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

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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Science translational medicine Jg. 8; H. 339; S. 339ra71
Hauptverfasser: Shono, Yusuke, Docampo, Melissa D, Peled, Jonathan U, Perobelli, Suelen M, Velardi, Enrico, Tsai, Jennifer J, Slingerland, Ann E, Smith, Odette M, Young, Lauren F, Gupta, Jyotsna, Lieberman, Sophia R, Jay, Hillary V, Ahr, Katya F, Porosnicu Rodriguez, Kori A, Xu, Ke, Calarfiore, Marco, Poeck, Hendrik, Caballero, Silvia, Devlin, Sean M, Rapaport, Franck, Dudakov, Jarrod A, Hanash, Alan M, Gyurkocza, Boglarka, Murphy, George F, Gomes, Camilla, Liu, Chen, Moss, Eli L, Falconer, Shannon B, Bhatt, Ami S, Taur, Ying, Pamer, Eric G, van den Brink, Marcel R M, Jenq, Robert R
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 18.05.2016
Schlagworte:
Animals
Anti-Bacterial Agents
CD4-Positive T-Lymphocytes - metabolism
Cilastatin - therapeutic use
Cilastatin, Imipenem Drug Combination
Colon - microbiology
Drug Combinations
Feces - microbiology
Female
Flow Cytometry
Gastrointestinal Microbiome - drug effects
Graft vs Host Disease - etiology
Graft vs Host Disease - microbiology
Graft vs Host Disease - mortality
Hematopoietic Stem Cell Transplantation - adverse effects
Humans
Imipenem - therapeutic use
Interleukin-23
Mice
Mice, Inbred C57BL
Penicillanic Acid - analogs & derivatives
Penicillanic Acid - therapeutic use
Phylogeny
Piperacillin - therapeutic use
Piperacillin, Tazobactam Drug Combination
Transplantation, Homologous - adverse effects
Verrucomicrobia - classification
Verrucomicrobia - drug effects
Verrucomicrobia - genetics
ISSN:1946-6242
Online-Zugang:Weitere Angaben
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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 piperacillin-tazobactam antibiotics was associated with increased GVHD-related mortality at 5 years (21.5% for imipenem-cilastatin-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 < 0.01 and P < 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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1946-6242
DOI:10.1126/scitranslmed.aaf2311