Implementation of EMR-based standardized antibiotic desensitization protocols and its impact on providers.

Background: As desensitization protocols become more readily available and published, more institutions are implementing them and searching for ways to streamline the process. There have been no published studies to date on the effect that electronic medical record systems (EMR) have on the safety and efficiency of ß-lactam antibiotic desensitization. Objective: The purpose of this study was to evaluate the changes in workflow, efficiency, and medical errors after implementation of ß-lactam antibiotic desensitization. Methods: A collaborative effort between the Allergy/Immunology Division and the Pharmacy Department led to the creation and implementation of antibiotic desensitization order sets. Pre- and postimplementation of ß-lactam antibiotic surveys were sent to pharmacists and allergy/immunology fellows and attendings at a single-center tertiary care center. Results: There were only 26 valid respondents (12.3%) to both the pre- and postimplementation surveys. The percentage of respondents who thought that the time needed to prepare desensitization materials was < 4 hours increased from 23% to 77% (p < 0.001). The percentage of respondents who thought that the time needed to input electronic desensitization orders was < 1 hour increased from 19% to 54% (p = 0.002). The percentage of respondents who identified zero errors increased from 42% to 92% (p = 0.001). The perception of the overall desensitization process efficiency significantly increased (p < 0.001). Conclusion: Creation of standardized electronic ß-lactam antibiotic desensitization order sets significantly decreased the time taken to order and prepare materials and increased overall efficiency.

Immune thrombocytopenia induced by beta-lactam antibiotics: Cross-reactions of responsible antibodies with other beta-lactam drugs.

BACKGROUND: Beta-lactam antibiotics are a relatively common cause of immune thrombocytopenia. Because the many beta-lactam drugs now in clinical use have structural similarities, when a patient experiences this complication the question of whether an alternative member of this drug family can safely be used often arises but there are little data available to guide this decision. STUDY DESIGN AND METHODS: Drug-dependent, platelet-reactive antibodies from 32 patients who experienced thrombocytopenia while being treated with a beta-lactam drug of the penam (piperacillin, etc.) or cephem (ceftriaxone etc.) groups were studied for serologic cross-reactivity with other drugs from these families using flow cytometry. Cross-reactions observed were analyzed for correlations with structural features of the drugs tested. RESULTS: Among 14 antibodies specific for penam drugs, five "strong" cross-reactions with other penam drugs were found. Among 18 antibodies specific for cephem drugs, 8 "strong cross-reactions were identified. Antibodies induced by penam drugs did not cross-react strongly with cephem drugs and vice versa. A strong correlation between cross-reactions and similar or identical R1 side groups of the beta-lactams studied was observed. DISCUSSION: The findings suggest that patients who experience immune thrombocytopenia while being treated with a beta-lactam of the penam group can safely be treated with a cephem drug and vice versa. If a patient is to be switched to another beta lactam within the same group, the likelihood of serologic cross-reactivity can be minimized by choosing an agent with a distinctly different R1 side group.

A Comprehensive Prospective Study of the Costs Associated With Evaluation of ß-Lactam Allergy.

BACKGROUND AND OBJECTIVE: Being labeled as allergic to penicillin (unverified ß-lactam allergy) can result in patients receiving broader-spectrum antibiotics than necessary that may be more toxic, less effective, and/or more expensive than alternative options. Objective: We aimed to evaluate the real costs of evaluating ß-lactam allergy. METHODS: We performed a prospective real-life observational study designed to evaluate all adult patients who consulted for suspected ß-lactam allergy over a 1-year period. Direct and indirect costs were systematically recorded. Direct health costs were calculated based on the number of visits and all additional and diagnostic tests performed, direct nonhealth costs based on the number of visits and the distance from their homes to the Allergy Department, and indirect costs based on absenteeism. RESULTS: A total of 296 patients with suspected allergy to ß-lactams were evaluated in our outpatient clinic from June 1, 2017 to May 31, 2018. Total direct health care costs were €28 176.70, with a mean (SD) cost of €95.19 (37.20). Direct nonhealth costs reached €6551.73, that is, €22.13 (40.44) per patient. Indirect health costs reached €20 769.20, with a mean of €70.17 (127.40). In summary, the total cost was €55 497.63, that is, a cost per patient of €187.49 (148.14). CONCLUSIONS: When all possible costs are taken into account, the evaluation of ß-lactam allergy is not expensive and can reduce future expense arising from unnecessary use of more expensive and less effective antibiotics.

Drug-specific history, skin and in vitro tests can reduce the need for drug provocation tests in betalactam-hypersensitivity.

