IID 09: Allergies to Beta Lactams and Other Antibiotics Flashcards
Type I Hypersensitivity Reaction
- Mechanism
- Onset
- Clinical Manifestations
IgE mediated
- mechanism: Ag → cross-linking of IgE bound to mast cells → release of vasoactive mediators
- onset: 0-2 hours
- clinical manifestations: anaphylaxis, urticaria, angioedema, respiratory distress, hypotension
Type II Hypersensitivity Reaction
- Mechanism
- Onset
- Clinical Manifestations
cytotoxic
- mechanism: Ab directed (IgG, IgM) against cell-surface Ag → cell destruction via antibody-dependent cell-mediated cytotoxicity (ADCC) or complement
- onset: 10 hours to weeks
- clinical manifestations: anemia, thrombocytopenia
Type III Hypersensitivity Reaction
- Mechanism
- Onset
- Clinical Manifestations
immune complex
- mechanism: Ag-Ab complexes deposited at various sites induces mast cell degranulation → damages tissue
- onset: 1-3 weeks
- clinical manifestations: serum sickness (fever, urticaria, vasculitis, arthritis/arthralgia)
Type IV Hypersensitivity Reaction
- Mechanism
- Onset
- Clinical Manifestations
T-cell mediated
- mechanism: memory TH1 cells release cytokines that recruit and activate macrophages
- onset: 2-14 days
- clinical manifestations: maculopapular rash, Stevens Johnson Syndrome
What are the patient-related factors that influence the likelihood of allergic drug reactions?
- age – males before puberty, females after puberty
- sex
- genetic
- prior reactions to the drug
- multiple drug allergies
- pharmacogenomics
What are the drug-related factors that influence the likelihood of allergic drug reactions?
- route of exposure – topical > oral > IV (skin has many immune cells that act as first line of defence)
- molecular weight
- severity of reaction influenced by the dose and duration
What information is needed to assess a patient’s drug allergy status?
- when the reaction occurred – and how soon it occurred after taking the drug
- what type of reaction – and characteristics of it
- did they go to the hospital visit – what did they do/give (ie. epinephrine means anaphylaxis, stop taking medication)
- route
- family history
- other antibiotics taken
- any other non-drug allergies
Beta Lactam Antibiotics
What is the best way to evaluate IgE-mediated penicillin allergy?
skin testing
Beta Lactam Antibiotics – Penicillins
What are the antigenic components of penicillins?
beta lactam ring and R side chain
Beta Lactam Antibiotics – Penicillins
What is cross-reactivity between penicillins due to?
shared Ag determinants:
- core: beta lactam ring
- R side chain
if patient has allergy to penicillin – should avoid all penicillins
Beta Lactam Antibiotics
Describe amoxicillin/ampicillin rashes.
- non-immunologic rash
- non-pruritic
- flat, blotchy, appears over days
Beta Lactam Antibiotics
What is the incidence of amoxicillin/ampicillin rashes greater with?
- concomitant viral infections (incidence 69-100%)
- chronic lymphocytic leukemia (CLL)
- hyperuricemia
- concomitant allopurinol
(not associated with an increased risk for future intolerance to penicillins)
Beta Lactam Antibiotics – Cephalosporins
Which generation results in more allergic reactions?
increased with 1st and 2nd generation vs. 3rd generation
- 3rd generation side chains thought to have less immunogenicity
Beta Lactam Antibiotics – Cephalosporins
Is there cross-reactivity between cephalosporins?
yes – side chains
- NOT beta lactam ring
Beta Lactam Antibiotics – Cephalosporins
1st Generation Cross-Reactivity
- cefazolin does not have a similar side chain to any other cephalosporin
- other 1st generation cephalosporins (cephalexin and cefadroxil) will cross-react with each other and some 2nd generation cephalosporins
Beta Lactam Antibiotics – Cephalosporins
2nd Generation Cross-Reactivity
cefaclor and cefprozil
- cross-react with each other
- cross-react with 1st generation cephalosporins – cephalexin, cefadroxil
cefoxitin and cefuroxime
- cross-react with each other
Beta Lactam Antibiotics – Cephalosporins
3rd/4th Generation Cross-Reactivity
- cefotaxime, ceftriaxone, and cefipime cross-react with each other
Penicillin-Cephalosporin Cross-Reactivity
What are the antigenic components?
- cross-reactivity due to similarities with side chains – NOT due to beta-lactam ring
- if a patient has anaphylaxis to penicillin → cephalosporin with different side chains are safe (less clear if ‘similarities’ with side chains)
Penicillin-Cephalosporin Cross-Reactivity
What cephalosporins do amoxicillin and ampicillin cross-react with?
- 1st generation: cephalexin, cefadroxil
- 2nd generation: ceflacor, cefprozil
Penicillin-Cephalosporin Cross-Reactivity
What cephalosporins does penicillin cross-react with?
- cefoxitin (2nd generation)
Penicillin-Cephalosporin Cross-Reactivity
What cephalosporins do cloxacillin and piperacillin/tazobactam cross-react with?
none – no cross-reactivity with cephalosporins
Beta Lactam Antibiotics – Carbapenems
What are the antigenic components of carbapenems?
beta-lactam ring
Beta Lactam Antibiotics – Carbapenems
What is the cross-reactivity of carbapenems?
if react to one carbapenem → react to all carbapenems
Penicillin-Carbapenem Cross-Reactivity
- cross-reactivity: ‘very low,’ < 1% or lower (issues with studies)
- considered safe to give carbapenems to a person with anaphylaxis to penicillins
Penicillin-Carbapenem Cross-Reactivity
What are the antigenic components?
- beta-lactam ring?
