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3. 2832. Gepotidacin Efficacy in E. coli Drug-Resistant Phenotypes: A Pooled Analysis of the EAGLE-2 and EAGLE-3 Randomized Controlled Trials in Uncomplicated Urinary Tract Infection

Author

Hooton, Thomas M, primary, Perry, Caroline R, additional, Janmohamed, Salim, additional, Sheets, Amanda, additional, Dennison, Jeremy, additional, Millns, Helen, additional, Jarvis, Emily, additional, Scangarella-Oman, Nicole E, additional, and Huang, Chun, additional

Published
2023
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5. 2837. Impact of Regulatory Guidelines on Therapeutic, Clinical, and Microbiological Success Rates in Uncomplicated Urinary Tract Infection: Results from a Two Phase 3 Randomized Controlled Trials of Oral Gepotidacin (EAGLE-2 and EAGLE-3)

Author

Wagenlehner, Florian, primary, Perry, Caroline R, additional, Hooton, Thomas M, additional, Scangarella-Oman, Nicole E, additional, Millns, Helen, additional, Jarvis, Emily, additional, Dennison, Jeremy, additional, Sheets, Amanda, additional, and Janmohamed, Salim, additional

Published
2023
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6. P31 Efficacy and safety of oral gepotidacin in the treatment of uncomplicated urinary tract infection: results of two randomized, multicentre Phase 3 trials (EAGLE-2 and EAGLE-3)

Author

Wagenlehner, Florian, primary, Perry, Caroline R, additional, Hooton, Thomas M, additional, Scangarella-Oman, Nicole E, additional, Millns, Helen, additional, (Ed) Feng, Hwa-ping, additional, Powell, Marcy, additional, Jarvis, Emily, additional, Dennison, Jeremy, additional, Sheets, Amanda, additional, Butler, Deborah, additional, Breton, John, additional, and Janmohamed, Salim, additional

Published
2023
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7. SOLITAIRE-IV: A Randomized, Double-Blind, Multicenter Study Comparing the Efficacy and Safety of Intravenous-to-Oral Solithromycin to Intravenous-to-Oral Moxifloxacin for Treatment of Community-Acquired Bacterial Pneumonia

Author

SOLITAIRE-IV Pneumonia Team, File, Thomas M., Rewerska, Barbara, Vucinić-Mihailović, Violeta, Gonong, Joven Roque V., Das, Anita F., Keedy, Kara, Taylor, David, Sheets, Amanda, Fernandes, Prabhavathi, Oldach, David, and Jamieson, Brian D.

Published
2016
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8. Identification of a novel trimeric autotransporter adhesin in the cryptic genospecies of Haemophilus

Author

Sheets, Amanda J., Grass, Susan A., Miller, Sara E., and St. Geme, Joseph W., III

Subjects
Hemophilus influenzae -- Physiological aspects, Hemophilus influenzae -- Research, Cell adhesion molecules -- Research, Cell adhesion molecules -- Physiological aspects, Biological sciences
Abstract

Haemophilus biotype IV strains belonging to the recently recognized Haemophilus cryptic genospecies are an important cause of maternal genital tract and neonatal systemic infections and initiate infection by colonizing the genital or respiratory epithelium. To gain insight into the mechanism of Haemophilus cryptic genospecies colonization, we began by examining prototype strain 1595 and three other strains for adherence to genital and respiratory epithelial cell lines. Strain 1595 and two of the three other strains demonstrated efficient adherence to all of the cell lines tested. With a stably adherent variant of strain 1595, we generated a Mariner transposon library and identified 16 nonadherent mutants. All of these mutants lacked surface fibers and contained an insertion in the same open reading frame, which encodes a 157-kDa protein designated Cha for cryptic haemophilus adhesin. Analysis of the predicted amino acid sequence of Cha revealed the presence of an N-terminal signal peptide and a C-terminal domain bearing homology to YadA-like and Hia-like trimeric autotransporters. Examination of the C-terminal 120 amino acids of Cha demonstrated mobility as a trimer on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the capacity to present the passenger domain of the Hia trimeric autotransporter on the bacterial surface. Southern analysis revealed that the gene that encodes Cha is conserved among clinical isolates of the Haemophilus cryptic genospecies and is absent from the closely related species Haemophilus influenzae. We speculate that Cha is important in the pathogenesis of disease due to the Haemophilus cryptic genospecies and is in part responsible for the apparent tissue tropism of this organism.

