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Certain broad-spectrum antibiotics linked to mortality in stem cell transplant recipients
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The use of broad-spectrum antibiotics, particularly piperacillin-tazobactam and Primaxin, for the treatment of neutropenic fever in allogeneic hematopoietic stem cell transplantation recipients was associated with an increased risk for mortality caused by graft-versus-host disease, according to recent findings.
Yusuke Shono, MD, PhD, research associate at Memorial Sloan Kettering Cancer Center, and colleagues linked the increase in mortality to the antibiotics’ strong activity against anaerobes in the gut microbiome.
“In the past, the use of broad-spectrum antibiotics in [allogeneic hematopoietic stem cell transplantation (allo-HSCT)] recipients had been thought to be protective against GVHD,” Shono and colleagues wrote. “Here, we demonstrate that use of antibiotics with a broader spectrum of activity, such as piperacillin-tazobactam and [Primaxin (imipenem-cilastatin, Merck)], leads to increased microbiota injury and increased GVHD severity.”
The researchers examined data from 857 allo-HSCT recipients who received antibiotics for neutropenic fever from May 1992 to July 2015 to determine whether certain antibiotics had an impact on complications related to GVHD. They assessed outcomes in patients treated with one of 12 antibiotics and compared them with patients who did not receive treatment.
Shono and colleagues reported that imipenem-cilastatin, which is the institution’s standard first-line therapy for neutropenic fever, and piperacillin-tazobactam, the institution’s recommended second-line treatment, were significantly associated with increased GVHD-related mortality. At 5 years, GVHD-related mortality was 21.5% in patients treated with imipenem-cilastatin vs. 13.1% in untreated patients (P = .025), and 19.8% in those treated with piperacillin-tazobactam vs. 11.9% in untreated patients (P = .007).
In contrast, cefepime and aztreonam, which are alternative first-line treatments for patients with penicillin allergies, were associated with a reduced risk for GVHD-related mortality.
Figure 1. A new study suggests that some antibiotics that disrupt the gut microbiome may worsen graft-versus-host disease in stem cell transplant patients.
Source: Val Altounian/Science Translational Medicine (2016)
A comparison of all four antibiotics demonstrated that exposure to imipenem-cilastatin and piperacillin-tazobactam was associated with an increased incidence of upper gastrointestinal (GI) GVHD (P = .002 and P = .045, respectively) and lower GI GVHD (P = .019 and P = .036, respectively), which is the most common form of GVHD-associated mortality. Further analysis involving 306 patients treated with imipenem-cilastatin or piperacillin-tazobactam and 77 patients treated with aztreonam or cefepime confirmed the first group of patients were at an increased risk for mortality (P = .029).
“Notably, piperacillin-tazobactam and imipenem-cilastatin are both highly active against obligately anaerobic bacteria, whereas cefepime and aztreonam have reduced activity against anaerobes,” Shono and colleagues wrote. “Thus, these results suggested that differences in the spectrum of activity of antibiotics used to treat neutropenic fever might modulate the subsequent frequency and severity of GVHD.”
A gene deep-sequencing investigation of stool specimens collected from patients who started one of the antibiotic treatments revealed that piperacillin-tazobactam therapy resulted in a greater loss of bacterial populations, including Bacteroidetes and Lactobacillus. The adverse effect of imipenem-cilastatin treatment was supported in an animal study.
“In conclusion, our results suggest that selecting antibiotics with a more limited spectrum of activity (especially against anaerobes) could prevent microbiota injury and thus reduce GVHD in the colon and GVHD-associated mortality,” Shono and colleagues wrote. “Although our results demonstrate associations between antibiotic treatment and clinical GVHD outcomes, we have not addressed or demonstrated causality. It would thus be interesting to see whether the findings can be confirmed retrospectively by other transplant centers and, more importantly, confirmed in a prospective clinical trial.” – by Stephanie Viguers
Disclosure: Shono reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.
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