BACKGROUND: Many patients report questionable drug hypersensitivity reactions (DHR) to betalactam antibiotics. A workup is required for objectivation. Direct drug provocation tests (DPTs) omitting a prior allergy workup are increasingly recommended as the primary diagnostic approach. However, apart from the risk of severe side effects, DPTs often are a scarce resource in overloaded healthcare-systems. We investigated how many cases can be solved by drug-specific history, drug-specific IgE, and skin tests obviating the need for DPT. METHODS: We conducted a chart review in a retrospective cohort of 932 patients in an allergy outpatient centre from 2016 to 2017. Patients had been submitted to drug-specific history and specific IgE-, skin prick-, intradermal- and patch-tests with early and late readings with a series of penicillins and cephalosporins but DPTs were no option. RESULTS: Overall, positive in vitro and/or skin tests were found in 96/932 (10.3%) patients. Drug-specific IgE was detected in 40/932 (4.3%) patients, 61/787 (7.8%) patients had positive skin tests. In vitro tests to Pencillin V showed the highest rate of positivity 24/479 (5.0%) and early readings of ampicillin the highest amongst the skin tests (3/49, 6.1%). Immediate skin tests were more often positive than delayed ones (75:45). The combination of all parameters including drug-specific history solved 346/932 (37.1%) cases while 586/932 (62.9%) remained unresolved. Self-reported DHR could be less often confirmed in females and young children (p < 0.05). CONCLUSIONS: Testing with betalactams applying simple, cheap, and safe skin and blood tests can solve a third of DHR-cases on a high throughput scale.

The use of in vivo and in vitro tests in children with beta lactam allergy

BACKGROUND: Drug allergies are reactions within the context of drug hypersensitivity reactions, which are caused by immunological mechanisms due to a previously sensitising drug. Beta-lactam antibiotics (BLA) are the leading agents causing drug hypersensitivity reactions in children. The aim of this study is to evaluate the diagnostic importance of in vivo and in vitro diagnostic tests in children with suspected immediate-type BLA hypersensitivity and to investigate the frequency of their use for the final diagnosis. METHODS: Patients admitted to the Outpatient Clinic of Division of Paediatric Allergy and Immunology with suspicion of immediate-type BLA hypersensitivity between December 2014 and December 2018 were investigated. Patients with a history of immediate reactions to BLA were examined by performing drug specific IgE, skin prick tests, intradermal tests and drug provocation tests (DPT). RESULTS: During the study period, 148 patients were admitted to our clinic with suspected immediate-type BLA hypersensitivity. Forty-eight patients completed all assessment steps and were enrolled in the study. It has been shown that 27 patients did not have drug allergy. BLA hypersensitivity was proven in 21 patients by using in vivo test algorithm. More than half of the patients were diagnosed via skin tests with culprit drug. CONCLUSION: Allergy work-up should be performed in patients with immediate reactions to BLA. A skin test can demonstrate BLA hypersensitivity in most patients. Thus, skin tests should be performed prior to the drug provocation test

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Multiparametric Highly Sensitive Chemiluminescence Immunoassay for Quantification of ß-Lactam-Specific Immunoglobulin E.

ß-lactams (BLCs) are the most widely used antibiotics and consequently the most common cause of drug allergy in the world. The diagnosis of drug allergy is complex and represents a serious challenge that includes a wide variety of methods. In vitro tests are based on the immunological determination of allergen-specific IgE, but the tests in the market lack the required sensitivity and specificity. In addition, the large sample volume, long incubation times, and single-plex configuration have brought their use into question to complement the clinical information. Here, we report a chemiluminescence immunoassay (CLIA) for multiparametric quantification of specific IgE to penicillin G, penicillin V, amoxicillin, and piperacillin, using histone H1 as a carrier. The developed CLIA allowed the determination of BLC-specific IgE below 0.1 IU/mL, thus allowing identification of allergic patients with better sensitivity, using only 25 µL of a sample (serum). The immunoassay was successfully applied in a cohort of 140 human serum samples, showing good sensitivity (64.6%) as well as specificity (100%), which significantly improve the predictive character of existing BLC-allergy in vitro tests.

Neo-antigens for the serological diagnosis of IgE-mediated drug allergic reactions to antibiotics cephalosporin, carbapenem and monobactam.

