scholarly journals Cross-Reactivity of Drug-Dependent Antibodies in Patients with Immune Thrombocytopenia Induced By Beta-Lactam Antibiotics

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2350-2350
Author(s):  
Matthew John Slaught ◽  
Daniel W. Bougie ◽  
Richard H. Aster
Keyword(s):  
Bacterial Infections ◽  
Immune Thrombocytopenia ◽  
Conflicts Of Interest ◽  
Cross Reactivity ◽  
Beta Lactam ◽  
Cross Reactions ◽  
Beta Lactam Antibiotics ◽  
Wide Range ◽  
Group 2 ◽  
Group 1

More than 50 beta lactam (BL) antibiotics are now in active use for treatment of a wide range of bacterial infections. BL antibiotics are among the most common drugs capable of inducing antibodies (DDAbs) that cause drug-induced immune thrombocytopenia (DITP). Most DDAbs are highly specific for the sensitizing drug but beta lactams all have a common core structure and many similarities among side groups that are added to augment potency and modify specificity, raising the possibility that a DDAb specific for one BL may cross-react with another. We studied DDAbs from 33 patients with DITP induced by 9 commonly used BL drugs to determine whether patterns of cross-reactivity exist that might influence the choice of an alternative antibiotic in a patient with BL-induced DITP. DDAbs were demonstrated in a flow cytometric assay considered to be "positive" when immunoglobulins in patient serum but not normal serum react with normal platelets in the presence, but not in the absence of drug (Blood 2018;131:1486). DDAbs detected in the 33 patients were specific for 9 different BL drugs that were divided into two groups, "penicillins" (Group 1) and cephalosporins (Group 2) on the basis of structural similarities (Figure 1). In Group 1 were 19 DDAbs specific for amoxicillin (2), nafcillin (4) and piperacillin (13). Structurally similar ampicillin and penicillin were also tested with these abs. In Group 2 were 14 DDAbs specific for cefadroxil (1), cefepime (2), ceftazidime (2), ceftizoxime (1), ceftriaxone (7) and cephalexin 1). Cross-reactions identified within these groups of DDAbs are shown in Tables 1 and 2. Cross-reactions, many quite strong (S) were observed among DDAbs specific for drugs in both structural groups (Tables 1 and 2). Particularly noteworthy were cross-reactions of the 19 Group 1 DDAbs with ampicillin (6) and penicillin (6) (Table 1) and of the 14 Group 2 DDAbs with cefepime (6), ceftizoxazole (6) and ceftriaxone (3) (Table 2). The findings show that platelet-specific DDAbs induced by beta lactam antibiotics, in contrast with those induced by medications like quinine, sulfamethoxazole and vancomycin, commonly cross-react with other antibiotics of this class. In patients with immune thrombocytopenia induced by a beta lactam antibiotic, it may be prudent to avoid switching to another beta lactam or, if this is necessary, to monitor platelet counts carefully. Disclosures No relevant conflicts of interest to declare.

scholarly journals Beta-lactamases and detection of beta-lactam resistance in Enterobacter spp.

1997 ◽  
Vol 41 (1) ◽  
pp. 35-39 ◽  
Author(s):  
J D Pitout ◽  
E S Moland ◽  
C C Sanders ◽  
K S Thomson ◽  
S R Fitzsimmons
Keyword(s):  
Disk Diffusion ◽  
Broth Microdilution ◽  
Beta Lactam ◽  
Disk Diffusion Test ◽  
Beta Lactamases ◽  
Beta Lactam Antibiotics ◽  
Resistant Strains ◽  
Group 2 ◽  
Susceptibility Tests ◽  
Group 1

Enterobacter spp. are becoming increasingly frequent nosocomial pathogens, and beta-lactam-resistant strains are on the increase, especially among isolates recovered from intensive care units. Therefore, a study was designed to characterize the beta-lactamases produced by 80 isolates of E. cloacae, E. aerogenes, E. taylorae, E. gergoviae, E. sakazakii, E. asburiae, and E. agglomerans by induction studies, spectrophotometric hydrolysis assays, and isoelectric focusing. The ability of broth microdilution and disk diffusion susceptibility tests to detect resistance to 16 beta-lactam antibiotics among these species was also assessed. All species except E. agglomerans, E. gergoviae, and some isolates of E. sakazakii were found to produce a Bush group 1 cephalosporinase that was expressed inducibly or constitutively at high levels. In addition, some strains also produced a Bush group 2 beta-lactamase. In comparisons of broth microdilution and disk diffusion tests, disk diffusion tests failed to detect resistance in 1 of 25 isolates resistant to aztreonam and 2 of 30 isolates resistant to ceftazidime. These results indicate that species of Enterobacter can possess a variety of beta-lactamases that are responsible for beta-lactam resistance in this genus and that the disk diffusion test may occasionally miss resistance in some strains.

