Impact of Amoxicillin-Clavulanate followed by Autologous Fecal Microbiota Transplantation on Fecal Microbiome Structure and Metabolic Potential

Bulow, Christopher; Langdon, Amy; Hink, Tiffany; Wallace, Meghan A.; Reske, Kimberly A.; Patel, Sanket; Sun, Xiaoqing; Seiler, Sondra; Jones, Susan; Kwon, Jennie H.; Dantas, Gautam; Dubberke, Erik R.

doi:10.1128/mspheredirect.00588-18

Cited by 18 publications

(18 citation statements)

References 57 publications

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“…While bacterial taxa possessing specific resistance genes cannot yet be determined with our metagenomics sequencing platform, these data are consistent with the fact that blaTEM genes are commonly found in Proteobacteria [29], and the emergence of beta-lactam resistant E. coli has been reported in dogs treated with oral amoxicillin [30] and amoxicillin/clavulanate [31]. Similarly, in humans, amoxicillin/clavulanate exposure resulted in enrichment for beta-lactamase genes in fecal resistomes, although the bacterial species harboring these genes were not evaluated [26].…”

Section: Discussionsupporting

confidence: 77%

“…However, data from the current canine study revealed that amoxicillin/clavulanate causes more alterations in gut microbiota composition than amoxicillin alone, suggesting that microbiome damage is a mechanism responsible for AAD. Amoxicillin/clavulanate is known to modify gut microbiome composition in humans [26,27], including overgrowth of Escherichia species [27], and co-administration of the probiotic, Saccharomyces boulardii, to healthy subjects with amoxicillin/clavulanate limited microbiome damage and reduced AAD rates [27]. To date, clinical analyses that directly compare gut microbiome alterations resulting from exposure to amoxicillin, amoxicillin/clavulanate, and/or amoxicillin/clavulanate formulations with differing amoxicillin/clavulanate ratios have not been reported.…”

Section: Discussionmentioning

confidence: 99%

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SYN-007, an Orally Administered Beta-Lactamase Enzyme, Protects the Gut Microbiome from Oral Amoxicillin/Clavulanate without Adversely Affecting Antibiotic Systemic Absorption in Dogs

et al. 2020

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Beta-lactamases, enzymes produced by bacteria to degrade beta-lactam antibiotics, have been harnessed as therapeutics to protect the gut microbiome from damage caused by antibiotics. Proof-of-concept of this approach using SYN-004 (ribaxamase), a beta-lactamase formulated for oral delivery with intravenous (IV) penicillins and cephalosporins, was demonstrated with animal models and in humans. Ribaxamase degraded ceftriaxone in the gastrointestinal tract, protected the gut microbiome, significantly reduced the incidence of Clostridioides difficile disease and attenuated emergence of antibiotic resistant organisms. SYN-007 is a delayed release formulation of ribaxamase intended for use with oral beta-lactams. In dogs treated with oral amoxicillin, SYN-007 diminished antibiotic-mediated microbiome disruption and reduced the emergence of antibiotic resistance without altering amoxicillin systemic absorption. Here, SYN-007 function in the presence of clavulanate, a beta-lactamase inhibitor, was investigated. Dogs received amoxicillin (40 mg/kg, orally (PO), three times a day (TID)) or the combined antibiotic/beta-lactamase inhibitor, amoxicillin/clavulanate (40 mg/kg amoxicillin, 5.7 mg/kg clavulanate, PO, TID) +/™ SYN-007 (10 mg, PO, TID) for five days. Serum amoxicillin levels were not significantly different +/™ SYN-007 compared to amoxicillin alone or amoxicillin/clavulanate alone as controls for both first and last doses, indicating SYN-007 did not interfere with systemic absorption of the antibiotic. Whole genome shotgun metagenomics analyses of the fecal microbiomes demonstrated both amoxicillin and amoxicillin/clavulanate significantly reduced diversity and increased the frequency of antibiotic resistance genes. Microbiome damage appeared more severe with amoxicillin/clavulanate. In contrast, with SYN-007, microbiome diversity was not significantly altered, and frequency of antibiotic resistance genes did not increase. Importantly, SYN-007 functioned in the presence of clavulanate to protect the gut microbiome indicating that SYN-007 activity was not inhibited by clavulanate in the dog gastrointestinal tract. SYN-007 has the potential to expand microbiome protection to beta-lactam/beta-lactamase inhibitor combinations delivered orally or systemically.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

SYN-007, an Orally Administered Beta-Lactamase Enzyme, Protects the Gut Microbiome from Oral Amoxicillin/Clavulanate without Adversely Affecting Antibiotic Systemic Absorption in Dogs

et al. 2020

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“…Multiple case reports have described successful decolonization of MDRO Klebsiella spp., Pseudomonas, and vancomycin-resistant enterococci with allo-FMT (reviewed in [110]), though no placebo-controlled trials have yet been conducted for this express purpose. Autologous FMT has been proposed as a mechanism to restore a pre-antibiotic microbiome baseline after disruption [59,106,112]. Similarly, probiotics, strains of beneficial bacteria consumed during or after the intervention, are thought to mitigate some of the negative consequences of antibiotics on the microbiome [113][114][115].…”

