length of stay
    • Consider third trimester referral for testing in patients with planned cesarean delivery, group B streptococcus colonization
  • Long term care facilities
    • Non-beta-lactam based therapies have higher risk for drug interactions
    • Higher risk for adverse effects
  • Hematology-oncology
    • Consider testing before chemotherapy or transplant (onset of of immunosuppression)
  • STD clinics
  • ICU patients?





Non-penicillin allergies?

Similar principles- patient history is key


  • Which drugs was the patient taking?
  • Dates of intake
  • Exact sequence of events
  • Underlying disease/Concomitant infections
  • Other drug administered at the same time/concomitant infections
  • Clinical morphology (at several time points)of rash
  • Histology of eosinophilia?

Intradermal testing-Non beta-lactams

  • Prick and intradermal tests less well standardized S
  • Some antibiotics are irritating even at low concentrations, making testing difficult
  • Special cellular activation tests may be available in some centers for some drugs

Approach to delayed-type hypersensitivity testing

  • Intradermal or patch testing with reading 24-72 hours
    • Low sensitivity, high specificity
  • Lymphocyte transformation testing
    • Available in specialized laboratories
    • Haptenization to become an antigen in vivo (hard to imitate in lab)

Sulfonamide hypersensitivity


  • Incidence 8%
  • Primarily cutaneous and GI tract
  • Only 3% are considered true hypersensitivity reactions.
    • Most common presentations are limited exanthems and fixed drug eruptions
    • However…sulfonamides are disproportionately associated with infrequent severe side effects (i.e. TEN, Stevens-Johnson Syndrome)
  • Mechanisms IgE-mediated are known to occur, but other poorly understood direct T-cell mediated mechanisms are more likely to be responsible
  • Higher incidence of reactions in patients with HIV/AIDS, tuberculosis

Mechanism of sulfonamide hypersensitivity

PENFAST score applied to sulfa allergies

Non-sensitizing allergic reactions


  • Mas-related G protein coupled receptor (MRGPRX2)
  • Neuromuscular blocking agents
  • Opioids
  • Radiocontrast media
  • Vancomycin, glycopeptides, fluoroquinolones
  • Complement-activation-related pseudoallergy (CARPA)
  • Liposomes, drug carriers

Vancomycin infusion reaction
“red man syndrome”

  • Vancomycin can also cause:
    • Hypotension, anaphylaxis
    • Maculopapular exanthems
    • Vasculitis E
    • Eosinophilia Exfoliative dermatitis/DRESS/Stephens-Johnson


  • Penicillin allergies are the most common “contraindication” to antibiotic therapy, but most histories do not represent true allergies
  • A systematic approach can be used to evaluate and potentially “de-label” patients with penicillin allergy
  • Cross-reactivity rates are low with current cephalosporins and carbapenems, but can alternatively be addressed through antibiotic challenges and skin testing
  • Desensitization can be attempted in specific cases when a particular antibiotic is needed for IgE-mediated reactions
  • Some antibiotics cause non-immune-related hypersensitivity reactions that can be managed by slowing infusions and administering antihistamines

References


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