Allergy Evaluation For Immediate Penicillin Allergy: Skin Test-Based Diagnostic Strategies and Cross-Reactivity With Other Beta-Lactam Antibiotics

9/6/21, 11:51 AM Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with
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Allergy evaluation for immediate penicillin allergy: Skin

test-based diagnostic strategies and cross-reactivity with
other beta-lactam antibiotics
Authors: Kimberly G Blumenthal, MD, MSc, Roland Solensky, MD
Section Editor: N Franklin Adkinson, Jr, MD
Deputy Editor: Anna M Feldweg, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2021. | This topic last updated: Sep 26, 2017.
INTRODUCTION
Penicillin allergy is the most common drug allergy reported by patients. Penicillins are one
group within the family of beta-lactam antibiotics, which also includes cephalosporins,
carbapenems, and monobactams. This topic will present diagnostic strategies used by allergy
specialists for evaluating a patient with suspected or confirmed immediate (ie, immunoglobulin
[Ig]E-mediated) allergy to penicillins. Studies of cross-reactivity between penicillins and other
beta-lactam antibiotics are also reviewed.
● An algorithmic approach to the use of related antibiotics, with or without access to allergy
consultation and penicillin skin testing, is discussed in detail separately ( algorithm 1).
(See "Choice of antibiotics in penicillin-allergic hospitalized patients".)
● Detailed discussions of immediate penicillin allergy and penicillin skin testing are found
elsewhere. (See "Penicillin allergy: Immediate reactions" and "Penicillin skin testing".)
● Delayed reactions to penicillins, ranging from maculopapular drug eruptions to severe

systemic reactions, are reviewed elsewhere. (See "Penicillin allergy: Delayed hypersensitivity
reactions".)
OVERVIEW
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9/6/21, 11:51 AM Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam…
Penicillin allergy is reported by up to 10 percent of patients. However, more than 90 percent of

patients with a reported penicillin allergy do not have IgE-mediated sensitivity when skin
testing is performed, either because they were inappropriately labeled as allergic or because
they had an earlier allergy that resolved with time [1-5]. Among patients with an IgE-mediated
penicillin allergy that has been confirmed with skin testing, available studies suggest that 97
percent will tolerate cephalosporins and 99 percent will tolerate carbapenems, as reviewed in
detail in this topic. However, despite these reassuring figures, beta-lactam drugs are among the
leading causes of drug-induced anaphylaxis, and there are methodologic issues with the data
that should be appreciated to understand the limitations of the literature.
GENERAL CONCEPTS
Features of immediate reactions — Immediate reactions to drugs typically involve flushing,

pruritus, urticaria, angioedema, bronchospasm, laryngeal edema, and/or hypotension,
although an array of other symptoms may be seen ( table 1). Signs and symptoms usually
begin within minutes to one hour or two of administration, beginning somewhat later for oral
compared with intravenous medications. The clinical manifestations of these reactions are
reviewed in more detail separately. (See "Penicillin allergy: Immediate reactions".)
Antigenic components of penicillins — There are multiple potentially antigenic epitopes in

penicillins. Patients with IgE-mediated allergy to penicillins may be reactive to:
● Allergenic epitopes arising from the core beta-lactam and adjacent ring structures, which
are found in penicillins, cephalosporins, carbapenems, and monobactams ( figure 1).
● Allergenic epitopes arising from the R-group side chains on the aminopenicillins (ie,
amoxicillin and ampicillin), which are not found in penicillin G or V or in the penicillin skin
testing reagents (derived from benzylpenicillin). Patients have been described who have
positive skin tests to the aminopenicillins but have negative skin testing to the penicillin G
skin testing reagents, presumably (although not proven) attributable to sensitization to the
R-group side chains in the aminopenicillins. These R groups are shared by certain
cephalosporins ( table 2). For example, amoxicillin has an R group that is identical to that
in cefadroxil, cefprozil, and cefatrizine. However, selective allergy to the aminopenicillins is
believed to be uncommon in most populations. (See 'Population differences' below.)
Multiple antibiotic allergy syndrome — "Multiple antibiotic allergy syndrome" is a term used

to describe individuals who develop allergic reactions (either IgE- or non-IgE-mediated) to two
or more non-cross-reacting antibiotics. Individuals with this syndrome have an increased

propensity to react to medications in general, for reasons that are not fully understood.
In studies of patients with allergies to structurally-related antibiotics, the concept of multiple

antibiotic allergy syndrome should be considered as a possible confounding factor that could
overestimate cross-reactivity [6]. This was illustrated in several large studies, which yielded
unexpected results attributable to multiple antibiotic allergy syndrome:
● In patients with a previously documented penicillin allergic-like event, the risk ratio for an
allergic-like event was higher not only for cephalosporins (10.1, CI 7.4-13.8) but also for the
structurally-unrelated sulfonamides (7.2, CI 3.8-13.5) [7].
● Another study evaluated the incidence of allergic reactions to antibiotics in patients who
had previously undergone penicillin skin testing [1]. Among these penicillin skin test-
positive patients, allergic reactions during the first post-testing antibiotic treatment
occurred more frequently with non-beta-lactam antibiotics (10.8 percent) than with
cephalosporins (2.4 percent) [1].
Thus, multiple antibiotic allergy syndrome may confound studies of potential cross-reactivity
unless appropriate controls are included. Specifically, patients who are allergic to one drug and
are challenged with a potentially related drug should theoretically also be challenged with an
unrelated antibiotic. However, this is rarely done for practical reasons.
Population differences — There may be variations in patterns of sensitization in different

populations, although this observation is based on very limited data. In the United States, most
patients with IgE-mediated penicillin allergy are sensitive to the beta-lactam core shared by all
beta-lactam drugs, and <0.5 percent are selectively allergic to aminopenicillins (ie, ampicillin
and amoxicillin) [8]. In contrast, in southern Europe (eg, Spain) where amoxicillin is widely
available without a prescription, up to one-third of patients are reported to be selectively
allergic to the aminopenicillins [9,10]. (See 'Patients reporting a past reaction to amoxicillin or
ampicillin' below.)
Side chain-specific sensitization to antipseudomonal penicillins (ie, ticarcillin and piperacillin)

has been observed among patients with cystic fibrosis, who often receive frequent high-dose
parenteral courses of semisynthetic penicillins [11].
Selective allergy to the aminopenicillins is presumed to be attributable to the R-group side

chains, although this has not been proven conclusively. R-group side chains are implicated
based on a small number of reports from investigators in Spain, in which patients with past
reactions to amoxicillin or ampicillin who were tolerant to penicillin G (via skin testing, in vitro
testing, or oral challenge) were challenged to cefadroxil or cephalexin, respectively ( table 3).
Overall, 11 of 45 (24 percent) reacted to a cephalosporin with identical R-group side chains,
indicating significant cross-sensitivity between agents with identical side chains [12-14].
Patients were not challenged to cephalosporins with dissimilar side chains for comparison.
These findings may not apply to countries in which amoxicillin is only available by prescription,
such as the United States, although the recommended approach is still to avoid cephalosporins
with identical R-group side chains in patients sensitized to aminopenicillins.
CEPHALOSPORINS
To determine if a patient with a reported immediate reaction to a penicillin can safely receive a
cephalosporin, the performance of penicillin skin testing is encouraged. Because most patients
have negative results, skin testing greatly simplifies future use of both penicillins and other
beta-lactam drugs.
Studies evaluating cross-reactivity between penicillins and cephalosporins in various groups of

