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SummaryBackgroundAntimicrobial resistance is a major public health threat, affecting not only humans but also animals and the environment. Although the “One Health” dimension of resistance is well recognized, data are lacking on the circulation of resistance, particularly in low-income countries. The World Health Organization has proposed a protocol called Tricycle, focusing on extended-spectrum beta-lactamase (ESBL)-Escherichia colisurveillance in the three sectors. We implemented Tricycle in Madagascar to assess ESBL-E. coliprevalence and describe intra- and inter-sector circulation of ESBL-E. coliand plasmids.Methods289 pregnant women, 246 farm chickens and 28 surface waters were sampled in Antananarivo (the capital city) area and tested for ESBL-E. coli. Isolates were sequenced by short-(Illumina) and long-(Nanopore) read methods.FindingsESBL-E. coliprevalence was 29·8%, 56·9% and 100% in pregnant women, chickens, and the environment, respectively. The wet season was associated with higher rates of carriage in humans (OR=3·1, 95%CI 1·8-5·3) and animals (OR=2·8 95%CI 1·7-4·8). Sequencing of 277 non-duplicated isolates (82, 118 and 77 from each sector, respectively) showed high genetic diversity (90 STs identified) with differences between sectors. Single nucleotide polymorphism (SNP) analysis revealed 169/277 (61%) isolates grouped into 44 clusters (≥2 isolates) of closely related isolates (blaCTX-M(77.6%blaCTX-M-15), chromosomally integrated in 57·4% (159/277) of isolates, and plasmidic in 40·8% (113/277). The 114 ESBL-carrying plasmids were mainly IncF (55·2%, n=63) and IncY (36·8%, n=42). The F31/36:A4:B1 (n=13) and F-:A-:B53 (n=8) subtypes, and all IncY plasmids, highly conserved, were observed in isolates of differing genetic backgrounds from all sectors.InterpretationDespite varying strain population structures in the three sectors, both ESBL-E. colistrains and plasmids are circulating among humans, chickens and the environment in the capital of Madagascar.FundingFondation Mérieux, INSERM, Université Paris Cité

Colistin is an antibiotic of last resort in the management of highly drug-resistant Enterobacterales infections. Travel to some destinations presents a high risk of acquiring multidrug-resistant Enterobacterales, but little data are available on the risk of acquiring colistin-resistant strains. Here, we use the VOYAG-R sample collection (2012-2013) in order to evaluate the rate of acquisition of colistin-resistant Enterobacterales, excluding species with intrinsic resistance (CRE), following travel to tropical regions.A total of 574 frozen stool samples of travellers returning from tropical regions was screened for colistin-resistant strains using ChromID Colistin R agar (bioMerieux®) after pre-enrichment culture with 1 mg/L of colistin. Genomes were obtained by Illumina sequencing and genetic determinants of colistin resistance (mutational events and mcr genes) were searched.A total of 22 travellers (3.8%) acquired colistin-resistant Enterobacterales carrying an mcr gene. Acquisition rates varied between visited regions: 9.2% (18/195) for Asia (Southeast Asia: 17/18), 2.2% (4/184) for Latin America (Peru: 4/4) and 0% from Africa (0/195). Acquired strains were predominantly Escherichia coli (92%) and carried mostly the mcr-1 variant (83%). E. coli strains belonged mainly to commensal phylogroups A and B1, and were genetically highly diverse (5 non-clonal Sequence Type (ST)10 and 17 ST singletons). Only four non mcr colistin-resistant strains (two E. coli and two Enterobacter cloacae complex) were identified. Among all the strains, two also carried extended-spectrum beta-lactamase (ESBL) genes.Travel to tropical regions, and particularly to Southeast Asia, is a risk factor for the acquisition of mcr-carrying Enterobacterales. This study highlights the community dissemination of mcr in humans as early as 2012, 4 years prior to its first published description.

