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Rapid Ultrasensitive Detection of Clostridiodes difficile Toxins in Stool Samples Using A Single-Molecule Counting Method
- Don Straus, Ann Zuniga, Alejandra Garces, Andrew Tempesta, Adam Williams, Bill Lauzier, Jennifer Hickey, Sadanand Gite, Selina Clancy, Yismel Rosario, Bruce Walsh, Jayson Bowers
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- Journal:
- Infection Control & Hospital Epidemiology / Volume 41 / Issue S1 / October 2020
- Published online by Cambridge University Press:
- 02 November 2020, pp. s450-s451
- Print publication:
- October 2020
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Background:Clostridiodes difficile infection is considered an urgent antibiotic resistance threat by the CDC, accounting for ∼225,000 hospitalizations, 12,800 deaths, and ∼$1 billion in healthcare costs in the United States in 2017. The presence of the secreted toxins that cause the devastating symptoms of this gastrointestinal infection are diagnostic of C. difficile infection (CDI). However, the rapid testing methods currently used to detect CDI lack accuracy. Enzyme immunoassays are specific but lack sensitivity because they do not detect CDI patients that have low levels of the toxins. Nucleic acid amplification tests (NAATs) are sensitive, but they lack specificity because they detect patients colonized with C. difficile in the dormant spore form that does not produce the toxins. This insufficiency has resulted in the adoption of complex multitest algorithms for C. difficile diagnosis. We present results for a new toxin test that demonstrates both high clinical sensitivity and clinical specificity for C. difficile toxin B on a fully automated benchtop platform. Methods: The detection technology uses nonmagnified digital imaging to count single toxin molecules that tether together target-specific magnetic and fluorescent particles. The 30-minute method includes the use of a dye cushion to eliminate wash steps and the need for time-consuming specimen preparation steps. We determined analytical performance characteristics of the test using negative clinical stool samples spiked with purified toxin. To assess clinical performance, we tested 785 stool samples from 5 clinical sites and compared the results with the cellular cytotoxicity neutralization assay (CCNA). Results: The test’s limit of detection for toxin B was 60 pg/mL. A comparison of the new test to the CCNA reference method gave 98% positive percentage agreement (83 of 85 samples) and 95% negative percentage agreement (667 of 700 samples). Conclusions: The new method demonstrated 96% accuracy compared to the gold standard for C. difficile toxin tests. The results also demonstrate an analytical sensitivity (limit of detection, 60 pg/mL). Thus, the test has the potential to detect CDI patients missed by enzyme immunoassay (EIA) tests due to their low analytical sensitivity. Because the test detects toxins directly, it is expected to have a lower false-positive rate than NAAT methods, which detect patients colonized with the non–toxin-producing spore form. A single accurate test for toxin-producing C. difficile could eliminate the need for multitest algorithms.
Funding: First Light Diagnostics, Inc., provided support for this study.
Disclosures: Donald Straus reports that he is the founder and chief scientific officer of First Light Diagnostics (FLDx) with salary and ownership interest in the form of stocks, stock options, and warrants. Adam Williams reports salary from First Light Diagnostics.
75 Formulation Properties of Long-acting Injectable Antipsychotics and the Impact on Administration: Focus on Aripiprazole Lauroxil
- Sarah Farwick, Magali Hickey, Jennifer Vandiver, Peter J Weiden
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, pp. 213-214
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Clinicians using long-acting injectable (LAI) antipsychotics may assume that there is uniformity in the injection technique for all LAIs. However, because LAIs have significant differences in their formulation, each requires a specific administration procedure. Here, we focus on how the formulation properties of the atypical LAI aripiprazole lauroxil impact its administration.
The history of LAI formulations is presented as a background to recent advances in formulation technology. A shared challenge for new LAIs is to adapt the formulation of insoluble drugs to aqueous-based suspensions.
The early LAIs kept the drug product dissolved as oil-based solutions, which were stable and did not require mixing prior to injection. However, oil-based solutions tend to be viscous and cause injection-site reactions (ISRs).
New LAI formulations tend to be aqueous-based suspensions and need to be resuspended or reconstituted before injection. Beyond this common element, formulation properties lead to differences in administration for each of the available LAIs.
We reviewed the formulations of LAIs indicated for the treatment of schizophrenia and how they impact instructions for use, with a focus on aripiprazole lauroxil.
