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  • Evaluation And Management Strategies for Beta-Lactam Antibiotics Induced Hypersensitivity Reactions: A Comprehensive Review

  • Photo Kailash Singh Bisht * Photo Asham Preet Saini Photo Shivam Sharma Photo Tarun Sharma

  • 1University Institute of Pharma Science, Chandigarh University, Gharuan, Mohali.
    2University Institute of Pharma Science, Chandigarh University, Gharuan, Mohali.
    3ISF College of Pharmacy, Moga, Punjab.
    4University Institute of Pharma Science, Chandigarh University, Gharuan, Mohali.

Abstract

Beta-lactam antibiotics are essential and extensively utilized medications for bacterial infections in clinical settings. Penicillin has the highest prevalence of inducing hypersensitivity reactions among beta-lactam antibiotics. This can lead to poor treatment outcomes, increased risk for antibiotic resistance, and high treatment expenses. With an increasing number of suspected cases of hypersensitivity reactions, it is essential to accurately diagnose them using sensitive skin testing and in-vitro methods, while minimizing the risk of serious adverse reactions. A thorough evaluation could efficiently work to remove allergy labels associated with penicillin and other beta-lactams. Managing hypersensitivity reactions is crucial as the severity of the reaction experienced by the patients varies depending on the type. In cases of true penicillin allergy, alternative beta-lactam antibiotics are recommended based on cross-reactivity evidence. This review highlights major beta-lactam hypersensitivity reactions, including their epidemiology, clinical manifestations, diagnostic approaches, and appropriate treatment options for managing the patients. The underlying objective is to promote the optimal use of beta-lactam antibiotics and reduce antibiotic resistance.

Keywords

antibiotics, beta-lactams, hypersensitivity reactions, penicillin, skin tests, desensitization.

Introduction

Beta-lactam (BL) antibiotics, which account for two-thirds of all commonly prescribed antibiotic agents, are considered the most effective drugs [1]. BL antibiotics are bactericidal drugs and are divided into penicillin, cephalosporins, carbapenems, and monobactams. They are structurally homogenous and contain the beta-lactam ring in their chemical composition [2]. Most bacterial infections commonly treated with BL antibiotics are infective endocarditis, community-acquired pneumonia, acute bacterial meningitis, liver abscess, and bacterial dysentery [3]. According to reports of European surveillance of antimicrobial consumption, amoxicillin is the most frequently prescribed antibiotic in Europe [4]. In clinical practice, hypersensitivity reactions (HSRs) are commonly associated with BL antibiotics [5]. Most patients with BL-HSRs do not experience true allergic reactions [6]. It is a frequent practice to recommend an alternative antimicrobial agent even if there is no known true allergic reaction to BL antibiotics [7], [8]. Alternative broad-spectrum antibiotics, such as vancomycin and quinolones, are frequently prescribed to patients. However, this can lead to low treatment outcomes, increased healthcare costs, longer hospital stays, and a higher rate of antibiotic resistance [9], [10]. Most people who self-report penicillin-allergic reactions could end up receiving these medications under complete medical evaluation, and if needed, desensitization therapy can be performed, which induces temporary tolerance in the patients [11]. This review focuses on the major HSRs induced by BL antibiotics and the diagnostic approaches available so far to evaluate these reactions effectively. It also shares an idea about the management and future directions, taking into consideration the limitations related to studies conducted on BL antibiotics-induced HSRs.

  1. Epidemiology and Risk Factors

Adverse drug reactions (ADRs) caused by HSRs account for up to 20% of all the reported ADRs, which affect almost 8% of the general population [12], [13]. Specifically, HSRs are frequently associated with BL antibiotics, encompassing penicillin, cephalosporins, carbapenems, and monobactams, with prevalence rates documented in 5%-15% of patient records. Penicillin is the most reported allergen, with a prevalence of 12.8% within the patient population studied [14]. In the USA, ADRs associated with Cephalosporin are recorded in around 1% to 2% of patient medical charts. [15]. 90% of children may go on to take these antibiotics without experiencing a clinical reaction, but 10% of parents report that their child encountered a suspected BL-HSR [16], [17]. However, most of the research fails to differentiate between HSRs and other types of ADRs. Extensive studies in drug allergy clinics show that only 10 to 20% of HSR suspicions are confirmed with further investigation. It is hard to get precise statistics on the prevalence and incidence of drug allergies due to the overdiagnosis caused by the absence of reaction investigation. In recent years, research has mostly focused on genetic risk factors. A small number of medicines have been found to have a substantial correlation with specific HSR phenotypes based on genetic polymorphisms and HLA haplotypes. These results may have a significant clinical impact on the medications prescribed to high-risk populations to prevent adverse responses [18].

