Cephalosporin Hypersensitivity Research Articles

Cephalosporin Allergy: Updates on Diagnostic Testing.

Cephalosporins are one of the most prescribed antibiotics worldwide and are implicated in a wide range of hypersensitivity reactions (HSR). This review summarizes recent updates in cephalosporin hypersensitivity with a focus on diagnostic testing. Reported testing strategies to evaluate different immediate and delayed cephalosporin HSR have included skin testing, in vitro testing, and diagnostic drug challenges. However, the diagnostic performance of in vivo and in vitro tests remains unclear across different hypersensitivity endotypes; adequately powered studies investigating the true positive and negative predictive value of these diagnostic modalities are needed using the reference standard of drug challenges to define cephalosporin hypersensitivity. Refinement of diagnostic testing should be guided by growth in our understanding of cephalosporin antigenic determinants. This growth will be crucial in driving further clarification of cross-reactivity between cephalosporins, and potentially delineating streamlined evaluation processes resulting in reduced unnecessary antibiotic avoidance.

MurA escape mutations uncouple peptidoglycan biosynthesis from PrkA signaling.

Gram-positive bacteria are protected by a thick mesh of peptidoglycan (PG) completely engulfing their cells. This PG network is the main component of the bacterial cell wall, it provides rigidity and acts as foundation for the attachment of other surface molecules. Biosynthesis of PG consumes a high amount of cellular resources and therefore requires careful adjustments to environmental conditions. An important switch in the control of PG biosynthesis of Listeria monocytogenes, a Gram-positive pathogen with a high infection fatality rate, is the serine/threonine protein kinase PrkA. A key substrate of this kinase is the small cytosolic protein ReoM. We have shown previously that ReoM phosphorylation regulates PG formation through control of MurA stability. MurA catalyzes the first step in PG biosynthesis and the current model suggests that phosphorylated ReoM prevents MurA degradation by the ClpCP protease. In contrast, conditions leading to ReoM dephosphorylation stimulate MurA degradation. How ReoM controls degradation of MurA and potential other substrates is not understood. Also, the individual contribution of the ~20 other known PrkA targets to PG biosynthesis regulation is unknown. We here present murA mutants which escape proteolytic degradation. The release of MurA from ClpCP-dependent proteolysis was able to activate PG biosynthesis and further enhanced the intrinsic cephalosporin resistance of L. monocytogenes. This latter effect required the RodA3/PBP B3 transglycosylase/transpeptidase pair. One murA escape mutation not only fully rescued an otherwise non-viable prkA mutant during growth in batch culture and inside macrophages but also overcompensated cephalosporin hypersensitivity. Our data collectively indicate that the main purpose of PrkA-mediated signaling in L. monocytogenes is control of MurA stability during standard laboratory growth conditions and intracellular growth in macrophages. These findings have important implications for the understanding of PG biosynthesis regulation and β-lactam resistance of L. monocytogenes and related Gram-positive bacteria.

Risk Stratification as a Predictive Factor for Cephalosporin Allergy: A Case-Controlled Study

Background: Compared to penicillin, cephalosporin allergies are less common in children, and their diagnostic approach is less standardized. A recent European Academy of Allergy and Clinical Immunology position paper provided a risk stratification system for patients with suspected β-lactam hypersensitivity reactions. Objective: This study aimed to evaluate risk stratification and predicting factors for confirmed cephalosporin hypersensitivity. Methods: The case-controlled study included patients with confirmed cephalosporin hypersensitivity (skin tests, n = 53; drug provocation, n = 19). For each patient, 2 age- and gender-matched control subjects were included in the study. Data were retrieved from patients’ records and analyzed retrospectively. Risk stratification was performed according to the severity of index reactions, which was initially divided as high and low risk and then further divided as immediate and nonimmediate. Results: According to risk stratification, the patient and control groups were divided as follows: high-risk immediate (66.7% vs. 13%, respectively), high-risk delayed (1.4% vs. 8.3%, respectively), low-risk immediate (16.7% vs. 16%, respectively), and low-risk delayed (15.3% vs. 62.9%, respectively). Immediate reactions (odds ratio [OR]: 12.1, 95% confidence interval [CI]: 9–24.8, p < 0.001) and high-risk reactions (OR: 7.8, 95% CI: 4.1–14.6, p < 0.001) were associated with confirmed cephalosporin hypersensitivity in univariate analysis. Multivariate regression analysis indicated that immediate reactions (OR: 7.5, 95% CI: 3.3–16.8, p < 0.001) and high-risk reactions (OR: 5.2, 95% CI: 2.1–12.9, p < 0.001) were significant risk factors for the prediction of cephalosporin hypersensitivity. Conclusion: This model can be applied in children with suspected cephalosporin allergy. Skin testing provides diagnostic information in high-risk patients with immediate reactions and reduces the need for drug provocation testing in these patients. It is highly likely to confirm the diagnosis of low-risk patients directly with provocation tests without skin tests. High-risk and immediate reactions were found to be predictive factors for confirmed cephalosporin allergy.

