Features of in vivo diagnostics of delayed drug hypersensitivity to beta-lactams

Background. Beta-lactams are the most widely used group of antibacterial agents. They are used for treating of infectious complications of varying severity, including urgent situations. The exclusion of the entire beta-lactam group not only leads to a significant increase in the cost of treatment, length of hospitalization and the formation of resistance of the flora to alternative antibiotics, but also may be life threatening in some cases. Therefore, correct diagnosis and establishement of the offending medication can prevent the development of allergic reactions and to avoid unreasonable lifelong bans on the use of certain medications, which often lead to a decrease of the effectiveness of treatment and increase its cost. The aim of the study was to develop the diagnostic and management algorithm and of of patients with presumptive diagnosis of delayed drug hypersensitivity to beta-lactams. Materials and methods. A comprehensive in-depth examination, including in vivo tests with beta-lactams was done in 53 patients (37 - 70% women, and 16 - 30% men) with a presumptive diagnosis of delayed drug hypersensitivity to beta-lactams. The minimum age at the time of the reaction was 4 years, the maximum age was 86 years, the average age was 37 years,the median was 38,5 years old. The minimum age at the time of testing was 6 years, the maximum age was 89 years, the average age was 44 years, median was 44 years old. Results. In the group of patients with delayed drug hypersensitivity to beta-lactams (n=21) the diagnosis was confirmed by skin testing in 19 (90,5%) patients, in 18 (85,7%) to aminopenicillins, and 1 (4,8%) to ceftriaxone. In 2 (9,5%) cases, the diagnosis was established using a drug provocation test: for amoxicillin (4,8%) and for ceftriaxone (4,8%). According to the obtained data, the specificity of skin tests for the diagnostics of delayed drug hypersensitivity to beta-lactams was 100%. In case of delayed drug hypersensitivity to aminopenicillins, the sensitivity of skin tests was 94,7%, the negative predictive value of skin tests was 93,7%, the overall accuracy of skin testing was 97%, and the incidence of false-negative results was 5,3%. Conclusion. Skin testing is promising and safe in the diagnositics of delayed drug hypersensitivity to beta-lactams. It allows to exclude unreasonable contraindications for the use of beta-lactams, thereby increasing the effectiveness of treatment while reducing economic costs.

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Systemic reaction during intradermal skin tests with beta-lactams

BMJ Case Reports ◽

10.1136/bcr-2020-240050 ◽

2021 ◽

Vol 14 (3) ◽

pp. e240050

Author(s):

Joana Carvalho ◽

Georgeta Oliveira

Keyword(s):

Skin Testing ◽

Drug Hypersensitivity ◽

Systemic Reaction ◽

Skin Tests ◽

Beta Lactam ◽

Provocation Tests ◽

Maculopapular Eruption ◽

Intradermal Tests ◽

Amoxicillin Clavulanate ◽

Immediate Reactions

Beta-lactam (BL) antibiotics are the most frequent cause of drug hypersensitivity in children, inducing both immediate and non-immediate reactions. Here we report a case of a 4-year-old child with a disseminated maculopapular exanthema 7 days after the first dose of amoxicillin–clavulanate, referred to our paediatric allergy department. Skin prick tests were negative. Intradermal tests were performed and, after 10 hours, indurated wheals larger than 10×10 mm with progressive erythema and disseminated maculopapular eruption were developed, related to amoxicillin and amoxicillin–clavulanate. Systemic reactions to BL skin tests are rarely reported and the majority are immediate reactions. This case illustrates a rare example of a non-immediate systemic reaction to intradermal tests, underlying the importance of skin testing before drug provocation tests in cases of moderate to severe non-immediate reactions.

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Addition of Ceftaroline to Daptomycin after Emergence of Daptomycin-Nonsusceptible Staphylococcus aureus during Therapy Improves Antibacterial Activity

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00797-12 ◽

2012 ◽

Vol 56 (10) ◽

pp. 5296-5302 ◽

Cited By ~ 76

Author(s):

Warren E. Rose ◽

Lucas T. Schulz ◽

David Andes ◽

Rob Striker ◽

Andrew D. Berti ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Combination Therapy ◽

