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1. A US-based national surveillance study for the susceptibility and epidemiology of Clostridioides difficile isolates with special reference to ridinilazole: 2020–2021

Author

Snydman, D. R., primary, McDermott, L. A., additional, Thorpe, C. M., additional, Goldstein, E. J. C., additional, Schuetz, A. N., additional, Johnson, S., additional, Gerding, D. N., additional, Gluck, L., additional, Bourdas, D., additional, Carroll, K. C., additional, Lancaster, C. K., additional, Garey, K. W., additional, Wang, Q., additional, Walk, S. T., additional, and Duperchy, E., additional

Published
2023
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4. Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Author

Mikus, M.S. Kolmert, J. Andersson, L.I. Östling, J. Knowles, R.G. Gómez, C. Ericsson, M. Thörngren, J.-O. Khoonsari, P.E. Dahlén, B. Kupczyk, M. de Meulder, B. Auffray, C. Bakke, P.S. Beghe, B. Bel, E.H. Caruso, M. Chanez, P. Chawes, B. Fowler, S.J. Gaga, M. Geiser, T. Gjomarkaj, M. Horváth, I. Howarth, P.H. Johnston, S.L. Joos, G. Krug, N. Montuschi, P. Musial, J. Niżankowska-Mogilnicka, E. Olsson, H.K. Papi, A. Rabe, K.F. Sandström, T. Shaw, D.E. Siafakas, N.M. Uhlén, M. Riley, J.H. Bates, S. Middelveld, R.J.M. Wheelock, C.E. Chung, K.F. Adcock, I.M. Sterk, P.J. Djukanovic, R. Nilsson, P. Dahlén, S.-E. James, A. Ahmed, H. Balgoma, D. Bansal, A.T. Baribaud, F. Bigler, J. Billing, B. Bisgaard, H. Boedigheimer, M.J. Bønnelykke, K. Brandsma, J. Brinkman, P. Bucchioni, E. Burg, D. Bush, A. Chaiboonchoe, A. Checa, T. Compton, C.H. Corfield, J. Cunoosamy, D. D’Amico, A. Emma, R. Erpenbeck, V.J. Erzen, D. Fichtner, K. Fitch, N. Fleming, L.J. Formaggio, E. Frey, U. Gahlemann, M. Goss, V. Guo, Y.-K. Hashimoto, S. Haughney, J. Hedlin, G. Hekking, P.-P.W. Higenbottam, T. Hohlfeld, J.M. Holweg, C.T.J. Knox, A.J. Konradsen, J. Lazarinis, N. Lefaudeux, D. Li, T. Loza, M.J. Lutter, R. Manta, A. Masefield, S. Matthews, J.G. Mazein, A. Meiser, A. Miralpeix, M. Mores, N. Murray, C.S. Myles, D. Naz, S. Nordlund, B. Pahus, L. Pandis, I. Pavlidis, S. Postle, A. Powel, P. Rao, N. Reinke, S. Roberts, A. Roberts, G. Rowe, A. Schofield, J.P.R. Seibold, W. Selby, A. Sigmund, R. Singer, F. Sjödin, M. Skipp, P.J. Sousa, A.R. Sun, K. Thornton, B. Uddin, M. van Aalderen, W.M. van Geest, M. Vestbo, J. Vissing, N.H. Wagener, A.H. Wagers, S.S. Weiszhart, Z. Wheelock, C.E. Wheelock, Å. Wilson, S.J. Yasinska, V. Brusselle, G.G. Campbell, D.A. Contoli, M. Damm, K. de Rudder, I. Delin, I. Devautour, C. Duplaga, M. Eduards, M. Ek, A. Ekström, T. Figiel, E. Gaber, F. Gauw, S. Gawlewicz-Mroczka, A. Gerding, D. Haque, S. Hewitt, L. Hiemstra, P.S. Holgate, S.T. Holloway, J. Kania, A. Kanniess, F. Karlsson, Ö. Kips, J.C. Kumlin, M. Lantz, A.-S. Lazarinis, N. Magnussen, H. Mallia, P. Martling, I. Meziane, L. Oikonomidou, E. Olsson, M. Pace, E. Papadopouli, E. Papadopoulos, N. Plataki, M. Profita, M. Reinius, L.E. Richter, K. Robinson, D.S. Romagnoli, M. Samara, K. Schelfhout, V. Skedinger, M. Stamataki, E. ten Brinke, A. Vachier, I. Wallén-Nielsen, E. van Veen, I. Weersink, E. Wilson, S.J. Yasinska, V. Zervas, E. Ziolkowska-Graca, B. U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcome) Study Group BIOAIR (Longitudinal Assessment of Clinical Course Biomarkers in Severe Chronic Airway Disease) Consortium

Abstract

Rationale Asthma phenotyping requires novel biomarker discovery. Objectives To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). Methods An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. Results In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. Conclusions The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA. © 2022 European Respiratory Society. All rights reserved.

