Adverse drug reactions occur in up to 20% of hospitalized patients and up to 25% of
ambulatory patients. Studies have found that up to 6% of all hospitalizations are
caused by an adverse drug event. Immunologically mediated adverse drug reactions
(also commonly referred to as drug allergy or hypersensitivity) account for about
one-third of all adverse drug reactions and may affect 10% to 15% of hospitalized
In one study of more than 36,000 hospitalized patients, 731 adverse
events were identified, with 1% being severe, life-threatening, allergic reactions.
The potential morbidity and mortality associated with allergic drug reactions can be
Adverse drug reactions resembling an immune response are called drug
1 Clinically, DHRs are commonly classified as
immediate or delayed depending on their onset during treatment. Immediate reactions
occur within a few hours of exposure and usually are mediated by IgE. Delayed
reactions will occur a few days after starting therapy and are typically mediated by
Immunologic Classification of Allergic Drug Reactions
Pathophysiology Clinical Symptoms Typical Chronology of the
Within 1–6 hours after the last
Cytopenia 5–15 days after the start of the
7–21 days after the start of the
Eczema 1–21 days after the start of the
IVb Th2 (IL-4 and IL-5) Eosinophilic
1 to several days after the start
2–6 weeks after the start of the
1–2 days after the start of the
4–28 days after the start of the
start of the eliciting drug (but
Source: Demoly P et al. International consensus on drug allergy. Allergy. 2014;69:420.
DHRs cannot be attributed to a single immunopathologic mechanism. Traditionally,
an allergic drug reaction was thought to occur in two phases, initial sensitization and
6 Most drugs are small molecules (<1,000 Da) and are unable
to stimulate an immune response. Sensitization occurs as a result of covalent binding
of a drug or a metabolite to a carrier protein in a process referred to as haptenation.
This drug–protein (or drug metabolite–protein) complex is sufficiently large to
induce the production of drug-specific T- or B-lymphocytes and IgM, IgG, and IgE.
On reexposure to the drug, the patient is likely to present with allergic symptoms.
Allergic reactions to β-lactam antibiotics occur by this mechanism. This theory,
however, cannot explain several allergic phenomena. For instance, some chemically
inert drugs (i.e., drugs that cannot form stable covalent bonds and do not have
reactive metabolites) can still elicit an allergic response. Lidocaine and mepivacaine
are examples. Furthermore, some patients have a strong allergic reaction to a drug on
initial exposure, and some allergic reactions rapidly occur after drug exposure, a
time period shorter than expected for the development of new antibodies. To account
for some of these observations, other models for explaining allergic reactions have
been proposed. The direct pharmacologic interaction concept offers one explanation
for these observations. This model suggests that some drugs are able to bind directly
to T-cell receptors in a reversible, non-covalent manner.
complex interacts with Major Histocompatibility Complex (MHC) molecules,
leading to activation and expansion of T-cells that are directed against the drug.
Recent studies have demonstrated an additional mechanism whereby abacavir and
endogenous peptide to be viewed as foreign and lead to the activation of T-cells.
This process is referred to as the altered repertoire model.
processes involved in allergic reactions are complex and might include some
combination of each theory. The three models of hapten sensitization, direct
pharmacologic interaction, and altered repertoire are not mutually exclusive.
Interested readers are referred to more in-depth reviews.
Factors known to affect the incidence of allergic reactions can be categorized as
being drug-related or patient-related.
3 Patients with histories of allergic rhinitis,
asthma, or atopic dermatitis who experience a systemic drug reaction tend to react
Children are less likely to become sensitized than adults, presumably because
children typically have less cumulative drug exposure.
patients experience allergic reactions (up to 2.3:1), although this may vary by type of
reaction, drug, patient age, and setting.
Familial occurrences of allergic reactions, although rare, have been reported.
patient’s ability to metabolize a drug is influenced by his or her genetic makeup and
may affect the incidence of DHRs.
