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Lack of Penicillin Resensitization in Patients With a History of Penicillin Allergy After Receiving Repeated Penicillin Courses
Roland Solensky, MD;
Harry S. Earl, MD;
Rebecca S. Gruchalla, MD, PhD
Arch Intern Med. 2002;162:822-826.
ABSTRACT
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Background Up to 10% of the population reports an allergy to penicillin, yet more
than 80% of these individuals lack penicillin-specific IgE antibodies. A negative
result on a penicillin skin test is highly accurate in identifying who can
safely receive the antibiotic at the time of testing. However, its negative
predictive value for future courses is unknown because it is uncertain whether
patients with a history of penicillin allergy are at risk of becoming resensitized.
Objective To determine the rate of penicillin resensitization in adult patients
with a history of penicillin allergy after they are challenged with repeated
courses of oral penicillin.
Methods Adult patients with a history of penicillin allergy consistent with
an IgE-mediated mechanism were recruited and underwent penicillin skin testing.
Those with negative skin test results were challenged with 3 successive 10-day
courses of penicillin V potassium (250 mg by mouth 3 times a day), providing
their penicillin skin test results remained negative prior to each course.
Patients with positive skin test results were not challenged.
Results Of 53 patients with initially negative skin test results, 46 completed
the protocol, and each tolerated all 3 courses of penicillin with negative
skin test results throughout. No patients had a converted skin test result
from negative to a positive, yielding a resensitization rate of 0% (upper
95% confidence interval, 2.1%).
Conclusions Adult patients with a history of penicillin allergy are not at increased
risk of resensitization after receiving 3 courses of oral penicillin. Because
a negative penicillin skin test result is predictive for subsequent oral administrations
beyond the time of testing, adult patients with a history of penicillin allergy
can be skin tested electively, which may avoid unnecessary treatment with
alternate broad-spectrum antibiotics.
INTRODUCTION
PENICILLIN ALLERGY is the most commonly reported medication allergy.
While up to 10% of patients report a history of penicillin allergy, numerous
studies have shown that more than 80% of these patients lack penicillin-specific
IgE antibodies and can receive the antibiotic safely.1-5
After the degradation products and immunogenic determinants of penicillin
were elucidated in the 1960s,6-8
penicillin skin testing became an accurate and valid method to detect the
presence or absence of penicillin-specific IgE antibodies. Importantly, penicillin
skin testing (when performed with major and minor determinants) has a very
high negative predictive value of greater than 99% for immediate-type reactions.3 When reactions have occurred in patients with negative
skin test results who were given penicillin, they were mild and not life threatening2-5; penicillin-induced
anaphylaxis has never been reported following a negative penicillin skin test
result (using major and minor determinants).9
Although a negative penicillin skin test result is highly accurate in
identifying who can safely receive the antibiotic at the time of testing,
its negative predictive value for future courses of penicillin is not known.10 There is a theoretical concern that some patients
with a history of penicillin allergy may be resensitized by a course of penicillin,
thus placing them at risk of developing an immediate allergic reaction if
they were to take the antibiotic again. For this reason, the drug hypersensitivity
practice parameter recommends that penicillin skin testing be repeated each
time an adult patient with a history of penicillin allergy receives the antibiotic
and that skin testing should be reserved for situations when there is an immediate
need for penicillin.10
Some data indicate that the resensitization rate (conversion of a negative
penicillin skin test result to a positive one) in children with a history
of penicillin allergy after they are challenged with a single oral course
of penicillin is low.2, 11 However,
in the adult population, to our knowledge, there are no published reports
addressing the issue of resensitization after oral penicillin. In addition,
the risk of resensitization after more than 1 course of penicillin has not
been evaluated in any patient population.
Our objective was to determine the rate of resensitization after repeated
courses of oral penicillin are given to adult patients who have a convincing
history of penicillin allergy but presently have a negative penicillin skin
test result. Our hypothesis was that the rate of resensitization would not
be higher than the 2% to 4% sensitization rate in the general nonallergic
population.3-4,12-13
SUBJECTS AND METHODS
Subjects were recruited among patients, staff, and students at University
of Texas Southwestern Medical Center and affiliated institutions, Dallas.