Published
2022

5. Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Author

Mikus, M. S., Kolmert, J., Andersson, L. I., Ostling, J., Knowles, R. G., Gomez, C., Ericsson, M., Thorngren, J. -O., Khoonsari, P. E., Dahlen, B., Kupczyk, M., de Meulder, B., Auffray, C., Bakke, P. S., Beghe, Bianca, Bel, E. H., Caruso, M., Chanez, P., Chawes, B., Fowler, S. J., Gaga, M., Geiser, T., Gjomarkaj, M., Horvath, I., Howarth, P. H., Johnston, S. L., Joos, G., Krug, N., Montuschi, P., Musial, J., Nizankowska-Mogilnicka, E., Olsson, H. K., Papi, A., Rabe, K. F., Sandstrom, T., Shaw, D. E., Siafakas, N. M., Uhlen, M., Riley, J. H., Bates, S., Middelveld, R. J. M., Wheelock, C. E., Chung, K. F., Adcock, I. M., Sterk, P. J., Djukanovic, R., Nilsson, P., Dahlen, S. -E., James, A., Ahmed, H., Balgoma, D., Bansal, A. T., Baribaud, F., Bigler, J., Billing, B., Bisgaard, H., Boedigheimer, M. J., Bonnelykke, K., Brandsma, J., Brinkman, P., Bucchioni, E., Burg, D., Bush, A., Chaiboonchoe, A., Checa, T., Compton, C. H., Corfield, J., Cunoosamy, D., D'Amico, A., Emma, R., Erpenbeck, V. J., Erzen, D., Fichtner, K., Fitch, N., Fleming, L. J., Formaggio, E., Frey, U., Gahlemann, M., Goss, V., Guo, Y. -K., Hashimoto, S., Haughney, J., Hedlin, G., Hekking, P. -P. W., Higenbottam, T., Hohlfeld, J. M., Holweg, C. T. J., Knox, A. J., Konradsen, J., Lazarinis, N., Lefaudeux, D., Li, T., Loza, M. J., Lutter, R., Manta, A., Masefield, S., Matthews, J. G., Mazein, A., Meiser, A., Miralpeix, M., Mores, N., Murray, C. S., Myles, D., Naz, S., Nordlund, B., Pahus, L., Pandis, I., Pavlidis, S., Postle, A., Powel, P., Rao, N., Reinke, S., Roberts, A., Roberts, G., Rowe, A., Schofield, J. P. R., Seibold, W., Selby, A., Sigmund, R., Singer, F., Sjodin, M., Skipp, P. J., Sousa, A. R., Sun, K., Thornton, B., Uddin, M., van Aalderen, W. M., van Geest, M., Vestbo, J., Vissing, N. H., Wagener, A. H., Wagers, S. S., Weiszhart, Z., Wheelock, A., Wilson, S. J., Yasinska, V., Brusselle, G. G., Campbell, D. A., Contoli, M., Damm, K., de Rudder, I., Delin, I., Devautour, C., Duplaga, M., Eduards, M., Ek, A., Ekstrom, T., Figiel, E., Gaber, F., Gauw, S., Gawlewicz-Mroczka, A., Gerding, D., Haque, S., Hewitt, L., Hiemstra, P. S., Holgate, S. T., Holloway, J., Kania, A., Kanniess, F., Karlsson, O., Kips, J. C., Kumlin, M., Lantz, A. -S., Magnussen, H., Mallia, P., Martling, I., Meziane, L., Oikonomidou, E., Olsson, M., Pace, E., Papadopouli, E., Papadopoulos, N., Plataki, M., Profita, M., Reinius, L. E., Richter, K., Robinson, D. S., Romagnoli, M., Samara, K., Schelfhout, V., Skedinger, M., Stamataki, E., ten Brinke, A., Vachier, I., Wallen-Nielsen, E., van Veen, I., Weersink, E., Zervas, E., and Ziolkowska-Graca, B.

Subjects
Blood Proteins, Humans, Inflammation, Proteomics, Severity of Illness Index, Steroids, Asthma, Quality of Life
Published
2022

12. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

Author

Wilcox, M. H., Gerding, D. N., Poxton, I. R., Kelly, C., Nathan, R., Birch, T., Cornely, O. A., Rahav, G., Bouza, E., Lee, C., Jenkin, G., Jensen, W., Kim, Y. -S., Yoshida, J., Gabryelski, L., Pedley, A., Eves, K., Tipping, R., Guris, D., Kartsonis, N., Playford G, Dorr M. -B., Mcgechie, D, Iredell, J, Allworth, A, Cheng, A, Choi, Nj, Thalhammer, F, Maieron, A, Wenisch, C, Meyer, B, Jacobs, F, Delmee, M, Peetermans, W, Giot, Jb, Munhoz, Al, Kallas, Eg, Ladeira, Jp, Bernstein, Cn, Grimard, D, Mcgeer, A, Poirier, A, Valiquette, L, Miller, M, Oughton, M, Trottier, S, Dolce, P, Smyth, D, Gambra, P, Palma, S, Rojas, L, Northland, R, Arellano, Mc, Perez, J, Barreto, Mf, Gomez, Jm, Ramirez, I, Correa, A, Onate, J, Rohacova, H, Stastnik, M, Zjevikova, A, Blazek, J, Kumpel, P, Petersen, Am, Gluud, Ll, Staugaard, Hm, Tvede, M, Glerup, H, Madsen, Sm, Helms, M, Naumann, R, Karthaus, M, Reinshagen, M, Raz, R, Giladi, M, Chowers, M, Bishara, J, Quirino, T, Castelli, F, Bassetti, M, Rizzardini, G, Vismara, E, Puoti, M, Viale, P, Menichetti, F, Cauda, R, Bonfanti, P, Franzetti, F, Gori, A, Minoli, L, Noriega, Er, Mills, Gd, Ritchie, S, Burns, A, Pithie, A, dos Santos RM, Aldomiro, F, Fernando, Pb, Rola, J, Reis, E, Van Zyl JH, Aboo, N, Richards, G, Hernandez, Mj, de Medrano VA, Prunonosa, Lm, Gonzalez, Jl, Reinoso, Jc, Martinez, Ar, Cisneros, Jd, Banos, Jr, Sheridan, R, Minton, J, Williams, J, Stanley, P, Guleri, A, Llewelyn, M, Todd, N, Barlow, G, Bacon, Ae, Baird, Im, Baxter, R, Zenilman, Jm, Beshay, M, Betts, Rf, Brettholz, Em, Buitrago, Mi, Carlson, Rw, Cook, Pp, Dupont, Hl, Foley, C, Freilich, B, Giron, Ja, Golan, Y, Green, S, Hall, Mc, Johnson, Dj, Jones, Rk, Graham, Dr, Kazimir, M, Keating, M, Brumble, Lm, Kumar, Pn, Liappis, Ap, Libke, R, Mehra, Pk, Overcash, Sj, Mullane, Km, Nguyen, Mh, Patel, Mc, Powers, Ck, Pullman, J, Keegan, J, Nepal, S, English, G, Ricci, Rl, Risi, Gf, Rodriguez, M, Schmitt, Cm, Sims, Md, Kamepalli, R, Tural, A, Vazquez, Ja, Alangaden, Gj, Weavind, Lm, Young, Ma, Chen, St, Liu, E, Nguyen, Hh, Alfonso, Tb, Muse, Dd, Orenstein, R, Yacyshyn, B, Gebhard, Re, Dinges, W, Bolton, M, Rubin, M, Kuemmerle, Jf, Limaye, Ap, Friedenberg, Ka, Hiemenz, Jw, Quadri, A, Martinez, Jv, Barcan, La, Cordova, E, Mykietiuk, A, Losso, M, Fedorak, Rn, Steiner, T, Gerson, M, Weiss, K, Dlouhy, P, Vitous, A, Benes, J, Husa, P, Knizek, P, Anttila, Vj, Broas, M, Camou, F, Postil, D, Launay, O, Corroyer-Simovic, B, Meynard, Jl, Schneider, S, Molina, Jm, Neau, D, Zalcman, G, Boutoille, D, Ostermann, H, Heinz, W, Reuter, S, Oren, I, Schiff, E, Umemoto, T, Masubuchi, T, Mukawa, K, Yasuda, K, Imokawa, S, Fukuda, K, Ohta, H, Harada, N, Fujii, S, Tamaki, S, Yasui, S, Furukawa, K, Takahashi, M, Uraoka, T, Watanabe, M, Ikehara, Y, Kodaira, M, Komatsu, H, Higashi, K, Taguchi, F, Ura, N, Serizawa, Y, Fukuchi, T, Ashikawa, T, Shabana, M, Okubo, M, Matsumoto, M, Kurihara, A, Miyasaka, E, Shimizu, M, Tominaga, H, Kubota, T, Kashiwazaki, M, Masuda, Y, Terasaki, S, Okafuji, H, Mieno, H, Urabe, T, Okamoto, E, Kajimura, M, Yamagishi, Y, Rydzewska, G, Mach, T, Ciechanowski, K, Podlasin, R, Tomasiewicz, K, Janczewska-Kazek, E, Czarnobilski, K, Halota, W, Gryglewska, B, Plesniak, R, Dabrowiecki, P, Lipowski, D, Simanenkov, V, Shcheglova, L, Uspenskiy, Y, Cheganov, A, Han, Ds, Kim, Js, Hong, Sp, Kim, Ti, Jang, Bi, Byeon, Js, Kim, E, Kim, Mj, Lee, J, Pai, H, Cheong, Hj, Lee, S, Loyarte, Ja, Gonzalez, Jc, Santiago, Eb, Lopez, Jr, Baranda, Jm, Viladomiu, As, Calbo, E, Lannergard, A, Falt, J, Gardlund, B, Andersson, Lm, Fraenkel, Cj, Rombo, L, Widmer, A, Chen, Yc, Sheng, Wh, Wang, Fd, Wang, Nc, Lee, Ch, Chen, Yh, Chuang, Yc, Unal, S, Ozaras, R, Esen, S, Ural, O, Ayaz, C, Sakarya, S, Celebi, A, Mistik, R, Bedimo, R, Bressler, A, Mckinley, Mj, Quirk, D, Talansky, Al, Agronin, Me, Akhrass, Fa, Ali, M, Alrabaa, Sf, Assi, Ma, Calfee, Dp, Carson, P, Mariani, Pg, Guerrero, D, Dubberke, Er, Hardi, R, Hazan-Steinberg, S, Itani, Km, Jauregui-Peredo, El, Kasabji, A, Hameed, M, Murillo, A, Odio, Aj, Shah, P, Braun, Ti, Slim, J, Sloan, L, Srinivasan, S, Tan, Mj, Clough, La, Herr, D, Miller, Lg, Dorfmeister, J, Khan, O, and Melik-Abrahamian, F.