Membrane Damage ◽

Beta Lactam ◽

Beta Lactams ◽

Bacterial Killing ◽

Content Type ◽

Cell Membrane Damage

ABSTRACTAntistaphylococcal beta-lactams enhance daptomycin activity and have been used successfully in combination for refractory methicillin-resistantStaphylococcus aureus(MRSA) infections. Ceftaroline possesses MRSA activity, but it is unknown if it improves the daptomycin potency comparably to other beta-lactams. We report a complex patient case of endocarditis who was treated with daptomycin in combination with ceftaroline, which resulted in clearance of a daptomycin-nonsusceptible strain. Anin vitropharmacokinetic/pharmacodynamic model of renal failure was used to simulate the development of daptomycin resistance and evaluate the microbiologic effects of daptomycin plus ceftaroline treatment. Combination therapy with daptomycin and ceftaroline restored daptomycin sensitivityin vivoand resulted in clearance of persistent blood cultures. Daptomycin susceptibilityin vitrowas increased in the presence of either ceftaroline or oxacillin. Daptomycin at 6 mg/kg of body weight every 48 h was bactericidal in the model but resulted in regrowth and daptomycin resistance (MIC, 2 to 4 μg/ml) with continued monotherapy. The addition of ceftaroline at 200 mg every 12 h after the emergence of daptomycin resistance enhanced bacterial killing. Importantly, daptomycin plus ceftaroline as the initial combination therapy produced rapid and sustained bactericidal activity and prevented daptomycin resistance. Bothin vivo- andin vitro-derived daptomycin resistance resulted in bacteria with more fluid cell membranes. After ceftaroline was added in the model, fluidity was restored to the level of the initialin vivoisolate. Daptomycin-resistant isolates required high daptomycin exposures (at least 10 mg/kg) to optimize cell membrane damage with daptomycin alone. Ceftaroline combined with daptomycin was effective in eliminating daptomycin-resistant MRSA, and these results further justify the potential use of daptomycin plus beta-lactam therapy for these refractory infections.

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PATTERNS OF RESPONSE AND DRUGS INVOLVED IN HYPERSENSITIVITY REACTIONS TO BETA-LACTAMS IN CHILDREN.

10.22541/au.161635658.84094563/v1 ◽

2021 ◽

Author(s):

Isabel Torres-Rojas ◽

Diana Perez ◽

Maria Luisa Somoza-Alvarez ◽

Elisa Haroun Diaz ◽

Ana María Prieto-Moreno Pfeifer ◽

...

Keyword(s):

Clavulanic Acid ◽

Skin Testing ◽

Drug Hypersensitivity ◽

Penicillin G ◽

Hypersensitivity Reactions ◽

Beta Lactams ◽

Provocation Tests ◽

Drug Challenge ◽

Immediate Reactions

Background Beta-lactams generate different allergenic determinants that induce selective or cross-reactive drug hypersensitivity reactions (DHRs). We aimed to identify the drugs involved, the selectivity of the response, the mechanism, and the value of the different diagnostic tests for establishing a diagnosis in children evaluated for DHRs to beta-lactams. Methods Prospective study evaluating children aged under 16 years reporting DHRs to beta-lactams. Reactions were classified as immediate and nonimmediate reactions. The work-up included sIgE, skin testing and drug provocation tests (DPTs) for immediate reactions and patch testing and DPTs for nonimmediate ones. Results Of the 510 included children, 133 were evaluated for immediate reactions and confirmed in 8.3%. Skin test/in vitro IgE contributed to diagnosing half of the cases. Selective reactions occurred with amoxicillin (63%), followed by common penicillin determinants (27%) and cephalosporins (0.9%). Among nonimmediate reactions (11,4% of the 377 children evaluated), most required DPTs, 52.7% of which were positive at 6–7 days of drug challenge. Selective reactions were identified with amoxicillin (80%), penicillin G (7.5%), cephalosporins (7.5%), and clavulanic acid (5%). Urticaria and maculopapular exanthema were the most frequent entities. Conclusions There were few confirmed cases of either type of reaction. Skin testing proved less valuable in nonimmediate reactions, over half of which would also have been lost in a short DPT protocol. Selective responders to amoxicillin were more likely to have nonimmediate reactions, while clavulanic acid-selectivity was exclusive to the nonimmediate typology. Over half the cases with DPTs required 6-7 days of treatment for DHR confirmation.

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Hypersensitivity reactions to non-steroidal anti-inflammatory drugs: results of an Austrian cohort study

Allergo Journal International ◽

10.1007/s40629-020-00134-6 ◽

2020 ◽

Vol 29 (7) ◽

pp. 227-232

Author(s):

Teresa Bangerl ◽

Brigitte Zahel ◽

Andrea Lueger ◽

Emmanuella Guenova ◽

Irena Angelova-Fischer ◽

...

