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Supportive Care

Impact of choice, timing, sequence and combination of broad-spectrum antibiotics on the outcome of allogeneic haematopoietic stem cell transplantation

Bone Marrow Transplantation volume 53, pages 52–57 (2018)Cite this article

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Abstract

Recent data link the incidence of intestinal GvHD (iGvHD) after allogeneic haematopoietic stem cell transplantation (aSCT) to exposure with piperacillin–tazobactam or imipenem–cilastatin. To assess relevance of timing, duration, sequence and combination of antibiotic treatment in this setting, we applied a time-dependent model to our aSCT cohort. Patients from the prospective Cologne Cohort of Neutropenic Patients (CoCoNut) undergoing aSCT from January 2007 to April 2013 were included into a time-dependent multivariate Cox proportional hazards regression model with backward-stepwise selection. In 399 eligible patients, cumulative antibiotic exposure (hazard ratio (HR) 2.46; 95% confidence interval (95% CI) 1.59–3.81; P<0.001) and exposure to sequential treatment with penicillin derivatives and carbapenems (HR 6.22, 95% CI 1.27–30.31), but not to the individual classes, were associated with iGvHD at day 100. Glycopeptides were assessed as a risk factor (HR 3.73, 95% CI 1.51–9.19), but not considered independent, since their use was dependent on previous exposure to penicillin derivatives and carbapenems. Patients with iGvHD presented with increased non-relapse mortality at day 365 (HR 3.51; 95% CI 2.10–5.89; P<0.001). We identified sequential exposure to penicillin derivatives and carbapenems as well as overall exposure to antibiotics as independent risk factors for iGVHD. Confirmation of these findings in larger, prospective cohorts is necessary.

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References

  1. Taur Y, Pamer EG . Microbiome mediation of infections in the cancer setting. Genome Med 2016; 8: 40.

    Article  Google Scholar 

  2. Copelan EA . Hematopoietic stem-cell transplantation. N Engl J Med 2006; 354: 1813–1826.

    Article  CAS  Google Scholar 

  3. Shono Y, Docampo MD, Peled JU, Perobelli SM, Velardi E, Tsai JJ et al. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med 2016; 8: 339ra371.

    Article  Google Scholar 

  4. Weber D, Oefner PJ, Dettmer K, Hiergeist A, Koestler J, Gessner A et al. Rifaximin preserves intestinal microbiota balance in patients undergoing allogeneic stem cell transplantation. Bone Marrow Transplant 2016; 51: 1087–1092.

    Article  CAS  Google Scholar 

  5. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. PLoS Med 2007; 4: e296.

    Article  Google Scholar 

  6. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106: 2912–2919.

    Article  CAS  Google Scholar 

  7. Polk RE, Fox C, Mahoney A, Letcavage J, MacDougall C . Measurement of adult antibacterial drug use in 130 US hospitals: comparison of defined daily dose and days of therapy. Clin Infect Dis 2007; 44: 664–670.

    Article  CAS  Google Scholar 

  8. Budczies J, Klauschen F, Sinn BV, Gyorffy B, Schmitt WD, Darb-Esfahani S et al. Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS ONE 2012; 7: e51862.

    Article  CAS  Google Scholar 

  9. R Core Team. R: A Language and Environment for Statistical Computing. 3.2.5 edn. R Foundation for Statistical Computing: Vienna, Austria, 2016.

  10. Grambsch PM, Therneau TM . Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 1994; 81: 515–526.

    Article  Google Scholar 

  11. Holler E, Butzhammer P, Schmid K, Hundsrucker C, Koestler J, Peter K et al. Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant 2014; 20: 640–645.

    Article  Google Scholar 

  12. Taur Y, Jenq RR, Perales MA, Littmann ER, Morjaria S, Ling L et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood 2014; 124: 1174–1182.

    Article  CAS  Google Scholar 

  13. Jenq RR, Taur Y, Devlin SM, Ponce DM, Goldberg JD, Ahr KF et al. Intestinal Blautia is associated with reduced death from graft-versus-host disease. Biol Blood Marrow Transplant 2015; 21: 1373–1383.

    Article  Google Scholar 

  14. Weber D, Oefner PJ, Hiergeist A, Koestler J, Gessner A, Weber M et al. Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome. Blood 2015; 126: 1723–1728.

    Article  CAS  Google Scholar 

  15. Mathewson ND, Jenq R, Mathew AV, Koenigsknecht M, Hanash A, Toubai T et al. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat Immunol 2016; 17: 505–513.

    Article  CAS  Google Scholar 

  16. Weisser M, Theilacker C, Sutter ST, Babikir R, Bertz H, Gotting T et al. Secular trends of bloodstream infections during neutropenia in 15,181 haematopoietic stem cell transplants: 13-year results from a European Multicentre Surveillance Study (ONKO-KISS). Clin Microbiol Infect 2017.