Subjects
0301 basic medicine, Male, Adolescent, Adult, Aged, Aged, 80 and over, Anti-Bacterial Agents, Antibodies, Monoclonal, Antibodies, Neutralizing, Clostridium Infections, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Infusions, Intravenous, Intention to Treat Analysis, Kaplan-Meier Estimate, Middle Aged, Secondary Prevention, Young Adult, Clostridium difficile, Clinical Trial, Phase III, Antibiotics, 0302 clinical medicine, Monoclonal, 80 and over, 030212 general & internal medicine, Medicine (all), Neutralizing, education.field_of_study, Research Support, Non-U.S. Gov't, General Medicine, Multicenter Study, Randomized Controlled Trial, Combination, Broadly Neutralizing Antibodies, Intravenous, medicine.medical_specialty, Infusions, medicine.drug_class, 030106 microbiology, Population, Placebo, Antibodies, 03 medical and health sciences, Pharmacotherapy, Drug Therapy, Internal medicine, Journal Article, medicine, education, Intention-to-treat analysis, Clostridioides difficile, business.industry, Interim analysis, Surgery, Bezlotoxumab, business
Abstract

BACKGROUND: Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively.METHODS: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population.RESULTS: In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, -10.1 percentage points; 95% confidence interval [CI], -15.9 to -4.3; PCONCLUSIONS: Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239 .).

Published
2017
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15. Correction for Cairns et al., “Comparative Genome Analysis and Global Phylogeny of the Toxin Variant Clostridium difficile PCR Ribotype 017 Reveals the Evolution of Two Independent Sublineages”

Author

Cairns, M. D., primary, Preston, M. D., additional, Hall, C. L., additional, Gerding, D. N., additional, Hawkey, P. M., additional, Kato, H., additional, Kim, H., additional, Kuijper, E. J., additional, Lawley, T. D., additional, Pituch, H., additional, Reid, S., additional, Kullin, B., additional, Riley, T. V., additional, Solomon, K., additional, Tsai, P. J., additional, Weese, J. S., additional, Stabler, R. A., additional, and Wren, B. W., additional

Published
2017
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16. Comparative Genome Analysis and Global Phylogeny of the Toxin Variant Clostridium difficile PCR Ribotype 017 Reveals the Evolution of Two Independent Sublineages

Author

Cairns, M. D., primary, Preston, M. D., additional, Hall, C. L., additional, Gerding, D. N., additional, Hawkey, P. M., additional, Kato, H., additional, Kim, H., additional, Kuijper, E. J., additional, Lawley, T. D., additional, Pituch, H., additional, Reid, S., additional, Kullin, B., additional, Riley, T. V., additional, Solomon, K., additional, Tsai, P. J., additional, Weese, J. S., additional, Stabler, R. A., additional, and Wren, B. W., additional

Published
2017
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17. Frequent exacerbators - a distinct phenotype of severe asthma

Author

Kupczyk, M. ten Brinke, A. Sterk, P.J. Bel, E.H. Papi, A. Chanez, P. Nizankowska-Mogilnicka, E. Gjomarkaj, M. Gaga, M. Brusselle, G. Dahlén, B. Dahlén, S.-E. Weersink, E. Papadopoulos, N. Oikonomidou, E. Zervas, E. Contoli, M. Pauwels, R.A. Joos, G.F. de Rudder, I. Schelfhout, V. Richter, K. Gerding, D. Magnussen, H. Siafakas, N.M. Tzortzaki, E. Samara, K. Plataki, M. Papadopouli, E. Szczeklik, A. Ziolkowska-Graca, B. Kania, A. Gawlewicz-Mroczka, A. Duplaga, M. Figiel, E. Rabe, K.F. Hiemstra, P.S. Gauw, S. van Veen, I. Kips, J.C. Johnston, S.L. Mallia, P. Campbell, D.A. Robinson, D.S. Kanniess, F. Fabbri, L.M. Romagnoli, M. Vachier, I. Devautour, C. Meziane, L. Vignola, A.M. Pace, E. Profita, M. Holgate, S.T. Howarth, P.H. Wilson, S.J. Hewitt, L. Holoway, J.

Abstract

Background: Exacerbations represent a major source of morbidity and mortality in asthma and are a prominent feature of poorly controlled, difficult-to-treat disease. Objective: The goal of our study was to provide a detailed characterization of the frequent exacerbator phenotype and to identify risk factors associated with frequent and seasonal exacerbations. Methods: Ninety-three severe asthmatics (SA) and 76 mild-to-moderate patients (MA) were screened and prospectively followed up for 1 year (NCT00555607). Medical history, baseline clinical data and biomarkers were used to assess risk factors for frequent exacerbations. Results: During the study, 104 exacerbations were recorded in the SA group and 18 in the MA. Frequent exacerbators were characterized by use of higher doses of inhaled (1700 vs. 800 μg) and oral (6.7 vs. 1.7 mg) glucocorticosteroids, worse asthma control (ACQ score 2.3 vs. 1.4), lower quality of life (SGRQ score 48.5 vs. 33.3), higher sputum eosinophils (25.7% vs. 8.2%) and a more rapid decline in FEV1/FVC ratio (-0.07 vs. -0.01 ΔFEV1/FVC, frequent vs. non-frequent, respectively, P 45 p.p.b. and a history of smoking were associated with an increased risk of frequent exacerbations (odds ratios: 4.32 and 2.90 respectively). Conclusion and Clinical Relevance: We were able to distinguish and characterize a subphenotype of asthma subjects - frequent exacerbators - who are significantly more prone to exacerbations. Patients with FeNO > 45 p.p.b. and a history of smoking are at increased risk of frequent exacerbations and require careful monitoring in clinical practice. © 2013 John Wiley & Sons Ltd.