  1. Hypersensitivity Reactions in Beta-Lactam Antibiotics Pathophysiology

ADRs represent undesired effects that occur at therapeutic doses of a medicine normally used for treatment, prophylaxis, or diagnostic purposes. The HSRs experienced by patients are ADRs, which are immunologically mediated [19]. These reactions are classified according to the Gell and Coombs classification of HSRs (1963) based on underlying mechanisms. This classification divides the reactions into four types: I, II, III, and IV with further subdivisions of types II and IV (table 1) [20], [21].

Table 1 Modern Classification of Hypersensitivity Reactions

 

Classification Type

Immunologic mechanism

Onset Time

Clinical examples

References

?

Mast cell-mediated reactions

IgE-dependent (anaphylactic)

Within 1-6 hours of exposure

Allergic rhinitis anaphylaxis, angioedema, asthma, urticaria

[19], [22]

?a

Antibody-mediated cytotoxic reactions (IgM/IgG antibodies), complement system frequently involved

<72 hours (about 3 days) but can be up to many days (5-15 days)

Immune cytopenia

[23]

IIb

Reactions involved autoantibodies stimulating cells

Hours to days

Chronic idiopathic urticaria, Graves’ disease

[23]

III

IgG and complement system or FcR (Immunocomplex deposition)

Few days to weeks (7-21 days)

Serum sickness, drug-induced lupus vasculitis

[24], [25]

?a

Th1 (IFN-γ) monocyte activation

Within 1-21 days (about 3 weeks)

Tuberculin test reactions. type1 diabetes, contact dermatitis

[21], [26], [27]

IVb

Th2 (IL-5 and IL-4) eosinophilic inflammation

Within 14-42 days (2-6 weeks)

Maculopapular exanthems, allergic rhinitis, persistent asthma, DRESS syndrome

[21], [26], [27]

IVc

Reactions mediated by cytotoxic CD8+ T cells

Within 1-2 days

SJS and/ or TEN, bullous exanthems

[21], [26], [27]

IVd

T cell-mediated neutrophilic inflammation (IL-8)

Within 1-2 days

AGEP, Behcet’s disease

[21], [26], [27]

IgE = Immunoglobulin E, IgM = Immunoglobulin M, FcR = Fc receptor, TEN = toxic epidermal necrolysis, IFN = interferon, IL = interleukin, AGEP = acute generalized exanthematous pustulosis, Th = T-helper cell, SJS = Stevens- Johnsons syndrome, DRESS =Drug Reaction with Eosinophilia and Systemic Symptoms.

BL antibiotics are considered the most frequent triggers of HSRs that are primarily mediated by two specific underlying types: immediate reactions (type I) and delayed reactions (type IV) [28]. Immediate HSRs are initiated when a drug allergen is sensitized by T helper type-2 (Th2) cells, which signals the B cells and regulates the formation of IgE antibodies. These IgE antibodies attach to IgE receptors on the external membrane of the basophils and mast cells, and when re-exposure occurs, the allergen cross-links to IgE antibodies on these cells (see figure 1) [29]. This process results in the dissemination of mediators of inflammation such as histamines and proteases within a few minutes of exposure as well as cytokines and interleukins after 4-8 hours of exposure [30], [31]. Delayed HSRs are intermediated by T-cells as compared to type I, type II, or type III, which are mainly associated with antibody formation. The major effector cells under this category are CD4+ and CD8+ T-cells [32]. The CD4+ T cells selectively activate and recruit other cells like macrophages and monocytes, which bring about phagocytosis and release several inflammatory mediators like interleukins (IL), a class under cytokines, to retain more cells at the site of inflammation. Antigen-presenting cells present the antigen to CD4+ T cells. These cells then divide into different T helper cells, including Th1 and Th2. The function of Th1 cells is to activate the macrophages and bring about phagocytosis, and Th2 cells lead to eosinophilic response and production of IgE and IgG4 (see figure 1) [33]. On the other hand, CD8+ cells act directly against the antigens or target cells without activating other cells like macrophages or monocytes. These cells release perforins and granzymes, which induce apoptosis and lead to cell death [34].

