The session includes four presentations which talk about penicillin allergy management, suspected allergy to non-beta lactam antibiotics, prescribing cephalosporins in penicillin-allergic patients and guidelines for approach to suspected antibiotic allergy.
The first session by Professor Jason Trubiano discussed the penicillin allergy management after the Penicillin Allergy Decision Rule (PENFAST) study. Penicillin allergy and antibiotic allergy presents a global prescribing problem. Penicillin allergy equals poor prescribing, but unfortunately does not lead to testing. One in ten patients in a hospital report penicillin allergy and it is associated with antimicrobial resistance, poor patient outcomes and poor hospital outcomes, including length of stay and hospital costs. A solution is to identify the penicillin allergy patients and then delabel (via direct oral challenge, DOC) which is the removal of the penicillin allergy. This can give a 10fold increase in antibiotic appropriateness. There are a set of clinical decision rules for penicillin allergy; however, they may need validity in their own setting. PENFAST is a clinical decision rule that was derived from over 1500 patients in Australia and the USA, 622 were in the prospective validation cohort. If there was a score < 3, 96.3% was a negative predictive value. The data was derived from both an inpatient and outpatient setting. It included both immediate and delayed phenotypes and immunocompromised patients (55%). The limitations of PENFAST were that it was a retrospective validation, there were a small number of SCAR phenotypes, the median age of 60 years and most scores were between 0 and 2. The steps in PENFAST include identifying the penicillin allergy patient, attain the phenotype, get the history and feed it to the PENFAST assessment tool which can provide an action which may be a DOC, skin testing or prescribing alternative beta lactams. While appointing an action with a score, it can be -giving a beta lactam after removing the allergy label, doing a DOC or prescribing any cephalosporin, or performing skin testing and avoiding beta-lactams. PENFAST is majorly being used in an inpatient setting in immunocompromised patients and for antimicrobial stewardship (AMS). In the regions of Australia, North America, Europe and other regions. A cohort studied by PENFAST which had 70% anaphylaxis episodes in 140 patients demonstrated that PENAFAST maintained its negative predictive value of 97.4 %. However, there is a need to validate this in randomized controlled trials and in health services implementation and adaptation through a digital arm. The application of PENFAST in the pediatric cohort of > 2000 children in Canada has demonstrated that it does not work. Although the negative predictive value is good, the area under the curve is poor. But, data from the adolescent group has good outcomes and PENFAST can be used in this group. While validation in pregnant women in amoxicillin challenge focusing on a very low risk, it was found that there was a PENFAST score of zero and a sensitivity of 98.1%. While using PENFAST in an emergency cohort looking at a change in prescription, it was found that those with low PENFAST score transitioned to beta lactams. DOC in inpatients settings which was conducted as a hospital surveillance (antibiotic labelling program) with multidisciplinary partnerships showed that 96% inpatients were negative on direct oral challenge. When applied to a cohort of sulfa allergy tested patients, it was found that the negative predictive value was retained at 98.1%. In conclusion, PENFAST is the only internationally validated penicillin clinical decision rule with data for both inpatient and the outpatient setting.