scholarly journals Quality of Oral Anticoagulation with Vitamin K Antagonists in 'Real-World' Patients: Lessons from a Six Years Audit Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1159-1159
Author(s):  
Fernanda Leite ◽  
Ângela Leite ◽  
Sara Ferreira ◽  
Jorge Coutinho
Keyword(s):  
Vitamin K ◽  
Therapeutic Range ◽  
Patient Population ◽  
Conflicts Of Interest ◽  
Vitamin K Antagonists ◽  
Recall Interval ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Introduction: Among patients receiving vitamin K antagonists (VKA) therapy, maintenance of an international normalized ratio (INR) in the therapeutic range is essential for treatment efficacy and safety. This requires regular monitoring and appropriate dose adjustment. It has been reported that anticoagulation clinics should aim for a time in therapeutic range (TTR) between 70-80% to optimize benefit and minimize the risk of adverse events. Previously (in a study between September 2006 and June 2012), we have reported that patients with longer INR recall interval (4-8 weeks) showed no decrease of monitoring quality and that it would be safe to increase time between measurements. Aim: Since actual recommendations for improving TTR include shortening INR recall interval (Lip et al. 2018) we aimed to evaluate the quality of anticoagulation monitoring after having increased time between measurements beyond the 4-8 weeks recall interval. Methodology: We retrospectively analyzed 37931 appointments of 6 consecutive years (July 2012 to July 2018) corresponding to 1587 patients that are regularly followed up at an outpatient Anticoagulation Clinic of a central hospital under anticoagulation for at least 8 weeks, using TTR determined by Rosendaal method. Patients were divided according to target INR in three groups: Group 1 with target INR 2-3, including 1430 patients corresponding to 30743 appointments with mean age 69±15 years (mean±SD), majority (46.4%) with atrial fibrillation (AF); Group 2 with target INR 2.5-3.5, including 125 patients corresponding to 5439 appointments with mean age 67±12 years, majority (85.6%) with mechanical heart valves; Group 3 with target INR 3-4, including 32 patients corresponding to 1749 appointments with mean age 62±14 years, majority (62.5%) with antiphospholipid syndrome. Descriptive statistics (mean, standard deviation, minimum, maximum, chi-square), inferential statistics (t-test, A-Nova and effect sizes) tests and correlations were performed. Results: The 1587 patient population, 50.5% male, mean age of 68±17 years and 90.1% in Group 1, showed a mortality of 18%. A point-biserial correlation was run to determine the relationship between mortality and gender, age, INR group and diagnostic. Mortality was correlated with diagnosis (57.2% with AF) (rpb = -.071, n = 1587, p = .004), male gender (60%) (rpb = -.089, n = 1587, p <.001) and age (75±12) (rpb = .175, n= 1587, p<.001) but not with INR group (rpb = -.017, n = 1587, p = .499). Indeed, between groups mortality was not different [Χ2(2)=.492; p=.782; φ=.018] nor mean age [F(2, 1584)=2.588; p=.078; η2=.003], but gender distribution was unequal [Χ2(2)= 10.815; p=.004; φ=.083] with male predominating in Group 1 (51.9%) and female in Group 2 (60.8%) and 3 (65.6%). Patients in Group 1, corresponding to 90.1% of the total population, had TTR of 72%, patients in Group 2 had TTR of 69% and patients in Group 3 had TTR of 60%. Comparatively to the previous study (2006-2012), we noticed a significant decrease in patient population / appointments size (2087/ 61988) (p <.001) with a decrease of TTR in Group 1 (1927 patients) (83%) and Group 2 (120 patients) (74%) but a TTR increase in Group 3 (40 patients) (54%) (p <.001). Conclusions and Discussion: More than 90% of the population under VKA treatment showed effective TTR which may infer safety in increasing INR recall interval. The TTR decrease with a smaller population may be explained by the introduction of direct oral anticoagulants in patients with less comorbidities. The increase of TTR in patients with higher INR target suggests a better management of patients under VKA therapy that is actually the only choice for challenging patients. Disclosures No relevant conflicts of interest to declare.

