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6. SARS-CoV-2 evolution during treatment of chronic infection

Author

Kemp, S. A., Collier, D. A., Datir, R. P., Ferreira, I. A. T. M., Gayed, S., Jahun, A., Hosmillo, M., Rees-Spear, C., Mlcochova, P., Lumb, I. U., Roberts, D. J., Chandra, A., Temperton, N., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O'Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Bullman, B., Dunmore, B. J., Fawke, S., Graf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Pond, N., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Bergamaschi, L., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Gleadall, N., Grenfell, R., Hinch, A., Huhn, O., Jackson, S., Jarvis, I., Lewis, D., Marsden, J., Nice, F., Okecha, G., Omarjee, O., Perera, M., Richoz, N., Romashova, V., Yarkoni, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Rossi, S., Selvan, M., Spencer, S., Yong, C., Ansaripour, A., Michael, A., Mwaura, L., Patterson, C., Polwarth, G., Polgarova, P., di Stefano, G., Fahey, C., Michel, R., Bong, S. -H., Coudert, J. D., Holmes, E., Allison, J., Butcher, H., Caputo, D., Clapham-Riley, D., Dewhurst, E., Furlong, A., Graves, B., Gray, J., Ivers, T., Kasanicki, M., Le Gresley, E., Linger, R., Meloy, S., Muldoon, F., Ovington, N., Papadia, S., Phelan, I., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Robson, S. C., Loman, N. J., Connor, T. R., Golubchik, T., Martinez Nunez, R. T., Ludden, C., Corden, S., Johnston, I., Bonsall, D., Smith, C. P., Awan, A. R., Bucca, G., Estee Torok, M., Saeed, K., Prieto, J. A., Jackson, D. K., Hamilton, W. L., Snell, L. B., Moore, C., Harrison, E. M., Goncalves, S., Fairley, D. J., Loose, M. W., Watkins, J., Livett, R., Moses, S., Amato, R., Nicholls, S., Bull, M., Smith, D. L., Barrett, J., Aanensen, D. M., Curran, M. D., Parmar, S., Aggarwal, D., Shepherd, J. G., Parker, M. D., Glaysher, S., Bashton, M., Underwood, A. P., Pacchiarini, N., Loveson, K. F., Carabelli, A. M., Templeton, K. E., Langford, C. F., Sillitoe, J., de Silva, T. I., Wang, D., Kwiatkowski, D., Rambaut, A., O'Grady, J., Cottrell, S., Holden, M. T. G., Thomson, E. C., Osman, H., Andersson, M., Chauhan, A. J., Hassan-Ibrahim, M. O., Lawniczak, M., Alderton, A., Chand, M., Constantinidou, C., Unnikrishnan, M., Darby, A. C., Hiscox, J. A., Paterson, S., Martincorena, I., Robertson, D. L., Volz, E. M., Page, A. J., Pybus, O. G., Bassett, A. R., Ariani, C. V., Spencer Chapman, M. H., K. K., Li, Shah, R. N., Jesudason, N. G., Taha, Y., Mchugh, M. P., Dewar, R., Jahun, A. S., Mcmurray, C., Pandey, S., Mckenna, J. P., Nelson, A., Young, G. R., Mccann, C. M., Elliott, S., Lowe, H., Temperton, B., Roy, S., Price, A., Rey, S., Wyles, M., Rooke, S., Shaaban, S., de Cesare, M., Letchford, L., Silveira, S., Pelosi, E., Wilson-Davies, E., O'Toole, A., Hesketh, A. R., Stark, R., du Plessis, L., Ruis, C., Adams, H., Bourgeois, Y., Michell, S. L., Gramatopoulos, D., Edgeworth, J., Breuer, J., Todd, J. A., Fraser, C., Buck, D., John, M., Kay, G. L., Palmer, S., Peacock, S. J., Heyburn, D., Weldon, D., Robinson, E., Mcnally, A., Muir, P., Vipond, I. B., Boyes, J., Sivaprakasam, V., Salluja, T., Dervisevic, S., Meader, E. J., Park, N. R., Oliver, K., Jeffries, A. R., Ott, S., da Silva Filipe, A., Simpson, D. A., Williams, C., Masoli, J. A. H., Knight, B. A., Jones, C. R., Koshy, C., Ash, A., Casey, A., Bosworth, A., Ratcliffe, L., Xu-McCrae, L., Pymont, H. M., Hutchings, S., Berry, L., Jones, K., Halstead, F., Davis, T., Holmes, C., Iturriza-Gomara, M., Lucaci, A. O., Randell, P. A., Cox, A., Madona, P., Harris, K. A., Brown, J. R., Mahungu, T. W., Irish-Tavares, D., Haque, T., Hart, J., Witele, E., Fenton, M. L., Liggett, S., Graham, C., Swindells, E., Collins, J., Eltringham, G., Campbell, S., Mcclure, P. C., Clark, G., Sloan, T. J., Jones, C., Lynch, J., Warne, B., Leonard, S., Durham, J., Williams, T., Haldenby, S. T., Storey, N., Alikhan, N. -F., Holmes, N., Carlile, M., Perry, M., Craine, N., Lyons, R. A., Beckett, A. H., Goudarzi, S., Fearn, C., Cook, K., Dent, H., Paul, H., Davies, R., Blane, B., Girgis, S. T., Beale, M. A., Bellis, K. L., Dorman, M. J., Drury, E., Kane, L., Kay, S., Mcguigan, S., Nelson, R., Prestwood, L., Rajatileka, S., Batra, R., Williams, R. J., Kristiansen, M., Green, A., Justice, A., Mahanama, A. I. K., Samaraweera, B., Hadjirin, N. F., Quick, J., Poplawski, R., Kermack, L. M., Reynolds, N., Hall, G., Chaudhry, Y., Pinckert, M. L., Georgana, I., Moll, R. J., Thornton, A., Myers, R., Stockton, J., Williams, C. A., Yew, W. C., Trotter, A. J., Trebes, A., MacIntyre-Cockett, G., Birchley, A., Adams, A., Plimmer, A., Gatica-Wilcox, B., Mckerr, C., Hilvers, E., Jones, H., Asad, H., Coombes, J., Evans, J. M., Fina, L., Gilbert, L., Graham, L., Cronin, M., Kumziene-Summerhayes, S., Taylor, S., Jones, S., Groves, D. C., Zhang, P., Gallis, M., Louka, S. F., Starinskij, I., Jackson, C., Gourtovaia, M., Tonkin-Hill, G., Lewis, K., Tovar-Corona, J. M., James, K., Baxter, L., Alam, M. T., Orton, R. J., Hughes, J., Vattipally, S., Ragonnet-Cronin, M., Nascimento, F. F., Jorgensen, D., Boyd, O., Geidelberg, L., Zarebski, A. E., Raghwani, J., Kraemer, M. U. G., Southgate, J., Lindsey, B. B., Freeman, T. M., Keatley, J. -P., Singer, J. B., de Oliveira Martins, L., Yeats, C. A., Abudahab, K., Taylor, B. E. W., Menegazzo, M., Danesh, J., Hogsden, W., Eldirdiri, S., Kenyon, A., Mason, J., Robinson, T. I., Holmes, A., Hartley, J. A., Curran, T., Mather, A. E., Shankar, G., Jones, R., Howe, R., Morgan, S., Wastenge, E., Chapman, M. R., Mookerjee, S., Stanley, R., Smith, W., Peto, T., Eyre, D., Crook, D., Vernet, G., Kitchen, C., Gulliver, H., Merrick, I., Guest, M., Munn, R., Bradley, D. T., Wyatt, T., Beaver, C., Foulser, L., Churcher, C. M., Brooks, E., Smith, K. S., Galai, K., Mcmanus, G. M., Bolt, F., Coll, F., Meadows, L., Attwood, S. W., Davies, A., De Lacy, E., Downing, F., Edwards, S., Scarlett, G. P., Jeremiah, S., Smith, N., Leek, D., Sridhar, S., Forrest, S., Cormie, C., Gill, H. K., Dias, J., Higginson, E. E., Maes, M., Young, J., Wantoch, M., Jamrozy, D., Lo, S., Patel, M., Hill, V., Bewshea, C. M., Ellard, S., Auckland, C., Harrison, I., Bishop, C., Chalker, V., Richter, A., Beggs, A., Best, A., Percival, B., Mirza, J., Megram, O., Mayhew, M., Crawford, L., Ashcroft, F., Moles-Garcia, E., Cumley, N., Hopes, R., Asamaphan, P., Niebel, M. O., Gunson, R. N., Bradley, A., Maclean, A., Mollett, G., Blacow, R., Bird, P., Helmer, T., Fallon, K., Tang, J., Hale, A. D., Macfarlane-Smith, L. R., Harper, K. L., Carden, H., Machin, N. W., Jackson, K. A., Ahmad, S. S. Y., George, R. P., Turtle, L., O'Toole, E., Watts, J., Breen, C., Cowell, A., Alcolea-Medina, A., Charalampous, T., Patel, A., Levett, L. J., Heaney, J., Rowan, A., Taylor, G. P., Shah, D., Atkinson, L., Lee, J. C. D., Westhorpe, A. P., Jannoo, R., Lowe, H. L., Karamani, A., Ensell, L., Chatterton, W., Pusok, M., Dadrah, A., Symmonds, A., Sluga, G., Molnar, Z., Baker, P., Bonner, S., Essex, S., Barton, E., Padgett, D., Scott, G., Greenaway, J., Payne, B. A. I., Burton-Fanning, S., Waugh, S., Raviprakash, V., Sheriff, N., Blakey, V., Williams, L. -A., Moore, J., Stonehouse, S., Smith, L., Davidson, R. K., Bedford, L., Coupland, L., Wright, V., Chappell, J. G., Tsoleridis, T., Ball, J., Khakh, M., Fleming, V. M., Lister, M. M., Howson-Wells, H. C., Boswell, T., Joseph, A., Willingham, I., Duckworth, N., Walsh, S., Wise, E., Moore, N., Mori, M., Cortes, N., Kidd, S., Williams, R., Gifford, L., Bicknell, K., Wyllie, S., Lloyd, A., Impey, R., Malone, C. S., Cogger, B. J., Levene, N., Monaghan, L., Keeley, A. J., Partridge, D. G., Raza, M., Evans, C., Johnson, K., Abnizova, I., Aigrain, L., Ali, M., Allen, L., Anderson, R., Ariani, C., Austin-Guest, S., Bala, S., Bassett, A., Battleday, K., Beal, J., Beale, M., Bellany, S., Bellerby, T., Bellis, K., Berger, D., Berriman, M., Betteridge, E., Bevan, P., Binley, S., Bishop, J., Blackburn, K., Bonfield, J., Boughton, N., Bowker, S., Brendler-Spaeth, T., Bronner, I., Brooklyn, T., Buddenborg, S. K., Bush, R., Caetano, C., Cagan, A., Carter, N., Cartwright, J., Monteiro, T. C., Chapman, L., Chillingworth, T. -J., Clapham, P., Clark, R., Clarke, A., Clarke, C., Cole, D., Cook, E., Coppola, M., Cornell, L., Cornwell, C., Corton, C., Crackett, A., Cranage, A., Craven, H., Craw, S., Crawford, M., Cutts, T., Dabrowska, M., Davies, M., Dawson, J., Day, C., Densem, A., Dibling, T., Dockree, C., Dodd, D., Dogga, S., Dougherty, M., Dove, A., Drummond, L., Dudek, M., Durrant, L., Easthope, E., Eckert, S., Ellis, P., Farr, B., Fenton, M., Ferrero, M., Flack, N., Fordham, H., Forsythe, G., Francis, M., Fraser, A., Freeman, A., Galvin, A., Garcia-Casado, M., Gedny, A., Girgis, S., Glover, J., Goodwin, S., Gould, O., Gray, A., Gray, E., Griffiths, C., Gu, Y., Guerin, F., Hamilton, W., Hanks, H., Harrison, E., Harrott, A., Harry, E., Harvison, J., Heath, P., Hernandez-Koutoucheva, A., Hobbs, R., Holland, D., Holmes, S., Hornett, G., Hough, N., Huckle, L., Hughes-Hallet, L., Hunter, A., Inglis, S., Iqbal, S., Jackson, A., Jackson, D., Verdejo, C. J., Jones, M., Kallepally, K., Kay, K., Keatley, J., Keith, A., King, A., Kitchin, L., Kleanthous, M., Klimekova, M., Korlevic, P., Krasheninnkova, K., Lane, G., Langford, C., Laverack, A., Law, K., Lensing, S., Lewis-Wade, A., Liddle, J., Lin, Q., Lindsay, S., Linsdell, S., Long, R., Lovell, J., Mack, J., Maddison, M., Makunin, A., Mamun, I., Mansfield, J., Marriott, N., Martin, M., Mayho, M., Mccarthy, S., Mcclintock, J., Mchugh, S., Mcminn, L., Meadows, C., Mobley, E., Moll, R., Morra, M., Morrow, L., Murie, K., Nash, S., Nathwani, C., Naydenova, P., Neaverson, A., Nerou, E., Nicholson, J., Nimz, T., Noell, G. G., O'Meara, S., Ohan, V., Olney, C., Ormond, D., Oszlanczi, A., Pang, Y. F., Pardubska, B., Park, N., Parmar, A., Patel, G., Payne, M., Peacock, S., Petersen, A., Plowman, D., Preston, T., Puethe, C., Quail, M., Rajan, D., Rance, R., Rawlings, S., Redshaw, N., Reynolds, J., Reynolds, M., Rice, S., Richardson, M., Roberts, C., Robinson, K., Robinson, M., Robinson, D., Rogers, H., Rojo, E. M., Roopra, D., Rose, M., Rudd, L., Sadri, R., Salmon, N., Saul, D., Schwach, F., Scott, C., Seekings, P., Shirley, L., Simms, A., Sinnott, M., Sivadasan, S., Siwek, B., Sizer, D., Skeldon, K., Skelton, J., Slater-Tunstill, J., Sloper, L., Smerdon, N., Smith, C., Smith, J., Smith, K., Smith, M., Smith, S., Smith, T., Sneade, L., Soria, C. D., Sousa, C., Souster, E., Sparkes, A., Spencer-Chapman, M., Squares, J., Steed, C., Stickland, T., Still, I., Stratton, M., Strickland, M., Swann, A., Swiatkowska, A., Sycamore, N., Swift, E., Symons, E., Szluha, S., Taluy, E., Tao, N., Taylor, K., Thompson, S., Thompson, M., Thomson, M., Thomson, N., Thurston, S., Toombs, D., Topping, B., Tovar-Corona, J., Ungureanu, D., Uphill, J., Urbanova, J., Jansen Van, P., Vancollie, V., Voak, P., Walker, D., Walker, M., Waller, M., Ward, G., Weatherhogg, C., Webb, N., Wells, A., Wells, E., Westwood, L., Whipp, T., Whiteley, T., Whitton, G., Whitwham, A., Widaa, S., Williams, M., Wilson, M., Wright, S., Farr, B. W., Quail, M. A., Thurston, S. A. J., Bronner, I. F., Redshaw, N. M., Lensing, S. V., Balcazar, C. E., Gallagher, M. D., Williamson, K. A., Stanton, T. D., Michelsen, M. L., Warwick-Dugdale, J., Manley, R., Farbos, A., Harrison, J. W., Sambles, C. M., Studholme, D. J., Lackenby, A., Mbisa, T., Platt, S., Miah, S., Bibby, D., Manso, C., Hubb, J., Dabrera, G., Ramsay, M., Bradshaw, D., Schaefer, U., Groves, N., Gallagher, E., Lee, D., Williams, D., Ellaby, N., Hartman, H., Manesis, N., Patel, V., Ledesma, J., Twohig, K. A., Allara, E., Pearson, C., Cheng, J. K. J., Bridgewater, H. E., Frost, L. R., Taylor-Joyce, G., Brown, P. E., Tong, L., Broos, A., Mair, D., Nichols, J., Carmichael, S. N., Smollett, K. L., Nomikou, K., Aranday-Cortes, E., Johnson, N., Nickbakhsh, S., Vamos, E. E., Hughes, M., Rainbow, L., Eccles, R., Nelson, C., Whitehead, M., Gregory, R., Gemmell, M., Wierzbicki, C., Webster, H. J., Fisher, C. L., Signell, A. W., Betancor, G., Wilson, H. D., Nebbia, G., Flaviani, F., Cerda, A. C., Merrill, T. V., Wilson, R. E., Cotic, M., Bayzid, N., Thompson, T., Acheson, E., Rushton, S., O'Brien, S., Baker, D. J., Rudder, S., Aydin, A., Sang, F., Debebe, J., Francois, S., Vasylyeva, T. I., Zamudio, M. E., Gutierrez, B., Marchbank, A., Maksimovic, J., Spellman, K., Mccluggage, K., Morgan, M., Beer, R., Afifi, S., Workman, T., Fuller, W., Bresner, C., Angyal, A., Green, L. R., Parsons, P. J., Tucker, R. M., Brown, R., Whiteley, M., Rowe, W., Siveroni, I., Le-Viet, T., Gaskin, A., Johnson, R., Sharrocks, K., Blane, E., Modis, Y., Leigh, K. E., Briggs, J. A. G., van Gils, M. J., Smith, K. G. C., Bradley, J. R., Doffinger, R., Ceron-Gutierrez, L., Barcenas-Morales, G., Pollock, D. D., Goldstein, R. A., Smielewska, A., Skittrall, J. P., Gouliouris, T., Goodfellow, I. G., Gkrania-Klotsas, E., Illingworth, C. J. R., Mccoy, L. E., Gupta, R. K., Medical Microbiology and Infection Prevention, AII - Infectious diseases, Collier, Dami A [0000-0001-5446-4423], Jahun, Aminu [0000-0002-4585-1701], Temperton, Nigel [0000-0002-7978-3815], Modis, Yorgo [0000-0002-6084-0429], Briggs, John AG [0000-0003-3990-6910], Goldstein, Richard A [0000-0001-5148-4672], Skittrall, Jordan P [0000-0002-8228-3758], Gkrania-Klotsas, Effrossyni [0000-0002-0930-8330], McCoy, Laura E [0000-0001-9503-7946], Gupta, Ravindra K [0000-0001-9751-1808], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Time Factors, viruses, Passive, Antibodies, Viral, CITIID-NIHR BioResource COVID-19 Collaboration, 2.1 Biological and endogenous factors, Viral, Aetiology, Neutralizing, Lung, Phylogeny, neutralising antibodies, Infectivity, education.field_of_study, Genome, Multidisciplinary, Alanine, biology, High-Throughput Nucleotide Sequencing, Viral Load, Spike Glycoprotein, Virus Shedding, Adenosine Monophosphate, Aged, Antibodies, Neutralizing, COVID-19, Chronic Disease, Genome, Viral, Humans, Immune Evasion, Immune Tolerance, Immunization, Passive, Immunosuppression Therapy, Mutagenesis, Mutant Proteins, Mutation, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Evolution, Molecular, Infectious Diseases, Pneumonia & Influenza, Antibody, Infection, Viral load, Biotechnology, Evolution, General Science & Technology, antibody escape, Convalescent plasma, 030106 microbiology, Population, evasion, Antibodies, Virus, Article, Vaccine Related, resistance, 03 medical and health sciences, Immune system, COVID-19 Genomics UK (COG-UK) Consortium, Biodefense, Genetics, Viral shedding, education, COVID-19 Serotherapy, QR355, Prevention, Wild type, Molecular, Pneumonia, Virology, COVID-19 Drug Treatment, Coronavirus, Emerging Infectious Diseases, Good Health and Well Being, 030104 developmental biology, biology.protein, Immunization, immune suppression, mutation
Abstract

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.