Published
2014

18. Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections

Author

Ballard, J, Collier, RJ, Carter, GP, Chakravorty, A, Tu, APN, Mileto, S, Schreiber, F, Li, L, Howarth, P, Clare, S, Cunningham, B, Sambol, SP, Cheknis, A, Figueroa, I, Johnson, S, Gerding, D, Rood, JI, Dougan, G, Lawley, TD, Lyras, D, Ballard, J, Collier, RJ, Carter, GP, Chakravorty, A, Tu, APN, Mileto, S, Schreiber, F, Li, L, Howarth, P, Clare, S, Cunningham, B, Sambol, SP, Cheknis, A, Figueroa, I, Johnson, S, Gerding, D, Rood, JI, Dougan, G, Lawley, TD, and Lyras, D

Abstract

UNLABELLED: Clostridium difficile is a leading cause of antibiotic-associated diarrhea, a significant animal pathogen, and a worldwide public health burden. Most disease-causing strains secrete two exotoxins, TcdA and TcdB, which are considered to be the primary virulence factors. Understanding the role that these toxins play in disease is essential for the rational design of urgently needed new therapeutics. However, their relative contributions to disease remain contentious. Using three different animal models, we show that TcdA(+) TcdB(-) mutants are attenuated in virulence in comparison to the wild-type (TcdA(+) TcdB(+)) strain, whereas TcdA(-) TcdB(+) mutants are fully virulent. We also show for the first time that TcdB alone is associated with both severe localized intestinal damage and systemic organ damage, suggesting that this toxin might be responsible for the onset of multiple organ dysfunction syndrome (MODS), a poorly characterized but often fatal complication of C. difficile infection (CDI). Finally, we show that TcdB is the primary factor responsible for inducing the in vivo host innate immune and inflammatory responses. Surprisingly, the animal infection model used was found to profoundly influence disease outcomes, a finding which has important ramifications for the validation of new therapeutics and future disease pathogenesis studies. Overall, our results show unequivocally that TcdB is the major virulence factor of C. difficile and provide new insights into the host response to C. difficile during infection. The results also highlight the critical nature of using appropriate and, when possible, multiple animal infection models when studying bacterial virulence mechanisms. IMPORTANCE: Clostridium difficile is a leading cause of antibiotic-associated diarrhea and an important hospital pathogen. TcdA and TcdB are thought to be the primary virulence factors responsible for disease symptoms of C. difficile infections (CDI). However, the individual con

Published
2015

21. Detection of exacerbations in asthma based on electronic diary data : results from the 1-year prospective BIOAIR study

Author

Kupczyk, M., Haque, S., Sterk, P. J., Nizankowska-Mogilnicka, E., Papi, A., Bel, E. H., Chanez, P., Dahlen, B., Gaga, M., Gjomarkaj, M., Howarth, P. H., Johnston, S. L., Joos, G. F., Kanniess, F., Tzortzaki, E., James, A., Middelveld, R. J. M., Dahlen, S.-E., Weersink, E., Papadopoulos, N., Oikonomidou, E., Zervas, E., Contoli, M., Pauwels, R. A., Brusselle, G., de Rudder, I., Schelfhout, V., Richter, K., Gerding, D., Magnussen, H., Siafakas, N. M., Samara, K., Plataki, M., Papadopouli, E., Szczeklik, A., Ziolkowska-Graca, B., Kania, A., Gawlewicz-Mroczka, A., Duplaga, M., Figiel, E., Rabe, K. F., Hiemstra, P. S., Gauw, S., van Veen, I., Kips, J. C., Mallia, P., Campbell, D. A., Robinson, D. S., Fabbri, L. M., Romagnoli, M., Vachier, I., Devautour, C., Meziane, L., Maurizio Vignola, A., Pace, E., Profita, M., Holgate, S. T., Wilson, S. J., Hewitt, L., Holoway, J., Damm, K., Delin, I., Eduards, M., Ek, A., Ekstrom, T., Gulich, A., Johansson, L. E., Karlsson, O., Kumlin, M., Martling, I., Skedinger, M., Amsterdam institute for Infection and Immunity, and Pulmonology

Subjects
2. Zero hunger, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Exacerbation, business.industry, medicine.disease, Electronic diary, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Asthma Control Questionnaire, medicine, Sputum, Medical history, 030212 general & internal medicine, medicine.symptom, business, Body mass index, Lung function, Asthma
Abstract

Background Objective measures are required that may be used as a proxy for exacerbations in asthma. The aim was to determine the sensitivity and specificity of electronic diary data to detect severe exacerbations (SEs) of asthma. A secondary aim was to identify phenotypic variables associated with a higher risk of exacerbation. Methods In the BIOAIR study, 169 patients with asthma (93 severe (SA); 76 mild to moderate (MA)) recorded lung function, symptoms and medication use in electronic diaries for 1 year. Data were analysed using receiver-operator characteristics curves and related to physician-diagnosed exacerbations. Medical history and baseline clinical data were used to assess risk of exacerbation. Results Of 122 physician-diagnosed exacerbations, 104 occurred in the SA group (1.1 per patient/year), 18 in the MA group (0.2 per patient/year) and 63 were severe using American Thoracic Society/European Respiratory Society criteria. During exacerbations, peak expiratory flow (PEF) and forced expiratory volume in 1 s significantly decreased, whereas day and night symptoms significantly increased. An algorithm combining a 20% decrease in PEF or a 20% increase in day symptoms on 2 consecutive days was able to detect SEs with 65% sensitivity and 95% specificity. The strongest risk factors for SEs were low Asthma Control Questionnaire score, sputum eosinophils ≥3%, body mass index >25 and low quality of life (St George9s Respiratory Questionnaire), with ORs between 3.61 and 2.22 (p Conclusions Regular electronic monitoring of PEF and asthma symptoms provides an acceptable sensitivity and specificity for the detection of SEs and may be suitable for personal internet-based monitoring of asthma control.

