Incidence and predictive biomarkers of Clostridioides difficile infection in hospitalized patients receiving broad-spectrum antibiotics

Cornelis H van Werkhoven, Annie Ducher, Matilda Berkell, Mohamed Mysara, Christine Lammens, Julian Torre-Cisneros, Jesús Rodríguez-Baño, Delia Herghea, Oliver A Cornely, Lena M Biehl, Louis Bernard, M Angeles Dominguez-Luzon, Sofia Maraki, Olivier Barraud, Maria Nica, Nathalie Jazmati, Frederique Sablier-Gallis, Jean de Gunzburg, France Mentré, Surbhi Malhotra-Kumar, Marc J M Bonten, Maria J G T Vehreschild, ANTICIPATE Study Group, Annemarie M S Engbers, Marieke J A de Regt, Herman Goossens, Basil Britto Xavier, Marie-Noelle Bouverne, Pieter Monsieurs, Uta Merle, Andreas Stallmach, Jan Rupp, Johannes Bogner, Christoph Lübbert, Gerda Silling, Oliver Witzke, Achilleas Gikas, George Daikos, Sotirios Tsiodras, Athanasios Skoutelis, Helen Sambatakou, Miquel Pujol, Jose M Aguado, Emilio Bouza, Javier Cobo, Benito Almirante, Simin A Florescu, Andrei Vata, Adriana Hristea, Mihaela Lupse, Deborah Postil, Jean-Michel Molina, Victoire De Lastours, Thomas Guimard, Jean-Philippe Talarmin, Xavier Duval, Odile Launay, Cornelis H van Werkhoven, Annie Ducher, Matilda Berkell, Mohamed Mysara, Christine Lammens, Julian Torre-Cisneros, Jesús Rodríguez-Baño, Delia Herghea, Oliver A Cornely, Lena M Biehl, Louis Bernard, M Angeles Dominguez-Luzon, Sofia Maraki, Olivier Barraud, Maria Nica, Nathalie Jazmati, Frederique Sablier-Gallis, Jean de Gunzburg, France Mentré, Surbhi Malhotra-Kumar, Marc J M Bonten, Maria J G T Vehreschild, ANTICIPATE Study Group, Annemarie M S Engbers, Marieke J A de Regt, Herman Goossens, Basil Britto Xavier, Marie-Noelle Bouverne, Pieter Monsieurs, Uta Merle, Andreas Stallmach, Jan Rupp, Johannes Bogner, Christoph Lübbert, Gerda Silling, Oliver Witzke, Achilleas Gikas, George Daikos, Sotirios Tsiodras, Athanasios Skoutelis, Helen Sambatakou, Miquel Pujol, Jose M Aguado, Emilio Bouza, Javier Cobo, Benito Almirante, Simin A Florescu, Andrei Vata, Adriana Hristea, Mihaela Lupse, Deborah Postil, Jean-Michel Molina, Victoire De Lastours, Thomas Guimard, Jean-Philippe Talarmin, Xavier Duval, Odile Launay

Abstract

Trial enrichment using gut microbiota derived biomarkers by high-risk individuals can improve the feasibility of randomized controlled trials for prevention of Clostridioides difficile infection (CDI). Here, we report in a prospective observational cohort study the incidence of CDI and assess potential clinical characteristics and biomarkers to predict CDI in 1,007 patients ≥ 50 years receiving newly initiated antibiotic treatment with penicillins plus a beta-lactamase inhibitor, 3rd/4th generation cephalosporins, carbapenems, fluoroquinolones or clindamycin from 34 European hospitals. The estimated 90-day cumulative incidences of a first CDI episode is 1.9% (95% CI 1.1-3.0). Carbapenem treatment (Hazard Ratio (95% CI): 5.3 (1.7-16.6)), toxigenic C. difficile rectal carriage (10.3 (3.2-33.1)), high intestinal abundance of Enterococcus spp. relative to Ruminococcus spp. (5.4 (2.1-18.7)), and low Shannon alpha diversity index as determined by 16 S rRNA gene profiling (9.7 (3.2-29.7)), but not normalized urinary 3-indoxyl sulfate levels, predicts an increased CDI risk.

Conflict of interest statement

C.Hv.W. received speaker fees from Pfizer and Merck/MSD, and non-financial research support from bioMérieux. A.D. and F.S. are employees and shareholders of Da Volterra, Paris. J.G. is a consultant and shareholder of Da Volterra. J.T.C. has received speaker and consultant fess from Pfizer, MSD, Shionogy, Menarini and research support from Pfizer. O.A.C. is supported by the German Federal Ministry of Research and Education, is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—CECAD, EXC 2030—390661388 and has received research grants from Actelion, Amplyx, Astellas, Basilea, Cidara, Da Volterra, F2G, Gilead, Janssen, Medicines Company, Melinta, Merck/MSD, Octapharma, Pfizer, Scynexis, is a consultant to Actelion, Allecra, Amplyx, Astellas, Basilea, Biosys, Cidara, Da Volterra, Entasis, F2G, Gilead, Matinas, MedPace, Menarini, Merck/MSD, Mylan, Nabriva, Noxxon, Octapharma, Paratek, Pfizer, PSI, Roche Diagnostics, Scynexis, and Shionogi, and received lecture honoraria from Al-Jazeera Pharmaceuticals, Astellas, Basilea, Gilead, Grupo Biotoscana, Merck/MSD and Pfizer. L.M.B. has received lecture honoraria from Astellas and Merck/MSD, and travel grants from 3M and Gilead. OB received speaker fees and/or travel grants from Pfizer, MSD, Roche and Sanofi and has been a consultant to bioMérieux and Mylan. F.M. is a consultant for Da Volterra, IPSEN, Servier and received research grants from Da Volterra, Sanofi and Servier. MJGTV has received research grants from 3M, Astellas Pharma, Da Volterra, Gilead Sciences, Glycom, MaaT Pharma, Merck/MSD, Organobalance, Seres Therapeutics; speaker fees from Astellas Pharma, Basilea, Gilead Sciences, Merck/MSD, Organobalance, Pfizer and has been a consultant to Alb Fils Kliniken GmbH, Astellas Pharma, Bio-Mérieux, Da Volterra, Ferring, MaaT Pharma, Merck/MSD. The remaining authors declare no competing interests.

Figures

Fig. 1. Inclusion flowchart.
Fig. 1. Inclusion flowchart.
*Based on 28 hospitals that provided screening data. Hospitals were requested to complete on the screening log for all screened patients up to March 23, 2017, and all eligible patients for the entire study period. Of the enrolled patients, 897 (89.1%) were enrolled in hospitals that provided screening data. **Subjects who signed informed consent but met one of the exclusion criteria at baseline. This includes 33 subjects from one side that applied an early consent procedure for subjects at high risk of receiving antibiotics in the near future. Abbreviations: AB antibiotics, CDI C. difficile infection, ICU intensive care unit, MD medical doctor.

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