β-lactam Allergies Flashcards
β-lactam Hypersensitivity
Reactions
Type I – Immediate hypersensitivity
manifestations
time it occurs
IgE mediated Gell and Coombs Immunopathic Classification System (Onset immediate – 30 minutes) (Late up to 72hr) Urticaria Laryngeal edema Angioedema Bronchoconstriction Allergic rhinitis Diarrhea
With or without
Hypotension
Cardiovascular collapse
β-lactam Hypersensitivity
Reactions
Type I – Immediate hypersensitivity
what mediates it
Anaphylactic reactions (onset < 1 hr)
Occur in 0.2% of 10,000 treatment courses of which 10% are fatal
Due to interaction between penicillin determinants and preformed IgE bound to mast cells or basophils
Patients at risk t1/2 IgE 10 - 1,000 days to indeterminate
Epinephrine is treatment of choice for acute treatment
Increased risk of fatality if patient taking β-blockers
we care cuz
can be fatal, penicillins are first line very effective, there are alternatives but needed for other organisms, few adverse effects
Urticaria
angioedema
which type of hypersens?
raised lesions in body
swelling of deeper dermis?, eyes, face, mouth, breathing difficulty
Type I
Type II – Cytotoxic Response
what mediates them?
time it occurs
Type II – Cytotoxic Response (> 72 hours)
Rare - usually only with high dose therapy
Penicillin determinants become bound to cells causing their destruction by IgG, IgM via complement activation
Hemolytic anemia, leukopenia, neutropenia, agranulocytosis, thrombocytopenia
May occur immediately with future administration if pre-existing antibodies therefore future administration not recommended
Type III – Immune Complexes
what mediates them?
time it occurs
(Onset 7-14 days)
Rare
IgG, IgM complexes with penicillin haptens
complexes lodge in tissue sites inducing complement
activation and neutrophil response causing further damage
interstitial nephritis, serum sickness, allergic vasculitis, and possibly drug fever
Type IV – Cell Mediated (Onset delayed)
Sensitized T-cells release cytokines that activate macrophages
or cytotoxic Tc cells which mediate direct cellular damage
Contact dermatitis from drug-sensitized T–cells
(onset 24 - 48hr)
all considered severe cutaneous rxns: do not rechallenge
DRESS 2-8 wks, resolution with stopping agent
SJS-TEN 4-28 day delay: <10% of body is SJS, > 30% is TEN
AGEP 24-48 hr: pustules
Maculopapular rash, morbilliform drug eruptions
Formerly considered to be idiopathic - now considered to be Type IV hypersensitivity
Onset > 72 hours
not to be stopped with this rxn, not true allergy
important to get hx odf allergy
Occurs in
3% receiving penicillin
0.2 - 9.5% receiving ampicillin or amoxicillin
90 - 100% of ampicillin treatments with Epstein-Barr Virus, Cytomegalovirus, Lymphocytic leukemia
Aminopenicillin Tx in patients with hyperuriciemia treated with allopurinol increases risk of rash from ~5 - 7.5% to ~15 - 20%
May resolve with continued use
Risk of Hypersensitivity Reactions
higher in which pt?
