Microbiota Disruption Induced by Early Use of Broad-Spectrum Antibiotics Is an Independent Risk Factor of Outcome after Allogeneic Stem Cell Transplantation

Abstract

In allogeneic stem cell transplantation (ASCT), systemic broad-spectrum antibiotics are frequently used for treatment of infectious complications, but their effect on microbiota composition is still poorly understood. Here, in a retrospective analysis of 621 patients, who underwent ASCT at the University Medical Center of Regensburg and Memorial Sloan Kettering Cancer Center in New York, we assessed the impact of timing of peri-transplant antibiotic treatment on intestinal microbiota composition as well as transplant-related mortality (TRM) and overall survival. Early exposure to antibiotics was associated with lower urinary 3-indoxyl sulfate levels (p<0.001) and a decrease in fecal abundance of commensal Clostridiales (p=0.03) compared to late antibiotic treatment, which was particularly significant (p=0.005) for Clostridium cluster XIVa in the Regensburg group. Earlier antibiotic treatment prior to ASCT was further associated with a higher TRM (34%, n=79/236) compared to post-ASCT (21% n=62/297, p=0.001) or no antibiotics (7% n=6/88, p<0.001). Timing of antibiotic treatment was the dominant independent risk factor for TRM (HR 2.0, p≤0.001) in multivariate analysis beside increase age (HR 2.15, p=0.004), reduced Karnofsky performance status (HR 1.47, p=0.03) and female donor/ male recipient sex combination (HR 1.56, p=0.02) A competing-risk analysis revealed the independent effect of early initiation of antibiotics on GvHD-related TRM (p=0.004) in contrast to infection-related TRM and relapse (p=ns). The poor outcome associated with early administration of antibiotic therapy that is active against commensal organisms, and specifically the possibly protective Clostridiales calls for the use of Clostridiales-sparing antibiotics and rapid restoration of microbiota diversity after cessation of antibiotic treatment.

Empiric antibiotic use in allogeneic hematopoietic cell transplantation: should we avoid anaerobe coverage?

“…33 Regarding the timing of systemic antibiotic administration and the impact on GVHD, a retrospective study of 621 patients showed that early exposure to antibiotics (between days 27 and 0) resulted in significant reduction of Clostridiales with higher GVHD-related mortality. 34 These results suggest that, in the setting of allo-HCT, strategies to maintain beneficial anaerobes can contribute to better prognosis of patients. Beneficial effect on allo-HCT outcomes by fecal microbiota transplant also advocates the advantage of preserving anaerobes.…”

The Gut Microbiota and Hematopoietic Stem Cell Transplantation: Challenges and Potentials

“…Another retrospective study indicated that the treatment of neutropenic fever with antibiotics such as imipenem-cilastatin and piperacillin-tazobactam was linked to increased GvHD-related mortality within 5 years [14]. Other recent studies also link prophylactic use of antibiotics to higher transplant-related mortality [15, 16]. …”

“…The use of broad-spectrum antibiotics clindamycin, piperacillin-tazobactam, and imipenem-cilastatin are linked to GvHD in patients [15]. In allo-HSCT patients, common pathogens are Gram-negative bacteria (Enterobacteriaceae) and Gram-positive bacteria such as coagulase-negative Staphylococci , Streptococcus viridans , Enterococcus , and Candida species.…”

New Insights into Graft-Versus-Host Disease and Graft Rejection

“…Various factors are thought to contribute to dysbiosis after allo-HCT, including the use of conditioning agents with gastrointestinal toxicity, changes in food intake, use of specific prophylactic antibiotics, and administration of broad-spectrum antibiotics for infectious complications. Interestingly, different broad-spectrum antibiotics are associated with distinct changes in the microbiome and with variable rates of severe GVHD, in both mice and humans (68,86). In addition, the occurrence of GVHD itself appears to influence changes in the microbiome, perhaps due to effects on the intestinal epithelium and on ILCs regulating the epithelium-microbiome interface (59,62,65,70,71).…”