Published
2021

7. The interplay between community and hospital Enterococcus faecium clones within health-care settings: a genomic analysis.

Author

van Hal, SJ, Willems, RJL, Gouliouris, T, Ballard, SA, Coque, TM, Hammerum, AM, Hegstad, K, Pinholt, M, Howden, BP, Malhotra-Kumar, S, Werner, G, Yanagihara, K, Earl, AM, Raven, KE, Corander, J, Bowden, R, Enterococcal Study Group, van Hal, SJ, Willems, RJL, Gouliouris, T, Ballard, SA, Coque, TM, Hammerum, AM, Hegstad, K, Pinholt, M, Howden, BP, Malhotra-Kumar, S, Werner, G, Yanagihara, K, Earl, AM, Raven, KE, Corander, J, Bowden, R, and Enterococcal Study Group

Abstract

BACKGROUND: The genomic relationships among Enterococcus faecium isolates are the subject of ongoing research that seeks to clarify the origins of observed lineages and the extent of horizontal gene transfer between them, and to robustly identify links between genotypes and phenotypes. E faecium is considered to form distinct groups-A and B-corresponding to isolates derived from patients who were hospitalised (A) and isolates from humans in the community (B). The additional separation of A into the so-called clades A1 and A2 remains an area of uncertainty. We aimed to investigate the relationships between A1 and non-A1 groups and explore the potential role of non-A1 isolates in shaping the population structure of hospital E faecium. METHODS: We collected short-read sequence data from invited groups that had previously published E faecium genome data. This hospital-based isolate collection could be separated into three groups (or clades, A1, A2, and B) by augmenting the study genomes with published sequences derived from human samples representing the previously defined genomic clusters. We performed phylogenetic analyses, by constructing maximum-likelihood phylogenetic trees, and identified historical recombination events. We assessed the pan-genome, did resistome analysis, and examined the genomic data to identify mobile genetic elements. Each genome underwent chromosome painting by use of ChromoPainter within FineSTRUCTURE software to assess ancestry and identify hybrid groups. We further assessed highly admixed regions to infer recombination directionality. FINDINGS: We assembled a collection of 1095 hospital E faecium sequences from 34 countries, further augmented by 33 published sequences. 997 (88%) of 1128 genomes clustered as A1, 92 (8%) as A2, and 39 (4%) as B. We showed that A1 probably emerged as a clone from within A2 and that, because of ongoing gene flow, hospital isolates currently identified as A2 represent a genetic continuum between A1 and community

Published
2022

10. The global dissemination of hospital clones of Enterococcus faecium

Author

van Hal, SJ, Willems, RJL, Gouliouris, T, Ballard, SA, Coque, TM, Hammerum, AM, Hegstad, K, Westh, HT, Howden, BP, Malhotra-Kumar, S, Werner, G, Yanagihara, K, Earl, AM, Raven, KE, Corander, J, Bowden, R, van Hal, SJ, Willems, RJL, Gouliouris, T, Ballard, SA, Coque, TM, Hammerum, AM, Hegstad, K, Westh, HT, Howden, BP, Malhotra-Kumar, S, Werner, G, Yanagihara, K, Earl, AM, Raven, KE, Corander, J, and Bowden, R

Abstract

BACKGROUND: The hospital-adapted A1 group of Enterococcus faecium remains an organism of significant concern in the context of drug-resistant hospital-associated infections. How this pathogen evolves and disseminates remains poorly understood. METHODS: A large, globally representative collection of short-read genomic data from the hospital-associated A1 group of Enterococcus faecium was assembled (n = 973). We analysed, using a novel analysis approach, global diversity in terms of both the dynamics of the accessory genome and homologous recombination among conserved genes. RESULTS: Two main modes of genomic evolution continue to shape E. faecium: the acquisition and loss of genes, including antimicrobial resistance genes, through mobile genetic elements including plasmids, and homologous recombination of the core genome. These events lead to new clones emerging at the local level, followed by the erosion of signals of clonality through recombination, and in some identifiable cases producing new clonal clusters. These patterns lead to new, emerging lineages which are able to spread globally over relatively short timeframes. CONCLUSIONS: The ability of A1 E. faecium to continually present new combinations of genes for potential selection suggests that controlling this pathogen will remain challenging but establishing a framework for understanding genomic evolution is likely to aid in tracking the threats posed by newly emerging lineages.

Published
2021

11. Vancomycin MIC as a predictor of outcome in MRSA bacteraemia in the UK context

Author

Hope, R., Blackburn, R. M., Verlander, N. Q., Johnson, A. P., Kearns, A., Hill, R., Hopkins, S., Sheridan, E., Livermore, D. M., Scarborough, M., Majumdar, S., Cunniffe, J., Farrington, M., Gouliouris, T., Marodi, C., Godwin, P., Tuck, A., Warren, R., Coe, P., Hassan, I., Mannion, P., Loudon, K., Youngs, E., Johnson, A., Lee, M., Weston, V., Guleri, A., Howe, R., Matthew, D., Cotterill, S., Todd, N., Patel, B., Mlangeni, D., Stockley, J. M., Spencer, R., Gardner, J., Thwaites, G., Kirby, A., Hopkins, S., Crook, D., Llewellyn, M., Price, J., Scarborough, M., Morris Jones, S., and Tilley, R.

Published
2013
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14. Comparison of two chromogenic media for the detection of vancomycin-resistant enterococcal carriage by nursing home residents

Author

Gouliouris, T, Blane, B, Brodrick, H, Raven, K, Ambridge, K, Kidney, A, Hadjirin, N, Török, M, Limmathurotsakul, D, Peacock, S, Peacock, Sharon [0000-0002-1718-2782], and Apollo - University of Cambridge Repository

Subjects
Microbiology (medical), Bacteriological Techniques, VRE, Enterococcus faecium, Bacteriology, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, Sensitivity and Specificity, Culture Media, Nursing Homes, Vancomycin-Resistant Enterococci, Detection, Feces, Infectious Diseases, Sensitivity, Chromogenic Compounds, Carrier State, Enterococcus faecalis, bacteria, Humans, Selectivity, Prospective Studies, Gram-Positive Bacterial Infections
Abstract

We compared ChromID VRE and Brilliance VRE media for the detection of vancomycin-resistant enterococci (VRE). Using a panel of 28 enterococcal isolates, 10 vanA Enterococcus faecium and three vanA Enterococcus faecalis isolates grew as per manufacturers’ instructions whilst growth of two vanC and eight vancomycin-susceptible enterococci was inhibited on both media. Important differences were noted in the selectivity and chromogenic properties of the two media for vanA Enterococcus raffinosus and vanB E. faecium. The two media were further evaluated using 295 stool samples from nursing home residents, 34 of which grew VRE (11.5%). ChromID and Brilliance had comparable sensitivity, which was increased markedly by prolonging incubation to 48 hours (from 29% to 82%, and from 41% to 85%, respectively) and by a pre-enrichment step (to 97% and 100%, respectively). Brilliance VRE agar had higher selectivity at 48 hours, and after pre-enrichment.

Published
2016

15. Duration of exposure to multiple antibiotics is associated with increased risk of VRE bacteraemia: a nested case-control study

Author

Gouliouris, T, Warne, B, Cartwright, E, Bedford, L, Weerasuriya, C, Raven, K, Brown, N, Török, M, Limmathurotsakul, D, Peacock, S, Warne, Ben [0000-0003-1326-0373], Peacock, Sharon [0000-0002-1718-2782], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Cross Infection, Time Factors, Bacteremia, Vancomycin Resistance, biochemical phenomena, metabolism, and nutrition, Middle Aged, bacterial infections and mycoses, United Kingdom, Anti-Bacterial Agents, Antimicrobial Stewardship, Intensive Care Units, Logistic Models, Risk Factors, Vancomycin, Case-Control Studies, Humans, Female, Enterococcus, Gram-Positive Bacterial Infections, Original Research, Aged, Retrospective Studies
Abstract

Background VRE bacteraemia has a high mortality and continues to defy control. Antibiotic risk factors for VRE bacteraemia have not been adequately defined. We aimed to determine the risk factors for VRE bacteraemia focusing on duration of antibiotic exposure. Methods A retrospective matched nested case-control study was conducted amongst hospitalized patients at Cambridge University Hospitals NHS Foundation Trust (CUH) from 1 January 2006 to 31 December 2012. Cases who developed a first episode of VRE bacteraemia were matched 1:1 to controls by length of stay, year, specialty and ward type. Independent risk factors for VRE bacteraemia were evaluated using conditional logistic regression. Results Two hundred and thirty-five cases were compared with 220 controls. Duration of exposure to parenteral vancomycin, fluoroquinolones and meropenem was independently associated with VRE bacteraemia. Compared with patients with no exposure to vancomycin, those who received courses of 1–3 days, 4–7 days or.7 days had a stepwise increase in risk of VRE bacteraemia [conditional OR (cOR) 1.2 (95% CI 0.4–3.8), 3.8 (95% CI 1.2–11.7) and 6.6 (95% CI 1.9–22.8), respectively]. Other risk factors were: presence of a central venous catheter (CVC) [cOR 8.7 (95% CI 2.6–29.5)]; neutropenia [cOR 15.5 (95% CI 4.2–57.0)]; hypoalbuminaemia [cOR 8.5 (95% CI 2.4–29.5)]; malignancy [cOR 4.4 (95% CI 1.6–12.0)]; gastrointestinal disease [cOR 12.4 (95% CI 4.2–36.8)]; and hepatobiliary disease [cOR 7.9 (95% CI 2.1–29.9)]. Conclusions Longer exposure to vancomycin, fluoroquinolones or meropenemwas associated with VRE bacteraemia. Antimicrobial stewardship interventions targeting high-risk antibiotics are required to complement infection control procedures against VRE bacteraemia.

