Drug Allergy

58

CHAPTER

Section 

I 

Drug Allergy and Anaphylaxis

Drug Allergy Roland Solensky • Louis M. Mendelson

The clinician is frequently confronted with patients who have histories of various medication allergies. In the pediatric population, antibiotics are by far the most commonly implicated medications in allergic reactions. This chapter will concentrate on the clinical management of pediatric patients who present with a history of drug allergy, and basic science will only be included as it relates to diagnosis and treatment. Due to space limitations, the entire wide spectrum of all drug hypersensitivity disorders cannot be addressed (Box 58-1) and for that discussion, the reader is referred to other texts.1,2 Instead, our discussion will focus on the most clinically relevant reactions – to antibiotics, aspirin (acetylsalicylic acid [ASA]) and other nonsteroidal antiinflam­ matory drugs (NSAIDs), and local anesthetics.

Etiology/Epidemiology Patients and physicians commonly refer to all adverse drug reactions (ADRs) as being ‘allergic’, but the term drug allergy, or drug hypersensitivity, should be applied only to those reactions that are known (or presumed) to be mediated by an immunologic mechanism. ADRs are broadly divided into predictable and unpredictable reactions (Table 58-1). The majority of ADRs are predictable in nature, and examples of these reactions include medication side effects (such as β-agonist-associated tremor) and drug-drug interactions (such as cardiac arrhythmia from the combination of terfenadine and erythromycin). Allergic reactions are a type of unpredictable reaction and they are thought to account for less than 10% of all ADRs. The overall incidence of allergic drug reactions is difficult to estimate accurately due to the wide spectrum of disorders they encompass and a lack of accurate diagnostic tests. Additionally, most studies on incidence of allergic drug reactions include only adult subjects. There are limited epidemiological data for specific types of hypersensitivity disorders in pediatric patients. For example, the incidence of anaphylaxis in children and adolescents who received intramuscular injections of penicillin G was 1.233 and 2.174 per 10 000 injections. In a large pediatric practice, 7.3% of children developed cutaneous eruptions due to oral antibiotics (although no testing or challenges were performed to confirm an allergy).5 While true drug allergy is relatively uncommon, many more children are labeled as being ‘allergic’ to various medications, particularly antibiotics such as penicillins, and end up carrying the label into adulthood. These patients are more likely to be treated with alternate antibiotics, which may be less effective, more toxic, more expensive and lead to the development and 616

spread of certain types of drug resistant bacteria.6–9 For example, vancomycin and fluoroquinolones are much more likely to be prescribed for patients who report a history of penicillin allergy.10–12 Hence, an important and often underappreciated aspect of drug allergy is the morbidity, mortality and economic cost associated with the unnecessary withholding of indicated therapy. Risk factors for the development of drug allergy are poorly understood and most of the limited data come from studies on penicillin allergy in adult subjects. The presence of atopy is not a risk factor for drug allergy,13 although patients with asthma may be more prone to having severe reactions (as is the case with food allergies14,15). The parental route of administration and repeated courses of the same or cross-reacting antibiotic appear to favor the development of immediate-type drug allergy.16 Genetic susceptibility has been described for several types of drug allergy.17–19 Patients with ‘multiple drug allergy syndrome’ have an inherent predilection to develop hypersensitivity reactions to more than one noncross-reacting medication.20–23 There is no single classification scheme that is able to account for all allergic drug reactions. The widely used Gell and Coombs classification scheme of type I to type IV hypersensitivity reactions can be applied to some drug-induced allergic reactions (Table 58-2). Recently, type IV reactions have been subdivided into four types according to the effector cell involved: IVa (macrophages), IVb (eosinophils), IVc (T cells), IVd (neutrophils).24 (Table 58-3). Certain reactions cannot be categorized into any classification scheme despite the fact that we have insight into their underlying mechanism. In other instances, reactions cannot be classified because the mechanism responsible for their elicitation is not understood. Most medications, due to their relatively small size, are unable to elicit an immune response independently. Drugs must first covalently bind to larger carrier molecules such as tissue or serum proteins to act as complete multivalent antigens. This process is called haptenation and the drugs act as haptens. The elicited immune response may be humoral (with the production of specific antibodies), cellular (with the generation of specific T cells), or both. Most drugs are not reactive in their native state and must be converted (either enzymatically or via spontaneous degradation) to reactive intermediates in order to bind to proteins. Frequently, the identity of the intermediates is not known, making it impossible to develop accurate diagnostic tests for drug allergy. The p-i concept (pharmacological interaction with immune receptors) is a recently described mechanism of drug allergy and it is an exception to the hapten hypothesis described above, since © 2010 Elsevier Ltd, Inc, BV DOI: 10.1016/B978-1-4377-0271-2.00058-4

BOX 58-1

Table 58-1  Classification of Adverse Drug Reactions

Partial List of Pediatric Drug Hypersensitivity Disorders

Predictable reactions occur in otherwise normal patients, are generally dose-dependent, and are related to the known pharmacologic actions of the drug. Unpredictable reactions occur only in susceptible individuals, are dose-independent, and are not related to the pharmacologic actions of the drug.

Multisystem Anaphylaxis Serum-sickness and serum sickness-like reactions Drug fever Hypersensitivity syndrome

Reactions

Example

Predictable

Lupus erythematosus-like syndrome

Overdosage

Acetaminophen – hepatic necrosis

Side-effect

Albuterol – tremor

Secondary effect

Clindamycin – Clostridium difficile pseudomembranous colitis

Drug-drug interaction

Terfenadine/erythromycin – torsade de pointes arrhythmia

Generalized lymphadenopathy

Skin Urticaria/angioedema Stevens-Johnson syndrome Toxic epidermal necrolysis Fixed drug eruption Maculopapular or morbilliform rashes

Unpredictable

Contact dermatitis

Intolerance

Aspirin – tinnitus (at usual dose)

Photosensitivity

Idiosyncratic

Chloroquine – hemolytic anemia in G6PD-deficient patient

Bone Marrow

Allergic

Penicillin – anaphylaxis

Hemolytic anemia

Pseudoallergic

Radiocontrast material – anaphylactoid reaction

Erythema nodosum

Thrombocytopenia

CHAPTER 58

Vasculitis

Drug Allergy

Neutropenia Aplastic anemia Eosinophilia

Lung Bronchospasm Pneumonitis Pulmonary edema Pulmonary infiltrates with eosinophilia

Kidney Interstitial nephritis Nephrotic syndrome

Liver Hepatitis Cholestasis

Table 58-2  Gell and Coombs Classification Scheme for Allergic Reactions

Type

Mechanism

Example

Type I

IgE antibodies leading to mast cell/ basophil degranulation

Penicillin – anaphylaxis

Type II

IgG/IgM-mediated cytotoxic reaction against cell surface

Quinidine – hemolytic anemia

Type III

Immune complex deposition reaction

Cephalexin – serum sickness

Type IV

Delayed T cell-mediated reaction

Neomycin – contact dermatitis

Heart Myocarditis

it requires neither haptenation nor formation of reactive intermediates. In this scheme, a drug binds noncovalently to a T cell receptor, which leads to an immune response via interaction with a major histocompatibility complex (MHC) receptor.24,25 No sensitization is required, since there is direct stimulation of memory and effector T cells, analogous to the concept of superantigens. It is not clear what proportion of allergic reactions to drugs, such as antibiotics, occur via the p-i mechanism vs the hapten mechanism.

Table 58-3  Subclassification of Gell and Coombs Type IV Allergic Reactions

Type

Mechanism

Example

Type IVa

TH1 cells activate macrophages/ monocytes by secreting interferon-γ

Tuberculin reaction

Type IVb

TH2 cells secrete IL-4, IL-5 and IL-13 which leads to eosinophilic activation

Maculopapular eruption with eosinophilia

Type IVc

Cytotoxic T cells (both CD4 and CD8) emigrate to tissues and result in cell death

Maculopapular and bullous eruptions

Type IVd

T cell-dependent neutrophilic inflammatory response

Acute generalized exanthematous pustulosis (AGEP)

Diagnostic Tests This section will familiarize the reader with the available diagnostic tests for antibiotic allergy. A full discussion of how to apply these tests in clinical situations follows in the Evaluation and Management section. ASA/NSAIDs and local anesthetics, which are diagnosed by provocative challenges rather than

617

O

O R

C

NH

S

CH3

R

C

Table 58-4  Commonly Used Penicillin Skin Testing Reagents NH

CH3

S

CH3

O

N

CH3 O

COOH

C NH

N H

COOH

Protein

Section    I    Drug Allergy and Anaphylaxis

Penicillins

Penicilloyl

O R

C

O NH

S

CH3 CH3

O

C OH

N H

Penicilloate

COOH

R

C

NH

S

CH2

Concentration

Comment

Penicilloyl-polylysine

6 × 10–5 M

Not commercially available presently

Penicillin G

10 000 units/ml

Commercially available

Penicilloate/penilloate

0.01 M

Not commercially available presently

Ampicillin (intravenous)

1–25 mg/mL

Commercially available

Amoxicillin (intravenous)

1–25 mg/mL

Not commercially available in the USA

CH3 CH3

N H

COOH

Penilloate

Figure 58-1  Structures of major and minor penicillin antigenic determinants. The R-group side chain determines the specific penicillin.

testing, are discussed only in the section on ‘Evaluation and Management’.

