Module 3 (of 3): Allergy Review *
Allergy to β-lactam Antibiotics
By Keith Teelucksingh, PharmD
Infectious Disease Pharmacist, Kaiser Permanente Vallejo
With contributions from Linh Van, PharmD
Infectious Disease Pharmacist, Kaiser Permanente Oakland
 See Notes
Goal

The goal of this presentation is to provide
pharmacists with up-to-date information regarding
penicillin allergy and the cross reactivity with related
antibiotics.
Objectives
After completing this module, the participant will be
able to:
1.
Describe the different types of allergy (per Gell
Coombs classification) as they relate to penicillin
and the β-lactam-related antibiotics.
2.
Be able to identify clinical situations where it is safe
or unsafe to use β-lactam-related antibiotics given a
patient’s allergy history.
Allergy to the β-lactam antibiotics

There are several classification schemes.
They can be applied to other drug classes but
are best characterized for the β-lactam
antibiotics:


Gell and Coombs
 Based on immunopathologic reactions (all of
which have been seen w/β-lactam antibiotics).
Levine
 Reactions specific to penicillin (PCN) according
to time of onset.
Gell Coombs Classification




Type
Type
Type
Type
I: IgE mediation
II: Antibody mediation
III: Immune complex mediation
IV: Delayed hypersensitivity reaction
Type I: IgE mediation

Serious and life threatening


Can include erythema, pruritis, urticaria (hives),
angioedema, bronchospasm, hypotension,
arrhythmias.
Mechanism

Interaction of β-lactam antigens with preformed
β-lactam specific IgE bound to mast cells 
causes release of histamine, proteases,
prostaglandins, leukotrienes.
Type I

Time course


(cont’d)
Usually starts <15 min after drug administration,
can also occur >1 hour after but less common.
Pearl:


If patient has type I hypersensitivity to PCN,
unless patient has tolerated before, probably
judicious to avoid cephalosporins. If unable to get
specific history as to what type of rash occurred
and in what timeframe, err on the side of caution.
If PCN use is absolutely indicated, consult allergy
for skin testing (e.g., PCN for neurosyphilis).
Type II: Antibody Mediation

Reactions


Hemolysis, thrombocytopenia, neutropenia,
interstitial nephritis
Mechanism

Result when β-lactam specific cytotoxic antibodies
(usually IgG or IgM) become attached to circulating
blood cells or renal interstitial cells that have βlactam antigens bound to their cell surface. The
antibody-antigen complex can activate complement
system (resulting in cell lysis), neutrophil or
macrophage attachment (leading to cell injury).
Type II

Time course


(cont’d)
Usually longer term, > 7 days
Pearl

Long term, high-dose β-lactam treatment
predisposes to this reaction (nafcillin for
endocarditis, high-dose Zosyn® for Pseudomonal
infection).
Type III: Immune Complex Mediation


Serum-sickness like reaction
Mechanism

β-lactam specific IgG or IgM antibodies may form
circulating complexes with β-lactam antigens.
These complexes can fix complement and lodge in
tissue sites, possibly causing serum sickness/drug
fever.
Type III


(cont’d)
Time course: 6–21 days after exposure
Pearl

Best example is classic serum-sickness like
reaction seen with cefaclor.
 Signs/symptoms: fever, arthralgia,
lymphadenopathy, skin eruption
Type IV: Delayed Hypersensitivity

Delayed hypersensitivity reaction


Contact dermatitis, delayed non-urticarial rashes.
Mechanism

T-cell mediated release of cytokines causing tissue
inflammation and injury.
Type IV


(cont’d)
Time course: not well defined
Pearl/example

Penicillin was available topically in the past, but
high rate of dermatitis led to its discontinuation as
a marketed product.
Idiopathic Reactions


Not included in Gell Coombs classification since
pathogenesis is not well defined.
Examples




Maculopapular reactions (rash, etc.)
 Occurs in 2 percent to 3 percent of penicillin
courses, usually late in treatment.
Eosinophilia
Stevens-Johnson syndrome
Exfoliative dermatitis
Choosing an Antibiotic