In humans the major histocompatibility
complex is encoded by a group of genes on chromosome 6 called the human
leucocyte antigen (HLA) system. Variations in HLA is probably the most important
genetic determinant of drug allergies.
Genetic differences in drug metabolizing enzymes can explain the predisposition to
drug allergy and hypersensitivity of some individuals.
expression of these polymorphisms include poor metabolizers (who possess
nonfunctional alleles and have reduced metabolic activity) and ultrarapid
metabolizers (who have multiple copies of functional genes and have enhanced
Slow acetylators are at risk for sulfonamide hypersensitivity and are also more
likely to develop antinuclear antibodies (ANA) and symptoms of systemic lupus
erythematosus (SLE) when treated with procainamide or hydralazine.
Anticonvulsant hypersensitivity syndrome, characterized by fever, generalized rash,
lymphadenopathy, and internal organ involvement, is most associated with aromatic
anticonvulsants (e.g., phenytoin, phenobarbital, and carbamazepine). Oxidation of
these compounds by cytochrome P-450 enzymes results in arene oxides that are
antigenic. Patients with a heritable deficiency in epoxide hydrolase cannot clear the
formed antigen and are at increased risk of a drug sensitivity syndrome also known as
DRESS (drug rash with eosinophilia and systemic symptoms).
might also be responsible for a serum sickness–like reaction to cefaclor.
While polymorphism in drug metabolizing enzymes is responsible for some
allergic reactions, variation in MHC appears to be more important.
polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the
repertoire of peptide antigens selected by different HLA allotypes. Several important
DHRs reactions are associated with specific HLA alleles.
12 For example, HLAB*1502 is associated with increased risk (OR 17.6) of SJS with Carbamazepine
(CBZ), phenytoin, and lamotrigine.
16 HLA-B*1502 occurs in 10% to 15% of
individuals from southern China, Thailand, Malaysia, Indonesia, the Philippines, and
Taiwan and has a prevalence rate of 2% to 4%, or higher, in other southern Asian
groups, including Indians. It is uncommon in Japan and Korea (<1%) and in European
The potentially life-threatening hypersensitivity syndrome seen with abacavir is
strongly associated with the HLA-B*5701 haplotype.
12,22–25 HLA-B*5701 in patients
predicted abacavir hypersensitivity 100% of the time, and its absence had a 97%
25 This haplotype appears more commonly in white patients
than in other ethnic groups and explains the predisposition of white patients to this
severe reaction. Genetic screening of patients for this haplotype before initiating
abacavir therapy has significantly reduced the occurrence of hypersensitivity
In the future, it is hoped that screening tests for HLA haplotypes
associated with a variety of allergic reactions will become widely available.
A more comprehensive and up-to-date listing of alleles associated with
immunologically mediated adverse drug reactions can be found at
Although genes clearly play a role in hypersensitivity reactions, environmental
factors (e.g., concomitant illness) also are implicated. For example, the incidence of
maculopapular rash with ampicillin therapy is significantly higher in patients with
Epstein–Barr virus infections (e.g., infectious mononucleosis), lymphocytic
Infection with herpes virus or Epstein–Barr virus has also been
26 and the occurrence of reactions to trimethoprim–
sulfamethoxazole in patients who are HIV-positive is about 10-fold higher than in the
22 Liver or kidney disease may alter the metabolism or
elimination of reactive drug metabolites, increasing the risk of an allergic response.
A history of an allergic reaction to a drug being considered for treatment, or one that
is immunochemically similar, is the most reliable risk factor for development of a
1,26 A commonly encountered example is the patient with
a history of a severe allergic reaction to penicillin, in whom all structurally related
penicillin compounds should be avoided, and in whom the possibility of a
hypersensitivity reaction should be considered when using other β-lactam
The dose, frequency of exposure, and route of administration can influence the
incidence of drug allergy. For example, penicillin-induced hemolytic anemia requires
high and sustained drug concentrations.