Penicillins The immunochemistry of penicillin, as it relates to immunoglobulin E (IgE)-mediated reactions, was elucidated in the 1960s,26–28 allowing for the development of validated diagnostic skin test reagents. Under physiologic conditions, 95% of penicillin spontaneously degrades to penicilloyl – also called the major antigenic determinant (Figure 58-1). The remaining portion of penicillin degrades mainly to penicilloate and penilloate, which, along with penicillin, are called the minor antigenic determinants (see Figure 58-1). Penicilloyl was commercially available for skin testing as Pre-Pen from 1974 until 2004, but since then it has been commercially unavailable in the USA (at the time of writing, Pre-Pen is expected to return to the market in late 2009). Penicillin G is available in an aqueous intravenous preparation. Penicilloate and penilloate, which are often produced in a mixture (minor determinant mixture [MDM]), are not commercially available in the USA. Nevertheless, many allergists have access to MDM,29 presumably from local medical centers. Penicillin skin testing is particularly useful because of its high negative predictive value. In large series that used both major and minor determinants, only 1–3% of skin test-negative patients experienced mild, self-limited reactions when challenged with penicillins.13,30,31 Approximately 10–20% of penicillin skin testpositive individuals are positive only to MDM (not Pre-Pen or penicillin G),13,30,32 therefore skin testing with Pre-Pen and penicillin G alone (without MDM) may fail to detect about 10–20% of truly allergic patients. Since about 10% of patients who report a penicillin allergy are truly allergic, omitting MDM from skin testing may fail to detect about 1–2% (10–20% of 10%) of ‘all comers’ who are labeled penicillin allergic. Over the last two decades, a subset of patients who are able to tolerate penicillin but develop allergic reactions to amoxicillin or ampicillin has been recognized.33 For unclear reasons, this type of selective allergy seems to be less common among patients in the USA32,34 (Louis Mendelson, personal communication) and much more common in patients from Southern Europe.35,36 618

Reagent

Patients selectively allergic to amoxicillin or ampicillin do not mount an immune response to the core β-lactam portion of the molecule, but rather form IgE antibodies directed against particular R group side chains (see Figure 58-1).33 Skin testing with major and minor penicillin determinants is negative, whereas nonirritating concentrations of the culprit aminopenicillin produce a positive response. For amoxicillin and ampicillin, concentrations up to 25 mg/mL have been reported to be nonirritating for intradermal testing.33,37 While the predictive value of such testing is not well established, a positive response is suggestive of an immediate-type allergy. Hence, for patients who reacted to amoxicillin or ampicillin, skin testing should be performed with this antibiotic in addition to the major and minor determinants. Table 58-4 summarizes the commonly used penicillin skin test reagents. Immediate-type penicillin skin testing should be performed only by experienced personnel in a setting prepared to treat possible allergic reactions. Epicutaneous testing should precede intradermal tests, and appropriate positive (histamine) and negative (normal saline) controls should be used. When carried out in this manner, penicillin skin testing is safe.13,30,31 A positive response to both prick and intradermal testing is defined by the diameter of the wheal, which should be 3 mm or greater than that of the negative control.1 There are no validated tests for penicillin-induced delayed maculopapular eruptions. Delayed intradermal skin tests and patch tests have been found to be positive in some patients by European investigators,38,39 but these findings have not been reproduced in the USA40 (and the authors’ unpublished observations in 50 patients). In vitro ELISA-type assays are commercially available for IgE directed at penicilloyl, penicillin, amoxicillin and ampicillin; however, their predictive values have not been defined. When performed in academic settings, the sensitivity of in vitro tests for penicilloyl-specific IgE was as low as 45%.41 Commercial assays have not been similarly analyzed. Additionally, there is no in vitro test for the minor penicillin determinants. A positive in vitro IgE test for penicillin suggests the presence of allergy, but a negative test does not reliably rule out an immediate-type allergy. The basophil activation test is another, more recently developed, in vitro test for penicillin and other β-lactam allergies. a Limited number of publications using the basophil activation test for penicillin allergy indicates it is inferior to penicillin skin testing.42,43

Non-Penicillin Antibiotics Unfortunately, for antibiotics other than penicillin, we generally lack insight into the relevant allergenic determinants that are produced by metabolism or degradation. As a result, there is no

available validated skin testing for these antibiotics. Skin testing with the native antibiotic can be helpful, since a positive response using a concentration that is known to be nonirritating suggests the presence of drug-specific IgE antibodies.1 A negative response, however, does not rule out an allergy. To determine a nonirritating concentration for a given antibiotic, one can refer to previous reports or skin test several nonallergic volunteers. A helpful reference is a recent report of nonirritating concentrations of 16 commonly used antibiotics, as determined in 25 healthy subjects (Table 58-5).44 The skin testing procedure, precautions, and interpretation for non-penicillins are identical to those outlined for penicillin earlier.

When Penicillin Skin Testing is Unavailable

When penicillin skin testing is available, the ideal time to perform skin testing for evaluation of penicillin allergy in children is Table 58-5  Nonirritating Concentrations of Commonly Used Antibiotics*

Antibiotic

Full-Strength Concentration (mg/mL)

Nonirritating Concentration (Dilution from Full Strength)

Cefotaxime

100

10-fold

Cefuroxime

100

10-fold

Cefazolin

330

10-fold

Ceftazidime

100

10-fold

Ceftriaxone

100

10-fold

Tobramycin

40

10-fold

Ticarcillin

200

10-fold

Clindamycin

150

10-fold

Trimethoprim-sulfa

80 (sulfa component)

100-fold

Gentamycin

40

100-fold

Aztreonam

50

1000-fold

Levofloxacin

25

1000-fold

Erythromycin

50

1000-fold

250

10 000-fold

Vancomycin

Nafcillin

50

10 000-fold

Azithromycin

100

10 000-fold

Drug Allergy

As discussed earlier, Pre-Pen is presently commercially unavailable and without it, penicillin skin testing is not recommended. Also, in remote areas, physicians may not have access to an allergist/immunologist to perform penicillin skin testing even if appropriate reagents are available. In these situations, elective evaluation of penicillin allergy is not recommended; instead, evaluation should be limited to patients who require treatment with penicillins. In the absence of penicillin skin testing, tests for serum penicillin-specific IgE may be utilized and, if positive, penicillins should be avoided or administered via rapid desensitization. A negative in vitro test lacks sufficient negative predictive value to rule out an allergy, therefore, depending on the history, penicillin should be administered either via graded challenge or rapid desensitization (see the section on ‘Treatment Options’). For example, if a patient reports a non-life-threatening reaction to penicillin more than 10 years ago, it is less likely that the patient is allergic, and penicillin may be administered via cautious graded challenge, particularly if it is given orally. (Figure 58-2.) For more recent and/or severe reactions, penicillin should be administered via rapid desensitization. (Figure 58-2.) Also, more caution needs to be exercised in patients being treated via the parenteral route. Patients who report reactions consistent with severe non-IgE-mediated reactions (such as Stevens Johnson syndrome [SJS], toxic epidermal necrolysis [TEN], interstitial

When Penicillin Skin Testing is Available

CHAPTER 58

Evaluation and Management

nephritis, or hepatitis) are not candidates for graded challenge or desensitization.

Data from Empedrad RB, Earl HS, Gruchalla RS. J Allergy Clin Immunol 2003; 112:629–630. *Skin testing was performed intradermally with intravenous formulations of the antibiotics.

History of penicillin allergy

Penicillin skin testing not available

Serum IgE for penicilloyl and penicillin

1. Give alternate antibiotic 2. Desensitize to penicillin

Depending on history, administer penicillin via cautious graded challenge or desensitization

No in vitro testing

If reaction distant (>10 years ago), not life-threatening, and treatment is oral, consider penicillin administration via cautious graded challenge

If reaction distant (>10 years ago), or recent, or treatment is parenteral, administer penicillin via rapid desensitization

Figure 58-2  Management of pediatric patients with a history of penicillin allergy without availability of penicillin skin testing. Evaluation should be limited to situations when treatment with penicillin is anticipated.