Keyword(s):

Skin Testing ◽

Drug Hypersensitivity ◽

Provocation Test ◽

Clinical History ◽

University Hospital ◽

Skin Tests ◽

Hypersensitivity Reactions ◽

Culprit Drug ◽

Inflammatory Drugs ◽

Anti Inflammatory

Summary Background Hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) is the second most common cause of drug hypersensitivity. Despite the importance of NSAIDs in routine analgesia only few studies have systematically addressed the question of tolerability in hypersensitive patients. Methods The authors retrospectively analysed 398 patients that were treated at the Department of Dermatology, Kepler University Hospital Linz, Austria, in the period 2012–2016 with a clinical history of NSAID hypersensitivity. Skin tests (skin prick and intracutaneous tests) to common NSAIDs were performed, followed by single-blinded, placebo-controlled drug challenge with either the culprit drug or an alternative NSAID. Results A total of 361 patients were subjected to skin testing. Of these, 25 patients (6.3%) showed a positive reaction to the culprit drug. According to the severity of the reaction in the medical history, 87 patients were exposed orally to the culprit drug (oral provocation test, OPT) after negative skin test and 255 patients received OPT with alternative NSAIDs according to established protocols. OPT with the culprit drug resulted in hypersensitivity reactions in 12 patients (13.79%). In terms of alternative NSAID testing, the three most commonly tested drugs were lornoxicam (192 OPTs), acetaminophen (156 OPTs) and celecoxib (133 OPTs) with tolerability rates in respectively 88.54% (hypersensitivity reactions, 11.46%), 92.31% (hypersensitivity reactions, 7.69%) and 91.73% (hypersensitivity reactions, 8.27%) of cases. Conclusion OPT with alternative NSAIDs are useful in patients with NSAID hypersensitivity as tolerability varies between the individual substances.

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High Histamine Control Concentration Leads to False Negative Allergy Skin Testing

American Journal of Rhinology and Allergy ◽

10.1177/19458924211008685 ◽

2021 ◽

pp. 194589242110086

Author(s):

Amulya Amirneni ◽

Jody Tversky

Keyword(s):

Skin Prick Test ◽

Skin Test ◽

Skin Testing ◽

False Negative ◽

The Other ◽

Skin Tests ◽

Prick Test ◽

Timothy Grass ◽

Significant Difference ◽

Dust Mite

Background Allergy skin test reliability depends on the reagents and controls selected. Histamine is used at 1 mg/ml and 6 mg/ml concentration but few studies address the rationale for selecting one versus the other and how this may impact diagnostic accuracy. Objective To determine the rate of false negative allergen skin tests responses between UniTest PC (using the 1 mg/mL histamine) and Quintip devices (using 6 mg/mL) for 4 common aeroallergens. Methods Subjects aged 18-65 with symptoms of allergy to cat and/or ragweed received skin testing with 4 aeroallergens (dust mite mix, timothy grass, ragweed, cat), histamine and control diluent. Those individuals who tested positive to cat or ragweed with one skin prick test (SPT) device but not the other then proceeded to nasal allergen challenge (NAC). The primary outcomes were the aeroallergen false negative rates and sensitivities of the skin test devices followed by nasal allergen (NAC). Results Twenty-five individuals were recruited and underwent a total of 300 SPTs. SPT to allergens (ragweed, dust mite, cat, and timothy grass) resulted in a statistically significant difference in wheal size among the two skin testing devices ( p value <0.0001, 0.0001, 0.0006, and 0.0053 respectively). Six NAC procedures were performed to cat/ragweed and 5 of 6 (83% were positive). The overall allergen sensitivity rate for UniTest and Quintip were 97% and 78% respectively with most false negatives due to the use of 6 mg/ml histamine control reagent. Conclusion Our study shows that 6 mg/ml concentration of histamine control reagent may contribute to a false interpretation of aeroallergen skin prick test results.

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Diagnosing and Managing Patients with Reactions to Radiocontrast Media

Current Treatment Options in Allergy ◽

10.1007/s40521-021-00287-x ◽

2021 ◽

Vol 8 (3) ◽

pp. 210-221

Author(s):

Knut Brockow

Keyword(s):

