Antibiotics raise stem cell transplant complication risk

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Some broad-spectrum antibiotics that disrupt the gut microbiome may raise the risk of complications from stem cell transplantation, according to a new study evaluating data from more than 850 transplant patients, as well as from mice.

The findings suggest that selecting antibiotics that spare “good” bacteria may help protect against graft-versus-host disease (GVHD), which occurs when transplanted donor cells, recognising their new home as foreign, attack the recipient’s body. Transplant patients vulnerable to life-threatening bacterial infections are often treated with broad-spectrum antibiotics.

To better understand the effects of antibiotic treatment on GVHD, Yusuke Shono and colleagues at the Memorial Sloan-Kettering Cancer Centre, New York City, mined the clinical records of 857 allogeneic hematopoietic stem cell transplant patients. Treatment with some broad-spectrum antibiotics, compared to antibiotics with more limited activity, correlated with greater risk of death from GVHD.

Analysis of stool samples from some of the patients revealed that broad-spectrum antibiotics perturbed the gut microbiome, killing off certain protective bugs. In mice treated with various antibiotic regimens following stem cell transplantation, those given broad-spectrum antibiotics developed more severe GVHD. The drugs seemed to spur the growth of bacteria known to degrade the protective mucus lining the colon, breaking down gut barrier function.

While the findings remain to be confirmed in clinical trials, they caution against the use of broad-spectrum antibiotics in transplant patients at risk of GVHD.

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
Y Shono; MD Docampo; JU Peled; SM Perobelli; E Velardi; JJ Tsai; AE Slingerland; OM Smith; LF Young; J Gupta; SR Lieberman; HV Jay; KF Ahr; KA Porosnicu Rodriguez; K Xu; M Calarfiore; H Poeck; S Caballero; SM Devlin; F Rapaport; JA Dudakov; AM Hanash; B Gyurkocza; Y Taur; EG Pamer; MRM van den Brink; RR Jenq; JU Peled; AM Hanash; B Gyurkocza; Y Taur; EG Pamer; M.R.M. van den Brink; R.R. Jenq.

Science Mag material
Science Translational Medicine abstract


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