Published
2013

23. Susceptibility ofClostridium difficileisolates from a Phase 2 clinical trial of cadazolid and vancomycin inC. difficileinfection

Author

Gerding, D. N., primary, Hecht, D. W., additional, Louie, T., additional, Nord, C. E., additional, Talbot, G. H., additional, Cornely, O. A., additional, Buitrago, M., additional, Best, E., additional, Sambol, S., additional, Osmolski, J. R., additional, Kracker, H., additional, Locher, H. H., additional, Charef, P., additional, and Wilcox, M., additional

Published
2015
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24. U.S.-Based National Sentinel Surveillance Study for the Epidemiology of Clostridium difficile-Associated Diarrheal Isolates and Their Susceptibility to Fidaxomicin

Author

Snydman, D. R., primary, McDermott, L. A., additional, Jacobus, N. V., additional, Thorpe, C., additional, Stone, S., additional, Jenkins, S. G., additional, Goldstein, E. J. C., additional, Patel, R., additional, Forbes, B. A., additional, Mirrett, S., additional, Johnson, S., additional, and Gerding, D. N., additional

Published
2015
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27. NAP1 Strain Type Predicts Outcomes From Clostridium difficile Infection

Author

See, I., primary, Mu, Y., additional, Cohen, J., additional, Beldavs, Z. G., additional, Winston, L. G., additional, Dumyati, G., additional, Holzbauer, S., additional, Dunn, J., additional, Farley, M. M., additional, Lyons, C., additional, Johnston, H., additional, Phipps, E., additional, Perlmutter, R., additional, Anderson, L., additional, Gerding, D. N., additional, and Lessa, F. C., additional

Published
2014
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28. Emergence and global spread of epidemic healthcare-associated Clostridium difficile

Author

He, M, Miyajima, F, Roberts, P, Ellison, L, Pickard, DJ, Martin, MJ, Connor, TR, Harris, SR, Fairley, D, Bamford, KB, D'Arc, S, Brazier, J, Brown, D, Coia, JE, Douce, G, Gerding, D, Kim, HJ, Koh, TH, Kato, H, Senoh, M, Louie, T, Michell, S, Butt, E, Peacock, SJ, Brown, NM, Riley, T, Songer, G, Wilcox, M, Pirmohamed, M, Kuijper, E, Hawkey, P, Wren, BW, Dougan, G, Parkhill, J, Lawley, TD, He, M, Miyajima, F, Roberts, P, Ellison, L, Pickard, DJ, Martin, MJ, Connor, TR, Harris, SR, Fairley, D, Bamford, KB, D'Arc, S, Brazier, J, Brown, D, Coia, JE, Douce, G, Gerding, D, Kim, HJ, Koh, TH, Kato, H, Senoh, M, Louie, T, Michell, S, Butt, E, Peacock, SJ, Brown, NM, Riley, T, Songer, G, Wilcox, M, Pirmohamed, M, Kuijper, E, Hawkey, P, Wren, BW, Dougan, G, Parkhill, J, and Lawley, TD

Abstract

Epidemic C. difficile (027/BI/NAP1) has rapidly emerged in the past decade as the leading cause of antibiotic-associated diarrhea worldwide. However, the key events in evolutionary history leading to its emergence and the subsequent patterns of global spread remain unknown. Here, we define the global population structure of C. difficile 027/BI/NAP1 using whole-genome sequencing and phylogenetic analysis. We show that two distinct epidemic lineages, FQR1 and FQR2, not one as previously thought, emerged in North America within a relatively short period after acquiring the same fluoroquinolone resistance-conferring mutation and a highly related conjugative transposon. The two epidemic lineages showed distinct patterns of global spread, and the FQR2 lineage spread more widely, leading to healthcare-associated outbreaks in the UK, continental Europe and Australia. Our analysis identifies key genetic changes linked to the rapid transcontinental dissemination of epidemic C. difficile 027/BI/NAP1 and highlights the routes by which it spreads through the global healthcare system.

