The Complex Clinical Picture of β-Lactam Hypersensitivity: Penicillins, Cephalosporins, Monobactams, Carbapenems, and Clavams
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Epidemiology
The prevalence and incidence of allergic reactions to BLs in the general population are not well known. Although the initial incidence decreased when contaminants were reduced and chemical synthesis was introduced, it was later counterbalanced by the increasing number of exposed populations.6 Data vary depending on the study, with over-reporting when patients are classified only by clinical history and under-reporting of mild and severe reactions.7
Early reports showed a frequency of allergic
BLs involved
BLs include a large number of chemical compounds that share a common structure and mechanism of action, and they are the first choice for the treatment of different bacterial diseases. Depending on their chemical structure, BLs are classified into 2 major classes, penicillins and cephalosporins, and 4 minor classes, monobactams, carbapenems, oxacephems, and clavams.
The basic structure of all BLs consists of a 4-member BL ring that, in penicillins, is connected with a 5-member thiazolidine ring
Clinical manifestations
The skin is the organ most frequently involved in hypersensitivity reactions to BLs, sometimes accompanied by systemic symptoms.5 In a minor proportion of cases, reactions may not involve the skin and are limited to just one or several organs, such as the liver, lung, kidney, hematopoietic system, or others. Different entities can be recognized depending on the mechanisms, time interval, dose, and duration of treatment and clinical manifestations (see Table 1).
Formation of Hapten-Carrier Conjugate
All BLs have the capacity to bind spontaneously to exogenous or endogenous proteins that can later be processed and recognized by the immunologic system.36, 37 The kinetics of binding to cell or serum proteins is rapid, generating hapten-carrier conjugates in a concentration-dependent manner.38 The first penicillin formulations were heterogeneous and contained BP aggregates and bacterial protein contaminants that were thought to be responsible for the high percentage of reactions.6 Because the
Diagnosis
The clinical history enables 2 approaches for diagnosing allergic reactions, immediate and nonimmediate, to BL. In both reactions, in vivo and in vitro methods can be performed.
Assessment of cross-reactivity
As a result of similarities in their structures, cross-reactivity, especially in type I immediate reactions, has been shown to exist among different penicillins and even between penicillins and first generation cephalosporins. Subjects who tested positive for PPL and/or MDM in skin testing have developed reactions with cloxacillin, AM, methicillin, or AX, among others.5, 11, 50, 52, 71 The discovery of side chain–specific determinants in immediate reactions and the observation that in
Natural evolution
Observations that in patients with clear anaphylactic reactions, the results of skin tests were not always positive and that positivity was in part caused by the time interval between drug occurrence and the time of evaluation led to the suspicion that time interval was critical in the evaluation. In a prospective study of allergic subjects who tested positive in skin tests at the initial evaluation, after a 5-year follow-up, only 40% of those with positive skin tests results to BP determinants
Desensitization
Desensitization has been shown to be useful in BL hypersensitivity, especially in immediate reactions. Oral and parenteral protocols have been published.79 Desensitization is indicated when a BL cannot be replaced or when a particular BL is more effective or has fewer side effects than other alternatives. Before desensitization, an accurate diagnosis needs to be done, and the benefits must outweigh the risks.
Summary
The world of BLs has changed over the years, with more BLs becoming involved, although penicillin, the initial sensitizing agent, is now less involved. Other BLs are taking on a relevant role, and AX is the drug most frequently involved. Sensitization is related with patterns of consumption. The latest widely used BL reported to produce allergic reactions is clavulanic acid. Any BL can induce a hypersensitivity response. Diagnosis in immediate reactions is less sensitive than earlier because
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This work was supported by Fondo de Invetigaciones Sanitarias (FIS)-Thematic Networks and Co-operative Research Centres: Red de Investigación de Reacciones Adversas a Alergenos y Fármacos (RD07/0064), FIS (PS09/01768) and Junta de Andalucia (PI-0243/2007).
The authors have nothing to disclose.