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

Abstract

After allogeneic hematopoietic stem cell transplantation (allo-HSCT), intestinal bacteria modulate risks of infection and graft-versus-host disease (GVHD). Neutropenic fever is common and treated with a choice of clinically equivalent antibiotics that target obligately anaerobic bacteria (anaerobes) to varying degrees. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillin-tazobactam was associated with increased GVHD-related mortality at 5 years (21.5% in imipenem-cilastatin-treated patients vs. 13.1% in untreated patients, p=0.025, and 19.8% in piperacillin-tazobactam-treated patients vs. 11.9% in 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 microbiota composition showed that piperacillin-tazobactam administration was associated with increased compositional perturbation. Studies in mouse models demonstrated similar effects of these antibiotics, as well as aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactm 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 differences in short-chain fatty acid concentrations or regulatory T cells numbers. Notably, imipenem-cilastatin treatment of mice with GVHD led to loss of the protective lining of mucus in the colon (p<0.01) and intestinal barrier function was compromised (p<0.05). Sequencing of mouse stool specimens showed expansion of Akkermansia muciniphila (p<0.001), a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation can contribute to murine GVHD. We demonstrate an underappreciated risk for antibiotics with activity against anaerobes to exacerbate colonic GVHD after transplant.

Bacterial bloodstream infections in the allogeneic hematopoietic cell transplant patient: new considerations for a persistent nemesis

“…141 In a retrospective analysis of 857 allo-HCT recipients, Shono et al found that empiric fever and neutropenia (F&N) therapy using imipenem-cilastatin and piperacillin-tazobactam antibiotics was associated with increased GvHD-related mortality at 5 years (21.5% for imipenem-cilastatin-treated patients vs 13.1% for untreated patients, P = 0.025; 19.8% for piperacillin-tazobactam-treated patients vs 11.9% for untreated patients, P = 0.007). 31 However, two other antibiotics also used to treat F&N, aztreonam and cefepime, were not associated with GvHD-related mortality (P = 0.78 and P = 0.98, respectively). Analysis of stool specimens from allo-HCT recipients showed that piperacillin-tazobactam administration was associated with perturbations in gut microbial composition.…”

“…30 In murine allo-HCT models, aGvHD causes a shift toward predominance of gram negative organisms, which, in turn, increases the risk for sepsis-related morbidity and mortality. 31 In addition, Paneth cells which selectively kill noncommensals through secretion of α-defensins are targeted by aGvHD. 32,33 Transplant-associated thrombotic microangiopathy TA-TMA causes generalized endothelial dysfunction that can progress to multi-organ injury and poor transplant outcome.…”

“…Analysis of stool specimens from allo-HCT recipients showed that piperacillin-tazobactam administration was associated with perturbations in gut microbial composition. 31 In addition, when compared to a contemporaneous hospital cohort, HCT recipients developed more resistance against commonly isolated bacterial organisms. These findings have important clinical implications regarding use and selection of both prophylactic and empiric antibiotic regimens.…”

The influence of gut-decontamination prophylactic antibiotics on acute graft-versus-host disease and survival following allogeneic hematopoietic stem cell transplantation

“…These results were further confirmed in a rodent model treated with different ATB. 24 When analyzing the entire cohort, we showed a faster lymphocytes and neutrophils recovery at day C14 in the no ATB group. However, this correlation was not maintained after correction for other clinical factors that are known to influence engraftment.…”

Gut microbiota and its role in cancer patients

“…Studies in mice also demonstrated aggravated graft-versus-host disease (GVHD) mortality with broad-spectrum antibiotics use and led to a loss of the protective mucus lining of the colon, compromised intestinal barrier function, as well as increased a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation may contribute to murine GVHD. [2] Among the most vulnerable populations susceptible to CDI are HSCT recipient, [8] where the incidence of CDI is as high as 25%. Vancomycin, metronidazole, and fidaxomicin are the first-line therapies for CDI; however, for hematopoietic cell transplantation patients, recurrent infection is common on cessation of antibiotic therapy, with severe cases being accompanied by a high incidence of mortality.…”