@article{a9dde3e8708c47a59359a4f4a5d6a6af,
title = "Anaerobic Antibiotics and the Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation",
abstract = "Certain anaerobic bacteria are important for maintenance of gut barrier integrity and immune tolerance and may influence the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a single-center retrospective cohort study of allogeneic HSCT recipients to evaluate associations between receipt of antibiotics with an anaerobic spectrum of activity and GVHD outcomes. We identified 1214 children and adults who developed febrile neutropenia between 7 days before and 28 days after HSCT and compared GVHD risk and mortality among patients who received anaerobic antibiotics (piperacillin-tazobactam or carbapenems; n = 491) to patients who received only antibiotics with minimal activity against anaerobes (aztreonam, cefepime, or ceftazidime; n = 723). We performed metagenomic sequencing of serial fecal samples from 36 pediatric patients to compare the effects of specific antibiotics on the gut metagenome. Receipt of anaerobic antibiotics was associated with higher hazards of acute gut/liver GVHD (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.03 to 1.54) and acute GVHD mortality (HR, 1.63; 95% CI, 1.08 to 2.46), but not chronic GVHD diagnosis (HR, 1.04; 95% CI: .84 to 1.28) or chronic GVHD mortality (HR, .88; 95% CI, .53 to 1.45). Anaerobic antibiotics resulted in decreased gut bacterial diversity, reduced abundances of Bifidobacteriales and Clostridiales, and loss of bacterial genes encoding butyrate biosynthesis enzymes from the gut metagenome. Acute gut/liver GVHD was preceded by a sharp decline in bacterial butyrate biosynthesis genes with antibiotic treatment. Our findings demonstrate that exposure to anaerobic antibiotics is associated with increased risks of acute gut/liver GVHD and acute GVHD mortality after allogeneic HSCT. Use of piperacillin-tazobactam or carbapenems should be reserved for febrile neutropenia cases in which anaerobic or multidrug-resistant infections are suspected.",
keywords = "Carbapenems, Febrile neutropenia, Gut microbiome, Piperacillin-tazobactam",
author = "Tanaka, {John S.} and Young, {Rebecca R.} and Heston, {Sarah M.} and Kirsten Jenkins and Spees, {Lisa P.} and Sung, {Anthony D.} and Kelly Corbet and Thompson, {Jillian C.} and Lauren Bohannon and Martin, {Paul L.} and Andre Stokhuyzen and Richard Vinesett and Ward, {Doyle V.} and Bhattarai, {Shakti K.} and Vanni Bucci and Mehreen Arshad and Seed, {Patrick C.} and Kelly, {Matthew S.}",
note = "Funding Information: Financial disclosure: This work was supported by research grants from the Derfner Foundation and the Children's Miracle Network. Other support was provided by the National Institute of Allergy and Infectious Diseases (K23AI135090 and UM1AI104681) and the National Center for Advancing Translational Sciences (5KL2TR001115 and UL1TR002553). L.P.S. was supported by the Agency for Healthcare Research and Quality (5T32HS000032) and the National Cancer Institute (5T32CA116339). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Conflict of interest statement: The authors have no conflicts of interest to declare. Authorship statement: J.S.T. and M.S.K. designed the research, collected data, performed data analysis, and wrote the manuscript. R.R.Y. and S.M.H. designed the research and performed data analysis. K.J. L.P.S. A.D.S, K.C. J.C.T. L.B. and R.V. collected data and assisted with data interpretation. P.L.M. A.S. D.V.W. S.K.B. V.B. M.A. and P.C.S. designed the research and assisted with data interpretation. All authors approved of the final version of the manuscript. Financial disclosure: See Acknowledgments on page 2059. Funding Information: Financial disclosure: This work was supported by research grants from the Derfner Foundation and the Children's Miracle Network. Other support was provided by the National Institute of Allergy and Infectious Diseases (K23AI135090 and UM1AI104681) and the National Center for Advancing Translational Sciences (5KL2TR001115 and UL1TR002553). L.P.S. was supported by the Agency for Healthcare Research and Quality (5T32HS000032) and the National Cancer Institute (5T32CA116339). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2020 American Society for Transplantation and Cellular Therapy",
year = "2020",
month = nov,
doi = "10.1016/j.bbmt.2020.07.011",
language = "English",
volume = "26",
pages = "2053--2060",
journal = "Biology of Blood and Marrow Transplantation",
issn = "1083-8791",
publisher = "Elsevier BV",
number = "11",
}