scholarly journals Pseudomonas aeruginosa Susceptibility Patterns and Associated Clinical Outcomes in People with Cystic Fibrosis following Approval of Aztreonam Lysine for Inhalation

2020 ◽  
pp. AAC.02327-20 ◽  
Author(s):  
Claire L Keating ◽  
Jonathan B Zuckerman ◽  
Pradeep K Singh ◽  
Matthew McKevitt ◽  
Oksana Gurtovaya ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Lung Function ◽  
Clinical Outcomes ◽  
Primary Endpoint ◽  
The United States ◽  
Study Endpoint ◽  
Primary Study ◽  
Antibiotic Exposure ◽  
Pulmonary Exacerbations

Rationale: Approval of aztreonam lysine for inhalation solution (AZLI) raised concerns that additional antibiotic exposure would potentially affect susceptibility profiles of Pseudomonas aeruginosa (PA) isolates from cystic fibrosis (CF) patients.Objective: This 5-year, prospective, observational study tracked susceptibility changes and clinical outcomes in CF patients in the United States with chronic PA infection.Methods: Sputum cultures were collected annually (2011-2016). The primary study endpoint was the proportion of subjects whose least susceptible PA isolate had an aztreonam minimum inhibitory concentration (MIC) that was >8 μg/mL (parenteral breakpoint) and increased ≥4-fold compared with the least susceptible isolate from the previous year. Annualized data for pulmonary exacerbations, hospitalizations, and FEV1% predicted were obtained from the CF Foundation Patient Registry and compared between subjects meeting/not meeting the primary endpoint.Results: 510 subjects were enrolled; 334 (65%) completed the study. A consistent proportion of evaluable subjects (13-22%) met the primary endpoint each year; and AZLI use during the previous 12 months was not associated with meeting the primary endpoint. While the annual decline in lung function was comparable for subjects meeting/not meeting the primary endpoint, more pulmonary exacerbations and hospitalizations were experienced by those who met it.Conclusions: Aztreonam susceptibility of PA remained consistent during the 5-year study. The relationship between PA isolate susceptibilities and clinical outcomes is complex; reduced susceptibility was not associated with accelerated decline in lung function, but was associated with more exacerbations and hospitalizations, likely reflecting increased overall antibiotic exposure.

scholarly journals 195. Antimicrobial Stewardship Incorporating New Antimicrobials for Use against Multi-Drug Resistant Pseudomonas aeruginosa in Cystic Fibrosis

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S102-S102
Author(s):  
Jinhee Jo ◽  
Anne J Gonzales-Luna ◽  
Kevin W Garey
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Clinical Outcomes ◽  
Antimicrobial Stewardship ◽  
Medical Center ◽  
Descriptive Analysis ◽  
The United States ◽  
Forced Expiratory Volume ◽  
Exacerbation Rate ◽  
Patient Demographics

Abstract Background Cystic fibrosis (CF) is a life-limiting genetic disease affecting approximately 80,000 people worldwide, including 30,000 in the United States. Chronic Pseudomonas aeruginosa (PA) infections in CF often develop to be multidrug-resistant (MDR) and are associated with worse clinical outcomes. Ceftolozane/Tazobactam (C/T) has shown benefits over other standards of therapy in selected populations with MDR-PA infections, but studies are lacking in the CF population. The objective of this study was to evaluate the current use and antimicrobial stewardship of C/T in CF patients with MDR-PA. Methods This is a retrospective study of hospitalized CF patients with infections due to positive cultures for MDR-PA from 2016–2019 at Baylor St. Luke’s Medical Center in Houston, Texas. Electronic medical records were reviewed for patient demographics, presence of infectious diseases (ID) consult, antibiotics use, and clinical outcomes. A descriptive analysis was performed to compare the patient demographics and clinical outcomes between patients receiving C/T-based and non-C/T therapies. Results A total of 56 CF patients with positive MDR-PA cultures were identified (18 receiving C/T and 38 receiving non-C/T antibiotics). Most MDR-PA was cultured from the lungs (94.6%, 54/56). Patient age, weight, and body mass index were similar between those receiving C/T and non-C/T therapies as was the overall duration of antibiotic therapy 16.3 (± 8.7) vs. 13.9 (± 3.5) days in C/T and non-C/T groups, respectively. More patients in the C/T group had severe forced expiratory volume in 1 s (FEV1) [£40%] at baseline (66.7% vs. 21.1%) and higher ICU admission rates (44.4% vs 2.6%). All C/T patients had an ID consult placed (3 ± 3.1 days after admission) but none in the non-C/T group. The 30-day recurrent pulmonary exacerbation rate was comparable between C/T and non-C/T groups (22.2% vs. 15.8%). Conclusion C/T was reserved for the sickest group of CF patients with severe FEV1. Given the devastating disease progression with MDR organisms in CF, new antibiotics with better clinical outcomes against chronic MDR-PA should be considered earlier in therapy for this population. Larger studies are warranted to analyze cost-effectiveness and clinical outcomes. Disclosures Kevin W. Garey, PharMD, MS, FASHP, Merck & Co. (Grant/Research Support, Scientific Research Study Investigator)