patients are reviewed in this section. An algorithmic approach to the use of cephalosporins in
penicillin-allergic patients is provided elsewhere. (See "Choice of antibiotics in penicillin-allergic
hospitalized patients".)
Studies estimating the risk of cross-reactivity — Among patients who report penicillin

reactions (but have not undergone confirmatory testing), between 0 and 8.1 percent will react if
given a cephalosporin ( table 4) [15-22]. The higher estimate is based upon retrospective
studies in which patients with a history of penicillin allergy were treated with cephalosporins
without preceding penicillin allergy testing (skin testing or in vitro testing). Such studies are the
source of warnings in the package inserts of cephalosporins, which state that the risk of cross-
sensitivity in penicillin-allergic patients may be as high as 10 percent. However, these studies
have several limitations that may lead to an overestimation of cross-reactivity.
● Among the five leading reports, two were from the 1970s, and cephalosporins produced
prior to 1980 are known to have been contaminated with trace amounts of penicillin [23].
● In vitro and skin testing studies with penicillin and cephalosporins showed a high degree of
immunologic cross-reactivity, although this does not consistently translate into clinical
cross-reactivity (ie, patients may have positive skin test results but not actually react to the
drug) [24-28].
● Most of these reports provided no information on the nature or severity of the

cephalosporin reactions. In the best designed studies, there were two reactions to
cephalosporins that were very questionable [15,16]. One of the reactions was an eczema
exacerbation after several days of cephalosporin treatment, and the other consisted only of
documentation in the anesthesia record of preoperative administration of hydrocortisone
and diphenhydramine in a patient on chronic glucocorticoid treatment.
● Most cephalosporin challenges in the available studies were carried out in open fashion,
rather than as single- or double-blinded challenges, so cross-reactivity may have been
overestimated.
In contrast, there are important factors to consider that could lead to an underestimation of
the cross-reactivity:
● There is a potentially strong selection bias in retrospective, real world studies, arising from
the fact that the clinicians would have used clinical judgement in choosing which patients
to treat with cephalosporins and which patients to treat with unrelated antibiotics.
Specifically, patients who reported a recent penicillin reaction that was convincing for
anaphylaxis were likely not selected to receive a cephalosporin. In the studies that provided
this information, clinicians chose to use cephalosporins in 25 percent [22], 57 percent [20],
and 85 percent [16] of the patients with prior penicillin allergy history, and this variability
could have influenced study results.
● A significant subset of the patients in these studies were likely not allergic to penicillin at
the time they were treated with cephalosporins, since large studies have shown >90
percent of all patients who report a penicillin reaction in the past have negative penicillin
skin test results [2,29-31]. (See "Penicillin allergy: Immediate reactions".)
Allergy evaluation and penicillin skin testing — To determine if a patient with a reported
immediate reaction to a penicillin can safely receive a cephalosporin, we perform penicillin skin
testing. Most patients will have negative results, which greatly simplifies future use of both
penicillins and other beta-lactam drugs.
Penicillin skin testing reagents are commercially available in many countries. Skin testing
should be performed by a clinician specifically trained in the technique (usually allergists).
Testing protocols are discussed in greater detail elsewhere. (See "Penicillin skin testing", section
on 'Procedure'.)
The results of penicillin skin testing can be used to guide management as follows:
Negative result — If penicillin skin testing is performed and is negative (no reaction), then
the patient is not at substantial risk of immediate allergy to penicillins. The absence of
immediate allergy should be confirmed by administering a single age-appropriate dose of the

penicillin to which the patient initially reacted, followed by one to two hours of observation to
ensure that an immediate reaction does not occur. This step is indicated because the negative
predictive value for penicillin skin testing with the combination of penicilloyl polylysine (PPL)
and penicillin G is high (about 98 percent), but not 100 percent. Also, confirming that the drug is
tolerated will maximize the confidence of the patient and other clinicians with using penicillins
in the future [32]. This is discussed in more detail elsewhere. (See "Penicillin skin testing",
section on 'Confirmatory challenge after negative skin testing'.)
Once immediate penicillin allergy has been excluded, patients may safely receive
cephalosporins as well, unless they have also reacted to a cephalosporin. If a patient has
reacted in the past to a specific cephalosporin, that cephalosporin and other cephalosporins
with similar R1-group side chains should be avoided, and other cephalosporins may warrant
skin test evaluation if the prior reaction was severe or recent.
Positive result — If penicillin skin testing is positive, then there is a high likelihood the
patient is allergic to penicillin, and 2 to 3 percent of these patients can be anticipated to react to
cephalosporins. This figure is based upon studies in which patients were tested with a full panel
of penicillin reagents (PPL, penicillin G, and/or the minor determinant mixture [MDM]), then
challenged with cephalosporins for an overall reaction rate of 3.4 percent ( table 5). If the
analysis is limited to studies published after 1980 (when cephalosporins were no longer
contaminated with penicillin), the reaction rate is reduced to 2 percent. Some investigators
additionally performed cephalosporin skin testing (on penicillin test-positive patients) prior to
cephalosporin administration and administered cephalosporins only if those tests were
negative (since ethical concerns prevented cephalosporin challenges in patients with positive
cephalosporin skin tests) [12,33-35].
Without precautions, some of these cephalosporin reactions could be severe or life-threatening.

Some experts advocate more caution with the first- and second-generation cephalosporins
compared with the later-generation agents, but the data are inconclusive. Therefore, options
for management are:
● Perform skin testing with the desired first- or second-generation cephalosporin and use the
results to guide therapy. (See "Cephalosporin hypersensitivity: Clinical manifestations and
diagnosis".)
● Administer a cephalosporin using a test dose procedure (or graded challenge). Test dosing
is usually only necessary the first time a cephalosporin is given after testing and evaluation.
If the test dose elicits no symptoms, the patient is proven not allergic to cephalosporins
and can receive them normally in the future. (See 'Test dosing (or graded challenge)'
below.)
● Administer a cephalosporin using an empiric desensitization (ie, empiric because the

patient's current sensitization status is unknown). This is the most cautious approach and
would usually be reserved for the patient whose past penicillin reaction was severe or who
had comorbidities or acute illness that would make him/her less likely to survive an
anaphylactic reaction. Desensitization techniques are reviewed separately. (See "Penicillin
allergy: Immediate reactions", section on 'Desensitization'.)
● If a more cautious approach is desired for a patient with positive penicillin skin testing, then
first- and second-generation cephalosporins would be given by empiric desensitization,
while later-generation agents could be given with a test dose procedure.
Penicillin skin testing is not available — If skin testing is not available, the clinician must
estimate the risk of a serious IgE-mediated reaction to a cephalosporin using the clinical history
and time elapsed since the penicillin reaction. Overall, between 90 and 99 percent of patients
who undergo penicillin skin testing have been shown to tolerate penicillin without an
immediate reaction and are therefore not at increased risk of immediate reactions to
cephalosporins either [1-5]. An algorithm that outlines treatment options based on risk
assessment is provided ( algorithm 1).
Patients reporting a past reaction to amoxicillin or ampicillin — If a patient reacted