Published
2008

13. SOLITAIRE-IV: A Randomized, Double-Blind, Multicenter Study Comparing the Efficacy and Safety of Intravenous-to-Oral Solithromycin to Intravenous-to-Oral Moxifloxacin for Treatment of Community-Acquired Bacterial Pneumonia

Author

File, Thomas M., primary, Rewerska, Barbara, additional, Vucinić-Mihailović, Violeta, additional, Gonong, Joven Roque V., additional, Das, Anita F., additional, Keedy, Kara, additional, Taylor, David, additional, Sheets, Amanda, additional, Fernandes, Prabhavathi, additional, Oldach, David, additional, and Jamieson, Brian D., additional

Published
2016
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14. Efficacy and safety of oral solithromycin versus oral moxifloxacin for treatment of community-acquired bacterial pneumonia: a global, double-blind, multicentre, randomised, active-controlled, non-inferiority trial (SOLITAIRE-ORAL)

Author

Barrera, Carlos M, primary, Mykietiuk, Analia, additional, Metev, Hristo, additional, Nitu, Mimi Floarea, additional, Karimjee, Najumuddin, additional, Doreski, Pablo Alexis, additional, Mitha, Ismail, additional, Tanaseanu, Cristina Mihaela, additional, Molina, Joseph McDermott, additional, Antonovsky, Yuri, additional, Van Rensburg, Dirkie Johanna, additional, Rowe, Brian H, additional, Flores-Figueroa, Jose, additional, Rewerska, Barbara, additional, Clark, Kay, additional, Keedy, Kara, additional, Sheets, Amanda, additional, Scott, Drusilla, additional, Horwith, Gary, additional, Das, Anita F, additional, Jamieson, Brian, additional, Fernandes, Prabhavathi, additional, and Oldach, David, additional

Published
2016
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15. Results from a Phase 3 trial in Moderate to Moderately Severe Community Acquired Bacterial Pneumonia (CABP) Treated As Outpatients With a New Oral Macrolide, Solithromycin

Author

Oldach, David, primary, Barrera, Carlos, additional, Rowe, Brian, additional, Nitu, Floarea Mimi, additional, Mykietiuk, Analia, additional, Metev, Hristo, additional, Laabs, Jessica, additional, Mitha, Ismail, additional, Tanaseanu, Cristina Mihaela, additional, McDermott Molina, Joseph, additional, Antonovsky, Yuri, additional, Van Rensburg, Dirkie Johanna, additional, Flores, Jose, additional, Sokolowska, Barbara, additional, Doreski, Alexis, additional, Das, Anita, additional, Clark, Kay, additional, Jamieson, Brian, additional, Sheets, Amanda, additional, Keedy, Kara, additional, and Fernandes, Prabhavathi, additional

Published
2015
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17. Characterization of Mycoplasma pneumoniae Infection and Outcomes in the SOLITAIRE-Oral, Global Phase 3 Clinical Trial for Solithromycin

Author

Oldach, David, primary, Metev, Hristo, additional, Mykietiuk, Analia, additional, Tanaseanu, Cristina Mihaela, additional, Das, Anita, additional, Jamieson, Brian, additional, Clark, Kay, additional, Sheets, Amanda, additional, Keedy, Kara, additional, Crabb, Donna, additional, Ratliff, Amy, additional, Waites, Ken, additional, and Fernandes, Prabhavathi, additional