Figure 1 Immediate and Delayed Hypersensitivity Reactions

This image illustrates the difference between immediate and delayed HSRs along with their proposed mechanism of action. Immediate HSRs are mediated by IgE antibodies and the degranulation from mast cells and basophil cells (release of mediators) results in hypersensitivity. Delayed Type HSRs involve inflammatory CD4+ T-cells, notably Th1 cells, and CD8+ T-cells. Sensitization of T-cells may activate cells such as macrophages, eosinophils, and neutrophils and in the process of destroying the allergen, these cells also cause local cell damage and inflammation.

  1. Clinical Manifestations

BL antibiotic-induced HSRs encompass a diverse range of reactions, including immediate and potentially life-threatening delayed reactions [35]. Immediate HSRs typically occur shortly after drug administration. These reactions are identified by manifestations involving the skin and/or mucosal tissues, such as itching, hives, reddening, and swelling, along with respiratory symptoms like bronchospasm, wheezing, or stridor [36]. Additionally, gastrointestinal problems such as abdominal pain, bloating, vomiting, or diarrhea may occur, along with other signs indicative of immediate reactions. Symptoms may become severe, causing low blood pressure, shock, multiple organ involvement, and anaphylaxis [37]. On the other hand, delayed reactions take more than 72 hours (about 3 days) to appear after drug administration and comprise acute interstitial nephritis (AIN), thrombocytopenia, serum sickness, drug fever, erythema multiforme (minor), SJS, and TEN [38]. These reactions are marked by pyrexia, skin eruptions or rashes, mucosal inflammation, edema, arthralgia, and lymphadenopathy [37].

  1. Diagnostic Approaches

In the medical evaluation, a comprehensive patient examination is essential for determining allergies complementary to BL antibiotics. The selection and outcome of diagnostic approaches significantly influence medical decisions, including the use of alternative medications, and post-allergy testing guidelines [39].

5.1 History Taking and Clinical Evaluation: An allergy history including symptoms, reaction onset and duration, and the management of the reaction must be taken into account during the evaluation of the suspected patients [37]. The comprehensive physical examination must cover all organ systems that are relevant to the clinical presentation [19]. The patient should be interrogated with a few relevant questions regarding any previous allergic reaction. Certain questions are included in Figure 2 to rule out penicillin allergies. Moreover, the diagnostic utility of clinical history is deemed strongly unreliable. Approaches like predictive models and clinical decision-making algorithms that utilize the medical history of the patients in cases of suspected allergic reactions to BL antibiotics have shown some ineffectiveness in accurately distinguishing between allergic and non-allergic individuals [40], [41].

Figure 2 Clinical history taking

This image depicts the essential information to be gathered during the clinical history taking of the patient. It also demonstrates the importance of asking specific questions by illustrating their relevance in uncovering certain details about the patient's allergic history.

5.2 Skin Testing Techniques: Skin testing (ST) is an effective method that is used for diagnosing immediate allergic reactions [42]. Since the occurrence of systemic reactions is rare (1%) in patients undergoing ST techniques such as skin prick tests or intradermal tests, it is regarded as a safe way of predicting allergic reactions [43]. Penicillin ST is usually performed using a major determinant, penicilloyl-polylysine (PRE-PEN), and minor determinants, penicillin G, penicilloate, and penilloate, and has a negative predictive value of 97%-99% [42], [44]. A positive allergic reaction is interpreted with a skin test that includes a 3 mm (about 0.12 in) diameter wheal or more, a larger surrounding flare, a positive result to histamine, and a negative result to the saline (control solution). ST is essential before performing intradermal testing to enhance safety as patients may experience systemic reactions during administration of intradermal reagents. In both skin and intradermal tests, similar reagents are used [45]. Moreover, cross-reactivity between penicillin and cephalosporins (first-generation) with identical side chains can be predicted using ST methods [46].