Published
2018

16. Primary pneumococcal peritonitis can be the first presentation of a familial complement factor I deficiency1.

Author

Ugrinovic, S., Firth, H., Kavanagh, D., Gouliouris, T., Gurugama, P., Baxendale, H., Lachmann, P. J., Kumararatne, D., and Gkrania‐Klotsas, E.

Subjects
PERITONITIS, STREPTOCOCCUS pneumoniae, PHAGOCYTOSIS
Abstract

Summary: Primary pneumococcal peritonitis is a rare infection that has been described in women but has not been previously linked with immunodeficiency. The complement system plays a central role in immune defence against Streptococcus pneumoniae and, in order to evade complement attack, pneumococci have evolved a large number of mechanisms that limit complement‐mediated opsonization and subsequent phagocytosis. We investigated an apparently immunocompetent woman with primary pneumococcal peritonitis and identified a family with deficiency for complement factor I. Primary pneumococcal peritonitis should be considered a possible primary immunodeficiency presentation. [ABSTRACT FROM AUTHOR]

Published
2020
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27. Service evaluation to establish the sensitivity, specificity and additional value of broad-range 16S rDNA PCR for the diagnosis of infective endocarditis from resected endocardial material in patients from eight UK and Ireland hospitals

Author

Harris, K. A., Yam, T., Jalili, S., Williams, O. M., Alshafi, K., Gouliouris, T., Munthali, P., NiRiain, U., and Hartley, J. C.

Subjects
Adult, DNA, Bacterial, Male, Microbiology (medical), bartonella, Adolescent, polymerase-chain-reaction, DNA, Ribosomal, Polymerase Chain Reaction, Sensitivity and Specificity, culture-negative endocarditis, Article, valves, Young Adult, Predictive Value of Tests, RNA, Ribosomal, 16S, Humans, guidelines, Pathology, Molecular, Child, Aged, Aged, 80 and over, Bacteria, Endocarditis, Infant, Middle Aged, Hospitals, United Kingdom, Infectious Diseases, etiologic diagnosis, Child, Preschool, Female, Ireland, Endocardium
Abstract

Infective endocarditis (IE) can be diagnosed in the clinical microbiology laboratory by culturing explanted heart valve material. We present a service evaluation that examines the sensitivity and specificity of a broad-range 16S rDNA polymerase chain reaction (PCR) assay for the detection of the causative microbe in culture-proven and culture-negative cases of IE. A clinical case-note review was performed for 151 patients, from eight UK and Ireland hospitals, whose endocardial specimens were referred to the Microbiology Laboratory at Great Ormond Street Hospital (GOSH) for broad-range 16S rDNA PCR over a 12-year period. PCR detects the causative microbe in 35/47 cases of culture-proven IE and provides an aetiological agent in 43/69 cases of culture-negative IE. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the 16S rDNA PCR assay were calculated for this series of selected samples using the clinical diagnosis of IE as the reference standard. The values obtained are as follows: sensitivity = 67 %, specificity = 91 %, PPV = 96 % and NPV = 46 %. A wide range of organisms are detected by PCR, with Streptococcus spp. detected most frequently and a relatively large number of cases of Bartonella spp. and Tropheryma whipplei IE. PCR testing of explanted heart valves is recommended in addition to culture techniques to increase diagnostic yield. The data describing the aetiological agents in a large UK and Ireland series of culture-negative IE will allow future development of the diagnostic algorithm to include real-time PCR assays targeted at specific organisms.

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28. Photoquiz. Holoinspiratory wheezing in a 46-year-old HIV-seropositive man

Author

Di Bella, S., Taglietti, F., Cicalini, S., Baiocchini, A., Maurizio Martini, Galluccio, G., Gouliouris, T., Petrosillo, N., Di Bella, S, Taglietti, F, Cicalini, S, Baiocchini, A, Martini, M, Galluccio, G, Gouliouris, T, and Petrosillo, N

Subjects
Male, Microscopy, Papilloma, Histocytochemistry, Papillomavirus Infections, HIV, Endoscopy, HIV Infections, Middle Aged, Trachea, AIDS, human papillomavirus, respiratory infection, Humans, Radiography, Thoracic, Tomography, X-Ray Computed, Lung, human papillomaviru, Respiratory Sounds
Abstract

NA

29. Sharing of carbapenemase-encoding plasmids between Enterobacteriaceae in UK sewage uncovered by MinION sequencing

Author

Ludden, C, Reuter, S, Judge, K, Gouliouris, T, Blane, B, Coll, F, Naydenova, P, Hunt, M, Tracey, A, Hopkins, K, Brown, N, Woodford, N, Parkhill, J, and Peacock, S

Subjects
DNA, Bacterial, Gene Transfer, Horizontal, Sewage, ESBL- producing Enterobacteriaceae, MinION, sequencing, Sequence Analysis, DNA, biochemical phenomena, metabolism, and nutrition, 6. Clean water, beta-Lactamases, 3. Good health, Carbapenem-Resistant Enterobacteriaceae, Bacterial Proteins, England, wastewater, Plasmids
Abstract

Dissemination of carbapenem resistance among pathogenic Gram-negative bacteria is a looming medical emergency. Efficient spread of resistance within and between bacterial species is facilitated by mobile genetic elements. We hypothesized that wastewater contributes to the dissemination of carbapenemase-producing Enterobacteriaceae (CPE), and studied this through a cross-sectional observational study of wastewater in the East of England. We isolated clinically relevant species of CPE in untreated and treated wastewater, confirming that waste treatment does not prevent release of CPE into the environment. We observed that CPE-positive plants were restricted to those in direct receipt of hospital waste, suggesting that hospital effluent may play a role in disseminating carbapenem resistance. We postulated that plasmids carrying carbapenemase genes were exchanged between bacterial hosts in sewage, and used short-read (Illumina) and long-read (MinION) technologies to characterize plasmids encoding resistance to antimicrobials and heavy metals. We demonstrated that different CPE species ($\textit{Enterobacter kobei}$ and $\textit{Raoultella ornithinolytica}$) isolated from wastewater from the same treatment plant shared two plasmids of 63 and 280 kb. The former plasmid conferred resistance to carbapenems ($bla_\text{OXA-48}$), and the latter to numerous drug classes and heavy metals. We also report the complete genome sequence for $\textit{Enterobacter kobei}$. Small, portable sequencing instruments such as the MinION have the potential to improve the quality of information gathered on antimicrobial resistance in the environment.

31. Primary pneumococcal peritonitis can be the first presentation of a familial complement factor I deficiency1.

Author

Ugrinovic, S., Firth, H., Kavanagh, D., Gouliouris, T., Gurugama, P., Baxendale, H., Lachmann, P. J., Kumararatne, D., and Gkrania‐Klotsas, E.

Subjects
*PERITONITIS, *STREPTOCOCCUS pneumoniae, *PHAGOCYTOSIS
Abstract

Summary: Primary pneumococcal peritonitis is a rare infection that has been described in women but has not been previously linked with immunodeficiency. The complement system plays a central role in immune defence against Streptococcus pneumoniae and, in order to evade complement attack, pneumococci have evolved a large number of mechanisms that limit complement‐mediated opsonization and subsequent phagocytosis. We investigated an apparently immunocompetent woman with primary pneumococcal peritonitis and identified a family with deficiency for complement factor I. Primary pneumococcal peritonitis should be considered a possible primary immunodeficiency presentation. [ABSTRACT FROM AUTHOR]

Published
2020
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33. Protective Role of Albumin in Clostridium difficile Infection: A Step Toward Solving the Puzzle

Author

Paolo Ascenzi, Alessandra di Masi, Nicola Petrosillo, Theodore Gouliouris, Stefano Di Bella, Simona Turla, Di Bella, S, DI MASI, Alessandra, Turla, S, Ascenzi, Paolo, Gouliouris, T, Petrosillo, N., di Masi, A, Ascenzi, P, and Petrosillo, N

Subjects
Microbiology (medical), Male, Infection Control, Epidemiology, business.industry, Clostridioides difficile, Albumin, Human serum albumin, Clostridium difficile, Virology, Article, Microbiology, Anti-Bacterial Agents, Infectious Diseases, Medicine, Infection control, Humans, Female, business, Enterocolitis, Pseudomembranous
Abstract

NA

Published
2015

34. Fecal microbiota transplantation (FMT) for Clostridium difficile infection: focus on immunocompromised patients

Author

Nicola Petrosillo, Theodore Gouliouris, Stefano Di Bella, Di Bella, S, Gouliouris, T, and Petrosillo, N