In β-lactam antibiotic IgE sensitivity,
frequent intermittent courses, rather than continuous therapy, are more likely to result
21 The route of administration is important in terms of the risk of
both sensitization and allergic reaction in a previously sensitized person. Topical
administration carries the greatest risk of sensitization, followed by subcutaneous,
intramuscular (IM), and oral routes. The intravenous (IV) route is the least sensitizing
28 However, in a patient who is already sensitized to a
specific medication, the risk of an allergic reaction to that medication is greatest
when it is given IV and least when given orally. This is thought to be a function of the
28 Multiple drug therapy is associated with a greater risk of
allergic reactions. This may be related to increased demands on metabolic pathways
from multiple drugs, leading to the accumulation of reactive metabolites.
Drugs as Allergens and Immunologic Classification
Although there are proposed changes to the nomenclature and classification of drug
the Gel and Coombs classification is the most common. In this system,
allergic drug reactions can be classified into one of four types (Table 32-1).
TYPE I: IMMEDIATE HYPERSENSITIVITY REACTIONS
Type I reactions are typically mediated by the immune globulin IgE. Initial exposure
to an antigen results in production of specific IgE antibodies that are expressed on the
surface of mast cells in the tissue and basophils in the blood. On reexposure, the
antigen cross-links with two or more surface-bound IgE antibodies causing the
release of several chemical mediators including histamine, tryptase, leukotrienes,
prostaglandins, and cyotkines.
A period of several weeks is required after initial exposure and sensitization
before a type I reaction can be elicited; once sensitized, however, a type I response
can be elicited within minutes as a result of existing antibodies. In addition, a type I
reaction can occur on reexposure to small amounts of drug administered by any
Immune-mediated anaphylaxis is the classic example of a type I reaction.
Reactions that clinically resemble anaphylaxis, but do not involve immunologic
mediators (antibodies), are termed anaphylactoid or pseudoallergic reactions (see
Cytotoxic reactions involve the interaction of IgG or IgM and can occur by three
different mechanisms (Table 32-1). Common clinical
manifestations of cytotoxic reactions include hemolytic anemia, thrombocytopenia,
and granulocytopenia. Penicillin-induced hemolytic anemia is the best-known
example of a cytotoxic drug reaction. This reaction typically appears after 7 days of
TYPE III: IMMUNE COMPLEX–MEDIATED REACTIONS
Immune complex–mediated reactions result from the formation of drug–antibody
complexes in serum, which often deposit in blood vessel walls, resulting in
activation of complement and endothelial cell injury.
sickness, these reactions typically manifest as fever, urticaria, arthralgia, and
lymphadenopathy 7 to 21 days after exposure.
TYPE IV: CELL-MEDIATED (DELAYED) REACTIONS
In cell-mediated (delayed) reactions, an antigen binds with sensitized T-cells.
Contact dermatitis is the most common manifestation of cell-mediated reactions,
although systemic reactions can occur. The variety of clinical manifestations of
delayed hypersensitivity has been attributed to distinct patterns of cytokine release
and effector-cell recruitment, based on the type of T-cells stimulated. Each pattern of
cytokine release recruits specific effector cells, such as macrophages, neutrophils, or
other T-cells, and is responsible for the unique clinical manifestations of the
reaction. Based on this understanding, type IV reactions have been further
subclassified as type IVa, type IVb, type IVc, and type IVd, corresponding to four
unique patterns of T-cell and effector-cell involvement.
An understanding of the immunologic mechanism can be helpful in the diagnosis
and treatment of an allergic reaction; however, the exact immunologic mechanism is
unknown for many allergic reactions to drugs.
In addition, patients often present
with several symptoms characteristic of more than one of the reactions described
herein. The use of many drugs concurrently also makes it difficult to identify the drug
responsible for the reaction. Therefore, a careful drug history and diagnostic tests are
often necessary for an appropriate diagnosis and treatment of a patient.
