Detrimental Effect of Broad-spectrum Antibiotics on Intestinal Microbiome Diversity in Patients After Allogeneic Stem Cell Transplantation: Lack of Commensal Sparing Antibiotics

Weber, Daniela; Hiergeist, Andreas; Weber, Markus; Dettmer, Katja; Wolff, Daniel; Hahn, J.; Herr, Wolfgang; Gessner, André; Holler, Ernst

doi:10.1093/cid/ciy711

Cited by 83 publications

(76 citation statements)

References 42 publications

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“…We hypothesize that this difference may reflect higher antibiotic sensitivity of the microbiome after prior insults because most patients in the allo‐HCT cohort had already received chemotherapy and been exposed to antibiotics. Diversity loss was associated with decreased representation of many genera, particularly obligate anaerobes, as demonstrated in previous studies . In contrast, Enterococcus (in both cohorts) and Lactobacillus (in the AL cohort) increased in relative abundance as diversity declined.…”

Section: Discussionsupporting

confidence: 77%

“…Previous studies found a correlation between more severe dysbiosis during the peritransplant period and worse clinical outcomes. Greater exposure to anti‐anaerobic antibiotics was associated with increased acute GVHD risk and higher mortality . E‐domination in previous allo‐HCT studies predicted Enterococcus bacteremia .…”

Section: Discussionmentioning

confidence: 85%

“…Greater exposure to antianaerobic antibiotics was associated with increased acute GVHD risk and higher mortality. 6,41,49 E-domination in previous allo-HCT studies predicted Enterococcus bacteremia. 4,44,50 Enterococcal BSIs occur in ~10% of patients with AL and allo-HCT recipients, are frequently multidrug-resistant, and increase mortality.…”

Section: B Amentioning

confidence: 83%

“…Diversity loss was associated with decreased representation of many genera, particularly obligate anaerobes, as demonstrated in previous studies. 5,40,41 In contrast, Enterococcus (in both cohorts) and Lactobacillus (in the AL cohort) increased in relative abundance as diversity declined. These genera are the most prevalent lactic acid bacteria in the human gut and potent bacteriocin producers, 42 a feature that may provide them with a competitive advantage in harsh ecosystems.…”

Section: B Amentioning

confidence: 92%

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Gut dysbiosis during antileukemia chemotherapy versus allogeneic hematopoietic cell transplantation

Rashidi

Kaiser

Graiziger

et al. 2019

Cancer

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Background In the field of malignant hematology, most microbiome studies have focused on recipients of allogeneic hematopoietic cell transplantation (allo‐HCT). As a result, this population has remained the primary target for novel microbiota therapeutics. Because the types of insults to the microbiome are similar during hematopoietic cell transplantation and intensive antileukemia therapy, this study evaluated whether the dysbiosis states are similar in the 2 settings. Methods This study compared gut microbiota assemblages and community domination states in 2 cohorts of patients: patients with intensively treated acute leukemia (AL) and allo‐HCT recipients. 16S ribosomal RNA gene profiling of thrice weekly stool samples was performed. Linear discriminant analysis effect size was used to determine differentially abundant taxa in groups of interest, and mixed modes were used to determine the predictors of microbiome states. Results Microbiome changes in both cohorts were characterized by a marked loss of diversity and domination of low‐diversity communities by Enterococcus. In the AL cohort, the relative abundance of Lactobacillus was also inversely correlated with diversity. Communities dominated by these genera were compositionally different. Conclusions Similarities in microbiota assemblages between the 2 cohorts support a broader scope for microbiota‐directed therapeutics than previously considered, whereas specific differences suggest a personalized aspect to such therapeutics with the possibility of a differential response.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 85%

Section: B Amentioning

confidence: 83%

Section: B Amentioning

confidence: 92%

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Gut dysbiosis during antileukemia chemotherapy versus allogeneic hematopoietic cell transplantation

Rashidi

Kaiser

Graiziger

et al. 2019

Cancer

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“…30 To our knowledge, few studies have examined the effects of single versus combination antibiotics on the gut microbiome. 31 While we observed a general decrease in diversity in response to antibiotics, our results also showed a distinct impact on microbiota structure and a shift in abundance of specific bacterial ASVs in each treatment group. These findings highlight the need to understand better the additive, antagonistic, synergistic, and non-linear effects of antibiotic treatments with regards to patient outcome.…”

Section: Discussionsupporting

confidence: 46%

Treatment-Specific Composition of Gut Microbiota Is Associated with Disease Remission in a Pediatric Crohn’s Disease Cohort

