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Article ; Online: Cephalosporin resistance, tolerance, and approaches to improve their activities.

Araten, Alison H / Brooks, Rachel S / Choi, Sarah D W / Esguerra, Laura L / Savchyn, Diana / Wu, Emily J / Leon, Gabrielle / Sniezek, Katherine J / Brynildsen, Mark P

The Journal of antibiotics

2023 Volume 77, Issue 3, Page(s) 135–146

Abstract: Cephalosporins comprise a β-lactam antibiotic class whose first members were discovered in 1945 from the fungus Cephalosporium acremonium. Their clinical use for Gram-negative bacterial infections is widespread due to their ability to traverse outer ... ...

Abstract	Cephalosporins comprise a β-lactam antibiotic class whose first members were discovered in 1945 from the fungus Cephalosporium acremonium. Their clinical use for Gram-negative bacterial infections is widespread due to their ability to traverse outer membranes through porins to gain access to the periplasm and disrupt peptidoglycan synthesis. More recent members of the cephalosporin class are administered as last resort treatments for complicated urinary tract infections, MRSA, and other multi-drug resistant pathogens, such as Neisseria gonorrhoeae. Unfortunately, there has been a global increase in cephalosporin-resistant strains, heteroresistance to this drug class has been a topic of increasing concern, and tolerance and persistence are recognized as potential causes of cephalosporin treatment failure. In this review, we summarize the cephalosporin antibiotic class from discovery to their mechanisms of action, and discuss the causes of cephalosporin treatment failure, which include resistance, tolerance, and phenomena when those qualities are exhibited by only small subpopulations of bacterial cultures (heteroresistance and persistence). Further, we discuss how recent efforts with cephalosporin conjugates and combination treatments aim to reinvigorate this antibiotic class.
MeSH term(s)	Humans ; Cephalosporin Resistance ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Cephalosporins/pharmacology ; Cephalosporins/therapeutic use ; Gram-Negative Bacterial Infections/drug therapy ; Neisseria gonorrhoeae ; Monobactams/therapeutic use
Chemical Substances	Anti-Bacterial Agents ; Cephalosporins ; Monobactams
Language	English
Publishing date	2023-12-19
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	390800-8
ISSN	1881-1469 ; 0021-8820 ; 0368-3532
ISSN (online)	1881-1469
ISSN	0021-8820 ; 0368-3532
DOI	10.1038/s41429-023-00687-y
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Article: Low Rate of Clinically Evident Extravascular Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with a Complement C5 Inhibitor: Results from a Large, Multicenter, US Real-World Study.

Shammo, Jamile / Gajra, Ajeet / Patel, Yogesh / Tomazos, Ioannis / Kish, Jonathan / Hill, Anita / Sierra, J Rafael / Araten, David

Journal of blood medicine

2022 Volume 13, Page(s) 425–437

Abstract: Purpose: Most patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with a complement protein 5 (C5) inhibitor achieve full control of terminal complement activity and intravascular hemolysis. The minority remains anemic and transfusion ... ...

Abstract	Purpose: Most patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with a complement protein 5 (C5) inhibitor achieve full control of terminal complement activity and intravascular hemolysis. The minority remains anemic and transfusion dependent despite this control. Etiology for ongoing anemia is multifactorial and includes bone marrow failure, breakthrough hemolysis, extravascular hemolysis (EVH) and nutritional deficiencies. Patients and methods: To evaluate the potential etiologies of hemoglobin levels <10 g/dL despite receiving C5 inhibitor therapy, we performed a retrospective US chart review of adult patients with PNH and treated for at least 12 months with eculizumab (n=53), ravulizumab (n=32), or eculizumab followed by ravulizumab (n=15). Clinically evident EVH was defined as at least one transfusion, reticulocyte count ≥120×10 Results: Treatment with C5 inhibitors significantly improved hemoglobin, lactate dehydrogenase, and number of transfusions versus baseline. Among the patients with hemoglobin <10 g/dL during the last 6 months of treatment (n=38), one patient (eculizumab) had clinically evident EVH, and 10 patients had active concomitant bone marrow failure. Bone marrow failure was a major contributor to hemoglobin <10 g/dL and transfusion dependence; clinically evident EVH was uncommon. Conclusion: A range of hematologic causes need to be considered when evaluating anemia in the presence of treatment with a C5 inhibitor.
Language	English
Publishing date	2022-08-12
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2587464-0
ISSN	1179-2736
ISSN	1179-2736
DOI	10.2147/JBM.S361863
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Article ; Online: Composite endpoint to evaluate complement inhibition therapy in patients with paroxysmal nocturnal hemoglobinuria.

