scholarly journals Expanded access use of rezafungin for salvage therapy of invasive Candida glabrata infection: A case report

2021 ◽  
Author(s):  
Alina Adeel ◽  
Ming D Qu ◽  
Efaza Siddiqui ◽  
Stuart M Levitz ◽  
Richard T Ellison
Keyword(s):  
Candida Glabrata ◽  
Graft Infection ◽  
Multidrug Resistant ◽  
Phase Iii ◽  
Vascular Graft Infection ◽  
Expanded Access ◽  
Mediastinal Infection ◽  
Phase Iii Trials ◽  
One Year ◽  
Long Acting

Abstract Rezafungin is a semi-synthetic, long acting echinocandin with broad spectrum activity against many Candida species (spp)., and Aspergillus spp., including subset of drug-resistant strains. It is currently in phase III trials and was found to be safe and effective for treatment of candidemia and/or invasive Candida infections in a phase II trial. However, there are no long-term safety or efficacy data. We report on the successful ongoing compassionate use of rezafungin obtained through expanded access for over one year in a patient with a multidrug-resistant Candida glabrata mediastinal infection from a vascular graft infection and retained foreign material.

scholarly journals The Potential Impact of Long-Acting Cabotegravir for HIV Prevention in South Africa: A Mathematical Modeling Study

2020 ◽  
Author(s):  
Jennifer A Smith ◽  
Geoffrey P Garnett ◽  
Timothy B Hallett
Keyword(s):  
South Africa ◽  
Hiv Risk ◽  
Adult Population ◽  
Phase Iii ◽  
Substantial Impact ◽  
Hiv Epidemic ◽  
Phase Iii Trials ◽  
Long Acting ◽  
Exposure Prophylaxis ◽  
The Impact

Abstract Background Although effective, some oral pre-exposure prophylaxis (PrEP) users face barriers to adherence using daily pills, which could be reduced by long-acting formulations. Long-acting cabotegravir (CAB LA) is a potential new injectable formulation for human immunodeficiency virus (HIV) PrEP being tested in phase III trials. Methods We use a mathematical model of the HIV epidemic in South Africa to simulate CAB LA uptake by population groups with different levels of HIV risk. We compare the trajectory of the HIV epidemic until 2050 with and without CAB LA to estimate the impact of the intervention. Results Delivering CAB LA to 10% of the adult population could avert more than 15% of new infections from 2023 to 2050. The impact would be lower but more efficient if delivered to populations at higher HIV risk: 127 person-years of CAB LA use would be required to avert one HIV infection within 5 years if used by all adults and 47 person-years if used only by the highest risk women. Conclusions If efficacious, a CAB LA intervention could have a substantial impact on the course of the HIV epidemic in South Africa. Uptake by those at the highest risk of infection, particularly young women, could improve the efficiency of any intervention.

scholarly journals In vitro activity of the new β-lactamase inhibitors relebactam and vaborbactam in combination with β-lactams against Mycobacterium abscessus complex clinical isolates

2018 ◽  
Author(s):  
Amit Kaushik ◽  
Nicole C. Ammerman ◽  
Jin Lee ◽  
Olumide Martins ◽  
Barry N Kreiswirth ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Mycobacterium Abscessus ◽  
Vitro Activity ◽  
Clinical Isolates ◽  
Phase Iii ◽  
In Vitro Activity ◽  
Intrinsic Resistance ◽  
Phase Iii Trials ◽  
Lactamase Inhibitor

Pulmonary disease due to infection with Mycobacterium abscessus complex (MABC) is notoriously difficult to treat, in large part due to MABC’s intrinsic resistance to most antibiotics, including β-lactams. MABC organisms express a broad-spectrum β-lactamase that is resistant to traditional β-lactam-based β-lactamase inhibitors but inhibited by a newer non-β-lactam-based β-lactamase inhibitor, avibactam. Consequently, the susceptibility of MABC to some β-lactams is increased in the presence of avibactam. Therefore, we hypothesized that two new non-β-lactam-based β-lactamase inhibitors, relebactam and vaborbactam, would also increase susceptibility of MABC to β-lactams. The objective of the present study was to evaluate the in vitro activity of various marketed β-lactams alone and in combination with either relebactam or vaborbactam against multidrug-resistant MABC clinical isolates. Our data demonstrate that both β-lactamase inhibitors significantly improved the anti-MABC activity of many carbapenems (including imipenem and meropenem) and cephalosporins (including cefepime, ceftaroline, and cefuroxime). As a meropenem/vaborbactam combination is now marketed and an imipenem/relebactam combination is currently in phase III trials, these fixed combinations may become the β-lactams of choice for the treatment of MABC infections. Furthermore, given the evolving interest in dual β-lactam regimens, our results identify select cephalosporins, such as cefuroxime, with superior activity in the presence of a β-lactamase inhibitor, deserving of further evaluation in combination with these carbapenem/β-lactamase inhibitor products.