Published
2013

29. Emergence and global spread of epidemic healthcare-associated Clostridium difficile

Author

He, M., Miyajima, F., Roberts, P., Ellison, L., Pickard, D.J., Martin, M.J., Connor, T.R., Harris, S.R., Fairley, D., Bamford, K.B., D'Arc, S., Brazier, J., Brown, D., Coia, J.E., Douce, G.l, Gerding, D., Kim, H.J., Koh, T.H., Kato, H., Senoh, M., Louie, T., Michell, S., Butt, E., Peacock, S.J., Brown, N.M., Riley, T., Songer, G., Wilcox, M., Pirmohamed, M., Kuijper, E., Hawkey, P.r, Wren, B.W., Dougan, G., Parkhill, J., Lawley, T.D., He, M., Miyajima, F., Roberts, P., Ellison, L., Pickard, D.J., Martin, M.J., Connor, T.R., Harris, S.R., Fairley, D., Bamford, K.B., D'Arc, S., Brazier, J., Brown, D., Coia, J.E., Douce, G.l, Gerding, D., Kim, H.J., Koh, T.H., Kato, H., Senoh, M., Louie, T., Michell, S., Butt, E., Peacock, S.J., Brown, N.M., Riley, T., Songer, G., Wilcox, M., Pirmohamed, M., Kuijper, E., Hawkey, P.r, Wren, B.W., Dougan, G., Parkhill, J., and Lawley, T.D.

Abstract

Epidemic C. difficile (027/BI/NAP1) has rapidly emerged in the past decade as the leading cause of antibiotic-associated diarrhea worldwide. However, the key events in evolutionary history leading to its emergence and the subsequent patterns of global spread remain unknown. Here, we define the global population structure of C. difficile 027/BI/NAP1 using whole-genome sequencing and phylogenetic analysis. We show that two distinct epidemic lineages, FQR1 and FQR2, not one as previously thought, emerged in North America within a relatively short period after acquiring the same fluoroquinolone resistance-conferring mutation and a highly related conjugative transposon. The two epidemic lineages showed distinct patterns of global spread, and the FQR2 lineage spread more widely, leading to healthcare-associated outbreaks in the UK, continental Europe and Australia. Our analysis identifies key genetic changes linked to the rapid transcontinental dissemination of epidemic C. difficile 027/BI/NAP1 and highlights the routes by which it spreads through the global healthcare system.

Published
2012

30. Utility of a Commercial PCR Assay and a Clinical Prediction Rule for Detection of Toxigenic Clostridium difficile in Asymptomatic Carriers

Author

Donskey, C. J., primary, Sunkesula, V. C. K., additional, Jencson, A. L., additional, Stone, N. D., additional, Gould, C. V., additional, McDonald, L. C., additional, Samore, M., additional, Mayer, J., additional, Pacheco, S., additional, Sambol, S., additional, Petrella, L., additional, Terry, D., additional, and Gerding, D. N., additional

Published
2013
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34. Comparative Genome Analysis and Global Phylogeny of the Toxin Variant Clostridium difficilePCR Ribotype 017 Reveals the Evolution of Two Independent Sublineages

Author

Cairns, M. D., Preston, M. D., Hall, C. L., Gerding, D. N., Hawkey, P. M., Kato, H., Kim, H., Kuijper, E. J., Lawley, T. D., Pituch, H., Reid, S., Kullin, B., Riley, T. V., Solomon, K., Tsai, P. J., Weese, J. S., Stabler, R. A., and Wren, B. W.

Abstract

ABSTRACTThe diarrheal pathogen Clostridium difficileconsists of at least six distinct evolutionary lineages. The RT017 lineage is anomalous, as strains only express toxin B, compared to strains from other lineages that produce toxins A and B and, occasionally, binary toxin. Historically, RT017 initially was reported in Asia but now has been reported worldwide. We used whole-genome sequencing and phylogenetic analysis to investigate the patterns of global spread and population structure of 277 RT017 isolates from animal and human origins from six continents, isolated between 1990 and 2013. We reveal two distinct evenly split sublineages (SL1 and SL2) of C. difficileRT017 that contain multiple independent clonal expansions. All 24 animal isolates were contained within SL1 along with human isolates, suggesting potential transmission between animals and humans. Genetic analyses revealed an overrepresentation of antibiotic resistance genes. Phylogeographic analyses show a North American origin for RT017, as has been found for the recently emerged epidemic RT027 lineage. Despite having only one toxin, RT017 strains have evolved in parallel from at least two independent sources and can readily transmit between continents.

Published
2017
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41. Laboratory detection of Clostridium difficile. A comparison of media and incubation systems.

Author

Mundy, L S, Shanholtzer, C J, Willard-Gallo, Karen, Gerding, D N, Peterson, L R, Mundy, L S, Shanholtzer, C J, Willard-Gallo, Karen, Gerding, D N, and Peterson, L R

Abstract

Parallel testing for culture recovery of Clostridium difficile was performed using three selective media in each of four anaerobic incubation environmental systems. Testing was completed on 67 stool samples from 60 hospitalized patients in whom C difficile-associated diarrhea was suspected. Three different media were evaluated: CCFA (modified cycloserine-cefoxitin-fructose agar), CCFA-PRAS (CCFA, prereduced-anaerobically-sterilized) and CMBA (modified cycloserine-mannitol-blood agar). The incubation systems compared were an anaerobic chamber (Model 800 Anaerobic Environmental System, Anaerobe Systems, San Jose, CA), the anaerobic jar (BBL, Cockeysville, MD), the anaerobic Bio-Bag (BBL), and the anaerobic pouch (BBL). C difficile was found in 16 samples collected from 15 patients. Comparing recovery on the various types of media in all four anaerobic atmospheres, C difficile was recovered on all (64) CCFA plates, 56 of 64 CCFA-PRAS plates, and 43 of 64 CMBA plates (P < .03 comparing CCFA and CMBA). Of the 48 plates in each incubation system that were inoculated with specimens positive for C difficile, the organism was recovered from 43 plates in the anaerobe chamber, 41 incubated in an anaerobe jar, 40 in the Bio-Bag, and 39 incubated in the GasPak pouch, all providing similar recovery of C difficile (P = .08). The CCFA-PRAS and CMBA media demonstrated less inhibition of normal stool flora compared to the CCFA. Overall CCFA that was anaerobically reduced at least 4 hours before use, and contained the original concentration of antimicrobial agents described by George and colleagues, was superior to CMBA for recovery of C. difficile., info:eu-repo/semantics/published

Published
1995

43. Activity of twenty-one antimicrobial agents including l-ofloxacin against quinolone-sensitive and -resistant, and methicillin-sensitive and -resistant Staphylococcus aureus.