All portions of the study were approved by the University of Texas Southwestern
Medical Center institutional review board. Inclusion criteria for patients
were aged 18 years or older and history of an allergic reaction to penicillin
consistent with an IgE-mediated mechanism. Exclusion criteria were pregnancy
and use of  -blockers. Patients who were unable to recall their previous
reaction and those who reported non–IgE-mediated type of reactions (including
Stevens-Johnson syndrome and toxic epidermal necrolysis) were excluded from
participation. Likewise, patients who selectively had reacted only to amoxicillin
or ampicillin (and not to penicillin) were not enrolled owing to to the possibility
that their sensitivity was specific to a side chain rather than the -lactam
portion of the molecule, which has been reported previously.14-15
Qualifying patients underwent penicillin skin testing at the initial
visit, and those who had negative skin test results were immediately challenged
with a single oral dose of 250 mg of penicillin V potassium. Patients were
observed for 30 minutes and then instructed to continue to take oral penicillin
for 10 days (250 mg by mouth 3 times a day). Additional skin tests and challenges
were performed in a similar manner outlined in Figure 1. Follow-up skin tests were performed at a minimum of 4
weeks after patients completed a given course of penicillin. Testing was not
performed before this time because of the theoretical concern that skin testing
sooner may result in a false-negative result due to patients being in a temporary
desensitized state.16 Patients whose skin test
result remained negative received 3 courses of penicillin and underwent 4
penicillin skin tests. Patients with a positive skin test result at any point
during the study would not be given further penicillin and therefore would
be removed from the protocol.
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Figure 1. Algorithm of the study protocol.
Penicillin skin testing at visits 2, 3, and 4 was performed at least 4 weeks
following the conclusion of the previous course of penicillin. The plus sign
indicates positive skin test result; the minus sign, negative skin test result.
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Penicillin skin testing was carried out in typical fashion using major
and minor determinants10 The reagents used
were 6 x 10-5M penicilloyl-polylysine (Pre-Pen; Hollister-Stier
Laboratories LLC, Spokane, Wash), 0.01M penicillin G sodium (Marsam Pharmaceuticals
Inc, Cherry Hill, NJ), 0.01M penicilloic acid, 1M histamine, and normal saline
solution. Penicilloic acid was prepared by alkaline hydrolysis of penicillin
G, and its purity was analyzed by nuclear magnetic resonance, as has been
described previously.17 Briefly, using 0.1N
sodium hydroxide, the pH of a penicillin G solution was adjusted to 12.0,
at which it was maintained for 20 minutes and then adjusted back to 7.0 with
0.1N hydrochloric acid. Both penicilloic acid and penicillin G solutions were
stored in single-use ampules, frozen, lyophilized, and reconstituted with
normal saline solution immediately prior to skin testing.
All skin tests were performed in duplicate and were interpreted in the
usual fashion outlined previously.18-19
First, prick/puncture tests were performed with penicillin reagents and controls.
A positive response was defined as a wheal of 3 x 3 mm or greater in
diameter compared with negative control, measured 15 minutes after application.
If prick test results with antigens were negative, intradermal tests were
performed by injecting an amount (approximately 0.03 mL) sufficient to produce
wheals measuring 4 x 4 mm in diameter. A positive response was defined
as a wheal that increased at least 2 x 2 mm in diameter compared with
negative control, measured 15 minutes after injection.
We sought to compare the resensitization rate in our patient sample
with the 2% to 4% sensitization rate reported in the general population (hence,
an average of 3%). Using a 1-proportion power analysis with a power level
of 0.99 and an  level of .05, 99 follow-up penicillin skin tests (hence,
33 patients each underwent 3 follow-up skin tests after 3 oral penicillin
challenges) were required to detect a 3% skin test conversion rate (from negative
to positive). Statistical analysis was carried out using the binomial test
with a 1-sided 95% confidence interval. We chose to treat the skin tests as
independent observations because the probability of testing positive in a
given subject was nondecreasing. The null hypothesis was that the proportion
of patients who had converted skin test results would be greater than 3%.