Subjects
Microbiology (medical), Adult, Male, medicine.medical_specialty, genetic structures, Gut flora, Inflammatory bowel disease, fecal transplant, Immunocompromised Host, Young Adult, Internal medicine, medicine, Humans, Pharmacology (medical), Aged, biology, Clostridioides difficile, fecal microbiota transplantation, Fecal bacteriotherapy, Clostridium difficile, Fecal Microbiota Transplantation, Middle Aged, medicine.disease, biology.organism_classification, Infectious Diseases, Treatment Outcome, Immunology, Clostridium Infections, Female, immunocompromise, Solid organ transplantation
Abstract

Clostridium difficile infection (CDI) is an emerging problem worldwide associated with significant morbidity, mortality, recurrence rates and healthcare costs. Immunosuppressed patients, including HIV-seropositive individuals, solid organ transplant recipients, patients with malignancies, hematopoietic stem cell transplant recipients, and patients with inflammatory bowel disease are increasingly recognized as being at higher risk of developing CDI where it may be associated with significant complications, recurrence, and mortality. Fecal microbiota transplantation (FMT) has proven to be an effective and safe procedure for the treatment of recurrent or refractory CDI in immunocompetent patients by restoring the gut microbiota and resistance to further recurrences. During the last two years the first data on FMT in immunocompromised patients began to appear in the medical literature. Herein we summarize the use of FMT for the treatment of CDI with a focus on immunocompromised patients.of FMT for the treatment of CDI with a focus on immunocompromised patients.

Published
2014

35. Efficacy of Air Cleaning Units for preventing SARS-CoV-2 and other hospital-acquired infections on medicine for older people wards: A quasi-experimental controlled before-and- after study.

Author

Brock RC, Goudie RJB, Peters C, Thaxter R, Gouliouris T, Illingworth CJR, Morris AC, Beggs CB, Butler M, and Keevil VL

Abstract

Background: Nosocomial infections are costly and airborne transmission is increasingly recognised as important for spread. Air Cleaning Units (ACUs) may reduce transmission but little research has focused on their effectiveness on open wards., Aim: Assess whether ACUs reduce nosocomial SARS-CoV-2, or other, infections on older adult inpatient wards., Methods: Quasi-experimental before-after study on two intervention-control ward pairs in a UK teaching hospital. Infections were identified using routinely collected electronic health records data during one year of ACU implementation and the preceding year ("core study period"). Extended analyses included 6 months additional data from one ward pair following ACU removal. Hazard ratios (HR) were estimated through Cox regression controlling for age, sex, ward and background infection risk. Time the ACUs were switched on was also recorded for intervention ward 2., Findings: ACUs were initially feasible but compliance reduced towards the end of the study (average operation in first vs second half of ACU time on intervention ward 2: 77% vs 53%). 8171 admissions >48hrs (6112 patients, median age 85yrs) were included. Overall, incidence of ward-acquired SARS-CoV-2 was 3.8%. ACU implementation was associated with a non-significant trend of lower hazard for SARS-CoV-2 infection (HR core study period 0.90, 95% CI 0.53, 1.52; extended study period 0.78, 95% CI 0.53, 1.14). Only 1.5% of admissions resulted in other notable ward-acquired infections., Conclusion: ACUs may reduce SARS-CoV-2 infection to a clinically-meaningfully degree. Larger studies could reduce uncertainty, perhaps using a cross-over design, and factors influencing acceptability to staff and patients should be further explored., Competing Interests: Declaration of Competing Interest CB is an expert witness in Module 3 of the UK Covid-19 Inquiry, and has received financial remuneration for his work in this capacity. MB and CP have undertaken work for FreshAirNHS, a non-profit campaigning organisation advocating for airborne mitigations within the NHS, they have not received any financial remunerations for this work. ACM sits on the scientific advisory board of Cambridge Infection Diagnostics and has received speaking fees from Biomerieux, Fischer and Paykel, ThermoFisher and Boston Scientific., (Copyright © 2024. Published by Elsevier Ltd.)

Published
2024
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36. Acceptability of Air Cleaning Units on Inpatient Wards: help for infection control or hindrance for ward occupants?

Author

Love C, Street A, Riddell E, Goudie RJB, Brock RC, Thaxter R, Gouliouris T, Conway Morris A, Beggs CB, Peters C, Butler MJ, Gould DJ, and Keevil VL

Abstract

Competing Interests: Declaration of Competing Interest CBB and DJG are expert witnesses in Module 3 of the UK Covid-19 Inquiry, receiving financial remuneration for work in this capacity. MB and CP have undertaken work for FreshAirNHS, a non-profit campaigning organisation advocating for airborne mitigations within the NHS, they have not received any financial remunerations for this work. ACM sits on the scientific advisory board of Cambridge Infection Diagnostics and has received speaking fees from Biomerieux, Fischer and Paykel, ThermoFisher and Boston Scientific. Other authors have no interests to declare.

Published
2024
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37. Short-duration selective decontamination of the digestive tract infection control does not contribute to increased antimicrobial resistance burden in a pilot cluster randomised trial (the ARCTIC Study).

Author

Kean IRL, Clark JA, Zhang Z, Daubney E, White D, Ferrando-Vivas P, Milla G, Cuthbertson B, Pappachan J, Klein N, Mouncey P, Rowan K, Myburgh J, Gouliouris T, Baker S, Parkhill J, Pathan N, and Arctic Research Team

Subjects
Humans, Pilot Projects, Male, Female, Child, Preschool, Child, Gastrointestinal Microbiome drug effects, Infection Control methods, Respiration, Artificial, Infant, Anti-Bacterial Agents therapeutic use, Anti-Bacterial Agents administration & dosage, Drug Resistance, Bacterial genetics, Gastrointestinal Tract microbiology, Oropharynx microbiology, Critical Illness therapy, Feces microbiology, Decontamination methods
Abstract

Objective: Selective decontamination of the digestive tract (SDD) is a well-studied but hotly contested medical intervention of enhanced infection control. Here, we aim to characterise the changes to the microbiome and antimicrobial resistance (AMR) gene profiles in critically ill children treated with SDD-enhanced infection control compared with conventional infection control., Design: We conducted shotgun metagenomic microbiome and resistome analysis on serial oropharyngeal and faecal samples collected from critically ill, mechanically ventilated patients in a pilot multicentre cluster randomised trial of SDD. The microbiome and AMR profiles were compared for longitudinal and intergroup changes. Of consented patients, faecal microbiome baseline samples were obtained in 89 critically ill children. Additionally, samples collected during and after critical illness were collected in 17 children treated with SDD-enhanced infection control and 19 children who received standard care., Results: SDD affected the alpha and beta diversity of critically ill children to a greater degree than standard care. At cessation of treatment, the microbiome of SDD patients was dominated by Actinomycetota, specifically Bifidobacterium, at the end of mechanical ventilation. Altered gut microbiota was evident in a subset of SDD-treated children who returned late longitudinal samples compared with children receiving standard care. Clinically relevant AMR gene burden was unaffected by the administration of SDD-enhanced infection control compared with standard care. SDD did not affect the composition of the oral microbiome compared with standard treatment., Conclusion: Short interventions of SDD caused a shift in the microbiome but not of the AMR gene pool in critically ill children at the end mechanical ventilation, compared with standard antimicrobial therapy., Competing Interests: Competing interests: IRLK was funded by Action for Medical Research. NP holds grants from Action for Medical Research, the NIHR and Addenbrookes Charitable Trust (ACT). SB is funded by the Wellcome Trust., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Published
2024
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38. Enhanced diagnosis of severe bacterial and fungal respiratory infection in children using a rapid syndromic array-case report.

Author

Clark JA, Gouliouris T, Conway Morris A, Curran MD, White D, Daubney E, Navapurkar V, Baker S, and Pathan N

Abstract

Background: A microbiological cause of infection is infrequently identified in critically unwell children with a respiratory infection. Molecular diagnostic arrays provide an alternative. These tests are becoming more broadly available, but little is known about how clinicians interpret the results to impact clinical decision making., Case Description: Here we describe three cases of bacterial and fungal lower respiratory tract infection (LRTI) diagnosed in the paediatric intensive care unit (PICU) using a custom 52 respiratory pathogen TaqMan array card (TAC). Firstly, an early diagnosis of Candida albicans pneumonia was made with the support of the TAC in a trauma patient who received prolonged mechanical ventilation. The pathogen was only identified on microbiological cultures after further clinical deterioration had occurred. Secondly, a rare case of psittacosis was identified in an adolescent with acute respiratory distress, initially suspected to have multisystem inflammatory syndrome in children (MIS-C). Finally, Haemophilus influenzae pneumonia was identified in an infant with recurrent apnoeas, initially treated for meningitis. Two diagnoses would not have been established using commercially available arrays, and pathogen-specific diagnoses were established faster than that of routine microbiological culture., Conclusions: The pathogens included on molecular arrays and interpretation by a multidisciplinary team are crucial in providing value to PICU diagnostic services. Molecular arrays have the potential to enhance early pathogen-specific diagnosis of LRTI in the PICU., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-525/coif). J.A.C. received PhD personal funding through the Gates Cambridge Trust and funding for the consumables for the research were provided by the Addenbrooke’s Charitable Trust, Cambridge University Hospitals. T.G. receives a salary from the NIHR Cambridge Biomedical Research Campus and participates in monitoring the PROMISE study. A.C.M. receives support from the Medical Research Council Clinician Scientist Fellowship and Wellcome Trust Clinical Research Career Development Fellowship, and has received speaker fees from BioMérieux, Boston Scientific and Fisher and Paykel. M.D.C. is the inventor of a patent held by the Secretary of State for Health (UK government) EP2788503, which covers some of the genetic sequences used in this study. V.N. is a founder, director, and shareholder in Cambridge Infection Diagnostics (CID), which is a commercial company aimed at developing molecular diagnostics in infection and antimicrobial and AMR stewardship. A.C.M. and S.B. are advisory board members of the CID. S.B. has received funding from Addenbrooke’s Charitable Trust, Cambridge University Hospitals, Wellcome Trust and Action Medical Research. N.P. has received funding from Action Medical Research, the Addenbrooke’s Charitable Trust, Cambridge University Hospitals and the Cambridge NIHR Biomedical Research Centre, and has received speaker fees from BioMérieux. The other authors have no conflicts of interest to declare., (2024 Translational Pediatrics. All rights reserved.)

