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Antibiotic impact on the gut resistome. a Stacked bar chart of summed length-corrected relative abundances (LCRA) of major antimicrobial resistance gene (ARG) classes at baseline (T0) and over the treatment period (T1–T3). The following ARG classes are depicted: aminoglycosides (AGly), beta-lactamases (Bla), fluoroquinolones (Flq), glycopeptides (Gly), macrolide-lincosamide-streptogramin (MLS), nitroimidazoles (Ntmdz), phenicols (Phe), sulfonamides (Sul), tetracyclines (tet), and trimethoprim (Tmt). b Trajectories of antimicrobial resistance genes quantification by LCRA before treatment (T0) and at the end of the observation period (T3) are shown for both antibiotic treatments. Pink data points are measurements at T0, purple data points at T3. Boxplots indicate the distribution of data. The connecting magenta line shows the means at each time point and their development under treatment. The p value is displayed at the top of each box and indicates statistical significant differences between T0 and T3 within each treatment cohort (paired t-test). Trends for LCRA changes are prominent but do not reach statistical significance. c Two-dimensional kernel estimation density of square root transformed LCRA values of sulfonamide and trimethoprim ARG classes in relation to the administered cumulative antibiotic dose in defined daily doses (DDD). ARG LCRA rises significantly with increasing doses of cotrimoxazole, but not under ciprofloxacin. d Based on multivariate regression modeling, the average percentage change of ARG class LCRA per defined daily dose (DDD) is illustrated for each treatment cohort. Bonferroni-corrected statistically significant differences between both antibiotics (LR p < 0.002) are presented by single asterisks. Significant differences in antimicrobial selection pressure were observed for aminoglycoside, CTX-M, glycopeptide, MLS, nitroimidazole, phenicol, sulfonamide, and trimethoprim ARGs. If an additional impact of concurrent medication was detected beside antibiotics in the multivariate models, this has been illustrated by different filling pattern. e Fluoroquinolone resistance-mediating mutation frequencies increase under ciprofloxacin exposure in patient 512 comparing baseline (T0) and endpoint (T3)
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Background:
The selection pressure exercised by antibiotic drugs is an important consideration for the wise stewardship of antimicrobial treatment programs. Treatment decisions are currently based on crude assumptions, and there is an urgent need to develop a more quantitative knowledge base that can enable predictions of the impact of individual...
Similar publications
Ongoing concerns over the presence and persistence of antimicrobial resistance (AMR), particularly in Gram-negative bacteria, continue to have significant global health impacts. The gastrointestinal tract, or ‘gut’, environment amplifies AMR in the human gut microbiome, even in the absence of antibiotics. It constitutes a complex and diverse commun...
Citations
... The influence of microbiome composition in shaping resistome structure has been widely described in human gut analyses [36,41,45] and in environmental samples [46]. In line with our results, Qiu et al [36]. ...
Background
People living with HIV (PLWH) are at increased risk of acquisition of multidrug resistant organisms due to higher rates of predisposing factors. The gut microbiome is the main reservoir of the collection of antimicrobial resistance determinants known as the gut resistome. In PLWH, changes in gut microbiome have been linked to immune activation and HIV-1 associated complications. Specifically, gut dysbiosis defined by low microbial gene richness has been linked to low Nadir CD4 + T-cell counts. Additionally, sexual preference has been shown to strongly influence gut microbiome composition in PLWH resulting in different Prevotella or Bacteroides enriched enterotypes, in MSM (men-who-have–sex-with-men) or no-MSM, respectively. To date, little is known about gut resistome composition in PLWH due to the scarcity of studies using shotgun metagenomics. The present study aimed to detect associations between different microbiome features linked to HIV-1 infection and gut resistome composition.
