Лечение или смертельная опасность: аллергия на Флемоклав Солютаб у ребенка

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Penicillin and related antibiotic allergy; skin testing; and desensitization
Liza C O’Dowd, MD

INTRODUCTION**Penicillin is the most commonly reported medication allergy, although many patients are not truly allergic [1-3]. Large studies, for example, have shown that at least 80 percent of individuals reporting penicillin allergy are able to tolerate treatment and have either been falsely labeled allergic or lost their sensitivity as a result of years of avoidance [4-6]. However, true penicillin allergy is not uncommon and is a leading cause of fatal drug reactions [7].

Adverse drug reactions to all medications combined are the cause of 2 to 5 percent of hospital admissions in the United States and complicate an additional 6 percent of hospitalizations [1,8].

The evaluation and desensitization of patients with suspected penicillin allergies will be reviewed here. The diagnosis and treatment of anaphylaxis is discussed separately. (See «Anaphylaxis in adults»).

EVALUATION OF PATIENTS WITH HISTORY OF PENICILLIN ALLERGY**Several types of allergic reactions can occur following the administration of penicillin (show table 1). Overall, 2 to 4 percent of allergic reactions are life-threatening [2,9,10]. Severe forms of drug allergy can occur via several mechanisms and include anaphylaxis (type I), Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug-induced hypersensitivity syndrome with multiorgan involvement (mechanism of the latter three reactions is uncharacterized). Type I reactions, which may present with anaphylaxis, angioedema, bronchospasm, or urticaria (hives) are the focus of this review.

History**It is important to verify the history of «allergy» since the patient may incorrectly assume a non-allergic side effect (especially a gastrointestinal side effect) to be allergic in origin.

Risk factors**Certain subgroups of patients are at higher risk for developing allergic reactions (of various types) to penicillins and related antibiotics [11-13]. Patients with HIV infection have higher rates of allergy to a variety of antibiotics, including amoxicillin [11]. Patients with cystic fibrosis frequently develop allergies to ticarcillin and piperacillin [12,13]. It is uncertain if these increased rates of reaction reflect the greater exposure to multiple drugs or are related to immunologic abnormalities associated with these diseases.

The development of exanthems in response to penicillins is well-described in patients during acute infectious mononucleosis and cytomegalovirus, although these types of reactions are distinct, as patients are generally able to tolerate the penicillin after recovering from the acute viral infection [14-17]. Non-pruritic, maculopapular rashes without other symptoms are reported in 3 to 7 percent of children taking amoxicillin, and are not considered a contraindication to future use of the causative drug [18,19].

Patients with a history of an allergic reaction to any drug have an increased incidence of reactions to other drugs. It has been estimated that patients with a history of penicillin allergy have a three-fold increased risk of reacting to any medication [20]. This phenomenon was well-illustrated in a review of 969 patients who had allergic reactions to sulfonamide antibiotics and were subsequently treated with nonantibiotic sulfonamides, including loop and thiazide diuretics and sulfonylureas [3]. These patients had an increased incidence of allergic reactions (including asthma, eczema, urticaria, dermatitis, Stevens-Johnson syndrome, and anaphylaxis) to the nonantibiotic sulfonamide (9.9 versus 1.6 percent in controls who had not had an prior allergic reaction to a sulfonamide antibiotic). However, their reaction rate to penicillin was even greater (14 percent). Thus, there was a greater incidence of reactivity to a non-related drug (penicillin) than to a related non-antibiotic sulfonamide, suggesting that the increased reactivity reflects a general predisposition to develop allergic reactions rather than a specific immunologic cross reactivity.

Assessing risk for anaphylaxis**Anaphylaxis from penicillin occurs with a frequency of one episode per 5000 to 10,000 courses of drug therapy [21]. Assessment of the risk is based upon a carefully obtained history coupled with skin testing when appropriate and available. Anaphylaxis can be identified by characteristic symptoms (show table 2). A high risk for anaphylaxis is suggested by a history of bronchospasm, angioedema, hypotension, or shock, particularly if these symptoms occurred within 30 minutes of drug administration during the prior year (show table 3). In contrast, people who report isolated maculopapular rashes without urticaria or pruritus are unlikely to have experienced an IgE-mediated reaction [22].

IgE-mediated penicillin allergy can be lost over time if a patient has successfully avoided exposure, with a minority of patients still being reactive after 20 years of avoidance. Thus, the time that has elapsed since the patient’s last reaction is also used to assess risk.

Our approach to the patient with a possible IgE-mediated penicillin allergy is summarized in the figure (show figure 1). Patients should ideally undergo a penicillin skin test (if available) if they have a history of penicillin or other beta-lactam allergy and require a beta-lactam antibiotic to treat a serious infection for which no other alternative antibiotic is appropriate [9,23]. (See «Penicillin skin testing» below).

At the moment, however, the supplies of commercially available PPL (the major determinant skin test reagent) have been withdrawn from the market within the United States and it is not clear when or if they will be re-introduced. If a reliable source of PPL is not available, skin testing will not reliably identify patients with allergic reactivity to penicillin, and should not be undertaken. In that case, a careful assessment of the patient’s history of reactions to penicillin or its derivatives must be used to assess risk.

PENICILLIN SKIN TESTING**Skin testing is the most reliable method of determining if a patient with a previous history of a penicillin allergy is at risk for an immediate hypersensitivity reaction upon rechallenge. Skin testing provides information about IgE-mediated, type 1 reactions only, and has no role in the evaluation of other types of reactions, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), other exfoliative dermatitides, erythema multiforme, hepatitis, or nephritis.

In vivo, penicillin and its metabolites function as haptens, or small molecular weight molecules that adhere to proteins to form hapten-protein complexes that are antigenic. When penicillin G is added to a solution of protein or human serum, the beta-lactam ring of the drug spontaneously opens and binds to proteins to form a benzylpenicilloyl determinant. Approximately 95 percent of the administered penicillin undergoes this process; this altered form is called benzylpenicilloyl or the «major determinant». Other metabolic products of penicillin metabolism include penicilloate and penilloate; these are called the «minor determinants» [9]. Many patients who are allergic to penicillin have formed IgE molecules to these metabolite-protein complexes, rather than to the parent drug. Therefore, skin testing must include reagents that will allow detection of these antibodies.

Reagents and technique**Skin testing for penicillin should ideally be performed with penicillin G and the major and minor determinants.

Although benzylpenicilloyl complexed to protein (the major determinant) was previously produced commercially as benzylpenicilloyl polysine (PPL or PrePen), it is currently unavailable.

IgE antibodies to minor determinants are generally responsible for anaphylactic reactions and can predict the likelihood of a more severe reaction. IgE antibodies to major determinants of penicillin in general mediate urticarial drug reactions in addition to anaphylactic reactions [9,24].

Skin testing usually takes between one and four hours to complete and should be performed by an allergist/immunologist. Prick/puncture testing is performed initially. If prick testing is negative, then intradermal testing is performed.

A positive skin test is defined by the development of a wheal and flare reaction to either antigenic determinant that is equal or larger in size to that associated with the histamine control, with the histamine control normally producing a wheal of at least three mm in diameter. (See «Overview of skin testing for allergic disease»).

Testing is complete when the patient either has a positive reaction to any reagent or completes the testing protocol. In most centers, testing is followed by the administration of a single dose of oral penicillin and a period of observation to confirm that the drug is tolerated.