The neutrophil to lymphocyte ratio in patients supported with extracorporeal membrane oxygenation

Perfusion ◽  
2018 ◽  
Vol 33 (7) ◽  
pp. 562-567 ◽  
Author(s):  
Gardner Yost ◽  
Geetha Bhat ◽  
Patroklos Pappas ◽  
Antone Tatooles
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Myocardial Damage ◽  
Neutrophil Infiltration ◽  
Neutrophil To Lymphocyte Ratio ◽  
Study Cohort ◽  
Lymphocyte Ratio ◽  
Membrane Oxygenation ◽  
Wide Range ◽  
Group 2 ◽  
Group 1

Introduction: The neutrophil to lymphocyte ratio (NLR) has proven to be a robust predictor of mortality in a wide range of cardiovascular diseases. This study investigated the predictive value of the NLR in patients supported by extracorporeal membrane oxygenation (ECMO) systems. Methods: This study included 107 patients who underwent ECMO implantation for cardiogenic shock. Median preoperative NLR was used to divide the cohort, with Group 1 NLR <14.2 and Group 2 with NLR ≥14.2. Survival, the primary outcome, was compared between groups. Results: The study cohort was composed of 64 (60%) males with an average age 53.1 ± 14.9 years. Patients in Group 1 had an average NLR of 7.5 ± 3.5 compared to 27.1 ± 19.9 in Group 2. Additionally, those in Group 2 had significantly higher preoperative blood urea nitrogen (BUN) and age. Survival analysis indicated a thirty-day survival of 56.2%, with significantly worsened mortality in patients with NLR greater than 14.2, p=0.047. Discussion: Our study shows the NLR has prognostic value in patients undergoing ECMO implantation. Leukocytes are known contributors to myocardial damage and neutrophil infiltration is associated with damage caused by myocardial ischemia.

Optimization of Plerixafor Utilization Based on Peripheral Blood CD34+ Count for Autologous Peripheral Blood Stem-Cell Collection

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-41
Author(s):  
Gaurav K. Gupta ◽  
Sera Perreault ◽  
Stuart Seropian ◽  
Christopher A. Tormey ◽  
Jeanne E. Hendrickson
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Medical Center ◽  
Tertiary Care ◽  
Peripheral Blood Cd34 ◽  
Tertiary Care Medical Center ◽  
Group 2 ◽  
Group 1

Introduction: Peripheral CD34+ cells may be mobilized using filgrastim (G-CSF) alone or in combination with chemotherapy. However, some patients also require plerixafor, an inhibitor of C-X-C chemokine receptor type-4, for adequate mobilization. Given its cost, judicious utilization of plerixafor is warranted. Material and Methods: A retrospective analysis of autologous stem-cell mobilization was performed at a tertiary-care medical center in adult patients with multiple myeloma and lymphoma; here we will focus on the utility of repeat plerixafor dosing. Patients were mobilized at the treating physician's discretion with filgrastim plus plerixafor or chemotherapy plus filgrastim plus plerixafor. Collections were initiated once peripheral CD34+ counts reached 20/µL (or 10/µL if chemotherapy mobilized); plerixafor was administered if these counts were not reached after 4 or 8 days, respectively, of filgrastim treatment. Results: Patients with multiple myeloma (86) or lymphoma (30) were evaluated. One hundred five were mobilized by filgrastim plus plerixafor and 11 by chemotherapy plus filgrastim plus plerixafor. No patient that received plerixafor with a CD34+ count &lt;5/µL after chemotherapy mobilized the next day. The end collection goal was achieved in 86 (81.9%) of the filgrastim plus plerixafor group and 7 (63.6%) of the chemotherapy plus filgrastim plus plerixafor group. Patients given at least one dose of plerixafor were divided into groups based on collection goal, peripheral blood CD34+ cell count after 1 dose and the first day collection yield: Group 1) Goal of 3x10^6/kg and CD34+ count ≥ 30 cell/µL vs &lt; 30 cell/µL; Group 2) Goal of 6x10^6/kg and ≥ 50% of collection goal after 1 day of collection vs CD34+ count &lt; 50 cell/µL or &lt; 50% of collection goal. Forty of 42 (95%) patients in Group 1 with a CD34+ count ≥ 30 cell/µL achieved their end collection goal after one plerixafor dose. Eighteen of 19 (95%) patients in Group 1 with a CD34+ count &lt;30 cell/µL received a second dose of plerixafor and 8 (44.4%) achieved their end collection goal. Twenty-eight of 32 (87.5%) patients in Group 2 with ≥ 50% of collection goal achieved on the first day of collection reached their end collection goal after one plerixafor dose. Nine of 12 (75%) patients in Group 2 with a CD34+ count of &lt; 50 cells/µL or &lt;50% collection goal received an additional dose of plerixafor and 6 (66.7%) achieved their end collection goal. Conclusion: Based on these data, we have developed the following repeat plerixafor dosing algorithm: 1) for a collection goal is 3x10^6/kg, administer a second dose of plerixafor if the CD34+ count on the first day of collection is &lt; 30 cell/µL, and 2) for a collection goal of 6x10^6/kg, administer a second dose of plerixafor if the CD34+ count on the first day of collection is &lt; 50 cell/µL or if the first day of collection yields &lt;50% of the end goal. This algorithm optimizes pharmacy, apheresis and stem cell processing resources. Disclosures No relevant conflicts of interest to declare.

