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 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.
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shono
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Docampo
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Medical College of Cornell University, New York, New York.|Adult BMT Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jonathan U
authors.initials: JU
authors.lastname: Peled
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Suelen M
authors.initials: SM
authors.lastname: Perobelli
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Velardi
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Tsai
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Slingerland
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Odette M
authors.initials: OM
authors.lastname: Smith
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Lauren F
authors.initials: LF
authors.lastname: Young
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Gupta
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sophia R
authors.initials: SR
authors.lastname: Lieberman
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Hillary V
authors.initials: HV
authors.lastname: Jay
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Katya F
authors.initials: KF
authors.lastname: Ahr
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kori A
authors.initials: KA
authors.lastname: Porosnicu Rodriguez
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Marco
authors.initials: M
authors.lastname: Calarfiore
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Poeck
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Silvia
authors.initials: S
authors.lastname: Caballero
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Devlin
authors.affiliation: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Franck
authors.initials: F
authors.lastname: Rapaport
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.|Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Dudakov
authors.affiliation: Weill Medical College of Cornell University, New York, New York.|Adult BMT Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Hanash
authors.affiliation: Weill Medical College of Cornell University, New York, New York.|Adult BMT Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Boglarka
authors.initials: B
authors.lastname: Gyurkocza
authors.affiliation: Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.affiliation: Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Camilla
authors.initials: C
authors.lastname: Gomes
authors.affiliation: Departments of Pathology and Laboratory Medicine, New Jersey Medical School and Robert Wood Johnson Medical School, Rutgers University, Newark, New Jersey.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Medicine and Genetics, Stanford University, Stanford, California.
authors.forename: Eli L
authors.initials: EL
authors.lastname: Moss
authors.affiliation: Department of Medicine and Genetics, Stanford University, Stanford, California.
authors.forename: Shannon B
authors.initials: SB
authors.lastname: Falconer
authors.affiliation: Department of Medicine and Genetics, Stanford University, Stanford, California.
authors.forename: Ami S
authors.initials: AS
authors.lastname: Bhatt
authors.affiliation: Weill Medical College of Cornell University, New York, New York.|Infectious Diseases Service, Lucille Castori Center for Microbes, Inflammation & Cancer, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ying
authors.initials: Y
authors.lastname: Taur
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Medical College of Cornell University, New York, New York.|Infectious Diseases Service, Lucille Castori Center for Microbes, Inflammation & Cancer, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Pamer
authors.affiliation: Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Medical College of Cornell University, New York, New York.|Adult BMT Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Marcel R M
authors.initials: MRM
authors.lastname: van den Brink
authors.affiliation: Weill Medical College of Cornell University, New York, New York.|Adult BMT Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Jenq
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D015377:Cilastatin / Q000627:therapeutic use; D000077728:Cilastatin, Imipenem Drug Combination; D003106:Colon / Q000382:microbiology; D004338:Drug Combinations; D005243:Feces / Q000382:microbiology; D005260:Female; D005434:Flow Cytometry; D000069196:Gastrointestinal Microbiome / Q000187:drug effects; D006086:Graft vs Host Disease / Q000209:etiology / Q000382:microbiology* / Q000401:mortality*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D015378:Imipenem / Q000627:therapeutic use; D053759:Interleukin-23; D051379:Mice; D008810:Mice, Inbred C57BL; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D010802:Phylogeny; D010878:Piperacillin / Q000627:therapeutic use; D000077725:Piperacillin, Tazobactam Drug Combination; D014184:Transplantation, Homologous / Q000009:adverse effects*; D061327:Verrucomicrobia / Q000145:classification / Q000187:drug effects / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D053759:Interleukin-23; D015377:Cilastatin; D000077725:Piperacillin, Tazobactam Drug Combination; D015378:Imipenem; D010397:Penicillanic Acid; D000077728:Cilastatin, Imipenem Drug Combination; D010878:Piperacillin