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1. Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial

Author

Scarborough, Matthew, Kamfose, Musa, de Veciana, Ana, Gordon, Nicola Claire, Peto, Leon, Pill, Gemma, Clarke, Tiphanie, Watson, Laura, Young, Bernadette, Griffiths, Dai, Vaughn, Ali, Anson, Luke, Liu, Elian, Perera, Sanuki, Rylance-Knight, Lydia, Cantell, Carmen, Moroney, Ruth, Edgeworth, Jonathan D, Thwaites, Guy, Bisnauthsing, Karen, Querol-Rubiera, Antonio, Gibbs, Charlotte, Patel, Amita, Hemsley, Carolyn, Goodman, Anna L, Wyncoll, Duncan, Biswas, Jason, Fitzpatrick, Jennifer, Roberts, Lizzie, Millard, James, Stone, Neil, Cape, Angela, Hurley, Lisa, Tam, Chi Kai, Nsutebu, Emmanuel, Hoyle, Marie-Claire, Maitland, Kate, Trainor, Leona, Reynolds, Helen, Harrison, Jennifer, Anson, Jim, Lewis, Joseph, Folb, Jonathan, Goodwin, Lynsey, Beeching, Nicholas, Dyas, Sarah, Winslow, Helen, Foote, Elizabeth, Roberts, Paul, Natarajan, Pavithra, Chrdle, Alex, Fenech, Manuel, Allsop, Hannah, Tilley, Robert, Austin-Hutchison, Rachel, Barrett, Louise, Brookes, Karen, Carwithen, Leanne, Conbeer, Andrew, Cunningham, Richard, Eglinton, Charlotte, Fok, Rosie, Gott, Hannah, Hughes, Shona, Jones, Lewis, Kalita, Maggie, King, Angela, March, Linda, Marner, Mike, Mynes, Tracey, Plant, Aiden, Price, Suzanne, Sercombe, Judy, Stolton, Alison, Wallis, Mark, West, Marie-Claire, Westcott, Jackie, Williams, Claire, Wosley, Rob, Yabsley, Leona, Greig, Julia, Butland, Laura, Sorrell, Julie, Mitchell, Tamara, Alli, Abiola, Meiring, James, Masake, Boingotlo, Rowson, Carlene, Smart, Lynne, Makey, Laura, Moll, Sarah, Cunningham, Jane, Ryalls, Kim, Birchall, Kathryn, Middle, Janet, Jackson, Yvonne, Swift, Diane, Cole, Joby, Subramanian, Bala, Okhuoya, Faith, Edwards, Maria, Bailey, Cheryl, Warren, Rebecca, Islam, Gayti, Ankcorn, Michael, Birchall, Sarah, Jones, Paul, Humphries, John, Booth, Stephen, Evan, Cariad, Wyllie, Sarah, Flatt, Andrew, Strakova, Lenka, Hayes, Maria, Valentine, Stacey, James, Clare, Wands, Mary, Cortes, Nicolas, Khan, Nisa, Porter, Robert, Martin, Zoe, Yip, Keith, Preedy, Helen, Chesterfield, Helen, Dobson, Tracey, Walker, Colin, Llewelyn, Martin, Dunne, Angela, Latter, Laura, Porges, Alison, Price, James, Paul, John, Behar, Laura, Robinson, Louise, Murray, Amy, Sargent, Tenessa, Ridley, Carrie, de Gordoa, Laura Ortiz-Ruiz, Gilliam, Deborah, McPherson, Carole, Matthews, Simon, Foreman, Emma, Jarghese, Rajesh, Beddoe, Alisha, Martin, Sebastien, Shaw, Sephora, Wlazly, Dominika, Cole, Maggie, Gihawi, Abraham, Cole, Kevin, Török, M Estée, Gouliouris, Theodore, Bedford, Luke, Saunderson, Rebecca B, Mariolis, Ilias, Bousfield, Rachel, Ramsay, Isobel, Greaves, Daniel, Aliyu, Sani, Cox, Kim, Mlemba, Lois, Whitehead, Lynne, Vyse, Naval, Bolton, Mark, Williams, John, Lambert, Pauline, Chadwick, David, Baillie, Kirsty, Cain, Martyn, Bellamy, Richard, Wong, Jason, Thompson, Jane, Vassallo, Helen, Skotnicka, Agnieszka, Boyce, Andrea, Donnelly, Anthony, Wilson, Peter, FitzGerald, Graham, Dean, Victoria, Warnes, Kristian, Reyes, Anna, Rahman, Saadia, Tsang, Lillian, Williams, Joanne, Morris-Jones, Stephen, Hopkins, Susan, Witness, Elen, Brady, Orla, Woodford, Elizabeth, Pettifer, Teresa, McCadden, Angela, Marks, Ben, Collier, Sophie, Mack, Damien, Warren, Simon, Brown, Colin, Lyons, Adrian, Taiyari, Sara, Mepham, Stephen, Sweeney, Anna, Brown, Li-An, Auckland, Cressida, Potter, Alison, Mandiza, Jess, Hough, Maxine, Williams, Sue, Renton, Caroline, Walters, Fiona, Nadolski, Maria, Evans, Andree, Tarrant, Polly, Curley, Katherine, Whiteley, Sophie, Halpin, Julia, Hutchings, Melanie, Todd, Shirley, Lohan, Christop, Chapter, Tamika, Folland, Emma, Colville, Alaric, Marden, Katy, Morgan, Marina, Porter, Rob, Baxter, Mel, Minton, Jane, Rippon, Sarah, Cevik, Muge, Chapman, Judith, Kemp, Tim, Vincent, Rachel, Osborne, Dave, Platt, Tracey, Calderwood, James, Cook, Bernadette, Bedford, Caroline, Galloway-Browne, Leanne, Abberley, Nadine, Attack, Kelly, Allen, Joanna, Lal, Pankaj, Harrison, Melanie, Stevenson, Sarah, Brooks, Carol, Harlow, Paula, Ewing, Jordan, Cooper, Shirley, Balancio-Tolentino, Roderick, O'Neil, Laura, Tagney, Rebecca, Shackcloth, Daniela, Planche, Tim, Fellows, James, Millett, Ruth, Studham, Jo, de Souza, Cherrelle, Howell, Geoffrey, Greaves, Hezron, Foncel, Ella, Kurup, Rahul, Briggs, Jack, Smith, Melody, Suarez, Cristina, Sorrentino, Giordana, Scobie, Antonia, Houston, Angela, Ahmad, Fozia, Breathnach, Aodhan, Chahuan, Rakhee, Wilkins, Katie, Guleri, Achyut, Waddington, Natalia, Sharma, Rashmi, Flegg, Peter, Kollipara, Veenu, Alam, Mazhar, Potter, Andrew, Donaldson, Stacey, Armer, Charlote, Frudd, Julie, Jeyaratnam, Dakshika, Joy, Manju, Mathews, Asha, Glass, Stephen K, Ajayi, Ayodele, Fife, Amanda, Qaiser, Saba, Sheehan, Sharon, Muñoz-Villaverde, Sergio, Yogo, Noah, De Abreu, Ines, Notcheva, Gaynor, Flanagan, Joanna, Watson, Cordelia, Sais, Efisia, Adedayo, Adetunji, Chu, Vicky, Shaw, Georgina, Graver, Michelle A, Palmer, Rebecca, Palmer, Donna, Haile, Senait, Gordon, Joanne, Mandar, Kirandip, Szypura, Weronika, Jenkins, Neil, Marange, Josephine, Shabangu, Vusumuzi, Moore, Katy, Lyons, Jill, Munang, Melinda, Sangombe, Mirriam, Moran, Ed, Hussain, Abid, Wiselka, Martin, Lewszuk, Adam, Batham, Sally, Ellis, Kate, Bahadur, Leila, White, Helena, Pareek, Manish, Sahota, Amandip, Coleman, Stephen, Pateman, Hilary, Kotecha, Atul, Sim, Christopher, Rosser, Andrew, Deane, Jill, Nendick, Richard, Aldridge, Catherine, Clarke, Anne, Wood, Michelle, Marshall, Adele, Stephenson, Lynsey, Matheson-Smith, Tracy, Sloss, John, Potts, Kathryn, Malkin, Joanne, Ftika, Lemonia, Raviprakash, Veena, Sutton, Julian, Malachira, Ahalya, Kean, Miranda, Criste, Kristine, Gladas, Kirsty, Andrews, Caroline, Hutchison, Clare, Adams, Ellen, Andrews, Janet, Romans, Belinda, Ridley, Nicola, Ekani, Melanie, Mitchell, Julie, Smith, Nicola, Clark, Tristan, Glover, Sarah, Reed, Robert, Yam, Tat, Burton, Holly, Said, Rasha, Harvey, David, Janvier, Amy, Jacob, Reni, Smalley, Chris, Fair, Alison, Lord, Susan, Ripalda, Kate, Wooldridge, Helen, Cotter, Luis, Cardoso, Gus, Strachan, Elaine, Kaler, Gagan, Mohamoodally, Adam, Lawrence, Emma, Prime, Zoe, Abrahams, Rachel, Price, David Ashley, Rigden, Lesley, Shewan, Laura, Cullen, Katherine, Emmerson, Ingrid, Martin, Karen, Wilson, Hesther, Higham, Charley, Taylor, Kathryn Louise, Ong, Edmund, Patel, Bijal, Bond, Helena, Gradwell, Janine, Widdrington, John, Graham, Clive, Thornthwaite, Sarah, Prentice, Scott, Poultney, Una, Crowther, Hannah, Fairlamb, Helen, Hetherington, Emily, Brewer, Chris, Banerjee, Suryabrata, Hamson, Clare, McSkeane, Anna, McWhinney, Paul, Sharratt, Paula, Thorpe, Joanne, Kimachia, Sue, Wilson, Helen, Jeffs, Benjamin, Masters, Leslie, Wilson, Jonathan, Platt, Judith, Burgess, Lisa, Chadwick, Paul, Jeans, Adam, Keatley, Claire, Moran, Amanda, Swann, Zoe, Pagett, Katherine, Peel, Alex, Howard, Jason, Meisner, Sarah, Maloney, Kate, Masdin, Avril, Wright, Louise, Barlow, Gavin, Crossman, Samantha, Lowthorpe, Vicki, Moore, Emma, Moss, Peter, Parkin, Angela, Wolstencroft, Adam, Warner, Bev, Tarbotton, Clare, Eyre, Alison, Anderson, Anne, Burdett, Tina, Driffill, Amy, Walker, Ann Sarah, Hudson, Fleur, Szubert, Alex, Cairns, Janet, Ward, Denise, Webb, Helen, Russell, Charlotte, Jackson, Brooke, Otiko, Damilola, Borg, Chiara, Masters, Lindsey, Islam, Zaheer, Díaz-Montaña, Carlos, Johnson, Debbie, Thwaites, Guy E, Szubert, Alexander, Wyllie, Sarah A, Armando, Gonzalez-Ruiz, Chadwick, Paul R, Gordon, N Claire, Price, David A, Nayar, Deepa, Török, M Estee, Llewelyn, Martin J, and Walker, A Sarah