Review of the Drug-infused Eye Implant—Ozurdex® (Dexamethasone Intravitreal Implant)

2011 ◽  
Vol 04 (02) ◽  
pp. 107 ◽  
Author(s):  
Careen Y Lowder ◽  
David A Hollander ◽  
◽  
Keyword(s):  
Cataract Extraction ◽  
Posterior Segment ◽  
Phase Iii ◽  
Repeated Treatment ◽  
Repeated Injection ◽  
Dexamethasone Intravitreal Implant ◽  
Inflammatory Conditions ◽  
Intravitreal Implant ◽  
Phase Iii Trials ◽  
One Year

Ozurdex® (dexamethasone intravitreal implant, Allergan, Inc., Irvine, CA) is an intravitreal implant designed to provide sustained, controlled release of dexamethasone to treat inflammatory conditions in the posterior segment of the eye. Ozurdex is approved by the US Food and Drug Administration for the treatment of macular edema (ME) following branch and central retinal vein occlusion (RVO) and for the treatment of non-infectious uveitis that involves the posterior segment. A single intravitreal injection of Ozurdex has been shown to improve visual acuity and reduce central retinal thickness in eyes with these conditions for up to six months. Increases in intraocular pressure are typically transient and controlled with topical medication. Repeated treatment with Ozurdex at a six-month interval has been shown to be safe and effective in patients with ME related to RVO. Although cataract progression has been noted upon repeated injection, cataract extraction has remained rare in clinical studies of up to one year in duration. Ozurdex has demonstrated efficacy in the treatment of diabetic ME (DME) and may be particularly valuable for treatment of ME in difficult-to-treat vitrectomized eyes. Ozurdex is currently under investigation in Phase III trials for the treatment of DME.

scholarly journals Current Prospects for the Fluoroquinolones as First-Line Tuberculosis Therapy

2011 ◽  
Vol 55 (12) ◽  
pp. 5421-5429 ◽  
Author(s):  
Howard Takiff ◽  
Elba Guerrero
Keyword(s):  
Multidrug Resistant ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
First Line ◽  
Current Standard ◽  
Standard Drug ◽  
First Line Therapy ◽  
Development Of Resistance ◽  
Mdr Tb ◽  
Phase Iii Trials

ABSTRACTWhile fluoroquinolones (FQs) have been successful in helping cure multidrug-resistant tuberculosis (MDR TB), studies in mice have suggested that if used as first-line agents they might reduce the duration of therapy required to cure drug-sensitive TB. The results of phase II trials with FQs as first-line agents have been mixed, but in at least three studies where moxifloxacin substituted for ethambutol, there was an increase in the early percentage of sputa that converted to negative for bacilli. Phase III trials are in progress to test the effectiveness of 4-month FQ-containing regimens, but there is concern that the widespread use of FQs for other infections could engender a high prevalence of FQ-resistant TB. However, several studies suggest that despite wide FQ use, the prevalence of FQ-resistant TB is low, and the majority of the resistance is low-level. The principal risk for resistance may be when FQs are used to treat nonspecific respiratory symptoms that are in fact TB, so curtailing this use of FQs could reduce the development of resistance and also the delays in TB diagnosis and treatment that have been documented when an FQ is given in this setting. While the future of FQs as first-line therapy will likely depend upon the results of the ongoing phase III trials, if they are to be effectively employed in high-TB-burden regions their use for community-acquired pneumonias should be restricted, the prevalence of FQ-resistant TB should be monitored, and the cost of the treatment should be comparable to that of current standard drug regimens.

scholarly journals Ranibizumab in Diabetic Macular Oedema – A Benefit–risk Analysis of Ranibizumab 0.5 mg PRN Versus Laser Treatment