5.3 Graded-dose Challenge: In contrast to ST, a graded-dose challenge (GDC) is regarded as the best approach for determining an individual’s ability to tolerate a drug [47]. It is the most definitive and safe method for removing a penicillin allergy label, where the drug is administered orally to assess tolerance in carefully selected low-risk individuals [48], [49]. A GDC is typically conducted when there is minimal suspicion of a true penicillin allergy, either due to an unclear medical history or a considerable time difference between the reported allergic reaction and the present evaluation of the reaction [50]. For the oral drug challenge, amoxicillin is typically recommended because it contains a potentially antigenic side chain and is the most prescribed BL antibiotic [37], [51]. A GDC consists of a single-step or two-step drug challenge. A single-step drug challenge provides a complete therapeutic dose of a drug in one step only, whereas a two-step challenge involves administering 1/10th of the full dose initially, followed by administering the full dose 40-60 minutes later [47], [52]. If the skin test findings or drug challenge are negative, BL antibiotics are considered safe to use. However, if the results are positive, it is considered best to avoid BL antibiotics, especially penicillin, by switching to alternative medications. In some cases where penicillin is required as a first-line drug, desensitization is advised. [38], [53]

5.4 In-vitro Tests: The major laboratory tests that are used for assessing immediate HSRs are the basophil activation test (BAT) and serum-specific IgE immunoassay (SsIgE) [54] [55]. Delayed HSRs are evaluated using procedures such as enzyme immunosorbent spot assays (ELISpot) and lymphocyte transformation tests (LTT) [54]. The LTT quantifies the specific memory T-cells when exposed to a particular antigen and has primarily been utilized for diagnoses of various cutaneous reactions, such as maculopapular eruptions (MPE), urticarial and fixed drug eruptions (FDE), that are caused by the use of medications such as BL antibiotics [56]. When used besides ST, SsIgE, and BAT can aid in determining the need to proceed with a graded-dose challenge, especially in high-risk patients [57]. The BAT assesses the activity of IgE antibodies by measuring their ability to trigger the activation of basophils when exposed to allergens using a method called flow cytometry [58]. Immunoassays that quantify specific IgE antibodies to BLs depend upon the detection of a drug-(hapten)-carrier-antibody complex using methods such as radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA) and fluorescent enzyme immunoassay (FEIA) [55], [56]. Quantification of IgE antibodies in vitro has certain benefits over ST as it is a less time-consuming and safer method, especially for those requiring special precautions, such as pregnant women, immunosuppressed patients, or patients in an unstable state where ST is contraindicated or inappropriate [59], [60] The tests performed for detecting penicillin-specific IgE in vitro do not definitively rule out penicillin allergy due to the variability in their sensitivity and specificity [20]. A gradual decline in the levels of specific IgE antibodies may cause reduced sensitivity of both the SsIgE and BAT [61]. Consequently, it is advised that these tests be conducted promptly following the reaction, preferably soon after its occurrence. Thus, due to the lower sensitivity of BL antibiotics, in-vitro tests are included only as an optional step in diagnosis [52], [60], [62].

Figure 3 In-Vitro Tests

This image illustrates the procedures to perform different in-vitro tests for the detection of different HSRs. In BAT, markers on basophil’s surface are analyzed to detect the presence of IgE antibodies. SsIgE immunoassay detects the amount of specific IgE antibodies using secondary antihuman IgE antibodies labeled with a radioisotope (RIA) or enzyme (ELISA and FEIA). In tests like LTT, peripheral blood mononuclear cells are cultured for adequate proliferation of allergen-specific cells. The stimulation index is calculated by comparing the rate of proliferation (counts per minute) with drug/ proliferation (counts per minute) without drug.

