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Broad-spectrum antibiotics may increase the severity of graft-versus-host disease (GVHD), according to research published in Science Translational Medicine.
Researchers evaluated the relationship between antibiotics and GVHD using data from more than 850 transplant patients and by conducting experiments in mice.
Their results suggested that selecting antibiotics that spare “good” bacteria may help protect patients from GVHD.
Results in patients
Yusuke Shono, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues conducted this study, first mining the clinical records of 857 patients who underwent allogeneic hematopoietic stem cell transplant
(HSCT).
The team found that patients who received imipenem-cilastatin and piperacillin-tazobactam antibiotics to treat neutropenic fever had a higher incidence of GVHD-related mortality at 5 years than patients who did not receive these drugs.
The incidence of GVHD-related death was 21.5% in patients who received imipenem-cilastatin and 13.1% in those who did not (P=0.025). The incidence was 19.8% in patients who received piperacillin-tazobactam and 11.9% in those who did not (P=0.007).
Two other antibiotics used to treat neutropenic fever, aztreonam and cefepime, were not associated with an increased risk of GVHD-related mortality.
The incidence of GVHD-related death was 13.8% in patients who received cefepime and 14.6% in those who did not (P=0.98). The incidence was 17.5% in patients who received aztreonam and 14.2% in those who did not (P=0.78).
The researchers also found that piperacillin-tazobactam and imipenem-cilastatin were both associated with an increased incidence of grade 2-4 GVHD (P=0.0167 and P=0.0165, respectively), upper gastrointestinal GVHD (P=0.002 and P=0.045, respectively), and lower gastrointestinal GVHD (P=0.019 and P=0.036, respectively).
When the team analyzed patients’ stool samples, they found that piperacillin-tazobactam perturbed the gut microbiome, killing off protective bacteria. The therapy was associated with a greater loss of Bacteroidetes and Lactobacillus, when compared to treatment with aztreonam or cefepime.
The change in abundance of Enterococcus, Akkermansia, and Erysipelotrichia was similar with the 3 therapies. But there was a trend toward a decrease in Clostridia and Actinobacteria with piperacillin-tazobactam.
The researchers said they could not assess the effects of imipenem-cilastatin on bacterial populations because, at their center, imipenem-cilastatin is almost always given to HSCT patients as second-line therapy for neutropenic fever.
Results in mice
In mice treated with various antibiotic regimens following HSCT, those given broad-spectrum antibiotics developed more severe GVHD.
Specifically, the researchers observed aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactam compared to aztreonam (P<0.01 and P<0.05, respectively).
They also found evidence of increased GVHD pathology localized in the colon of mice that received imipenem-cilastatin (P<0.05). Mice with GVHD that received imipenem-cilastatin experienced loss of the protective mucus lining of the colon (P<0.01) and compromised intestinal barrier function (P<0.05).
When the researchers sequenced stool samples from mice with GVHD that received imipenem-cilastatin, they saw an increase in Akkermansia muciniphila (P<0.001), a commensal bacterium with mucus-degrading capabilities. They said this raises the possibility that mucus degradation may contribute to murine GVHD.
The researchers noted that these findings must be confirmed in clinical trials, but they caution against the use of broad-spectrum antibiotics in HSCT patients at risk of GVHD. 
Broad-spectrum antibiotics may increase the severity of graft-versus-host disease (GVHD), according to research published in Science Translational Medicine.
Researchers evaluated the relationship between antibiotics and GVHD using data from more than 850 transplant patients and by conducting experiments in mice.
Their results suggested that selecting antibiotics that spare “good” bacteria may help protect patients from GVHD.
Results in patients
Yusuke Shono, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues conducted this study, first mining the clinical records of 857 patients who underwent allogeneic hematopoietic stem cell transplant
(HSCT).
The team found that patients who received imipenem-cilastatin and piperacillin-tazobactam antibiotics to treat neutropenic fever had a higher incidence of GVHD-related mortality at 5 years than patients who did not receive these drugs.
The incidence of GVHD-related death was 21.5% in patients who received imipenem-cilastatin and 13.1% in those who did not (P=0.025). The incidence was 19.8% in patients who received piperacillin-tazobactam and 11.9% in those who did not (P=0.007).
Two other antibiotics used to treat neutropenic fever, aztreonam and cefepime, were not associated with an increased risk of GVHD-related mortality.
The incidence of GVHD-related death was 13.8% in patients who received cefepime and 14.6% in those who did not (P=0.98). The incidence was 17.5% in patients who received aztreonam and 14.2% in those who did not (P=0.78).
The researchers also found that piperacillin-tazobactam and imipenem-cilastatin were both associated with an increased incidence of grade 2-4 GVHD (P=0.0167 and P=0.0165, respectively), upper gastrointestinal GVHD (P=0.002 and P=0.045, respectively), and lower gastrointestinal GVHD (P=0.019 and P=0.036, respectively).