2017 ◽  
Vol 13 (02) ◽  
pp. 91 ◽  
Author(s):  
Focke Ziemssen ◽  
Alan Cruess ◽  
Cornelia Dunger-Baldauf ◽  
Philippe Margaron ◽  
Howard Snow ◽  
...  
Keyword(s):  
Macular Oedema ◽  
Risk Measures ◽  
Diabetic Macular Oedema ◽  
Risk Profile ◽  
Phase Iii ◽  
Action Team ◽  
Venous Thromboembolic Events ◽  
Venous Thromboembolic ◽  
Phase Iii Trials ◽  
One Year

Introduction: The structured Benefit–risk Action Team (BRAT) approach aims to assist healthcare decision makers in treatment assessments. We applied BRAT to compare the benefit–risk profile of ranibizumab 0.5 mg versus laser photocoagulation for the treatment of diabetic macular oedema (DMO). Methods: One-year data for the ranibizumab 0.5 mg pro re nata (PRN) and laser arms of the phase III trials RESPOND (NCT01135914; n=220), RESTORE (NCT00687804; n=345), and REVEAL (NCT00989989; n=396) were included in the analysis. The benefit measures included ≥10 letters gain/avoidance of loss in best-corrected visual acuity (BCVA), achieving central retinal thickness (CRT) <275 μm, and 25-item Visual Function Questionnaire (VFQ-25) outcomes. The risks measures included endophthalmitis, intraocular pressure increase, hypertension, proteinuria, arterial/venous thromboembolic events and deaths. Results: Ranibizumab treatment provided significant benefits compared with laser for ≥10 letter BCVA gain at month 12 (387/1,000 versus 152/1,000 patients), CRT <275 μm at 12 months (474/1,000 versus 348/1,000 patients), and improvement of ≥6.06 on the VFQ-25 near activities subscale (325/1,000 versus 245/1,000 patients). Results for the risk measures were similar for both treatments. Conclusions: Superior clinically relevant outcomes were observed with ranibizumab 0.5 mg PRN compared with laser without compromising on safety. This analysis further supports the positive benefit–risk profile of ranibizumab 0.5 mg PRN.

scholarly journals P504 Effectiveness and safety of ustekinumab maintenance therapy in 103 patients with real-world ulcerative colitis: A GETAID multicentre cohort study

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S486-S487
Author(s):  
M Fumery ◽  
J Filippi ◽  
V Abitbol ◽  
A Biron ◽  
D Laharie ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Cohort Study ◽  
Adverse Events ◽  
Real World ◽  
Clinical Remission ◽  
Real Life ◽  
Phase Iii ◽  
Phase Iii Trials ◽  
One Year

Abstract Background Phase III trials have demonstrated the efficacy and safety of ustekinumab in moderate-to-severe ulcerative colitis (UC), but no real-life long-term data is currently available. Methods From January to September 2019, all consecutive patients with active UC treated with ustekinumab in a GETAID centre were included. Patients were evaluated at week 52. Remission was defined by a partial Mayo Clinic score ≤ 2. The aim of the present study was to assess long-term effectiveness and safety of ustekinumab in UC. Results 103 UC patients (62 men; mean age: 41.2 ± 16.2 years; 52% pancolitis E3) were included in 21 centres. History of immunomodulator, anti-TNF and vedolizumab therapies was noted in 84.5%, 99.0% and 85.4% of the cases, respectively. At week 54, 44 (43%) patients discontinued ustekinumab, for lack of efficacy (n=41), pregnancy (n=1), persistence of eczematiform lesions (n=1) or personal decision (n=1). Cumulative probabilities of ustekinumab persistence were 96.1%, 81.6%, 71.7%, and 58.4% after 3, 6, 9, and 12 months, respectively. In multivariate analysis, a CRP&gt;5 mg/L at week 0 (OR=2.91, CI95%[1.15–7.36]; p=0.02) and concomitant steroids at week 0 (OR=3.05, CI95%[1.30–7.14]; p=0.01) were significantly associated with ustekinumab discontinuation within one year. The overall rate of steroid-free clinical remission at week 52 was 32% of whom 71% had null rectal bleeding and stool frequency subscores. Ten patients (9.7%) underwent colectomy within a median of 6.7 [4.3–10.6] months. Adverse events were observed in 15 (16.9%) patients, of whom 4 (4.5%) had severe adverse events including three patients with exacerbation of UC leading to hospitalization, and a 62 years-old men who died from a myocardial infarction four months after ustekinumab initiation. Conclusion In this real-world cohort study that included patients with refractory ulcerative colitis to multiple therapies, more than one-half of patients were still treated by ustekinumab and one-third were in steroid-free clinical remission, after 52 weeks.

