Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice Journal Article


Authors: Shono, Y.; Docampo, M. D.; Peled, J. U.; Perobelli, S. M.; Velardi, E.; Tsai, J. J.; Slingerland, A. E.; Smith, O. M.; Young, L. F.; Gupta, J.; Lieberman, S. R.; Jay, H. V.; Ahr, K. F.; Porosnicu Rodriguez, K. A.; Xu, K.; Calafiore, M.; Poeck, H.; Caballero, S.; Devlin, S. M.; Rapaport, F.; Dudakov, J. A.; Hanash, A. M.; Gyurkocza, B.; Murphy, G. F.; Gomes, C.; Liu, C.; Moss, E. L.; Falconer, S. B.; Bhatt, A. S.; Taur, Y.; Pamer, E. G.; Van Den Brink, M. R. M.; Jenq, R. R.
Article Title: Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice
Abstract: Intestinal bacteria may modulate the risk of infection and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients often develop neutropenic fever, which is treated with antibiotics that may target anaerobic bacteria in the gut. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillintazobactam antibiotics was associated with increased GVHD-related mortality at 5 years (21.5% for imipenemcilastatin-treated patients versus 13.1% for untreated patients, P = 0.025; 19.8% for piperacillin-tazobactam-treated patients versus 11.9% for untreated patients, P = 0.007). However, two other antibiotics also used to treat neutropenic fever, aztreonam and cefepime, were not associated with GVHD-related mortality (P = 0.78 and P = 0.98, respectively). Analysis of stool specimens from allo-HSCT recipients showed that piperacillin-tazobactam administration was associated with perturbation of gut microbial composition. Studies in mice demonstrated aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactam compared to aztreonam (P < 0.01andP < 0.05, respectively). We found pathological evidence for increased GVHD in the colon of imipenem-cilastatin-treated mice (P < 0.05), but no difference in the concentration of short-chain fatty acids or numbers of regulatory T cells. Notably, imipenem-cilastatin treatment of mice with GVHD led to loss of the protective mucus lining of the colon (P < 0.01)and the compromising of intestinal barrier function (P < 0.05). Sequencing of mouse stool specimens showed an increase in Akkermansia muciniphila (P < 0.001), a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation may contribute to murine GVHD. We demonstrate an underappreciated risk for the treatment of allo-HSCT recipients with antibiotics that may exacerbate GVHD in the colon. © 2016, American Association for the Advancement of Science. All rights reserved.
Journal Title: Science Translational Medicine
Volume: 8
Issue: 339
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2016-05-18
Start Page: 339ra71
Language: English
DOI: 10.1126/scitranslmed.aaf2311
PROVIDER: scopus
PUBMED: 27194729
PMCID: PMC4991773
DOI/URL:
Notes: Article -- Export Date: 1 July 2016 -- Source: Scopus
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