Published
2015
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22. Development of an Optical Tweezers Methodology to Separate Single Cells and Single Mitochondria to Determine the Location of Heteroplasmy in Mitochondrial DNA

Author

Deckman, Koren Holland, primary, Kishore, Rani, additional, Albanetti, Thomas, additional, Peery, Sarah, additional, Knipe, Ashley, additional, Sheets, Amanda, additional, Boire, Nicholas, additional, Reiner, Joseph E, additional, Helmerson, Kristian, additional, and Levin, Barbara C, additional

Published
2006
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23. Contribution of BordetellaFilamentous Hemagglutinin and Adenylate Cyclase Toxin to Suppression and Evasion of Interleukin-17-Mediated Inflammation

Author

Henderson, Michael W., Inatsuka, Carol S., Sheets, Amanda J., Williams, Corinne L., Benaron, David J., Donato, Gina M., Gray, Mary C., Hewlett, Erik L., and Cotter, Peggy A.

Abstract

ABSTRACTBordetella pertussisand Bordetella bronchisepticaestablish respiratory infections with notorious efficiency. Our previous studies showed that the fhaBgenes of B. pertussisand B. bronchiseptica, which encode filamentous hemagglutinin (FHA), are functionally interchangeable and provided evidence that FHA-deficient B. bronchisepticainduces more inflammation in the lungs of mice than wild-type B. bronchiseptica. We show here that the robust inflammatory response to FHA-deficient B. bronchisepticais characterized by the early and sustained influx of interleukin-17 (IL-17)-positive neutrophils and macrophages and, at 72 h postinoculation, IL-17-positive CD4+T cells, suggesting that FHA allows the bacteria to suppress the development of an IL-17-mediated inflammatory response. We also show that the cyaAgenes of B. pertussisand B. bronchiseptica, which encode adenylate cyclase toxin (ACT), are functionally interchangeable and that ACT, specifically its catalytic activity, is required for B. bronchisepticato resist phagocytic clearance but is neither required for nor inhibitory of the induction of inflammation if bacteria are present in numbers sufficient to persist during the first 3 days postinoculation. Incubation of bone marrow-derived macrophages with a ?cyaAstrain caused decreased production of IL-1ß and increased production of tumor necrosis factor alpha (TNF-a) and IL-12, while incubation with a ?cyaA?fhaBstrain caused increased production of IL-23. These data suggest that FHA and ACT both contribute to suppress the recruitment of neutrophils and the development of an IL-17-mediated immune response. To our knowledge, this is the first demonstration of a microbial pathogen suppressing IL-17-mediated inflammation in vivoas a strategy to evade innate immunity.

Published
2012
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24. Cooperative Roles for Fimbria and Filamentous Hemagglutinin in Bordetella Adherence and Immune Modulation

Author

Cotter, Peggy A., Scheller, Erich V., Melvin, Jeffrey A., and Sheets, Amanda J.

Subjects
respiratory system, human activities, respiratory tract diseases, 3. Good health
Abstract