Background: Over the last decade, studies unraveled the cancer-immune dialogue in the setting of immune checkpoint inhibitors (ICI) and influenced by the gut microbiota. The first evidence of the key role of the microbiota in ICI modulation was observed during antibiotics (ATB) treatment, where altering the microbiota composition by ATB inhibited ICI responses. DAV132 (DAV) is an orally administered colon-targeted ATB adsorbent capsules designed to prevent ATB-induced dysbiosis. We investigated whether DAV co-administered with ATB could prevent ATB-related dysbiosis and ICI response. Methods: 72 human healthy volunteers (HV) were randomized to receive either IV ceftazidime-avibactam (CZA) or Piperacillin tazobactam (PTZ) alone or in combination with oral DAV. CZA and PTZ plasmatic and fecal pharmacodynamic levels were measured using HPLC-MS/MS. Microbiome was profiled with metagenomics at different timepoints. FMT experiments in germ-free mice were performed using fecal samples from HV from the trial, before (D1) or after 6 days (D6) of CZA or PTZ+/-DAV; subsequently mice were inoculated with MCA205 or B16 tumors and treated with anti-PD-1. Tumor infiltrating lymphocytes (TILs) were analyzed by flow cytometry. Results: DAV did not impact plasmatic CZA or PTZ concentrations, but significantly reduced ceftazidime and piperacillin concentrations in feces compared to ATB groups alone. DAV significantly prevented the reduction in microbiota alpha-diversity at D6 and was associated with a rapid return to baseline microbiota. 50 and 43 metagenomics species were preserved in the CZA+DAV vs CZA, or PTZ-DAV vs PTZ such as Faecalibacterium praunistzii, Alistipes Spp and Blautia obeum. FMT in germ-free mice using feces collected at D1 exhibited a significant anti-PD-1 activity. This anti-tumor response was inhibited in two tumors models in mice transplanted with D6 feces from patients in the CZA or PTZ alone groups. Conversely, the anti-tumor response was maintained in mice transplanted with D6 feces from HV treated with CZA+DAV or PTZ+DAV groups. Flow cytometry on TILs demonstrated that CZA decreased CD8+T cell and CD8+/Treg ratio compared to CZA+DAV. Conclusions: DAV prevented ATB-induced dysbiosis in HV treated with CZA or PTZ without influencing plasmatic concentrations. In avatar mice FMT from HV treated with CZA+DAV was able to preserve anti-PD-1 efficacy. These results provide rationale to launch clinical trials combining DAV in patients on ATB amenable to ICI. Citation Format: Meriem Messaoudene, Nathalie Saint-Lu, Frédérique Sablier-Gallis, Stéphanie Ferreira, Mayra Ponce, Clément Le Bescop, Thomas Loppinet, Tanguy Corbel, Céline Féger, Fabien Vitry, Antoine Andremont, Jean de Gunzburg, Bertrand Routy. Prevention of antibiotic-induced dysbiosis in human volunteers by DAV132 and preservation of responsiveness to anti-PD-1 demonstrated by transplantation of human feces into tumor-bearing mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5882.

Travel to tropical regions is associated with high risk of acquiring extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) that are typically cleared in less than 3 months following return. The conditions leading to persistent carriage that exceeds 3 months in some travellers require investigation. Whole-genome sequencing (Illumina MiSeq) was performed on the 82 ESBL-E isolates detected upon return and 1, 2, 3, 6 and 12 months later from the stools of 11 long-term (>3 months) ESBL-E carriers following travel abroad. One to five different ESBL Escherichia coli strains were detected per traveller upon return, and this diminished to one after 3 months. Long-term carriage was due to the presence of the same ESBL E. coli strain, for more than 3 months, in 9 out of 11 travellers, belonging to epidemic sequence type complexes (STc 10, 14, 38, 69, 131 and 648). The mean carriage duration of strains belonging to phylogroups B2/D/F, associated with extra-intestinal virulence, was higher than that for commensal-associated A/B1/E phylogroups (3.5 vs 0.5 months, P=0.021). Genes encoding iron capture systems (fyuA, irp), toxins (senB, sat), adhesins (flu, daaF, afa/nfaE, pap, ecpA) and colicin (cjrA) were more often present in persistent strains than in transient ones. Single-nucleotide polymorphism (SNP) analysis in persistent strains showed a maximum divergence of eight SNPs over 12 months without signs of adaptation. Genomic plasticity was observed during the follow-up with the loss or gain of mobile genetic elements such as plasmids, integrons and/or transposons that may contain resistance genes at different points in the follow-up. Long-term colonization of ESBL-E following travel is primarily due to the acquisition of E. coli strains belonging to epidemic clones and harbouring ‘virulence genes’, allowing good adaptation to the intestinal microbiota.

Background DAV132 (colon-targeted adsorbent) has prevented antibiotic-induced effects on microbiota in healthy volunteers. Objectives To assess DAV132 safety and biological efficacy in patients. Patients and methods An open-label, randomized [stratification: fluoroquinolone (FQ) indication] multicentre trial comparing DAV132 (7.5 g, 3 times a day, orally) with No-DAV132 in hospitalized patients requiring 5–21 day treatment with FQs and at risk of Clostridioides difficile infection (CDI). FQ and DAV132 were started simultaneously, DAV132 was administered for 48 h more, and patients were followed up for 51 days. The primary endpoint was the rate of adverse events (AEs) independently adjudicated as related to DAV132 and/or FQ. The planned sample size of 260 patients would provide a 95% CI of ±11.4%, assuming a 33% treatment-related AE rate. Plasma and faecal FQ concentrations, intestinal microbiota diversity, intestinal colonization with C. difficile, MDR bacteria and yeasts, and ex vivo resistance to C. difficile faecal colonization were assessed. Results Two hundred and forty-three patients (median age 71 years; 96% with chronic comorbidity) were included (No-DAV132, n = 120; DAV132, n = 123). DAV132- and/or FQ-related AEs did not differ significantly: 18 (14.8%) versus 13 (10.8%) in DAV132 versus No-DAV132 patients (difference 3.9%; 95% CI: −4.7 to 12.6). Day 4 FQ plasma levels were unaffected. DAV132 was associated with a >98% reduction in faecal FQ levels (Day 4 to end of treatment; P < 0.001), less impaired microbiota diversity (Shannon index; P = 0.003), increased ex vivo resistance to C. difficile colonization (P = 0.0003) and less frequent FQ-induced VRE acquisition (P = 0.01). Conclusions In FQ-treated hospitalized patients, DAV132 was well tolerated, and FQ plasma concentrations unaffected. DAV132 preserved intestinal microbiota diversity and C. difficile colonization resistance.