Evaluation of Clinical Properties and Diagnostic Test Results of Cephalosporin Allergy in Children

Introduction: Beta-lactams (BLs) are one of the most frequent causes of drug hypersensitivity reactions (HRs), and cephalosporins are a widely used subclass of BLs, especially in children. The aim of this study was to evaluate the clinical features and diagnostic test results of pediatric patients evaluated for suspected cephalosporin allergy. Methods: This study included patients who presented to our pediatric allergy clinic with a history of reactions attributed to cephalosporins between January 1, 2011, and December 31, 2019, and whose diagnostic tests were completed for the diagnosis. Results: This study included 120 pediatric patients and 69 (57.5%) of them were girls. The median age was 38.63 (interquartile range 10.5–85.7) months. Reactions occurring within 1 h of drug intake were reported in 33 patients (27.5%). Reactions were maculopapular rash in 55 (45.8%) patients, urticaria and/or angioedema in 49 (40.8%), anaphylaxis in 11 (9.2%), severe cutaneous drug reaction in 4 (3.3%), and fixed drug reaction in 1 patient (0.83%). The most frequently suspected agent was cefixime in 41 patients (34.2%). In total, 30 (25%) patients were diagnosed as having cephalosporin hypersensitivity. Confirmation of HRs was also significantly more frequent among patients who were older (p: 0.000), who had taken the drug parenterally (p: 0.000) and with immediate reactions (p: 0.000). Conclusion: Cephalosporin allergy has been confirmed in approximately one-fourth of the patients evaluated for suspected cephalosporin allergy. Confirmation of HRs was significantly more common among patients who were older, had immediate reactions, and had taken the drug parenterally.

Cephalosporin Hypersensitivity: Descriptive Analysis, Cross-Reactivity, and Risk Factors

Cephalosporins, which belong to the beta-lactam therapeutic class, are increasingly used throughout the world. Few large studies on this issue have been conducted, and most of them have been performed as part of penicillin hypersensitivity studies. We described our 26-year experience exploring cephalosporin drug hypersensitivity, from which we identified epidemiological and cross-reactivity data. We included 476 patients who reported drug hypersensitivity reaction (DHR) to cephalosporin and underwent an allergy workup between January 1992 and July 2018 in the Allergy Unit of the University Hospital of Montpellier (France). According to their structural side chain R1 homology, we worked with 4 classes of cephalosporins. Logistic regression analysis was used to search for risk factors for hypersensitivity to cephalosporin (positive skin test [ST] or drug provocation test [DPT] results). Cephalosporin hypersensitivity was proven in 22.3% of the patients referred in our Unit, according to positive ST (51.9%) or DPT to the culprit drug (48.1%). One in 5 patients were children, and cephalosporin hypersensitivity was confirmed in 15% (47.6% of them by means of ST). In the cephalosporin hypersensitive population, initial reactions were mostly immediate (68.9%) and anaphylactic (72.7%). Cross-reactivity with aminopenicillins was the most frequent pattern of cross-reactivity. In multivariate analysis, immediate reactions (odds ratio [OR]= 3, 95% confidence interval [CI] [1.6-5.5], P < .001), anaphylactic shock (OR= 6.5, 95% CI [3.3-13.1], P < .001) and anaphylaxis (OR= 3.1, 95% CI [1.6-6.1], P < .001), and multiple reactions to the same or several cephalosporins (OR= 2.0, 95% CI [1-3.5], P= .04) were statistically associated with confirmed DHR. DPT was generally safe, but elicited anaphylaxis in 20% of patients. Systemic reactions during skin testing occurred in 9.1% of positive patients, almost always related to anaphylactic index reactions. Nonimmediate confirmed DHR to cephalosporins were rare and occurred in less than 10% of the positive patients. Almost a quarter of the tested patients were confirmed as hypersensitive to cephalosporins; sensitivity of skin testing was 51.9%, and thus, half of the positive patients needed a DPT to prove the diagnosis.