Author

Peterson, L R, Cooper, I, Willard-Gallo, Karen, Fasching, C E, Sinn, L M, Shanholtzer, C J, Gerding, D N, Peterson, L R, Cooper, I, Willard-Gallo, Karen, Fasching, C E, Sinn, L M, Shanholtzer, C J, and Gerding, D N

Abstract

There is a need to identify alternative agents to vancomycin for the treatment of infections with methicillin-resistant Staphylococcus aureus (MRSA). One candidate is the l isomer of ofloxacin (DR-3355). We tested 520 frozen MRSA isolates, 248 fresh MRSA isolates, and 375 fresh methicillin-susceptible S. aureus (MSSA) isolates from Minnesota, and 600 clinical isolates of S. aureus (150 MRSA and 450 MSSA) from Illinois. Over 90% of the MRSA strains were resistant to 32 micrograms/ml of oxacillin. Of the 520 frozen MRSA, 24% were susceptible to < or = 2 micrograms/ml ofloxacin, and an additional 74% were susceptible to ofloxacin between 8 and 16 micrograms/ml. More than 98% of all strains were susceptible to < or = 16 micrograms/ml ofloxacin or l-ofloxacin. All the quinolones had a bimodal distribution of in vitro activity, but for only ofloxacin and l-ofloxacin was activity confined to a very narrow range., info:eu-repo/semantics/published

Published
1994

44. GyrA sequence analysis of Staphylococcus aureus and methicillin-resistant S. aureus strains selected, in vitro, for high-level ciprofloxacin resistance.

Author

Peterson, L R, Willard-Gallo, Karen, Sinn, L M, Fasching, C E, Gerding, D N, Peterson, L R, Willard-Gallo, Karen, Sinn, L M, Fasching, C E, and Gerding, D N

Abstract

Four methicillin-susceptible Staphylococcus aureus and eight methicillin-resistant S. aureus (MRSA) isolates, all of which were ciprofloxacin susceptible (MIC < 2.0 micrograms/ml) were manipulated, in vitro, to achieve high-level ciprofloxacin resistance by means of up to 14 passages onto media containing increasing concentrations of ciprofloxacin. Resistance to ciprofloxacin at a concentration of at least 512 micrograms/ml was achieved in all 12 isolates tested. This resistance was continually detected during weekly passage on antibiotic-free media for 12 weeks. The parent and daughter cells from four strains had their gyrA sequenced from amino acid (aa) codons 70-100, the region of previous mutations in high level quinolone-resistant S. aureus. Mutations at aa codon 84 were seen in three of four strains, but appeared at varying levels of ciprofloxacin resistance. High-level resistance of S. aureus and MRSA to ciprofloxacin can be developed in vitro using multiple exposures to incremental concentrations of the drug. It is apparently due to multiple mechanisms and, once established, remains stable over time., info:eu-repo/semantics/published

Published
1993

45. Comparison of the VIDAS Clostridium difficile toxin A immunoassay with C. difficile culture and cytotoxin and latex tests.

Author

Shanholtzer, C J, Willard-Gallo, Karen, Holter, J J, Olson, M M, Gerding, D N, Peterson, L R, Shanholtzer, C J, Willard-Gallo, Karen, Holter, J J, Olson, M M, Gerding, D N, and Peterson, L R

Abstract

The VIDAS Clostridium difficile toxin A immunoassay (CDA) is a new, automated, enzyme-linked fluorescent-antibody assay for detection of C. difficile toxin A antigen in stool specimens. Simultaneous, parallel testing was performed by using the VIDAS CDA, the Culturette brand CDT latex test for C. difficile antigens, and conventional laboratory cell culture tests for C. difficile, cytotoxicity and C. difficile culture. One hundred ninety-four consecutive fresh soft or liquid stool samples submitted for C. difficile testing between July and September 1990 were evaluated. Of the 194 samples tested, 19 (10%) were from 16 patients who met our case definition for C. difficile-associated disease. The in vitro tests were evaluated in relation to two forms of a clinical case definition. In one form, a positive culture for toxin-producing C. difficile or a positive cytotoxin result obtained directly from the stool specimen was required as laboratory evidence of C. difficile. In the other, a positive result of any of the four laboratory tests was accepted for the laboratory portion of the case definition. No significant difference between the sensitivity of the VIDAS CDA and that of the Culturette brand CDT latex test was found (48 to 58% sensitivity for the CDT latex test and 52 to 63% sensitivity for the VIDAS CDA compared with 93 to 100% sensitivity for culture and 70 to 100% sensitivity for cytotoxin testing). The performance of the VIDAS CDA, however, was hampered by a high percentage of tests (19%) which gave an uninterpretable result., info:eu-repo/semantics/published

Published
1992

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