Subcutaneous daratumumab (DARA SC) plus lenalidomide versus lenalidomide alone as maintenance therapy in patients (pts) with newly diagnosed multiple myeloma (NDMM) who are minimal residual disease (MRD) positive after frontline autologous stem cell transplant (ASCT): The phase 3 AURIGA study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS8054-TPS8054
Author(s):  
Nina Shah ◽  
Sharmila Patel ◽  
Huiling Pei ◽  
Ming Qi ◽  
Maria Krevvata ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Primary Endpoint ◽  
Conversion Rate ◽  
Residual Disease ◽  
The United States ◽  
Study Endpoint ◽  
Primary Study ◽  
Cell Transplant ◽  
Open Label ◽  
Phase 3

TPS8054 Background: DARA, a human anti-CD38 IgGκ monoclonal antibody, is approved in many countries as monotherapy in relapsed/refractory MM (RRMM) and in combination with standard of care (SoC) in RRMM and NDMM. However, no clinical studies have yet compared DARA maintenance versus SoC maintenance. The ongoing phase 3 AURIGA study will evaluate the addition of DARA to lenalidomide maintenance among pts with NDMM who are MRD positive after SoC induction and ASCT. The primary endpoint is the conversion rate to MRD negativity after 1 year of maintenance therapy. Methods: This open-label, multicenter, randomized phase 3 study will enroll approximately 214 pts in the United States aged 18-79 years with NDMM who receive ≥4 cycles of induction followed by ASCT. Pts must enroll within 6 months of ASCT, be naïve for anti-CD38 treatment, have a very good partial response or better per IMWG criteria, and be MRD positive at a threshold of 10–5 by next generation sequencing (NGS) within 30 days of screening. Pts will be stratified by cytogenetic risk (high vs standard/unknown) and randomized 1:1 to 28-day cycles of lenalidomide maintenance (10 mg PO; D1-28 [dose increasing to 15 mg if tolerated]) ± DARA SC (DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE® drug delivery technology, Halozyme, Inc., San Diego, CA, USA; QW Cycle 1-2, Q2W Cycles 3-6, Q4W C7+). Treatment will continue for up to 36 cycles or until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint is MRD conversion rate after 12 months of maintenance treatment, defined as the proportion of pts who achieve MRD negativity (10–5) by NGS. Additional MRD assessments occur after 18, 24, and 36 months of maintenance. While MRD negativity is associated with improved long-term outcomes for pts with MM and is an emerging, validated prognostic factor, this study is among the first to use MRD negativity as a primary study endpoint. Importantly, MRD negativity allows for earlier efficacy assessment than traditional endpoints such as progression-free survival (PFS) and overall survival (OS). Secondary endpoints include overall MRD conversion rate at any time, sustained MRD negativity lasting ≥12 months, PFS, OS, response rates, duration of complete response, changes in health-related quality of life, and safety. Due to the COVID-19 pandemic, this study has been amended to improve enrollment access by allowing up to 12 months from start of induction therapy to ASCT to mitigate against ASCT delays and to allow greater flexibility for screening and laboratory assessments. Clinical trial information: NCT03901963.