RESUME Le developpement et la rapidite des transports et des communications creent des opportunites pour la diffusion et l’implantation de maladies infectieuses. A cote d’evenements comme le virus de l’immunodeficience humaine (VIH), le syndrome respiratoire aigu severe lie a un coronavirus (SRAS), le chikungunya, le virus de la grippe A H1N1v pandemique, il faut signaler le risque de diffusion de bacteries pathogenes resistantes aux antibiotiques. Le rapatriement de francais en provenance de l’etranger, et la prise en charge sanitaire d’etrangers en France, expose la population francaise a des bacteries multiresistantes par une transmission interhumaine. La surveillance et le controle de la diffusion de pathogenes emergents multiresistants aux antibiotiques importes en France fait partie des priorites de securite sanitaire.

Objectives: Intestinal carriage with extended spectrum β-lactamase Enterobacteriaceae (ESBL-E) and carbapenemase-producing Enterobacteriaceae (CPE) can persist for months. We aimed to evaluate whether oral antibiotics followed by faecal microbiota transplantation (FMT) can eradicate intestinal carriage with ESBL-E/CPE.Methods: Randomized, open-label, superiority trial in four tertiary-care centres (Geneva (G), Paris (P), Utrecht (U), Tel Aviv (T)). Non-immunocompromised adult patients were randomized 1: 1 to either no intervention (control) or a 5-day course of oral antibiotics (colistin sulphate 2 × 106 IU 4×/day; neomycin sulphate 500 mg 4×/day) followed by frozen FMT obtained from unrelated healthy donors. The primary outcome was detectable intestinal carriage of ESBL-E/CPE by stool culture 35-48 days after randomization (V4). ClinicalTrials.govNCT02472600. The trial was funded by the European Commission (FP7).Results: Thirty-nine patients (G = 14; P = 16; U = 7; T = 2) colonized by ESBL-E (n = 36) and/or CPE (n = 11) were enrolled between February 2016 and June 2017. In the intention-to-treat analysis 9/22 (41%) patients assigned to the intervention arm were negative for ESBL-E/CPE at V4 (1/22 not receiving the intervention imputed as positive) whereas in the control arm 5/17 (29%) patients were negative (one lost to follow up imputed as negative) resulting in an OR for decolonization success of 1.7 (95% CI 0.4-6.4). Study drugs were well tolerated overall but three patients in the intervention group prematurely stopped the study antibiotics because of diarrhoea (all received FMT).Conclusions: Non-absorbable antibiotics followed by FMT slightly decreased ESBL-E/CPE carriage compared with controls; this difference was not statistically significant, potentially due to early trial termination. Further clinical investigations seem warranted.

Escherichia coli is the leading cause of bloodstream infection (BSI). The incidence of E. coli BSI caused by antibiotic-resistant strains is increasing. We aimed to describe the nationwide incidence and resistance profile of E. coli BSI in Israel and its impact on mortality, to compare E. coli BSI mortality with all-cause mortality, and community-onset with hospital-onset E. coli BSIs.We used mandatory BSI surveillance reports submitted by all Israeli hospitals to the Ministry of Health and the national death registry. All E. coli BSIs from 1 January 2018 to 31 December 31 2019 in patients aged 18 and over were included.A total of 11 113 E. coli BSIs occurred in 10 218 patients; 85% (9012/10 583) were community onset. Median age was 76 (IQR 65-85), and 57% (6304/11 113) of cases occurred in women. The annual incidence was 92.5 per 100 000 population. Antibiotic resistance was frequent and significantly more common in hospital-onset than in community-onset BSI; 65% (1021/1571) vs. 45% (4049/9012) were multidrug-resistant (MDR) (p 0.001). The case fatality rate (CFR) was higher following hospital-onset BSI than community-onset: 23% (276/1214) vs. 12% (926/7620) at 14 days, 31% (378/1214) vs. 16% (1244/7620) at 30 days, and 55% (418/766) vs. 34% (1645/4903) at 1 year (p 0.001 for all comparisons). The 1-year CFR was 47% (1258/2707) for MDR vs. 28% (928/3281) for non-MDR (p 0.001). The annual mortality rate was 31.0 per 100 000 population, comprising 4.2% (31.0/734.8) of all causes of deaths.E. coli BSI carries a high burden, with a large proportion of MDR isolates, which are associated with increased incidence and CFR.

