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Antibiotic Allergy

This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal
guidelines, when they exist. The article ends with the authors' clinical recommendations.
A 55-year-old woman presents to the hospital with cellulitis. She reports a history of
urticaria 30 years earlier associated with taking penicillin for a respiratory tract infection. Should
cephalosporins be avoided? More generally, how should patients with a history of allergy to
antibiotics be evaluated and treated?

The Clinical Problem

Although allergic reactions to antibiotics account for only a small proportion of reported
adverse drug reactions, they are associated with substantial morbidity and mortality and
increased health care costs.1-3 Estimates of the prevalence of antibiotic allergy vary widely.1-3
Any organ may be affected, but the skin is most commonly involved. Data from the Boston
Collaborative Drug Surveillance Program1 indicate a 2.2 percent frequency of cutaneous drug
reactions among hospitalized patients, with the antibiotics amoxicillin, trimethoprim
sulfamethoxazole, and ampicillin the most commonly implicated agents. More recently, a sixmonth prospective analysis in France showed a prevalence of cutaneous drug eruptions of 3.6 per
1000 hospitalized patients; antibiotics accounted for 55 percent of cases.4

Pathogenetic Features
Allergic reactions are, by definition, immunologically mediated. A single drug may
initiate multiple immune responses, and multiple antigenic determinants may be formed from a
single drug.5,6 For instance, a major antigenic determinant and several minor determinants have
been identified for penicillin
Figure 1

General Structure of Penicillin and Important Major and Minor Allergenic Determinants.7
T cells play a predominant role in delayed hypersensitivity reactions, including antibioticinduced maculopapular eruptions
Figure 2

Maculopapular Rash Associated with Flucloxacillin Allergy.),8

whereas drug-specific IgE antibodies cause urticarial reactions
Figure 3

Urticaria Associated with Ampicillin Allergy.

A classification of drug-induced immune responses is in the Supplementary Appendix, available
with the full text of this article at www.nejm.org.

Clinical Features
The clinical features of antibiotic allergy are highly variable in terms of the type and severity of
the reaction and the organ systems affected
Table 1

Antibiotic-Induced Allergic Reactions. Factors such as the type of drug used, the nature
of the disease being treated, and the immune status of the patient are all believed to play an
important role in the clinical expression of these responses.9 The most common reactions to
antibiotics are maculopapular skin eruptions, urticaria, and pruritus.1,10 These reactions typically
occur days to weeks after initial exposure to a drug (during which sensitization occurs), although
on secondary exposure, the reaction usually occurs much sooner, sometimes within minutes to
hours.11 Occasionally, a hypersensitivity syndrome develops that is characterized by fever,
eosinophilia, and other extracutaneous manifestations.12
Some antibiotics also affect organs other than the skin. For instance, the combination of
amoxicillin and clavulanic acid can cause cholestatic liver injury, whereas hemolysis and
cytopenias, most likely caused by drug-specific antibodies, are reported with high-dose penicillin
and cephalosporin therapy.13 Severe reactions such as anaphylaxis, mediated by drug-specific
IgE antibodies, are rare. Although anaphylaxis may theoretically occur with any antibiotic, only
the frequency of penicillin-induced anaphylaxis is well described (1 in 5000 to 10,000 courses of
drug therapy).14

Special Cases
Human Immunodeficiency Virus
Patients infected with the human immunodeficiency virus (HIV) have a higher frequency
of allergic reactions to a range of antimicrobial agents (including sulfamethoxazole, amoxicillin,
clindamycin, dapsone, and amithiozone) than do persons without HIV infection.15
Hypersensitivity to trimethoprimsulfamethoxazole occurs in 20 to 80 percent of patients
infected with HIV, as compared with 1 to 3 percent of persons not infected with HIV.16 These
high rates of reaction are not well understood but may be caused by altered drug metabolism,
decreased glutathione levels, or both.15,17

Cystic Fibrosis

In approximately 30 percent of patients with cystic fibrosis, allergy develops to one or

more antibiotics.18 Piperacillin, ceftazidime, and ticarcillin have been most commonly
implicated, with the risk being higher after parenteral administration than after oral
administration. Repeated exposure to antibiotics and immune hyperresponsiveness are thought to
underlie the high prevalence of allergic reactions in patients with this disease.19

Infectious Mononucleosis
The likelihood of cutaneous reactions to penicillins and other antimicrobial agents is
increased among patients with infectious mononucleosis.20,21 Although the mechanism of these
drug reactions is not clear, the viral infection may alter the immune status of the host.22 In such
cases, the implicated agent can be readministered safely once the viral infection has resolved.23

Strategies and Evidence

Clinical Assessment
Medical history taking is critical in the evaluation of antibiotic allergy24 and in
distinguishing allergic reactions from other adverse reactions


Algorithm for the Management of Antibiotic Allergy.