4 to 6-fold greater risk of reaction to penicillin if previous penicillin reaction
parenteral or high dose therapy ↑ risk
Hypersensitivity reactions most common age 20 - 49 yrs
Older adults and small children have reduced risk
but ↑ morbidity with older adult if reaction occurs
true allergy uncommon in young children
atopy does not ↑ incidence of reaction
History of Penicillin Allergy
no hx –> 2% actually allergic, 10% will claim
yes hx –? 65-93% neg skin test, treat with penicillin will lead to 1-3% cutaneous rxn only
7-35% pos skin test, higher risk 50-70% anaphylaxis, accelerated urticaria
see slide 20
Penicillin Allergy
Discrepancy due to several factors
Only 10% of those with a history of penicillin allergy will have allergic reaction if challenged (Mandel 2010)
When tested 80 – 90% of patients with a history of penicillin allergy will have negative skin tests
Discrepancy due to several factors
may not have been a true allergic reaction
may have been a predictable reaction or
effect of the underlying illness
Patients with type 1 penicillin allergy tend to lose penicillin-specific IgE antibodies over time. 10% per year, ppl will not react to pen antymore if true IgE mediated
- need to know when it happened, the longer it has been, the less likely it will happen
Penicillin/Cephalosporin
Cross-Hypersensitivity
Increasing evidence suggests most hypersensitivity
reactions to cephalosporins likely directed at the R group side chain rather than the β-lactam ring structure
R1 side chain of most 1st generation cephalosporins more structurally similar to some penicillins
Side chains of 3rd generation cephalosporins are dissimilar bto those of penicillins
hx of pen: could by core, but if only to R1, they may only react to amoxicillin
cephalosporins with diff side chains, it should be fine if IgE rxn
Examples of Effect of Side Chain
Cross-reactivity between amoxicillin and cephalosporins
with identical R group side chains was higher than for penicillin skin test-positive patients.
12 - 38% patients allergic to amoxicillin, but able to tolerate penicillin, reacted to cefadroxil (with identical R group)
Amoxicillin allergic patients should avoid (same R group) cefadroxil, cefprozil, or undergo rapid induction of drug tolerance
Ampicillin allergic patients should avoid cephalexin
if allergic to amoxicillin avoid:
ampicillin, cefadroxil, cefprozil, cephalexin
if allergic to penicillinavoid:
cefoxitine
Groups of β-lactams with
Similar Side Chains
cefazolin (1st gen has no cross-sensistivity)
cefexime is different ( maybe closest to G3)
group 1:
Penicillin
Cefoxitin
group 2: amox, ampicillin, cefadroxil, cephalexin, cefuroxime
group 3: cefotaxime, ceftriaxone, cefepime
group 4: cefuroxime, cefoxitin
group 5: ceftazdime, aztreonam, ceftolozane (Z’s EXCEPT cefprozil)
Penicillin/Cephalosporin
Cross-Hypersensitivity
Physician-documented cephalosporin-associated anaphylaxis
~2.9 - fold more common in individuals with histories of penicillin
allergy than in individuals with no history of drug allergy
3 of 127,125 courses; 95% CI, 0-1/19,880 vs
7 of 845,923 courses; 95% CI, 1/467,290-1/69,396)
Difference not statistically significant
Studies show approximately 2% of penicillin skin test-positive patients react to cephalosporins
But - some of these may be anaphylactic reactions
Unfortunately, use of penicillin skin-testing for cephalosporin allergy is not reliable
Skin testing for cephalosporins is not standardized, but a positive skin test using non-irritating concentration of a cephalosporin (10-
fold dilution) suggests drug-specific IgE antibodies.
Unfortunately, a negative skin test does not rule out allergy (negative predictive value is unknown).
Management of β-lactam Allergy
Start by completing a thorough allergy assessment
Specific agent received (and route)
Date of reaction(s)
Timing of reaction onset (following exposure to the agent)
Description of reaction and how it was managed
Concurrent medications at the time of the reaction
Exposure to any β-lactams since reaction
Document! (including documentation of what was successfully administered, rechallenges)
Avoid all β-lactams (penicillins, cephalosporins,
carbapenems) if history of severe non-IGE-mediated
reactions to penicillins, including:
hemolytic anemia, serum sickness interstitial nephritis, hepatitis Severe cutaneous reactions: Stevens-Johnson syndrome (SJS) Toxic epidermal necrolysis (TEN) Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Exfoliative dermatitis Acute generalized exanthematous pustulosis (AGEP)
If true IgE-mediated reaction to a cephalosporin with
respiratory difficulty, hypotension, or hives
Avoid that cephalosporin
Avoid penicillins/other cephalosporins with similar side chains
Can use other cephalosporins/penicillins with dissimilar side chain (or a carbapenem, if appropriate for the infection)
Educate patient on risk vs benefit of proposed β-lactam
Effectiveness and adverse effect potential vs alternative agents
If the patient had a reaction to a β-lactam that is
not IgE-mediated AND not severe
it is safe to administer other β-lactams
Penicillin Skin Testing
qualified person to test
Skin Testing only useful for Type I (IgE-mediated) allergic reactions
Only patients with Type I allergy (anaphylaxis, urticaria, angioedema, wheezing, etc) should be tested
Testing should not be performed for patients with other reactions (e.g., Stevens-Johnson Syndrome, hemolytic anemia, neutropenia, interstitial nephritis, hepatitis, etc.)
