Antibiotic allergy

Abstract

Antibiotics are the commonest cause of life-threatening immune-mediated drug reactions that are considered off-target, including anaphylaxis, and organ-specific and severe cutaneous adverse reactions. However, many antibiotic reactions documented as allergies were unknown or not remembered by the patient, cutaneous reactions unrelated to drug hypersensitivity, drug-infection interactions, or drug intolerances. Although such reactions pose negligible risk to patients, they currently represent a global threat to public health. Antibiotic allergy labels result in displacement of first-line therapies for antibiotic prophylaxis and treatment. A penicillin allergy label, in particular, is associated with increased use of broad-spectrum and non-β-lactam antibiotics, which results in increased adverse events and antibiotic resistance. Most patients labelled as allergic to penicillins are not allergic when appropriately stratified for risk, tested, and re-challenged. Given the public health importance of penicillin allergy, this Review provides a global update on antibiotic allergy epidemiology, classification, mechanisms, and management.

Figure 1:

Classification of on-target and off-target ADRS Pink panel illustrates an example of an on-target ADR. Blue panel (left) illustrates non-immunologically-mediated off-target effects: direct cellular toxicity or disruption of normal physiology, interaction with non-immune receptors, and interaction with immune receptors (eg, non-IgE-mediated mast-cell activation via G-protein coupled receptors). Blue panel (right) shows immunologically mediated adaptive immune responses (antibody-mediated [eg, IgE] immediate reactions or T-cell-mediated delayed reactions). Predisposition to both on-target and off-target reactions is driven by genetic variation, but also ecological factors that can vary over the course of an individual’s lifetime. ADR=adverse drug reaction. Bid=BH3 interacting-domain death. C difficile=Clostridioides difficile. ER=endoplasmic reticulum. FcεR1=high-affinity IgE receptor. HSR=hypersensitivity reaction. MRGPRX2=MAS-related G-protein coupled receptor member X2. PKC=protein kinase C. PLCβ=phospholipase C β. ROS=reactive oxygen species. TCR=T cell receptor. UPR=unfolded protein response. *Dose-dependent. Reproduced from Peter et al.^[2]

Figure 2:

β-Lactam structure and cross-reactivity β-Lactam antibiotics include penicillins, cephalosporins, carbapenems, and monobactams. Cross-reactivity is possible through the core β-lactam ring, adjacent thiazolidine (penicillin) or dihydrothiazine (cephalosporin) ring, and also from a side chain, R1, or R2 group (left panel). Cephalosporins have both an R1 and R2 group and penicillins only an R1. Despite varied mechanisms, true cross-reactivity is largely based on R1 side chains. Identical side chains in patients with IgE-mediated allergy pose the highest risk. However, cross-reactivity from side chains that are similar, but not identical, and from R2 group similarity is possible and reported. The centre panel demonstrates the structure and rates of cross-reactivity between penicillins, cephalosporins, carbapenems, and monobactams. The right panel details the most clinically important cross-reactivity considerations. *Except for shared group aminopenicillins and cephalosporins. †Monobactams have no shared cross-reactivity with other β-lactams, with the exception for aztreonam and ceftazidime, which share an identical R1. ‡Amoxicillin and ampicillin are structurally similar aminopenicillins and should be considered clinically cross-reactive with each other and the respective cephalosporins with shared R1 groups listed in the figure. Similar considerations exist for the aminocephalosporins.

Figure 3:

Patient-reported history for risk stratification When limited allergy details are available, patient-reported historical details can be used to distinguish patients at high and low risk. In the case of penicillin allergy, patients with low risk histories are unlikely to be allergic and could be referred on large scales for allergy evaluations. When details are available about the purported reaction, the following questions are important components of the drug allergy history. (1) What were the symptoms? (raised, red, itchy spots with each lesion lasting less than 24 h [hives or urticaria]; swelling of the mouth, eyes, lips, or tongue [angioedema]; blisters or ulcers involving the lips, mouth, eyes, urethra, vagina, or peeling skin [severe type IV HSRs, SCARs]; respiratory or haemodynamic changes [anaphylaxis]; joint pains [serum sickness and serum-sickness like reaction]; organs involvement such as kidneys, lungs, or liver [severe type IV HSRs]). (2) What was the timing of the reaction after taking penicillin [minutes, hours, or days later]? Was it after the first dose or after multiple doses? (3) How long ago did the reaction happen? (4) How was the reaction treated? Was there a need for urgent care or was epinephrine administered? (5) Has the patient tolerated similar medications, such as ampicillin, amoxicillin, or cephalexin since the penicillin reaction?

Figure 4:

Diagnostic approach to antibiotic allergy Immediate reactions commonly occur within 1 h but can occur up to 6 h after drug administration. Serum tryptase drawn 30–90 min after reaction onset is a useful biomarker to help differentiate anaphylaxis from non-IgE-mediated mast-cell activation. Drug-specific diagnostic tests for immediate reactions include (A) epicutaneous skin testing (ie, prick, puncture, or scratch) and (B) intradermal skin testing. The definition of a positive penicillin skin test varies globally.^[–98] Delayed reactions typically occur in more than 6 h and up to 8 weeks after drug exposure and can occur after drug discontinuation. Testing for delayed reactions varies geographically and is not standardised. In-vivo testing for delayed reactions can include (C) patch testing, in which non-irritant drug concentrations in a base vehicle are applied by a Finn chamber and adhesive tape for 48 h and are read at 96 h and 1 week, or (D) delayed intradermal testing, in which results are read 24 h and 48 h after the drug solution is injected. Drug challenge, when safe to perform, is often the final step to confirm or exclude a drug allergy, after negative epicutaneous, immediate or delayed intradermal, or patch testing. In immediate reactions, drug challenges can feature a single full dose or be graded, with 2 to 3 dosing increments. In delayed reactions, dosing can be continued for multiple days but might be considered to be an unnecessary exposure to antibiotics. Drug challenge is contraindicated for SCAR and single-organ disease. Several additional ex-vivo and in-vitro diagnostic options are available in some subspecialty centres but are currently at the level of research tools that require further validation. See appendix. ALDEN=an algorithm for assessment of drug causality in Stevens-Johnson syndrome and toxic epidermal necrolysis. ELISpot=enzyme-linked immunosorbent assay. Naranjo=an adverse drug reaction probability scale that can be used to assess causality for any adverse drug reaction. PPL=penicilloyl-polylysine. RegiSCAR=the European Registry of Severe Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples group. SCAR=severe cutaneous adverse reaction.

Figure 5:

Treatment algorithm for patients with penicillin allergy histories This algorithm, adapted from expert opinion, published studies, and guidelines,^[93,127,128] can be used to identify how to optimally prescribe β-lactam antibiotics acutely to patients with prior penicillin allergies. Reactions are divided into those with immediate and delayed onset, with reactions subsequently grouped as severe and non-severe. ADR=adverse drug reaction. AGEP=acute generalised exanthematous pustulosis. AIN=acute interstitial nephritis. DRESS=drug reaction with eosinophilia and systemic symptoms. SJS/TEN=Stevens-Johnson syndrome and toxic epidermal necrolysis. *Non-immune mediated ADRs are typically pharmacologically predictable side effects which do not preclude penicillin usage. †SCARS include DRESS, SJS/TEN, and AGEP (table 2).