Kulasekararaj, Austin / Glasmacher, Axel / Liu, Peng / Szer, Jeff / Araten, David / Rauch, Geraldine / Gwaltney, Chad / Sierra, J Rafael / Lee, Jong Wook

European journal of haematology

2022 Volume 108, Issue 5, Page(s) 391–402

Abstract: This study developed and explored a novel composite endpoint to assess the overall impact that treatment can have on patients living with paroxysmal nocturnal hemoglobinuria (PNH). Candidate composite endpoint variables were selected by a group of ... ...

Abstract	This study developed and explored a novel composite endpoint to assess the overall impact that treatment can have on patients living with paroxysmal nocturnal hemoglobinuria (PNH). Candidate composite endpoint variables were selected by a group of experts and included: lactate dehydrogenase levels as a measure of intravascular hemolysis; complete terminal complement inhibition; absence of major adverse vascular events, including thrombosis; absence of any adverse events leading to death or discontinuation of study treatment; transfusion avoidance; and improvements in fatigue-related quality of life as determined by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. From these variables, a novel composite endpoint was constructed and explored using data collected in the ravulizumab PNH Study 301 (NCT02946463). Thresholds were defined and reported for each candidate variable. Five of the six candidate variables were included in the final composite endpoint; the FACIT-Fatigue score was excluded. Composite endpoint criterion was defined as patients meeting all five selected individual component thresholds. All patients in the ravulizumab arm achieved complete terminal complement inhibition and a reduction in lactate dehydrogenase levels; 51.2% and 41.3% of patients in the ravulizumab arm and eculizumab arm, respectively, achieved all composite endpoint component thresholds (treatment difference: 9.4%; 95% confidence interval: -3.0, 21.5). The composite endpoint provided a single and simultaneous measurement of overall benefit for patients receiving treatment for PNH. Use of the composite endpoint in future PNH research is recommended to determine clinical benefit, and its use in health technology assessments should be evaluated.
MeSH term(s)	Fatigue ; Hemoglobinuria, Paroxysmal/diagnosis ; Hemoglobinuria, Paroxysmal/drug therapy ; Hemolysis ; Humans ; Lactate Dehydrogenases ; Quality of Life
Chemical Substances	Lactate Dehydrogenases (EC 1.1.-)
Language	English
Publishing date	2022-03-01
Publishing country	England
Document type	Journal Article
ZDB-ID	392482-8
ISSN	1600-0609 ; 0902-4441
ISSN (online)	1600-0609
ISSN	0902-4441
DOI	10.1111/ejh.13746
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Article ; Online: Analysis of platelets by flow cytometry in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH).

Araten, David J / Boxer, Daniel / Zamechek, Leah / Sherman, Erik / Nardi, Michael

Blood cells, molecules & diseases

2019 Volume 80, Page(s) 102372

Abstract: The marked pro-thrombotic tendency in PNH is likely to be at least partly due to the population of platelets derived from the abnormal stem cell clone. However, identification of GPI (-) platelets by flow cytometry can be technically difficult. Here we ... ...

Abstract	The marked pro-thrombotic tendency in PNH is likely to be at least partly due to the population of platelets derived from the abnormal stem cell clone. However, identification of GPI (-) platelets by flow cytometry can be technically difficult. Here we describe a technique that involves the addition of aspirin immediately after the separation of platelet rich plasma and the use of gel filtration to isolate platelets away from plasma proteins and other blood cells. In a study of 92 analyses of samples from 50 patients, we have demonstrated that the percentage of PNH platelets correlates well with the percentage of PNH granulocytes. We also provide data on several cases where there was an extreme discrepancy between the proportion of PNH granulocytes and red cells; in these cases, the demonstration of abnormal platelets suggests that the patient is likely to be at risk of thrombosis. We believe this test will be potentially useful in the evaluation of samples from such patients and may serve as a tool to investigate the causes of hypercoagulability in PNH.
MeSH term(s)	Biomarkers ; Blood Coagulation ; Blood Platelets/metabolism ; Cell Fractionation/methods ; Erythrocytes/metabolism ; Flow Cytometry/methods ; Granulocytes/metabolism ; Hemoglobinuria, Paroxysmal/blood ; Hemoglobinuria, Paroxysmal/complications ; Hemoglobinuria, Paroxysmal/diagnosis ; Humans ; Platelet Function Tests ; ROC Curve ; Thrombosis/etiology
Chemical Substances	Biomarkers
Language	English
Publishing date	2019-10-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1237083-6
ISSN	1096-0961 ; 1079-9796
ISSN (online)	1096-0961
ISSN	1079-9796
DOI	10.1016/j.bcmd.2019.102372
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Book ; Online: Mild clinical course of covid-19 in 3 patients receiving therapeutic monoclonal antibodies targeting c5 complement for hematologic disorders