Results
Using shotgun metagenomics we characterized the gut resistome composition of 129 HIV-1 infected subjects showing different HIV clinical profiles and 27 HIV-1 negative controls from a cross-sectional observational study conducted in Barcelona, Spain. Most no-MSM showed a Bacteroides-enriched enterotype and low microbial gene richness microbiomes. We did not identify differences in resistome diversity and composition according to HIV-1 infection or immune status. However, gut resistome was more diverse in MSM group, Prevotella-enriched enterotype and gut micorbiomes with high microbial gene richness compared to no-MSM group, Bacteroides-enriched enterotype and gut microbiomes with low microbial gene richness. Additionally, gut resistome beta-diversity was different according to the defined groups and we identified a set of differentially abundant antimicrobial resistance determinants based on the established categories.
Conclusions
Our findings reveal a significant correlation between gut resistome composition and various host variables commonly associated with gut microbiome, including microbiome enterotype, microbial gene richness, and sexual preference. These host variables have been previously linked to immune activation and lower Nadir CD4 + T-Cell counts, which are prognostic factors of HIV-related comorbidities. This study provides new insights into the relationship between antibiotic resistance and clinical characteristics of PLWH.
... For the optimized use of antimicrobial drugs or appropriate stewardship of antimicrobial treatment programmes, an important consideration is the selection pressure exerted by antibiotics and the impact of individual drugs on the human microbiome and resistome (i.e. the collective assemblage of antimicrobial-resistant genes, ARGs) [5]. Previous studies have explored potential changes in the human microbiome and resistome following antimicrobial treatments [5][6][7][8]. ...
... For the optimized use of antimicrobial drugs or appropriate stewardship of antimicrobial treatment programmes, an important consideration is the selection pressure exerted by antibiotics and the impact of individual drugs on the human microbiome and resistome (i.e. the collective assemblage of antimicrobial-resistant genes, ARGs) [5]. Previous studies have explored potential changes in the human microbiome and resistome following antimicrobial treatments [5][6][7][8]. Palleja et al. [6] reported a significant decrease in the species diversity of stool microbiota in healthy young adults 4 and 8 days after antimicrobial treatment, followed by recovery to a near-baseline composition within 1.5 months. Another study reported that the stool microbiota could be significantly disturbed for up to several months depending on the type of antimicrobial administered, whereas the salivary microbiota was much more stable than the stool microbiota [8]. ...
Monitoring antibiotic-resistant bacteria (ARB) and understanding the effects of antimicrobial drugs on the human microbiome and resistome are crucial for public health. However, no study has investigated the association between antimicrobial treatment and the microbiome–resistome relationship in long-term care facilities, where residents act as reservoirs of ARB but are not included in the national surveillance for ARB. We conducted shotgun metagenome sequencing of oral and stool samples from long-term care facility residents and explored the effects of antimicrobial treatment on the human microbiome and resistome using two types of comparisons: cross-sectional comparisons based on antimicrobial treatment history in the past 6 months and within-subject comparisons between stool samples before, during and 2–4 weeks after treatment using a single antimicrobial drug. Cross-sectional analysis revealed two characteristics in the group with a history of antimicrobial treatment: the archaeon Methanobrevibacter was the only taxon that significantly increased in abundance, and the total abundance of antimicrobial resistance genes (ARGs) was also significantly higher. Within-subject comparisons showed that taxonomic diversity did not decrease during treatment, suggesting that the effect of the prescription of a single antimicrobial drug in usual clinical treatment on the gut microbiota is likely to be smaller than previously thought, even among very elderly people. Additional analysis of the detection limit of ARGs revealed that they could not be detected when contig coverage was <2.0. This study is the first to report the effects of usual antimicrobial treatments on the microbiome and resistome of long-term care facility residents.
... Various plasmidome approaches have been made in diverse environments, such as cow rumen (Brown Kav et al., 2020), rat cecum (Jorgensen et al., 2014b), human gut (Suzuki et al., 2019;Willmann et al., 2019), soil (Luo et al., 2016), sediments (Mootapally et al., 2021), surface water (Perez et al., 2020), groundwater (Kothari et al., 2019), and extensively in wastewater (Ferreira et al., 2019;Li et al., 2015;Li et al., 2012;Zhang et al., 2011). However, the methodologies in previous studies were compromised in terms of biased targets and lack of needed bioinformatic tools. ...