619

History of penicillin allergy

Skin test with Pre-Pen, penicillin G, and MDM

Section    I    Drug Allergy and Anaphylaxis

() Give penicillin

()

Skin test with Pre-Pen and penicillin G only (MDM not available) ()

1. Give alternate antibiotic 2. Desensitize to penicillin

() 1. Give penicillin via graded challenge 2. Desensitize if reaction severe and recent

History of amoxicillin allergy

Skin test with Pre-Pen, penicillin G, MDM, and amoxicillin

() Give amoxicillin

()

Skin test with Pre-Pen and penicillin G only (either MDM or amoxicillin not available) ()

1. Give alternate antibiotic 2. Desensitize to amoxicillin

() 1. Give amoxicillin via graded challenge 2. Desensitize if reaction severe and recent

when they are well and not in immediate need of the antibiotic.45 Testing in acute situations, when children are sick, is often difficult if not impossible to accomplish. Patient reaction history alone, without skin testing, cannot reliably rule out an allergy to penicillin;46,47 therefore, even patients with vague reaction histories are candidates for penicillin skin testing. Up to 10% of patients carry a label of penicillin allergy, but about 90% of them lack penicillin-specific IgE and are able to receive penicillins safely.13,45,48,49 These children are commonly denied access, not only to penicillins but also to other β-lactams, which leaves the clinician with few acceptable antibiotic choices. Often, once a label of penicillin allergy is made, it is carried indefinitely into adulthood. Patients with a history of penicillin allergy are frequently treated with broad-spectrum antibiotics,8,9,12 the use of which contributes to the development of multiple-drug-resistant bacteria.7,50 It is known that more judicious use of broad-spectrum antibiotics can help reduce the spread of antibiotic resistance.51,52 One way to achieve this goal is to identify, via ‘elective’ skin testing, the numerous children and adolescents who are mistakenly labeled as ‘penicillin allergic’. If penicillin skin testing is positive, penicillins should be avoided and alternative antibiotics should be used (Figure 58-3). If the patient develops an absolute need for penicillin, rapid desensitization can be performed (see the section on ‘Treatment Options’). In the vast majority of children with a history of penicillin allergy, skin testing is negative. Despite the test’s excellent negative predictive value, patients, their parents, and referring physicians are frequently reluctant to ‘trust’ the results, and consequently β-lactam antibiotics are not prescribed.53,54 To unequivocally prove the medication’s safety and to alleviate patients’ and physicians’ concerns, an oral challenge with the identical antibiotic that caused the previous reaction should be performed. 620

Figure 58-3  Management of pediatric patients with a history of penicillin or amoxicillin allergy when penicillin skin testing is available. Ideally, skin testing is performed electively, not in situations of acute need.

In the past, there was theoretical concern that patients might become re-sensitized (or redevelop their allergy) as a result of a course of penicillin, placing them at risk of an immediate reaction during subsequent exposure. However, evidence does not suggest that children are at increased risk of becoming re-sensitized. Mendelson and colleagues45 reported that among 240 history-positive/skin test-negative children and adolescents, only 1% converted to a positive skin test following a course of penicillin. These findings have been confirmed in an additional 1500 pediatric patients by the authors (unpublished observations). Patients whose histories are clearly consistent with severe nonIgE-mediated reactions (such as SJS, TEN, interstitial nephritis, or hepatitis) should not undergo penicillin skin testing and penicillins should be avoided indefinitely.

Cephalosporins Patients with a History of Penicillin Allergy Penicillins and cephalosporins share a common β-lactam ring (Figure 58-4) and early in vitro studies indicated extensive immunologic cross-reactivity between these compounds.55 Recent studies of patients with a history of penicillin allergy treated with cephalosporins (without prior penicillin skin testing) demonstrated much lower reaction rates than ones performed in the 1970s (see Table 58-6). This observation may be partially due to the fact that, prior to 1980, cephalosporins were contaminated by trace amounts of penicillin.56 Results of studies of this type are limited by the fact that patients were not proven to be penicillinallergic at the time of cephalosporin administration, and the vast majority likely lacked penicillin-specific IgE at the time of treatment with cephalosporins. More informative clinical studies are

O R

C

O NH

CH3

S

R1

C

CH3

O

N

N C R2

Cephalosporins

O C

C

O

COOH

Penicillins

R

S

NH

R1 NH

H3C

O

N

O

Monobactams

N

COOH

Carbapenems

Figure 58-4  Structures of β-lactam antibiotics, all of which share a common four-member β-lactam ring.

Table 58-6  Summary of Reports in Which Cephalosporins Were Administered to Patients with a History of Penicillin Allergy (No Skin Testing Performed)

Cephalosporin Reaction Rate History of Penicillin Allergy

No History of Penicillin Allergy

Comments

Dash (1975)96

7.7% (25/324)

0.8% (140/17 216)

No reaction details

8.1% (57/701)

1.9% (285/15 007)

No reaction details

0.33% (1/300)

0.04% (1/2431)

Reaction questionable

0.17% (1/606)

0.06% (15/22 664)

Reaction = eczema

8.4% (7/83)

N/A

Reactions convincing

Petz (1978)97 Goodman et al (2001)

98

99

Daulat et al (2004)

Fonacier et al (2005)

100

Drug Allergy

Reference (year)

CHAPTER 58

SO3H

S R2

CH

those in which patients with positive penicillin skin tests are challenged with cephalosporins (Table 58-7), and overall, only 3.4% of patients reacted to cephalosporins. Patients who are selectively allergic to aminopenicillins, based on limited data, exhibit higher rates of cross-reactivity with cephalosporins that share an identical R-group side chain (such as amoxicillin and cefadroxil).37,57 Therefore, more caution should be exercised in patients who are selectively allergic to aminopenicillins when they are treated with cephalosporins that contain identical R-group side chains. Tables 58-8 and 58-9 list groups of β-lactam antibiotics that share identical R1 or R2 group side chains. Figure 58-5 outlines the clinical approach to children with a history of penicillin allergy who require treatment with cephalosporins. When penicillin skin testing is available, ideally children should be tested when they are well and not in immediate need of antibiotic therapy (to optimize choice of antibiotic therapy, as discussed previously). Since 90% or more will be penicillin skin test-negative, they are not at increased risk of

Table 58-7  Summary of Reports in Which Cephalosporins Were Administered to Patients with Positive Penicillin Skin Tests*

Reference

No. of Patients

Girard45 46

Assem and Vickers 101

No. of Reactions (%)

Reaction(s) to Cephalosporin

Skin Test

23

2 (8.7)

Cephaloridine

No

3

3 (100)

Cephaloridine

No

3

0

Yes

Solley et al102

27

0

No

103

62

1 (1.6)

Not noted

No

17

2 (11.8)

Cefamandole

No

Warrington et al

Saxon et al

104

Blanca et al

105

Shepherd and Burton Audicana et al

106

107

Pichichero

Novalbos et al

108

Macy34 Romano58 109

Greenberger and Klemens 49

Park

TOTAL

9

0

No

12

0

Yes

39

2 (5.1%)

23

0

42

1 (2.4%)

75

0

Yes

6

0

No

37

2 (5.4%)

377

13 (3.4%)

Cefaclor and ?

No Yes

Cefixime

Not noted

No

No

*All patients had positive skin test responses to Pre-Pen, Penicillin G, and/or minor determinant mixture. Patients negative to the major and minor penicillin determinants but positive to amoxicillin or ampicillin are not included.

621

Section    I    Drug Allergy and Anaphylaxis

Table 58-8  Groups of β-Lactam Antibiotics that Share Identical R1-Group Side Chains. Each Column Represents a Group with Identical R1 Side Chains. Brand Names Are Included for Commercially Available β-Lactams Amoxicillin (Amoxil)

Ampicillin (Principen)

Ceftriaxone (Rocephin)

Cefoxitin (Mefoxin)

Cefamandole (Mandol)

Ceftazidime (Ceftaz, Fortaz)

Cefadroxil (Duracef)

Cefaclor (Ceclor)

Cefotaxime (Claforan)

Cephaloridine

Cefonicid (Monocid)

Aztreonam (Azactam)

Cefprozil (Cefzil)

Cephalexin (Keflex)

Cefpodoxime (Vantin)

Cephalothin

Cefatrizine

Cephradine (Velosef)

Cefditoren (Spectracef)

Cephaloglycin

Ceftizoxime (Cefizox)

Loracarbef (Lorabid)

Cefmenoxime (Cefmax)

Table 58-9  Groups of β-Lactam Antibiotics that Share Identical R2-Group Side Chains. Each Column Represents a Group with Identical R2 Side Chains. Brand Names Are Included for Commercially Available β-Lactams. Cephalexin (Keflex)

Cefotaxime (Claforan)