Araten, D. J. / Michael Belmont, H. / Schaefer-Cutillo, J. / Iyengar, A. / Mattoo, A. / Reddy, R.

Journal Articles

2020

Abstract: Am J Case Rep, 2020. Objective: Rare co-existance of disease or pathology Background: Patients ...

Abstract	© Am J Case Rep, 2020. Objective: Rare co-existance of disease or pathology Background: Patients receiving immunosuppressive therapies might be more susceptible to COVID-19. Conversely, an exaggerated inflammatory response to the SARS-CoV-2 infection might be blunted by certain forms of immunosuppression, which could be protective. Indeed, there are data from animal models demonstrating that complement may be a part of the pathophysiology of coronavirus infections. There is also evidence from an autopsy series demonstrating complement deposition in the lungs of patients with COVID-19. This raises the question of whether patients on anti-complement therapy could be protected from COVID-19. Case Reports: Case 1 is a 39-year-old woman with an approximately 20-year history of paroxysmal nocturnal hemoglobinuria (PNH), who had recently been switched from treatment with eculizumab to ravulizumab prior to SARS-CoV-2 infection. Case 2 is a 54-year-old woman with a cadaveric renal transplant for lupus nephritis, complicated by thrombotic microangiopathy, who was maintained on eculizumab, which she started several months before she developed the SARS-CoV-2 infection. Case 3 is a 60-year-old woman with a 14-year history of PNH, who had been treated with eculizumab since 2012, and was diagnosed with COVID-19 at the time of her scheduled infusion. All 3 patients had a relatively mild course of COVID-19. Conclusions: We see no evidence of increased susceptibility to SARS-CoV-2 in these patients on anti-complement therapy, which might actually have accounted for the mild course of infection. The effect of anti-complement therapy on COVID-19 disease needs to be determined in clinical trials.
Keywords	covid19
Subject code	616
Publishing date	2020-01-01T08:00:00Z
Publisher	Donald and Barbara Zucker School of Medicine Academic Works
Publishing country	us
Document type	Book ; Online
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Article ; Online: MSH6 haploinsufficiency at relapse contributes to the development of thiopurine resistance in pediatric B-lymphoblastic leukemia.

Evensen, Nikki A / Madhusoodhan, P Pallavi / Meyer, Julia / Saliba, Jason / Chowdhury, Ashfiyah / Araten, David J / Nersting, Jacob / Bhatla, Teena / Vincent, Tiffaney L / Teachey, David / Hunger, Stephen P / Yang, Jun / Schmiegelow, Kjeld / Carroll, William L

Haematologica

2018 Volume 103, Issue 5, Page(s) 830–839

Abstract: Survival of children with relapsed acute lymphoblastic leukemia is poor, and understanding mechanisms underlying resistance is essential to developing new therapy. Relapse-specific heterozygous deletions ... ...

Abstract	Survival of children with relapsed acute lymphoblastic leukemia is poor, and understanding mechanisms underlying resistance is essential to developing new therapy. Relapse-specific heterozygous deletions in
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Child ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/physiology ; Drug Resistance, Neoplasm ; Haploinsufficiency ; Humans ; Mice, Inbred NOD ; Mice, SCID ; Mutation ; Neoplasm Recurrence, Local/drug therapy ; Neoplasm Recurrence, Local/genetics ; Neoplasm Recurrence, Local/pathology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Prognosis ; Thioguanine/pharmacology ; Tumor Cells, Cultured
Chemical Substances	Antineoplastic Agents ; DNA-Binding Proteins ; G-T mismatch-binding protein ; Msh6 protein, mouse ; Thioguanine (FTK8U1GZNX)
Language	English
Publishing date	2018-02-15
Publishing country	Italy
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2017.176362
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Article: Allogeneic bone marrow transplantation for paroxysmal nocturnal hemoglobinuria.