A healthy, intact gut microbiota is often resistant to colonization by gastrointestinal pathogens. During periods of dysbiosis, however, organisms such as Clostridioides difficile can thrive. We describe an optimized in vitro colonization resistance assay for C. difficile in stool (CRACS) and demonstrate the utility of this assay by assessing changes in colonization resistance following antibiotic exposure. Fecal samples were obtained from healthy volunteers (n = 6) and from healthy subjects receiving 5 days of moxifloxacin (n = 11) or no antibiotics (n = 10). Samples were separated and either not manipulated (raw) or sterilized (autoclaved or filtered) prior to inoculation with C. difficile ribotype 027 spores and anaerobic incubation for 72 h. Different methods of storing fecal samples were also investigated in order to optimize the CRACS. In healthy, raw fecal samples, incubation with spores did not lead to increased C. difficile total viable counts (TVCs) or cytotoxin detection. In contrast, increased C. difficile TVCs and cytotoxin detection occurred in sterilized healthy fecal samples or those from antibiotic-treated individuals. The CRACS was functional with fecal samples stored at either 4°C or −80°C but not with those stored with glycerol (12% or 30% [vol/vol]). Our data show that the CRACS successfully models in vitro the loss of colonization resistance and subsequent C. difficile proliferation and toxin production. The CRACS could be used as a proxy for C. difficile infection in clinical studies or to determine if an individual is at risk of developing C. difficile infection or other potential infections occurring due to a loss of colonization resistance.

The introductions of advanced antibiotics have triggered complex versions of resistant genes in gram-negative bacteria. In a generation witness limited discovery of antibiotics makes this phenomenon a major public health threat. This study aims to establish the fecal carriage rate of multidrug-resistant Enterobacteriaceae strains among food handlers. Data was extracted from a prospective cross-sectional study – ‘Prevalence and risk factors of fecal carriage of Extended Spectrum β-Lactamase producing Enterobacteriaceae amongst food handlers in Lower Basic Schools in West Coast region of The Gambia. The study enrolled 600 randomly selected food handlers (565 of which had complete data set) from 60 lower basic schools in 7 districts in the West Coast Region of The Gambia. Stool samples were collected from the participants and screened for resistance to cefotaxim. Isolated organisms were further tested for susceptibility to cephalosporins, carbapenems, fluoroquinolones and other families of antimicrobials as per Clinical Standard Laboratory Institute guidelines. The association of risk factors to fecal carriage of resistant Enterobacteriacea was performed using Pearson Chi squared and fishers exact (P Results confirmed that the prevalence of Enterobacteriaceae by resistance to cefotaxime was 15.8%. 23 genus and 89 species of resistant strains were isolated. All isolates were 100% resistant to cephalosporins such as ceftriazone, cefotaxime and cefuroxime, except ceftazidime (92%). Resistance to ciprofloxacin (fluoroquinolone) was measured at 50%. Only 1.2% was resistant to imipenem (carbapenem). Most isolates were resistant to ampicillin, nitrofurantoine, erythromycin, tetracycline and cotrimaxole. Majority of the identified Enterobacteriaceae wereEnterobacter aerogene(14%),Klebsiella pneumoniea(12%) andEscherichia coli(7%). This study found a high prevalence of fecal carriage multi-drug resistant Enterobacteriaceae among food handlers, mostly women, in The Gambia. The irrational prescription and use of antibiotics is a major risk factor for the proliferation of antibiotic resistance. Well-conducted surveillance is essential to implement effective control measures for the spread of antibiotic resistance urgently receommended.

Homeostasis of the intestinal microbiota is currently recognized as a major contributor to human health. Furthermore, intestinal dysbiosis is associated with a multitude of consequences, including intestinal colonization by antibiotic-resistant or pathogenic bacteria, such as Clostridioides difficile, and reduced efficacy of promising anticancer immunotherapies. By far, the most immediate and drastic exposure leading to dysbiosis is antibiotic treatment. Many attempts have been made to prevent or repair antibiotic-associated dysbiosis. Here, we review these innovations and the difficulties associated with their development.

International audience

Background Antibiotic resistance is a major concern for public and environmental health. The role played by the environment in disseminating resistance is increasingly considered, as well as its capacity for mitigation. We reviewed the literature on strategies to control dissemination of antibiotic-resistant bacteria (ARB), antibiotic resistance genes (ARG) and mobile genetic elements (MGE) in the environment. Methods This systematic review focused on three main strategies: (i) restriction of antibiotic use (S1), (ii) treatments of liquid/solid matrices (S2) and (iii) management of natural environment (S3). Articles were collected from seven scientific databases until July 2017 and from Web of Science until June 2018. Only studies reporting measurements of ARB, ARG or MGE in environmental samples were included. An evidence map was drawn from metadata extracted from all studies eligible for S1, S2 and S3. Subsets of studies were assessed for internal and external validity to perform narrative and quantitative syntheses. A meta-analysis was carried out to assess the effects of organic waste treatments (random-effect models). Review findings Nine hundred and thirty-one articles representing 1316 individual studies (n) were eligible for S1 (n = 59), S2 (n = 781) and S3 (n = 476) strategies, respectively. Effects of interventions to control the dissemination of antibiotic resistance in the environment were primarily studied in strategy S2. A partial efficiency of wastewater treatment plants (WWTPs) to reduce antibiotic resistance in treated effluent was reported in 118 high validity studies. In spite of the heterogeneity in published results, the meta-analysis showed that composting and drying were efficient treatments to reduce the relative abundance of ARG and MGE in organic waste, by 84% [65%; 93%] and 98% [80%; 100%], respectively. The effect of anaerobic digestion was not statistically significant (51% reduction [− 2%; 77%]) when organic waste treatments were compared together in the same model. Studies in strategies S1 and S3 mainly assessed the effects of exposure to sources of contamination. For instance, 28 medium/high validity studies showed an increase of antibiotic resistance in aquatic environments at the WWTP discharge point. Some of these studies also showed a decrease of resistance as the distance from the WWTP increases, related to a natural resilience capacity of aquatic environments. Concerning wildlife, nine medium/high validity studies showed that animals exposed to anthropogenic activities carried more ARB. Conclusions and implications Knowledge gaps were identified for the relationship between restriction of antibiotic use and variation of antibiotic resistance in the environment, as well as on possible interventions in situ in natural environment. Organic waste treatments with thermophilic phase (> 50 °C) should be implemented before the use/release of organic waste in the environment. More investigation should be conducted with the datasets available in this review to determine the treatment efficiency on ARG carried by specific bacterial communities.