specifically to amoxicillin or ampicillin (the aminopenicillins) in the past, there may be a higher
risk of reaction to cephalosporins with identical R1-group side chains ( table 3). For example,
if a patient had an immediate reaction to amoxicillin in the past, that patient may be sensitized
to the beta-lactam core in all penicillins or to amoxicillin only. Selective allergy to the
aminopenicillins is believed to be uncommon in most areas of the world. (See 'Population
differences' above.)
Selective allergy confirmed by skin testing — Selective allergy to amoxicillin or ampicillin

can only be determined with certainty with skin testing (ie, negative skin testing with PPL,
penicillin G, and penicilloate/penilloate, but positive to amoxicillin or ampicillin). Skin testing
protocols are discussed separately. If skin test solutions of amoxicillin or ampicillin are not
available, a selective allergy can also be diagnosed by challenging the patient with one of these
drugs after negative benzylpenicillin skin testing. (See "Penicillin skin testing", section on
'Aminopenicillins'.)
Patients confirmed to be selectively allergic to amoxicillin or ampicillin should avoid

cephalosporins with identical R-group side chains or receive them via a desensitization protocol
( table 2). Alternatively, needed cephalosporins may be evaluated by skin testing. Such
patients may receive cephalosporins with dissimilar side chains normally.
The data regarding clinical cross-reactivity among drugs with similar (but not identical) side
chains are even more limited. Some investigators have proposed that patients who have
reacted to a drug with a specific R group avoid all agents with similar (as opposed to identical) R
groups [36], although there are no clinical data upon which to base this recommendation.
CARBAPENEMS
Carbapenems (ie, imipenem, meropenem, doripenem, and ertapenem) share a common beta-
lactam ring with penicillins and hence the potential for allergic cross-reactivity ( figure 1).
However, accumulated data suggest that less than 1 percent of penicillin-allergic patients react
to carbapenems. Despite this, many drug information systems continue to list anaphylactic
reactions to beta-lactam antibiotics as a contraindication to the use of carbapenems.
The following studies support a low rate of clinical cross-reactivity between penicillin and
carbapenems:
● An early study of 40 patients found a relatively high rate of skin test cross-reactivity
between carbapenems and penicillins. However, patients were not challenged to confirm
allergy (ie, clinical cross-reactivity was not demonstrated), and the method of skin testing to
carbapenems used in this early paper has not been validated [37].
● A 2014 systematic review found that among 854 patients with past penicillin reactions
(including proven, suspected, or possibly IgE-mediated), 4.3 percent experienced any type
of hypersensitivity reaction to a carbapenem [38]. Of the 295 patients with positive skin
tests to penicillin, only 1 individual (0.3 percent) had a reaction that was possibly IgE-
mediated to a carbapenem.
● In several studies, collectively including more than 500 adults and children, penicillin
sensitization was confirmed with skin testing, and patients were then skin tested to
imipenem or meropenem. If skin testing to the carbapenem was negative, a challenge with
that carbapenem was performed [39-42]. Just one percent of the total group had positive
carbapenem skin tests and were not challenged. The remaining 99 percent had negative
carbapenem skin tests and tolerated the carbapenem.
● In a study of 212 patients, among whom there was a relatively high rate of anaphylaxis,
penicillin (or amoxicillin) allergy was confirmed by clinical history plus positive skin testing,
and all patients were then skin tested with imipenem (maximum intradermal concentration
0.5 mg/mL), meropenem (1 mg/mL), and ertapenem (1 mg/mL) [43]. None had positive skin
tests to the carbapenems. Of the 212 patients, 211 consented to graded challenges with
each carbapenem, and all patients tolerated all three drugs.
Recommended approach — Based on these data, we recommend an approach to patients

with a history of penicillin allergy who require treatment with carbapenems that is analogous to
that described above for cephalosporins:
● If penicillin skin testing is available and is negative, patients may safely receive
carbapenems.
● If penicillin skin testing is positive, the patient's chance of reacting to the carbapenem is <1
percent, and the carbapenem may be administered via a test dose procedure. One expert
prefers the approach of skin testing to penicillin as well as carbapenems, and if penicillin
testing is positive and carbapenem testing is negative, then the carbapenem of choice can
be given without a test dose [43].
● If penicillin skin testing is unavailable, then carbapenems can either be given normally if
the patient's reaction to penicillin was mild or remote or the carbapenem may also be
administered via graded challenge if the penicillin reaction was more severe.
MONOBACTAMS (AZTREONAM)
Aztreonam is the only clinically available monobactam, and it has a monocyclic beta-lactam
structure ( figure 1). In vitro studies and skin testing studies demonstrated no immunologic
cross-reactivity between penicillin and aztreonam [44,45]. Likewise, aztreonam challenges of
penicillin skin test-positive patients revealed no reactions [46-48]. Based on this evidence,
patients with a history of penicillin allergy may safely receive aztreonam [49].
Of note, cross-reactivity between aztreonam and the third-generation cephalosporin

ceftazidime has been reported, presumably related to their identical side chains. This is
discussed separately. (See "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin
testing, and cross-reactivity with other beta-lactam antibiotics", section on 'Carbapenems and
monobactams'.)
TEST DOSING (OR GRADED CHALLENGE)
Test doses (also called graded challenges) are indicated to exclude immediate allergic reactions.
The purpose of a test dose is to expose the patient to a small amount of drug, followed by a
period of close observation, in case there is a reaction.
Indications and precautions — Test dosing is appropriate only when immediate allergy to

the tested antibiotic is judged to be unlikely after careful consideration of the details of
the past reaction. Examples include the following:
● Patients who had a mild past reaction to penicillin that lacked features of an IgE-mediated
allergy ( table 1).
● Patients who had a mild past reaction to penicillin that occurred more than 10 years ago,
even if it involved hives or angioedema, since approximately 80 percent of patients with
IgE-mediated penicillin allergy have lost the sensitivity after 10 years. (See "Penicillin
allergy: Immediate reactions", section on 'Time elapsed since the reaction'.)
In contrast, if a patient's history is vague but some element of it suggests a serious IgE-
mediated reaction (eg, "My mother said that I could not breathe"), then the more cautious
approach of performing a rapid empiric drug desensitization is warranted (assuming skin
testing is not available). (See "Penicillin allergy: Immediate reactions", section on
'Desensitization'.)
Most graded challenges can safely be carried out in an office without intravenous access. H1
antihistamines and epinephrine (intramuscular) should be readily available. Because graded
challenges will not prevent or circumvent an immediate allergic reaction, the clinician must be
prepared to recognize and treat such a reaction if one occurs. If an epinephrine autoinjector is
not available, the appropriate concentration and dose of intramuscular epinephrine for that
patient should be calculated in advance so that there are no delays or dosing errors if it is
needed. (See "Anaphylaxis: Emergency treatment", section on 'Epinephrine'.)
Treatment with beta-adrenergic blocking medications should be withheld for 24 hours before
challenge if feasible, as these medications can interfere with treatment of anaphylaxis should a
reaction occur. Patients with asthma, chronic obstructive lung disease, or other pulmonary
diseases should be optimally controlled prior to undergoing challenge.
Procedure — When graded challenges are performed to exclude immediate allergic reactions,