Bordetella fimbriae (FIM) are generally considered to function as adhesins despite a lack of experimental evidence supporting this conclusion for Bordetella pertussis and evidence against a requirement for FIM in adherence of Bordetella bronchiseptica to mammalian cell lines. Using B.bronchiseptica and mice, we developed an in vivo adherence assay that revealed that FIM do function as critically important adhesins in the lower respiratory tract. In the first few days postinoculation, FIM-deficient B.bronchiseptica induced a more robust inflammatory response than wild-type bacteria did, suggesting that FIM, like filamentous hemagglutinin (FHA), allow B.bronchiseptica to suppress the innate immune response to infection. Localization analyses indicated that FIM are required for efficient attachment to airway epithelium, as bacteria lacking FIM localized to alveoli. FHA-deficient bacteria, in contrast, localized to airways. Bacteria unable to produce both FIM and FHA localized to alveoli and caused increased inflammation and histopathology identical to that caused by FIM-deficient bacteria, demonstrating that lack of FIM is epistatic to lack of FHA. Coinoculation experiments provided evidence that wild-type B.bronchiseptica suppresses inflammation locally within the respiratory tract and that both FHA and FIM are required for defense against clearance by the innate immune system. Altogether, our data suggest that FIM-mediated adherence to airway epithelium is a critical first step in Bordetella infection that allows FHA-dependent interactions to mediate tight adherence, suppression of inflammation, and resistance to inflammatory cell-mediated clearance. Our results suggest that mucosal antibodies capable of blocking FIM-mediated interactions could prevent bacterial colonization of the lower respiratory tract.IMPORTANCEAlthough fimbriae (FIM) have been shown to be important mediators of adherence for many bacterial pathogens, there is surprisingly little experimental evidence supporting this role for Bordetella fimbria. Our results provide the first demonstration that Bordetella FIM function as adhesins in vivo, specifically to airway epithelium. Furthermore, our results suggest that FIM mediate initial interactions with airway epithelial cells that are followed by tight filamentous hemagglutinin (FHA)-mediated binding and that together, FIM and FHA allow Bordetella to suppress inflammation, leading to prolonged colonization. Given the shortcoming of the current acellular component pertussis (aP) vaccine in preventing colonization, these findings suggest that generation of antibodies capable of blocking FIM-mediated adherence could potentially prevent Bordetella colonization.

25. Cooperative Roles for Fimbria and Filamentous Hemagglutinin in BordetellaAdherence and Immune Modulation

Author

Scheller, Erich V., Melvin, Jeffrey A., Sheets, Amanda J., and Cotter, Peggy A.

Abstract

ABSTRACTBordetellafimbriae (FIM) are generally considered to function as adhesins despite a lack of experimental evidence supporting this conclusion for Bordetella pertussisand evidence against a requirement for FIM in adherence of Bordetella bronchisepticato mammalian cell lines. Using B. bronchisepticaand mice, we developed an in vivoadherence assay that revealed that FIM do function as critically important adhesins in the lower respiratory tract. In the first few days postinoculation, FIM-deficient B. bronchisepticainduced a more robust inflammatory response than wild-type bacteria did, suggesting that FIM, like filamentous hemagglutinin (FHA), allow B. bronchisepticato suppress the innate immune response to infection. Localization analyses indicated that FIM are required for efficient attachment to airway epithelium, as bacteria lacking FIM localized to alveoli. FHA-deficient bacteria, in contrast, localized to airways. Bacteria unable to produce both FIM and FHA localized to alveoli and caused increased inflammation and histopathology identical to that caused by FIM-deficient bacteria, demonstrating that lack of FIM is epistatic to lack of FHA. Coinoculation experiments provided evidence that wild-type B. bronchisepticasuppresses inflammation locally within the respiratory tract and that both FHA and FIM are required for defense against clearance by the innate immune system. Altogether, our data suggest that FIM-mediated adherence to airway epithelium is a critical first step in Bordetellainfection that allows FHA-dependent interactions to mediate tight adherence, suppression of inflammation, and resistance to inflammatory cell-mediated clearance. Our results suggest that mucosal antibodies capable of blocking FIM-mediated interactions could prevent bacterial colonization of the lower respiratory tract.IMPORTANCEAlthough fimbriae (FIM) have been shown to be important mediators of adherence for many bacterial pathogens, there is surprisingly little experimental evidence supporting this role for Bordetellafimbria. Our results provide the first demonstration that BordetellaFIM function as adhesins in vivo, specifically to airway epithelium. Furthermore, our results suggest that FIM mediate initial interactions with airway epithelial cells that are followed by tight filamentous hemagglutinin (FHA)-mediated binding and that together, FIM and FHA allow Bordetellato suppress inflammation, leading to prolonged colonization. Given the shortcoming of the current acellular component pertussis (aP) vaccine in preventing colonization, these findings suggest that generation of antibodies capable of blocking FIM-mediated adherence could potentially prevent Bordetellacolonization.

Published
2015
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