Short and long-term survival in metastatic pancreatic adenocarcinoma, 1993-2013.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 232-232 ◽  
Author(s):  
Talia Golan ◽  
Tal Sela ◽  
Ofer Margalit ◽  
Uri Amit ◽  
Naama Halpern ◽  
...  
Keyword(s):  
Marital Status ◽  
Tumor Location ◽  
Population Based ◽  
Phase Iii ◽  
Term Survival ◽  
Modest Improvement ◽  
Kaplan Meier ◽  
Phase Iii Trials ◽  
Study Population ◽  
One Year

232 Background: Over the previous two decades several new agents have been approved for the treatment of metastatic pancreatic cancer (mPDAC). Their efficacy was demonstrated amongst highly selected patients that participate in randomized phase III trials, hence it is not clear to what extent these advances are reflected within the broader mPDAC population. We performed a population-based survival analysis of newly diagnosed patients who presented with mPDAC. Methods: Survival statistics were extracted from the Survival, Epidemiology and End Results (SEER) Database for patients diagnosed with mPDAC between 1993-2013. Demographic variables collected included age, gender, race, and marital status. Tumor characteristics collected included location and grade. Survival was analyzed using the Kaplan-Meier method and proportional hazard models as appropriate. Exclusion criteria included diagnosis at autopsy, unknown histology and pancreatic neuroendocrine tumors. Results: The study population consisted of 57,263 patients diagnosed with mPDAC from 1993-2013, 52% male, median age 69 years (range 15-104). Prognosis correlated with age, gender, race, marital status, tumor location, grade and year of diagnosis. Median overall survival (OS) stayed stable at 2 months between 1993 and 2013. Improvements in OS were seen for all patients, but especially for younger patients ( < 50 years of age) and more recent year of diagnosis group (2009-2013). The percentage of patients who died within two months of initial diagnosis decreased between 1993 and 2013 (from 63.5% to 50.6%, p < 0.0001). The subgroup of patients achieving longer-term survival has increased, with 12-month survival improving from 4.9 % to 12.7% (p < 0.0001) between 1993 and 2013. Conclusions: There has been a continuous but modest improvement in OS of patients diagnosed with mPDAC between 1993 and 2013. The percentage of patients living beyond one year has significantly increased over time; however the percentage of patients dying within 2 months has only slightly decreased.

scholarly journals FIM-1, a New Acquired Metallo-β-Lactamase from a Pseudomonas aeruginosa Clinical Isolate from Italy

2012 ◽  
Vol 57 (1) ◽  
pp. 410-416 ◽  
Author(s):  
Simona Pollini ◽  
Simona Maradei ◽  
Patrizia Pecile ◽  
Giuseppe Olivo ◽  
Francesco Luzzaro ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Isolate ◽  
Graft Infection ◽  
Clinical Importance ◽  
Multidrug Resistant ◽  
Amino Acid Identity ◽  
Vascular Graft Infection ◽  
Methoxy Derivative ◽  
Content Type ◽  
E Coli

ABSTRACTAcquired metallo-β-lactamases (MBLs) are resistance determinants of increasing clinical importance in Gram-negative bacterial pathogens, which confer a broad-spectrum β-lactam resistance, including carbapenems. Several such enzymes have been described since the 1990s. In the present study, a novel acquired MBL, named FIM-1, was identified and characterized. TheblaFIM-1gene was cloned from a multidrug-resistantPseudomonas aeruginosaclinical isolate (FI-14/157) cultured from a patient with a vascular graft infection in Florence, Italy. The isolate belonged in the sequence type 235 epidemic clonal lineage. The FIM-1 enzyme is a member of subclass B1 and, among acquired MBLs, exhibited the highest similarity (ca. 40% amino acid identity) with NDM-type enzymes. InP. aeruginosaFI-14/157, theblaFIM-1gene was apparently inserted into the chromosome and associated with ISCR19-like elements that were likely involved in the capture and mobilization of this MBL gene. Transfer experiments of theblaFIM-1gene to anEscherichia colistrain or anotherP. aeruginosastrain by conjugation or electrotransformation were not successful. The FIM-1 protein was produced inE. coliand purified by two chromatography steps. Analysis of the kinetic parameters, carried out with the purified enzyme, revealed that FIM-1 has a broad substrate specificity, with a preference for penicillins (except the 6α-methoxy derivative temocillin) and carbapenems. Aztreonam was not hydrolyzed. Detection of this novel type of acquired MBL in aP. aeruginosaclinical isolate underscores the increasing diversity of such enzymes that can be encountered in the clinical setting.