New antigens deriving from -lloyl and -llanyl, major and minor determinants, respectively, were produced for ß-lactam antibiotics cefuroxime, cefotaxime, ceftriaxone, meropenem and aztreonam. Twenty ß-lactam antigens were produced using human serum albumin and histone H1 as carrier proteins. Antigens were tested by multiplex in vitro immunoassays and evaluated based on the detection of specific IgG and IgE in the serum samples. Both major and minor determinants were appropriate antigens for detecting specific anti-ß-lactam IgG in immunised rabbit sera. In a cohort of 37 allergic patients, we observed that only the minor determinants (-llanyl antigens) were suitable for determining specific anti-ß-lactam IgE antibodies with high sensitivity (< 0.01 IU/mL; 24 ng/L) and specificity (100%). These findings reveal that not only the haptenisation of ß-lactam antibiotics renders improved molecular recognition events when the 4-member ß-lactam ring remains unmodified, but also may contribute to develop promising minor antigens suitable for detecting specific IgE-mediated allergic reactions. This will facilitate the development of sensitive and selective multiplexed in vitro tests for drug-allergy diagnoses to antibiotics cephalosporin, carbapenem and monobactam.

The use of in vivo and in vitro tests in children with beta lactam allergy.

BACKGROUND: Drug allergies are reactions within the context of drug hypersensitivity reactions, which are caused by immunological mechanisms due to a previously sensitising drug. Beta-lactam antibiotics (BLA) are the leading agents causing drug hypersensitivity reactions in children. The aim of this study is to evaluate the diagnostic importance of in vivo and in vitro diagnostic tests in children with suspected immediate-type BLA hypersensitivity and to investigate the frequency of their use for the final diagnosis. METHODS: Patients admitted to the Outpatient Clinic of Division of Paediatric Allergy and Immunology with suspicion of immediate-type BLA hypersensitivity between December 2014 and December 2018 were investigated. Patients with a history of immediate reactions to BLA were examined by performing drug specific IgE, skin prick tests, intradermal tests and drug provocation tests (DPT). RESULTS: During the study period, 148 patients were admitted to our clinic with suspected immediate-type BLA hypersensitivity. Forty-eight patients completed all assessment steps and were enrolled in the study. It has been shown that 27 patients did not have drug allergy. BLA hypersensitivity was proven in 21 patients by using in vivo test algorithm. More than half of the patients were diagnosed via skin tests with culprit drug. CONCLUSION: Allergy work-up should be performed in patients with immediate reactions to BLA. A skin test can demonstrate BLA hypersensitivity in most patients. Thus, skin tests should be performed prior to the drug provocation test.

Adding a second skin prick test reading and modifying the cut-off for beta-lactam-specific IgE enhances the sensitivity in the routine diagnostic workup for immediate beta-lactam hypersensitivity.

BACKGROUND: Beta-lactam (BL)-antibiotics are the most frequent reason for drug-induced hypersensitivity reactions. Because they are more efficient, less toxic, and less costly than other antibiotics, confirmation or exclusion of BL allergy is worthwhile. However, allergy tests for drug allergies are often false-negative. OBJECTIVES: To evaluate the components of a stepwise diagnostic algorithm for immediate BL hypersensitivity with regard to sensitivity (SENS). METHODS: Consecutive patients with suspected allergy to BL antibiotics were retrospectively analyzed with regard to increasing sensitivity (plausible history of immediate BL hypersensitivity serving as external criterion) of (i) skin prick test (SPT) by adding a second reading (n = 746), (ii) BL-specific IgE-determination in vitro at two cut-offs (n = 539), and (iii) adding in vivo testing of minor and major BL determinants (n = 288). RESULTS: In the history-based population indicative of immediate BL hypersensitivity (n = 457), SPT with a sole 20-minute reading identified 99 (SENS: 0.21) and SPT with 20- and 40-minute-reading identified 133 cases (SENS: 0.29). in vitro specific IgE-examination identified 31 positives at a cut-off ≥0.35 kUA/L (5.8% of tested) and 99 at cut-off ≥0.11 kUA/L (18.4% of tested). In 203 SPT-negative individuals, immediate BL hypersensitivity was identified by additional tests: in 79 by specific IgE (cut-off ≥0.11 kUA/L) (thereof 53 identified solely by this test) and in 150 by in vivo testing of BL determinants in combination with Penicillin and Ampicillin intradermally (thereof 124 solely by this test); in 26 individuals both additional tests were positive. The combination of the three outpatient-based test modalities-(i) optimized SPT, (ii) specific IgE at optimized cut-off, and (iii) in vivo testing of BL determinants/Penicillin/Ampicillin-identified altogether 336/457 individuals with immediate BL-hypersensitivity (SENS: 0.73), whereas the combination of the two (i) + (ii) identified 212/457 (SENS: 0.46); (i) + (iii) 283/457 (SENS: 0.61). CONCLUSIONS: To overcome the low sensitivity of allergological tests, optimized reading times of the SPT of BL, a lower cut-off for in vitro detection of BL-specific IgE, and intradermal testing of Penicillin, Ampicillin, and BL-determinants contribute to overall sensitivity under real life conditions to diagnose immediate BL-hypersensitivity.