Published
2024
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39. Evaluating the impact of genomic epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) on hospital infection prevention and control decisions.

Author

Blane B, Raven KE, Brown NM, Harrison EM, Coll F, Thaxter R, Enoch DA, Gouliouris T, Leek D, Girgis ST, Akram A, Matuszewska M, Rhodes P, Parkhill J, and Peacock SJ

Subjects
Humans, Prospective Studies, Genomics, Methicillin-Resistant Staphylococcus aureus genetics, Cross Infection microbiology, Staphylococcal Infections microbiology
Abstract

Genomic epidemiology enhances the ability to detect and refute methicillin-resistant Staphylococcus aureus (MRSA) outbreaks in healthcare settings, but its routine introduction requires further evidence of benefits for patients and resource utilization. We performed a 12 month prospective study at Cambridge University Hospitals NHS Foundation Trust in the UK to capture its impact on hospital infection prevention and control (IPC) decisions. MRSA-positive samples were identified via the hospital microbiology laboratory between November 2018 and November 2019. We included samples from in-patients, clinic out-patients, people reviewed in the Emergency Department and healthcare workers screened by Occupational Health. We sequenced the first MRSA isolate from 823 consecutive individuals, defined their pairwise genetic relatedness, and sought epidemiological links in the hospital and community. Genomic analysis of 823 MRSA isolates identified 72 genetic clusters of two or more isolates containing 339/823 (41 %) of the cases. Epidemiological links were identified between two or more cases for 190 (23 %) individuals in 34/72 clusters. Weekly genomic epidemiology updates were shared with the IPC team, culminating in 49 face-to-face meetings and 21 written communications. Seventeen clusters were identified that were consistent with hospital MRSA transmission, discussion of which led to additional IPC actions in 14 of these. Two outbreaks were also identified where transmission had occurred in the community prior to hospital presentation; these were escalated to relevant IPC teams. We identified 38 instances where two or more in-patients shared a ward location on overlapping dates but carried unrelated MRSA isolates (pseudo-outbreaks); research data led to de-escalation of investigations in six of these. Our findings provide further support for the routine use of genomic epidemiology to enhance and target IPC resources.

Published
2024
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40. Impact of penicillin allergy labels on surgical site infections in a large UK cohort of gastrointestinal surgery patients.

Author

Jones NK, Tom B, Simillis C, Bennet J, Gourgiotis S, Griffin J, Blaza H, Nasser S, Baker S, and Gouliouris T

Abstract

Objectives: Studies in the USA, Canada and France have reported higher surgical site infection (SSI) risk in patients with a penicillin allergy label (PAL). Here, we investigate the association between PALs and SSI in the UK, a country with distinct epidemiology of infecting pathogens and range of antimicrobial regimens in routine use., Methods: Electronic health records and national SSI surveillance data were collated for a retrospective cohort of gastrointestinal surgery patients at Cambridge University Hospitals NHS Foundation Trust from 1 January 2015 to 31 December 2021. Univariable and multivariable logistic regression were used to examine the effects of PALs and the use of non-β-lactam-based prophylaxis on likelihood of SSI, 30 day post-operative mortality, 7 day post-operative acute kidney injury and 60 day post-operative infection/colonization with antimicrobial-resistant bacteria or Clostridioides difficile ., Results: Our data comprised 3644 patients and 4085 operations; 461 were undertaken in the presence of PALs (11.3%). SSI was detected after 435/4085 (10.7%) operations. Neither the presence of PALs, nor the use of non-β-lactam-based prophylaxis were found to be associated with SSI: adjusted OR (aOR) 0.90 (95% CI 0.65-1.25) and 1.20 (0.88-1.62), respectively. PALs were independently associated with increased odds of newly identified MRSA infection/colonization in the 60 days after surgery: aOR 2.71 (95% CI 1.13-6.49). Negative association was observed for newly identified infection/colonization with third-generation cephalosporin-resistant Gram-negative bacteria: aOR 0.38 (95% CI 0.16-0.89)., Conclusions: No evidence was found for an association between PALs and the likelihood of SSI in this large UK cohort, suggesting significant international variation in the impact of PALs on surgical patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Published
2024
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41. Use of selective gut decontamination in critically ill children: PICnIC a pilot RCT and mixed-methods study.

Author

Brown A, Ferrando-Vivas P, Popa M, de la Fuente GM, Pappachan J, Cuthbertson BH, Drikite L, Feltbower R, Gouliouris T, Sale I, Shulman R, Tume LN, Myburgh J, Woolfall K, Harrison DA, Mouncey PR, Rowan K, and Pathan N

Subjects
Adult, Child, Humans, Critical Illness therapy, Pandemics, England, Decontamination, Cross Infection
Abstract

Background: Healthcare-associated infections are a major cause of morbidity and mortality in critically ill children. In adults, data suggest the use of selective decontamination of the digestive tract may reduce the incidence of healthcare-associated infections. Selective decontamination of the digestive tract has not been evaluated in the paediatric intensive care unit population., Objectives: To determine the feasibility of conducting a multicentre, cluster-randomised controlled trial in critically ill children comparing selective decontamination of the digestive tract with standard infection control., Design: Parallel-group pilot cluster-randomised controlled trial with an integrated mixed-methods study., Setting: Six paediatric intensive care units in England., Participants: Children (> 37 weeks corrected gestational age, up to 16 years) requiring mechanical ventilation expected to last for at least 48 hours were eligible for the PICnIC pilot cluster-randomised controlled trial. During the ecology periods, all children admitted to the paediatric intensive care units were eligible. Parents/legal guardians of recruited patients and healthcare professionals working in paediatric intensive care units were eligible for inclusion in the mixed-methods study., Interventions: The interventions in the PICnIC pilot cluster-randomised controlled trial included administration of selective decontamination of the digestive tract as oro-pharyngeal paste and as a suspension given by enteric tube during the period of mechanical ventilation., Main Outcome Measures: The decision as to whether a definitive cluster-randomised controlled trial is feasible is based on multiple outcomes, including (but not limited to): (1) willingness and ability to recruit eligible patients; (2) adherence to the selective decontamination of the digestive tract intervention; (3) acceptability of the definitive cluster-randomised controlled trial; (4) estimation of recruitment rate; and (5) understanding of potential clinical and ecological outcome measures., Results: A total of 368 children (85% of all those who were eligible) were enrolled in the PICnIC pilot cluster-randomised controlled trial across six paediatric intensive care units: 207 in the baseline phase (Period One) and 161 in the intervention period (Period Two). In sites delivering selective decontamination of the digestive tract, the majority (98%) of children received at least one dose of selective decontamination of the digestive tract, and of these, 68% commenced within the first 6 hours. Consent for the collection of additional swabs was low (44%), though data completeness for potential outcomes, including microbiology data from routine clinical swab testing, was excellent. Recruited children were representative of the wider paediatric intensive care unit population. Overall, 3.6 children/site/week were recruited compared with the potential recruitment rate for a definitive cluster-randomised controlled trial of 3 children/site/week, based on data from all UK paediatric intensive care units. The proposed trial, including consent and selective decontamination of the digestive tract, was acceptable to parents and staff with adaptations, including training to improve consent and communication, and adaptations to the administration protocol for the paste and ecology monitoring. Clinical outcomes that were considered important included duration of organ failure and hospital stay, healthcare-acquired infections and survival., Limitations: The delivery of the pilot cluster-randomised controlled trial was disrupted by the COVID-19 pandemic, which led to slow set-up of sites, and a lack of face-to face training., Conclusions: PICnIC's findings indicate that a definitive cluster-randomised controlled trial in selective decontamination of the digestive tract in paediatric intensive care units is feasible with the inclusion modifications, which would need to be included in a definitive cluster-randomised controlled trial to ensure that the efficiency of trial processes is maximised., Future Work: A definitive trial that incorporates the protocol adaptations and outcomes arising from this study is feasible and should be conducted., Trial Registration: This trial is registered as ISRCTN40310490., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/152/01) and is published in full in Health Technology Assessment ; Vol. 28, No. 8. See the NIHR Funding and Awards website for further award information.

Published
2024
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42. Antibiotic resistance determination using Enterococcus faecium whole-genome sequences: a diagnostic accuracy study using genotypic and phenotypic data.