Evaluating Immediate Reactions to Cephalosporins: Time Is of the Essence

Few studies have assessed the diagnostic value of cephalosporin skin tests in patients with immediate reactions to these β-lactams. To evaluate the usefulness of skin tests and challenges in assessing such subjects. We conducted a prospective study of 236 consecutive subjects who had suffered 249 immediate reactions (mostly anaphylaxis) to cephalosporins. Skin tests were performed with penicillin reagents and suspected cephalosporins. Serum specific IgE assays (ImmunoCAP) were also carried out for penicillins and cefaclor. Subjects with negative results underwent challenges with the suspected cephalosporins; patients with negative results who had been assessed more than 6 months after their reactions were reevaluated. In the first allergy workup, an IgE-mediated hypersensitivity to cephalosporins was diagnosed in 164 (69.5%) of the 236 patients on the basis of skin test (162 patients) or cefaclor ImmunoCAP positivity (2 patients). Of the 72 patients with negative results, 55 underwent cephalosporin challenges; 3 reacted. Twenty subjects were reevaluated after cephalosporin negative challenges, with a conversion to cephalosporin skin test positivity occurring in 5 of the 6 subjects who had had anaphylactic reactions and in none of the remaining 14 subjects with other reactions. Overall, an immediate hypersensitivity to cephalosporins was diagnosed in 172 patients (of whom it was diagnosed in 5 after retesting). Most immediate reactions to cephalosporins are IgE-mediated. Cephalosporin skin testing is a useful tool for evaluating these reactions. IgE-mediated cephalosporin hypersensitivity may be a transient condition; therefore, allergy examinations should be repeated in patients with negative results who experienced anaphylaxis more than 6 months before the allergy workup, including challenges.

Cephalosporin Allergy: Current Understanding and Future Challenges

Cephalosporins are commonly used antibiotics both in hospitalized patients and in outpatients. Hypersensitivity reactions to cephalosporins are becoming increasingly common with a wide range of immunopathologic mechanisms. Cephalosporins are one of the leading causes for perioperative anaphylaxis and severe cutaneous adverse reactions. Patients allergic to cephalosporins tend to tolerate cephalosporins with disparate R1 side chains but may react to other beta-lactams with common R1 side chains. Skin testing for cephalosporins has not been well validated but appears to have a good negative predictive value for cephalosporins with disparate R1 side chains. Invitro tests including basophil activation tests have lower sensitivity when compared with skin testing. Rapid drug desensitization procedures are safe and effective and have been used successfully for immediate and some nonimmediate cephalosporin reactions. Many gaps in knowledge still exist regarding cephalosporin hypersensitivity.

Results of Intradermal Skin Testing with Cefazolin according to a History of Hypersensitivity to Antibiotics.

BackgroundThe relationship between cephalosporin hypersensitivity and a history of β-lactam hypersensitivity is unclear. We evaluated the usefulness of routine intradermal cefazolin skin testing and its relationship with the history of β-lactam hypersensitivity.MethodsThe electronic medical records of patients who underwent intradermal cefazolin (0.3 mg/mL) skin testing without negative controls from January 2010 to January 2011 at Seoul National University Bundang Hospital were evaluated. The history of β-lactam hypersensitivity of the patients was taken. Immediate adverse reactions after cefazolin injection were evaluated by searching the electronic medical records for key words and reviewing consultation documents of allergy specialists or dermatologists. The medical records of the patients were reviewed by an allergist.ResultsThere were 13,153 cases of cefazolin skin testing over the 13-month study period. Among the 12,969 cases with negative skin test results, 8 had immediate hypersensitivity related to cefazolin (0.06%). The negative predictive value of cefazolin skin testing alone was 99.94%. The overall positivity rate of cefazolin skin tests was 1.4% (184/13,153). Of the cases with a history of allergy to β-lactams, 15% (6/40) showed a positive cefazolin skin test result compared to only 1.36% (178/13,113) of cases with no such history (P < 0.001) including some false-positive tests.ConclusionThe results suggest that routine screening involving cefazolin skin testing without negative controls is not useful for all patients, but could be helpful for those with a history of β-lactam hypersensitivity, although a large prospective study is needed to confirm this.