Cefuroxime (Ceftin)

Cefotetan (Cefotan)

Cefaclor (Ceclor)

Ceftibuten (Cedax)

Cefadroxil (Duricef)

Cephalothin

Cefoxitin (Mefoxin)

Cephradine (Velosef)

Cephaloglycin

Cefmetazole

Cefamandole (Mandol)

Loracarbef (Lorabid)

Ceftizoxime (Cefizox)

Cephapirin (Cefadyl)

Cefpiramide

History of penicillin allergy

Penicillin skin testing not available

Penicillin skin testing available

Penicillin skin testing

Administer cephalosporin via full dose or graded challenge, depending on reaction history, clinical stability of patient, and route of administration

Give cephalosporin

Administer cephalosporin via graded challenge or desensitization

having allergic reactions to cephalosporins and therefore can receive them safely. If skin testing is positive, the clinician has the option of administering the cephalosporin via graded challenge or rapid desensitization (see Figure 58-5). Under most circumstances, we recommend a graded challenge (see the section on ‘Treatment Options’), given that the likelihood of reacting is only about 2–3% (Table 58-6). If penicillin skin testing is unavailable, depending on the reaction history, the likelihood that the patient is penicillin-allergic, the clinical stability of the patient, and the route of administration (oral vs parenteral), cephalosporins may be administered via either full dose or graded challenge.1 Skin testing with cephalosporins (using a nonirritating concentration) prior to administering them to patients with a history of penicillin allergy may be considered, based on limited data.58

Patients with a History of Cephalosporin Allergy The evaluation of patients with a history of cephalosporin allergy who require the same or another cephalosporin is limited by lack 622

Figure 58-5  Administration of cephalosporins to pediatric patients with a history of penicillin allergy.

of standardized validated cephalosporin skin test reagents (see Figure 58-6). Skin testing with nonirritating concentrations of native cephalosporins can be of some value, especially if it is positive, but its negative predictive value is uncertain. Additionally, there are no definitive data on the extent of cross-reactivity among different cephalosporins, and hence, the safety of administering a given cephalosporin to a patient who has previously experienced an allergic reaction to another cephalosporin is not known. The general belief is that the allergic response to cephalosporins is directed at the R group side chains, rather than the β-lactam portion of the molecule and that patients who have reacted to one cephalosporin can tolerate other cephalosporins with dissimilar side chains. Recent investigations into potential allergic crossreactivity among cephalosporins using cephalosporin skin testing or in vitro IgE testing places some doubt on this theory.59–62 Collectively, approximately half of the 95 subjects demonstrated a positive test only to the cephalosporin that caused their reaction, whereas the other half showed positive tests to more than one cephalosporin, including ones with dissimilar R-group side

History of cephalosporin allergy

Penicillin skin testing

(–) Give penicillin

(+) 1. Give alternate antibiotic 2. Desensitize to penicillin

History of cephalosporin allergy

Skin testing with same cephalosporin that caused reaction

(+)

(–)

Skin testing with different cephalosporin using nonirritating concentration

(+)

1. Give alternate antibiotic 2. Desensitize to cephalosporin

(–)

1. Give cephalosporin via graded challenge 2. Desensitize to severe and recent cephalosporin reaction

chains.59–62 The results suggest that some cephalosporin-allergic patients form cross-reacting IgE antibodies, but none of the patients were challenged to confirm this suspicion. Additionally, there are no published series of patients allergic to a given cephalosporin challenged with alternate cephalosporins.

Other β-Lactam Antibiotics Monobactams Monobactams differ from other β-lactams by their monocyclic ring structure (see Figure 58-4), and aztreonam is the prototype drug in this class. In vitro studies showed no immunologic crossreactivity between aztreonam and either penicillin or cephalosporins, with the exception of ceftazidime, which shares an R group side chain identical with aztreonam.63 Lack of clinical crossreactivity has been confirmed in numerous penicillin skin testpositive subjects who were challenged and tolerated aztreonam.64,65 Therefore, patients who are allergic to penicillins or cephalosporins (except for ceftazidime) can safely receive aztreonam. Conversely, patients who have reacted to aztreonam can safely receive penicillins and cephalosporins (except for ceftazidime).

Carbapenems Allergic cross-reactivity between penicillin and carbapenems has been studied via retrospective evaluation of hospitalized patients with a history of penicillin allergy who were treated with imipenem or meropenem. (see Table 58-10). Most of these reports demonstrated somewhat increased rates of reactions to carbap-

Drug Allergy

1. Give alternate antibiotic 2. Desensitize to cephalosporin 3. Give cephalosporin via cautious graded challenge if reaction distant or vague

CHAPTER 58

If cephalosporin skin testing not available, give cephalosporin with dissimilar side chain via graded challenge

Figure 58-6  Management of pediatric patients with a history of cephalosporin allergy. (From Bernstein IL, Gruchalla RS, Lee RE, et al. Ann Allergy Asthma Immunol 1999;83:665–700.)

Table 58-10  Summary of Reports in Which Carbapenems Were Administered to Patients with a History of Penicillin Allergy (No Skin Testing Performed)

Carbapenem Reaction Rate Reference

History of No History of Penicillin Allergy Penicillin Allergy P value

McConnell et al110

6.3% (4/63)

N/A

N/A

11% (11/100)

2.7% (3/111)

0.024

9.2% (15/163)

3.9% (4/103)

0.164

0% (0/110)

N/A

N/A

Prescott et al

111

112

Sodhi et al

113

Cunha et al

enems in patients with a history of penicillin allergy compared to those without a history. However, none of these patients underwent penicillin skin testing to indicate whether the patient was allergic at the time of treatment with carbapenbems and it is highly likely that the vast majority were not penicillin-allergic. Carbapenem challenges in penicillin skin test-positive patients have been reported in three recent studies (see Table 58-11).66–68 Combining the results, 317 penicillin skin test-positive patients tolerated carbapenems (and each was also carbapenem skin testnegative), whereas 3 patients had positive skin tests to carbapenems and were not challenged. Hence, the data on allergic cross-reactivity between penicillin and carbapenems is very similar to that for penicillin/cephalosporins. Therefore, the 623

Table 58-11  Summary of Reports in Which Carbapenems Were Administered to Patients with Positive Penicillin Skin Tests (All Patients Were Also Skin Tested with Carbapenems)

Reference

No. of Patients

No. of Reactions

Carbapenem Given

Comment

Romano A66

110

0

Imipenem

One patient imipenem skin test-positive

67

103

0

Meropenem

One patient meropenem skin test-positive

107

0

Meropenem

One patient meropenem skin test-positive

Romano A

68

Section    I    Drug Allergy and Anaphylaxis

Atanaskovic

clinical approach to carbapenem administration in patients with a history of penicillin allergy is analogous to what was described for cephalosporins.

Non-β-Lactam Antibiotics The lack of reliable diagnostic tests for non-β-lactam antibiotics makes evaluation of children who have reacted to one of these medications more challenging. As discussed earlier, some information can be gleaned from skin testing with nonirritating concentrations of the native antibiotics, but an immediate-type allergy cannot be ruled out. Consequently, unlike penicillin allergy, it is not practical to evaluate these patients on an elective basis. Unless the previous reaction was clearly predictable in nature, such as emesis from erythromycin, the medication should be avoided in the future. Evaluation with skin testing should be performed only if readministration of the culprit antibiotic is being considered. This commonly occurs in patients who have reacted to several different antibiotics and are ‘running out’ of antibiotic choices. If skin testing with a nonirritating concentration of the antibiotic is positive, the medication should be avoided. If such a patient develops an absolute need for the antibiotic, acute desensitization should be performed. If skin testing is negative, either desensitization or a graded challenge can be performed, depending on the ‘strength’ of the history of the previous reaction. The total dose of the antibiotic used in skin testing can be used as a starting point for desensitization or graded challenge (see the section on ‘Treatment Options’). Patients who previously experienced SJS, TEN, or other serious non-IgEmediated reactions, should not be given the same antibiotic. Aside from the β-lactams, the two most commonly used antibiotics in children are macrolides and sulfonamides; a brief discussion of these antibiotics follows.