Distinctive Features of Allergic Reactions
The first step in the diagnosis of an allergic drug reaction is to recognize and
differentiate it from other adverse drug reactions. This can be accomplished by
having a good understanding of the distinctive features of allergic drug reactions
QUESTION 1: J.A., a 73-year-old woman, is admitted with an infected decubitus ulcer. Cultures reveal
The single most informative diagnostic procedure for allergic drug reactions is a
detailed drug history (Table 32-3), which is helpful in obtaining the information
necessary to determine whether a reaction represents a drug allergy and in identifying
the culprit drug. In inquiring about prior allergic and medication encounters, it is
important to document the drugs to which the patient has or has not previously
reacted. This can alert the clinician about certain types of compounds to which the
patient is likely to react. The acquired information allows the clinician to
characterize the drug reaction and to appreciate how such a reaction might be
manifested in the patient on exposure to the same, or an immunologically similar,
Clinical Features of Allergic Drug Reactions
Occur only in susceptible individuals
Have no correlation with known pharmacologic properties of the drug
Require an induction period on primary exposure but not on readministration
Can occur with doses far below therapeutic range
Can affect most organs, but commonly involves the skin
Most commonly manifests as an erythematous or maculopapular rash, but includes angioedema, serum
sickness syndrome, anaphylaxis, and asthma
Occur in a small proportion of the population (10%–15%)
Desensitization may be possible
Demoly P et al. International consensus on drug allergy. Allergy. 2014;69:420.
Reason medication was prescribed
Nature and severity of reaction
treatment did the reaction occur)
When did the reaction occur (days to weeks vs. months to years)
Similar reactions in family members
Prior exposure to the same or structurally related medications
Prior diagnostic testing or rechallenge
Other medical problems (if any)
The temporal relationship between drugs and reactions is often the strongest piece
of evidence implicating an allergic reaction to a particular agent. Drugs that the
patient has received for long continuous periods before the onset of a reaction are
less likely to be implicated than drugs that have been recently initiated or restarted.
Equally important is to determine when an adverse reaction has occurred. Many
compounds have been reformulated over the years, resulting in removal of sensitizing
impurities (e.g., penicillin and vancomycin). Therefore, it is possible that
reexposure to the agent will not result in an adverse event. Inquiring about whether
the patient has received the drug since the first episode by asking the patient about
other brands or names of other drugs in the same class (e.g., amoxicillin and
ampicillin) will assist in determining whether the patient is likely to react to the drug
on reexposure. It is usually helpful to chart all the drugs the patient is currently
taking, their dose, and start and stop dates of use. This can be compared with the
onset and disappearance of the reaction.
is it likely that J.A. is allergic to penicillin?
Several pieces of information in the drug history obtained from J.A. can be used to
determine the likelihood of an allergic reaction to penicillin. J.A.’s rash appeared
less than a day after initiation of ampicillin and other drugs had not been added;
therefore, the rash probably was caused by ampicillin.
Another important method of identifying a potential drug-induced allergic reaction
is to examine the patient’s medication list to determine whether the patient is
receiving an agent that commonly is implicated in causing the exhibited allergic
manifestation. For example, amoxicillin and ampicillin are two of the top three drugs
implicated in drug-induced rash.
J.A. received penicillin previously without experiencing any adverse effects until
an urticarial rash (a relatively common allergic manifestation) developed on
subsequent exposure. This sequence of events follows the typical pattern of an
allergic reaction. Allergic reactions commonly require an induction period to
sensitize the person to the antigen; however, once sensitized, allergic symptoms
typically occur immediately on reexposure.
26 Therefore, a prior exposure to the same
or structurally related compounds needs to be documented.
Finally, it is important to evaluate other medical problems that can elicit or mimic
a reaction resembling drug allergy (see the “Associated Illness” section). Rashes to
ampicillin commonly occur in patients with concurrent Epstein–Barr virus
32 J.A. denies having a viral infection at the time of her rash, thereby
strengthening the case that the rash was likely a manifestation of an allergic reaction.