IgE-mediated hypersensitivity to cephalosporins: Cross-reactivity and tolerability of alternative cephalosporins

Studies regarding the cross-reactivity and tolerability of alternative cephalosporins in large samples of subjects with an IgE-mediated hypersensitivity to cephalosporins are lacking. We sought to evaluate the possibility of using alternative cephalosporins in subjects with cephalosporin allergy who especially require them. One hundred two subjects with immediate reactions to cephalosporins and positive skin test results to the responsible drugs underwent serum specific IgE assays with cefaclor and skin tests with different cephalosporins. Subjects were classified in 4 groups: group A, positive responses to 1 or more of ceftriaxone, cefuroxime, cefotaxime, cefepime, cefodizime, and ceftazidime; group B, positive responses to aminocephalosporins; group C, positive responses to cephalosporins other than those belonging to the aforementioned groups; and group D, positive responses to cephalosporins belonging to 2 different groups. Group Asubjects underwent challenges with cefaclor, cefazolin, and ceftibuten; group B participants underwent challenges with cefuroxime axetil, ceftriaxone, cefazolin, and ceftibuten; and group C and D subjects underwent challenges with some of the aforementioned cephalosporins selected on the basis of their patterns of positivity. There were 73 subjects in group A, 13 in group B, 7 in group C, and 9 in group D. Challenges with alternative cephalosporins (ceftibuten in 101, cefazolin in 96, cefaclor in 82, and cefuroxime axetil and ceftriaxone in 22 subjects) were well tolerated. Cephalosporin hypersensitivity does not seem to be a class hypersensitivity. Subjects with cephalosporin allergy who especially require alternative cephalosporins might be treated with compounds that have side-chain determinants different from those of the responsible cephalosporins and have negative pretreatment skin test responses.

Use of cephalosporins in patients with immediate penicillin hypersensitivity: cross-reactivity revisited.

A 10% cross-reactivity rate is commonly cited between penicillins and cephalosporins. However, this figure originated from studies in the 1960s and 1970s which included first-generation cephalosporins with similar side-chains to penicillins. Cephalosporins were frequently contaminated by trace amount of penicillins at that time. The side-chain hypothesis for beta-lactam hypersensitivity is supported by abundant scientific evidence. Newer generations of cephalosporins possess side-chains that are dissimilar to those of penicillins, leading to low cross-reactivity. In the assessment of cross-reactivity between penicillins and cephalosporins, one has to take into account the background beta-lactam hypersensitivity, which occurs in up to 10% of patients. Cross-reactivity based on skin testing or in-vitro test occurs in up to 50% and 69% of cases, respectively. Clinical reactivity and drug challenge test suggest an average cross-reactivity rate of only 4.3%. For third- and fourth-generation cephalosporins, the rate is probably less than 1%. Recent international guidelines are in keeping with a low cross-reactivity rate. Despite that, the medical community in Hong Kong remains unnecessarily skeptical. Use of cephalosporins in patients with penicillin hypersensitivity begins with detailed history and physical examination. Clinicians can choose a cephalosporin with a different side-chain. Skin test for penicillin is not predictive of cephalosporin hypersensitivity, while cephalosporin skin test is not sensitive. Drug provocation test by experienced personnel remains the best way to exclude or confirm the diagnosis of drug hypersensitivity and to find a safe alternative for future use. A personalised approach to cross-reactivity is advocated.

Allergic diseases of the skin and drug allergies – 2010. Intradermal skin testing with cefazolin regardless of the history of hypersensitivity to antibiotics

Background There have been no standard methods to predict the hypersensitivity to cephalosporin. The relationship between cephalosporin hypersensitivity and history of beta-lactam hypersensitivity is not clear. This retrospective study is to evaluate the reliability of routine prophylactic skin test with cefazolin in general population and the relationship between results of cefazolin skin testing and the history of beta-lactam hypersensitivity.

Evaluation of Immediate Allergic Reactions to Cephalosporins in Non-Penicillin-Allergic Patients

Background: Cephalosporins can induce severe or life-threatening IgE-mediated reactions in some individuals. In this study, we wish to describe a group of non-penicillin-allergic patients who were evaluated for immediate allergic reactions to cephalosporins. Methods: The patients were assessed by skin tests with the culprit cephalosporin as well as with other cephalosporins and penicillins. If indicated, oral challenge testing was performed. Results: Six patients were assessed. A total of 42 skin tests and 20 oral challenges were performed. In 4 patients, skin tests included the causative drug; in 2 patients, the diagnosis of a cephalosporin allergy was made by skin test; in 4 patients, the diagnosis of a cephalosporin hypersensitivity was made by oral challenge. In 96.9% of the oral challenges, which were done using medications with no structural side chain similarities to the culprit drug, no adverse reaction occurred. Conclusion: A positive skin test to cephalosporin implies the presence of drug-specific IgE antibodies. Cephalosporins without side chain similarities are suggested to patients with cephalosporin reactions and no β-lactam reactivity.