RESULTS
Characteristics of the enrolled patients are given in Table 1. At the initial visit, 58 patients underwent penicillin
skin testing. Five patients (9%) had positive skin test results and were not
included in further analysis; 53 patients had negative results and thus were
enrolled in the study. In the group with negative skin test results, 25 (47%)
of the patients reported a history of urticaria or angioedema to penicillin,
9 (17%) had experienced anaphylaxis, and 19 (36%) had developed a pruritic
rash. Approximately two thirds of the patients reported a history of atopy,
and about a third reported a history of drug allergy to another medication
in addition to penicillin. The mean length of time elapsed since a patient's
previous reaction to penicillin was 25 years.
Of the 53 patients with negative skin test results, 46 completed the
protocol. Each of these individuals tolerated all 3 courses of penicillin
and had negative skin test results throughout (Figure 2). The 7 patients who withdrew from the study prior to completing
the protocol are described below. Because no patients had a skin test result
that converted from negative to positive, the resensitization rate was 0%.
Applying the binomial test to the 142 skin tests following the penicillin
courses (48 skin tests following the first course; 48 following the second
course; and 46 following the third course), the 1-sided upper 95% confidence
interval was 0.021 (or 2.1%), allowing us to reject the null hypothesis.
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Figure 2. Summary of the results. None of
46 patients who completed the protocol had a converted penicillin skin test
result from negative to positive.
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Of the 7 patients who withdrew from the study, 2 experienced adverse
reactions that were possibly allergic in nature, but additional investigation
revealed that they were not resensitized. The first patient developed pruritus
limited to the groin on the second day of his first course of penicillin,
which was not associated with a rash or any other symptoms. The second patient
developed hives (by history, not visualized) on the 10th day of her second
course of penicillin. Both of these patients had another penicillin skin test
performed at least 4 weeks following their reactions, and both maintained
negative skin test results (indicating they were not resensitized). Moreover,
the second patient was challenged and tolerated a single full 250-mg oral
dose of penicillin V potassium, further proving she had not developed penicillin-specific
IgE antibodies. The first patient elected not to be challenged with penicillin.
Both patients preferred not to continue the study. Because the first patient
did not complete a single full course of penicillin, he was not included in
the statistical analysis. The second patient was included in the analysis
as having had 2 negative skin test results following the first 2 courses of
penicillin before dropping out of the study (Figure 2).
The remaining 5 patients withdrew from the study because of relocation
(2 patients), changed mind about participation (1 patient), vaginal yeast
infection (1 patient), and noncompliance with follow-up (1 patient). Of these
5, 4 withdrew prior to the second penicillin skin test. One patient moved
after she had tolerated all 3 courses of penicillin, but before her fourth
skin test could be performed.
COMMENT
In this study, we have demonstrated for the first time that adult patients
with a history of penicillin allergy but currently a negative penicillin skin
test result are not at an increased risk of becoming resensitized by taking
3 oral courses of the antibiotic. Our results indicate that in adult patients
with a history of penicillin allergy, a negative penicillin skin test result
is predictive beyond the time of immediate administration and skin testing
may not need to be repeated each time a patient requires treatment with the
medication. A recent survey of practicing allergists highlighted the lack
of a consensus opinion regarding the predictive value of penicillin skin testing
and resensitization.20 In this study, 32% of
responder allergists stated that a negative penicillin skin test result is
predictive only for immediate administration, 34% believed it to have no time
limitation, while others found it predictive for periods ranging from 24 hours
to 1 year.20 Similarly, the percentage of allergists
who would repeat penicillin skin testing in patients with a history of penicillin
allergy who had since tolerated a course of penicillin ranged widely between
18% and 80%, depending on the patient's reaction history. The authors of the
survey concluded that the observed variations in clinical practice were partially
due to a lack of scientifically based information regarding penicillin resensitization.20
To our knowledge, penicillin resensitization after oral challenge has
been studied only in pediatric patients with a history of penicillin allergy,
following only a single course with the antibiotic. Mendelson et al2 challenged children with a single 10-day course of
penicillin V potassium and found a skin test conversion rate of 1.5%, while
Pichichero et al,11 using a similar protocol,
found a resensitization rate of 14%. The latter study differed from the former
in that some children were skin tested and challenged with -lactams
other than penicillin (including cephalosporins) and only included patients
who had physician-documented reactions. In the adult population, there are
2 published reports, both of which evaluated resensitization after a single
course with a parentally administered -lactam antibiotic. Parker et
al21 studied a group of 18 patients, 3 (16%)
of whom had a converted penicillin skin test result from negative to positive
following a course with an intravenous -lactam antibiotic. Lopez-Serrano
et al22 found a resensitization rate of 5%
in adult patients after they were challenged with intramuscular penicillin
(plus oral amoxicillin) over several days. Because the resensitization rate
appears to be higher when adult patients are challenged parentally, it is
possible that our results (using oral penicillin) cannot be generalized to
patients who receive penicillin intravenously or intramuscularly.