Plasmids have been a concern in the dissemination and evolution of antibiotic resistance in the environment. In this study, we investigated the total pool of plasmids (plasmidome) and its derived antibiotic resistance genes (ARGs) in different compartments of urban water systems (UWSs) in three European countries representing different antibiotic usage regimes. We applied a direct plasmidome approach using wet-lab methods to enrich circular DNA in the samples, followed by shotgun sequencing and in silico contig circularisation. We identified 9,538 novel sequences in a total of 10,942 recovered circular plasmids. Of these, 66 were identified as conjugative, 1,896 mobilisable and 8,970 non-mobilisable plasmids. The UWSs’ plasmidome was dominated by small plasmids (≤10 Kbp) representing a broad diversity of mobility (MOB) types and incompatibility (Inc) groups. A shared collection of plasmids from different countries was detected in all treatment compartments, and plasmids could be source-tracked in the UWSs. More than half of the ARGs-encoding plasmids carried mobility genes for mobilisation/conjugation. The richness and abundance of ARGs-encoding plasmids generally decreased with the flow, while we observed that non-mobilisable ARGs-harbouring plasmids maintained their abundance in the Spanish wastewater treatment plant. Overall, our work unravels that the UWS plasmidome is dominated by cryptic (i.e., non-mobilisable, non-typeable and previously unknown) plasmids. Considering that some of these plasmids carried ARGs, were prevalent across three countries and could persist throughout the UWSs compartments, these results should alarm and call for attention.
... Antibiotics are the main drivers of microbiota diversity loss in HCT recipients (34,35) and specific antibiotic exposure patterns (types and timing) were associated with higher risk for aGVHD in a recent analysis (36). According to the results of the current analysis connecting pre-FMT microbiota diversity, microbiota modulation by FMT, and grade II-IV aGVHD, antibiotic exposures early after HCT may be used as an eligibility criterion in future prophylactic FMT trials. ...
Purpose
Intestinal microbiota disruptions early after allogeneic hematopoietic cell transplantation have been associated with increased risk for acute GVHD (aGVHD). In our recent randomized phase II trial of oral, encapsulated, third-party fecal microbiota transplantation (FMT) versus placebo, FMT at the time of neutrophil recovery was safe and ameliorated dysbiosis. Here, we evaluated in post hoc analysis whether donor microbiota engraftment after FMT may protect against aGVHD.
Experimental Design
We analyzed pre- and post-FMT stool samples and estimated donor microbiota engraftment (a preplanned secondary endpoint) by determining the fraction of post-FMT microbiota formed by unique donor taxa (donor microbiota fraction; dMf).
Results
dMf was higher in patients who later developed grade I or no aGVHD (median 33.9%; range, 1.6%–74.3%) than those who developed grade II–IV aGVHD (median 25.3%; range, 2.2%–34.8%; P = 0.006). The cumulative incidence of grade II–IV aGVHD by day 180 was lower in the group with greater-than-median dMf than the group with less-than-median dMf [14.3% (95% confidence interval, CI, 2.1–37.5) vs. 76.9% (95% CI, 39.7–92.8), P = 0.008]. The only determinant of dMf in cross-validated least absolute shrinkage and selection operator (LASSO)-regularized regression was the patient's pre-FMT microbiota diversity (Pearson correlation coefficient −0.82, P = 1.6 × 10−9), indicating more potent microbiota modulation by FMT in patients with more severe dysbiosis. Microbiota network analysis revealed major rewiring including changes in the most central nodes, without emergence of keystone species, as a potential mechanism of FMT effect.
Conclusions
FMT may have protective effects against aGVHD, especially in patients with more severe microbiota disruptions.
... The Raymond et al. [54] cohort is composed of healthy participants that were treated twice a day with an oral dose of cefprozil for 7 days (A_CEF). The Willmann et al. [17] study provides two different cohorts of hematological patients receiving prophylactic antibiotics during a mean period of 6 days. One cohort was treated with ciprofloxacin (A_CIP) and the other with cotrimoxazole (A_COT). ...