  1. Evaluation And Management

A greater part of the patient population who claim penicillin allergy can undergo a thorough evaluation and, if necessary, treatment, enabling them to safely receive penicillin or other BL antibiotics. This approach not only minimizes reliance on broad-spectrum antibiotics but also reduces healthcare costs and prevents the emergence of multi-drug-resistant pathogens [26]. Penicillin allergy labels can lead to suboptimal treatment decisions, such as prescribing vancomycin for methicillin-susceptible Staphylococcus aureus (MSSA) bacteria when nafcillin and cefazolin are more effective options [63]. In patients exhibiting symptoms like Immediate reactions, subsequent negative evaluation outcomes could arise from numerous factors, such as specific IgE antibodies diminishing over time or earlier symptoms being attributable to an underlying illness rather than a reaction to penicillin [20]. Thus, it is essential to perform a proper evaluation to exclude penicillin allergy labels, as they are more prevalent than the other BL antibiotics. If the allergy label is found to be true based on diagnosis or allergy history, then it must be differentiated either into immediate or delayed HSRs since management strategies vary in both cases based on the seriousness and duration of the reaction [64].

Figure 4 Algorithm depicting evaluation and management of Immediate and Delayed HSRs.

6.1 Immediate reactions: Allergy history, risk factors, and diagnostic tests are certain factors considered while evaluating patients. Patients have a low probability of experiencing an immediate or Immediate HSR if they have no allergic history or negative penicillin ST results [38]. Patients with low-risk factors (family medical history of penicillin, pruritis without skin eruptions/rash, or certain reactions without IgE hypersensitivity features > 10 years) can safely administer amoxicillin or undergo a GDC with amoxicillin orally under medical supervision. Moderate risk patients with a history of urticarial or severe rashes with pruritis, or reactions with Immediate features other than anaphylaxis, should be examined initially by penicillin ST, followed by a GDC if the skin test is negative. Among the high-risk patients, (history of anaphylaxis or BL’s induced allergy, positive penicillin skin tests), a thorough evaluation must be performed before initiating the therapy [64]. Higher-risk patients may receive help from drug desensitization or by switching to alternative antibiotics. In certain cases, such as the treatment of neurosyphilis, where penicillin or other BL antibiotics are superior to alternative options, the desensitization process is reserved [50], [65].

6.2 Delayed reactions: Patients having a clinical history of severe Delayed reactions, such as DRESS, SJS, TEN, AIN, hepatitis, or hemolytic anemia are not recommended a GDC and desensitization [20], [66]. Evidence of cross-reactivity or long-term antibiotic re-challenge for these reactions is limited. Many studies have shown chronic immunological responses to antibiotics and suggested avoiding re-exposure to any potentially cross-reactive medication [67]. Evaluation of BL allergy labels must also be initiated in different population groups such as children, pregnant women, geriatrics, cancer patients, and those requiring surgical prophylaxis as discussed (table 2).

Table 2 Evaluation in Special Population Groups

 

Population Groups

Need For Allergy Evaluation

References

Surgical Prophylaxis

first-generation cephalosporins, like cefazolin, are more effective in surgical prophylaxis but penicillin-allergic patients are often prescribed alternatives such as vancomycin and clindamycin

[68], [69]

Pediatrics

Viral infection-related exanthem (maculopapular exanthema) and interaction of drug-infection (Epstein-Barr virus and aminopenicillin) must be considered while evaluating for penicillin allergy in children.

[70], [71]

Pregnant women

Amoxicillin and cephalexin are used for managing various bacterial infections (syphilis and urinary tract infections) in pregnant women. But penicillin allergy labels promote the use of inferior alternative drugs which results in complications.

[72], [73]

Cancer patients

Such patients are often prescribed BL antibiotics for the management of conditions such as fever and neutropenia, which also increases the prevalence of allergy labels in them. Evaluation is essential in cancer patients to improve clinical decisions and treatment outcomes.

[74], [75]

Geriatrics

With advancing age, the prevalence of allergy labels in patients increases and is associated with the use of alternative medications. Fluoroquinolones, when used as an alternative to penicillin, increase the risk of Clostridium difficile infections and drug-drug interactions in geriatrics.