Sulfonamides Sulfonamide drugs are those that contain an SO2-NH2 moiety. The majority of adverse reactions to sulfonamide antibiotics are non-IgE-mediated delayed cutaneous reactions.69 They vary from benign, self-limited maculopapular/morbilliform eruptions to severe, potentially life-threatening reactions such as SJS and TEN. Metabolism of sulfonamides produces a number of reactive intermediates that appear to play a pivotal role in various allergic reactions.69 Despite this knowledge, there are no in vitro or in vivo tests that can predict a patient’s risk of developing an adverse reaction to sulfonamides. A provocative challenge with a sulfonamide remains the only way to determine whether a patient is truly allergic, but this should be reserved for cases in which alternate antibiotics cannot be substituted and if the previous reaction was not severe. Due to the propensity of sulfonamides to cause severe cutaneous reactions such as SJS and TEN, most children who have reacted to a member of the family should simply avoid all sulfonamide antibiotics. There are struc624

tural differences between sulfonamide antibiotics and nonantibiotic sulfonamides (such as diuretics, oral hypoglycemics, carbonic anhydrase inhibitors, celecoxib and sumatriptan), in that the latter lack an N4 aromatic amine and an N1 substituted ring. These structural features are important in mediating allergic reactions to sulfonamide antibiotics and a growing body of clinical evidence indicates there is no increased risk of reactions to nonantibiotic sulfonamides in patients with a history of allergy to sulfonamide antibiotics.23,70 Patients with human immunodeficiency virus (HIV) are at particularly high risk of developing various cutaneous reactions from sulfonamides.69 Unfortunately, these patients are also likely to require treatment with trimethoprim-sulfamethoxazole (TMPSMX), since it is the antibiotic of choice for both prophylaxis and acute treatment of Pneumocystis carinii pneumonia. Various TMP-SMX ‘desensitization’ protocols ranging in length from a few hours to several weeks have been reported in adult and pediatric patients with HIV.71–73 ‘Desensitization’ may be a misnomer for these procedures because randomized trials of rechallenge (single dose) vs desensitization demonstrated no differences in the success rates.74,75

Macrolides Hypersensitivity reactions to macrolides, particularly IgE-mediated ones, appear to be less common compared to β-lactam and sulfonamide antibiotics. While there are no published studies addressing the degree of allergic cross-reactivity among the different macrolides, our clinical experience is that it is low. This observation may partly be due to the structural difference between azithromycin (which is an azalide) and erythromycin or clarithromycin. Furthermore, it is possible that passage of time between the initial macrolide reaction and when a patient is treated with another macrolide resulted in resolution of the allergy. There is evidence for waning of allergy to macrolides from studies in which patients with suspected macrolide were challenged with the same antibiotic to which they reacted previously. Of 209 adult patients with a convincing history of immediate-type allergy to macrolides, only 22 (10.5%) reacted to the same macrolide antibiotic during a supervised graded challenge.76,77 Therefore, in children who have reacted to a given macrolide antibiotic, it is reasonable to evaluate the safety of another macrolide when treatment is anticipated. This can be done via skin testing (using a nonirritating concentration of the native antibiotic) followed by graded challenge, assuming testing is negative. If testing is positive and there is an absolute need to treat the patient with a macrolide, rapid desensitization can be performed.

Local Anesthetics True hypersensitivity reactions to local anesthetics in children are uncommon and usually consist of a delayed contact dermatitis;

Epicutaneous skin test with the full-strength drug (–) Intradermal test with 1:100 dilution of the drug

Table 58-12  Benzoate Esters and Amides Constituting the Two Major Classes of Local Anesthetics*

(+) (+)

Test with another amide anesthetic

(–) Proceed with test dosing: 1. Subcutaneously inject 0.1cc of 1:10 dilution of the drug 2. Subcutaneously inject 0.1cc of the full-strength drug 3. Subcutaneously inject 1cc of the full-strength drug

Figure 58-7  Management of pediatric patients with previous reactions to local anesthetics. Intervals between steps are 15 minutes. Generally, an amide is used because the benzoate esters cross-react immunologically whereas the amides do not, and frequently patients do not know which drug they reacted to previously. (Data from Patterson R, DeSwarte RD, Greenberger PA, et al. Allergy Proc 1994; 15:239–264.)

Aspirin and Other Nonsteroidal Antiinflammatory Drugs Aspirin (acetylsalicylic acid [ASA]) and other NSAIDs have been associated with five types of allergic and pseudo-allergic reactions (Table 58-13).79 Reactions that are caused by modifying effects on arachidonic acid metabolism – namely respiratory reactions (in patients with aspirin-exacerbated respiratory disease [AERD]) and urticarial reactions (in patients with underlying chronic idiopathic urticaria) show cross-reactivity with other NSAIDs, as one would expect. Patients with AERD, however, can safely receive tartrazine, azo and nonazo dyes, sulfites, monosodium glutamate, and usual doses of acetaminophen (although a minority of patients experiences mild reactions above 1000 mg).79,80 Recently, drugs that selectively block the cyclooxygenase-2 (COX-2) enzyme, such as celecoxib, have also been found to be safe in patients with AERD81 and virtually all aspirin-sensitive patients with chronic idiopathic urticaria.82

Examples of Trade Names

Benzocaine

Topical

Orajel, Hurricane, Lanacaine, many others

Butamben picrate

Topical

Butesin

Chloroprocaine

Injectable

Nesacaine

Cocaine

Topical

Cocaine

Procaine

Injectable

Novocain

Proparacaine

Ophthalmic

Alcaine, Opthcaine, Opthetic

Tetracaine

Injectable, topical, ophthalmic

Pontocaine

Bupivacaine

Injectable

Marcaine, Sensorcaine

Dibucaine

Topical

Nupercaine

Etidocaine

Injectable

Duranest, Durnest MPF

Lidocaine

Injectable, topical

Xylocaine, Dilocaine, Nervocaine, many others

Mepivacaine

Injectable

Carbocaine, Polocaine, Isocaine

Prilocaine

Injectable

Citanest

Ropivacaine

Injectable

Naropin

Topical

EMLA

Benzoate Esters

Amides

Drug Allergy

anaphylaxis from local anesthetics occurs very rarely, if ever.78 Most adverse reactions are vasovagal, anxiety or toxic reactions, or predictable side-effects of epinephrine. Unfortunately, patients who experience any adverse reaction are frequently labeled as being ‘allergic’ and told to avoid all ‘caines’ in the future. Evaluation of children with a supposed allergy to local anesthetics serves to alleviate dentists’ and physicians’ concerns and may prevent these patients from being subjected to the increased risk of general anesthesia. Figure 58-7 summarizes the approach to children with previous reactions to local anesthetics. Data from patch testing suggest there is cross-reactivity among the benzoate esters but not among the amides (Table 58-12).78 While these findings may have no significance on immediate-type reactions, it is generally recommended that if a patient previously reacted to an ester, an amide should be used in evaluation for re-administration. If the identity of the previous local anesthetic is not known or if it was an amide, another amide can be used. Additionally, during skin testing and challenge, one should attempt to employ the same agent that will subsequently be used by the dentist or physician.

Available Forms

CHAPTER 58

May safely administer drug in future

Generic Name

Combination Lidocaine/Prilocaine

*Patch testing data indicate there is cross-reactivity among the esters but not the amides.

Unlike respiratory reactions, acute urticarial or anaphylactic reactions in otherwise normal individuals are medication specific (Table 58-13). Hence it is reasonable to perform graded challenges in these individuals with another NSAID to identify an agent that can be safely used in the future. Not uncommonly, patients with acute urticarial reactions are mistakenly told to avoid all NSAIDs indefinitely. With the exception of respiratory reactions in asthmatics, there are no data on the incidences of these reactions in children; however, clinical experience suggests that it is low. This observation may be partly the result of the infrequent use of ASA caused by concerns of Reye’s syndrome in children. The incidence of ASA sensitivity in children with asthma has been investigated in six prospective studies in which blinded oral challenges were performed.83–88 The rate of positive challenges varied from 0% to 28%, and there was a trend for more respiratory reactions in adolescents compared to younger children. Overall, the data indicate that ASA sensitivity in asthmatic children under the age of 10 years is rare, but thereafter it begins to approach the reported incidence in adults. Patients with AERD, whose nasal disease or asthma is poorly controlled with use of medications, are candidates for ASA desensitization. This procedure, unlike the one described for antibiotic desensitization in the Treatment Options section below, involves administration of ASA in order to cautiously induce a respiratory reaction, following which patients enter a refractory phase that can be maintained with continued administration of ASA. Long-term studies of patients maintained on chronic ASA 625

Section    I    Drug Allergy and Anaphylaxis

Table 58-13  Major Types of Hypersensitivity Reactions to ASA and Other NSAIDs

Reaction Type

Underlying Disease

Cross-Reactions

COX-1 Inhibition

Other Immunologic Mechanisms

Cross-reacting respiratory

Asthma, rhinitis, polyposis

ASA/NSAIDs

Yes

None

Cross-reacting urticaria

Chronic urticaria

ASA/NSAIDs

Yes

None

Urticaria/anaphylaxis

None

None

No

IgE-mediated (presumed)

Aseptic meningitis (only NSAIDs)

None

None

No

Delayed hypersensitivity (presumed)

Hypersensitivity pneumonitis (only NSAIDs)

None

None

No

Delayed hypersensitivity (presumed)

Modified from Stevenson DD. Immunol Allergy Clin North Am 1998;18:773–798. ASA, acetylsalicylic acid (aspirin); NSAIDs, nonsteroidal antiinflammatory drugs; COX, cyclooxygenase; IgE, immunoglobulin E.

