Among recipients of allogeneic hematopoietic cell transplantation (allo-HCT), gram-negative intestinal colonization is highly predictive of bloodstream infections. In addition, and fluoroquinolones appear to influence gut colonization, effecting a reduction in infections caused by some bacteria, while increasing or not affecting the infection rate of others. Furthermore, the study authors observed an association between initial intestinal colonization with Ruminococcaceae and Bacteroidetes and protection against gram-negative bloodstream infections. These results were published in Clinical Infectious Diseases

Allogeneic hematopoietic cell transplantation is an intense, potentially curative treatment for some leukemias and lymphomas and multiple myeloma.  As a result of pretransplant treatment, patients become neutropenic, develop mucosal barrier injuries and are thus at high risk for bloodstream infections (65% are caused by gram negative bacteria). Previous research by the study authors indicated significant changes in the gut microbiome of patients undergoing allo-HCT, which often preceded bloodstream infections.

To better understand how intestinal microbiota composition is connected to such infections, the fecal samples of adult patients undergoing allo-HCT at the Memorial Sloan Kettering Cancer Center between 2009 and 2018 were analyzed using 16S rRNA gene sequencing. Participants had been enrolled in a fecal collection banking study from which samples were collected, aliquoted, and frozen for storage within 24 hours. Participants with fewer than 3 samples, or whose first sample was collected post–hematopoietic cell infusion, were excluded. Cause-specific Cox proportional hazard models were used to predict gram-negative bloodstream infection via intestinal domination by gram-negative bacteria (relative abundance >30%). Analyses of intestinal microbiota composition were performed at the genus level.

A total of 696 participants undergoing 708 allo-HCTs met criteria for analysis and were followed for a median of 22 days per participant. With an average of 1 fecal sample taken every 3.5 days, a total of 4768 fecal samples were collected, and 200,658,526 high-quality 16S rRNA gene sequences were obtained (average 42,084 per sample). Of the 696 participants, 53 (7.5%) developed gram negative infections (1 participant developed 2, for a total of 54 infections). The specific genus level organisms encountered were Citrobacter, Escherichia, Klebsiella, Neisseria, Pseudomonas, Sphingomonas, and Stenotrophomonas. Participants receiving fluoroquinolone prophylaxis had fewer gram negative bloodstream infections compared with those who did not (6.3% vs 11.4%). Compared with nonfluoroquinolone-prophylaxed participants, fluoroquinolone-prophylaxed participants more frequently experienced E coli breakthrough in both intestinal colonization and bloodstream infection.

An association was found between gram negative intestinal domination and subsequent bloodstream infection independent of other predictive factors, including a history of gram negative infection, age, sex, antibiotic prophylaxis, ex-vivo T-cell depletion, initial Proteobacteria colonization, and fluoroquinolone administration. Among the participants with gram negative bloodstream infection, a high degree of organism-specific concordance was observed between peak abundances and bloodstream infection, with corresponding peak abundances detectable in 85%, although these varied. Higher peak abundances appeared to be more predictive for bloodstream infection; 44% of detected bloodstream infections demonstrated intestinal domination (>30% relative abundance). Although high abundances and percentage colonization were observed in Serratia and Haemophilus, bloodstream infections with these microbes were not detected.

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Fluoroquinolone prophylaxis was associated with lower average abundances of specific gram negative genera, including Klebsiella, Citrobacter, Enterobacter, and Desulfovibrio. However, the abundances of other bacterial groups, including Escherichia, Pseudomonas, and Stenotrophomonas, were unchanged or even increased. An association was found between initial Ruminococcaceae and Bacteroidetes colonization and protection against gram-negative bloodstream infection.

Investigators concluded that “our study highlights the gut origins of gram-negative bloodstream infections during neutropenia in patients undergoing allo-HCT. The connection between the intestinal microbiota composition and risk for bacteremia allows us to better understand the pathogenesis of bloodstream infection. Enhanced understanding of the factors contributing to the risk of bacteremia may help to devise strategies to prevent these complications or to develop prognostic or diagnostic testing that predict the infectious risk.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Stoma I, Littmann ER, Peled JU, et al. Compositional flux within the intestinal microbiota and risk for bloodstream infection with gram-negative bacteria [published online January 24, 2020]. Clin Infect Dis. doi: 10.1093/cid/ciaa068