Background
A growing body of evidence suggests that the gut microbiota is strongly linked to general human health. Microbiome-directed interventions, such as diet and exercise, are acknowledged as a viable and achievable strategy for preventing disorders and improving human health. However, due to the significant inter-individual diversity of the gut microbiota between subjects, lifestyle recommendations are expected to have distinct and highly variable impacts to the microbiome structure.
Results
Here, through a large-scale meta-analysis including 1448 shotgun metagenomics samples obtained longitudinally from 396 individuals during lifestyle studies, we revealed Bacteroides stercoris, Prevotella copri, and Bacteroides vulgatus as biomarkers of microbiota’s resistance to structural changes, and aromatic and non-aromatic amino acid biosynthesis as important regulator of microbiome dynamics. We established criteria for distinguishing between significant compositional changes from normal microbiota fluctuation and classified individuals based on their level of response. We further developed a machine learning model for predicting “responders” and “non-responders” independently of the type of intervention with an area under the curve of up to 0.86 in external validation cohorts of different ethnicities.
Conclusions
We propose here that microbiome-based stratification is possible for identifying individuals with highly plastic or highly resistant microbial structures. Identifying subjects that will not respond to generalized lifestyle therapeutic interventions targeting the restructuring of gut microbiota is important to ensure that primary end-points of clinical studies are reached.
2m7TsyyzrZ6DMn35dcSWgYVideo Abstract
... Three different mouse models have reproduced the superior capacity of vancomycin to decrease alpha diversity or increase pathogen susceptibility compared to more than five other antibiotic agents or combinations (including ampicillin, azithromycin, ciprofloxacin and ciprofloxacinmetronidazole) 46,56,57 . Relative to cotrimoxazole and nitrofurantoin, ciprofloxacin has been shown to cause a greater reduction in species richness (less than twofold) and beta diversity 58,59 , in addition to its effect in depleting Bifidobacterium and Ruminococcus spp. Azithromycin has been widely explored (in clinical trials of >1,000 children across sub-Saharan Africa) on its own and in comparison to other antibiotics [60][61][62][63][64][65][66] . ...
... Importantly, the effects of antibiotics on the gut resistome vary substantially depending on the nature of the administered drug 33,52,59,114,123 . For instance, in one study involving healthy adults, oral administration of azithromycin (a macrolide) or cefpodoxime (a cephalosporin) resulted in an increased relative abundance of ARGs, whereas no changes in the relative ARG abundance were observed on oral administration of levofloxacin (a fluoroquinolone) 33 . ...
... Similar post-treatment effects of macrolides [62][63][64][65][66]123 , cephalosporins 119,120 and fluoroquinolones 59 on the relative abundance of ARGs have been reported elsewhere for diverse population segments (for example, children and elderly, healthy and diseased). Nonetheless, the effects of various antibiotic classes and individual antibiotics on the human gut resistome remain largely unexplored; reports focusing on single-treatment agents remain few and far between 33,59,62,[119][120][121]123 , with investigations of the resistome changes commonly involving combinations of antibiotics 32,34,122 or with retrospective cohorts with variable treatment regimens, doses and durations 114,116,118,129 (Table 1). Moreover, factors beyond the treatment agent can affect resistome dynamics during treatment, further obscuring our understanding of the antibiotic-induced resistome changes. ...
Antibiotic-mediated perturbation of the gut microbiome is associated with numerous infectious and autoimmune diseases of the gastrointestinal tract. Yet, as the gut microbiome is a complex ecological network of microorganisms, the effects of antibiotics can be highly variable. With the advent of multi-omic approaches for systems-level profiling of microbial communities, we are beginning to identify microbiome-intrinsic and microbiome-extrinsic factors that affect microbiome dynamics during antibiotic exposure and subsequent recovery. In this Review, we discuss factors that influence restructuring of the gut microbiome on antibiotic exposure. We present an overview of the currently complex picture of treatment-induced changes to the microbial community and highlight essential considerations for future investigations of antibiotic-specific outcomes. Finally, we provide a synopsis of available strategies to minimize antibiotic-induced damage or to restore the pretreatment architectures of the gut microbial community.