Table 58-14  Penicillin Oral Desensitization Protocol

Step*

Penicillin (mg/mL)

Amount (mL)

Dose Given (mg)

Cumulative Dose (mg)

1

0.5

0.1

0.05

0.05

2

0.5

0.2

0.1

0.15

3

0.5

0.4

0.2

0.35

4

0.5

0.8

0.4

0.75

5

0.5

1.6

0.8

1.55

6

0.5

3.2

1.6

3.15

7

0.5

6.4

3.2

8

5

1.2

6

12.35

9

5

2.4

12

24.35

10

5

5

25

49.35

11

50

1

50

100

12

50

2

100

200

13

50

4

200

400

14

50

8

400

800

6.35

Observe patient for 30 minutes, then give full therapeutic dose by the desired route. *Interval between doses is 15 minutes. Modified from Sullivan TJ. Drug allergy. In: Middleton E, Reed CE, Ellis EF, et al, eds. Allergy: principles and practice, 4th edn. St Louis: Mosby; 1993.

desensitization demonstrated improved clinical outcomes for both upper and lower respiratory diseases.89–91 ASA desensitization is rarely performed in children, because severe, poorly controlled AERD is encountered very infrequently in the pediatric population. Full discussion of ASA desensitization is beyond the scope of this chapter and the reader is referred to other texts.1,79

Treatment Options Desensitization Rapid desensitization to an antibiotic should be considered in children who have an IgE-mediated allergy, and no acceptable alternative treatment is available. Desensitization is an induction of temporary tolerance, which converts a child who is highly allergic to a drug to a state in which the child can tolerate treatment with the medication. Although most published desensitization protocols involve penicillin, the principle has been applied successfully to other antibiotics, including cephalosporins, 626

sulfonamides, vancomycin, macrolides, quinolones, aminoglycosides, pentamidine, and antituberculin agents.72 Rapid desensitization is thought to somehow render mast cells unresponsive to the drug used in the procedure, but the exact immunologic mechanism is unknown. Desensitization can be performed either by the oral or intravenous route. Tables 58-14 and 58-15 list representative protocols for penicillin desensitization, and these can be modified and used for other classes of antibiotics. Several principles of management have been derived from studies on penicillin desensitization,92–95 and presumably they hold true for other antibiotics also. First, the amount of drug the patient tolerated during skin testing determines a safe initial dose for desensitization, which generally translates to 1/10 000 or less of the full therapeutic dose. Second, doubling the dose every 15 minutes until the recommended dose is reached is effective in nearly all instances. Mild reactions occur in about a third of patients, but no fatal or life-threatening reactions have been reported. Third, desensitization does not prevent non-IgE reactions such as serum sickness, hemolytic anemia, or interstitial nephritis from occurring. Fourth, for the patient to remain in a

Table 58-15  Penicillin Intravenous Desensitization Protocol Using a Continuous Infusion Pump

Step*

Penicillin (mg/mL)

Amount (mL)

Dose Given (mg)

Cumulative Dose (mg)

0.001

4

0.001

0.001

2

0.001

8

0.002

0.003

3

0.001

16

0.004

0.007

4

0.001

32

0.008

0.015

5

0.001

60

0.015

0.03

6

0.001

120

0.03

0.06

7

0.001

240

0.06

0.12

8

0.1

5

0.125

0.245

9

0.1

10

0.25

0.495

10

0.1

20

0.5

1

11

0.1

40

1

2

12

0.1

80

2

4

13

0.1

160

4

8

14

10

3

7.5

15

15

10

6

15

30

16

10

12

30

17

10

25

62.5

18

10

50

125

19

10

100

250

500

20

10

200

500

1000

CHAPTER 58

1

60 123

Drug Allergy

250

Observe patient for 30 minutes, then give full therapeutic dose by the desired route. *Interval between doses is 15 minutes.

desensitized state, it is necessary to continue treatment with the antibiotic. If treatment is stopped, the patient reverts back to being allergic and is again at risk of developing anaphylaxis and desensitization would need to be repeated. Rapid desensitization should be performed only by a physician experienced in the procedure, in a monitored setting (inpatient or outpatient), with intravenous access and necessary medications and equipment to treat anaphylaxis. Pharmacy staff should be consulted prior to the procedure to assist with preparation of the required drug dilutions. Generally, oral desensitization is preferred because it is assumed to be safer, but taste may be an issue in younger children or some medications may not be available in an oral form, in which case the intravenous route can be used. Patients should not be pretreated with corticosteroids or antihistamines because they may mask early signs of an allergic reaction. Treatment with β-adrenergic blocking medications should temporarily be withheld before desensitization. Patients should be continually observed for the presence of IgE-mediated allergic symptoms, along with regular monitoring of vital signs and peak expiratory flow values. Before the procedure, patients with asthma or other pulmonary disease should be optimally controlled. If mild reactions occur, they should be treated and the dose not be advanced until they have resolved.

Graded Challenge Graded challenge, also known as test dosing, refers to cautious administration of a medication to a patient who is unlikely to be

truly allergic to it.1 Unlike desensitization, test dosing does not modify the immune response to a drug. Graded challenges are most commonly undertaken with medications for which testing cannot adequately rule out an allergy. Examples include nonpenicillin antibiotics, penicillins (when Pre-Pen or MDM is not available) and cephalosporin administration in penicillin-allergic patients. Children who previously experienced severe reactions or who are suspected to be allergic to a medication should undergo desensitization rather than graded challenge. Most graded challenges can be safely carried out in an office without intravenous access but with preparedness to treat potential allergic reactions including anaphylaxis. The pace of the challenge and degree of caution exercised depend on the likelihood that the patient may be allergic and the physician’s experience and comfort level with the procedure. Generally, the starting dose is 1/10 to 1/100 of the full dose and approximately 5- to 10-fold increasing doses are administered every 30 to 60 minutes until the full therapeutic dose is reached. At the first sign of any allergic reaction, the procedure should be abandoned and the patient should be treated appropriately. If at a later point the patient requires the medication, it should be administered via desensitization.

Conclusions Children commonly experience adverse reactions to medications, many of which are falsely labeled as being allergic and subsequently avoided due to a fear of causing a severe life627

BOX 58-2  Key concepts Drug Allergy • Children are commonly labeled as being allergic to various medications and a thorough allergy evaluation can help determine which patients are truly at risk of a severe reaction.

Section    I    Drug Allergy and Anaphylaxis

• The majority of children labeled as allergic to medications, particularly antibiotics, can take them without fear of a severe reaction. • The ideal time to evaluate drug allergy in children is when they are well and not in acute need of treatment.

BOX 58-3  Therapeutic principles 1. Penicillin allergy a. About 10% of children are labeled as being ‘penicillin allergic’. b. The vast majority of children with the label of penicillin allergy can safely take all β-lactam antibiotics without fear of an allergic reaction. c. The ideal way to determine whether a child has an IgEmediated allergy to penicillin is by skin testing with the appropriate penicillin reagents, followed by an oral challenge (assuming the test is negative). d. When penicillin skin testing is possible, the ideal time to evaluate penicillin allergy in children is when they are well and not in immediate need of antibiotic treatment. e. When penicillin skin testing is not possible, evaluation of penicillin allergy should be limited to children who are likely to require treatment with it. f. Physicians should make an effort to evaluate penicillin allergy in children and not allow them to unnecessarily carry the label into adulthood. 2. Allergy to nonpenicillin antibiotics a. There are no validated skin testing reagents to accurately rule out an IgE-mediated allergy. b. Skin testing with nonirritating concentrations of antibiotics can assist the clinician in evaluating a possible allergy. c. Graded challenge or desensitization can be used in situations where need for an antibiotic arises. 3. Allergy to local anesthetics a. True immediate-type allergic reactions to local anesthetics are very rare. b. Skin testing followed by graded challenge rules out an allergy to local anesthetics in virtually all children. 4. Aspirin (acetylsalicylic acid [ASA])/nonsteroidal antiinflammatory drug (NSAID) allergy a. Reactions to ASA and NSAIDs are less frequent in children than they are in adults. b. Reactions in patients with underlying asthma or chronic urticaria are cross-reactive among all NSAIDs. c. Reactions in patients without underlying asthma or chronic urticaria, including anaphylaxis/angioedema/urticaria, are medication specific.

threatening reaction (Box 58-2). If a child has reacted to several different medications, such as antibiotics, physicians are often at their ‘wit’s end’ about how to approach future inevitable treatment courses. Likewise, parents of patients are apprehensive and concerned that their child may ‘die’ because of a lack of safe 628

medications. Using the tools (Box 58-3) discussed in this chapter, physicians can play an important role in helping to sort out which medications a child can safely receive, and in many cases prevent them from needlessly being labeled as allergic for the rest of their lives.