ß-Lactam allergy and risk of multidrug-resistant bacteria in the intensive care unit: A cohort study.

Patients identified as allergic to ß-lactams are frequently exposed to treatment with broad-spectrum antibiotics. However, the risk of carriage of extended-spectrum ß-lactamase (ESBL)-producing isolates in this population has been poorly investigated. The aim of this study was to evaluate the characteristics and clinical outcomes of patients admitted to the intensive care unit (ICU) with and without declared ß-lactam allergy at admission. A retrospective monocentric study was performed including adult patients admitted to the ICU between 2007 and 2012. The presence of multidrug-resistant bacteria was documented in rectal and nasal swabs at admission and discharge. Patients labelled allergic to ß-lactams and unlabelled patients were compared. Patients labelled allergic had significantly higher rates of ESBL at admission (13.3% vs. 4.3%; P = 0.0220) and discharge (20.0% vs. 9.0%; P = 0.0460) compared with unlabelled patients, but no significant difference in rates of ESBL acquisition in the ICU was detected. No differences in mortality, duration of hospitalisation or typical risk factors for ESBL acquisition (intubation, central venous catheter and duration of hospitalisation) were reported. No differences in carriage of methicillin-resistant Staphylococcus aureus were detected. This study showed that patients with declared ß-lactam allergy had a higher risk of ESBL carriage at ICU admission and discharge.

The negative predictive value of 5-day drug provocation test in nonimmediate beta-lactam allergy in children.

BACKGROUND: Extending the drug provocation test (DPT) period is recommended for patients with suspected nonimmediate beta-lactam antibiotic (BLA) allergy and negative DPT. No consensus has been reached regarding the duration of prolonged provocation. OBJECTIVE: We aimed to determine the negative predictive value (NPV) of the 5-day extended DPT. METHODS: Parents of patients with suspected nonimmediate mild cutaneous reactions with BLAs who had been subjected to 5-day DPT with culprit drugs were questioned by telephone interview about reexposure to the tested drug. Patients with reported reaction during reexposure were reevaluated. Skin tests and serum-specific immunoglobulin E (IgE) analysis were not performed before first DPT. RESULTS: A total of 355 patients had negative results in 5-day DPT. The median age at DPT was 4.2 years, and 52.9% were male. The families of 255 patients (72%) could be contacted. Of these 255 patients, 179 (70%) had used the same drug, and reactions were reported for 6 (3.4%) of those patients, who were subsequently reevaluated. Five of the 6 patients had DPT with amoxicillin-clavulanate and 1 with cefixime. When detailed history was taken, 2 of the 5 patients with amoxicillin-clavulanate reaction were found to have used the drug unintentionally after their reaction to reexposure and did not have any symptoms. One of the patients underwent allergy workup and tested negative, and the other 2 refused the test. The patient with reported cefixime reaction underwent repeated allergy workup and tested negative. Therefore, the NPV of 5-day prolonged DPT was 98.9%. CONCLUSION: The 5-day prolonged DPT has high NPV and seems appropriate in duration for children with suspected nonimmediate-BLA allergy.

Atopy can be an interfering factor in genetic association studies of beta-lactam allergy

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[Allergic Reactions to Betalactams in Pediatrics: Recommendations for diagnosis and treatment]. / Reacciones alérgicas a betalactámicos en pediatría: recomendaciones para su diagnóstico y tratamiento.

The Allergic Reactions to Betalactam Antibiotics are adverse events that cannot be explained by their pharmacological action, but mediated by an immunological mechanism. They are the most frequent cause of drug allergy in the world. Betalactam antibiotics include penicillins, cephalosporins, carbapenems, monobactams, cefems (moxalactam, cefoxitin), and clavulanic acid. They can produce immediate, accelerated or delayed allergic reactions. Its diagnostic methodology is complex and it is carried out by well-defined stages. Its timely diagnosis is very important due to the risk involved and the associated costs that demand the alternative use of other antibiotics that supplant them.