When the team analyzed patients’ stool samples, they found that piperacillin-tazobactam perturbed the gut microbiome, killing off protective bacteria. The therapy was associated with a greater loss of Bacteroidetes and Lactobacillus, when compared to treatment with aztreonam or cefepime.
The change in abundance of Enterococcus, Akkermansia, and Erysipelotrichia was similar with the 3 therapies. But there was a trend toward a decrease in Clostridia and Actinobacteria with piperacillin-tazobactam.
The researchers said they could not assess the effects of imipenem-cilastatin on bacterial populations because, at their center, imipenem-cilastatin is almost always given to HSCT patients as second-line therapy for neutropenic fever.
Results in mice
In mice treated with various antibiotic regimens following HSCT, those given broad-spectrum antibiotics developed more severe GVHD.
Specifically, the researchers observed aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactam compared to aztreonam (P<0.01 and P<0.05, respectively).
They also found evidence of increased GVHD pathology localized in the colon of mice that received imipenem-cilastatin (P<0.05). Mice with GVHD that received imipenem-cilastatin experienced loss of the protective mucus lining of the colon (P<0.01) and compromised intestinal barrier function (P<0.05).
When the researchers sequenced stool samples from mice with GVHD that received imipenem-cilastatin, they saw an increase in Akkermansia muciniphila (P<0.001), a commensal bacterium with mucus-degrading capabilities. They said this raises the possibility that mucus degradation may contribute to murine GVHD.
The researchers noted that these findings must be confirmed in clinical trials, but they caution against the use of broad-spectrum antibiotics in HSCT patients at risk of GVHD.
Broad-spectrum antibiotics may increase the severity of graft-versus-host disease (GVHD), according to research published in Science Translational Medicine.
Researchers evaluated the relationship between antibiotics and GVHD using data from more than 850 transplant patients and by conducting experiments in mice.
Their results suggested that selecting antibiotics that spare “good” bacteria may help protect patients from GVHD.
Results in patients
Yusuke Shono, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues conducted this study, first mining the clinical records of 857 patients who underwent allogeneic hematopoietic stem cell transplant
(HSCT).
The team found that patients who received imipenem-cilastatin and piperacillin-tazobactam antibiotics to treat neutropenic fever had a higher incidence of GVHD-related mortality at 5 years than patients who did not receive these drugs.
The incidence of GVHD-related death was 21.5% in patients who received imipenem-cilastatin and 13.1% in those who did not (P=0.025). The incidence was 19.8% in patients who received piperacillin-tazobactam and 11.9% in those who did not (P=0.007).
Two other antibiotics used to treat neutropenic fever, aztreonam and cefepime, were not associated with an increased risk of GVHD-related mortality.
The incidence of GVHD-related death was 13.8% in patients who received cefepime and 14.6% in those who did not (P=0.98). The incidence was 17.5% in patients who received aztreonam and 14.2% in those who did not (P=0.78).
The researchers also found that piperacillin-tazobactam and imipenem-cilastatin were both associated with an increased incidence of grade 2-4 GVHD (P=0.0167 and P=0.0165, respectively), upper gastrointestinal GVHD (P=0.002 and P=0.045, respectively), and lower gastrointestinal GVHD (P=0.019 and P=0.036, respectively).
When the team analyzed patients’ stool samples, they found that piperacillin-tazobactam perturbed the gut microbiome, killing off protective bacteria. The therapy was associated with a greater loss of Bacteroidetes and Lactobacillus, when compared to treatment with aztreonam or cefepime.
The change in abundance of Enterococcus, Akkermansia, and Erysipelotrichia was similar with the 3 therapies. But there was a trend toward a decrease in Clostridia and Actinobacteria with piperacillin-tazobactam.
The researchers said they could not assess the effects of imipenem-cilastatin on bacterial populations because, at their center, imipenem-cilastatin is almost always given to HSCT patients as second-line therapy for neutropenic fever.
Results in mice
In mice treated with various antibiotic regimens following HSCT, those given broad-spectrum antibiotics developed more severe GVHD.
Specifically, the researchers observed aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactam compared to aztreonam (P<0.01 and P<0.05, respectively).
They also found evidence of increased GVHD pathology localized in the colon of mice that received imipenem-cilastatin (P<0.05). Mice with GVHD that received imipenem-cilastatin experienced loss of the protective mucus lining of the colon (P<0.01) and compromised intestinal barrier function (P<0.05).
When the researchers sequenced stool samples from mice with GVHD that received imipenem-cilastatin, they saw an increase in Akkermansia muciniphila (P<0.001), a commensal bacterium with mucus-degrading capabilities. They said this raises the possibility that mucus degradation may contribute to murine GVHD.
The researchers noted that these findings must be confirmed in clinical trials, but they caution against the use of broad-spectrum antibiotics in HSCT patients at risk of GVHD.