References 1. Solensky R, Khan D, Bloomberg GR, et al. Drug hypersensitivity: an updated practice parameter. Ann Allergy Asthma Immunol 2009; in press. 2. Volcheck GW, Hagan JB, Li JT, editors. Drug hypersensitivity. Immunol Allergy Clin North Am 2004;23:345-543. 3. International Rheumatic Fever Study Group. Allergic reactions to longterm benzathine penicillin prophylaxis for rheumatic fever. Lancet 1991;337:1308-10. 4. Napoli DC, Neeno TA. Anaphylaxis to benzathine penicillin G. Pediatr Asthma Allergy Immunol 2000;14:329-32. 5. Ibia EO, Schwartz RH, Wiederman BL. Antibiotic rashes in children: a survey in a private practice setting. Arch Dermatol 2000;136:849-54. 6. MacLaughlin EJ, Saseen JJ, Malone DC. Costs of beta-lactam allergies: selection and costs of antibiotics for patients with a reported beta-lactam allergy. Arch Fam Med 2000;9:722-6. 7. Martinez JA, Ruthazer R, Hansjosten K, et al. Role of environmental contamination as a risk factor for acquisition of vancomycin-resistant enterococci in patients treated in a medical intestive care unit. Arch Intern Med 2003;163:1905-12. 8. Puchner TC, Zacharisen MC. A survey of antibiotic prescribing and knowledge of penicillin allergy. Ann Allergy Asthma Immunol 2002: 24-9. 9. Solensky R, Earl HS, Gruchalla RS. Clinical approach to penicillin allergic patients: a survey. Ann Allergy Asthma Immunol 2000;84:329-33. 10. Cieslak PR, Strausbaugh LJ, Fleming DW, et al. Vancomycin in Oregon: who’s using it and why. Infect Control Hosp Epidemiol 1999;20:557-60. 11. Kwan T, Lin F, Ngai B, et al. Vancomycin use in 2 Ontario tertiary care hospitals: a survey. Clin Invest Med 1999;22:256-64. 12. Lee CE, Zembower TR, Fotis MA, et al. The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance. Arch Intern Med 2000;160: 2819-22. 13. Gadde J, Spence M, Wheeler B, et al. Clinical experience with penicillin skin testing in a large inner-city STD Clinic. JAMA 1993;270: 2456-63. 14. Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol 2001;107:191-3. 15. Bock SA, Munoz-Furlong A, Sampson HA. Further fatalities caused by anaphylactic reactions to food, 2001-2006. J Allergy Clin Immunol 2007;119:1016-8. 16. Adkinson NF. Risk factors for drug allergy. J Allergy Clin Immunol 1984;74:567-72. 17. Roujeau JC, Huynh TN, Bracq C, et al. Genetic susceptibility to toxic epidermal necrolysis. Arch Dermatol 1987;123:1171-3. 18. Yang CW, Hung SI, Juo CG, et al. HLA-B*1502-bound peptides: implications for the pathogenesis of carbamazepine-induced Stevens-Johnson syndrome. J Allergy Clin Immunol 2007;120:870-7. 19. Yang J, Qiao H, Zhang Y, et al. HLA-DRB genotype and specific IgE responses in patients with allergies to penicillins. Chin Med J 2006;119:458-66. 20. Asero R. Detection of patients with multiple drug allergy syndrome by elective tolerance tests. Ann Allergy Asthma Immunol 1998;80: 185-8. 21. Kamada MM, Twarog F, Leung DYM. Multiple antibiotic sensitivity in a pediatric population. Allergy Proc 1991;12:347-50. 22. Moseley EK, Sullivan TJ. Allergic reactions to antimicrobial drugs in patients with a history of prior drug allergy (abstract). J Allergy Clin Immunol 1991;87:226. 23. Strom BL, Schinnar R, Apter AJ, et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med 2003;349:1628-35. 24. Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med 2003;139:683-93. 25. Schmid DA, Depta JP, Luthi M, et al. Transfection of drug-specific T cell receptors into hybridoma cells: tools to monitor drug interaction with T cell receptors and evaluate cross-reactivity to related compounds. Mol Pharmacol 2006;70:356-65. 26. Levine BB, Ovary Z. Studies on the mechanism of the formation of the penicillin antigen. III. The N-(D-alpha-benzyl-penicilloyl) group as an antigenic determinant responsible for hypersensitivity to penicillin G. J Exp Med 1961;114:875-904.

Drug Allergy

55. Abraham GN, Petz LD, Fudenberg HH. Immunohaematological crossallergenicity between penicillin and cephalothin in humans. Clin Exp Immunol 1968;3:343-57. 56. Pedersen-Bjergaard J. Specific hyposensitization of patients with penicillin allergy. Acta Allergol 1969;24:333-61. 57. 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;98:671-7. 58. Romano A, Gueant-Rodriguez RM, Viola M, et al. Cross-reactivity and tolerability of cephalosporins in patients with immediate hypersensitivity to penicillins. Ann Intern Med 2004;141:16-22. 59. Antunez C, Blanca-Lopez N, Torres MJ, et al. Immediate allergic reactions to cephalosporins: evaluation of cross-reactivity with a panel of penicillins and cephalosporins. J Allergy Clin Immunol 2006;117: 404-10. 60. Romano A, Gueant-Rodriguez RM, Viola M, et al. Diagnosing immediate reactions to cephalosporins. Clin Exp Allergy 2005;35:1234-42. 61. Romano A, Mayorga C, Torres MJ, et al. Immediate allergic reactions to cephalosporins: cross reactivity and selective responses. J Allergy Clin Immunol 2000;106:1177-83. 62. Romano A, Quaratino D, Aimone-Gastin I, et al. Cephalosporin allergy: characterization of unique and cross-reacting cephalosporin antigens. Int J Immunopathol Pharmacol 1997;10:187-91. 63. Saxon A, Swabb EA, Adkinson NF. Investigation into the immunologic cross-reactivity of aztreonam with other beta-lactam antibiotics. Am J Med 1985;78(Suppl 2A):19-26. 64. Adkinson NF. Immunogenicity and cross-allergenicity of aztreonam. Am J Med 1990;88(Suppl 3C):S3-14. 65. Vega JM, Blanca M, Garcia JJ, et al. Tolerance to aztreonam in patients allergic to betalactam antibiotics. Allergy 1991;46:196-202. 66. Atanaskovic-Markovic M, Gaeta F, Medjo B, et al. Tolerability of meropenem in children with IgE-mediated hypersensitivity to penicillins. Allergy 2008;63:237-40. 67. Romano A, Viola M, Gueant-Rodriguez RM, et al. Tolerability of meropenem in patients with IgE-mediated hypersensitivity to penicillins. Ann Intern Med 2007;146:266-9. 68. Romano A, Viola M, Gueant-Rodriquez RA, et al. Imipenem in patients with immediate hypersensitivity to penicillins. N Engl J Med 2006;354: 2835-7. 69. Dibbern DA, Montanaro A. Allergies to sulfonamide antibiotics and sulfu-containing drugs. Ann Allergy Asthma Immunol 2008;100:91-100. 70. Patterson R, Bello AE, Lefkowith F. Immunologic tolerability profile of celecoxib. Clin Ther 1999;21:2065-79. 71. Demoly P, Messaad D, Sahla H, et al. Six-hour trimethoprim-sulfamethoxazole-graded challenge in HIV-infected patients. J Allergy Clin Immunol 1998;102:1033-6. 72. Solensky R. Drug desensitization. Immunol Allergy Clin N Am 2004;24:425-43. 73. Yango MC, Kim K, Evans R. Oral desensitization to trimethoprim-sulfamethoxazole in pediatric patients. Immunol Allergy Practice 1992;56: 17-24. 74. Bonfanti P, Pusterla L, Parazzini F, et al. The effectiveness of desensitization versus rechallenge treatment in HIV-positive patients with previous hypersensitivity to TMP-SMX: a randomized multicentric study. Biomed Pharmacother 2000;54:45-9. 75. Leoung GS, Stanford JF, Giordano MF, et al. Trimethoprim-sulfamethoxazole (TMP-SMZ) dose escalation versus direct rechallenge for Pneumocystis carinii pnemonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ. J Infect Dis 2001;184:992-7. 76. Benahmed S, Scaramuzza C, Messaad D, et al. The accuracy of the diagnosis of suspected macrolide antibiotic hypersensitivity: results of a single-blinded trial. Allergy 2004;59:1130-3. 77. Messaad D, Sahla H, Benahmed S, et al. Drug provocation tests in patients with a history suggesting an immediate drug hypersensitivity reaction. Ann Intern Med 2004;140:1001-6. 78. Soto-Aguilar MC, deSchazo RD, Dawson ES. Approach to the patient with suspected local anesthetic sensitivity. Immunol Allergy Clin N Am 1998;18:851-65. 79. Stevenson DD. Aspirin and NSAID sensitivity. Immunol Allergy Clin N Am 2004;24:491-505. 80. Settipane RA, Shrank PJ, Simon RA, et al. Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects. J Allergy Clin Immunol 1995;96:480-5. 81. Woessner K, Simon RA, Stevenson DD. The safety of celecoxib in aspirin exacerbated respiratory disease. Arthritis Rheum 2002;46:2201-6. 82. Viola M, Quaratino D, Gaeta F, et al. Celecoxib tolerability in patients with hypersensitivity (mainly cutaneous reactions) to nonsteroidal antiinflammatory drugs. Int Arch Allergy Immunol 2005;137:145-50. 83. Debley JS, Carter ER, Gibson RL, et al. The prevalence of ibuprofensensitive asthma in children: a randomized controlled bronchoprovocation challenge study. J Pediatr 2005;47:233-88.