patients should not be pretreated with antihistamines or glucocorticoids because these agents
may mask early signs of an allergic reaction.
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Challenges to exclude immediate reactions can be performed in a variety of ways. The starting
dose is usually 1/4th or 1/10th of the full dose. The patient is observed for 30 to 60 minutes after
this initial dose, then if no symptoms develop, a full dose is given and the patient is observed
for another 30 to 60 minutes.
As an example, a test dose for oral cephalexin could be performed as follows, using a standard
oral suspension (250 mg/5 mL): Give 1/10th of a dose (25 mg or 0.5 mL of the full strength
suspension, given with a glass of water), followed by 60 minutes of observation. If no
symptoms, give 250 mg, followed by 60 minutes of observation.
Interpretation — Although simple in theory, graded challenges can require experience to

interpret. A minority of patients develop nonspecific symptoms during the procedure, which
can mimic symptoms of true allergy [50]. Most commonly, these include perioral tingling,
pruritus without urticaria, throat and lip discomfort, headache, tachycardia, and nausea. These
may be anxiety-related, and spending time with the patient explaining the safety of challenge
procedures in advance may help to reduce the incidence of these nonspecific reactions.
● If the patient develops convincing signs and symptoms consistent with an immediate
reaction during or shortly after the graded challenge (within a few hours of receiving the
full dose), no further drug should be given, and symptoms should be treated appropriately.
These patients should be diagnosed with IgE-mediated allergy. If they require the drug in
question in the future, it should be administered via a formal desensitization protocol. (See
"Penicillin allergy: Immediate reactions", section on 'Desensitization'.)
● If only subjective symptoms are reported, repeat challenge including placebo controls and
masked observations may occasionally be warranted.
● Patients with a negative challenge may still develop delayed reactions to the drug in
question, but these should not be serious. This was illustrated in a multicenter study of 118
history-positive patients who had both negative skin tests and negative challenges to beta-
lactams and were subsequently treated with a beta-lactam [51]. The negative predictive
value of the evaluation was 94 percent for any type of reaction. Nine patients experienced
symptoms with re-exposure, all of which were mild and delayed (beginning >1 hour after
administration). Symptoms consisted of urticaria in five patients, exanthema in three, and
one undefined cutaneous reaction.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Drug allergy and
hypersensitivity".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Beyond the Basics topic (see "Patient education: Allergy to penicillin and related antibiotics
(Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● Penicillin-allergic patients can often be treated with cephalosporins and carbapenems,

although safe administration requires an understanding of what is known about cross-
reactivity patterns among different beta-lactams. More than 90 percent of patients with a
reported penicillin allergy do not have immunoglobulin (Ig)E-mediated sensitivity when skin
testing is performed, either because they were inappropriately labeled as allergic or
because they had an earlier allergy that resolved with time. Even among patients with an
IgE-mediated penicillin allergy that has been confirmed with skin testing, available studies
suggest that 97 percent will tolerate cephalosporins and 99 percent will tolerate
carbapenems. Still, beta-lactam reactions can be severe, and the goal of an allergy
evaluation is to clarify that individual's specific risk, based upon available data and the
details of the patient's past reaction(s). (See 'Overview' above.)
● Immediate reactions to drugs typically involve flushing, pruritus, urticaria, angioedema,

bronchospasm, laryngeal edema, and/or hypotension, although an array of other
symptoms may be seen ( table 1). Signs and symptoms usually begin within minutes to
one hour or two of administration. The allergens that are believed important for these
reactions arise from the core beta-lactam ring structure, which is common to penicillins,
cephalosporins, carbapenems, and monobactams ( figure 1). However, patients may also
react selectively to the aminopenicillins (amoxicillin and ampicillin), although this has
largely been described in Spain and may not be a widespread phenomenon. (See 'General
concepts' above.)
● To determine if a patient with a reported immediate reaction to a penicillin can safely

receive a cephalosporin, the performance of penicillin skin testing is encouraged. (See
'Cephalosporins' above.)
• If penicillin skin testing is negative (no reaction), then the patient is not at substantial
risk of immediate allergy to penicillins or cephalosporins, unless he/she has also
reacted to a cephalosporin, in which case that cephalosporin and others with identical
side chains should be avoided. Demonstrating that the patient has a negative skin test
to the desired cephalosporins further increases safety. (See 'Negative result' above.)
• If penicillin skin testing is positive, then there is a high likelihood that the patient is
allergic to penicillin, and 2 to 3 percent of these patients can be anticipated to react to
cephalosporins. Without precautions, some of these reactions could be severe or life-
threatening. The patient should either be treated with an unrelated antibiotic or if a
cephalosporin is strongly indicated, it should be given by a test dose procedure or by
empiric desensitization, depending upon the severity of the previous penicillin reaction
and other factors. Demonstrating that the patient has a negative skin test to the
desired cephalosporin further increases safety. (See 'Positive result' above.)
• If skin testing is not available, the clinician must estimate the risk of a serious IgE-
mediated reaction to a cephalosporin using the clinical history and time elapsed since
the penicillin reaction. The best designed studies suggest that 90 to 99 percent of all
patients reporting a penicillin allergy (who do not undergo skin test evaluation) will
tolerate a cephalosporin. An approach based on risk assessment is shown in the
algorithm ( algorithm 1).
● Patients who reacted initially to amoxicillin or ampicillin should undergo the same risk
assessment as penicillin-allergic patients. In addition, if the patient lives in an area of the
world (eg, southern Europe) in which selective allergy to amoxicillin or ampicillin is
relatively common, they should avoid cephalosporins with identical R-group side chains if
they have positive skin tests to aminopenicillins or receive these cephalosporins via graded
challenge or desensitization ( table 2). (See 'Patients reporting a past reaction to

amoxicillin or ampicillin' above.)
● To determine if a patient with a reported immediate reaction to a penicillin can safely

receive a carbapenem, the approach is similar to that for cephalosporins, although the rate
of cross-reactivity is lower, and there are no additional concerns related to side chains. (See
'Carbapenems' above.)
• If penicillin skin testing is available and is negative, patients may safely receive
carbapenems.
• If penicillin skin testing is positive or unavailable, the carbapenem may be