Published
2018
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2. Defining persistent Staphylococcus aureus bacteraemia: secondary analysis of a prospective cohort study

Author

Kuehl, Richard, Morata, Laura, Boeing, Christian, Subirana, Isaac, Seifert, Harald, Rieg, Siegbert, Kern, Winfried V., Kim, Hong Bin, Kim, Eu Suk, Liao, Chun-Hsing, Tilley, Robert, Lopez-Cortés, Luis Eduardo, Llewelyn, Martin J., Fowler, Vance G., Thwaites, Guy, Cisneros, José Miguel, Scarborough, Matt, Nsutebu, Emmanuel, Gurgui Ferrer, Mercedes, Pérez, José L., Barlow, Gavin, Hopkins, Susan, Ternavasio-de la Vega, Hugo Guillermo, Török, Estée, Wilson, Peter, Kaasch, Achim J., Soriano, Alex, Bernasch, Christian, Jung, Norma, Lamarca Soria, Karuna, Rivera Martínez, Maria Alba, Prim, Nuria, Martínez, José Antonio, Marcos, Miguel, Baño, Jesús Rodríguez, De Cueto, Marina, Sung, Kyoung-Ho, Kim, Chung-Jong, Kang, Chang Kyung, Park, Jung In, Morris-Jones, Stephen, Kamfose, Musa, Young, Bernadette, Gott, Hannah, Gouliouris, Theodore, Bedford, Luke, Price, James, Kern, Winfried V, Llewelyn, Martin J, Fowler, Vance G, Pérez, José L, Török, M Estée, and Kaasch, Achim J

Published
2020
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3. Rapid implementation of SARS-CoV-2 sequencing to investigate cases of health-care associated COVID-19: a prospective genomic surveillance study

Author

Meredith, Luke W, Hamilton, William L, Warne, Ben, Houldcroft, Charlotte J, Hosmillo, Myra, Jahun, Aminu S, Curran, Martin D, Parmar, Surendra, Caller, Laura G, Caddy, Sarah L, Khokhar, Fahad A, Yakovleva, Anna, Hall, Grant, Feltwell, Theresa, Forrest, Sally, Sridhar, Sushmita, Weekes, Michael P, Baker, Stephen, Brown, Nicholas, Moore, Elinor, Popay, Ashley, Roddick, Iain, Reacher, Mark, Gouliouris, Theodore, Peacock, Sharon J, Dougan, Gordon, Török, M Estée, and Goodfellow, Ian

Published
2020
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10. A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus

Author

Hepburn, Lucy, Prajsnar, Tomasz K., Klapholz, Catherine, Moreno, Pablo, Loynes, Catherine A., Ogryzko, Nikolay V., Brown, Karen, Schiebler, Mark, Hegyi, Krisztina, Antrobus, Robin, Hammond, Katherine L., Connolly, John, Ochoa, Bernardo, Bryant, Clare, Otto, Michael, Surewaard, Bas, Seneviratne, Suranjith L., Grogono, Dorothy M., Cachat, Julien, Ny, Tor, Kaser, Arthur, Török, M. Estée, Peacock, Sharon J., Holden, Matthew, Blundell, Tom, Wang, Lihui, Ligoxygakis, Petros, Minichiello, Liliana, Woods, C. Geoff, Foster, Simon J., Renshaw, Stephen A., and Floto, R. Andres

Published
2014

12. Timing of Initiation of Antiretroviral Therapy in Human Immunodeficiency Virus (HIV)—Associated Tuberculous Meningitis

Author

Török, M. Estee, Yen, Nguyen Thi Bich, Chau, Tran Thi Hong, Mai, Nguyen Thi Hoang, Phu, Nguyen Hoan, Mai, Pham Phuong, Dung, Nguyen Thi, Van Vinh Chau, Nguyen, Bang, Nguyen Duc, Tien, Nguyen Anh, Minh, N. H., Hien, Nguyen Quang, Thai, Phan Vuong Khac, Dong, Doan The, Anh, Do Thi Tuong, Thoa, Nguyen Thi Cam, Hai, Nguyen Ngoc, Lan, Nguyen Ngoc, Lan, Nguyen Thi Ngoc, Quy, Hoang Thi, Dung, Nguyen Huy, Hien, Tran Tinh, Chinh, Nguyen Tran, Simmons, Cameron Paul, Jong, Menno de, Wolbers, Marcel, and Farrar, Jeremy James

Published
2011
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14. ARREST: Adjunctive Rifampicin to Reduce Early mortality from STaphylococcus aureus bacteraemia: a multi-centre, randomised, blinded, placebo controlled trial : The ARREST RCT

Author

Thwaites, Guy E, Scarborough, Matthew, Szubert, Alexander, Saramago Goncalves, Pedro, Soares, Marta, Bostock, Jennifer, Nsutebu, Emmanuel, Tilley, Robert, Cunningham, Richard, Greig, Julia, Wyllie, Sarah A, Wilson, Peter, Auckland, Cressida, Cairns, Janet, Ward, Denise, Lal, Pankaj, Guleri, Achyut, Jenkins, Neil, Sutton, Julian, Wiselka, Martin, Armando, Gonzalez-Ruiz, Graham, Clive, Chadwick, Paul R, Barlow, Gavin, Gordon, N Claire, Young, Bernadette, Meisner, Sarah, McWhinney, Paul, Price, David A, Harvey, David, Nayar, Deepa, Jeyaratnam, Dakshika, Planche, Timothy, Minton, Jane, Hudson, Fleur, Hopkins, Susan, Williams, John, Török, M Estee, Llewelyn, Martin J, Edgeworth, Jonathan D, and Walker, A Sarah

Abstract

Background: Staphylococcus aureus bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early S. aureus killing, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. Objectives: To determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Secondary objectives included evaluating the impact of rifampicin on all-cause mortality, clinically defined failure/recurrence or death, toxicity, resistance emergence, and duration of bacteraemia; and assessing the cost-effectiveness of rifampicin. Design: Parallel-group, randomised (1: 1), blinded, placebo-controlled multicentre trial. Setting: UK NHS trust hospitals. Participants: Adult inpatients (≥ 18 years) with meticillin-resistant or susceptible S. aureus grown from one or more blood cultures, who had received < 96 hours of antibiotic therapy for the current infection, and without contraindications to rifampicin. Interventions: Adjunctive rifampicin (600–900 mg/day, oral or intravenous) or placebo for 14 days in addition to standard antibiotic therapy. Investigators and patients were blinded to trial treatment. Follow-up was for 12 weeks (assessments at 3, 7, 10 and 14 days, weekly until discharge and final assessment at 12 weeks post randomisation). Main outcome measures: The primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Results: Between December 2012 and October 2016, 758 eligible participants from 29 UK hospitals were randomised: 370 to rifampicin and 388 to placebo. The median age was 65 years [interquartile range (IQR) 50–76 years]. A total of 485 (64.0%) infections were community acquired and 132 (17.4%) were nosocomial; 47 (6.2%) were caused by meticillin-resistant S. aureus. A total of 301 (39.7%) participants had an initial deep infection focus. Standard antibiotics were given for a median of 29 days (IQR 18–45 days) and 619 (81.7%) participants received flucloxacillin. By 12 weeks, 62 out of 370 (16.8%) patients taking rifampicin versus 71 out of 388 (18.3%) participants taking the placebo experienced bacteriological (microbiologically confirmed) failure/recurrence or died [absolute risk difference –1.4%, 95% confidence interval (CI) –7.0% to 4.3%; hazard ratio 0.96, 95% CI 0.68 to 1.35; p = 0.81]. There were 4 (1.1%) and 5 (1.3%) bacteriological failures (p = 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences (p = 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence (p = 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death (p = 0.84), all-cause mortality (p = 0.60), serious (p = 0.17) or grade 3/4 (p = 0.36) adverse events (AEs). However, 63 (17.0%) participants in the rifampicin group versus 39 (10.1%) participants in the placebo group experienced antibiotic or trial drug-modifying AEs (p = 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions (p = 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode of S. aureus bacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs (p = 0.14). After adjustment, the effect of rifampicin on total quality-adjusted life-years (QALYs) was positive (0.004 QALYs), but not statistically significant (standard error 0.004 QALYs). Conclusions: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S. aureus bacteraemia. Future work: Given the substantial mortality, other antibiotic combinations or improved source management should be investigated. Trial registrations: Current Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001.