[15], [64]

Cross-Reactivity and Alternative Antibiotic Choices

Earlier studies reported a higher rate of cross-reactivity between BLs (penicillin and cephalosporins) due to the consumption of some first-generation cephalosporins, which were found to be contaminated with traces of penicillin [76]. Some studies suggest that only 1-3% of the allergic patients to penicillin show a positive test for cephalosporins. Thus, the probability of patients showing a cephalosporin allergy is quite low [77]. Few pieces of evidence suggest that cross-reactivity is more frequent due to a similar side chain (R1) than the common BL ring. As a result, cephalosporins of the first and second generation are more cross-reactive with penicillin [78]. Penicillin and cephalosporins exhibit a varying rate of cross-reactivity; for instance, penicillin G and cephalosporins (cephalothin, cefamandole) show a cross-reactivity of 5.6%. Another example is amino-penicillin and amino-cephalosporins, whose reported cross-reactivity is 16.5% [79].  Patients showing allergic reactions to aminopenicillin, like amoxicillin, could tolerate other penicillin (penicillin G and penicillin V) but not cephalosporins having similar R1 side chains [80]. Patients with reported allergies to amoxicillin must avoid cefadroxil, cefprozil, and cefatrizine, while other cephalosporins like cephalexin, cefaclor, cephradine, and cephaloglycin should be avoided in ampicillin-allergic patients. Diagnosis with ST is essential in patients with penicillin allergy before starting with cephalosporins, including cefuroxime, cefazolin, cefixime, ceftriaxone, and cefpodoxime, to rule out any immunogenic response [81], [82]. Cross-reactivity is also possible among different classes of cephalosporins if they share the same R1 side chain, especially in cefuroxime, cefotaxime, cefodizine, and ceftriaxone. Thus, patients with cephalosporin allergy are recommended alternative cephalosporins sharing different side chain determinants [83]. A recent trial found the cross-reactivity rate between carbapenems (meropenem) and penicillin to be only 0.9% among patients testing positive for penicillin. Since the incidence of cross-reactivity is low, the avoidance of carbapenems in penicillin-allergic patients should be reconsidered [84]. Aztreonam is the only monobactam currently used in clinical practice. Few studies and clinical trial evidence indicate the absence of potential cross-reactivity among monobactams and penicillin. Monobactams have shown cross-reactivity with ceftazidime due to similar side chains.

6.4 Role of Desensitization in Treatment with Beta-Lactam Antibiotics

Desensitization is accurately characterized as the induction of drug tolerance for a short term by administering lower doses of the recommended drug (below the level that triggers an HSR) to alter the patient’s response to medication [86]. The underlying goal of this process is to safely administer the drug at its full therapeutic dose [87]. The mechanisms underlying mast cell desensitization are not well recognized, but they may involve the antigen/IgE/FcεRI complexes and the activation of inhibitory receptors present on the mast cells through cross-linking. Additionally, desensitization may involve a decrease in the levels of Syk, an upstream signal-transducing molecule, which is essential for the activation and signaling of mast cell IgE receptors [88]. The practice of antimicrobial desensitization is majorly in patients with BL-HSRs; however, protocols vary in formulation, beginning dose, number of levels, and frequency of dosing (table 3). Rapid drug desensitization (RDD) involves doubling the dose every 15 minutes until reaching the full therapeutic dose of the drug [65], [89]. RDD renders the mast cells under-responsive to a medication acting as an allergen and introduces temporary tolerance in hypersensitive patients. In the case of penicillin desensitization, the initial dose is administered via oral or intravenous (IV) routes [90]. The tolerance achieved through drug desensitization diminishes within a few days after the drug is discontinued. This implies that the desensitization process needs to be repeated each time the patient is re-exposed to the specific drug following a period of discontinuation [91].