administered via a test dose procedure.
● Aztreonam is the only monobactam available for clinical use. There is no evidence of
immunologic cross-reactivity between penicillins and monobactams, and penicillin-allergic
patients may receive aztreonam normally. (See 'Monobactams (aztreonam)' above.)
● Test doses (also called graded challenges) are indicated to exclude immediate allergic
reactions when a reaction is believed to be unlikely and skin testing is not available or does
not fully answer the clinical question. The purpose of a test dose is to expose the patient to
a small amount of drug, followed by a period of close observation, in case there is a
reaction. (See 'Test dosing (or graded challenge)' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Macy E, Burchette RJ. Oral antibiotic adverse reactions after penicillin skin testing: multi-
year follow-up. Allergy 2002; 57:1151.
2. Park M, Markus P, Matesic D, Li JT. Safety and effectiveness of a preoperative allergy clinic in
decreasing vancomycin use in patients with a history of penicillin allergy. Ann Allergy
Asthma Immunol 2006; 97:681.
3. del Real GA, Rose ME, Ramirez-Atamoros MT, et al. Penicillin skin testing in patients with a
history of beta-lactam allergy. Ann Allergy Asthma Immunol 2007; 98:355.
4. Rimawi RH, Cook PP, Gooch M, et al. The impact of penicillin skin testing on clinical practice
and antimicrobial stewardship. J Hosp Med 2013; 8:341.
5. Raja AS, Lindsell CJ, Bernstein JA, et al. The use of penicillin skin testing to assess the
prevalence of penicillin allergy in an emergency department setting. Ann Emerg Med 2009;
54:72.
6. Asero R. Detection of patients with multiple drug allergy syndrome by elective tolerance
tests. Ann Allergy Asthma Immunol 1998; 80:185.
7. Apter AJ, Kinman JL, Bilker WB, et al. Is there cross-reactivity between penicillins and
cephalosporins? Am J Med 2006; 119:354.e11.
8. Mendelson L, personal communication.
9. Bousquet PJ, Co-Minh HB, Arnoux B, et al. Importance of mixture of minor determinants
and benzylpenicilloyl poly-L-lysine skin testing in the diagnosis of beta-lactam allergy. J
Allergy Clin Immunol 2005; 115:1314.
10. Romano A, Bousquet-Rouanet L, Viola M, et al. Benzylpenicillin skin testing is still important
in diagnosing immediate hypersensitivity reactions to penicillins. Allergy 2009; 64:249.
11. Moss RB, Babin S, Hsu YP, et al. Allergy to semisynthetic penicillins in cystic fibrosis. J
Pediatr 1984; 104:460.
12. Audicana M, Bernaola G, Urrutia I, et al. Allergic reactions to betalactams: studies in a

group of patients allergic to penicillin and evaluation of cross-reactivity with cephalosporin.
Allergy 1994; 49:108.
13. Miranda A, Blanca M, Vega JM, et al. Cross-reactivity between a penicillin and a
cephalosporin with the same side chain. J Allergy Clin Immunol 1996; 98:671.
14. Sastre J, Quijano LD, Novalbos A, et al. Clinical cross-reactivity between amoxicillin and
cephadroxil in patients allergic to amoxicillin and with good tolerance of penicillin. Allergy
1996; 51:383.
15. Daulat S, Solensky R, Earl HS, et al. Safety of cephalosporin administration to patients with
histories of penicillin allergy. J Allergy Clin Immunol 2004; 113:1220.
16. Goodman EJ, Morgan MJ, Johnson PA, et al. Cephalosporins can be given to penicillin-
allergic patients who do not exhibit an anaphylactic response. J Clin Anesth 2001; 13:561.
17. Petz LD. Immunologic cross-reactivity between penicillins and cephalosporins: a review. J
Infect Dis 1978; 137 Suppl:S74.
18. Dash CH. Penicillin allergy and the cephalosporins. J Antimicrob Chemother 1975; 1:107.
19. Fonacier L, Hirschberg R, Gerson S. Adverse drug reactions to a cephalosporins in
hospitalized patients with a history of penicillin allergy. Allergy Asthma Proc 2005; 26:135.
20. MacPherson RD, Willcox C, Chow C, Wang A. Anaesthetist's responses to patients' self-
reported drug allergies. Br J Anaesth 2006; 97:634.
21. Crotty DJ, Chen XJ, Scipione MR, et al. Allergic Reactions in Hospitalized Patients With a Self-
Reported Penicillin Allergy Who Receive a Cephalosporin or Meropenem. J Pharm Pract
2017; 30:42.
22. Beltran RJ, Kako H, Chovanec T, et al. Penicillin allergy and surgical prophylaxis:
Cephalosporin cross-reactivity risk in a pediatric tertiary care center. J Pediatr Surg 2015;
50:856.
23. Pederson-Bjergaard J. Cephalothin in the treatment of penicillin sensitive patients. Acta
Allergol 1967; 22:299.
24. Abraham GN, Petz LD, Fudenberg HH. Immunohaematological cross-allergenicity between
penicillin and cephalothin in humans. Clin Exp Immunol 1968; 3:343.
25. Assem ES, Vickers MR. Tests for penicillin allergy in man. II. The immunological cross-
reaction between penicillins and cephalosporins. Immunology 1974; 27:255.
26. Batchelor FR, Dewdney JM, Weston RD, Wheeler AW. The immunogenicity of cephalosporin
derivatives and their cross-reaction with penicillin. Immunology 1966; 10:21.
27. Levine BB. Antigenicity and cross-reactivity of penicillins and cephalosporins. J Infect Dis
1973; 128:Suppl:S364.
28. Girard JP. Common antigenic determinants of penicillin G, ampicillin and the
cephalosporins demonstrated in men. Int Arch Allergy Appl Immunol 1968; 33:428.
29. Mendelson LM, Ressler C, Rosen JP, Selcow JE. Routine elective penicillin allergy skin testing
in children and adolescents: study of sensitization. J Allergy Clin Immunol 1984; 73:76.
30. Sogn DD, Evans R 3rd, Shepherd GM, et al. Results of the National Institute of Allergy and
Infectious Diseases Collaborative Clinical Trial to test the predictive value of skin testing
with major and minor penicillin derivatives in hospitalized adults. Arch Intern Med 1992;
152:1025.
31. Gadde J, Spence M, Wheeler B, Adkinson NF Jr. Clinical experience with penicillin skin
testing in a large inner-city STD clinic. JAMA 1993; 270:2456.
32. Warrington RJ, Burton R, Tsai E. The value of routine penicillin allergy skin testing in an
outpatient population. Allergy Asthma Proc 2003; 24:199.
33. Romano A, Guéant-Rodriguez RM, Viola M, et al. Cross-reactivity and tolerability of
cephalosporins in patients with immediate hypersensitivity to penicillins. Ann Intern Med
2004; 141:16.
34. Novalbos A, Sastre J, Cuesta J, et al. Lack of allergic cross-reactivity to cephalosporins
among patients allergic to penicillins. Clin Exp Allergy 2001; 31:438.
35. Warrington RJ, Simons FE, Ho HW, Gorski BA. Diagnosis of penicillin allergy by skin testing:
the Manitoba experience. Can Med Assoc J 1978; 118:787.
36. Pichichero ME. A review of evidence supporting the American Academy of Pediatrics
recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients.
Pediatrics 2005; 115:1048.
37. Saxon A, Adelman DC, Patel A, et al. Imipenem cross-reactivity with penicillin in humans. J
38. Kula B, Djordjevic G, Robinson JL. A systematic review: can one prescribe carbapenems to
patients with IgE-mediated allergy to penicillins or cephalosporins? Clin Infect Dis 2014;
59:1113.
39. Atanasković-Marković M, Gaeta F, Medjo B, et al. Tolerability of meropenem in children with
IgE-mediated hypersensitivity to penicillins. Allergy 2008; 63:237.
40. Romano A, Viola M, Guéant-Rodriguez RM, et al. Brief communication: tolerability of
meropenem in patients with IgE-mediated hypersensitivity to penicillins. Ann Intern Med
2007; 146:266.
41. Romano A, Viola M, Guéant-Rodriguez RM, et al. Imipenem in patients with immediate
hypersensitivity to penicillins. N Engl J Med 2006; 354:2835.
42. Atanasković-Marković M, Gaeta F, Gavrović-Jankulović M, et al. Tolerability of imipenem in
children with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol 2009;
124:167.
43. Gaeta F, Valluzzi RL, Alonzi C, et al. Tolerability of aztreonam and carbapenems in patients
with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol 2015; 135:972.
44. Saxon A, Swabb EA, Adkinson NF Jr. Investigation into the immunologic cross-reactivity of
aztreonam with other beta-lactam antibiotics. Am J Med 1985; 78:19.
45. Adkinson NF Jr, Saxon A, Spence MR, Swabb EA. Cross-allergenicity and immunogenicity of
aztreonam. Rev Infect Dis 1985; 7 Suppl 4:S613.
46. Adkinson NF Jr. Immunogenicity and cross-allergenicity of aztreonam. Am J Med 1990;
88:12S.
47. Vega JM, Blanca M, García JJ, et al. Tolerance to aztreonam in patients allergic to beta-
lactam antibiotics. Allergy 1991; 46:196.
48. Patriarca G, Schiavino D, Lombardo C, et al. Tolerability of aztreonam in patients with IgE-
mediated hypersensitivity to beta-lactams. Int J Immunopathol Pharmacol 2008; 21:375.
49. Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and
Immunology, American College of Allergy, Asthma and Immunology, Joint Council of
Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann
Allergy Asthma Immunol 2010; 105:259.
50. Liccardi G, Senna G, Russo M, et al. Evaluation of the nocebo effect during oral challenge in
patients with adverse drug reactions. J Investig Allergol Clin Immunol 2004; 14:104.
51. Demoly P, Romano A, Botelho C, et al. Determining the negative predictive value of
provocation tests with beta-lactams. Allergy 2010; 65:327.
Topic 2087 Version 22.0
GRAPHICS
Approach to the patient with a past penicillin reaction who requires antibiotics
This algorithm is intended for use in conjunction with the UpToDate content on choice of antibiotics in penicillin-allergic hospitalize
procedures can be performed in an appropriately monitored setting with the staff and equipment needed to manage allergic react
IgE: immunoglobulin E.
* Ask the following:

1. What exactly were the symptoms?
Raised, red, itchy spots with each lesion lasting less than 24 hours (hives/urticaria)?
Swelling of the mouth, eyes, lips, or tongue (angioedema)?
Blisters or ulcers involving the lips, mouth, eyes, urethra, vagina, or peeling skin (seen in SJS, TEN, other severe type IV reaction
Respiratory or hemodynamic changes (anaphylaxis)?
Joint pains (seen in serum sickness)?
Did the reaction involve organs like the kidneys, lungs, or liver (seen in DRESS, other severe type IV reactions)?
2. What was the timing of the reaction after taking penicillin: Minutes, hours, or days later? Was it after the first dose or after multiple d
3. How long ago did the reaction happen? (After 10 years of avoidance, only 20% of patients with IgE-mediated penicillin allergy will sti
4. How was the reaction treated? Was there a need for urgent care or was adrenaline/epinephrine administered?
5. Has the patient tolerated similar medications, such as ampicillin, amoxicillin, or cephalexin since the penicillin reaction?
¶ Isolated mild hives, without other symptoms of an IgE-mediated reaction, can often occur in the setting of an infection. Patients with this h
for a recurrent serious reaction.
Δ This algorithm is intended for use in conjunction with additional UpToDate content. For a description of how to safely perform a TEST DOS
◊ Consult allergist to perform skin testing. If skin testing is not possible, patient may still be able to receive penicillins or first- or second-gene
UpToDate topic on rapid drug desensitization for immediate hypersensitivity reactions.
Original figure modified for this publication. Blumenthal KG, Shenoy ES, Varughese CA, et al. Impact of a clinical guideline for prescribing antibiotics
used with the permission of Elsevier Inc. All rights reserved.
Graphic 112936 Version 5.0
Immediate allergic reactions to drugs (IgE-mediated or non-IgE-mediated): Possible signs and

symptoms
Skin
Itching*
Urticaria*
Angioedema*
Warmth
Flushing
Other exanthema
Eyes, ears, nose
Periorbital edema*
Rhinorrhea*
Nasal itching*
Nasal congestion*
Ocular itching
Tearing
Conjunctival injection and/or edema
Sneezing
Mouth
Itching or tingling of lips, tongue, oral mucosa*

