Guideline on diagnostic procedures for suspected hypersensitivity to beta-lactam antibiotics: Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) in collaboration with the German Society of Allergology (AeDA), German Society for Pediatric Allergology and Environmental Medicine (GPA), the German Contact Dermatitis Research Group (DKG), the Austrian Society for Allergology and Immunology (ÖGAI), and the Paul-Ehrlich Society for Chemotherapy (PEG)

Abstract

This guideline on diagnostic procedures for suspected beta-lactam antibiotic (BLA) hypersensitivity was written by the German and Austrian professional associations for allergology, and the Paul-Ehrlich Society for Chemotherapy in a consensus procedure according to the criteria of the German Association of Scientific Medical Societies. BLA such as penicillins and cephalosporins represent the drug group that most frequently triggers drug allergies. However, the frequency of reports of suspected allergy in patient histories clearly exceeds the number of confirmed cases. The large number of suspected BLA allergies has a significant impact on, e.g., the quality of treatment received by the individual patient and the costs to society as a whole. Allergies to BLA are based on different immunological mechanisms and often manifest as maculopapular exanthema, as well as anaphylaxis; and there are also a number of less frequent special clinical manifestations of drug allergic reactions. All BLA have a beta-lactam ring. BLA are categorized into different classes: penicillins, cephalosporins, carbapenems, monobactams, and beta-lactamase inhibitors with different chemical structures. Knowledge of possible cross-reactivity is of considerable clinical significance. Whereas allergy to the common beta-lactam ring occurs in only a small percentage of all BLA allergic patients, cross-reactivity due to side chain similarities, such as aminopenicillins and aminocephalosporins, and even methoxyimino cephalosporins, are more common. However, the overall picture is complex and its elucidation may require further research. Diagnostic procedures used in BLA allergy are usually made up of four components: patient history, laboratory diagnostics, skin testing (which is particularly important), and drug provocation testing. The diagnostic approach - even in cases where the need to administer a BLA is acute - is guided by patient history and risk - benefit ratio in the individual case. Here again, further studies are required to extend the present state of knowledge. Performing allergy testing for suspected BLA hypersensitivity is urgently recommended not only in the interests of providing the patient with good medical care, but also due to the immense impact of putative BLA allergies on society as a whole.

Keywords: allergy; beta-lactam antibiotics; cephalosporin; drug hypersensitivity; penicillin.

Figure 1.. Assumptions on the probability of allergic cross-reactions between the various beta-lactam antibiotics. These assumptions are based on structural similarities or structural differences in the R1 side chain; published data are scant or lacking.

Figure 2.. Diagnostic algorithm for immediate reactions to a beta-lactam antibiotic. An individual benefit–risk assessment should be carried out before and after each diagnostic step. ^aSince positive in vitro testing does not necessarily mean that the positive results are clinically relevant, the physician has the option to decide on a case-by-case basis to continue in vivo testing. However, depending on the individual case, the decision to discontinue further diagnostic steps may also be taken if in vitro testing is positive, either on the basis of sufficiently evaluated evidence of hypersensitivity in the patient history and in vitro testing, or in the case of a negative bene-fit-risk assessment. ^bAssuming only the suspected BLA has been tested to date: test BP, AX, other alternative preparations, as well as PPL/BP-OL and MD. Alternative preparations need to be determined individually according to the sensitization pattern. A possible test series for alternative preparations in adults includes: BP, phenoxymethylpenicillin, amoxicillin, ampicillin, cefuroxime, cefaclor, cefpodoxime, cefixime, and ceftazidime. For children: BP, phenoxymethylpenicillin, amoxicillin, ampicillin, cefuroxime, cefaclor, and ceftazidime. ^cIf the suspected drug is not tested and administered in DPT, avoidance is recommended and only the BLA tolerated in DPT should be approved. An allergy passport should be issued accordingly. BLA = beta-lactam antibiotic; IDT = intradermal skin test; SPT = skin prick test; BP = benzylpenicillin; AX = amoxicillin; DPT = drug provocation test.

Figure 3.. Diagnostic algorithm for suspected maculopapular exanthema to a beta-lactam antibiotic. An individual benefit–risk assessment should be carried out before and after each diagnostic step. ^aSince positive in vitro testing does not necessarily mean that the positive results are clinically relevant, the physician has the option to decide on a case-by-case basis to continue in vivo testing. However, depending on the individual case, the decision to discontinue further diagnostic steps may also be taken if in vitro testing is positive, either on the basis of sufficiently evaluated evidence of hypersensitivity in the patient history and in vitro testing, or in the case of a negative benefit–risk assessment. ^bAssuming only the suspected BLA has been tested to date: test BP, AX, other alternative preparations. Alternative preparations need to be determined according to the sensitization pattern. A possible test series for alternative preparations in adults includes: BP, phenoxymethylpenicillin, amoxicillin, ampicillin, cefuroxime, cefaclor, cefpodoxime, cefixime, and ceftazidime. For children: BP, phenoxymethylpenicillin, amoxicillin, ampicillin, cefuroxime, cefaclor, and ceftazidime. ^cIf the suspected drug is not tested and administered as part of DPT, avoidance is recommended and only the BLA tolerated in DPT should be approved. An allergy passport should be issued accordingly. BLA = beta-lactam antibiotic; SPT = skin prick test; IDT = dermal skin testing, BP = benzylpenicillin, AX = amoxicillin; DPT = drug provocation test.

Figure 4.. Recommendations for patients with suspected BLA hypersensitivity in cases where treatment is urgently indicated.

Figure 5.. Example of an allergy passport. For a patient with anaphylaxis to cefuroxime who tested positive to other cephalosporins with a methoxyimino group in the R1 side chain (cefotaxime, ceftriaxone) at skin testing, but who exhibited tolerance to the central beta lactam ring structure and an unrelated cephalosporin side chain at skin testing and provocation testing with penicillin V and cefalexin [148].

Figure 6.. Example of an allergy passport. For a patient with maculopaplar exanthema to amoxicillin for whom beta-lactams with an amino group in the R1 side chain (ampicillin, cefaclor, cephalexin, cefadroxil) were prohibited due to anticipated cross-reactivity, but who exhibited tolerance to the central beta-lactam ring structure and an unrelated cephalosporin side chain at skin testing and provocation testing with penicillin V and cefuroxime [148].