Persistency of Pseudomonas aeruginosa in sputum cultures and clinical outcomes in adult patients with cystic fibrosis

2011 ◽  
Vol 31 (7) ◽  
pp. 1603-1610 ◽  
Author(s):  
A. Burkett ◽  
K. L. Vandemheen ◽  
T. Giesbrecht-Lewis ◽  
K. Ramotar ◽  
W. Ferris ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Clinical Outcomes ◽  
Adult Patients

scholarly journals Effect of pulmonary exacerbations treated with oral antibiotics on clinical outcomes in cystic fibrosis

Thorax ◽  
2016 ◽  
Vol 72 (4) ◽  
pp. 327-332 ◽  
Author(s):  
Sanja Stanojevic ◽  
Alexandra McDonald ◽  
Valerie Waters ◽  
Sarah MacDonald ◽  
Eric Horton ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Outcomes ◽  
Oral Antibiotics ◽  
Pulmonary Exacerbations

Updated results of European Organization for Research and Treatment of Cancer (EORTC) phase 2 trial 1202 cabazitaxel in patients with metastatic or inoperable locally advanced dedifferentiated liposarcoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11518-11518
Author(s):  
Roberta Sanfilippo ◽  
Richard L Hayward ◽  
Jammbe Musoro ◽  
Charlotte Benson ◽  
Michael Gordon Leahy ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase Iii ◽  
Dedifferentiated Liposarcoma ◽  
Study Endpoint ◽  
Primary Study ◽  
Primary Analysis ◽  
European Organization ◽  
Experimental Drugs

11518 Background: Treatment options for patients with unresectable and/or metastatic dedifferentiated liposarcoma (DDLPS) are limited. The most effective agents include doxorubicin, ifosfamide, trabectedin and eribulin, but, in general, objective response rates (ORR) and progression free survival (PFS) are modest. Cabazitaxel exerts its effect through inhibition of microtubular disassembly and has been shown to be relatively safe, effective and well-tolerated. EORTC 1202 assessed whether cabazitaxel demonstrated sufficient antitumor activity in patients with metastatic or inoperable locally advanced DD LPS to justify further investigation in a phase III setting. Methods: This was an international multi-center, open label single arm phase II trial. The clinical cut-off date for the primary analysis was performed on August 31, 2020. Data base lock was performed on February 2, 2021. Eligible patients with metastatic or inoperable locally advanced DD LPS, after a centralized pathological review, were treated with cabazitaxel 25mg/m² IV infusion over 1 hour every 21 days. Primary endpoint was PFS rate at 12 weeks assessed by local investigator per RECIST 1.1. Based on a Simon two-stage design, at least 4 out of 17 (Stage 1) and 11 out of 37 (Stage 2) eligible and evaluable patients who are progression-free at 12 weeks were needed. Currently, a centralized radiological assessment is ongoing. Results: Forty patients were registered by 10 institutions in 4 countries between March 2015 and March 2019, with 2 patients being ineligible. One patient was still on treatment at the clinical cut-off date. The number of cycles ranged from 1 to 30, with a median of 5; 26 patients (65%) received at least 4 cycles of cabazitaxel. PFS at 12 weeks was 55% (conditional 1-sided 95% CI 40.8-100), achieving the primary study endpoint. The median FU was 21.6 months, median PFS was 6 months and median OS 21 months. RR was 8% with one CR and two PR. Twenty-three(60.5%) pts had a SD. Disease control (PR+SD) was achieved in 26 patients (68%). The most common cabazitaxel -related grade >3 adverse events in all 40 registered patients were Neutrophil count decreased (50%), febrile neutropenia (25%), fatigue (12.5%), and anemia (10%). There were no cabazitaxel-related deaths. Conclusions: EORTC 1202 met its primary endpoint, with 21/38 pts (55%) being progression-free at 12 weeks. Results of this trial confirm activity of cabazitaxel in patients with metastatic or inoperable locally advanced DD LPS and looks interesting if compared to the other available options and experimental drugs recently reported in this patient population. Clinical trial information: NCT01913652.