To prevent antibiotic-induced perturbations on gut microbiota, DAV132, a novel colon-targeted adsorbent, which sequesters antibiotic residues in the lower gastrointestinal tract, was developed. We built an integrated pharmacological model of how DAV132 reduces fecal free moxifloxacin and preserves gut microbiota. We used plasma and fecal free moxifloxacin concentrations, and Shannon diversity index from 16S ribosomal RNA gene metagenomics analysis of fecal microbiota, of 143 healthy volunteers assigned randomly to receive moxifloxacin only, or with 10 DAV132 dose regimens, or to a control group. We modeled reduced fecal moxifloxacin concentrations using a transit model for DAV132 kinetics and a Michaelis-Menten model with an effect of the amount of activated charcoal on adsorption efficacy. Changes in moxifloxacin-induced perturbations on gut microbiota diversity were then quantified through a turnover model with the Emax model. With the developed model, the efficiency of pharmacokinetic antagonism and its consequences on gut microbiota diversity were quantified.

SETTING: Tuberculosis (TB) incidence is declining overall in France, but not in Paris where some areas remain relative hot spots for TB.OBJECTIVES: To obtain a better knowledge of local TB epidemiology in order to facilitate control measures.DESIGN: Analysis of demographic data of TB patients diagnosed at the Bichat-Claude Bernard Hospital from 2007 to 2016, with spoligotyping of Mycobacterium tuberculosis complex isolates.RESULTS: During the study period, 1096 TB patients were analysed. The incidence of TB diagnosis was stable, averaging 115 patients per year, predominantly males (71%), foreign-born (81%), with pulmonary TB (77%) and negative HIV serology (88%). The mean age of foreign-born TB patients decreased over the study period, most significantly in recent arrivals in France, whose average age decreased by two years (P = 0.001). The time period between arrival in France and being diagnosed with active TB decreased annually significantly by 0.75 years (P = 0.02). The proportion of L4.6.2/Cameroon and L2/Beijing sub-lineages increased annually by 0.7% (P < 0.05). Multi-drug resistant strains, representing 4% of all strains, increased annually by 0.75% (P = 0.03)CONCLUSION: The number of TB patients remained high in northern Paris and the surrounding suburbs, suggesting the need for increased control measures.

National audience; La crise qui résulte de la montée des résistances bactériennes menace la santé humaine, animale et environnementale. L’impact sanitaire et économique de la crise est massif. Alors que l’alerte est largement donnée et que des mécanismes et des programmes d’aide à l’innovation pour lutter contre l’antibiorésistance ont été mis en place, force est de constater que les nouveaux produits antibiotiques proposés n’arrivent pas à trouver une rentabilité économique leur permettant d’atteindre le marché et d’être au service des patients et de la communauté. Par ailleurs, il est nécessaire de développer des outils/indicateurs pour définir les interventions probantes en matière de lutte contre l’antibiorésistance. Les travaux de réflexion relatés dans cet article sont concentrés sur ces deux aspects de la recherche translationnelle : – la prévention et l’impact en santé de la problématique antibiorésistance, et – les spécificités de la recherche clinique pour innover en matière de lutte contre l’antibiorésistance. Cet article, issu des réflexions d’un groupe d’experts français, propose des solutions directement opérationnelles qui pourraient être mises en place rapidement et transformer radicalement la qualité et la quantité de nos moyens de lutte.

Refers to : Marie-Cécile Ploy, Antoine Andremont, Bruno Valtier, Claire Le Jeunne - Antibiorésistance : outils pour une recherche translationnelle efficace - Therapies, Volume 75, Issue 1, January–February 2020, Pages 1-6; National audience; The rising emergence of bacterial resistances has led to a crisis which threatens human, animal and environmental health. The impact of the emergency is enormous in terms of public health and economics. Although there is a global awareness of the warnings and programmes supporting innovative actions to combat fight against antibiotic resistance, it must be admitted that proposed new antibiotics fail to find the economic profitability necessary for them to reach the market and become available for patients and the community. Moreover, it is necessary to develop tools/indicators to define effective interventions against antibiotic resistance. The work of the think-tank reported in this article concentrated on two aspects of translational research: - prevention and the impact on health of the antibiotic resistance issue, and - the specific requirements of clinical research leading to innovation in the fight against antibiotic resistance. This article, which reflects the thoughts of a group of French experts, proposes directly operational solutions which could be rapidly implemented and radically transform the quality and quantity of our resources available for the combat.