  17. Klastersky J, de Naurois J, Rolston K, Rapoport B, Maschmeyer G, Aapro M et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol 2016; 27 (suppl 5): v111–v118.

    Article  CAS  Google Scholar 

  18. Averbuch D, Orasch C, Cordonnier C, Livermore DM, Mikulska M, Viscoli C et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica 2013; 98: 1826–1835.

    Article  Google Scholar 

  19. Paul M, Dickstein Y, Borok S, Vidal L, Leibovici L . Empirical antibiotics targeting Gram-positive bacteria for the treatment of febrile neutropenic patients with cancer. Cochrane Database Syst Rev 2014; 1: CD003914.

    Google Scholar 

  20. Biehl LM, Schmidt-Hieber M, Liss B, Cornely OA, Vehreschild MJ . Colonization and infection with extended spectrum beta-lactamase producing Enterobacteriaceae in high-risk patients—review of the literature from a clinical perspective. Crit Rev Microbiol 2016; 42: 1–16.

    Article  CAS  Google Scholar 

  21. Paul M, Dickstein Y, Schlesinger A, Grozinsky-Glasberg S, Soares-Weiser K, Leibovici L . Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropenia. Cochrane Database Syst Rev 2013; 6: CD003038.

    Google Scholar 

  22. Paul M, Yahav D, Bivas A, Fraser A, Leibovici L . Anti-pseudomonal beta-lactams for the initial, empirical, treatment of febrile neutropenia: comparison of beta-lactams. Cochrane Database Syst Rev 2010; 11: CD005197.

    Google Scholar 

  23. Gyssens IC, Kern WV, Livermore DM,, Ecil ajvoEEI, ESCMID Eo. The role of antibiotic stewardship in limiting antibacterial resistance among hematology patients. Haematologica 2013; 98: 1821–1825.

    Article  Google Scholar 

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Acknowledgements

We thank our medical documentation assistants Sandra Fuhrmann and Frank Müller for their help in electronic data capture.

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Authors and Affiliations

  1. Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany

    F Farowski, V Bücker, J J Vehreschild, L Biehl, R Cruz-Aguilar, C Scheid, U Holtick, O A Cornely & M J G T Vehreschild

  2. German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany

    F Farowski, J J Vehreschild, L Biehl, R Cruz-Aguilar, N Jazmati, O A Cornely & M J G T Vehreschild

  3. Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, Cologne, Germany

    N Jazmati & H Wisplinghoff

  4. Clinical Trials Centre Cologne, ZKS Köln, Cologne, Germany,

    O A Cornely

  5. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany,

    O A Cornely

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  1. F Farowski
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  2. V Bücker
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  10. O A Cornely
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Correspondence to M J G T Vehreschild.

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Competing interests

FF received travel grants from Astellas and MSD. MJGTV is a consultant to Berlin Chemie, MSD/Merck and Astellas Pharma; has served at the speakers’ bureau of Astellas Pharma, Basilea, Gilead Sciences, Merck/MSD, Organobalance and Pfizer; received research funding from 3M, Astellas Pharma, DaVolterra, Gilead Sciences, Merck/MSD, Organobalance and Seres Therapeutics. JJV is a consultant to Basilea, MSD/Merck and Astellas Pharma; has served at the speakers’ bureau of: Basilea, Pfizer, Merck/MSD, Gilead Sciences and Astellas Pharma; received research funding from Astellas Pharma, Basilea, Merck/MSD and Gilead Sciences. LMB has received lecture honoraria from Astellas and MSD and travel grants from 3M and Gilead. NJ received payments for lectures from MSD, travel grant from IMDx (Qiagen) and research funding from DaVolterra. OAC is supported by the German Federal Ministry of Research and Education and the European Commission, and has received research grants from, is an advisor to, or received lecture honoraria from, Actelion, Amplyx, Anacor, Aranis, Astellas, AstraZeneca, Basilea, Bayer, Cidara, Da Volterra, Duke University (NIH UM1AI104681), F2G, Gilead, GSK, Janssen Pharmaceuticals, Leeds University, Matinas, MedPace, Melinta Therapeutics, Menarini Ricerche, Merck/MSD, Miltenyi, Paratek Pharmaceuticals, Pfizer, Rempex, Roche, Sanofi Pasteur, Scynexis, Seres, Summit, The Medicine Company, Vical, Vifor. The remaining authors declare no conflict of interest.

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Farowski, F., Bücker, V., Vehreschild, J. et al. Impact of choice, timing, sequence and combination of broad-spectrum antibiotics on the outcome of allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant 53, 52–57 (2018). https://doi.org/10.1038/bmt.2017.203

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