This information is important, since overdiagnosis of allergic reactions can lead to
unnecessary use of more costly antimicrobial agents and may promote the development of
resistant microorganisms.15
Table 2

Checklist for Distinguishing Immune-Mediated Reactions from Nonimmune-Mediated

Reactions. provides questions, the answers to which may help determine whether a reaction is
immunologically mediated and, if so, the type of immune mechanism responsible. Whenever
possible, patients who are being evaluated for possible antibiotic allergy should be encouraged to
provide all medical records related to previous adverse drug reactions. Table 1 summarizes the
most common reactions associated with various antibiotic classes.27

Diagnostic Tests
Skin Testing
Skin testing may be used to detect allergen-specific IgE antibodies. However, with the
exception of penicillin, the relevant immunogens (which may be derived from an unidentified
drug metabolite or degradation product) are not known for most drugs. Thus, there are no valid
in vivo or in vitro diagnostic reagents available for identifying most antibiotic-specific IgE
antibodies. Although the parent antibiotic compound may be used in testing by allergy
specialists, a negative response on a skin test cannot be interpreted to mean that IgE antibodies
are absent.28 Rather, a negative result may simply indicate insufficient sensitivity of the assay
technique or, more likely, that the appropriate drug immunogen was not used in testing.
Skin testing is highly accurate for the identification of penicillin allergy, however. The
clinically relevant antigenic determinants for penicillin are well characterized and include the
important penicillin determinant penicilloyl polylysine and multiple minor determinants. Skin
testing is performed with penicilloyl polylysine and either penicillin G diluted to 10,000 U per
milliliter or a mixture of minor determinants that usually includes a 102 M mixture of benzyl
penicilloate, benzyl penilloate, and benzyl-n-propylamine.29 Skin-prick testing with full-strength
materials is done first, and if these tests are negative at 15 minutes, they are followed by
intracutaneous testing. An increase in the wheal diameter of at least 3 mm (as compared with the
negative control) in the presence of erythema constitutes a positive test. Less than 20 percent of
patients who report a history of penicillin allergy have detectable penicillin-specific IgE

antibodies at the time of testing.30-32 Negative skin testing indicates that the previous reaction
was not IgE-mediated or that the antibodies are no longer present; in either case, penicillin can
be administered again with minimal risk of an immediate reaction (no more than 4 percent, an
incidence similar to that in the general population33,34). Although penicilloyl polylysine has
recently become unavailable commercially owing to manufacturing issues related to the
production of a low-volume product, production is expected to resume in the future.

Other Testing
Skin testing is not predictive for drug reactions that are not mediated by IgE. In such
cases, other tests may be useful but must be performed during or soon after the reaction. A
positive Coombs' test indicates cell-bound antibodies (e.g., penicillin-induced hemolytic
anemia), and low complement levels may indicate the involvement of the complement cascade
(e.g., minocycline-induced serum-sicknesslike reaction35). Levels of serum tryptase, a mastcellspecific neutral protease that indicates systemic mast-cell activation, have been shown to be
elevated for several hours after anaphylactic drug reactions.36
Drug-specific T cells, which are involved in some hypersensitivity reactions, may be
detected with the use of in vitro lymphocyte transformation tests, which are widely used in
Europe but not approved for use in the United States. This test involves mixing lymphocytes
from the patient with the drug that elicited the reaction. If drug-specific T cells are present, a
proliferative response may result; proliferation, as measured by the incorporation of tritiated
thymidine in the presence of the drug, is compared with that in the absence of the drug.37 A
positive test result indicates that the patient has been sensitized to the drug. However,
sensitization may be present even in the absence of any clinical manifestations, and positive test
results have been demonstrated in both immediate and delayed antibiotic-induced reactions
caused by -lactam drugs, sulfonamides, and quinolones.37 Until this test is further validated, it is
best considered a research tool.
Provocation testing, which involves the administration of approximately three to six
increasing doses of a drug up to the usual daily dose, may be used to confirm drug
hypersensitivity.38 However, provocation testing carries a clear risk of a reaction similar to the
previous immediate hypersensivity reaction, although subsequent reactions are generally milder
and briefer than the original reaction. In one study, the overall rate of such reactions during
provocation testing was 17.6 percent.38 Thus, such testing should be performed only by
experienced personnel in a setting in which equipment for cardiopulmonary resuscitation is