scholarly journals Structure-Based Modification of an Anti-neuraminidase Human Antibody Restores Protection Efficacy against the Drifted Influenza Virus

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Haihai Jiang ◽  
Weiyu Peng ◽  
Jianxun Qi ◽  
Yan Chai ◽  
Hao Song ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Influenza Virus ◽  
Antibody Fragment ◽  
Salt Bridge ◽  
Cross Reactivity ◽  
Human Antibody ◽  
Influenza Strain ◽  
Group 2 ◽  
Fragment Antigen Binding ◽  
Group 1

ABSTRACT Here, we investigate a monoclonal antibody, Z2B3, isolated from an H7N9-infected patient, that exhibited cross-reactivity to both N9 (group 2) and a broad range of seasonal and avian N1 (group 1) proteins but lost activity to the N1 with the substitution K432E. This substitution exists in 99.25% of seasonal influenza strains after 2013. The NA-Z2B3 complex structures indicated that Z2B3 binds within the conserved active site of the neuraminidase (NA) protein. A salt bridge between D102 in Z2B3 and K432 in NA plays an important role in binding. Structure-based modification of Z2B3 with D102R in heavy chain reversed the salt bridge and restored the binding and inhibition of N1 with E432. Furthermore, Z2B3-D102R can protect mice from A/Serbia/NS-601/2014 H1N1 virus (NA contains E432) infection while the wild-type Z2B3 antibody shows no protection. This study demonstrates that a broadly reactive and protective antibody to NA can be in principle edited to restore binding and inhibition to recently drifted N1 NA and regain protection against the variant influenza strain. IMPORTANCE The immune system produces antibodies to protect the human body from harmful invaders. The monoclonal antibody (MAb) is one kind of effective antivirals. In this study, we isolated an antibody (Z2B3) from an H7N9 influenza virus-infected child. It shows cross-reactivity to both group 1 (N1) and group 2 (N9) neuraminidases (NAs) but is sensitive to N1 NA with a K432E substitution. Structural analysis of the NA-antibody fragment antigen-binding (Fab) complex provides a clue for antibody modification, and the modified antibody restored binding and inhibition to recently drifted N1 NA and regained protection against the variant influenza strain. This finding suggests that antibodies to NA may be a useful therapy and can be in principle edited to defeat drifted influenza virus.

scholarly journals Suspected penicillin allergy: risk assessment using an algorithm as an antibiotic stewardship project

2020 ◽  
Vol 29 (6) ◽  
pp. 174-180
Author(s):  
Christiane Querbach ◽  
Tilo Biedermann ◽  
Dirk H. Busch ◽  
Rüdiger Eisenhart-Rothe ◽  
Susanne Feihl ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Bacterial Infections ◽  
University Hospital ◽  
Beta Lactam ◽  
Delayed Reaction ◽  
Allergy Testing ◽  
Beta Lactam Antibiotics ◽  
Patient Reported ◽  
Provocation Testing ◽  
Reliable Solution

Summary Background Beta-lactam antibiotics (BLA) are the treatment of choice for a large number of bacterial infections. Putative BLA allergies are often reported by patients, but rarely confirmed. Many patients do not receive BLA due to suspected allergy. There is no systematic approach to risk stratification in the case of a history of suspected BLA allergy. Methods Using the available stratification programs and taking current guidelines into account, an algorithm for risk stratification, including recommendations on the use of antibiotics in cases of compellingly indicated BLA despite suspected BLA allergy, was formulated by the authors for their maximum care university hospital. Results The hospital is in great need of recommendations on how to deal with BLA allergies. Patient-reported information in the history forms the basis for classifying the reactions into four risk categories: (1) BLA allergy excluded, (2) benign delayed reaction, (3) immediate reaction, and (4) severe cutaneous and extracutaneous drug reaction. Recommendations strictly depend on this classification and range from use of full-dose BLA or use of BLA under certain conditions (e.g., two-stage dose escalation, non-cross-reactive BLA only) to prohibiting all BLA and the use of alternative non-BLA. In case of suspected immediate or delayed allergic reactions, there is an additional recommendation regarding subsequent allergy testing during a symptom-free interval. Conclusion Triage of patients with suspected BLA is urgently required. While allergy testing, including provocation testing, represents the most reliable solution, this is not feasible in all patients due to the high prevalence of BLA allergies. The risk stratification algorithm developed for the authors’ hospital represents a tool suitable to making a contribution to rational antibiotic therapy.