Skin Testing ◽

Drug Hypersensitivity ◽

Skin Tests ◽

Hypersensitivity Reactions ◽

Positive Skin ◽

Provocation Tests ◽

Ring Molecules ◽

Allergic Skin ◽

Drug Hypersensitivity Reactions ◽

Drug Provocation Tests

Abstract Purpose of the review Iodinated radio contrast media (RCM) belong to the most common elicitors of drug hypersensitivity reactions (HR). Urticaria or anaphylaxis may occur ≤ 1(−6) hour(s) (immediate HR) and exanthems (non-immediate HR) develop > 6 h after application of RCM. Evidence for an immunologic mechanism of RCM HR against the different RCM benzene ring molecules and the benefit of allergological testing in patients with previous hypersensitivity reactions is progressively increasing. Recent findings Positive skin tests can confirm allergy in patients with previous reactions to RCM and help to select alternative better tolerated RCMs. Severe hypersensitivity reactions are mainly caused by an allergic mechanism, whereas the majority of non-severe reactions appear to be non-allergic. Skin testing is highly recommended to help identify allergic hypersensitivity reactions and to select alternatives. Using structurally different RCM is more effective than premedication for the prevention of future reactions. Drug provocation tests to RCM have been increasingly used, but are not yet standardized among different centers. Summary In patients with previous severe hypersensitivity reactions to RCM, skin testing is recommended. For future RCM-enhanced examinations in patients with previous reactions, structurally different, skin test-negative preparations should be applied. Drug provocation tests do confirm or exclude RCM hypersensitivity or may demonstrate tolerability of alternative RCMs.

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Distinct Subpopulations of Intravalvular Methicillin-Resistant Staphylococcus aureus with Variable Susceptibility to Daptomycin in Tricuspid Valve Endocarditis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01593-19 ◽

2020 ◽

Vol 64 (3) ◽

Author(s):

Christopher R. Miller ◽

Somrita Dey ◽

Paula D. Smolenski ◽

Pushkar S. Kulkarni ◽

Jonathan M. Monk ◽

...

Keyword(s):

Methicillin Resistant Staphylococcus Aureus ◽

Beta Lactam ◽

Beta Lactams ◽

Content Type ◽

Peripheral Blood Culture ◽

Genomic Analyses ◽

Pharmacokinetic Simulations ◽

Selection Of

ABSTRACT We present a case of endocarditis wherein organisms cultured from different valve leaflets yielded different daptomycin susceptibilities from each other and from organisms obtained from peripheral blood culture. Genomic analyses showed mutations in mprF, purR, and agrA. Pharmacokinetic simulations showed consistent activity of daptomycin plus beta-lactam against all subpopulations. This represents an opportunity to understand S. aureus evolution and fitness in vivo on daptomycin therapy and the role of beta-lactams to prevent the selection of daptomycin-resistant subpopulations.

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Mild to moderate hypersensitivity reactions to beta-lactams in children: a single-centre retrospective review

BMJ Paediatrics Open ◽

10.1136/bmjpo-2019-000435 ◽

2019 ◽

Vol 3 (1) ◽

pp. e000435 ◽

Cited By ~ 5

Author(s):

Leticia Vila ◽

Vanesa Garcia ◽

Oihana Martinez Azcona ◽

Loreley Pineiro ◽

Angela Meijide ◽

...

Keyword(s):

Drug Hypersensitivity ◽

Skin Tests ◽

Penicillin G ◽

Hypersensitivity Reactions ◽

Beta Lactam ◽

Patch Tests ◽

Provocation Tests ◽

Delayed Reactions ◽

Diagnostic Work ◽

Low Sensitivity

ObjectiveBeta-lactam (BL) antibiotics are the most reported drugs in hypersensitivity reactions in children. More than 90% of these children tolerate the suspected drug after diagnostic work-up. Skin tests (STs) show low sensitivity. Our aim was to assess the performance of drug provocation tests (DPTs) without previous ST in mild and moderate delayed reactions and to propose a new DPT protocol.Design of the studyCharts from 213 children under 15 years of age referred for suspected BL allergy from 2011 to 1013 were reviewed. Prick, intradermal and patch tests were performed with major determinant penicilloyl-polylysine, minor determinant mixture, amoxicillin (AMX), cefuroxime, penicillin G and AMX–clavulamate. Children with negative skin tests underwent DPT. After an initial full dose of antibiotic, DPT was carried on for 3 days at home in patients reacting within the first 3 days of treatment. If the reaction took place from day 4 on of treatment, patients took the antibiotic for 5 days.ResultsWe included 108 girls and 105 boys. Mean age at the time of reaction was 3.66±3.06 years. 195 patients (91.5%) reacted to one BL. 154 reactions (67.2%) were non-immediate. Mild to moderate skin manifestations were most frequently reported. AMX–clavulanate was the most frequently involved (63.4%). DPT confirmed the diagnosis of drug hypersensitivity in 17 (7.3%) cases. These 17 patients had negative ST.ConclusionIn mild and moderate cases of BL hypersensitivity, diagnosis can be performed by DPT without previous ST

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The Contradiction of Drug Allergy in Patients with Cystic Fibrosis and Review of the Literature

10.22541/au.161538684.40504015/v1 ◽

2021 ◽

Author(s):

Gokcen Dilsa Tugcu ◽

Nagehan Emiralioğlu ◽

Ebru Yalçın ◽

Umit Sahiner ◽

Deniz Doğru ◽

...