Fluoroquinolone treatments induce dysbiosis of the intestinal microbiota, resulting in loss of resistance to colonization by exogenous bacteria such as Clostridioides difficile that may cause severe diarrhea in humans and lethal infection in hamsters. We show here that DAV131A, a charcoal-based adsorbent, decreases the intestinal levels of the fluoroquinolone antibiotics levofloxacin and ciprofloxacin in hamsters, protects their intestinal microbiota, and prevents lethal infection by C. difficile .

ObjectivesRoutine amoxicillin for children with uncomplicated severe acute malnutrition raises concerns of increasing antibiotic resistance. We performed an ancillary study nested within a double-blind, placebo-controlled trial in Niger testing the role of routine 7 day amoxicillin therapy in nutritional recovery of children 6 to 59 months of age with uncomplicated severe acute malnutrition.MethodsWe screened 472 children for rectal carriage of ESBL-producing Enterobacteriaceae (ESBL-E) as well as their household siblings under 5 years old, at baseline and Week 1 (W1) and Week 4 (W4) after start of therapy, and characterized strains by WGS. ClinicalTrials.gov: NCT01613547.ResultsCarriage in index children at baseline was similar in the amoxicillin and the placebo groups (33.8% versus 27.9%, P = 0.17). However, acquisition of ESBL-E in index children at W1 was higher in the amoxicillin group than in the placebo group (53.7% versus 32.2%, adjusted risk ratio = 2.29, P = 0.001). Among 209 index and sibling households possibly exposed to ESBL-E transmission, 16 (7.7%) had paired strains differing by ≤10 SNPs, suggesting a high probability of transmission. This was more frequent in households from the amoxicillin group than from the placebo group [11.5% (12/104) versus 3.8% (4/105), P = 0.04].ConclusionsAmong children exposed to amoxicillin, ESBL-E colonization was more frequent and the risk of transmission to siblings higher. Routine amoxicillin should be carefully balanced with the risks associated with ESBL-E colonization.

Immune checkpoint inhibitors (ICIs) have dramatically improved patient outcomes in a variety of tumor types, but with variable efficacy. Recent research has suggested that antibiotic-induced disruption of the microbiota may impact ICI efficacy. We performed a systematic review and meta-analysis of studies that assessed the impact of antibiotic use on the survival of patients diagnosed with NSCLC and treated with ICI. We systematically searched Medline, the Cochrane Library, and major oncology conferences proceedings. Eligible studies mentioned hazard ratio or Kaplan–Meier curves for progression-free survival (PFS) or overall survival (OS) based on antibiotic exposure before or during ICI treatment. We identified 23 eligible studies. The impact of antibiotics was then evaluated in 2208 patients for PFS and 5560 for OS. For both PFS and OS meta-analyses, the between-study heterogeneity was high (Higgins and Thompson I2 of 69% and 80%, respectively). The pooled hazard ratio was 1.47 (95% confidence interval [CI]: 1.13–1.90) for PFS and 1.69 (95% CI: 1.25–2.29) for OS revealing a significantly reduced survival in patients with NSCLC exposed to antibiotics. The median OS was reduced on average by 6.7 months (95% CI: 5.1–8.4) in the patients exposed to antibiotics. The effect seems to depend on the time window of exposure with stronger effects reported when the patients took antibiotics [−60 days; +60 days] around ICI initiation. In patients with NSCLC, the findings of the meta-analysis indicate that antibiotic use before or during treatment with ICI leads to a median OS decreased by more than 6 months. Specifically, exposure shortly before or after ICI initiation seems to be particularly detrimental, whereas antibiotic use later during disease course does not seem to alter survival. Because PFS and OS were difficult to compare between studies owing to heterogeneity and the multiple confounding factors identified, further studies are needed to strengthen the understanding of this phenomenon.

Background Enterobacteriaceae have become increasingly resistant, especially due to the acquisition and spread of extended-spectrum beta-lactamases (ESBLs), which confer resistance to the majority of beta-lactams. Multi-resistant Enterobacteriaceae (MRE) were first isolated in hospitals, but now they are disseminating in the community setting, mostly in low and middle income countries. Consequently, the increasing number of international travels leads to the importation of MRE from high-prevalence to low-prevalence countries. Methods The Pubmed database was used to conduct research from 1980 to 2016 by combining the following key words: travel, antibiotic resistance, ESBL, Enterobacteriaceae, genomic, metagenomic, urinary tract infection, infection. Results The research found that the MRE acquisition rates in healthy travellers from low-prevalence countries ranged from 21% to 51% depending on the study design and the visited geographic regions. After a trip to Asia and especially to South Asia, the acquisition rate could reach 85%. A trip to Africa or to the Middle East was associated with lower rates but still worrisome (13–44%). Digestive disorder, diarrhoea and antibiotics used during travel are major risks factors associated with the acquisition of MRE. Travel to endemic areas has also been identified as a risk factor for MRE infection, including urinary tract infections. Conclusion Travellers are at high risk of MRE acquisition and consequently of MRE infection. This risk should not be ignored by general practitioners. To reduce the risk of acquisition and subsequent transmission to relatives, travellers should be given recommendations prior to their travel.

