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I. Henig et al.
differed between the two groups, with an increase in pathogenic species such as E. coli in the formula-receiving group. Despite the fact that human milk oligosaccharides are metabolized to SCFA by the commensal bacteria, butyrate levels in the stool were similar in both groups. Moreover, no significant difference in the rate of grade 2- 4 acute GI GvHD between the groups was revealed. However, the limited size of this study calls for cautious interpretation of these encouraging results.84 Overall, dietary interventions emerge as a promising way to shape the intestinal microbiota during allo-HSCT. However, results are too preliminary and more research is required before implementing any of these methods.
Antibiotic treatment
The antibiotic treatment applied during the transplanta- tion course is the main factor affecting the microbiome. Quinolone prophylaxis during afebrile neutropenia and systemic broad-spectrum antibiotic treatment with piperacillin-tazobactam or meropenem are widely accept- ed.85-87 However, data demonstrate that the use of other antibiotics can better preserve gut beneficial commensals and is associated with improved outcomes.
The study from the University of Regensburg in Germany employed the non-absorbable antibiotic rifax- imin and compared it to ciprofloxacin and metronidazole used in a historic cohort of patients for infection prophylax- is during allo-HSCT.45 Antibiotics were given from day -8 up to engraftment. The urine 3-indoxyl sulfate (3-IS) level was measured as a marker of microbiome diversity.88 In the rifaximin cohort, the pre-engraftment 3-IS levels were sig- nificantly higher without an increase in the sepsis rate or colonization with pathogenic bacteria. This group had sig- nificantly lower TRM, prolonged OS and the acute GI GvHD rate tended to be lower in these patients. The observed advantage remained evident even in patients who later received systemic antibiotics for neutropenic fever. 45
Given the major role of microbiome diversity preserva- tion during allo-HSCT and an association of impaired diversity with acute GI GvHD and adverse patient out- come, Weber et al. further compared the effects of various prophylactic and systemic antibiotics in an attempt to identify the ones that could spare commensal bacteria.89 At 10 days post-transplant, the patient groups receiving rifaximin without systemic antibiotics or rifaximin with systemic antibiotics maintained their microbiome diversi- ty and Clostridia abundance and had higher 3-IS levels compared to patients treated with ciprofloxacin/metron- idazole ± systemic antibiotics. These results suggest that rifaximin could better preserve microbiome diversity even when systemic broad-spectrum antibiotics are adminis- tered during transplantation. Moreover, in the study con- ducted in two Canadian hospitals and assessing the effect of antibiotic prophylaxis or treatment given before day 0 on frequency of aGvHD and mortality, the authors com- pared the outcome of a cohort of patients exposed to antibiotics (n=239) to those who did not receive this ther- apy (n=261).90 The antibiotic-receiving group demonstrat- ed a significantly higher incidence of grade 2-4 aGvHD and significantly shorter OS at 1, 2 and 10 years post- transplant, indicating an association between the deleteri- ous effect of such treatment on intestinal bacteria and inferior patient outcome.
Importantly, early start of systemic antibiotics (before engraftment) was found to be associated with a lower 3-
IS urine level and decreased Clostridia abundance in the stool. Furthermore, the TRM rate in such cases was higher than in patients who did not require systemic antibiotics during HSCT or started them after engraftment.91
Similarly, systemic treatment with piperacillin-tazobac- tam and meropenem was reported to correlate with decreased microbiome diversity during the transplanta- tion37 and significant loss of commensal anaerobic bacte- ria.92 In pediatric patients, Simms-Waldrip et al.93 found that higher load of anti-anaerobic antibiotics was associat- ed with a significant decrease in anti-inflammatory Clostridia (AIC) abundance, and in patients with aGvHD the abundance decrease was severe (10-log fold) com- pared to patients without GvHD. In a mouse allo-HSCT model, clindamycin administration was associated with AIC decrease and more severe GvHD, while re-adminis- tration of AIC increased its levels in the gut and improved survival.93 Additionally, Lee et al.94 compared patients who did not require any systemic antibiotic treatment during the transplantation course with those who received cefepime and those who were treated with carbapenem antibiotics. The carbapenem group displayed a significant loss of microbial diversity at engraftment and an increased rate of acute GI GvHD (32.1%) compared to the no- antibiotics group (11.6%). Interestingly, the cefepime group retained a diverse microbiome, demonstrating only a trend to a higher GI GvHD rate (26.4%).
Furthermore, a large multicenter study retrospectively evaluating 857 patients revealed that the use of piperacillin-tazobactam and imipenem-cilastatin was associated with increased 5-year GvHD-related mortali- ty,95 while this was not observed in patients receiving cefepime and aztreonam. The former antibiotics caused a significant decrease in abundance of Bacteroidetes and Lactobacillus compared to the latter ones. These results suggest that some antibiotics may be more beneficial than others in the setting of allo-HSCT, and that this beneficial effect is related to the antibiotic ability to be less detri- mental to intestinal commensal bacteria.95 Findings in the pediatric setting were consistent with these data, and exposure to anti-anaerobic antibiotics was reported to result in a significant decrease in butyrate-producing bac- teria and the butyrate level in luminal content by day +14. Pediatric patients who later developed aGvHD had a sig- nificantly lower butyrate level at that time point than patients without GvHD.96
It was also demonstrated that specific antibiotic use dur- ing allo-HSCT could change the abundance of specific taxa which was associated with BSI risk. In a cohort of 94 patients, Taur Y et al.50 found that domination of the gut microbiome (abundance ≥30%) by single bacterial taxa Enterococcus and Streptococcus occurred at the peri-engraft- ment period (days +10 to +20) in two thirds of the patients. However, treatment with metronidazole increased the risk for enterococcal domination by 3-fold, and this domination elevated the risk for VRE bacteremia by 9-fold. Altogether, these data establish an essential role of antibiotics in disrupting or preserving the intestinal microbiota during allo-HSCT.
Case 1: conclusions
Several issues should be considered in decision-making regarding the appropriate management of this case. This
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haematologica | 2021; 106(4)