Between Penicillins and Cephalosporins
to the potential for cross-sensitivity reactions, patients
allergic to penicillin are generally not administered cephalosporins.
This issue is complex because it has been difficult to quantify
the amount of cross-sensitivity reactions that occur between
penicillins and cephalosporins. Evaluating the allergenicity
of each class individually and assessing how these compounds
relate to one another may contribute to a better understanding
of this cross-sensitivity.
The frequency of adverse reactions
to penicillin in the general population ranges from 0.7% to
10%, with anaphylactic reactions occurring in about 0.004%
to 0.015% of patients. Comparatively, the overall incidence
of adverse reactions to cephalosporins ranges from 1% to 10%,
with anaphylactic reactions occurring in less than 0.02% of
patients. Common adverse reactions in both classes include
maculopapular or morbilliform skin rash, eosinophilia, drug
fever, and gastrointestinal symptoms. The less common anaphylactic
reactions manifest as severe urticaria, laryngeal edema, angioedema,
wheezing, or hypotension. These anaphylactic reactions are
immune mediated. Specific IgE antibodies recognize and bind
to various constituents of the penicillin or cephalosporin
moiety and initiate the activation of mast cells resulting
in release of its mediators. Skin testing for IgE mediated
reactions can be useful to determine if a patient has a true
allergy. Although recommended, the main drawbacks to skin
testing are the limited availability and additional costs
associated with these diagnostic tools.
The incidence of cross sensitivity
between penicillins and cephalosporins has been reported to
be as high as 10%. Manufacturers of all cephalosporins explicitly
state in their product labeling that patients with previous
hypersensitivity reactions to penicillins should be given
cephalosporins cautiously as serious acute allergic reactions
may occur. This concept of increased probability of cross
sensitivity between penicillins and cephalosporins arose from
the fact that both classes share a common beta-lactam ring
and have a similar spectrum of allergic reactions. To date,
numerous clinical studies have tried to quantify the actual
rate of cross sensitivity with mixed results.
Initial studies reported extremely
high rates of cross sensitivity between penicillins and first
generation cephalosporins. In 1966, Thoburn et al reported
a cross sensitivity rate of 18.2% in patients with a history
of penicillin allergy who were subsequently challenged with
cephalothin, a first-generation cephalosporin. The elevated
rates of cross sensitivity seen in early trials may have been
due to contamination with penicillin during the manufacturing
process of cephalosporins. Early first generation cephalosporins,
such as cephalothin, contained trace amounts of penicillin
(0.05 units/gram of cephalothin). This small amount of penicillin
may have contributed to an elevated cross sensitivity rate.
In 1978, Petz performed an
extensive review of cephalosporin clinical trial data involving
15,708 study subjects. Petz recorded the number of allergic
reactions to cephalosporins in penicillin allergic and non-allergic
subjects. Subjects were treated with any one of the following
agents: cephaloridine, cephalothin, cephalexin, cefazolin,
or cefamandole. Overall, 701 patients were allergic to penicillin,
and of these 57 (8.1%) had an allergic reaction to a cephalosporin.
In the remaining 15,007 non-allergic patients, 285 (1.9%)
patients had an allergic reaction to one of the cephalosporins.
Thus, the author concluded that there is a four-fold increase
in the risk of developing an allergic reaction to cephalosporins
when given to patients with a history of penicillin allergy.
A recent review article by
Kelkar et al in the September 2001 New England Journal
of Medicine summarized several studies on the cross sensitivity
between penicillins and cephalosporins. The authors concluded
that the risk of an allergic reaction to a cephalosporin was
up to eight times higher in patients with a history of penicillin
allergy versus non-allergic patients. The authors also stated
that patients with a history of anaphylactic reactions secondary
to penicillin had a significantly higher rate of positive
skin tests for penicillin allergy.
Currently, studies on the
cross sensitivity between penicillins and cephalosporins have
shifted from retrospective reviews of clinical data to performing
prospective studies. For many years, the beta-lactam ring
has been considered the main antigenic determinant of IgE
mediated allergic reactions. However, recent focus has been
on the side-chain moieties attached to the ring structure.
Some cephalosporins share an identical side-chain with certain
penicillin formulations. For example, cephalexin and ampicillin
have identical side-chain structures, and amoxicillin and
cephadroxil also have identical side-chain structures. These
side-chain moieties appear to play a role in eliciting an
antigenic IgE mediated allergic reaction. Multiple studies
have tested the theory by challenging penicillin allergic
patients with cephalosporin agents with the identical side-chains
versus cephalosporins that have differing side-chains.
Miranda et al studied 21 patients
with a history of amoxicillin allergy. The authors challenged
these patients with cefadroxil, a cephalosporin with an identical
side-chain, and cefamandole, a cephalosporin with a different
side-chain. Eight patients (38%) had a positive response to
cefadroxil manifesting as pruritus, erythema, or maculopapules.
None of the patients reacted to cefamandole. In addition,
Novalbos et al studied 41 patients with a history of penicillin
allergy. The authors challenged these patients with 3 cephalosporins
that did not share the same side-chain as penicillin. All
patients tolerated the 3 cephalosporins when administered
via the intramuscular route. Both studies found that patients
with a history of penicillin allergy tolerated cephalosporins
with a different side-chain.
A clear rate of cross sensitivity
exists between the penicillins and cephalosporins. Patients
with a penicillin allergy are at an increased risk of developing
an adverse reaction to a cephalosporin. When determining if
treatment with a cephalosporin is appropriate in a penicillin
allergic patient, the following factors should be considered:
- Obtain a detailed history
from the patient on the type of reaction
- Classify the reaction
as non-life threatening versus anaphylactic
- Skin test patients to
assess true allergy
- Choose a cephalosporin
with different side chain moieties from the original offending
These factors may aid in directing
therapy towards an appropriate beta-lactam antibiotic.
1. Salkind AR, Cuddy PG, Foxworth
JW. Is the patient allergic to penicillin? JAMA 2001;285(19):2498-505.
2. Anne S, Reisman RE. Risk
of administering cephalosporin antibiotics to patients with histories of penicillin allergy. Ann Allergy Asthma Immunol
3. Kelkar PS, Li JT. Cephalosporin
allergy. New Engl J Med 2001;345(11):804-9.
4. Thoburn R, Johnson JE III,
Cluff LE. Studies on the epidemiology of adverse
reactions IV: the relationship of cephalothin and penicillin
allergy. JAMA 1966;194:345-8.
5. Petz LD. Immunologic cross-reactivity
between penicillins and cephalosporins: a review. J Infec Dis 1978;137:S74-9.
6. Miranda A, Blanca M etal.
Cross-reactivity between a penicillin and a cephalosporin with the same side chain. J Allergy Clin Immunol 1996;98(3):671-677.
7. Novalbos A, Sastre J et
al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to pencillins. Clin Exp Allergy 2001;31:438-43.