Aripiprazole monohydrate and olanzapine pamoate are lyophilized powders that require reconstitution before administration and should be injected slowly. Risperidone is formulated as microspheres in powder form that require reconstitution before injection, although the injection speed is not specified. Paliperidone palmitate is a ready-to-use aqueous suspension of crystalline particles and should be injected slowly. Aripiprazole lauroxil is an aqueous-based, ready-to-use suspension of crystalline particles. Unlike other LAIs, the formulation of aripiprazole lauroxil contains particles that are loosely associated to facilitate resuspension. Because loosely associated suspensions are shear-thinning, meaning the viscosity of the formulation decreases with higher injection force, the injection must be given rapidly. Vigorous shaking and rapid injection are key aspects of administration and have been accepted by patients and investigators in clinical trials. In a pivotal phase 3 study of aripiprazole lauroxil, the incidence of ISRs was low (3.9% and 5.8% for aripiprazole lauroxil 441mg and 882mg , respectively) and mostly associated with the first injection.
Advances in formulation technology have increased LAI options for patients with schizophrenia. The aripiprazole lauroxil formulation differs from other LAIs in that the particles are loosely associated to support use as a ready-to-use pre-filled syringe. Because the suspension is shear-thinning, aripiprazole lauroxil requires rapid injection, which is not required when using other LAIs. An understanding of the differences in formulation design and how they impact the specific techniques associated with an LAI is essential for successful administration.
Funding Acknowledgements: This study was funded by Alkermes, Inc.
Contributors
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- By Linda S. Aglio, Cyrus Ahmadi Yazdi, Syed Irfan Qasim Ali, Caryn Barnet, Jessica Bauerle, Felicity Billings, Evan Blaney, Beverly Chang, Christopher Chen, Zinaida Chepurny, Hyung Sun Choi, Allison Clark, Lauren J. Cornella, Lisa Crossley, Michael D’Ambra, Galina Davidyuk, Whitney de Luna, Manisha S. Desai, Sukumar P. Desai, Kelly G. Elterman, Michaela K. Farber, Iuliu Fat, Jaida Fitzgerald, Devon Flaherty, John A. Fox, Gyorgy Frendl, Rejean Gareau, Joseph M. Garfield, Andrea Girnius, Laverne D. Gugino, J. Tasker Gundy, Carly C. Guthrie, Lisa M. Hammond, M. Tariq Hanifi, James Hardy, Philip M. Hartigan, Thomas Hickey, Richard Hsu, Mohab Ibrahim, David Janfaza, Yuka Kiyota, Suzanne Klainer, Benjamin Kloesel, Hanjo Ko, Bhavani Kodali, Vesela Kovacheva, J. Matthew Kynes, Robert W. Lekowski, Joyce Lo, Jeffrey Lu, Alvaro A. Macias, Zahra M. Malik, Erich N. Marks, Brendan McGinn, Jonathan R. Meserve, Annette Mizuguchi, Srdjan S. Nedeljkovic, Ju-Mei Ng, Michael Nguyen, Olutoyin Okanlawon, Jennifer Oliver, Krishna Parekh, Jessica Patterson, Christian Peccora, Pete Pelletier, Sujatha Pentakota, James H. Philip, Marc Philip T. Pimentel, Timothy D. Quinn, Elizabeth M. Rickerson, Susan L. Sager, Julia Serber, Shaheen Shaikh, Stanton Shernan, David Silver, Alissa Sodickson, Pingping Song, George P. Topulos, Agnieszka Trzcinka, Richard D. Urman, Rosemary Uzomba, Joshua Vacanti, Assia Valovska, Michael Vaninetti, Scott W. Vaughan, Kamen Vlassakov, Christopher Voscopoulos, Emily L. Wang, Laura Westfall, Zhiling Xiong, Stephanie Yacoubian, Dongdong Yao, Martin Zammert, Maksim Zayaruzny, Jose Luis Zeballos, Natthasorn Zinboonyahgoon, Jie Zhou
- Edited by Linda S. Aglio, Robert W. Lekowski, Richard D. Urman
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- Book:
- Essential Clinical Anesthesia Review
- Published online:
- 05 February 2015
- Print publication:
- 08 January 2015, pp xi-xvi
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