Platelet Function and Activation in Patients with Immune Thrombocytopenia Treated with Eltrombopag: Comparison with Steroid-Treated and Untreated Patients,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3280-3280
Author(s):  
Johanna Haselboeck ◽  
Alexandra Kaider ◽  
Ingrid Pabinger ◽  
Simon Panzer
Keyword(s):  
Platelet Count ◽  
Treatment Group ◽  
Prospective Study ◽  
Platelet Function ◽  
Immune Thrombocytopenia ◽  
Steroid Treatment ◽  
Group 3 ◽  
Group 2 ◽  
Group 1 ◽  
Normally Distributed

Abstract Abstract 3280 Background: Eltrombopag has recently been approved for treatment in immune thrombocytopenia (ITP). Studies on platelet function in eltrombopag-treated patients in comparison to steroid-treated or untreated ITP patients are not available. Objectives: To assess the function of eltrombopag-induced platelets, we compared platelets from eltrombopag-treated patients to those from ITP patients treated with steroids and a group of patients without treatment in a prospective study (ClinicalTrials.gov number NCT00888901). Patients/Methods: We compared platelet function in patients treated with eltrombopag after treatment-induced platelet rise (group 1) to those under steroid treatment (group 2) and ITP patients without treatment (group 3) in a non-randomized prospective study. Platelet function was assessed by adhesion under high shear conditions (surface coverage, SC), P-selectin expression, and formation of platelet-monocyte aggregates (PMA) after treatment induced platelet rise or, in group 3, in patients with ITP without treatment and platelet count between 50–100×109/L at the time of inclusion. Data are given as median [quartiles]. Correlations of the outcome measures are described by the Spearman correlation coefficient. In case of normally distributed data, analysis of variance (ANOVA) and of covariance (ANCOVA) models and in case of non-normally distributed parameters the nonparametric Kruskal-Wallis test were used to compare the groups Results: Eleven patients (female=9) were included in the treatment group with eltrombopag (group 1), thirteen (female=5) in the steroid treatment (group 2) and 6 patients as untreated controls (group 3). None of these patients developed severe bleeding during the study period, none received rescue medication. Four/30 patients were not included in the final analysis, three because they had no treatment induced platelet rise (1 on eltrombopag and 2 on steroids) and 1 because of aspirin medication. Thus, ten patients on eltrombopag, ten patients on steroid treatment and 6 untreated patients were evaluated in the comparative analyses of platelet function. Platelet counts [x109/L] were 48.25 [45.00–59.00] in group 1 after eltrombopag-induced platelet rise, 82.75 [78.50–112.00] in group 2 and 69.25 [65.00–73.00] in group 3. SC was highest in steroid-treated patients (11.25% [8.10–14.00%]) compared to eltrombopag-treated (5.80% [1.80–9.00%]) and untreated (5.03% [3.80–6.20%]) patients and correlated significantly with the platelet count (r=0.72, p<0.0001). There were no differences in P-selectin expression [GeoMFI] (1.15 [0.47–2.77] in group 1, 0.27 [0.10–0.99] in group 2 and 0.59 [0.47–1.44] in group 3; p=0.34) and PMA levels (6.19% [3.91–21.39%] in group 1, 9.73% [1.88–13.29%] in group 2, and 6.56% [4.82–8.43%] in group 3; p=0.93) between the groups. Two patients developed venous thromboses during eltrombopag treatment. No characteristic alteration of platelet function and activation was identified in those 2 patients when compared to the other eltrombopag-treated patients. Conclusions: We proofed a good functional competence of eltrombopag-induced platelets. No substantial hyper-reactivity of eltrombopag-induced platelets in comparison to those of steroid-treated and untreated patients was determined. Disclosures: Pabinger: GlaxoSmithKline: Research Funding, Speakers Bureau. Panzer:GlaxoSmithKline: Speakers Bureau.

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