Long-Acting HIV Drugs for Treatment and Prevention

2019 ◽  
Vol 70 (1) ◽  
pp. 137-150 ◽  
Author(s):  
Roy M. Gulick ◽  
Charles Flexner
Keyword(s):  
Drug Regimen ◽  
Antiretroviral Drugs ◽  
Hiv Treatment ◽  
Phase Iii ◽  
Treatment And Prevention ◽  
Drug Concentrations ◽  
Phase Iii Trials ◽  
Long Acting ◽  
Hiv Drugs ◽  
Exposure Prophylaxis

Antiretroviral drugs have revolutionized the treatment and prevention of HIV infection; however, adherence is critical for sustained efficacy. Current HIV treatment consists of three-drug regimens, and current HIV pre-exposure prophylaxis (PrEP) consists of a two-drug regimen; both generally require adherence to once-daily dosing. Long-acting formulations are useful in the treatment and prevention of other conditions (e.g., contraceptives, antipsychotics) and help promote adherence. Newer long-acting formulations of approved and investigational antiretroviral drugs in existing and newer mechanistic classes are under study for HIV treatment and prevention, including some phase III trials. Although long-acting antiretroviral drugs hold promise, some clinical challenges exist, including managing side effects, drug-drug interactions, pregnancy, and long-lasting drug concentrations that could lead to the development of drug resistance. This review aims to summarize currently available information on long-acting antiretroviral drugs for HIV treatment and prevention.

Carboplatin-based chemotherapy (C) versus immunotherapy (IO) in metastatic urothelial carcinoma (mUC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16003-e16003
Author(s):  
Emily Feld ◽  
Joanna Harton ◽  
Neal J. Meropol ◽  
Blythe J.S. Adamson ◽  
Ravi Bharat Parikh ◽  
...  
Keyword(s):  
Treatment Decision ◽  
Phase Iii ◽  
Treatment Decision Making ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
Safety Alert ◽  
Before And After ◽  
Phase Iii Trials ◽  
Inform Treatment Decision ◽  
One Year

e16003 Background: There are limited data comparing first-line (1L) C versus IO in cisplatin-ineligible mUC patients. The primary evidence guiding treatment decisions was a May 2018 Food and Drug Administration (FDA) safety alert based on early review of two ongoing phase III trials, reporting shorter survival in PD-L1 negative patients receiving IO relative to chemotherapy. Final results from these trials are unknown and may not be applicable to a real-world cohort. Methods: We conducted a retrospective cohort study of mUC patients receiving 1L C or IO from January 1, 2011 to May 18, 2018 using the Flatiron Health electronic health record-derived database. The primary outcome was overall survival (OS) from start of 1L treatment to date of death. We compared 12- and 36-month OS, and hazard ratios before and after 12 months. Propensity score-based inverse probability of treatment weighting (IPTW) was used to address confounding in Kaplan-Meier (KM) and Cox multivariable regression model estimates of comparative-effectiveness. Results: Of 2,243 patients, 562 received IO and 1,681 received C. Baseline characteristics were balanced between groups, with few exceptions (Table). In the first 12 months, IO was associated with an increased hazard of death compared to C (HR 1.38, 95% CI 1.16-1.66). Among patients who survived one year, survival was improved with IO compared to C (HR 0.50, 95% CI 0.27-0.92). Conclusions: In routine clinical practice, 1L IO was associated with inferior 12-month OS relative to C, but superior OS beyond 12 months. Clinicians and patients should carefully consider how to balance the early benefit of C against the late benefit of IO. Currently pending trial results will contribute additional evidence to inform treatment decision making. [Table: see text]

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