Angioedema of lips, tongue, or uvula*
Metallic taste
Throat
Itching*
Sense of constriction or swelling in throat*
Change in voice quality*
Difficulty swallowing*
Stridor*
Hoarseness
Drooling
Lungs
Shortness of breath*
Chest tightness*
Repetitive cough*
Wheezing*
Drop in oxygen saturation, cyanosis
Cardiovascular
Lightheadedness/faintness/dizziness*
Tachycardia or occasionally, bradycardia*
Hypotension*
Syncope/loss of consciousness
Palpitations
Tunnel vision
Difficulty hearing
Urinary or fecal incontinence
Cardiac arrest
Gastrointestinal
Nausea
Vomiting
Abdominal cramping or pain
Diarrhea
Gynecologic
Vaginal itching
Uterine cramping or bleeding
Neurologic
Anxiety
Sense of impending doom
Altered mental status/confusion
Seizures
Immediate reactions to drugs often present with combinations of the signs and symptoms listed in the table. Those bolded and
marked with an asterisk (*) are more consistent and representative than the others, and one or more of these should be
present to consider the reaction immediate.
IgE: immunoglobulin E.
Structure of penicillins and related beta-lactam drugs
Structure of the beta-lactam antibiotics. Arrows point to the beta-lactam rings.
R: side chain group.
Cephalosporins and penicillins with identical side chains
Amoxicillin:
Ampicillin:
Has side chains that are identical to: Has side chains that are identical to:
Cefadroxil Cefaclor
Cefprozil Cephalexin
Cefatrizine Cephradine
Cephaloglycin
Loracarbef (a carbacephem)
List of cephalosporins that share identical R1-group side chains with R-group side chain of amoxicillin and ampicillin. Note that
clinical cross-reactivity has only been reported among beta-lactams with identical side chains and not among those with similar
side chains.
Cross-reactivity between penicillins and cephalosporins with identical side chains
Cephalosporin with
Study Selective allergy to Reaction rate (%)
identical side chain
Audicana (1994) [1] Ampicillin Cephalexin 1 of 10 (10)
Sastre (1996) [2] Amoxicillin Cefadroxil 2 of 16 (12)
Miranda (1996) [3] Amoxicillin Cefadroxil 8 of 21 (38)
Total 11 of 47 (23)
Summary of patients proven to be selectively allergic to amoxicillin or ampicillin challenged with cephalosporins that contain
identical R1 side chains.
References:
1. Audicana M, Bernaola G, Urrutia I, et al. Allergic reactions to betalactams: studies in a group of patients allergic to penicillin and
evaluation of cross-reactivity with cephalosporin. Allergy 1994; 49:108.
2. Sastre J, Quijano LD, Novalbos A, et al. Clinical cross-reactivity between amoxicillin and cephadroxil in patients allergic to amoxicillin and
with good tolerance of penicillin. Allergy 1996; 51:383.
3. Miranda A, Blanca M, Vega JM, et al. Cross-reactivity between a penicillin and a cephalosporin with the same side chain. J Allergy Clin
Immunol 1996; 98:671.
Results of cephalosporin challenges in patients with histories of penicillin allergy
Cephalosporin reaction rate

Cephalosporins Type of reaction
Study History of penicillin No history of administered (causative drug)

allergy (%) penicillin allergy (%)
Dash (1975) [1] 25 of 324 (7.7%) 140 of 17,216 (0.8%) Cephalexin and No details given
cephaloridine
Petz (1978) [2] 57 of 701 (8.1%) 285 of 15,007 (1.9%) Cephalexin, No details given
cephaloridine,
cephalothin, cefazolin,
and cefamandole
Goodman (2001) [3] 1 of 300 (0.3%) 1 of 2431 (0.04%) Cefazolin (in all but one Reaction was
patient) questionable
Daulat (2004) [4] 1 of 606 (0.17%) 15 of 22,664 (0.07%) First generation (42%) Reaction was eczema
(cefazolin)
Second generation
(21%)
Third/fourth
generation (37%)
Fonacier (2005) [5] 7 of 83 (8.4%) Not applicable First generation (59%) Reactions were
convincing:
(Cephalexin-1)
Second generation (Cefaclor-2,

(8.4%) cefuroxime-2)
Third generation (25%) (Cefixime-1,

ceftriaxone-1)
Fourth generation (7%)
MacPherson (2006) [6] 0 of 84 (0) Not applicable Cefazolin, cefotetan,

ceftriaxone
Crotty (2015) [7] 7 of 186 (3.8%) Not applicable Cephalexin, cefoxitin, Six of seven reactions
ceftriaxone, and were due to cefepime;
cefepime three of seven
reactions were
immediate
Beltran (2015) [8] 1 of 153 (0.7%) Not applicable Cefazolin (84%) Reaction was urticarial
Cefoxitin (17%) (cefazolin)
Summary of studies of cephalosporin challenges in patients with a history of penicillin allergy without preceding penicillin
allergy testing.
References:
1. Dash CH. Penicillin allergy and the cephalosporins. J Antimicrob Chemother 1975; 1:107.
2. Petz LD. Immunologic cross-reactivity between penicillins and cephalosporins: a review. J Infect Dis 1978; 137 Suppl:S74.
3. Goodman EJ, Morgan MJ, Johnson PA, et al. Cephalosporins can be given to penicillin-allergic patients who do not exhibit an
anaphylactic response. J Clin Anesth 2001; 13:561.
4. Daulat S, Solensky R, Earl HS, et al. Safety of cephalosporin administration to patients with histories of penicillin allergy. J Allergy Clin
Immunol 2004; 113:1220.
5. Fonacier L, Hirschberg R, Gerson S. Adverse drug reactions to a cephalosporins in hospitalized patients with a history of penicillin allergy.
Allergy Asthma Proc 2005; 26:135.
6. MacPherson RD, Willcox C, Chow C, Wang A. Anaesthetist's responses to patients' self-reported drug allergies. Br J Anaesth 2006; 97:634.
7. Crotty DJ, Chen XJ, Scipione MR, et al. Allergic Reactions in Hospitalized Patients With a Self-Reported Penicillin Allergy Who Receive a
Cephalosporin or Meropenem. J Pharm Pract 2015.
8. Beltran RJ, Kako H, Chovanec T, et al. Penicillin allergy and surgical prophylaxis: Cephalosporin cross-reactivity risk in a pediatric tertiary
care center. J Pediatr Surg 2015; 50:856.
Use of cephalosporins in patients with positive skin tests to penicillin
Number of Number of Cephalosporin

Study Comment
patients reactions (%) skin testing
Girard (1968) [1] 23 2 (8.7) No Both reactions to

cephaloridine
Assem (1974) [2] 3 3 (100) No All reactions to

cephaloridine
Warrington (1978) [3] 3 0 Yes
Solley (1982) [4] 27 0 No
Saxon (1987) [5] 62 1 (1.6) No Cephalosporin not

noted
Blanca (1989) [6] 16 2 (12.5) No Both reactions to

cefamandole
Shepherd (1993) [7] 9 0 No
Audicana (1994) [8] 12 0 Yes
Pichichero (1998) [9] 39 2 (5.1) No Reaction to cefaclor

and ?
Novalbos (2001) [10] 23 0 Yes
Macy (2002) [11] 42 1 (2.4) No Reaction to cefixime
Romano (2004) [12] 75 0 Yes
Greenberger (2005) [13] 6 0 No
Park (2010) [14] 85 2 (2.4) No Reactions to cefazolin,