... There is an increasing appreciation of the harms associated with indiscriminate use of antibiotics associated with the lack of diagnostic clarity. These harms include long-term changes to the human microbiome, especially within the gut, but also with the possibility of deleterious effects to the microbiomes of the urinary tract (urobiome) and the vagina through the eradication of beneficial microbes that would normally play a role in preventing clinically important infections and the selection of undetected antibiotic-resistant microbes (5,6). ...
Diagnosis and treatment of urinary tract infections (UTIs) remains stagnant. The presumption that a patient either has a UTI or does not (binary choice) is inappropriately simplistic. Laboratory diagnostic tests have not advanced for decades. The goal of UTI treatment has not been rigorously defined and may increase the prescription of potentially harmful, inappropriate antibiotics. Despite the high incidence of UTI diagnoses, the high cost of UTI treatment, and increasing concerns associated with antimicrobial resistance, the development of novel and more accurate UTI tests has not been considered a priority, in part due to the general perception that current UTI care is already sufficient. In this review, we discuss the importance of improving UTI diagnostic testing to improve treatment outcomes. We discuss the problems associated with UTI diagnosis. Urinary microbes are alive and exist in both healthy and symptomatic individuals—urine is not sterile. We specifically outline the limitations of standard urine culture methods used by clinical microbiology laboratories, explaining clearly why such methods cannot be considered to be the “gold standard,” as standard culture methods underreport most of the urinary tract microbes, including some acknowledged and many emerging uropathogens. We do not recommend abandonment of this test, as no universally accepted substitute yet exists. However, we strongly encourage the development of new and improved diagnostic tests that can both improve outcomes and preserve antibiotic stewardship.
... It is, thus, one of the most common drugs concurrently prescribed with MPA and other immunosuppressive agents during post-transplantation periods or in other MPA-indicated conditions [18]. TMP-SMX has been shown to affect the abundance, diversity, and composition of gut microbiota [19,20]. Additionally, it exhibits antibacterial activity against β-glucuronidasepositive bacteria [21]. ...
Mycophenolic acid (MPA) and trimethoprim-sulfamethoxazole (TMP-SMX) are commonly prescribed together in certain groups of patients, including solid organ transplant recipients. However, little is known about the pharmacokinetic drug–drug interactions (DDIs) between these two medications. Therefore, the present study aimed to determine the effects of TMP-SMX on MPA pharmacokinetics in humans and to find out the relationship between MPA pharmacokinetics and gut microbiota alteration. This study enrolled 16 healthy volunteers to take a single oral dose of 1000 mg mycophenolate mofetil (MMF), a prodrug of MPA, administered without and with concurrent use of TMP-SMX (320/1600 mg/day) for five days. The pharmacokinetic parameters of MPA and its glucuronide (MPAG) were measured using high-performance liquid chromatography. The composition of gut microbiota in stool samples was profiled using a 16S rRNA metagenomic sequencing technique during pre- and post-TMP-SMX treatment. Relative abundance, bacterial co-occurrence networks, and correlations between bacterial abundance and pharmacokinetic parameters were investigated. The results showed a significant decrease in systemic MPA exposure when TMP-SMX was coadministered with MMF. Analysis of the gut microbiome revealed altered relative abundance of two enriched genera, namely the genus Bacteroides and Faecalibacterium, following TMP-SMX treatment. The relative abundance of the genera Bacteroides, [Eubacterium] coprostanoligenes group, [Eubacterium] eligens group, and Ruminococcus appeared to be significantly correlated with systemic MPA exposure. Coadministration of TMP-SMX with MMF resulted in a reduction in systemic MPA exposure. The pharmacokinetic DDIs between these two drugs were attributed to the effect of TMP-SMX, a broad-spectrum antibiotic, on gut microbiota-mediated MPA metabolism.