Drug Desensitization
For reactions that are presumed to be mediated by IgE, drug desensitization may be
performed if the implicated agent is required for treatment.29 Desensitization is performed by a
person with appropriate training, typically in a hospital setting. It involves the administration of
increasing amounts of the antibiotic slowly over a period of hours until a therapeutic dose is
reached. The typical starting dose is in micrograms; the route of administration may be oral or
intravenous, but the oral route appears to be associated with fewer reactions. Doses are doubled

every 15 to 30 minutes; therapeutic levels can be obtained in most cases within 4 to 5

hours.29,39 The patient is monitored closely throughout the procedure, and antihistamines and
inhaled -agonists are given for urticarial reactions and bronchospasm, respectively. If a mild
reaction (e.g., flushing or urticaria) occurs, the procedure may resume at the last tolerated dose;
if a reaction is severe (hypotension or severe bronchospasm), the procedure should be aborted
and an alternative antibiotic selected.
The mechanism by which clinical tolerance is achieved is unclear, but it is thought to involve
antigen-specific mast-cell desensitization.40 Since maintenance of a desensitized state requires
the continuous presence of the drug, desensitization must be repeated if the antibiotic is required
again later.
In a recent retrospective report,41 desensitization for IgE-mediated drug allergy was successful in
43 of 57 cases (75 percent). Eleven desensitizations (19 percent) were complicated by severe
allergic reactions, either during the procedure (anaphylaxis) or days after its completion (serum
sickness); three were terminated for reasons other than allergic reactions. In most cases of failed
desensitization, the drug reaction did not appear to be solely mediated by IgE. Desensitization
appears more likely to fail in patients with cystic fibrosis.19,41

Graded Challenge
For reactions that are not considered to be mediated by IgE, management depends on the
clinical manifestations of the previous reaction. For maculopapular eruptions, the specialist may
consider a graded drug challenge, which is equivalent to provocation testing.29 Initial starting
doses are generally higher than those used for desensitization (milligrams vs. micrograms), and
the interval between doses varies, ranging from hours to days or even weeks. The patient is
monitored for adverse reactions, which are most commonly cutaneous. The decision whether to
discontinue an antibiotic if a reaction occurs depends on the nature of the reaction; bullous
lesions or those involving mucous membranes warrant withdrawal of the drug, whereas it may be
reasonable to treat through milder reactions, such as maculopapular eruptions, with the use of
antihistamines, corticosteroids, or both as needed.
During drug readministration, repeated hypersensitivity reactions (morbilliform
eruptions, fever, or both) have been noted in 58 percent of patients with the acquired
immunodeficiency syndrome who have had previous reactions to sulfamethoxazole.42 Several
graded-challenge procedures have been used successfully in such patients. An analysis of several
studies showed that readministration of sulfamethoxazole with the use of an incremental-dosing
regimen permitted the use of the drug in more than 75 percent of treated patients.43 Repeated
administration is contraindicated, however, after any life-threatening reaction that is not
mediated by IgE (e.g., drug-induced hemolytic anemia, immune-complex reactions, the Stevens
Johnson syndrome, and toxic epidermal necrolysis).

Cephalosporin in Patients with Penicillin Allergy

Penicillins and cephalosporins share a -lactam ring structure, making cross-reactivity a
concern. Although a rate of cross-reactivity of more than 10 percent has been reported, this
figure must be interpreted with caution since it is based on retrospective studies in which
penicillin allergy was not routinely confirmed by skin testing, and at least some of the reactions