Toxic epidermal necrolysis managed with immunoglobulin

We thank the reader for critical appraisal of our report and kind remarks. The reply to queries raised by him is as follows; Our patient had presented with fever and was receiving antibiotics at the time of presentation which was the reason of negative cultures. Sepsis is the most debilitating complication in TEN and is one of the leading causes of mortality [1]. Patient had onset of TEN following therapy for fever, cough and sore throat and was continuing antibiotics till consultation in the emergency at our centre. In presence of >80% body surface area involvement with purulent mucositis of the oral and urethra and urinalysis full of pus cells, infection was very much evident which prompted us to continue with changed antibiotics despite culture reports being negative. Lastly, offering antibiotic therapy after obtaining culture positive reports and or signs of septic shock seems purely academic and sometimes dangerous in day to day practice. IgE mediated hypersensitivities are well known to be cross reactive between cephalosporins and penicillins, however, non IgE mediated hypersensitivities usually are not cross reactive. Patients with a prior immediate hypersensitivity reaction to penicillin should generally not be treated with cephalosporin unless: Penicillin or cephalosporin skin testing, if available, is negative or a graded challenge with the cephalosporin can be given under careful observation by an allergist. A history of a rash or unclear reaction to penicillin does not necessarily preclude administration of cephalosporins [2]. Moreover, there is not a single report of TEN attributable to piperacillin till date on medline search. Only single case report putatively linking cephalosporin hypersensitivity to Meropenem induced TEN has been reported [3]. This does not preclude the use of other beta lactam antibiotics, it just merits caution. Compared to sulfonamides antibiotics, other sulfonamides like sulfonylurea, thiazides etc do not show cross sensitivity just because of the structural similarities. It may be other metabolites of the drugs that can induce TEN or individuals with metabolic defects or polymorphisms in cytochrome metabolizing enzymes are predisposed to TEN. It will be too hasty to generalize and blame beta lactam structure as the cause of TEN. Our patient did not have immediate hypersensitivity reaction to cephalosporins hence Tazobactum Piperacillin was continued under supervision. Regarding IgE mediated allergic reaction to piperacillin in a case of ceftriaxone induced TEN, the reason is evident in the case report itself, if the reader would have cared to read the paper carefully. This patient had received piperacillin before ceftriaxone administration that could have sensitized him and led to IgE mediated Type I hypersensitivity reaction, subsequently. Moreover TEN is mediated by T cells and macrophages/monocytes, and is unrelated to B cell mediated effects. Lastly, the SCORTEN score of 3 was arrived at based on following criteria, age >40 years, tachycardia (>120) and BSA >80% involvement. Regarding the biopsy confirmation of the diagnosis, the clinical presentation was so characteristic and therefore it was needless to subject already critical patient to an invasive procedure which would have been purely academic without any additional advantage. On the basis of experience in one case, we are not advocating IVIg as panacea for all the cases of TEN, rather since there are not many reports of similar experience from our country we thought it prudent to share our experience with medical fraternity to increase the awareness. Moreover, after the index case, we have treated three more cases of TEN with IVIg and one patient died. This patient had presented with severe neutropenia (absolute neutrophil count <200/µl) and respiratory tract infection. We encourage other centers from our country to share their experience with therapy of TEN. As far as the rationale of IVIg is concerned, there is ample evidence both in vitro [4] and clinical to recommend its use in such a life threatening condition [1, 5]. The numbers of studies that question the efficacy of IVIg are small with small patient population as compared to numbers of studies that report benefit with large number of patients. Since randomized placebo controlled trial is virtually impossible for such a rare and sporadic adverse event, it's up to readers to decide which school of thought to follow. Regarding the discontinuation of the offending agent and intensive supportive therapy, it cannot be over emphasized and we agree with the reader but since the aim of our case report was to highlight the beneficial effect of IVIg in addition to these measures, we discussed more about IVIg. However, we never intend to sideline the significance of these measures.