The pathophysiology behind different clinical manifestations of allergy to beta lactam is different. The immune reactions as per the Coombs and Gell category, there is unspecific specific mast cell activation and drug hypersensitivity. In type IV sensitization, the delayed hypersensitivity has different mechanisms where there is involvement of lymphocytes in different inflammatory cells and cytokines depending on clinical manifestation. The types of reactions can be subdivided based on clinical manifestations and the cells or antigens which are responsible for the localization of cells and the cytokines that drive the inflammation. PENFAST, as a diagnostic tool for the non-beta lactam allergies, requires a detailed history with pictures of clinical morphology as the clinical manifestations may evolve during the course of the allergy. It is also important to have information of the drugs and their date of intake, the exact sequence of events, underlying disease, concomitant infections and drug allergies. Diagnosing an allergy can be made through prick and intradermal tests, specific IgE assays, cellular activation such tests which are available in specialized laboratories and are validated for single non-beta lactam antibiotics only. For diagnosing delayed type hypersensitivity, intradermal test/patch test and lymphocyte transformation test can be performed (LTT). Among the different drug groups, macrolides produce hypersensitivity reactions in about 3% of treatments; however, the allergic determinants are not known. Recently, an HLA risk factor has been defined for hypersensitivity to clarithromycin in the Han-Chinese population. Isolated urticaria can appear several hours after first intake of macrolide and uncomplicated maculo-papular exanthem are most frequent. There is low cross-reactivity (20%) among macrolides. Fluoroquinolones have 2% hypersensitivity in unselected in-patients (immediate type and delayed type hypersensitivity). Only one third of those patients have a recurrence of the clinical manifestation. There has been an increased hypersensitivity reaction in the last 20 years which is mainly due to levofloxacin and moxifloxacin. Skin test is an issue with fluoroquinolones as there is no test concentration that can be recommended for testing. There are a number of drugs which activate Mas-related G protein-coupled receptors which generate immediate type hypersensitivity symptoms without an immunological mediated mechanism. Drug-induced anaphylaxis can occur in drug-naive patients who have not been exposed to that drug before. This could occur due to cross-reactivity, non-IgE dependent mechanism non-specific histamine release. For fluoroquinolones in immediate hypersensitivity, skin tests are unreliable as they have a high irritative potential. In delayed hypersensitivity to fluoroquinolones, uncomplicated maculo-papular exanthem is common. In glycopeptide antibiotics, skin tests and cellular activation assays are useful as they help differentiate immediate type allergy from Red Man's syndrome. There is a direct correlation in Red Man’s syndrome and vancomycin infusion right rate and the dose; faster the infusion, more activated is the receptor more pronounced are the clinical symptoms. Sulfonamides have immunologic effects in 2 to 3% of the population. IgE mediated reactions are infrequent. But in HIV and tuberculosis patients, there is a disproportionately high percentage of severe drug reactions. Skin tests are well established and helpful and the positive reactions are highly specific. LTT is an important additional tool in specialized laboratories. Aminoglycosides are used topically and intravenously and there are rare cases of immediate type and delayed type hypersensitivity. They are more frequent in children and cystic fibrosis patients. Pharmacological tolerance induction can be done successfully in these patients.
Cephalosporins and penicillins are the drugs that frequently induce allergic reactions constitute about 15% of all adverse reactions, affecting more than 7% of the general population. There is a classification of hypersensitivity reactions to beta lactam based on underlying immunological mechanisms. These include allergic reactions mediated by IgG antibodies and T-cells and the pharmacological interaction. The other classification divides the reactions into immediate reaction (1-6 hours after drug intake) and delayed or non-immediate reaction (3-12 days after drug intake). The structure of side-chains is responsible for a cross-reactivity between penicillins, cephalosporins or other beta lactams. While reporting hypersensitivity reaction to beta lactams, the goals are to confirm or exclude allergy to the beta lactams and in case of allergies, find safe alternatives, particularly among other beta lactam. The diagnosis of beta lactam hypersensitivity reactions require clinical history about possible antibiotic allergies, practice description of morphology and the chronology of your reactions and time elapsed between administration of the drug and the appearance of the symptoms. The diagnostic workup should be ideally performed 4 to 6 weeks after complete resolution of all clinical symptoms and screening of subjects without a prior history of a particular drug or reaction is not recommended. Cross-reactivity among drug manifests when the drug is not previously administered elicits hypersensitivity reaction because of a pre-existing sensitization of the structurally related compounds or because of a common pharmacological characteristic. Cross-reactivity between benzylpenicillins and the and the1st and the early 2nd generation cephalosporin, has been reported to occur in about 10% and for 3rd generation is about 2 to 3% of penicillin-allergic patients. For selecting cephalosporins in penicillin-allergic patients, a meta-analysis (articles between 1966-2005) shows there is no increased allergic reaction with 2nd- or 3rd generation cephalosporins. Another meta-analysis showed that cross-reactivity varied with degree of similarity between R1 side chains. A study has also shown that in subjects with proven IgE-mediated allergy to penicillins, the rate of positive cephalosporin skin test ranges from 0 to 33.3%. The rate of positive response to cephalosporin challenges ranged from 5.6% to 38% in penicillins-allergic subjects. Among the paediatric population, there is only one study which showed the rate of cross-reactivity between cephalosporins and penicillins varied between 0.22 and 23.9%. The European Academy of Allergy Clinical Immunology, British Society of Allergy and Clinical Immunology and the USA practical parameter recommend that in penicillin-allergic patients, therefore, skin testing with cephalosporins that have the side chains different from those of penicillin- followed, in case of a negative result by graded challenges has proved to be safe method to administer these alternative beta lactams. In graded challenges, usually an initial double dose of one tenth of the maximum single unit dose (MSUD) is administered, and in case of negative result, one hour later a full MSUD. In the patient with a mild or moderate, a non-immediate reaction to penicillins who require a cephalosporin, if there is no time to wait for delayed reading of pre-treatment skin tests, giving a full dose of structurally non-related cephalosporin can be considered as the increase risk does not concern an immediate reaction, such as anaphylaxis, but that of an exanthema recurrence. Patients with a history of SCARS-associated with penicillins treatment should avoid all penicillins and cephalosporins, especially those structurally related to the responsible penicillins. In subjects with IgG-mediated hypersensitivity towards cephalosporins, the risk of positive allergy test responses with alternative cephalosporins is not connected only with the structural similarities among their side-chain determinants. Cephalosporin allergy subjects might be treated with alternative cephalosporins that have side chains different from those of the responsible compounds and are negative in pre-treatment skin tests.
In clinical practice, the main challenge is to discriminate between true allergic reactions and all other kinds of reactions. The notion that patients with an allergy label are truly allergic, leads to more frequent use of less effective antimicrobial regimens, increased use of broad spectrum antibiotics, and hence to higher costs and side effects and limits the options for future and development of AMR. There are no protocols or guidelines dealing with antibiotic allergy and the estimates from IDSA do not provide good guidelines on this topic yet. In the Netherlands, a guideline on antibiotic allergy was developed. The guideline focuses on hospital setting, bedside setting and some of the recommendations are specifically applied in primary care. The aim of the guideline was to define prevailing professional standards and to formulate general recommendations of the anti-microbial treatment of patients who report an antibiotic allergy. The guidelines used grades and methodology to grade the evidence which was underlying the recommendation. They also attributed strengths to the recommendation to give guidance to whether clinicians should really or maybe only consider implementing the recommendation. The guideline navigation panel had a systematic approach to recommend the use of a drug after an allergic reaction from the same class or a different class. The guideline had 60 recommendations which were based on immediate type and delayed type allergies. The guideline strongly recommends that a detailed antibiotic allergy history should be performed in the patients with documented or (self) reported allergy. For cross-allergic reactions, the similarity of penicillins is due to formation of Penicilloyl-polylysine (PPL). For cephalosporins with dissimilar side chains as suspected with penicillin, the risk of cross allergic reactions is quite low. For cephalosporins with similar identical side chains to culprit penicillin, it increases to 5 to 17%. The guidelines recommend that patients with suspected or proven immediate type allergy to penicillins can receive cephalosporins, only those with dissimilar side chains, irrespective of severity and time since index reactions. In patients with non-beta-lactam allergy, the guidelines recommend avoiding re-exposure to the culprit non-beta lactam. With respect to the severity of reaction, the guidelines used both sets of criteria- symptomatology and the consequences. The guideline recommends that in case of a severe delayed reaction, it should not be challenged without the consultation of a multidisciplinary team. In case of non-severe delayed type reactions re-exposure to the culprit antibiotic or beta lactam is allowed after 1 year. In case of non-severe immediate type reactions re-exposure to the culprit antibiotic or beta lactam is allowed after 5 years in a controlled setting. The guideline does not handle the issue of bedside testing. The guideline was implemented in hospitals, symposia, educational workshops and campaigns. It was integrated in local antibiotic formularia. The guideline is in the English language. In summary, there is now sufficient scientific data and expertise available to have a practical guideline to handle those patients with a label or a suspected antibiotic energy. Even without allergy testing. After a targeted history and search of relevant data, a rational decision can be made about how to act on a reported antibiotic allergy.
European Congress of Clinical Microbiology and Infectious Disease 2023, 15th April - 18th April 2023, Copenhagen, Denmark