Las reacciones alérgicas a antibióticos betalactámicos son eventos adversos no explicables por su acción farmacológica, sino mediados por un mecanismo inmunológico. Son la causa más frecuente de alergia a los fármacos en el mundo. Incluyen penicilinas, cefalosporinas, carbapenems, monobactámicos, cefems (moxalactam, cefoxitina) y ácido clavulánico. Pueden producir reacciones alérgicas inmediatas, aceleradas o tardías. Su metodología diagnóstica es compleja y se realiza por etapas bien definidas. Es muy importante su diagnóstico oportuno, debido al riesgo que implican y a los costos asociados, que demandan el uso alternativo de otros antibióticos que los reemplacen.

Short and extended provocation tests have similar negative predictive value in non-immediate hypersensitivity to beta-lactams in children

Introduction and objectives: Drug provocation tests (DPTs) are the gold-standard method to diagnose non-immediate hypersensitivity reactions (NIHSR) to beta-lactam antibiotics (BL) in children. Our aim was to compare the negative predictive value (NPV) of one-day (short) DPT versus 3-7 days (extended) DPT for the diagnosis of NIHSR to BL in paediatric age. A secondary aim was to compare confidence on drug re-exposure after short and extended negative DPTs. Methods: The occurrence of HSR on drug re-exposure and drug refusal after negative diagnostic DPTs were evaluated in children/adolescents with a history of NIHSR to BL using a questionnaire performed six months to ten years after DPT. Patients were divided into two groups according to the protocol performed: short DPT vs. extended DPT. Results: We enrolled 212 children and adolescents (86 females, 126 males, mean age at DPT 5.52 years, p25 = 3 years, p75 = 7.25 years): 69 tested with short DPT, and 143 with extended DPT. The NPV of both types of DPT together was 95.2%. The NPV of short DPT was 97.5% and the NPV of extended DPT was 93.8% (p = 0.419). After negative DPT, beta-lactams were refused by carers in 14.75% of the children requiring subsequent treatment, 6.98% in the short DPT group and 18.99% in the extended DPT group (p = 0.074). Conclusions: In our paediatric sample, prolonging drug administration did not increase the NPV of diagnostic DPT for NIHSR to BL or reduce drug refusal. Altogether, the data here reported suggest that, however intuitive, prolonging DPT is not beneficial in the parameters analysed

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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. In vitro 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.

Antibiotic Allergy in Children: More than Just a Label.

Within the broad category of adverse drug reactions in children, there has been a recent focus specifically on the evaluation of children with antibiotic allergy, in particular, beta-lactam allergy. The potential consequences of being labeled beta-lactam allergy are increasingly recognized. Appropriate evaluation of children with suspected reactions to antibiotics is essential as it is increasingly being recognized that the label of "penicillin allergy" is associated with adverse health and economic outcomes. This review will focus on the 3 main classes of antibiotics reported to cause allergic reactions in children: beta lactams (penicillin derivatives and cephalosporins), macrolides, and sulfonamides. This article is a narrative review of the prevalence, diagnosis, and management of different types of antibiotic allergies in children. Our review reveals that antibiotic allergy is often overreported and not appropriately diagnosed in the pediatric age groups. There is a recent shift in the diagnostic paradigm from the use of skin tests and if negative challenges to the use of challenge only in the pediatric age group. Larger studies to establish the usefulness and safety of this new approach as well as updated guidelines are needed.

Engineering Dual Variable Domains for the Generation of Site-Specific Antibody-Drug Conjugates.

Site-specific antibody-drug conjugate (ADC) technologies are highly desirable for the production of therapeutics with well-defined biochemical and pharmacological characteristics. We have developed a strategy to produce site-specific ADCs using a highly reactive lysine residue embedded in a dual-variable-domain (DVD) format. Here we provide protocols for the engineering, expression, and purification of the DVDs used for this strategy. We also provide a protocol for DVD-drug conjugation and describe methods for their biochemical characterization, including a catalytic assay to monitor conjugation efficiency.

Das Kreuz mit der Kreuzallergie: Betalaktamantibiotika-Allergie.

Hypersensitivity reactions to betalactam antibiotics are the most commonly mentioned drug allergies. Up to 10 percent of patients report to suffer from a penicillin allergy. However, classical side effects of antibiotics are often misdiagnosed as an allergy. Many of these patients with suspected betalactam allergy tolerate betalactam antibiotics well. Therefore, a thorough allergy workup is essential to confirm a suspected allergy or to enable again a treatment with betalactam antibiotics. Most important is a good documentation as skin- and in-vitro tests have a reduced sensitivity. Gold standard is the provocation test to help exclude a supposed allergy or to test alternative, potential cross reactive betalactam antibiotics. Cross-reactions between penicillins and cephalosporins, especially cephalosporins of the third and fourth generation are unusual. Cross reactions to carbapenem antibiotics are rare.