Sprockett

Fischer

Boneh

et al. 2018

Preprint

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We investigated the impact of metronidazole and metronidazole plus azithromycin on the gut microbiota in pediatric Crohn's disease. Disease remission was associated with a treatment-specific microbiota configuration, and could be predicted based on pre-antibiotic microbiota profiles.3 Abstract Background: The beneficial effects of antibiotics in Crohn's disease (CD) depend in part on the gut microbiota but are inadequately understood. We investigated the impact of metronidazole (MET) and metronidazole plus azithromycin (MET+AZ) on the microbiota in pediatric CD, and the use of microbiota features as classifiers or predictors of disease remission.Methods: 16S rRNA-based microbiota profiling was performed on stool samples from 67 patients in a multinational, randomized, controlled, longitudinal, 12-week trial of MET vs.MET+AZ in children with mild to moderate CD. Profiles were analyzed together with disease activity, and then used to construct Random Forest models to classify remission or predict treatment response.Results: Both MET and MET+AZ significantly decreased diversity of the microbiota and caused large treatment-specific shifts in microbiota structure at week 4. Disease remission was associated with a treatment-specific microbiota configuration. Random Forest models constructed from microbiota profiles pre-and during antibiotic treatment with metronidazole accurately classified disease remission in this treatment group (AUC of 0.879, 95% CI 0.683, 0.9877; sensitivity 0.7778; specificity 1.000, P < 0.001). A Random Forest model trained on preantibiotic microbiota profiles predicted disease remission at week 4 with modest accuracy (AUC of 0.8, P = 0.24). Conclusions:MET and MET+AZ antibiotic regimens in pediatric CD lead to distinct gut microbiota structures at remission. It may be possible to classify and predict remission based in part on microbiota profiles, but larger cohorts will be needed to realize this goal.

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Analysis of Antibiotic Exposure and Development of Acute Graft-vs-Host Disease Following Allogeneic Hematopoietic Cell Transplantation

et al. 2023

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ImportanceCertain antibiotic exposures have been associated with increased rates of acute graft-vs-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Since antibiotic exposure can both affect and be affected by infections, analyzing time-dependent exposure in the presence of multiple potential confounders, including prior antibiotic exposures, poses specific analytical challenges, necessitating both a large sample size and unique approaches.ObjectiveTo identify antibiotics and antibiotic exposure timeframes associated with subsequent aGVHD.Design, Setting, and ParticipantsThis cohort study assessed allo-HCT at a single center from 2010 to 2021. Participants included all patients aged at least 18 years who underwent their first T-replete allo-HCT, with at least 6 months of follow-up. Data were analyzed from August 1 to December 15, 2022.ExposuresAntibiotics between 7 days before and 30 days after transplant.Main Outcomes and MeasuresThe primary outcome was grade II to IV aGVHD. The secondary outcome was grade III to IV aGVHD. Data were analyzed using 3 orthogonal methods: conventional Cox proportional hazard regression, marginal structural models, and machine learning.ResultsA total of 2023 patients (median [range] age, 55 [18-78] years; 1153 [57%] male) were eligible. Weeks 1 and 2 after HCT were the highest-risk intervals, with multiple antibiotic exposures associated with higher rates of subsequent aGVHD. In particular, exposure to carbapenems during weeks 1 and 2 after allo-HCT was consistently associated with increased risk of aGVHD (minimum hazard ratio [HR] among models, 2.75; 95% CI, 1.77-4.28), as was week 1 after allo-HCT exposure to combinations of penicillins with a β-lactamase inhibitor (minimum HR among models, 6.55; 95% CI, 2.35-18.20).Conclusions and RelevanceIn this cohort study of allo-HCT recipients, antibiotic choices and schedules in the early course of transplantation were associated with aGVHD rates. These findings should be considered in antibiotic stewardship programs.

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Detrimental Effect of Broad-spectrum Antibiotics on Intestinal Microbiome Diversity in Patients After Allogeneic Stem Cell Transplantation: Lack of Commensal Sparing Antibiotics

Cited by 83 publications

References 42 publications

Gut dysbiosis during antileukemia chemotherapy versus allogeneic hematopoietic cell transplantation

Gut dysbiosis during antileukemia chemotherapy versus allogeneic hematopoietic cell transplantation

Treatment-Specific Composition of Gut Microbiota Is Associated with Disease Remission in a Pediatric Crohn’s Disease Cohort

Analysis of Antibiotic Exposure and Development of Acute Graft-vs-Host Disease Following Allogeneic Hematopoietic Cell Transplantation

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