Background: Acute Myeloid Leukemia (AML) and high-risk Myelodysplastic Syndrome (MDS) patients frequently receive antibiotics (ABX) for febrile neutropenia (prophylaxis or empirical treatment) or for suspected or documented bacterial infections. ABX affect the composition of the human intestinal microbiome and the resulting dysbiosis can have important consequences for patients including Clostridioides difficile infections (CDI). The reported cumulative incidence of CDI in patients with AML varies from 9 to 24% in the first 120 days following the start of induction chemotherapy and from 8 to 31% after allogeneic Hematopoietic Stem Cell Transplant (allo-HSCT). In patients undergoing allo-HSCT, acute Graft-versus-Host Disease (GvHD) and GvHD-related mortality are other important complications associated with intestinal dysbiosis, as shown in experimental studies in mice and retrospective analyses in humans. DAV132 is a microbiome protective therapy that can be administered concomitantly with oral or intravenous ABX. It has been primarily developed for adsorbing antibiotic residues in the distal ileum and colon in order to preserve the integrity of the gut microbiome, without impacting antimicrobial pharmacokinetics. Randomized clinical trials conducted to date, both in heathy volunteers and in patients, showed that DAV132 adsorbed residues of ABX in the colon and protected the intestinal microbiome from the dysbiosis induced by ABX while preserving their bioavailability. In addition, DAV132 was safely used in hospitalized patients receiving (multiple) concomitant drugs. Study Design and Methods: MICROCARE is a multicenter, randomized, placebo-controlled, parallel-arm phase 3 clinical trial. A total of 900 patients (randomized 1:1 to either DAV132 or placebo) are planned to be enrolled in approximately 80 study sites worldwide. The primary objective of this study is to evaluate the efficacy of DAV132 in preventing CDI in patients with newly diagnosed AML or high-risk MDS treated with intensive chemotherapy. In addition, the study aims to determine whether the protection of the intestinal microbiome with DAV132 can reduce the incidence of colonization with multidrug-resistant bacteria, bacteremia, and acute GvHD, and improve the long-term outcomes of transplanted patients. Randomization will be stratified by (i) site, and (ii) use of ABX within 30 days before inclusion and/or history of CDI. During the cycle of induction chemotherapy, DAV132 will be administered to patients every day until neutrophil recovery, regardless of the administration of ABX treatment. After neutrophil recovery and up to day 120, DAV132 will be administered every time an ABX treatment is given, for the length of the ABX treatment plus 2 days. The primary analysis of this study is the comparison of the time to CDI between DAV132 patients versus placebo patients up to 120 days after randomization. This will be analyzed using the cause-specific Cox proportional hazards model, whereby time to CDI is the outcome of interest, and mortality will be considered as competing event. In the primary outcome, a cause-specific Cox model will be used assuming that the impact of DAV132 on mortality is negligible; this will be confirmed in a secondary analysis. Secondary and exploratory endpoints include the rate of patients with ABX-associated diarrhea, the rate of patients with a gut colonization by resistant bacteria or a bloodstream infection, the diversity of the gut microbiome, the incidence of acute GvHD and overall survival. Two interim analyses will be performed at approximately 35 and 50 CDI events. Study status: Recruitment of patients in the study is starting in multiple countries in Europe. A first patient has been randomized in July 2021. Topics: Microbiome; CDI; GvHD; Dysbiosis; Antibiotics Disclosure: This work is supported by the IMI Joint Undertaking (JU) (grant 115523), Combatting Bacterial Resistance in Europe, with resources including financial contribution from the EU's Seventh Framework Programme and in-kind contributions from Da Volterra, a company part of the European Federation of Pharmaceutical Industries and Associations (EFPIA). Disclosures Vehreschild: 3M: Research Funding; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; Biontech: Research Funding; Da Volterra: Consultancy, Research Funding, Speakers Bureau; Evonik: Research Funding; Gilead Sciences: Consultancy, Research Funding, Speakers Bureau; Glycom: Research Funding; Immunic AG: Consultancy, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Research Funding; Merck/MSD: Consultancy, Research Funding, Speakers Bureau; Organobalance: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Seres Therapeutics: Research Funding; Takeda Pharmaceutical: Research Funding; Alb Fils Kliniken GmbH: Consultancy, Speakers Bureau; Arderypharm: Consultancy, Speakers Bureau; Basilea: Consultancy, Speakers Bureau; Bio-Mérieux: Consultancy, Speakers Bureau; Farmak International Holding GmbH: Consultancy, Honoraria, Speakers Bureau; Ferring: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; SocraTec R&D GmbH: Consultancy, Speakers Bureau. Dane: Da Volterra: Consultancy. Mentré: Da Volterra: Consultancy. Burdet: Da Volterra: Consultancy; Mylan: Consultancy. Sablier-Gallis: Da Volterra: Current Employment, Current holder of individual stocks in a privately-held company. Andremont: Da Volterra: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria. de Gunzburg: Da Volterra: Consultancy, Current holder of individual stocks in a privately-held company. Buffet: Da Volterra: Current Employment. Wilcox: Da Volterra: Consultancy, Research Funding. Cornely: Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis: Other: Grants or Contracts. Bonten: Merck/MSD: Research Funding; Janssen Vaccines: Consultancy, Speakers Bureau; OM Pharma: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding. Vitry: Da Volterra: Current Employment.