cephalexin
Ahmed (2012) [15] 21 0 No
Total 446 13 (2.9)
Summary of penicillin skin test-positive patients challenged with cephalosporins, excluding patients selectively allergic to
amoxicillin or ampicillin (skin test-positive to an aminopenicillin, but negative to penicillin G-derived major and minor
determinants).
References:
1. Girard JP. Common antigenic determinants of penicillin G, ampicillin and the cephalosporins demonstrated in men. Int Arch Allergy Appl
Immunol 1968; 33:428.
2. Assem ES, Vickers MR. Tests for penicillin allergy in man. II. The immunological cross-reaction between penicillins and cephalosporins.
Immunology 1974; 27:255.
3. Warrington RJ, Simons FE, Ho HW, Gorski BA. Diagnosis of penicillin allergy by skin testing: the Manitoba experience. Can Med Assoc J
1978; 118:787.
4. Solley, GO, Gleich GJ, Van Dellen RG. Penicillin allergy: Clinical experience with a battery of skin-test reagents. J Allergy Clin Immunol
1982; 69:238.
5. Saxon A, Beall GN, Rohr AS, Adelman DC. Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med 1987; 107:204.
6. Blanca M, Fernandez J, Miranda A, et al. Cross-reactivity between penicillins and cephalosporins: Clinical and immunologic studies. J
7. Shepherd GM, Burton DA. Administration of cephalosporin antibiotics to patients with a history of penicillin allergy. J Allergy Clin
Immunol 1993; 91:262
8. Audicana M, Bernaola G, Urrutia I, et al. Allergic reactions to betalactams: studies in a group of patients allergic to penicillin and
evaluation of cross-reactivity with cephalosporin. Allergy 1994; 49:108.
9. Pichichero ME, Pichichero DM. Diagnosis of penicillin, amoxicillin, and cephalosporin allergy: reliability of examination assessed by skin
testing and oral challenge. J Pediatr 1998; 132:137.
10. Novalbos A, Sastre J, Cuesta J, et al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins. Clin Exp
Allergy 2001; 31:438.
11. Macy E, Burchette RJ. Oral antibiotic adverse reactions after penicillin skin testing: multi-year follow-up. Allergy 2002; 57:1151.
12. Romano A, Guéant-Rodriguez RM, Viola M, et al. Cross-reactivity and tolerability of cephalosporins in patients with immediate
hypersensitivity to penicillins. Ann Intern Med 2004; 141:16.
13. Greenberger PA, Klemens JC. Utility of penicillin major and minor determinants for identification of allergic reactions to cephalosporins. J
Allergy Clin Immunol 2005; 115:S182
14. Park MA, Koch CA, Klemawesch P, et al. Increased adverse drug reactions to cephalosporins in penicillin allergy patients with positive
penicillin skin test. Int Arch Allergy Immunol 2010; 153:268.
15. Ahmed KA, Fox SJ, Frigas E, Park MA. Clinical outcome in the use of cephalosporins in pediatric patients with a history of penicillin
allergy. Int Arch Allergy Immunol 2012; 158:405.
Contributor Disclosures
Kimberly G Blumenthal, MD, MSc Other Financial Interest: Licensed clinical decision support tool related
to beta-lactam allergy evaluation. Roland Solensky, MD Grant/Research/Clinical Trial Support:
Stallergenes Greer [Allergic rhinitis]; ALK [Allergic rhinitis]; GSK [Asthma]. Consultant/Advisory Boards: ALK
[Allergic rhinitis]. N Franklin Adkinson, Jr, MD Equity Ownership/Stock Options: AllerQuest [Penicillin
allergy diagnosis]. Consultant/Advisory Boards: ViiV Healthcare; Amgen; Merck; AMAG Pharma; Cour
Pharma; Biomarin; aTryPharma; Global Blood Therapeutics; Takeda Pharma [Hypersensitivity reactions
and anaphylaxis in drugs under development]; Genzyme/Sanofi; Aeglea; Vertex Pharma; IQVIA [DSMB for
drug products under development]. Anna M Feldweg, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

Allergy Evaluation For Immediate Penicillin Allergy: Skin Test-Based Diagnostic Strategies and Cross-Reactivity With Other Beta-Lactam Antibiotics

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9/6/21, 11:51 AM Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with

ity with other beta-lactam…

Official reprint from UpToDate®

Allergy evaluation for immediate penicillin allergy: Skin

● Delayed reactions to penicillins, ranging from maculopapular drug eruptions to severe

Penicillin allergy is reported by up to 10 percent of patients. However, more than 90 percent of

Features of immediate reactions — Immediate reactions to drugs typically involve flushing,

Antigenic components of penicillins — There are multiple potentially antigenic epitopes in

Multiple antibiotic allergy syndrome — "Multiple antibiotic allergy syndrome" is a term used

or more non-cross-reacting antibiotics. Individuals with this syndrome have an increased

In studies of patients with allergies to structurally-related antibiotics, the concept of multiple

Population differences — There may be variations in patterns of sensitization in different

Side chain-specific sensitization to antipseudomonal penicillins (ie, ticarcillin and piperacillin)

Selective allergy to the aminopenicillins is presumed to be attributable to the R-group side

Studies evaluating cross-reactivity between penicillins and cephalosporins in various groups of

Studies estimating the risk of cross-reactivity — Among patients who report penicillin

● Most of these reports provided no information on the nature or severity of the

immediate allergy should be confirmed by administering a single age-appropriate dose of the

Without precautions, some of these cephalosporin reactions could be severe or life-threatening.

● Administer a cephalosporin using an empiric desensitization (ie, empiric because the

Patients reporting a past reaction to amoxicillin or ampicillin — If a patient reacted

Selective allergy confirmed by skin testing — Selective allergy to amoxicillin or ampicillin

Patients confirmed to be selectively allergic to amoxicillin or ampicillin should avoid

Recommended approach — Based on these data, we recommend an approach to patients

Of note, cross-reactivity between aztreonam and the third-generation cephalosporin

TEST DOSING (OR GRADED CHALLENGE)

Indications and precautions — Test dosing is appropriate only when immediate allergy to

Procedure — When graded challenges are performed to exclude immediate allergic reactions,

Interpretation — Although simple in theory, graded challenges can require experience to

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

● Penicillin-allergic patients can often be treated with cephalosporins and carbapenems,

● Immediate reactions to drugs typically involve flushing, pruritus, urticaria, angioedema,

● To determine if a patient with a reported immediate reaction to a penicillin can safely

challenge or desensitization ( table 2). (See 'Patients reporting a past reaction to

● To determine if a patient with a reported immediate reaction to a penicillin can safely

• If penicillin skin testing is positive or unavailable, the carbapenem may be

Use of UpToDate is subject to the Subscription and License Agreement.

12. Audicana M, Bernaola G, Urrutia I, et al. Allergic reactions to betalactams: studies in a

* Ask the following:

Graphic 112936 Version 5.0

Immediate allergic reactions to drugs (IgE-mediated or non-IgE-mediated): Possible signs and

Eyes, ears, nose

Itching or tingling of lips, tongue, oral mucosa*

Graphic 100732 Version 5.0

Structure of penicillins and related beta-lactam drugs

Structure of the beta-lactam antibiotics. Arrows point to the beta-lactam rings.

R: side chain group.

Graphic 79230 Version 9.0

Cephalosporins and penicillins with identical side chains

Graphic 75589 Version 5.0

Cross-reactivity between penicillins and cephalosporins with identical side chains

Audicana (1994) [1] Ampicillin Cephalexin 1 of 10 (10)

Sastre (1996) [2] Amoxicillin Cefadroxil 2 of 16 (12)

Miranda (1996) [3] Amoxicillin Cefadroxil 8 of 21 (38)

Graphic 82718 Version 9.0

Results of cephalosporin challenges in patients with histories of penicillin allergy

Cephalosporin reaction rate

Study History of penicillin No history of administered (causative drug)

Second generation (Cefaclor-2,

Third generation (25%) (Cefixime-1,

Fourth generation (7%)