were probably not immune-mediated.44 Available data, although based on small numbers,
suggest an increased risk of cephalosporin reactions among patients with positive results on
penicillin skin tests. In a review combining data from 11 studies of cephalosporin administration
in patients with a history of penicillin allergy,45 cephalosporin reactions were found to have
occurred in 6 of 135 patients with positive skin-test results for penicillin allergy (4.4 percent), as
compared with only 2 of 351 with negative skin tests (0.6 percent).
Whereas most patients who have a history of penicillin allergy will tolerate
cephalosporins, indiscriminate administration cannot be recommended, especially for patients
who have had life-threatening reactions.29 Among 12 cases of fatal anaphylaxis caused by
antibiotics in the United Kingdom from 1992 to 1997, 6 cases occurred after the first dose of a
cephalosporin, and 3 of the 6 patients were known to have penicillin allergy.46
For patients with a history of penicillin allergy who require a cephalosporin, treatment
depends on whether the previous reaction was mediated by IgE.29,47 Skin testing is warranted if
the reaction was consistent with an IgE-mediated mechanism or if the history is unclear. In one
study, one third of patients with positive results on skin tests had unclear or vague histories of
penicillin allergy.48 If testing is positive and a cephalosporin is considered necessary, then
desensitization should be performed with the use of the particular cephalosporin chosen for
treatment. A possible alternative is to perform a graded challenge with the cephalosporin,29 but
the risk of anaphylaxis, although low, must be recognized.29 If the history is inconsistent with an
IgE-mediated mechanism, it is considered safe to initiate a graded challenge without previous
skin testing.

Sulfonamide Allergy
For patients who have a history of allergy to sulfonamide antibiotics, concern has been
raised about the use of other sulfonamide-containing drugs (diuretics, sulfonylureas, and
celecoxib). However, sulfonamide antimicrobial agents (sulfamethoxazole, sulfadiazine,
sulfisoxazole, and sulfacetamide) differ from other sulfonamide-containing medications by
having an aromatic amine group at the N4 position and a substituted ring at the N1 position;
these groups are not found in nonantibiotic sulfonamide-containing drugs. Thus, despite productlabeling warnings, cross-reactivity between these two groups of sulfonamides is believed to be
In a large observational study,51 patients with a history of allergy to sulfonamide
antibiotics had an increased risk of an allergic reaction to nonantibiotic sulfonamides, as
compared with patients without such a history (adjusted odds ratio, 2.8; 95 percent confidence
interval, 2.1 to 3.7), and were even more likely to have a reaction to penicillin (adjusted odds
ratio, 3.9; 95 percent confidence interval, 3.5 to 4.3). These results suggest that the association
between an allergy to sulfonamide antibiotics and subsequent reactions to nonantibiotic
sulfonamide drugs is probably attributable to a predisposition to allergic reactions in general, as
opposed to cross-reactivity between sulfonamide-containing antibiotics and nonantibiotic
drugs.51 However, the results must be interpreted with caution, given the retrospective design and
the use of diagnosis codes to categorize reactions, which probably resulted in some
misclassification of nonallergic reactions as allergic reactions.

Areas of Uncertainty
The mechanisms underlying antibiotic allergy have not been clearly elucidated. This
understanding is needed to facilitate the development of better diagnostic tools and drugs that are
less immunogenic. Better understanding is needed of factors mediating individual susceptibility
to allergic reactions to antibiotics. A few studies have evaluated the role of majorhistocompatibility-complex polymorphisms in the predisposition of patients to drug
reactions,52,53 but these findings need to be confirmed and expanded.
Some patients have reported adverse reactions to many chemically unrelated antibiotics.
The existence of the so-called multiple drug allergy syndrome is controversial,54,55 and accepted
diagnostic tests are needed to document drug allergy in these patients.

The American Academy of Allergy, Asthma and Immunology, the American College of
Allergy, Asthma and Immunology, and the Joint Task Force on Practice Parameters for Allergy
and Immunology have developed practice guidelines for the management of drug allergy29,47 on
the basis of evidence and expert opinion. The recommendations in the present review are
consistent with these guidelines.

Conclusions and Recommendations

Patients who report a history of antibiotic allergy require a careful assessment of the
nature of the reaction to determine the likelihood that it was immunologically mediated. For
patients whose history suggests an IgE-mediated reaction to penicillin, such as the case described
in the vignette, skin testing is indicated, if available, before they receive another -lactam
antibiotic. If test results are negative, the -lactam agent may be administered. If test results are
positive or testing cannot be done, the drug should be avoided or a desensitization procedure
should be performed.

Source Information
From the University of Texas Southwestern Medical Center, Dallas (R.S.G.); and the
Department of Pharmacology, University of Liverpool, Liverpool, United Kingdom (M.P.).
Address reprint requests to Dr. Gruchalla at the University of Texas Southwestern
Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8859, or at

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Jurnal Penyakit Kulit dan Kelamin

Antibiotic Allergy

Nama : Nurul Ratna Sari

NIM : 10542 0110 09