Our study differs from previous investigations in several ways. First
and most importantly, we challenged patients with repeated courses of penicillin
rather than just a single course. This scenario better simulates real-life
situations in which patients are likely to receive more than 1 antibiotic
course over time. We believe that the design of our protocol was optimal to
detect any possible resensitization because it is known that repeated exposure
to a medication is more likely to produce sensitization in a previously nonallergic
individual.23
Second, unlike previous investigations, we sought to only include patients
who had reaction histories consistent with an IgE-mediated–type reaction
because presumably these individuals would be the ones at highest risk of
becoming resensitized. It is likely that among "all comers" labeled as having
"penicillin allergy," there exist many patients erroneously labeled as "penicillin
allergic." By taking a detailed history and reviewing medical records when
possible, we attempted to minimize the possibility of including patients who
had not previously experienced a penicillin-induced IgE-type reaction. Admittedly,
because we relied on historical information, we cannot be certain that the
patients' previous reactions were due to the presence of penicillin-specific
IgE antibodies.
It could be argued that, ideally, one should prospectively follow penicillin-allergic
patients and challenge them once their penicillin skin test results convert
from positive to negative. Unfortunately, because it may take years or decades
for patients to lose their penicillin sensitivity, such a prospective study
would be difficult to perform.
A third difference between our study and others is that our protocol
excluded patients who previously had reacted only to extended spectrum penicillins
or cephalosporins (and not to penicillin itself). It is possible that some
patients who experienced previous reactions to other -lactams had a
sensitivity to a side chain (that is specific to a particular compound), rather
than to the common -lactam component. The true allergy status of such
patients cannot be accurately determined because skin testing with compounds
other than penicillin determinants has not been validated and may produce
false-positive or false-negative results.
One limitation to our study is that most enrolled patients had distant
reaction histories. This selection bias was unintentional and probably due
to the following factors: (1) considerable time is required for penicillin-allergic
patients to lose their sensitivity, (2) patients with recent reactions and
vivid memories of them may be less likely to consent to be challenged with
penicillin, and (3) because the use of penicillin has declined in recent years
in favor of extended-spectrum penicillins, cephalosporins, and other classes
of antibiotics, fewer patients are being treated with (and hence reacting
to) penicillin itself. We cannot determine if our results would have been
different had most patients experienced recent, as opposed to distant, reactions.
Nevertheless, among the group of 46 subjects who completed the protocol, none
of the 6 patients who had experienced reactions within the last 10 years became
resensitized.