- side chains very different → antigenic components likely very different
Beta Lactams
Type II Reactions
drug specific – avoid offending agent
Beta Lactams
Type III Reactions
avoid all beta lactams
Beta Lactams
Type IV Reactions
avoid all beta lactams
Sulfonamides
What are some sulfonamides? (6)
- antimicrobials (sulfamethoxazole)
- diuretics (hydrochlorothiazide, furosemide)
- celecoxib
- oral hypoglycemics
- carbonic anhydrase inhibitors (acetazolamide)
- triptans (sumatriptan, etc.)
Sulfonamides
Is there cross-reactivity between antimicrobial sulfa and non-antimicrobial sulfa drugs?
- not well quantified
- likely very low due to differences in chemical structure
Sulfonamides
What is the Type 1 reaction mechanism?
- IgE has NO affinity for the sulfonamide group
- has some affinity for other parts of the sulfamethoxazole molecule
- some drugs share these parts but no evidence of cross-reactivity (dapsone, benzocaine, acebutolol, procainamide)
Sulfonamides
What are allergic reactions with non-antibiotic sulfas?
predisposition to allergic reactions vs. cross reactivity with sulfa antibiotics
Sulfonamides
Describe non-Type 1 reactions.
- via direct cytotoxicity or types II, III, or IV reactions
- clinical presentations vary widely
- delayed cutaneous reactions (fever → rash):
morbilliform eruptions (bumpy, patches), erythema multiforme (red, patches), Stevens Johnson (can be fatal, or life-altering with significant morbidity), TEN (toxic epidermal necrolysis)
Sulfonamides – Non-Type 1 Reactions
Sulfamethoxazole
produce reactive metabolites (hydroxylamines)
Sulfonamides – Non-Type 1 Reactions
Slow Acetylators, People with Glutathione Deficiency
increase risk
Sulfonamides
Is there cross-reactivity between sulfonamide antibiotics and non-antibiotics?
no
- sulfa moeity unfairly blamed and maligned
Trimethoprim-Sulfamethoxazole
Which patients have increased rates of ADRs?
- patients with HIV: 50-80% (rate ↑ as CD4 count ↓)
- other immunocompromised patients: 10%
Fluoroquinolones
Most reactions are either…
- immediate (IgE mediated, type I)
- delayed (cell-mediated, type IV)
but some severe types II-IV reported
Fluoroquinolones
Describe immediate reactions.
- some IgE, some non-IgE mechanisms
- unclear if skin testing useful
Fluoroquinolones
Describe cross-reactivity.
if allergic to one → avoid entire class
- frequent cross-reactivity but poorly described
What can be done to treat drug allergies?
- discontinue the medication
- treat adverse clinical signs and symptoms
- substitute (if necessary) a different agent
What can be used to treat adverse clinical signs and symptoms?
- H1 antagonists
- corticosteroids
- epinephrine
What information should be collected when investigating drug allergies?
- symptoms, physical findings
- what was the drug
- prior exposure
- timing of reaction
- description of reaction
- concomitant drugs
- how was the reaction managed
- receive same or related drug(s) since
- similar symptoms when not taking the drug?
- any concomitant medical condition that might promote reactions to certain drugs
What test can be used to confirm drug allergy investigations?
skin test
What does skin testing predict?
immediate, IgE-mediated reactions (type I) only
What CAN’T skin testing predict?
risk for non-IgE-mediated reactions (non-urticarial drug rashes)
What agents can be tested by skin testing?
- relevant allergenic metabolite(s) identified
- available for testing
What are the limitations of skin testing?
- for many drugs, the antigen is a metabolite – parent drug not useful
- predictive value unclear (sensitivity?)
- cannot use if patient has had a serious reaction (SJS/TEN, vasculitis, etc.)
- does not predict cross-reactions
- very rare, but systemic reactions can occur
Skin Testing
Describe the IgE-mediated reaction to penicillin.
- ↑ risk for IgE-mediated and non-IgE-mediated reactions with subsequent use
- tend to lose sensitivity if no exposure
- 50% skin test negative at 5 years
- 75-80% skin test negative after 10 years
Drug Challenge
- if history indicates unlikely allergic reactions or skin test negative
- to confirm: no reaction is expected
- used to exclude hypersensitivity where history vague/non-specific
- oral or IV
- generally start with 50% or smaller amount of normal dose then repeat with full dose
- monitoring
Allergy Management
- avoidance
- find non-cross-reacting drugs
- premedication: not useful – H1 antihistamines not effective in preventing anaphylactic shock, may mask early signs
- documentation
- patient education
- Medic-Alert® bracelet
- desensitization
When might desensitization be considered?
- if patient has history of allergic reaction to drug (swelling, anaphylaxis, shortness of breath)
- if no reasonable drug therapy alternatives
- if drug necessary for severe life-threatening infection
What does desensitization do?
can reduce risk of anaphylactic reactions
- but does NOT reduce risk of other types of reactions (exfoliative dermatitis, SJS)
What is the mechanism of desensitization?
unclear – possibly basophils and mast cells develop tolerance on exposure to antigen
Describe the desensitization process.
- in hospital
- resuscitation equipment and MD nearby
- discuss risks and benefits with patient
- prior to initiating: patient should be stable
- approximately 1/3 patients → mild transient allergic reaction during desensitization period and/or during treatment period
- once desensitization protocol begins, it should not be interrupted unless severe reaction occurs
- antihistamines and/or epinephrine to treat reactions
- lapse between doses of ≥ 24 hours may → reemergence of sensitivity
Summary
- good allergy history is essential
- penicillins – cross react with each other
- carbapenems – cross react with each other
- cephalosporins – depends on side chain
- cross reactivity between penicillin allergy and cephalosporins depends – side chain
- cross reactivity between penicillin allergy and carbapenem: none
- cefazolin – does not share side chain with any other beta lactam