Published
2018

15. Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT

Author

Thwaites, Guy E, primary, Scarborough, Matthew, additional, Szubert, Alexander, additional, Saramago Goncalves, Pedro, additional, Soares, Marta, additional, Bostock, Jennifer, additional, Nsutebu, Emmanuel, additional, Tilley, Robert, additional, Cunningham, Richard, additional, Greig, Julia, additional, Wyllie, Sarah A, additional, Wilson, Peter, additional, Auckland, Cressida, additional, Cairns, Janet, additional, Ward, Denise, additional, Lal, Pankaj, additional, Guleri, Achyut, additional, Jenkins, Neil, additional, Sutton, Julian, additional, Wiselka, Martin, additional, Armando, Gonzalez-Ruiz, additional, Graham, Clive, additional, Chadwick, Paul R, additional, Barlow, Gavin, additional, Gordon, N Claire, additional, Young, Bernadette, additional, Meisner, Sarah, additional, McWhinney, Paul, additional, Price, David A, additional, Harvey, David, additional, Nayar, Deepa, additional, Jeyaratnam, Dakshika, additional, Planche, Timothy, additional, Minton, Jane, additional, Hudson, Fleur, additional, Hopkins, Susan, additional, Williams, John, additional, Török, M Estee, additional, Llewelyn, Martin J, additional, Edgeworth, Jonathan D, additional, and Walker, A Sarah, additional

Published
2018
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16. Applying prospective genomic surveillance to support investigation of hospital-onset COVID-19

Author

Curran, Martin D, Parmar, Surendra, Hosmillo, Myra, Chaudhry, Yasmin, Pinckert, Malte L, Georgana, Iliana, Izuagbe, Rhys, Ferris, Mark, Workman, Chris, Jones, Nick K, Rivett, Lucy, Sparkes, Dominic, Routledge, Matthew, Enoch, David, Whitehorn, James, Moody, Christine, Brennan, Liam, Smith, Richard, Tsui, Rachel, Bousfield, Rachel, Pocock, Joanna, Toleman, Michelle, Payne, Helen, Coscione, Suny, Myers, Chloe, Sharrocks, Katherine, Ravji, Pooja, Leong, Clare, Ramsay, Isobel, Hamilton, William L, Fieldman, Tom, Jahun, Aminu, Warne, Ben, Illingworth, Christopher J R, Jackson, Chris, Blane, Beth, Moore, Elinor, Weekes, Michael P, Peacock, Sharon J, De Angelis, Daniela, Goodfellow, Ian, Gouliouris, Theodore, and Török, M Estée

Published
2021
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17. Transmission of methicillin-resistant $\textit{Staphylococcus aureus}$ in long-term care facilities and their related healthcare networks

Author

Harrison, Ewan, Ludden, Catherine, Brodrick, Hayley J, Blane, Beth, Brennan, Gráinne, Morris, Dearbháile, Coll, Francesc, Reuter, Sandra, Brown, Nicholas M, Holmes, Mark, O’Connell, Brian, Parkhill, Julian, Török, M Estee, Cormican, Martin, Peacock, Sharon, Harrison, Ewan [0000-0003-2720-0507], Ludden, Catherine [0000-0001-9503-0744], Holmes, Mark [0000-0002-5454-1625], Parkhill, Julian [0000-0002-7069-5958], Peacock, Sharon [0000-0002-1718-2782], and Apollo - University of Cambridge Repository

Subjects
nursing home, $\textit{Staphylococcus aureus}$, whole-genome sequencing, transmission, MRSA, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, molecular epidemiology, long-term care facilities
Abstract

$\textbf{Background:}$ Long-term care facilities (LTCF) are potential reservoirs for methicillin-resistant $\textit{Staphylococcus aureus}$ (MRSA), control of which may reduce MRSA transmission and infection elsewhere in the healthcare system. Whole-genome sequencing (WGS) has been used successfully to understand MRSA epidemiology and transmission in hospitals and has the potential to identify transmission between these and LTCF. $\textbf{Methods:}$ Two prospective observational studies of MRSA carriage were conducted in LTCF in England and Ireland. MRSA isolates were whole-genome sequenced and analyzed using established methods. Genomic data were available for MRSA isolated in the local healthcare systems (isolates submitted by hospitals and general practitioners). $\textbf{Results:}$ We sequenced a total of 181 MRSA isolates from the two study sites. The majority of MRSA were multilocus sequence type (ST)22. WGS identified one likely transmission event between residents in the English LTCF and three putative transmission events in the Irish LTCF. WGS also identified closely related isolates present in colonized Irish residents and their immediate environment. Based on phylogenetic reconstruction, closely related MRSA clades were identified between the LTCF and their healthcare referral network, together with putative MRSA acquisition by LTCF residents during hospital admission. $\textbf{Conclusions:}$ These data confirm that MRSA is transmitted between residents of LTCF and is both acquired and transmitted to others in referral hospitals and beyond. Our data present compelling evidence for the importance of environmental contamination in MRSA transmission, reinforcing the importance of environmental cleaning. The use of WGS in this study highlights the need to consider infection control in hospitals and community healthcare facilities as a continuum., UKCRC Translational Infection Research (TIR) Initiative, Medical Research Council (Grant ID: G1000803), Biotechnology and Biological Sciences Research Council, National Institute for Health Research, Chief Scientist Office of the Scottish Government Health Directorate, Hospital Infection Society (Major Research Grant), Wellcome Trust (Grant ID: 098051), Academy of Medical Sciences, Health Foundation, National Institute for Health Research Cambridge Biomedical Research Centre, This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13073-016-0353-5

Published
2016
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18. Transmission of methicillin-resistant Staphylococcus aureus in long-term care facilities and their related healthcare networks

Author

Harrison, Ewan M, Ludden, Catherine, Brodrick, Hayley J, Blane, Beth, Brennan, Gráinne, Morris, Dearbháile, Coll, Francesc, Reuter, Sandra, Brown, Nicholas M, Holmes, Mark A, O'Connell, Brian, Parkhill, Julian, Török, M Estee, Cormican, Martin, Peacock, Sharon J, Harrison, Ewan [0000-0003-2720-0507], Ludden, Catherine [0000-0001-9503-0744], Holmes, Mark [0000-0002-5454-1625], Parkhill, Julian [0000-0002-7069-5958], Peacock, Sharon [0000-0002-1718-2782], and Apollo - University of Cambridge Repository

Subjects
Adult, DNA, Bacterial, Male, Methicillin-Resistant Staphylococcus aureus, Staphylococcus aureus, MRSA, Genetics, Transmission, Humans, Genetics(clinical), Prospective Studies, Molecular Biology, Aged, Aged, 80 and over, Whole-genome sequencing, Cross Infection, Infection Control, Long-term care facilities, Nursing home, Research, High-Throughput Nucleotide Sequencing, Middle Aged, Staphylococcal Infections, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, Long-Term Care, United Kingdom, Molecular epidemiology, Health Facility Environment, Molecular Medicine, Female, Multilocus Sequence Typing
Abstract

Background Long-term care facilities (LTCF) are potential reservoirs for methicillin-resistant Staphylococcus aureus (MRSA), control of which may reduce MRSA transmission and infection elsewhere in the healthcare system. Whole-genome sequencing (WGS) has been used successfully to understand MRSA epidemiology and transmission in hospitals and has the potential to identify transmission between these and LTCF. Methods Two prospective observational studies of MRSA carriage were conducted in LTCF in England and Ireland. MRSA isolates were whole-genome sequenced and analyzed using established methods. Genomic data were available for MRSA isolated in the local healthcare systems (isolates submitted by hospitals and general practitioners). Results We sequenced a total of 181 MRSA isolates from the two study sites. The majority of MRSA were multilocus sequence type (ST)22. WGS identified one likely transmission event between residents in the English LTCF and three putative transmission events in the Irish LTCF. WGS also identified closely related isolates present in colonized Irish residents and their immediate environment. Based on phylogenetic reconstruction, closely related MRSA clades were identified between the LTCF and their healthcare referral network, together with putative MRSA acquisition by LTCF residents during hospital admission. Conclusions These data confirm that MRSA is transmitted between residents of LTCF and is both acquired and transmitted to others in referral hospitals and beyond. Our data present compelling evidence for the importance of environmental contamination in MRSA transmission, reinforcing the importance of environmental cleaning. The use of WGS in this study highlights the need to consider infection control in hospitals and community healthcare facilities as a continuum. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0353-5) contains supplementary material, which is available to authorized users.