 

Table 3 Desensitization

 

Characteristics of desensitization protocol for penicillin

References

Indications

Benefits must outweigh the associated risks

No better and safer alternatives are available (e.g. treatment of pregnant women with syphilis)

[92], [93]

Contraindications

Relative cases: anaphylactic reaction, hepatic, renal, or cardiac disease, AGEP

Absolute cases:  asthma, poorly controlled CVD, COPD, SJS, TEN, DRESS

[92], [93]

Initial dose

Micrograms (dilutions of 1:100 or 1:1000 of the desired therapeutic concentration, followed by a gradual increase in the concentration)

[91], [94]

Protocol duration and routes of administration

Oral- 4 to 8 hours with interval between doses 15-30 mins

Intravenous- 4 to 8 hours with interval between doses 15 mins

[95]

Duration of drug tolerance

Temporary as the tolerance of the drug is lost 24 to 36 hours (about 1 and a half days) after discontinuation of the drug

[95]

Potential outcomes

Activation of inhibitory receptors present on the mast cells and diminishing the response of mast cells

Safe administration of the medication during the intended period

[94]

AGEP- acute generalized exanthematous pustulosis, COPD- chronic obstructive pulmonary disease, CVD- cardiovascular disease, DRESS- drug rash with eosinophilia and systemic syndrome SJS- Stevens-Johnson syndrome, TEN- toxic epidermal necrolysis,
  1. Antimicrobial Stewardship Programs in Beta-Lactams Allergy

Antimicrobial stewardship programs aim to provide rational therapy to patients while minimizing the adverse effects. The reported BL allergies have been linked to the use of less effective alternatives with poor treatment outcomes. Few studies suggest that replacing anti-staphylococcal BLs (such as oxacillin and nafcillin) with vancomycin can lead to higher rates of treatment failure and an increase in vancomycin-resistant bacteria [96]. Implementation of BL allergy testing and other safety procedures through antimicrobial stewardship guidelines have demonstrated the safe administration of BL antibiotics in patients. Moreover, this reduces the use of restricted antibiotics and decreases the length of hospital stay and healthcare costs [97].

  1. Future Directions

De-labeling research outlines crucial areas of focus to advance the field of penicillin allergy management. Validation and implementation of point-of-care tools, evidence-based de-labelling strategies, and the creation of a toolkit for antibiotic allergy management are needed [98]. It is necessary to re-evaluate, update, and standardize in-vivo tests, improve the sensitivity of in-vitro tests, and develop methods to identify and treat patients with suspected drug allergies, as there is substantial variation in current medical practice among centers [99]. Nanotechnology can be particularly useful in improving immunoassays by enhancing the process of identifying specific IgE antibodies. In vitro tests have seen significant advancements in recent years and offer several benefits in diagnosing drug allergies, such as accurate measurements, complete safety, controlled testing conditions, and the ability to store samples for a long time when it comes to serologic tests. Additionally, these tests have been modified to keep up with the discovery of new BL compounds [100].

  1. CONCLUSION

BL antibiotics-induced HSRs are widely reported in patients which impacts the treatment outcomes and clinical decision making. The need to remove unnecessary allergy labels draws the focus on various diagnostic approaches such as ST and in-vitro techniques. In addition to this, a comprehensive history-taking process aids in collecting relevant data about HSRs in suspected patients. Desensitization protocols manage true penicillin allergy cases by ensuring the safe administration of BLs with the underlying principle of induction of temporary tolerance in patients. Understanding the cross-reactivity among BL antibiotics helps in selecting the safest alternative. The major impact of HSR testing lies in ruling out non-allergic cases and delabeling patients with irrelevant allergy labels of penicillin and other BL antibiotics. Thus, by addressing these areas, healthcare professionals aim to improve the accuracy of diagnosis to enhance patient care and promote antimicrobial stewardship practices.

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Kailash Singh Bisht
Corresponding author

University Institute of Pharma Science, Chandigarh University, Gharuan, Mohali.

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Asham Preet Saini
Co-author

University Institute of Pharma Science, Chandigarh University, Gharuan, Mohali.

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Shivam Sharma
Co-author

University Institute of Pharma Science, Chandigarh University, Gharuan, Mohali.

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Tarun Sharma
Co-author

ISF College of Pharmacy, Moga, Punjab.

Asham Preet Saini, Shivam Sharma, Tarun Sharma, Kailash Singh Bisht*, Evaluation and Management Strategies for Beta-Lactam Antibiotics Induced Hypersensitivity Reactions: A Comprehensive Review, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 3, 3188-3206 https://doi.org/10.5281/zenodo.15110977

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