There are no products available for testing for cephalosporin allergy (or other antibacterials)
Patients with negative skin test results to penicillin major and minor determinants may receive penicillin with minimal risk of an IgE-mediated reaction
tential Value of
Penicillin Skin Testing
Penicillin allergy is reported in ~ 1/10 persons, but ~9/10 who report penicillin allergy proven tolerant to penicillin with penicillin testing
Of 30 million US patients thought to be penicillin allergic, an estimated 28.5 million are not
Penicillin allergy associated with
Longer hospital stay
More antibacterial use, possibly broader spectrum (more vancomycin, macrolides, clindamycin, FQs, 3rd Gen Cephalosporins, etc)
Found increased prevalence of C. difficile (23%), MRSA (14%), and VRE (30%
What if the patient has a positive
penicillin skin test and antibacterial
treatment is required?
3 options
A few options:
1. an alternate non-β-lactam antibacterial
2. administration of a non-penicillin β-lactam (often by
graded challenge)
3. administration of penicillin by rapid induction of drug
tolerance (desensitization)
Graded Challenge
Give 1/100 of therapeutic dose; if no reaction, 30-60 minutes later give 1/10 of therapeutic dose; if no reaction, 30-60 minutes later give full therapeutic dose
At the first sign of any allergic reaction the patient should be treated and procedure should be abandoned
If patient requires the medication at a later point it should only be administered through formal desensitization
Patients with severe non-IgE mediated reactions e.g StevensJohnson syndrome, TEN, nephritis, hemolytic anemia, hepatitis, etc are not candidates for graded challenge
Temporary Induction of Drug
Tolerance (Desensitization)
you know they are allergic but need to use it anyway
what is drug tolerance?
Drug Tolerance
defined as a state in which a patient with a drug allergy will tolerate a drug without an adverse reaction
(does not indicate a permanent state of tolerance or that the mechanism involved was immunologic tolerance)
Induction of drug tolerance modifies a patient’s response to a drug to temporarily allow it to be given safely
Achieved by administration of incremental doses of the drug
incrementally increase dose
Induction of drug tolerance should almost never be performed if reaction history consistent with a severe non-IgE-mediated reaction
Desensitization
only temporary
will become sensitive again
Only in patients
with severe IgE-mediated reaction and/or skin test positive
when there are no alternatives
(e.g., syphilis in pregnancy)
Protocols for oral and injectable desensitization available
Oral safer and recommended
Once desensitization complete must start penicillin immediately
Effectiveness usually lost within 2 days after cessation of penicillin therapy, therefore must be redone if future course of penicillin needed
Desensitization must be done in a safe environment allowing for resuscitation
see chart on slide 49
PCN negatuve
oral dose of amox 250mg
can be relabelled
Mrs. R is a 55 year old ♀ who presents to your
pharmacy with a prescription for cefuroxime. On
her file, you notice that it states that she has a
penicillin allergy, with no further information. She
confirms that she has had a reaction to a
penicillin in the past
penicillin, hives, 12 years ago, not hospitalized, no rechallenged, using for pneumonia outpatient
not at high risk of cefuroxime
dissimilar side chain
long time ago, lost a lot of antibodies
not severe non-IGE rxn