Keyword(s):

Cystic Fibrosis ◽

Drug Allergy ◽

Drug Hypersensitivity ◽

Skin Tests ◽

Beta Lactam ◽

Provocation Tests ◽

Maculopapular Eruption ◽

Drug Hypersensitivity Reactions ◽

Amoxicillin Clavulanic Acid ◽

Multiple Drugs

Background: Cystic fibrosis (CF) is reported to be a risk factor for drug hypersensitivity. However, there is conflicting data about true prevalence of drug allergy in children with CF. Methods: The suspicious drug hypersensitivity reactions (DHR) of children with CF were enquired by European Network for Drug Allergy (ENDA) questionnaire and skin tests and/or drug provocation tests were performed according to established guidelines. Results: Two hundred and nineteen children (48.9% boys; median [IQR] age, 8.4 years [4.8-12.4 years]) with cystic fibrosis were included in the study, from whom 22 patients with 24 suspected DHRs were evaluated. Most of the suspected DHRs were non-immediate (n=16, 66.6%) type and the offending drugs were amoxicillin clavulanic acid (n=7), macrolides (n=4), trimethoprim sulfamethoxazole (TMP/SMX) (n=2), piperacillin tazobactam (n=1), pancrelipase (n=1) and ursodeoxycholic acid (n=1). Eight (33.3%) of the DHRs were classified as immediate [ceftriaxone (n=2), ceftazidim (n=2), meropenem (n=1), ambisome (n=2), vancomycin (n=1)]. The main presenting clinical presentations were maculopapular eruption (41.6%) and urticaria (37.5%), accompanied by angioedema (8.3%), flushing (12.5%) and vomiting (8.3%). Nine skin tests (with beta-lactam protocol in 6 patients) and 24 DPTs were performed and none of the skin tests revealed a positive result, however 2 DPTs with TMP/SMX were positive. Conclusion: Actual drug allergy was demonstrated in 2 of 219 patients (0.9%) with nonbeta-lactam antibiotics. These results conflict with previous researches that showed higher drug allergy rates but were consistent with some recent studies. Numerous and long-term use of multiple drugs during management of cystic fibrosis may contribute to tolerance development.

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The Role of Skin Tests in the Prevention and Diagnosis of Hypersensitivity Reactions to Platinum Agents in Gynecological Cancer: A Single-Center Italian Retrospective Study

Cancers ◽

10.3390/cancers13215468 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5468

Author(s):

Ilaria Puxeddu ◽

Fiorella Petrelli ◽

Maria Elena Guerrieri ◽

Stefania Cosio ◽

Isabella Del Corso ◽

...

Keyword(s):

Skin Test ◽

Gynecological Cancer ◽

False Negative ◽

Cross Reactivity ◽

Skin Tests ◽

Type I ◽

Hypersensitivity Reactions ◽

Platinum Agents

Background: Hypersensitivity reactions (HSR)s to platinum agents are increasing in frequency, due to their extensive use and repeated exposures in patients with increased life expectancy. The aims of our study are to analyze the frequency of both type I and type IV HSRs in patients with gynecological cancer treated with carboplatin (CBDCA) and/or cisplatin (CDDP), to evaluate the role of skin tests in the diagnosis and prevention of HSRs. Methods: From 2011 to 2018, we evaluated 124 consecutive female patients previously treated with CBDCA and/or CDDP for gynecological cancer. All patients, including those with and without HSR to previous platinum-based therapy, underwent in-vivo skin tests for platinum agents before starting the second or more therapeutic lines. To reduce the risk of false negative results, patients with a negative skin test at the first evaluation were re-tested after 3 weeks from the platinum re-exposure. Results: Among the 124 patients evaluated, 58 (47%) experienced HSRs to at least one platinum agent: 35% were to CBDCA, 5% to CDDP, 7% to both. Fifty-six of the 58 HSRs were classified as immediate and two delayed. Skin tests confirmed an IgE-dependent mechanism in 67% of patients with immediate-HSRs to CBDCA and identified a cross-reactivity between platinum agents in 18% of patients. Moreover, among those who had never developed an HSRs during platinum-based therapy, in-vivo skin tests identified 12% of sensitized patients. Conclusions: On the basis of our findings, skin test for platinum agents is a simple and sensitive tool for the diagnosis and prevention of HSRs to CBDCA and/or CDDP and can be useful for detecting possible cross-reactivity among platinum agents.

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