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27. Levine BB, Redmond AP. Minor haptenic determinant-specific reagins of penicillin hypersensitivity in man. Int Arch Allergy Appl Immunol 1969;35:445-55. 28. Parker CW, deWeck AL, Kern M, et al. The preparation and some properties of penicillenic acid derivatives relevant to penicillin hypersensitivity. J Exp Med 1962;115:803-19. 29. Wickern GM, Nish WA, Bitner AS, et al. Allergy to beta-lactams: a survey of current practices. J Allergy Clin Immunol 1994;94:725-31. 30. Sogn DD, Evans R, 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;152:1025-32. 31. Sullivan TJ, Wedner HJ, Shatz GS, et al. Skin testing to detect penicillin allergy. J Allergy Clin Immunol 1981;68:171-80. 32. Macy E, Richter PK, Falkoff R, et al. Skin testing with penicilloate and penilloate prepared by an improved method: amoxicillin oral challenge in patients with negative skin test responses to penicillin reagents. J Allergy Clin Immunol 1997;100:586-91. 33. Blanca M, Vega JM, Garcia J, et al. Allergy to penicillin with good tolerance to other penicillins: study of the incidence in subjects allergic to betalactams. Clin Exp Allergy 1990;20:475-81. 34. Macy E, Burchette R. Oral antibiotic adverse reactions after penicillin skin testing: multi-year follow-up. Allergy 2002;57:1151-8. 35. Blanca M, Mayorga C, Torres MJ, et al. Clinical evaluation of Pharmacia CAP System RAST FEIA amoxicilloyl and benzylpenicilloyl in patients with penicillin allergy. Allergy 2001;56:862-70. 36. 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: 1314-6. 37. 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;51:383-6. 38. Romano A, Quaratino D, DiFonso M, et al. A diagnostic protocol for evaluating nonimmediate reactions to aminopenicillins. J Allergy Clin Immunol 1999;103:1186-90. 39. Romano A, Quaratino D, Papa G, et al. Aminopenicillin allergy. Arch Dis Child 1997;76:513-7. 40. Primeau MN, Hamilton RG, Whitmore E, et al. Negative patch tests and skin tests in patients with delayed cutaneous to penicillins (abstract). J Allergy Clin Immunol 2002;109:S267. 41. Romano A, Di Fonso M, Papa G, et al. Evaluation of adverse cutaneous reactins to aminopenicillins with emphasis on those manifested by maculopapular rashes. Allergy 1995;50:113-8. 42. Sanz ML, Gamboa PM, Antepara I, et al. Flow cytometric basophil activation test by detection of CD63 expression in patients with immediatetype reactions to betalactam antibiotics. Clin Exp Allergy 2002;32: 277-86. 43. Torres MJ, Padial A, Mayorga C, et al. The diagnostic interpretation of basophil activation test in immediate allergic reactions to betalactams. Clin Exp Allergy 2004;34:1768-75. 44. Empedrad R, Darter AL, Earl HS, et al. Nonirritating intradermal skin test concentrations for commonly prescribed antibiotics. J Allergy Clin Immunol 2003;112:629-30. 45. Mendelson LM, Ressler C, Rosen JP, et al. Routine elective penicillin allergy skin testing in children and adolescents: study of sensitization. J Allergy Clin Immunol 1984;73:76-81. 46. Solensky R, Earl HS, Gruchalla RS. Penicillin allergy: prevalence of vague history in skin test-positive patients. Ann Allergy Asthma Immunol 2000;85:195-9. 47. Wong BBL, Keith PK, Waserman S. Clinical history as a predictor of penicillin skin test outcome. Ann Allergy Asthma Immunol 2006;97. 48. Jost BC, Wedner HJ, Bloomberg GR. Elective penicillin skin testing in a pediatric outpatient setting. Ann Allergy Asthma Immunol 2006;97: 807-12. 49. Park M, Markus P, Matesic D, et al. 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: 681-7. 50. Murray BE. Vancomycin-resistant enterococcal infections. N Engl J Med 2000;342:710-21. 51. Hospital Infection Control Practices Advisory Committee Hospital. Recommendations for preventing the spread of vancomycin resistance. MMWR 1995;44(RR-12):1-13. 52. Rao GG. Risk factors for the spread of antibiotic-resistant bacteria. Drugs 1998;55:323-30. 53. Lacuesta GA, Moote DW, Payton K, et al. Follow-up of patients with negative skin tests to penicillin (abstract). J Allergy Clin Immunol 2002;109:S143. 54. Warrington RJ, Burton R, Tsai E. The value of routine penicillin allergy skin testing in an outpatient population. Allergy Asthma Proc 2003;24: 199-202.

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Section    I    Drug Allergy and Anaphylaxis

84. Fisher TJ, Guilfoile TD, Kesarwala HH, et al. Adverse pulmonary responses to aspirin and acetaminophen in chronic childhood asthma. Pediatrics 1983;71:313-8. 85. Rachelefsky GS, Coulson A, Siegel SC, et al. Aspirin intolerance in chronic childhood asthma: detected by oral challenge. Pediatrics 1975;56: 443-8. 86. Schuhl JF, Pereyra JG. Oral acetylsalicylic acid (aspirin) challenge in asthmatic children. Clin Allergy 1979;9:83-8. 87. Towns SJ, Mellis CM. Role of acetyl salicylic acid and sodium metabisulfite in chronic childhood asthma. Pediatrics 1984;73:631-7. 88. Vedanthan PK, Menon MM, Bell TD, et al. Aspirin and tartrazine oral challenge: incidence of adverse response in chronic childhood asthma. J Allergy Clin Immunol 1977;60:8-13. 89. Berges-Gimeno MP, Simon RA, Stevenson DD. Long-term treatment with aspirin desensitization in asthmatic patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2003;111:180-6. 90. Stevenson DD, Hankammer MA, Mathison DA, et al. Aspirin desensitization treatment of aspirin-sensitive patients with rhinosinusitis-asthma: long-term outcomes. J Allergy Clin Immunol 1996;98:751-8. 91. Sweet JM, Stevenson DD, Simon RA, et al. Long-term effects of aspirin desensitization-treatment for aspirin-sensitive rhinosinusitis-asthma. J Allergy Clin Immunol 1990;85:59-65. 92. Borish L, Tamir R, Rosenwasser LJ. Intravenous desensitization to betalactam antibiotics. J Allergy Clin Immunol 1987;80:314-9. 93. Stark BJ, Earl HS, Gross GN, et al. Acute and chronic desensitization of penicillin-allergic patients using oral penicillin. J Allergy Clin Immunol 1987;79:523-32. 94. Sullivan TJ, Yecies LD, Shatz GS, et al. Desensitization of patients allergic to penicillin using orally administered beta-lactam antibiotics. J Allergy Clin Immunol 1982;69:275-82. 95. Wendel GD, Stark BJ, Jamison RB, et al. Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med 1985;312:1229-32. 96. Dash CH. Penicillin allergy and the cephalosporins. J Antimicrob Chemother 1975;1(Suppl):107-18. 97. Petz LD. Immunologic cross-reactivity between penicillins and cephalosporins: a review. J Infect Dis 1978;137(Suppl):S74-9. 98. 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. 99. Daulat SB, Solensky R, Earl HS, et al. Safety of cephalosporin administration to patients with histories of penicillin allergy. J Allergy Clin Immunol 2004;113:1220-2.

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