CASE 32-1, QUESTION 3: Would skin testing for penicillin allergy be appropriate for J.A.?
Although J.A.’s medication history strongly suggests that she is allergic to
penicillin, a skin test and a drug rechallenge would more firmly establish her drug
allergy. Penicillin degrades to major determinants (95%) and minor determinants
(5%). Penicilloyl, the primary metabolite of penicillin, is referred to as the major
determinant. The other derivatives are referred to as minor determinants. Of these,
the parent compound (penicillin), penicilloate, and penilloate are the minor
determinants most associated with allergic reactions. The terms major determinant
and minor determinant refer to the frequency of antibody formation to these antigenic
penicillin metabolite–protein complexes. These terms do not describe the severity of
the allergic reaction. Indeed, the major determinant is thought to be responsible for
accelerated reactions, but not anaphylaxis. The minor determinants are responsible
for anaphylaxis and immediate systemic reactions.
Skin testing with these determinants is used to identify which patients have IgE
antibodies to penicillin and which do not. The skin-testing antigen for the major
determinant of penicillin is commercially available as penicilloyl polylysine (PPL;
Pre-Pen), which was recently reintroduced into the United States after several years
33 Skin testing using Pre-Pen is a safe and effective procedure (Table 32-
4), with less than 1% of positive responders developing systemic reactions.
those in whom a false-negative response occurred, reactions were mild after
penicillin administration and, in most cases, did not require drug discontinuation.
Skin testing with PPL identifies 80% of patients allergic to penicillin. When PPL is
supplemented with skin tests for the minor determinants of penicillin, 99.5% of
penicillin-allergic patients can be identified.
26 Of the minor determinants, only
penicillin G is available in the United States, although a minor determinant mixture is
marketed in Europe and Australia.
The negative predictive value of skin testing was demonstrated when 34
purportedly “penicillin-allergic patients” needed β-lactam antibiotics during
hospitalization. Each subsequently tested negative to penicillin skin-testing and no
allergic drug reactions occurred.
Penicillin and its metabolites become antigenic when combined with proteins and
can precipitate a hypersensitivity reaction in a patient on reexposure. In patients with
a history of penicillin hypersensitivity, skin test reactivity is affected by the length of
time since the allergic reaction and by the nature of the past reaction. Skin test
positivity is greatest 6 to 12 months after a reaction and decreases with time. Skin
test positivity in one study was found to be only 40% of patients with a history of
anaphylaxis, 17% with urticaria, and 7% for maculopapular rashes.
should not be performed in patients receiving antihistamines because they block the
response to the antigen and can result in misinterpretation. In patients receiving
-receptor antagonists) or when skin testing is not
possible because of severe skin disease, in vitro assays to detect drug-specific IgE
antibodies have been developed for the major and minor determinants of penicillin.
To determine whether skin testing is appropriate for J.A., the risks and benefits
must be weighed. Because the time of the last reaction was approximately 2 years
ago, J.A. may still retain some skin-test positivity if the previous reaction was truly
an allergic response to ampicillin. Testing with PPL (major determinant) and
penicillin G (minor determinant) could be useful in determining whether J.A. is likely
to experience an urticarial or anaphylactic reaction to penicillin or its derivatives.
That J.A. is currently receiving prednisone should not alter the interpretation of the
skin test results because the corticosteroids minimally affect the IgE-mediated
immediate hypersensitivity reactions. The risks of developing serious systemic
reactions to penicillin skin testing are minimal.
The most practical approach to penicillin-allergic patients is simply to avoid the
drug. In the unlikely situation in which treatment with a penicillin is essential,
penicillin skin testing would be useful.
CASE 32-1, QUESTION 4: J.A. received a scratch test with PPL, which was negative; however, an
intradermal test was positive. What treatment options are available to J.A. for her infection?
