Anaerobic Antibiotics and the Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

John S. Tanaka; Rebecca R. Young; Sarah M. Heston; Kirsten Jenkins; Lisa P. Spees; Anthony D. Sung; Kelly Corbet; Jillian C. Thompson; Lauren Bohannon; Paul L. Martin; Andre Stokhuyzen; Richard Vinesett; Doyle V. Ward; Shakti K. Bhattarai; Vanni Bucci; Mehreen Arshad; Patrick C. Seed; Matthew S. Kelly

doi:10.1016/j.bbmt.2020.07.011

Anaerobic Antibiotics and the Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

John S. Tanaka, Rebecca R. Young, Sarah M. Heston, Kirsten Jenkins, Lisa P. Spees, Anthony D. Sung, Kelly Corbet, Jillian C. Thompson, Lauren Bohannon, Paul L. Martin, Andre Stokhuyzen, Richard Vinesett, Doyle V. Ward, Shakti K. Bhattarai, Vanni Bucci, Mehreen Arshad, Patrick C. Seed, Matthew S. Kelly

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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.

Original language	English
Pages (from-to)	2053-2060
Number of pages	8
Journal	Biology of Blood and Marrow Transplantation
Volume	26
Issue number	11
DOIs	https://doi.org/10.1016/j.bbmt.2020.07.011
Publication status	Published - Nov 2020
Externally published	Yes

Keywords

Carbapenems
Febrile neutropenia
Gut microbiome
Piperacillin-tazobactam

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10.1016/j.bbmt.2020.07.011

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Tanaka, J. S., Young, R. R., Heston, S. M., Jenkins, K., Spees, L. P., Sung, A. D., Corbet, K., Thompson, J. C., Bohannon, L., Martin, P. L., Stokhuyzen, A., Vinesett, R., Ward, D. V., Bhattarai, S. K., Bucci, V., Arshad, M., Seed, P. C., & Kelly, M. S. (2020). Anaerobic Antibiotics and the Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation. Biology of Blood and Marrow Transplantation, 26(11), 2053-2060. https://doi.org/10.1016/j.bbmt.2020.07.011

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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 = "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",

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Tanaka, JS, Young, RR, Heston, SM, Jenkins, K, Spees, LP, Sung, AD, Corbet, K, Thompson, JC, Bohannon, L, Martin, PL, Stokhuyzen, A, Vinesett, R, Ward, DV, Bhattarai, SK, Bucci, V, Arshad, M, Seed, PC & Kelly, MS 2020, 'Anaerobic Antibiotics and the Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation', Biology of Blood and Marrow Transplantation, vol. 26, no. 11, pp. 2053-2060. https://doi.org/10.1016/j.bbmt.2020.07.011

TY - JOUR

T1 - Anaerobic Antibiotics and the Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

AU - Tanaka, John S.

AU - Young, Rebecca R.

AU - Heston, Sarah M.

AU - Jenkins, Kirsten

AU - Spees, Lisa P.

AU - Sung, Anthony D.

AU - Corbet, Kelly

AU - Thompson, Jillian C.

AU - Bohannon, Lauren

AU - Martin, Paul L.

AU - Stokhuyzen, Andre

AU - Vinesett, Richard

AU - Ward, Doyle V.

AU - Bhattarai, Shakti K.

AU - Bucci, Vanni

AU - Arshad, Mehreen

AU - Seed, Patrick C.

AU - Kelly, Matthew S.

PY - 2020/11

Y1 - 2020/11

N2 - 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.

AB - 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.

KW - Carbapenems

KW - Febrile neutropenia

KW - Gut microbiome

KW - Piperacillin-tazobactam

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U2 - 10.1016/j.bbmt.2020.07.011

DO - 10.1016/j.bbmt.2020.07.011

M3 - Article

C2 - 32682948

AN - SCOPUS:85089451449

SN - 1083-8791

VL - 26

SP - 2053

EP - 2060

JO - Biology of Blood and Marrow Transplantation

JF - Biology of Blood and Marrow Transplantation

IS - 11

ER -

Anaerobic Antibiotics and the Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

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Keywords

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