Published
2016

19. Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial

Author

Thwaites, Guy E, primary, Scarborough, Matthew, additional, Szubert, Alexander, additional, Nsutebu, Emmanuel, additional, Tilley, Robert, additional, Greig, Julia, additional, Wyllie, Sarah A, additional, Wilson, Peter, additional, Auckland, Cressida, additional, Cairns, Janet, additional, Ward, Denise, additional, Lal, Pankaj, additional, Guleri, Achyut, additional, Jenkins, Neil, additional, Sutton, Julian, additional, Wiselka, Martin, additional, Armando, Gonzalez-Ruiz, additional, Graham, Clive, additional, Chadwick, Paul R, additional, Barlow, Gavin, additional, Gordon, N Claire, additional, Young, Bernadette, additional, Meisner, Sarah, additional, McWhinney, Paul, additional, Price, David A, additional, Harvey, David, additional, Nayar, Deepa, additional, Jeyaratnam, Dakshika, additional, Planche, Tim, additional, Minton, Jane, additional, Hudson, Fleur, additional, Hopkins, Susan, additional, Williams, John, additional, Török, M Estee, additional, Llewelyn, Martin J, additional, Edgeworth, Jonathan D, additional, Walker, A Sarah, additional, Kamfose, Musa, additional, de Veciana, Ana, additional, Gordon, Nicola Claire, additional, Peto, Leon, additional, Pill, Gemma, additional, Clarke, Tiphanie, additional, Watson, Laura, additional, Griffiths, Dai, additional, Vaughn, Ali, additional, Anson, Luke, additional, Liu, Elian, additional, Perera, Sanuki, additional, Rylance-Knight, Lydia, additional, Cantell, Carmen, additional, Moroney, Ruth, additional, Thwaites, Guy, additional, Bisnauthsing, Karen, additional, Querol-Rubiera, Antonio, additional, Gibbs, Charlotte, additional, Patel, Amita, additional, Hemsley, Carolyn, additional, Goodman, Anna L, additional, Wyncoll, Duncan, additional, Biswas, Jason, additional, Fitzpatrick, Jennifer, additional, Roberts, Lizzie, additional, Millard, James, additional, Stone, Neil, additional, Cape, Angela, additional, Hurley, Lisa, additional, Tam, Chi Kai, additional, Hoyle, Marie-Claire, additional, Maitland, Kate, additional, Trainor, Leona, additional, Reynolds, Helen, additional, Harrison, Jennifer, additional, Anson, Jim, additional, Lewis, Joseph, additional, Folb, Jonathan, additional, Goodwin, Lynsey, additional, Beeching, Nicholas, additional, Dyas, Sarah, additional, Winslow, Helen, additional, Foote, Elizabeth, additional, Roberts, Paul, additional, Natarajan, Pavithra, additional, Chrdle, Alex, additional, Fenech, Manuel, additional, Allsop, Hannah, additional, Austin-Hutchison, Rachel, additional, Barrett, Louise, additional, Brookes, Karen, additional, Carwithen, Leanne, additional, Conbeer, Andrew, additional, Cunningham, Richard, additional, Eglinton, Charlotte, additional, Fok, Rosie, additional, Gott, Hannah, additional, Hughes, Shona, additional, Jones, Lewis, additional, Kalita, Maggie, additional, King, Angela, additional, March, Linda, additional, Marner, Mike, additional, Mynes, Tracey, additional, Plant, Aiden, additional, Price, Suzanne, additional, Sercombe, Judy, additional, Stolton, Alison, additional, Wallis, Mark, additional, West, Marie-Claire, additional, Westcott, Jackie, additional, Williams, Claire, additional, Wosley, Rob, additional, Yabsley, Leona, additional, Butland, Laura, additional, Sorrell, Julie, additional, Mitchell, Tamara, additional, Alli, Abiola, additional, Meiring, James, additional, Masake, Boingotlo, additional, Rowson, Carlene, additional, Smart, Lynne, additional, Makey, Laura, additional, Moll, Sarah, additional, Cunningham, Jane, additional, Ryalls, Kim, additional, Birchall, Kathryn, additional, Middle, Janet, additional, Jackson, Yvonne, additional, Swift, Diane, additional, Cole, Joby, additional, Subramanian, Bala, additional, Okhuoya, Faith, additional, Edwards, Maria, additional, Bailey, Cheryl, additional, Warren, Rebecca, additional, Islam, Gayti, additional, Ankcorn, Michael, additional, Birchall, Sarah, additional, Jones, Paul, additional, Humphries, John, additional, Booth, Stephen, additional, Evan, Cariad, additional, Wyllie, Sarah, additional, Flatt, Andrew, additional, Strakova, Lenka, additional, Hayes, Maria, additional, Valentine, Stacey, additional, James, Clare, additional, Wands, Mary, additional, Cortes, Nicolas, additional, Khan, Nisa, additional, Porter, Robert, additional, Martin, Zoe, additional, Yip, Keith, additional, Preedy, Helen, additional, Chesterfield, Helen, additional, Dobson, Tracey, additional, Walker, Colin, additional, Llewelyn, Martin, additional, Dunne, Angela, additional, Latter, Laura, additional, Porges, Alison, additional, Price, James, additional, Paul, John, additional, Behar, Laura, additional, Robinson, Louise, additional, Murray, Amy, additional, Sargent, Tenessa, additional, Ridley, Carrie, additional, de Gordoa, Laura Ortiz-Ruiz, additional, Gilliam, Deborah, additional, McPherson, Carole, additional, Matthews, Simon, additional, Foreman, Emma, additional, Jarghese, Rajesh, additional, Beddoe, Alisha, additional, Martin, Sebastien, additional, Shaw, Sephora, additional, Wlazly, Dominika, additional, Cole, Maggie, additional, Gihawi, Abraham, additional, Cole, Kevin, additional, Török, M Estée, additional, Gouliouris, Theodore, additional, Bedford, Luke, additional, Saunderson, Rebecca B, additional, Mariolis, Ilias, additional, Bousfield, Rachel, additional, Ramsay, Isobel, additional, Greaves, Daniel, additional, Aliyu, Sani, additional, Cox, Kim, additional, Mlemba, Lois, additional, Whitehead, Lynne, additional, Vyse, Naval, additional, Bolton, Mark, additional, Lambert, Pauline, additional, Chadwick, David, additional, Baillie, Kirsty, additional, Cain, Martyn, additional, Bellamy, Richard, additional, Wong, Jason, additional, Thompson, Jane, additional, Vassallo, Helen, additional, Skotnicka, Agnieszka, additional, Boyce, Andrea, additional, Donnelly, Anthony, additional, FitzGerald, Graham, additional, Dean, Victoria, additional, Warnes, Kristian, additional, Reyes, Anna, additional, Rahman, Saadia, additional, Tsang, Lillian, additional, Williams, Joanne, additional, Morris-Jones, Stephen, additional, Witness, Elen, additional, Brady, Orla, additional, Woodford, Elizabeth, additional, Pettifer, Teresa, additional, McCadden, Angela, additional, Marks, Ben, additional, Collier, Sophie, additional, Mack, Damien, additional, Warren, Simon, additional, Brown, Colin, additional, Lyons, Adrian, additional, Taiyari, Sara, additional, Mepham, Stephen, additional, Sweeney, Anna, additional, Brown, Li-An, additional, Potter, Alison, additional, Mandiza, Jess, additional, Hough, Maxine, additional, Williams, Sue, additional, Renton, Caroline, additional, Walters, Fiona, additional, Nadolski, Maria, additional, Evans, Andree, additional, Tarrant, Polly, additional, Curley, Katherine, additional, Whiteley, Sophie, additional, Halpin, Julia, additional, Hutchings, Melanie, additional, Todd, Shirley, additional, Lohan, Christop, additional, Chapter, Tamika, additional, Folland, Emma, additional, Colville, Alaric, additional, Marden, Katy, additional, Morgan, Marina, additional, Porter, Rob, additional, Baxter, Mel, additional, Rippon, Sarah, additional, Cevik, Muge, additional, Chapman, Judith, additional, Kemp, Tim, additional, Vincent, Rachel, additional, Osborne, Dave, additional, Platt, Tracey, additional, Calderwood, James, additional, Cook, Bernadette, additional, Bedford, Caroline, additional, Galloway-Browne, Leanne, additional, Abberley, Nadine, additional, Attack, Kelly, additional, Allen, Joanna, additional, Harrison, Melanie, additional, Stevenson, Sarah, additional, Brooks, Carol, additional, Harlow, Paula, additional, Ewing, Jordan, additional, Cooper, Shirley, additional, Balancio-Tolentino, Roderick, additional, O'Neil, Laura, additional, Tagney, Rebecca, additional, Shackcloth, Daniela, additional, Fellows, James, additional, Millett, Ruth, additional, Studham, Jo, additional, de Souza, Cherrelle, additional, Howell, Geoffrey, additional, Greaves, Hezron, additional, Foncel, Ella, additional, Kurup, Rahul, additional, Briggs, Jack, additional, Smith, Melody, additional, Suarez, Cristina, additional, Sorrentino, Giordana, additional, Scobie, Antonia, additional, Houston, Angela, additional, Ahmad, Fozia, additional, Breathnach, Aodhan, additional, Chahuan, Rakhee, additional, Wilkins, Katie, additional, Waddington, Natalia, additional, Sharma, Rashmi, additional, Flegg, Peter, additional, Kollipara, Veenu, additional, Alam, Mazhar, additional, Potter, Andrew, additional, Donaldson, Stacey, additional, Armer, Charlote, additional, Frudd, Julie, additional, Joy, Manju, additional, Mathews, Asha, additional, Glass, Stephen K, additional, Ajayi, Ayodele, additional, Fife, Amanda, additional, Qaiser, Saba, additional, Sheehan, Sharon, additional, Muñoz-Villaverde, Sergio, additional, Yogo, Noah, additional, De Abreu, Ines, additional, Notcheva, Gaynor, additional, Flanagan, Joanna, additional, Watson, Cordelia, additional, Sais, Efisia, additional, Adedayo, Adetunji, additional, Chu, Vicky, additional, Shaw, Georgina, additional, Graver, Michelle A, additional, Palmer, Rebecca, additional, Palmer, Donna, additional, Haile, Senait, additional, Gordon, Joanne, additional, Mandar, Kirandip, additional, Szypura, Weronika, additional, Marange, Josephine, additional, Shabangu, Vusumuzi, additional, Moore, Katy, additional, Lyons, Jill, additional, Munang, Melinda, additional, Sangombe, Mirriam, additional, Moran, Ed, additional, Hussain, Abid, additional, Lewszuk, Adam, additional, Batham, Sally, additional, Ellis, Kate, additional, Bahadur, Leila, additional, White, Helena, additional, Pareek, Manish, additional, Sahota, Amandip, additional, Coleman, Stephen, additional, Pateman, Hilary, additional, Kotecha, Atul, additional, Sim, Christopher, additional, Rosser, Andrew, additional, Deane, Jill, additional, Nendick, Richard, additional, Aldridge, Catherine, additional, Clarke, Anne, additional, Wood, Michelle, additional, Marshall, Adele, additional, Stephenson, Lynsey, additional, Matheson-Smith, Tracy, additional, Sloss, John, additional, Potts, Kathryn, additional, Malkin, Joanne, additional, Ftika, Lemonia, additional, Raviprakash, Veena, additional, Malachira, Ahalya, additional, Kean, Miranda, additional, Criste, Kristine, additional, Gladas, Kirsty, additional, Andrews, Caroline, additional, Hutchison, Clare, additional, Adams, Ellen, additional, Andrews, Janet, additional, Romans, Belinda, additional, Ridley, Nicola, additional, Ekani, Melanie, additional, Mitchell, Julie, additional, Smith, Nicola, additional, Clark, Tristan, additional, Glover, Sarah, additional, Reed, Robert, additional, Yam, Tat, additional, Burton, Holly, additional, Said, Rasha, additional, Janvier, Amy, additional, Jacob, Reni, additional, Smalley, Chris, additional, Fair, Alison, additional, Lord, Susan, additional, Ripalda, Kate, additional, Wooldridge, Helen, additional, Cotter, Luis, additional, Cardoso, Gus, additional, Strachan, Elaine, additional, Kaler, Gagan, additional, Mohamoodally, Adam, additional, Lawrence, Emma, additional, Prime, Zoe, additional, Abrahams, Rachel, additional, Price, David Ashley, additional, Rigden, Lesley, additional, Shewan, Laura, additional, Cullen, Katherine, additional, Emmerson, Ingrid, additional, Martin, Karen, additional, Wilson, Hesther, additional, Higham, Charley, additional, Taylor, Kathryn Louise, additional, Ong, Edmund, additional, Patel, Bijal, additional, Bond, Helena, additional, Gradwell, Janine, additional, Widdrington, John, additional, Thornthwaite, Sarah, additional, Prentice, Scott, additional, Poultney, Una, additional, Crowther, Hannah, additional, Fairlamb, Helen, additional, Hetherington, Emily, additional, Brewer, Chris, additional, Banerjee, Suryabrata, additional, Hamson, Clare, additional, McSkeane, Anna, additional, Sharratt, Paula, additional, Thorpe, Joanne, additional, Kimachia, Sue, additional, Wilson, Helen, additional, Jeffs, Benjamin, additional, Masters, Leslie, additional, Wilson, Jonathan, additional, Platt, Judith, additional, Burgess, Lisa, additional, Chadwick, Paul, additional, Jeans, Adam, additional, Keatley, Claire, additional, Moran, Amanda, additional, Swann, Zoe, additional, Pagett, Katherine, additional, Peel, Alex, additional, Howard, Jason, additional, Maloney, Kate, additional, Masdin, Avril, additional, Wright, Louise, additional, Crossman, Samantha, additional, Lowthorpe, Vicki, additional, Moore, Emma, additional, Moss, Peter, additional, Parkin, Angela, additional, Wolstencroft, Adam, additional, Warner, Bev, additional, Tarbotton, Clare, additional, Eyre, Alison, additional, Anderson, Anne, additional, Burdett, Tina, additional, Driffill, Amy, additional, Walker, Ann Sarah, additional, Szubert, Alex, additional, Webb, Helen, additional, Russell, Charlotte, additional, Jackson, Brooke, additional, Otiko, Damilola, additional, Borg, Chiara, additional, Masters, Lindsey, additional, Islam, Zaheer, additional, Díaz-Montaña, Carlos, additional, and Johnson, Debbie, additional