Penicillin Skin Testing Procedure
Agent Procedure Interpretation
Penicilloyl polylysine (PrePen)
No wheal or erythema or wheal <5 mm in diameter
after 15 minutes: proceed with intradermal test.
Major determinant Wheal or erythema of 5 to 15 mm in diameter or more
within 15 minutes: choose alternative agent, consider
desensitization if no other alternatives exist.
PPL Intradermal test: inject Read at 20 minutes. Negative response: no increase in
size of original bleb and no greater than reaction at
Positive response: itching and increase in size of
original bleb to at least 5 mm and greater than saline
control: choose alternative agent; consider
desensitization if no other alternatives exist.
Same as scratch test with PPL (see above).
Penicillin G potassium Intradermal test: 0.002 mL
Same as intradermal test with PPL (see above).
Source: Pre-Pen benzylpenicilloyl polylysine injection solution [package insert].
Round Rock, TX: ALK-Abelló, Inc; 2015.
http://penallergytest.com/app/uploads/sites/2/Pre-Pen-Package-Insert.pdf
All penicillin derivatives should be avoided because J.A. had a positive skin-test
intradermal instillation) has been proposed, no prospective studies have evaluated
this approach and this practice is not without risk.
38,39 Therefore, clinicians must rely
on cross-reactivity data to determine whether a non-penicillin β-lactam antibiotic
(e.g., a cephalosporin) can be used in a penicillin-allergic patient.
Cross-reactivity (i.e., cross-antigenicity) between penicillin and cephalosporins
has been reported in 5% to 15% of patients
recollection of patients of an allergic history rather than by objective skin tests.
The risk of a cephalosporin reaction in a patient with a penicillin allergy
40 The risk of a serious allergic reaction with the use of an
advanced-generation cephalosporin in a penicillin-allergic patient might be no
greater than the risk of any alternative antibiotic.
41 The cross-reactivity between
recognized to be responsible for a significant portion of allergic reactions within and
between the penicillin and cephalosporins families.
with immediate allergic reactions to cephalosporins, less than 20% reacted to
penicillin determinants (i.e., skin test positivity, radioallergosorbent testing
(Radioallergosorbent testing is a radioimmune test to detect IgE
antibodies responsible for hypersensitivity.) This cross-reactivity between penicillin
and cephalosporins is significantly less than earlier reports (up to 50%); however,
the results of this study could be attributable to the greater use of third-generation,
rather than the first-generation cephalosporins, which share more chemical structure
similarities with the penicillins. Additional support for the importance of side-chain–
specific reactions of β-lactams comes from observational data noting that 30% of
patients with immediate reactions to penicillins were selective for amoxicillin.
patients with allergy to amoxicillin, studies have found 2% to 38% cross-reactivity
with the cephalosporin cefadroxil; both drugs share the same side chain.
allergic to ampicillin may also have a greater risk of allergic reaction to
cephalosporins that share the same side chain, such as cephalexin, cefaclor,
cephradine, and loracarbef. Some patients also have multiple drug allergies and
could manifest an allergic reaction to these drugs (and others that are not β-lactams)
in a manner similar to their penicillin reaction.
Cross-reactivity between penicillins and carbapenems (imipenem, meropenem,
ertapenem, doripenem) and monobactams (e.g., aztreonam) has also been studied.
One hundred twelve patients with a history of immediate reactions to a penicillin and
a positive skin test to penicillin underwent skin testing with imipenem– cilastatin.
One patient (0.9%) had a positive skin test. One hundred ten of the remaining 111
patients received gradually increasing IM doses of imipenem–cilastatin with no
44 Similarly, 108 children with a history of an immediate
hypersensitivity reaction to a penicillin and a positive skin test underwent
intradermal skin testing to meropenem. One child (0.9%) had a positive skin test. The
remaining 107 subjects received increasing doses of IM meropenem with no
45 There also does not appear to be significant cross-reactivity
between penicillins and the monobactam aztreonam.
have an identical side-chain, however, and there is evidence of cross-reactivity
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