Author

Coll F, Gouliouris T, Blane B, Yeats CA, Raven KE, Ludden C, Khokhar FA, Wilson HJ, Roberts LW, Harrison EM, Horner CS, Le TH, Nguyen TH, Nguyen VT, Brown NM, Holmes MA, Parkhill J, Estee Török M, and Peacock SJ

Subjects
Vancomycin pharmacology, Linezolid, Tigecycline, Teicoplanin, Retrospective Studies, Anti-Bacterial Agents pharmacology, Ampicillin pharmacology, Drug Resistance, Microbial, Ciprofloxacin, Phenotype, Gentamicins, Streptomycin, Enterococcus faecium genetics, Daptomycin
Abstract

Background: DNA sequencing could become an alternative to in vitro antibiotic susceptibility testing (AST) methods for determining antibiotic resistance by detecting genetic determinants associated with decreased antibiotic susceptibility. Here, we aimed to assess and improve the accuracy of antibiotic resistance determination from Enterococcus faecium genomes for diagnosis and surveillance purposes., Methods: In this retrospective diagnostic accuracy study, we first conducted a literature search in PubMed on Jan 14, 2021, to compile a catalogue of genes and mutations predictive of antibiotic resistance in E faecium. We then evaluated the diagnostic accuracy of this database to determine susceptibility to 12 different, clinically relevant antibiotics using a diverse population of 4382 E faecium isolates with available whole-genome sequences and in vitro culture-based AST phenotypes. Isolates were obtained from various sources in 11 countries worldwide between 2000 and 2018. We included isolates tested with broth microdilution, Vitek 2, and disc diffusion, and antibiotics with at least 50 susceptible and 50 resistant isolates. Phenotypic resistance was derived from raw minimum inhibitory concentrations and measured inhibition diameters, and harmonised primarily using the breakpoints set by the European Committee on Antimicrobial Susceptibility Testing. A bioinformatics pipeline was developed to process raw sequencing reads, identify antibiotic resistance genetic determinants, and report genotypic resistance. We used our curated database, as well as ResFinder, AMRFinderPlus, and LRE-Finder, to assess the accuracy of genotypic predictions against phenotypic resistance., Findings: We curated a catalogue of 228 genetic markers involved in resistance to 12 antibiotics in E faecium. Very accurate genotypic predictions were obtained for ampicillin (sensitivity 99·7% [95% CI 99·5-99·9] and specificity 97·9% [95·8-99·0]), ciprofloxacin (98·0% [96·4-98·9] and 98·8% [95·9-99·7]), vancomycin (98·8% [98·3-99·2] and 98·8% [98·0-99·3]), and linezolid resistance (after re-testing false negatives: 100·0% [90·8-100·0] and 98·3% [97·8-98·7]). High sensitivity was obtained for tetracycline (99·5% [99·1-99·7]), teicoplanin (98·9% [98·4-99·3]), and high-level resistance to aminoglycosides (97·7% [96·6-98·4] for streptomycin and 96·8% [95·8-97·5] for gentamicin), although at lower specificity (60-90%). Sensitivity was expectedly low for daptomycin (73·6% [65·1-80·6]) and tigecycline (38·3% [27·1-51·0]), for which the genetic basis of resistance is not fully characterised. Compared with other antibiotic resistance databases and bioinformatic tools, our curated database was similarly accurate at detecting resistance to ciprofloxacin and linezolid and high-level resistance to streptomycin and gentamicin, but had better sensitivity for detecting resistance to ampicillin, tigecycline, daptomycin, and quinupristin-dalfopristin, and better specificity for ampicillin, vancomycin, teicoplanin, and tetracycline resistance. In a validation dataset of 382 isolates, similar or improved diagnostic accuracies were also achieved., Interpretation: To our knowledge, this work represents the largest published evaluation to date of the accuracy of antibiotic susceptibility predictions from E faecium genomes. The results and resources will facilitate the adoption of whole-genome sequencing as a tool for the diagnosis and surveillance of antimicrobial resistance in E faecium. A complete characterisation of the genetic basis of resistance to last-line antibiotics, and the mechanisms mediating antibiotic resistance silencing, are needed to close the remaining sensitivity and specificity gaps in genotypic predictions., Funding: Wellcome Trust, UK Department of Health, British Society for Antimicrobial Chemotherapy, Academy of Medical Sciences and the Health Foundation, Medical Research Council Newton Fund, Vietnamese Ministry of Science and Technology, and European Society of Clinical Microbiology and Infectious Disease., Competing Interests: Declaration of interests SJP and JP are consultants to Next Gen Diagnostics. SJP is also a consultant for Specific Technologies. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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43. Selective digestive tract decontamination to prevent healthcare associated infections in critically ill children: the PICNIC multicentre randomised pilot clinical trial.

Author

Pathan N, Woolfall K, Popa M, de la Fuente GM, Ferrando-Vivas P, Brown A, Gouliouris T, Tume LN, Shulman R, Cuthbertson BH, Sale I, Feltbower RG, Myburgh J, Pappachan J, Harrison D, Mouncey P, and Rowan K

Subjects
Adult, Humans, Child, Critical Illness therapy, Pilot Projects, Gastrointestinal Tract, Decontamination methods, Cross Infection epidemiology
Abstract

Healthcare-associated infections (HCAIs) are a major cause of morbidity and mortality in critically ill children. Data from adult studies suggest Selective Decontamination of the Digestive tract (SDD) may reduce the incidence of HCAIs and improve survival. There are no data from randomised clinical trials in the paediatric setting. An open label, parallel group pilot cRCT and mixed-methods perspectives study was conducted in six paediatric intensive care units (PICUs) in England. Participants were children (> 37 weeks corrected gestational age, up to 16 years) requiring mechanical ventilation expected to last for at least 48 h. Sites undertook standard care for a period of 9 weeks and were randomised into 3 sites which continued standard care and 3 where SDD was incorporated into infection control practice for eligible children. Interviews and focus groups were conducted for parents and staff working in PICU. 434 children fulfilled eligibility criteria, of whom 368 (85%) were enrolled. This included 207 in the baseline phase (Period One) and 161 in the intervention period (Period Two). In sites delivering SDD, the majority (98%) of children received at least one dose of SDD and of these, 68% commenced within the first 6 h. Whilst admission swabs were collected in 91% of enrolled children, consent for the collection of additional swabs was low (44%). Recruited children were representative of the wider PICU population. Overall, 3.6 children/site/week were recruited compared with the potential recruitment rate for a definitive cRCT of 3 children/site/week, based on data from all UK PICUs. Parents (n = 65) and staff (n = 44) were supportive of the aims of the study, suggesting adaptations for a larger definitive trial including formulation and administration of SDD paste, approaches to consent and ecology monitoring. Stakeholders identified preferred clinical outcomes, focusing on complications of critical illness and quality-of-life. A definitive cRCT in SDD to prevent HCAIs in critically ill children is feasible but should include adaptations to ecology monitoring along with the dosing schedule and packaging into a paediatric specific format. A definitive study is supported by the findings with adaptations to ecology monitoring and SDD administration.Trial Registration: ISRCTN40310490 Registered 30/10/2020., (© 2023. The Author(s).)

Published
2023
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44. Rapid Detection of Antimicrobial Resistance Genes in Critically Ill Children Using a Custom TaqMan Array Card.

Author

Clark JA, Curran MD, Gouliouris T, Conway Morris A, Bousfield R, Navapurkar V, Kean IRL, Daubney E, White D, Baker S, and Pathan N

Abstract

Bacteria are identified in only 22% of critically ill children with respiratory infections treated with antimicrobial therapy. Once an organism is isolated, antimicrobial susceptibility results (phenotypic testing) can take another day. A rapid diagnostic test identifying antimicrobial resistance (AMR) genes could help clinicians make earlier, informed antimicrobial decisions. Here we aimed to validate a custom AMR gene TaqMan Array Card (AMR-TAC) for the first time and assess its feasibility as a screening tool in critically ill children. An AMR-TAC was developed using a combination of commercial and bespoke targets capable of detecting 23 AMR genes. This was validated using isolates with known phenotypic resistance. The card was then tested on lower respiratory tract and faecal samples obtained from mechanically ventilated children in a single-centre observational study of respiratory infection. There were 82 children with samples available, with a median age of 1.2 years. Major comorbidity was present in 29 (35%) children. A bacterial respiratory pathogen was identified in 13/82 (16%) of children, of which 4/13 (31%) had phenotypic AMR. One AMR gene was detected in 49/82 (60%), and multiple AMR genes were detected in 14/82 (17%) children. Most AMR gene detections were not associated with the identification of phenotypic AMR. AMR genes are commonly detected in samples collected from mechanically ventilated children with suspected respiratory infections. AMR-TAC may have a role as an adjunct test in selected children in whom there is a high suspicion of antimicrobial treatment failure.

Published
2023
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45. The clinical, genomic, and microbiological profile of invasive multi-drug resistant Escherichia coli in a major teaching hospital in the United Kingdom.

Author

Hamilton WL, Coscione S, Maes M, Warne B, Pike LJ, Khokhar FA, Blane B, Brown NM, Gouliouris T, Dougan G, Török ME, and Baker S

Subjects
Humans, Escherichia coli genetics, Hospitals, Teaching, United Kingdom epidemiology, England, Genomics, Escherichia coli Infections epidemiology, Sepsis
Abstract

Escherichia coli is a ubiquitous component of the human gut microbiome, but is also a common pathogen, causing around 40, 000 bloodstream infections (BSI) in the United Kingdom (UK) annually. The number of E. coli BSI has increased over the last decade in the UK, and emerging antimicrobial resistance (AMR) profiles threaten treatment options. Here, we combined clinical, epidemiological, and whole genome sequencing data with high content imaging to characterise over 300 E. coli isolates associated with BSI in a large teaching hospital in the East of England. Overall, only a limited number of sequence types (ST) were responsible for the majority of organisms causing invasive disease. The most abundant (20 % of all isolates) was ST131, of which around 90 % comprised the pandemic O25b:H4 group. ST131-O25b:H4 isolates were frequently multi-drug resistant (MDR), with a high prevalence of extended spectrum β-lactamases (ESBL) and fluoroquinolone resistance. There was no association between AMR phenotypes and the source of E. coli bacteraemia or whether the infection was healthcare-associated. Several clusters of ST131 were genetically similar, potentially suggesting a shared transmission network. However, there was no clear epidemiological associations between these cases, and they included organisms from both healthcare-associated and non-healthcare-associated origins. The majority of ST131 isolates exhibited strong binding with an anti-O25b antibody, raising the possibility of developing rapid diagnostics targeting this pathogen. In summary, our data suggest that a restricted set of MDR E. coli populations can be maintained and spread across both community and healthcare settings in this location, contributing disproportionately to invasive disease and AMR.