Section: Therapeutics To Ameliorate Microbiome and Resistome Disruptionmentioning

confidence: 99%

Understanding the impact of antibiotic perturbation on the human microbiome

2020

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The human gut microbiome is a dynamic collection of bacteria, archaea, fungi, and viruses that performs essential functions for immune development, pathogen colonization resistance, and food metabolism. Perturbation of the gut microbiome’s ecological balance, commonly by antibiotics, can cause and exacerbate diseases. To predict and successfully rescue such perturbations, first, we must understand the underlying taxonomic and functional dynamics of the microbiome as it changes throughout infancy, childhood, and adulthood. We offer an overview of the healthy gut bacterial architecture over these life stages and comment on vulnerability to short and long courses of antibiotics. Second, the resilience of the microbiome after antibiotic perturbation depends on key characteristics, such as the nature, timing, duration, and spectrum of a course of antibiotics, as well as microbiome modulatory factors such as age, travel, underlying illness, antibiotic resistance pattern, and diet. In this review, we discuss acute and chronic antibiotic perturbations to the microbiome and resistome in the context of microbiome stability and dynamics. We specifically discuss key taxonomic and resistance gene changes that accompany antibiotic treatment of neonates, children, and adults. Restoration of a healthy gut microbial ecosystem after routine antibiotics will require rationally managed exposure to specific antibiotics and microbes. To that end, we review the use of fecal microbiota transplantation and probiotics to direct recolonization of the gut ecosystem. We conclude with our perspectives on how best to assess, predict, and aid recovery of the microbiome after antibiotic perturbation.

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“…FMT may also colonize missing flora after vancomycin exposure with priority to restore the dysbiosis. For recurrent of Clostridium difficile infection, several researchers have suggested that FMT is a superior method to oral vancomycin for the treatment [21,22], and combinations of them would be a better choice attributed to restore the intestinal microbiota [23,24]. The clinical application of FMT also includes inflammatory bowel disease, diabetes mellitus, liver cirrhosis, gut-brain disease, and others [54].…”

Section: Fmt Restored Microbiome Composition and Genesmentioning

confidence: 99%

“…Fecal microbiota transplantation (FMT) is the introduction of feces from a healthy donor into the intestinal tract of someone with disrupted microbiota, which has been confirmed superior to oral vancomycin for the treatment of Clostridium difficile infection [21,22]. And combination of FMT with vancomycin could be a better choice to treat this kind of infection [23,24]. However, there is limited information on using fecal microbiota transplantation (FMT) for restoration of intestinal microbiome affected by antibiotics.…”

mentioning

confidence: 99%

Human disease-related pathways increasing with opportunistic pathogens bloom in intestinal microbiome after vancomycin exposure and restoration with fecal transplantation by simulator of the human intestinal microbial ecosystem (SHIME)

Liu

Wang

et al. 2019

Preprint

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Background: Antibiotics are growing reported to cause human intestinal microbial disorders with increasing abundances of opportunistic pathogens, and fecal microbiota transplantation (FMT) has been confirmed to restore the dysbiosis of gut flora in many kinds of intestinal disease. However, to date, few studies have focused on the bloomed opportunistic pathogens associated human disease-related pathways as well as antibiotic resistance genes (ARGs) after vancomycin exposure, and there is limited information on using FMT for restoration of intestinal microbiome affected by antibiotics. Methods: This study investigated effects of vancomycin on the opportunistic pathogens, human disease-related pathways as well as ARGs in human gut, and the restoration of intestinal microbiome by FMT. Using the simulator of the human intestinal microbial ecosystem (SHIME), two reactors (representing the ascending and descending colon, respectively) were inoculated with human intestinal microbiota from a healthy adult volunteer who did not suffer from gastrointestinal diseases or take any antibiotic in the previous six months. Samples were collected from the reactors at six-time points (before treatment, after seven days of individual 10 mg/L, 100 mg/L, 1000 mg/L vancomycin treatment, 14 days following the termination of vancomycin and 14 days following FMT). The intestinal microbiome composition and function were analyzed using 16S rRNA gene sequencing and High-throughput Quantitative PCR (HT-qPCR).Results: Vancomycin treatment substantially increased human disease-related pathways and decreased abundances of ARGs. Besides, the bloomed opportunistic pathogens including Achromobacter, Klebsiella, and Pseudomonas, caused by vancomycin exposure, were positively correlated with human disease-related pathways. The microbiota abundance and genes of human disease-related pathways and antibiotic resistance showed a remarkable return towards baseline after FMT, but not for natural recovery. Conclusions: These findings suggest that impacts of vancomycin on human gut are profound and FMT will be a promising strategy in clinical application that can restore the dysbiosis of gut microbiota, which may be valuable for directing future work.

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Impact of Amoxicillin-Clavulanate followed by Autologous Fecal Microbiota Transplantation on Fecal Microbiome Structure and Metabolic Potential

Cited by 18 publications

References 57 publications

SYN-007, an Orally Administered Beta-Lactamase Enzyme, Protects the Gut Microbiome from Oral Amoxicillin/Clavulanate without Adversely Affecting Antibiotic Systemic Absorption in Dogs

SYN-007, an Orally Administered Beta-Lactamase Enzyme, Protects the Gut Microbiome from Oral Amoxicillin/Clavulanate without Adversely Affecting Antibiotic Systemic Absorption in Dogs

Understanding the impact of antibiotic perturbation on the human microbiome

Human disease-related pathways increasing with opportunistic pathogens bloom in intestinal microbiome after vancomycin exposure and restoration with fecal transplantation by simulator of the human intestinal microbial ecosystem (SHIME)

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