Always note the REACTION to a given drug
Nausea, vomiting, GI upset are NOT allergic
reactions.
Rash reactions:

Need to either clarify type of rash and onset or err
on side of caution and use alternative agents with
low chance of cross reactivity.
Cross-Reactivity
If patient is allergic to:
1.
Penicillin
Can this be used?
Penicillin-class drug
(amoxicillin, ampicillin, etc.)
2.
Penicillin
Cephalosporin
3.
Cephalosporin
Penicillin
4.
Penicillin
Carbapenem
Penicillin – Penicillin Class



If patient has IgE mediated reaction to penicillin,
likely to have similar reaction to ampicillin,
amoxicillin, dicloxacillin and piperacillin.
Patients with allergy to penicillin may be prone to
allergic reactions to drugs in general.
Aztreonam seems to be safe to use even in patients
with Type I reactions. Use caution in patients with
ceftazidime allergy, since these drugs have the
same side chain. Reactions still can occur but tend
to be very rare.
Penicillin – Cephalosporin



Incidence may have been higher with earlier
preparations of cephalosporins .
In general, patients with documented Type I
reactions to penicillin should not be challenged
with a cephalosporin unless there is
documentation that patient has tolerated
cephalosporins in the past.
No good answer at this time.
Cephalosporin - Penicillin
Allergic reactions to cephalosporins in the general
population tend to be rare.
 Chance of cross-reactivity between patients with
cephalosporin allergy being exposed to penicillin may
be higher (50 percent) with first-generation
cephalosporins than that with second or third
generation (~10 percent).
For example, if a patient is allergic to cefazolin and
exposed to a penicillin-class drug, s/he may be more
likely to have an allergic reaction. If the patient is
allergic to either cefuroxime or ceftriaxone, s/he may be
less likely to have an allergic reaction to a penicillinclass drug.


Penicillin – Carbapenem



Incidence was thought to be close to 50 percent.
Emerging data suggests that carbapenems may
be safe to use in patients with Type I penicillin
allergy.
Some data to suggest that patients with type IV
reactions to penicillins will have a ~5 percent
chance of cross-reaction with carbapenems
(imipenem).
References
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Chen, S. Serum sickness. http://emedicine.com
Weiss, M., Adkinson, N. Chapter 24: β-lactam Allergy. Mandell, Bennett & Dolin.
Principles and Practice of Infectious Disease. 7th ed. 2009.
Robinson, et al. Practical aspects of choosing an antibiotic for patients with a reported
allergy to an antibiotic. Clin Infect Dis. 2002 Jul 1;35(1):26-31.
Patriarca, et al. Tolerability of aztreonam in patients with IgE-mediated hypersensitivity
to beta-lactams. Int J Immunopathol Pharmacol. 2008 Apr-Jun;21(2):375-9.
Schiavino, et al.Cross-reactivity and tolerability of imipenem in patients with delayedtype, cell-mediated hypersensitivity to beta-lactams. Allergy 2009 Apr 14.
Romano, et al. Brief communication: tolerability of meropenem in patients with IgEmediated hypersensitivity to penicillin. Ann Intern Med. 2007 Feb 20;146(4):266-9
Prescott, et al. Incidence of carbapenem-associated allergic-type reactions among
patients with versus patients without a reported penicillin allergy. Clin Infect Dis. 2004
Apr 15;38(8):1102-7
Acknowledgments
Thank you to the following individuals for their support
of and/or assistance with this program:




Dan Dong, Pharm D, Area Pharmacy Director
Kaiser Permanente East Bay Service Area
Kathleen Hiroshima, Pharm D, Drug Information Services
Kaiser Permanente California Regions
Matangi Venkateswaran, Pharm D, Inpatient Quality-Clinical
Supervisor, Kaiser Permanente Central Valley Service Area
Sam S Lee, Pharm D, Inpatient Pharmacy Supervisor
Kaiser Permanente Santa Rosa
Conclusion *
This concludes Module 3 of the Review of
Basic Principles and Selected Antimicrobials.
Upon completion of Modules 1, 2 and 3, you
may proceed to the post-test and evaluation.
Thank you for participating in this continuing
education program.
 See Notes