scholarly journals Publisher Correction: Early detection of pulmonary exacerbations in children with Cystic Fibrosis by electronic home monitoring of symptoms and lung function

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Marieke van Horck ◽  
Bjorn Winkens ◽  
Geertjan Wesseling ◽  
Dillys van Vliet ◽  
Kim van de Kant ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Early Detection ◽  
Home Monitoring ◽  
Pulmonary Exacerbations

scholarly journals Prevalence and impact of oprD mutations in Pseudomonas aeruginosa strains in cystic fibrosis

2019 ◽  
Author(s):  
Laura J. Sherrard ◽  
Bryan A. Wee ◽  
Christine Duplancic ◽  
Kay A. Ramsay ◽  
Keyur A. Dave ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Lung Function ◽  
Hazard Rate ◽  
Carbapenem Resistance ◽  
Adverse Outcomes ◽  
Nonsense Mutations ◽  
Allelic Variants ◽  
Novel Variants

ABSTRACTDefective OprD porins contribute to carbapenem resistance and may be important in Pseudomonas aeruginosa adaptation to cystic fibrosis airways. It is unclear whether oprD mutations are fixed in populations of shared strains that are transmitted between patients or whether novel variants arise during infection. We investigated oprD sequences and antimicrobial resistance of two common Australian shared strains, constructed P. aeruginosa mutants with the most common oprD allelic variants and compared characteristics between patients with or without evidence of infection with strains harbouring these variants. Our data show that three independently acquired nonsense mutations arising from a 1-base pair substitution are fixed in strain sub-lineages. These nonsense mutations are likely to contribute to reduced carbapenem susceptibility in the sub-lineages without compromising in vitro fitness. Not only was lung function worse among patients infected with strains harbouring the nonsense mutations than those without, but they also had an increased hazard rate of lung transplantation/death. Our findings further highlight that understanding adaptive changes may help to distinguish patients with greater adverse outcomes despite infection with the same strain.

scholarly journals Most of Staphylococcus aureus and Pseudomonas aeruginosa co-infecting isolates coexist, a condition that may impact clinical outcomes in Cystic Fibrosis patients

2020 ◽  
Author(s):  
Paul Briaud ◽  
Sylvère Bastien ◽  
Laura Camus ◽  
Marie Boyadjian ◽  
Philippe Reix ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Multivariate Analysis ◽  
Natural History ◽  
Clinical Outcomes ◽  
Bacterial Colonization ◽  
Childhood And Adolescence ◽  
History Of

AbstractStaphylococcus aureus (SA) is the major colonizer of the lung of cystic fibrosis (CF) patient during childhood and adolescence. As patient aged, the prevalence of SA decreases and Pseudomonas aeruginosa (PA) becomes the major pathogen infecting adult lungs. Nonetheless, SA remains significant and patients harbouring both SA and PA are frequently found in worldwide cohort. Impact of coinfection remains controversial. Furthermore, co-infecting isolates may compete or coexist. The aim of this study was to analyse if co-infection and coexistence of SA and PA could lead to worse clinical outcomes. The clinical and bacteriological data of 212 Lyon CF patients were collected retrospectively, and patients were ranked into three groups, SA only (n=112), PA only (n=48) or SA plus PA (n=52). In addition, SA and PA isolates from co-infecting patients were tested in vitro to define their interaction profile. Sixty five percent (n=34) of SA/PA pairs coexist. Using univariate and multivariate analysis, we confirm that SA patients have a clinical condition less severe than others, and PA induce a poor outcome independently of the presence of SA. FEV1 is lower in patients infected by competition strain pairs than in those infected by coexisting strain pairs compared to SA mono-infection. Coexistence between SA and PA may be an important step in the natural history of lung bacterial colonization within CF patients.

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