Published
2023
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46. Soft Tissue Infection of Immunocompetent Man with Cat-Derived Globicatella Species.

Author

Jones NK, Coelho J, Logan JMJ, Broughton K, Hopkins KL, Pichon B, Potterill I, Wan Y, Reid AWN, and Gouliouris T

Subjects
Animals, Cats, RNA, Ribosomal, 16S genetics, Bacteria genetics, Gram-Positive Bacterial Infections microbiology, Soft Tissue Infections diagnosis, Soft Tissue Infections drug therapy, Aerococcaceae genetics
Abstract

We report a novel Globicatella species causing extensive soft tissue infection in a man bitten by a stray domestic cat in the United Kingdom. We identified this bacterium by 16S rRNA gene sequencing, whole-genome sequencing, and biochemical profiling and determined antimicrobial drug susceptibility.

Published
2023
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47. Long-read sequencing reveals genomic diversity and associated plasmid movement of carbapenemase-producing bacteria in a UK hospital over 6 years.

Author

Roberts LW, Enoch DA, Khokhar F, Blackwell GA, Wilson H, Warne B, Gouliouris T, Iqbal Z, and Török ME

Subjects
Humans, Retrospective Studies, Plasmids genetics, Escherichia coli genetics, Genomics, United Kingdom epidemiology, Klebsiella pneumoniae genetics, Hospitals
Abstract

Healthcare-associated infections (HCAIs) affect the most vulnerable people in society and are increasingly difficult to treat in the face of mounting antimicrobial resistance (AMR). Routine surveillance represents an effective way of understanding the circulation and burden of bacterial resistance and transmission in hospital settings. Here, we used whole-genome sequencing (WGS) to retrospectively analyse carbapenemase-producing Gram-negative bacteria from a single hospital in the UK over 6 years ( n =165). We found that the vast majority of isolates were either hospital-onset (HAI) or HCAI. Most carbapenemase-producing organisms were carriage isolates, with 71 % isolated from screening (rectal) swabs. Using WGS, we identified 15 species, the most common being Escherichia coli and Klebsiella pneumoniae . Only one significant clonal outbreak occurred during the study period and involved a sequence type (ST)78 K . pneumoniae carrying bla NDM-1 on an IncFIB/IncHI1B plasmid. Contextualization with public data revealed little evidence of this ST outside of the study hospital, warranting ongoing surveillance. Carbapenemase genes were found on plasmids in 86 % of isolates, the most common types being bla NDM - and bla OXA -type alleles. Using long-read sequencing, we determined that approximately 30 % of isolates with carbapenemase genes on plasmids had acquired them via horizontal transmission. Overall, a national framework to collate more contextual genomic data, particularly for plasmids and resistant bacteria in the community, is needed to better understand how carbapenemase genes are transmitted in the UK.

Published
2023
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48. Characterizing Antibiotic Allergy Labels in a Large UK Hospital Population to Inform Antimicrobial Stewardship and Delabeling Assessment Strategy.

Author

Jones NK, Morris B, Santos R, Nasser S, and Gouliouris T

Subjects
Humans, Retrospective Studies, Anti-Bacterial Agents adverse effects, Penicillins adverse effects, Hospitals, United Kingdom epidemiology, Antimicrobial Stewardship, Drug Hypersensitivity diagnosis, Drug Hypersensitivity epidemiology
Abstract

Background: Antibiotic allergy labels are important barriers to treatment and antimicrobial stewardship, but their prevalence in UK hospitals is poorly described., Objective: To ascertain the prevalence and characteristics of antibiotic allergy labels in a large UK hospital setting and estimate the proportion of penicillin allergy labels for which point-of-care (POC) delabeling assessment would be appropriate., Methods: Electronic health records data were analyzed from all patients treated at Cambridge University Hospitals NHS Foundation Trust in 2019. Validated POC delabeling risk stratification criteria were retrospectively applied to penicillin allergy labels., Results: Recorded reactions to antibiotics were present in 11.8% of all patients (32,148 of 273,216), 16.3% of inpatients (13,874 of 85,230), and 9.7% of outpatients (18,274 of 187,986). Penicillins were the commonest reaction precipitant described (9.0% of patients; 24,646 of 273,216), followed by sulfonamides/trimethoprim (1.4%; 3869 of 273,216) and macrolides/lincosamides (1.3%; 3644 of 273,216). A total of 3.9% of inpatients had recorded reactions to >1 antibiotic class (3348 of 85,230). Cutaneous manifestations were the most commonly described reaction features (40.7% of labels; 15,821 of 38,902). Of 15,949 labels describing probable or possible penicillin "allergy" with sufficient detail to allow for the retrospective assessment of POC delabeling suitability, 1702 were deemed suitable for removal or downgrading of the label to "intolerance" without further investigation (10.7%), 11,887 were appropriate for POC assessment using an oral penicillin challenge (OPC) or OPC with prior bedside skin testing (74.5%), and 2360 were identified as unsuitable for any form of POC assessment (14.8%)., Conclusions: Antibiotic allergy labels are highly prevalent in a UK hospital setting. A large proportion of penicillin allergy labels may be suitable for POC delabeling assessment., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Published
2023
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49. The rapid detection of respiratory pathogens in critically ill children.

Author

Clark JA, Conway Morris A, Curran MD, White D, Daubney E, Kean IRL, Navapurkar V, Bartholdson Scott J, Maes M, Bousfield R, Török ME, Inwald D, Zhang Z, Agrawal S, Kanaris C, Khokhar F, Gouliouris T, Baker S, and Pathan N

Subjects
Humans, Child, Prospective Studies, Critical Illness, Bacteria, Bronchoalveolar Lavage Fluid microbiology, Pneumonia diagnosis, Respiratory Tract Infections diagnosis
Abstract

Purpose: Respiratory infections are the most common reason for admission to paediatric intensive care units (PICU). Most patients with lower respiratory tract infection (LRTI) receive broad-spectrum antimicrobials, despite low rates of bacterial culture confirmation. Here, we evaluated a molecular diagnostic test for LRTI to inform the better use of antimicrobials., Methods: The Rapid Assay for Sick Children with Acute Lung infection Study was a single-centre, prospective, observational cohort study of mechanically ventilated children (> 37/40 weeks corrected gestation to 18 years) with suspected community acquired or ventilator-associated LRTI. We evaluated the use of a 52-pathogen custom TaqMan Array Card (TAC) to identify pathogens in non-bronchoscopic bronchoalveolar lavage (mini-BAL) samples. TAC results were compared to routine microbiology testing. Primary study outcomes were sensitivity and specificity of TAC, and time to result., Results: We enrolled 100 patients, all of whom were tested with TAC and 91 of whom had matching culture samples. TAC had a sensitivity of 89.5% (95% confidence interval (CI 95 ) 66.9-98.7) and specificity of 97.9% (CI 95 97.2-98.5) compared to routine bacterial and fungal culture. TAC took a median 25.8 h (IQR 9.1-29.8 h) from sample collection to result. Culture was significantly slower: median 110.4 h (IQR 85.2-141.6 h) for a positive result and median 69.4 h (IQR 52.8-78.6) for a negative result., Conclusions: TAC is a reliable and rapid adjunct diagnostic approach for LRTI in critically ill children, with the potential to aid early rationalisation of antimicrobial therapy., (© 2023. The Author(s).)

Published
2023
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50. Machine Learning for Antimicrobial Resistance Prediction: Current Practice, Limitations, and Clinical Perspective.

Author

Kim JI, Maguire F, Tsang KK, Gouliouris T, Peacock SJ, McAllister TA, McArthur AG, and Beiko RG

Subjects
Machine Learning, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Drug Resistance, Bacterial genetics
Abstract

Antimicrobial resistance (AMR) is a global health crisis that poses a great threat to modern medicine. Effective prevention strategies are urgently required to slow the emergence and further dissemination of AMR. Given the availability of data sets encompassing hundreds or thousands of pathogen genomes, machine learning (ML) is increasingly being used to predict resistance to different antibiotics in pathogens based on gene content and genome composition. A key objective of this work is to advocate for the incorporation of ML into front-line settings but also highlight the further refinements that are necessary to safely and confidently incorporate these methods. The question of what to predict is not trivial given the existence of different quantitative and qualitative laboratory measures of AMR. ML models typically treat genes as independent predictors, with no consideration of structural and functional linkages; they also may not be accurate when new mutational variants of known AMR genes emerge. Finally, to have the technology trusted by end users in public health settings, ML models need to be transparent and explainable to ensure that the basis for prediction is clear. We strongly advocate that the next set of AMR-ML studies should focus on the refinement of these limitations to be able to bridge the gap to diagnostic implementation.

Published
2022
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