Another potential limitation is that our subjects, unlike real-life
clinical patients, were not sick at the time they received penicillin. Some
non–IgE-mediated reactions to medications are known to occur with much
higher frequency in the presence of certain concomitant viral infections;
the 2 most notable examples are cutaneous eruptions secondary to ampicillin
use in patients with Epstein-Barr virus and eruptions due to sulfamethoxazole
use in patients with human immunodeficiency virus.24-25
However, we are unaware of any descriptions of similar associations between
infections and IgE-mediated reactions to medications. Additionally, in his
clinical practice, one of us (H.E.) has repeated penicillin skin tests on
several patients with a history of penicillin allergy in a manner similar
to our protocol, the only difference being that these patients were ill and
in need of a penicillin-class antibiotic. Some of these patients have been
skin tested up to 5 times over a period of years, and none has become resensitized
(unpublished data, 2000). Therefore, we believe it is unlikely that inclusion
of sick patients in need of antibiotic treatment would have yielded different
results.
It has been observed that physicians frequently choose to treat patients
with a history of penicillin allergy with alternate broad-spectrum antibiotics.26-27 The emergence of multiple drug-resistant
bacteria in recent years is thought to be largely due to the unnecessary use
of broad-spectrum antibiotics,28-32
and the overall added cost to health care resulting from multiple drug–resistant
organisms has been estimated to be over $4 billion annually.33
To help curtail the spread of multiple drug–resistant organisms,
the Centers for Disease Control and Prevention and others have recommended
more judicious use of broad-spectrum antibiotics.29, 34-35
One method to help achieve this goal would be for allergists to identify by
penicillin skin testing the many adult patients labeled penicillin allergic
who lack penicillin-specific IgE antibodies and who could receive penicillin-class
antibiotics safely. Furthermore, because our data suggest that a single penicillin
skin test is predictive not only for immediate administration but also for
future courses with the antibiotic, skin testing may not need to be repeated
each time a patient with a history of penicillin allergy requires treatment.
Rather, allergists could perform penicillin skin testing on an elective basis
when the patient is well and not in need of antibiotic treatment. Because
patients and physicians may not "trust" the negative result of a penicillin
skin test (despite its very high negative predictive value), in clinical practice,
an oral challenge with penicillin may be required to unequivocally prove its
safety.
Unfortunately, the applicability of our results is somewhat limited
by the fact that minor penicillin determinants (other than penicillin G) have
yet to be approved by the Food and Drug Administration and therefore remain
unavailable for widespread clinical use. Despite this fact, in a recent survey,
over 40% of practicing allergists reported performing skin tests with minor
determinants (which they presumably obtained from local medical centers).20 Nonetheless, patients with a history of penicillin
allergy can still be evaluated by allergists, and important and useful information
can be obtained by skin testing solely with penicilloyl-polylysine and penicillin
G.10
In summary, we have shown that adult patients who have lost their penicillin
hypersensitivity are not at increased risk of becoming resensitized after
taking repeated oral courses of the antibiotic. Our results extend the negative
predictive value of penicillin skin testing beyond a single course and, hence,
increase the usefulness of a single negative skin test result. Allergists
can play a valuable role in clinical medicine by helping identify those patients
labeled penicillin allergic who could receive penicillin-class antibiotics
safely. In light of the increasing prevalence of multiple drug–resistant
bacteria, rising cost of treatment, and recommendations to decrease the unnecessary
use of broad-spectrum antibiotics, we believe that elective penicillin skin
testing of adults with a history of penicillin allergy makes clinical and
economic sense.
AUTHOR INFORMATION
Accepted for publication July 31, 2001.
There was no outside financial support for the project, but some complimentary
samples of penicilloyl-polylysine (Pre-Pen) used in skin testing were provided
to us by the manufacturer, Hollister-Stier, who was not involved in the design
of the protocol, analysis of the data or any other phase of the project.
Preliminary findings from the project were presented orally in abstract
form at the annual meeting of the American Academy of Allergy, Asthma and
Immunology, San Diego, Calif, March 6, 2000.
We would like to thank Linda Hynan, PhD (University of Texas Southwestern
Medical Center), for her assistance with the statistical analysis.
Corresponding author and reprints: Roland Solensky, MD, The Corvallis
Clinic, 3680 NW Samaritan Dr, Corvallis, OR 97330 (e-mail: rtsolen{at}prodigy.net).
From the Department of Internal Medicine, Division of Allergy and Immunology,
University of Texas Southwestern Medical Center, Dallas.
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