Araten, D J / Luzzatto, L

Haematologica

2000 Volume 85, Issue 1, Page(s) 1–2

MeSH term(s)	Bone Marrow Transplantation/adverse effects ; Bone Marrow Transplantation/standards ; Graft vs Host Disease/etiology ; Graft vs Host Disease/prevention & control ; Hemoglobinuria, Paroxysmal/therapy ; Humans ; Immunosuppression ; Myeloablative Agonists/adverse effects ; Myeloablative Agonists/therapeutic use ; Survival Rate ; Transplantation Conditioning ; Transplantation, Homologous/adverse effects ; Transplantation, Homologous/standards
Chemical Substances	Myeloablative Agonists
Language	English
Publishing date	2000-01
Publishing country	Italy
Document type	Comment ; Editorial
ZDB-ID	2333-4
ISSN	1592-8721 ; 0390-6078 ; 0017-6567
ISSN (online)	1592-8721
ISSN	0390-6078 ; 0017-6567
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Article ; Online: Leukemic blasts with the paroxysmal nocturnal hemoglobinuria phenotype in children with acute lymphoblastic leukemia.

Araten, David J / Sanders, Katie J / Anscher, Dan / Zamechek, Leah / Hunger, Stephen P / Ibrahim, Sherif

The American journal of pathology

2012 Volume 181, Issue 5, Page(s) 1862–1869

Abstract: It has been proposed that genomic instability is essential to account for the multiplicity of mutations often seen in malignancies. Using the X-linked PIG-A gene as a sentinel gene for spontaneous inactivating somatic mutations, we previously showed that ...

Abstract	It has been proposed that genomic instability is essential to account for the multiplicity of mutations often seen in malignancies. Using the X-linked PIG-A gene as a sentinel gene for spontaneous inactivating somatic mutations, we previously showed that healthy individuals harbor granulocytes with the PIG-A mutant (paroxysmal nocturnal hemoglobinuria) phenotype at a median frequency (f) of ∼12 × 10(-6). Herein, we used a similar approach to determine f in blast cells derived from 19 individuals with acute lymphoblastic leukemia (ALL) and in immortalized Epstein-Barr virus-transformed B-cell cultures (human B-lymphoblastoid cell lines) from 19 healthy donors. The B-lymphoblastoid cell lines exhibited a unimodal distribution, with a median f value of 11 × 10(-6). In contrast, analysis of the f values for the ALL samples revealed at least two distinct populations: one population, representing approximately half of the samples (n = 10), had a median f value of 13 × 10(-6), and the remaining samples (n = 9) had a median f value of 566 × 10(-6). We conclude that in ALL, there are two distinct phenotypes with respect to hypermutability, which we hypothesize will correlate with the number of pathogenic mutations required to produce the leukemia.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; B-Lymphocytes/pathology ; Blast Crisis/complications ; Blast Crisis/pathology ; Case-Control Studies ; Cell Line ; Child ; Child, Preschool ; Female ; Flow Cytometry ; Hemoglobinuria, Paroxysmal/complications ; Hemoglobinuria, Paroxysmal/pathology ; Humans ; Male ; Middle Aged ; Phenotype ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Tissue Donors ; Young Adult
Language	English
Publishing date	2012-08-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2012.07.025
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Article ; Online: Changing prognosis in paroxysmal nocturnal haemoglobinuria disease subcategories: an analysis of the International PNH Registry.

Socié, G / Schrezenmeier, H / Muus, P / Lisukov, I / Röth, A / Kulasekararaj, A / Lee, J W / Araten, D / Hill, A / Brodsky, R / Urbano-Ispizua, A / Szer, J / Wilson, A / Hillmen, P

Internal medicine journal

2016 Volume 46, Issue 9, Page(s) 1044–1053

Abstract: Background: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare disease. Although much progress has been made in the understanding of the pathophysiology of the disease, far less is known with respect to the clinical outcomes of patients with PNH. Few ... ...