Published
2018
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20. Convergent evolution and topologically disruptive polymorphisms among multidrug-resistant tuberculosis in Peru

Author

Grandjean, Louis, primary, Gilman, Robert H., additional, Iwamoto, Tomatada, additional, Köser, Claudio U., additional, Coronel, Jorge, additional, Zimic, Mirko, additional, Török, M. Estee, additional, Ayabina, Diepreye, additional, Kendall, Michelle, additional, Fraser, Christophe, additional, Harris, Simon, additional, Parkhill, Julian, additional, Peacock, Sharon J., additional, Moore, David A. J., additional, and Colijn, Caroline, additional

Published
2017
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21. Drug-resistance mechanisms and tuberculosis drugs

Author

Köser, Claudio U, Javid, Babak, Liddell, Kathleen, Ellington, Matthew J, Feuerriegel, Silke, Niemann, Stefan, Brown, Nicholas M, Burman, William J, Abubakar, Ibrahim, Ismail, Nazir A, Moore, David, Peacock, Sharon J, and Török, M Estée

Published
2015
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25. Adjunctive rifampicin for Staphylococcus aureusbacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial

Author

Thwaites, Guy E, Scarborough, Matthew, Szubert, Alexander, Nsutebu, Emmanuel, Tilley, Robert, Greig, Julia, Wyllie, Sarah A, Wilson, Peter, Auckland, Cressida, Cairns, Janet, Ward, Denise, Lal, Pankaj, Guleri, Achyut, Jenkins, Neil, Sutton, Julian, Wiselka, Martin, Armando, Gonzalez-Ruiz, Graham, Clive, Chadwick, Paul R, Barlow, Gavin, Gordon, N Claire, Young, Bernadette, Meisner, Sarah, McWhinney, Paul, Price, David A, Harvey, David, Nayar, Deepa, Jeyaratnam, Dakshika, Planche, Tim, Minton, Jane, Hudson, Fleur, Hopkins, Susan, Williams, John, Török, M Estee, Llewelyn, Martin J, Edgeworth, Jonathan D, Walker, A Sarah, Scarborough, Matthew, Kamfose, Musa, de Veciana, Ana, Gordon, Nicola Claire, Peto, Leon, Pill, Gemma, Clarke, Tiphanie, Watson, Laura, Young, Bernadette, Griffiths, Dai, Vaughn, Ali, Anson, Luke, Liu, Elian, Perera, Sanuki, Rylance-Knight, Lydia, Cantell, Carmen, Moroney, Ruth, Edgeworth, Jonathan D, Thwaites, Guy, Bisnauthsing, Karen, Querol-Rubiera, Antonio, Gibbs, Charlotte, Patel, Amita, Hemsley, Carolyn, Goodman, Anna L, Wyncoll, Duncan, Biswas, Jason, Fitzpatrick, Jennifer, Roberts, Lizzie, Millard, James, Stone, Neil, Cape, Angela, Hurley, Lisa, Tam, Chi Kai, Nsutebu, Emmanuel, Hoyle, Marie-Claire, Maitland, Kate, Trainor, Leona, Reynolds, Helen, Harrison, Jennifer, Anson, Jim, Lewis, Joseph, Folb, Jonathan, Goodwin, Lynsey, Beeching, Nicholas, Dyas, Sarah, Winslow, Helen, Foote, Elizabeth, Roberts, Paul, Natarajan, Pavithra, Chrdle, Alex, Fenech, Manuel, Allsop, Hannah, Tilley, Robert, Austin-Hutchison, Rachel, Barrett, Louise, Brookes, Karen, Carwithen, Leanne, Conbeer, Andrew, Cunningham, Richard, Eglinton, Charlotte, Fok, Rosie, Gott, Hannah, Hughes, Shona, Jones, Lewis, Kalita, Maggie, King, Angela, March, Linda, Marner, Mike, Mynes, Tracey, Plant, Aiden, Price, Suzanne, Sercombe, Judy, Stolton, Alison, Wallis, Mark, West, Marie-Claire, Westcott, Jackie, Williams, Claire, Wosley, Rob, Yabsley, Leona, Greig, Julia, Butland, Laura, Sorrell, Julie, Mitchell, Tamara, Alli, Abiola, Meiring, James, Masake, Boingotlo, Rowson, Carlene, Smart, Lynne, Makey, Laura, Moll, Sarah, Cunningham, Jane, Ryalls, Kim, Birchall, Kathryn, Middle, Janet, Jackson, Yvonne, Swift, Diane, Cole, Joby, Subramanian, Bala, Okhuoya, Faith, Edwards, Maria, Bailey, Cheryl, Warren, Rebecca, Islam, Gayti, Ankcorn, Michael, Birchall, Sarah, Jones, Paul, Humphries, John, Booth, Stephen, Evan, Cariad, Wyllie, Sarah, Flatt, Andrew, Strakova, Lenka, Hayes, Maria, Valentine, Stacey, James, Clare, Wands, Mary, Cortes, Nicolas, Khan, Nisa, Porter, Robert, Martin, Zoe, Yip, Keith, Preedy, Helen, Chesterfield, Helen, Dobson, Tracey, Walker, Colin, Llewelyn, Martin, Dunne, Angela, Latter, Laura, Porges, Alison, Price, James, Paul, John, Behar, Laura, Robinson, Louise, Murray, Amy, Fitzpatrick, Jennifer, Sargent, Tenessa, Ridley, Carrie, de Gordoa, Laura Ortiz-Ruiz, Gilliam, Deborah, McPherson, Carole, Matthews, Simon, Foreman, Emma, Jarghese, Rajesh, Beddoe, Alisha, Martin, Sebastien, Shaw, Sephora, Wlazly, Dominika, Cole, Maggie, Gihawi, Abraham, Cole, Kevin, Török, M Estée, Gouliouris, Theodore, Bedford, Luke, Saunderson, Rebecca B, Mariolis, Ilias, Bousfield, Rachel, Ramsay, Isobel, Greaves, Daniel, Aliyu, Sani, Cox, Kim, Mlemba, Lois, Whitehead, Lynne, Vyse, Naval, Bolton, Mark, Williams, John, Lambert, Pauline, Chadwick, David, Baillie, Kirsty, Cain, Martyn, Bellamy, Richard, Wong, Jason, Thompson, Jane, Vassallo, Helen, Skotnicka, Agnieszka, Boyce, Andrea, Donnelly, Anthony, Wilson, Peter, FitzGerald, Graham, Dean, Victoria, Warnes, Kristian, Reyes, Anna, Rahman, Saadia, Tsang, Lillian, Williams, Joanne, Morris-Jones, Stephen, Hopkins, Susan, Witness, Elen, Brady, Orla, Woodford, Elizabeth, Pettifer, Teresa, McCadden, Angela, Marks, Ben, Collier, Sophie, Mack, Damien, Warren, Simon, Brown, Colin, Lyons, Adrian, Taiyari, Sara, Mepham, Stephen, Sweeney, Anna, Brown, Li-An, Auckland, Cressida, Potter, Alison, Mandiza, Jess, Hough, Maxine, Williams, Sue, Renton, Caroline, Walters, Fiona, Nadolski, Maria, Evans, Andree, Tarrant, Polly, Curley, Katherine, Whiteley, Sophie, Halpin, Julia, Hutchings, Melanie, Todd, Shirley, Lohan, Christop, Chapter, Tamika, Folland, Emma, Colville, Alaric, Marden, Katy, Morgan, Marina, Fok, Rosie, Porter, Rob, Baxter, Mel, Minton, Jane, Rippon, Sarah, Cevik, Muge, Chapman, Judith, Kemp, Tim, Vincent, Rachel, Osborne, Dave, Platt, Tracey, Calderwood, James, Cook, Bernadette, Bedford, Caroline, Galloway-Browne, Leanne, Abberley, Nadine, Attack, Kelly, Allen, Joanna, Lal, Pankaj, Harrison, Melanie, Stevenson, Sarah, Brooks, Carol, Harlow, Paula, Ewing, Jordan, Cooper, Shirley, Balancio-Tolentino, Roderick, O'Neil, Laura, Tagney, Rebecca, Shackcloth, Daniela, Planche, Tim, Fellows, James, Millett, Ruth, Studham, Jo, de Souza, Cherrelle, Howell, Geoffrey, Greaves, Hezron, Foncel, Ella, Kurup, Rahul, Briggs, Jack, Smith, Melody, Suarez, Cristina, Sorrentino, Giordana, Scobie, Antonia, Houston, Angela, Ahmad, Fozia, Breathnach, Aodhan, Chahuan, Rakhee, Wilkins, Katie, Guleri, Achyut, Waddington, Natalia, Sharma, Rashmi, Flegg, Peter, Kollipara, Veenu, Alam, Mazhar, Potter, Andrew, Donaldson, Stacey, Armer, Charlote, Frudd, Julie, Jeyaratnam, Dakshika, Joy, Manju, Mathews, Asha, Glass, Stephen K, Ajayi, Ayodele, Fife, Amanda, Qaiser, Saba, Sheehan, Sharon, Muñoz-Villaverde, Sergio, Yogo, Noah, De Abreu, Ines, Notcheva, Gaynor, Flanagan, Joanna, Watson, Cordelia, Sais, Efisia, Adedayo, Adetunji, Chu, Vicky, Shaw, Georgina, Graver, Michelle A, Palmer, Rebecca, Palmer, Donna, Haile, Senait, Gordon, Joanne, Tam, Chi Kai, Mandar, Kirandip, Szypura, Weronika, Jenkins, Neil, Marange, Josephine, Shabangu, Vusumuzi, Moore, Katy, Lyons, Jill, Munang, Melinda, Sangombe, Mirriam, Moran, Ed, Hussain, Abid, Wiselka, Martin, Lewszuk, Adam, Batham, Sally, Ellis, Kate, Bahadur, Leila, White, Helena, Pareek, Manish, Sahota, Amandip, Coleman, Stephen, Pateman, Hilary, Kotecha, Atul, Sim, Christopher, Rosser, Andrew, Deane, Jill, Nendick, Richard, Aldridge, Catherine, Clarke, Anne, Wood, Michelle, Marshall, Adele, Stephenson, Lynsey, Matheson-Smith, Tracy, Sloss, John, Potts, Kathryn, Malkin, Joanne, Ftika, Lemonia, Raviprakash, Veena, Sutton, Julian, Malachira, Ahalya, Kean, Miranda, Criste, Kristine, Gladas, Kirsty, Andrews, Caroline, Hutchison, Clare, Adams, Ellen, Andrews, Janet, Romans, Belinda, Ridley, Nicola, Ekani, Melanie, Mitchell, Julie, Smith, Nicola, Clark, Tristan, Glover, Sarah, Reed, Robert, Yam, Tat, Burton, Holly, Said, Rasha, Harvey, David, Janvier, Amy, Jacob, Reni, Smalley, Chris, Fair, Alison, Lord, Susan, Ripalda, Kate, Wooldridge, Helen, Cotter, Luis, Cardoso, Gus, Strachan, Elaine, Kaler, Gagan, Mohamoodally, Adam, Lawrence, Emma, Prime, Zoe, Abrahams, Rachel, Price, David Ashley, Rigden, Lesley, Shewan, Laura, Cullen, Katherine, Emmerson, Ingrid, Martin, Karen, Wilson, Hesther, Higham, Charley, Taylor, Kathryn Louise, Ong, Edmund, Patel, Bijal, Bond, Helena, Gradwell, Janine, Widdrington, John, Graham, Clive, Thornthwaite, Sarah, Prentice, Scott, Poultney, Una, Crowther, Hannah, Fairlamb, Helen, Hetherington, Emily, Brewer, Chris, Banerjee, Suryabrata, Hamson, Clare, McSkeane, Anna, McWhinney, Paul, Sharratt, Paula, Thorpe, Joanne, Kimachia, Sue, Wilson, Helen, Jeffs, Benjamin, Masters, Leslie, Wilson, Jonathan, Platt, Judith, Burgess, Lisa, Chadwick, Paul, Jeans, Adam, Keatley, Claire, Moran, Amanda, Swann, Zoe, Pagett, Katherine, Peel, Alex, Howard, Jason, Meisner, Sarah, Maloney, Kate, Masdin, Avril, Wright, Louise, Barlow, Gavin, Crossman, Samantha, Lowthorpe, Vicki, Moore, Emma, Moss, Peter, Parkin, Angela, Wolstencroft, Adam, Warner, Bev, Tarbotton, Clare, Eyre, Alison, Anderson, Anne, Burdett, Tina, Driffill, Amy, Walker, Ann Sarah, Hudson, Fleur, Szubert, Alex, Cairns, Janet, Ward, Denise, Webb, Helen, Russell, Charlotte, Jackson, Brooke, Otiko, Damilola, Borg, Chiara, Masters, Lindsey, Islam, Zaheer, Díaz-Montaña, Carlos, and Johnson, Debbie

Abstract

Staphylococcus aureusbacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureuskilling, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.