... It is shown, however, that the interaction of various extrahepatic organ failures leads to an exponential increase in mortality of up to 90% in 28 days in ACLF. In particular, BSI after bacterial and/or fungal translocation through the intestinal epithelium is a common complication in patients with ACLF and is associated with high morbidity and mortality (105)(106)(107). The worldwide increase in infections with multidrug-resistant pathogens further complicates the prevention and treatment of BSI in these patients (108). ...
Liver cirrhosis is the end stage of all chronic liver diseases and contributes significantly to overall mortality of 2% globally. The age-standardized mortality from liver cirrhosis in Europe is between 10 and 20% and can be explained not only by the development of liver cancer but also by the acute deterioration in the patient's overall condition. The development of complications including accumulation of fluid in the abdomen (ascites), bleeding in the gastrointestinal tract (variceal bleeding), bacterial infections or a decrease in brain function (hepatic encephalopathy) defines an acute decompensation that requires therapy, and often leads to acute-on-chronic liver failure (ACLF) by different precipitating events. However, due to its complexity and organ-spanning nature, the pathogenesis of ACLF is poorly understood, and the common underlying mechanisms leading to the development of organ dysfunction or failure in ACLF are still elusive. Apart from general intensive care interventions, there are no specific therapy options for ACLF. Liver transplantation is often not possible in these patients due to contraindications and a lack of prioritization. In this review, we describe the framework of the ACLF-I project consortium funded by the Hessian Ministry of Higher Education, Research and the Arts (HMWK) based on existing findings and will provide answers to these open questions.
... Intestinal colonization with Multi-Drug Resistant Organisms (MDROs) capable of producing Extended-Spectrum b-Lactamases (ESBLs) and/or carbapenemases is a global concern since these organisms can cause life-threatening opportunistic infections (Weinstein, 2012). Intestinal colonization by MDROs is often a result of antibiotic consumption that selects for these organisms and allows them to overgrow and dominate the intestinal microbiome (Willmann et al., 2019). This dominance poses an additional threat since it is linked to higher rates of infections (Sun et al., 2021) and transmission of MDROs (Lerner et al., 2015). ...
Introduction
Intestinal colonization by Multi-Drug Resistant Organisms (MDROs) can pose a threat on the health of critically ill patients. The extent of colonization by these organisms is related to previous antibiotic treatments and their ability to cause infections among adult patients. The aim of this study is to determine the relationship between the intestinal Relative Loads (RLs) of selected antibiotic resistance genes, antibiotic consumption and extra-intestinal spread among critically ill pediatric patients.
Methods
RLs of bla CTX-M-1-Family, bla OXA-1, bla OXA-48 and bla VIM were determined in 382 rectal swabs obtained from 90 pediatric critically ill patients using qPCRs. The RLs were compared to the patients’ demographics, antibiotic consumption, and detection of MDROs from extra-intestinal sites. 16SrDNA metagenomic sequencing was performed for 40 samples and clonality analyses were done for representative isolates.
Results and discussion
76 (74.45%) patients from which 340 (89.01%) rectal swabs were collected had at least one swab that was positive for one of the tested genes. Routine cultures did not identify carbapenemases in 32 (45.1%) and 78 (58.2%) swabs that were positive by PCR for bla OXA-48 and blaVIM, respectively. RLs of above 6.5% were associated with extra-intestinal spread of blaOXA-48-harboring MDROs. Consumption of carbapenems, non-carbapenem β-lactams, and glycopeptides were statistically associated with testing negative for bla CTX-M-1-Family and bla OXA-1 while the consumption of trimethoprim/sulfamethoxazole and aminoglycosides was associated with testing negative for blaOXA-48 (P<0.05). In conclusion, targeted qPCRs can be used to determine the extent of intestinal dominance by antibiotic resistant opportunistic pathogens and their potential to cause extra-intestinal infections among a critically ill pediatric population.