Abstract	Background: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare disease. Although much progress has been made in the understanding of the pathophysiology of the disease, far less is known with respect to the clinical outcomes of patients with PNH. Few retrospective studies provide survival estimates, and even fewer have explored the clinical heterogeneity of the disease. Haemolytic and aplastic anaemia (AA) forms of the disease have been recognised as main disease categories, with the haemolytic form being associated with the worst prognosis by the largest studied cohort some years ago. Aims: To describe mortality and causes of death in PNH overall and by PNH classification and to evaluate risk factors associated with mortality. Methods: We analysed data of 2356 patients enrolled in the International PNH Registry with multivariate analyses, using time-dependent covariates. Patients were classified into haemolytic, AA/PNH syndrome or intermediate PNH. Results: Overall, 122 (5.2%) patients died after enrolment, the incidence according to subcategories being 5.1, 11.7, 2.0 and 4.8% for patients with haemolytic PNH, AA-PNH, intermediate and insufficient data respectively. Older age and decreased performance status also affected survival in multivariate analysis. Improved outcome of patients with haemolytic PNH suggests that eculizumab treatment in PNH may be associated with improved survival. Conclusion: A detailed analysis of clinical presentations and causes of death in patients with PNH, overall and by disease subcategories, provide evidence that in the current era, patients with haemolytic PNH are no longer those who harbour the worst prognosis. This finding differs sharply from what has been previously reported.
MeSH term(s)	Adult ; Anemia, Aplastic/epidemiology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Cause of Death ; Erythrocyte Transfusion ; Female ; France ; Hemoglobinuria, Paroxysmal/classification ; Hemoglobinuria, Paroxysmal/mortality ; Hemoglobinuria, Paroxysmal/therapy ; Humans ; Incidence ; Male ; Middle Aged ; Multivariate Analysis ; Prognosis ; Registries ; Retrospective Studies ; Risk Factors ; Survival Analysis ; Thrombosis/epidemiology
Chemical Substances	Antibodies, Monoclonal, Humanized ; eculizumab (A3ULP0F556)
Language	English
Publishing date	2016-09
Publishing country	Australia
Document type	Journal Article
ZDB-ID	2045436-3
ISSN	1445-5994 ; 1444-0903
ISSN (online)	1445-5994
ISSN	1444-0903
DOI	10.1111/imj.13160
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Article: Clonal populations of hematopoietic cells with paroxysmal nocturnal hemoglobinuria genotype and phenotype are present in normal individuals.

Araten, D J / Nafa, K / Pakdeesuwan, K / Luzzatto, L

Proceedings of the National Academy of Sciences of the United States of America

1999 Volume 96, Issue 9, Page(s) 5209–5214

Abstract: In paroxysmal nocturnal hemoglobinuria (PNH), acquired somatic mutations in the PIG-A gene give rise to clonal populations of red blood cells unable to express proteins linked to the membrane by a glycosylphosphatidylinositol anchor. These proteins ... ...

Abstract	In paroxysmal nocturnal hemoglobinuria (PNH), acquired somatic mutations in the PIG-A gene give rise to clonal populations of red blood cells unable to express proteins linked to the membrane by a glycosylphosphatidylinositol anchor. These proteins include the complement inhibitors CD55 and CD59, and this explains the hypersensitivity to complement of red cells in PNH patients, manifested by intravascular hemolysis. The factors that determine to what extent mutant clones expand have not yet been pinpointed; it has been suggested that existing PNH clones may have a conditional growth advantage depending on some factor (e.g., autoimmune) present in the marrow environment of PNH patients. Using flow cytometric analysis of granulocytes, we now have identified cells that have the PNH phenotype, at an average frequency of 22 per million (range 10-51 per million) in nine normal individuals. These rare cells were collected by flow sorting, and exons 2 and 6 of the PIG-A gene were amplified by nested PCR. We found PIG-A mutations in six cases: four missense, one frameshift, and one nonsense mutation. PNH red blood cells also were identified at a frequency of eight per million. Thus, small clones with PIG-A mutations exist commonly in normal individuals, showing clearly that PIG-A gene mutations are not sufficient for the development of PNH. Because PIG-A encodes an enzyme essential for the expression of a host of surface proteins, the PIG-A gene provides a highly sensitive system for the study of somatic mutations in hematopoietic cells.
MeSH term(s)	Adult ; Aged ; Clone Cells ; Flow Cytometry ; Hematopoietic Stem Cells/pathology ; Hematopoietic Stem Cells/physiology ; Hemoglobinuria, Paroxysmal/blood ; Hemoglobinuria, Paroxysmal/genetics ; Hemoglobinuria, Paroxysmal/pathology ; Humans ; Male ; Membrane Proteins/genetics ; Middle Aged ; Mutation ; Phenotype
Chemical Substances	Membrane Proteins ; phosphatidylinositol glycan-class A protein
Language	English
Publishing date	1999-04-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.96.9.5209
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