Published
2018
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27. Convergent evolution and topologically disruptive polymorphisms among multidrug-resistant tuberculosis in Peru

Author

Grandjean, Louis, Gilman, Robert H, Iwamoto, Tomatada, Köser, Claudio U, Coronel, Jorge, Zimic, Mirko, Török, M Estee, Ayabina, Diepreye, Kendall, Michelle, Fraser, Christophe, Harris, Simon, Parkhill, Julian, Peacock, Sharon J, Moore, David AJ, and Colijn, Caroline

Subjects
Adult, Male, Mycobacterium tuberculosis, Polymorphism, Single Nucleotide, 3. Good health, Young Adult, Genes, Bacterial, Drug Resistance, Multiple, Bacterial, Mutation, Peru, Tuberculosis, Multidrug-Resistant, Humans, Female, Phylogeny
Abstract

BACKGROUND: Multidrug-resistant tuberculosis poses a major threat to the success of tuberculosis control programs worldwide. Understanding how drug-resistant tuberculosis evolves can inform the development of new therapeutic and preventive strategies. METHODS: Here, we use novel genome-wide analysis techniques to identify polymorphisms that are associated with drug resistance, adaptive evolution and the structure of the phylogenetic tree. A total of 471 samples from different patients collected between 2009 and 2013 in the Lima suburbs of Callao and Lima South were sequenced on the Illumina MiSeq platform with 150bp paired-end reads. After alignment to the reference H37Rv genome, variants were called using standardized methodology. Genome-wide analysis was undertaken using custom written scripts implemented in R software. RESULTS: High quality homoplastic single nucleotide polymorphisms were observed in genes known to confer drug resistance as well as genes in the Mycobacterium tuberculosis ESX secreted protein pathway, pks12, and close to toxin/anti-toxin pairs. Correlation of homoplastic variant sites identified that many were significantly correlated, suggestive of epistasis. Variation in genes coding for ESX secreted proteins also significantly disrupted phylogenetic structure. Mutations in ESX genes in key antigenic epitope positions were also found to disrupt tree topology. CONCLUSION: Variation in these genes have a biologically plausible effect on immunogenicity and virulence. This makes functional characterization warranted to determine the effects of these polymorphisms on bacterial fitness and transmission.

28. Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial

Author

Thwaites, Guy E, Scarborough, Matthew, Szubert, Alexander, Nsutebu, Emmanuel, Tilley, Robert, Greig, Julia, Wyllie, Sarah A, Wilson, Peter, Auckland, Cressida, Cairns, Janet, Ward, Denise, Lal, Pankaj, Guleri, Achyut, Jenkins, Neil, Sutton, Julian, Wiselka, Martin, Armando, Gonzalez-Ruiz, Graham, Clive, Chadwick, Paul R, Barlow, Gavin, Gordon, N Claire, Young, Bernadette, Meisner, Sarah, McWhinney, Paul, Price, David A, Harvey, David, Nayar, Deepa, Jeyaratnam, Dakshika, Planche, Tim, Minton, Jane, Hudson, Fleur, Hopkins, Susan, Williams, John, Török, M Estee, Llewelyn, Martin J, Edgeworth, Jonathan D, Walker, A Sarah, and United Kingdom Clinical Infection Research Group (UKCIRG)

Subjects
Male, Cross Infection, Administration, Oral, Bacteremia, Middle Aged, Staphylococcal Infections, Drug Administration Schedule, 3. Good health, Community-Acquired Infections, Double-Blind Method, Humans, Administration, Intravenous, Female, Treatment Failure, Rifampin, Antibiotics, Antitubercular, Aged
Abstract

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment.

29. Transmission of methicillin-resistant Staphylococcus aureus in long-term care facilities and their related healthcare networks

Author

Harrison, Ewan M, Ludden, Catherine, Brodrick, Hayley J, Blane, Beth, Brennan, Gráinne, Morris, Dearbháile, Coll, Francesc, Reuter, Sandra, Brown, Nicholas M, Holmes, Mark A, O'Connell, Brian, Parkhill, Julian, Török, M Estee, Cormican, Martin, and Peacock, Sharon J

Subjects
Adult, DNA, Bacterial, Male, Methicillin-Resistant Staphylococcus aureus, Staphylococcus aureus, MRSA, Transmission, Humans, Prospective Studies, Aged, Aged, 80 and over, Whole-genome sequencing, Cross Infection, Infection Control, Long-term care facilities, Nursing home, High-Throughput Nucleotide Sequencing, biochemical phenomena, metabolism, and nutrition, Middle Aged, Staphylococcal Infections, bacterial infections and mycoses, Long-Term Care, United Kingdom, 3. Good health, Molecular epidemiology, Health Facility Environment, Female, Multilocus Sequence Typing
Abstract

BACKGROUND: Long-term care facilities (LTCF) are potential reservoirs for methicillin-resistant Staphylococcus aureus (MRSA), control of which may reduce MRSA transmission and infection elsewhere in the healthcare system. Whole-genome sequencing (WGS) has been used successfully to understand MRSA epidemiology and transmission in hospitals and has the potential to identify transmission between these and LTCF. METHODS: Two prospective observational studies of MRSA carriage were conducted in LTCF in England and Ireland. MRSA isolates were whole-genome sequenced and analyzed using established methods. Genomic data were available for MRSA isolated in the local healthcare systems (isolates submitted by hospitals and general practitioners). RESULTS: We sequenced a total of 181 MRSA isolates from the two study sites. The majority of MRSA were multilocus sequence type (ST)22. WGS identified one likely transmission event between residents in the English LTCF and three putative transmission events in the Irish LTCF. WGS also identified closely related isolates present in colonized Irish residents and their immediate environment. Based on phylogenetic reconstruction, closely related MRSA clades were identified between the LTCF and their healthcare referral network, together with putative MRSA acquisition by LTCF residents during hospital admission. CONCLUSIONS: These data confirm that MRSA is transmitted between residents of LTCF and is both acquired and transmitted to others in referral hospitals and beyond. Our data present compelling evidence for the importance of environmental contamination in MRSA transmission, reinforcing the importance of environmental cleaning. The use of WGS in this study highlights the need to consider infection control in hospitals and community healthcare facilities as a continuum.

30. Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT

Author

Dakshika Jeyaratnam, Achyut Guleri, Denise Ward, Gonzalez-Ruiz Armando, Martin Wiselka, Julia Greig, Clive Graham, R. Cunningham, Bernadette C. Young, David Harvey, Jonathan D. Edgeworth, Paul R. Chadwick, Matthew Scarborough, Janet Cairns, Guy E. Thwaites, Robert Tilley, Julian Sutton, M. Estée Török, Paul McWhinney, John Williams, Peter R. Wilson, A. Sarah Walker, Deepa Nayar, Pankaj Lal, Gavin Barlow, Emmanuel Nsutebu, Marta Soares, Neil Jenkins, Alexander J. Szubert, Pedro Saramago Goncalves, Sarah A Wyllie, Jennifer Bostock, Cressida Auckland, David Price, Jane Minton, N. Claire Gordon, Susan Hopkins, Sarah Meisner, T. Planche, Fleur Hudson, Martin J. Llewelyn, Thwaites, Guy E [0000-0002-2858-2087], Scarborough, Matthew [0000-0002-0455-0785], Saramago Goncalves, Pedro [0000-0001-9063-8590], Soares, Marta [0000-0003-1579-8513], Bostock, Jennifer [0000-0001-9261-9350], Cunningham, Richard [0000-0002-6081-2153], Young, Bernadette [0000-0001-6071-6770], Hopkins, Susan [0000-0001-5179-5702], Török, M Estee [0000-0001-9098-8590], Llewelyn, Martin J [0000-0002-6811-1124], and Apollo - University of Cambridge Repository

Subjects
Male, 0301 basic medicine, Staphylococcus aureus, medicine.medical_specialty, lcsh:Medical technology, Cost-Benefit Analysis, 030106 microbiology, Bacteremia, Placebo, law.invention, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, Bacteriological Failure, law, Interquartile range, Internal medicine, Drug Resistance, Bacterial, medicine, Humans, 030212 general & internal medicine, Aged, business.industry, Health Policy, Hazard ratio, Middle Aged, Staphylococcal Infections, bacterial infections and mycoses, R1, United Kingdom, Anti-Bacterial Agents, Clinical trial, lcsh:R855-855.5, R852, Quality of Life, Drug Therapy, Combination, Female, Quality-Adjusted Life Years, Flucloxacillin, Health Expenditures, Rifampin, business, Models, Econometric, Rifampicin, Research Article, medicine.drug
Abstract

BackgroundStaphylococcus aureusbacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance earlyS. aureuskilling, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death.ObjectivesTo determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Secondary objectives included evaluating the impact of rifampicin on all-cause mortality, clinically defined failure/recurrence or death, toxicity, resistance emergence, and duration of bacteraemia; and assessing the cost-effectiveness of rifampicin.DesignParallel-group, randomised (1 : 1), blinded, placebo-controlled multicentre trial.SettingUK NHS trust hospitals.ParticipantsAdult inpatients (≥ 18 years) with meticillin-resistant or susceptibleS. aureusgrown from one or more blood cultures, who had received InterventionsAdjunctive rifampicin (600–900 mg/day, oral or intravenous) or placebo for 14 days in addition to standard antibiotic therapy. Investigators and patients were blinded to trial treatment. Follow-up was for 12 weeks (assessments at 3, 7, 10 and 14 days, weekly until discharge and final assessment at 12 weeks post randomisation).Main outcome measuresThe primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation.ResultsBetween December 2012 and October 2016, 758 eligible participants from 29 UK hospitals were randomised: 370 to rifampicin and 388 to placebo. The median age was 65 years [interquartile range (IQR) 50–76 years]. A total of 485 (64.0%) infections were community acquired and 132 (17.4%) were nosocomial; 47 (6.2%) were caused by meticillin-resistantS. aureus. A total of 301 (39.7%) participants had an initial deep infection focus. Standard antibiotics were given for a median of 29 days (IQR 18–45 days) and 619 (81.7%) participants received flucloxacillin. By 12 weeks, 62 out of 370 (16.8%) patients taking rifampicin versus 71 out of 388 (18.3%) participants taking the placebo experienced bacteriological (microbiologically confirmed) failure/recurrence or died [absolute risk difference –1.4%, 95% confidence interval (CI) –7.0% to 4.3%; hazard ratio 0.96, 95% CI 0.68 to 1.35;p = 0.81]. There were 4 (1.1%) and 5 (1.3%) bacteriological failures (p = 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences (p = 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence (p = 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death (p = 0.84), all-cause mortality (p = 0.60), serious (p = 0.17) or grade 3/4 (p = 0.36) adverse events (AEs). However, 63 (17.0%) participants in the rifampicin group versus 39 (10.1%) participants in the placebo group experienced antibiotic or trial drug-modifying AEs (p = 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions (p = 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode ofS. aureusbacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs (p = 0.14). After adjustment, the effect of rifampicin on total quality-adjusted life-years (QALYs) was positive (0.004 QALYs), but not statistically significant (standard error 0.004 QALYs).ConclusionsAdjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults withS. aureusbacteraemia.Future workGiven the substantial mortality, other antibiotic combinations or improved source management should be investigated.Trial registrationsCurrent Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 22, No. 59. See the NIHR Journals Library website for further project information.

