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
Urticaria and 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
Risk of cross-reactivity related to cephalosporin sidechain
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