Published
2018

31. Convergent evolution and topologically disruptive polymorphisms among multidrug-resistant tuberculosis in Peru

Author

Sharon J. Peacock, Claudio U. Köser, M. Estee Török, Jorge Coronel, Mirko Zimic, Caroline Colijn, Diepreye Ayabina, Robert H. Gilman, David Moore, Louis Grandjean, Christophe Fraser, Julian Parkhill, Simon R. Harris, Michelle Kendall, Tomatada Iwamoto, Engineering & Physical Science Research Council (EPSRC), Mokrousov, I, Grandjean, Louis [0000-0002-1457-8327], Iwamoto, Tomatada [0000-0002-2650-0308], Köser, Claudio U [0000-0002-0232-846X], Török, M Estee [0000-0001-9098-8590], Harris, Simon [0000-0003-1512-6194], Parkhill, Julian [0000-0002-7069-5958], Peacock, Sharon J [0000-0002-1718-2782], Colijn, Caroline [0000-0001-6097-6708], and Apollo - University of Cambridge Repository

Subjects
Bacterial Diseases, Male, 0301 basic medicine, Extensively Drug-Resistant Tuberculosis, Plant Science, Plant Roots, Biochemistry, Genome, 0302 clinical medicine, Drug Resistance, Multiple, Bacterial, Peru, Tuberculosis, Multidrug-Resistant, Medicine and Health Sciences, Phylogeny, Data Management, Genetics, Immune System Proteins, Multidisciplinary, biology, Phylogenetic tree, Plant Anatomy, Phylogenetic Analysis, 3. Good health, Phylogenetics, Actinobacteria, Infectious Diseases, Medicine, Female, Research Article, Adult, Computer and Information Sciences, General Science & Technology, Science, Immunology, Single-nucleotide polymorphism, Microbiology, Polymorphism, Single Nucleotide, Mycobacterium tuberculosis, Young Adult, 03 medical and health sciences, Microbial Control, MD Multidisciplinary, Tuberculosis, Multidrug-Resistant/microbiology, medicine, Tuberculosis, Humans, Evolutionary Systematics, Gene, Taxonomy, Pharmacology, Evolutionary Biology, Bacteria, Organisms, Mycobacterium tuberculosis/drug effects/genetics, Biology and Life Sciences, Proteins, Extensively drug-resistant tuberculosis, Tropical Diseases, biology.organism_classification, medicine.disease, Root Structure, Drug Resistance, Multiple, Bacterial/genetics, 030104 developmental biology, Genes, Bacterial, purl.org/pe-repo/ocde/ford#3.02.07 [https], Antibiotic Resistance, Mutation, Epistasis, Antimicrobial Resistance, 030217 neurology & neurosurgery
Abstract

Background Multidrug-resistant tuberculosis poses a major threat to the success of tuberculosis control programs worldwide. Understanding how drug-resistant tuberculosis evolves can inform the development of new therapeutic and preventive strategies. Methods Here, we use novel genome-wide analysis techniques to identify polymorphisms that are associated with drug resistance, adaptive evolution and the structure of the phylogenetic tree. A total of 471 samples from different patients collected between 2009 and 2013 in the Lima suburbs of Callao and Lima South were sequenced on the Illumina MiSeq platform with 150bp paired-end reads. After alignment to the reference H37Rv genome, variants were called using standardized methodology. Genome-wide analysis was undertaken using custom written scripts implemented in R software. Results High quality homoplastic single nucleotide polymorphisms were observed in genes known to confer drug resistance as well as genes in the Mycobacterium tuberculosis ESX secreted protein pathway, pks12, and close to toxin/anti-toxin pairs. Correlation of homoplastic variant sites identified that many were significantly correlated, suggestive of epistasis. Variation in genes coding for ESX secreted proteins also significantly disrupted phylogenetic structure. Mutations in ESX genes in key antigenic epitope positions were also found to disrupt tree topology. Conclusions Variation in these genes have a biologically plausible effect on immunogenicity and virulence. This makes functional characterization warranted to determine the effects of these polymorphisms on bacterial fitness and transmission.

Published
2017

32. Transmission of methicillin-resistant Staphylococcus aureus in long-term care facilities and their related healthcare networks.

Author

Harrison EM, Ludden C, Brodrick HJ, Blane B, Brennan G, Morris D, Coll F, Reuter S, Brown NM, Holmes MA, O'Connell B, Parkhill J, Török ME, Cormican M, and Peacock SJ

Subjects
Adult, Aged, Aged, 80 and over, Cross Infection epidemiology, Cross Infection microbiology, Cross Infection prevention & control, Female, Health Facility Environment organization & administration, High-Throughput Nucleotide Sequencing, Humans, Infection Control, Long-Term Care, Male, Methicillin-Resistant Staphylococcus aureus isolation & purification, Middle Aged, Multilocus Sequence Typing, Prospective Studies, Staphylococcal Infections epidemiology, Staphylococcal Infections microbiology, Staphylococcal Infections prevention & control, United Kingdom epidemiology, Cross Infection transmission, DNA, Bacterial genetics, Methicillin-Resistant Staphylococcus aureus genetics, Staphylococcal Infections transmission
Abstract

Background: Long-term care facilities (LTCF) are potential reservoirs for methicillin-resistant Staphylococcus aureus (MRSA), control of which may reduce MRSA transmission and infection elsewhere in the healthcare system. Whole-genome sequencing (WGS) has been used successfully to understand MRSA epidemiology and transmission in hospitals and has the potential to identify transmission between these and LTCF., Methods: Two prospective observational studies of MRSA carriage were conducted in LTCF in England and Ireland. MRSA isolates were whole-genome sequenced and analyzed using established methods. Genomic data were available for MRSA isolated in the local healthcare systems (isolates submitted by hospitals and general practitioners)., Results: We sequenced a total of 181 MRSA isolates from the two study sites. The majority of MRSA were multilocus sequence type (ST)22. WGS identified one likely transmission event between residents in the English LTCF and three putative transmission events in the Irish LTCF. WGS also identified closely related isolates present in colonized Irish residents and their immediate environment. Based on phylogenetic reconstruction, closely related MRSA clades were identified between the LTCF and their healthcare referral network, together with putative MRSA acquisition by LTCF residents during hospital admission., Conclusions: These data confirm that MRSA is transmitted between residents of LTCF and is both acquired and transmitted to others in referral hospitals and beyond. Our data present compelling evidence for the importance of environmental contamination in MRSA transmission, reinforcing the importance of environmental cleaning. The use of WGS in this study highlights the need to consider infection control in hospitals and community healthcare facilities as a continuum.

Published
2016
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33. Outpatient parenteral antimicrobial therapy: Recent developments and future prospects.

Author

Török ME, Chapman AL, Lessing MP, Sanderson F, and Seaton RA

Subjects
Aminoglycosides administration & dosage, Aminoglycosides pharmacology, Aminoglycosides therapeutic use, Anti-Bacterial Agents pharmacology, Anti-Infective Agents therapeutic use, Daptomycin administration & dosage, Daptomycin pharmacology, Daptomycin therapeutic use, Dosage Forms, Ertapenem, Humans, Infusions, Parenteral, Lipoglycopeptides, Teicoplanin administration & dosage, Teicoplanin analogs & derivatives, Teicoplanin pharmacology, Teicoplanin therapeutic use, beta-Lactams administration & dosage, beta-Lactams pharmacology, beta-Lactams therapeutic use, Ambulatory Care, Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents therapeutic use, Anti-Infective Agents administration & dosage
Abstract

Patients with serious infections requiring parenteral antimicrobial therapy are usually hospitalized for treatment. For certain conditions, however, administration of parenteral antibiotics outside the hospital setting may be safe, efficacious, convenient for patients and cost-beneficial. Outpatient parenteral antimicrobial therapy (OPAT) was developed in the US initially and its use has expanded globally during the past three decades. A wide variety of infections are amenable to treatment by OPAT. Once-daily agents such as ceftriaxone or teicoplanin and, more recently, antimicrobials such as ertapenem or daptomycin have been used for OPAT. The use of higher doses and less-frequent dosing of existing agents is being explored, and exciting new developments include the emergence of agents with broader-spectrum activity against drug-resistant organisms and the use of antifungal agents in the OPAT setting. Future prospects in OPAT include the use of more recently launched drugs such as telavancin, as well as drugs in development, including dalbavancin (Durata Therapeutics Inc) and omadacycline (PTK-0796; Novartis AG/PARATEK Pharmaceuticals Inc). This review outlines recent developments in, and future prospects for, the antimicrobial agents used in OPAT.

Published
2010

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