Background Antibiotics elicit intestinal dysbiosis with short and long-term deleterious effects. A colon-targeted adsorbent, DAV132, prevents dysbiosis in healthy humans and may protect antibiotic-treated patients. Methods Hospitalized patients receiving oral/iv fluoroquinolones (FQ) for the treatment of or prophylaxis of febrile neutropenia were randomized to receive DAV132 (7.5g tid orally), or not, during FQ receipt and followed up 51d. Plasma FQ levels were assessed at D4 (LC-MS/MS). Feces were collected during and up to 30d after FQ receipt for assessment of free fecal FQ levels (LC-MS/MS), gut microbiome α/β diversity (16S rRNA), resistance to colonization by C. difficile (Cd; ex-vivo proliferation). Relatedness of adverse events (AEs) to drugs was adjudicated by blinded independent experts. Results 243 patients from 23 sites, median age 71y, ≥1 chronic comorbidity 95%, received levofloxacin (43%), ciprofloxacin (40%) or moxifloxacin (18%) for (79% iv). During receipt, fecal FQ levels were lowered by >97% with DAV132 vs. No DAV132 (p< 0.0001), whilst plasma levels did not change significantly. Microbiome diversity was significantly protected with DAV132 using all metrics, e.g. the change from D1 of Shannon index at End-of-FQ (difference of means at End-of-FQ 0.42, 95% CI: 0.085; 0.752). The proportions of patients with DAV132- and/or FQ-related AEs (primary endpoint) did not differ significantly (14.8 vs. 10.8%, difference of proportions: 3.9%; 95% CI: -4.7; 12.6). No Cd infection occurred. Resistance to colonization by Cd was reduced in stools of patients receiving FQ only, but was maintained in those of patients who also received DAV132 (p=0.035). The acquisition of fecal carriage of vancomycin-resistant enterococci (VRE) was reduced with DAV132 (p=0.019). Figure 1: a. Free fluoroquinolones fecal concentration (mean ± SEM, µg/g) over time per FQ treatment group; b. Change of Shannon Index from baseline (mean ± SEM) over time Conclusion DAV132 was well tolerated in elderly hospitalized patients with comorbidities. It neither altered antibiotic plasma levels nor elicited changes in concomitant drugs regimens. Intestinal microbiota diversity was protected and resistance to colonization by Cd was preserved. DAV132 is a promising, novel product to prevent antibiotic-induced intestinal dysbiosis. Disclosures Annie Ducher, MD, Da Volterra (Employee, Shareholder) Maria J.G.T. Vehreschild, n/a, 3M (Grant/Research Support)Astellas Pharma (Grant/Research Support)Astellas Pharma (Consultant)Astellas Pharma (Speaker's Bureau)Basilea (Speaker's Bureau)Berlin Chemie (Consultant)Da Volterra (Grant/Research Support)Da Volterra (Grant/Research Support)Gilead (Grant/Research Support)Gilead (Speaker's Bureau)Merck/MSD (Speaker's Bureau)Merck/MSD (Grant/Research Support)MSD/Merck (Consultant)Organobalance (Grant/Research Support)Organobalance (Speaker's Bureau)Pfizer (Speaker's Bureau)Seres Therapeutics (Grant/Research Support) Thomas J. Louie, MD, Da Volterra (Consultant) Oliver A. Cornely, MD, Actelion (Consultant, Grant/Research Support, Speaker's Bureau)Al Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Consultant, Grant/Research Support, Speaker's Bureau)Amplyx (Consultant, Grant/Research Support, Speaker's Bureau)Astellas (Consultant, Grant/Research Support, Speaker's Bureau)Basilea (Consultant, Grant/Research Support, Speaker's Bureau)Biosys UK Limited (Consultant, Grant/Research Support, Speaker's Bureau)Cidara (Consultant, Grant/Research Support, Speaker's Bureau)Da Volterra (Consultant, Grant/Research Support, Speaker's Bureau)Entasis (Consultant, Grant/Research Support, Speaker's Bureau)European Commission (Grant/Research Support)F2G (Consultant, Grant/Research Support, Speaker's Bureau)German Federal Ministry of Research andEducation (Grant/Research Support)Gilead (Consultant, Grant/Research Support, Speaker's Bureau)Grupo Biotoscana (Consultant, Grant/Research Support, Speaker's Bureau)Janssen Pharmaceuticals (Consultant, Grant/Research Support, Speaker's Bureau)Matinas (Consultant, Grant/Research Support, Speaker's Bureau)MedicinesCompany (Consultant, Grant/Research Support, Speaker's Bureau)MedPace (Consultant, Grant/Research Support, Speaker's Bureau)Melinta Therapeutics (Consultant, Grant/Research Support, Speaker's Bureau)Menarini Ricerche (Consultant, Grant/Research Support, Speaker's Bureau)Merck/MSD (Consultant, Grant/Research Support, Speaker's Bureau)Mylan Pharmaceuticals (Consultant)Nabriva (Consultant)Noxxon (Consultant)Octapharma (Consultant, Grant/Research Support, Speaker's Bureau)Paratek Pharmaceuticals (Consultant, Grant/Research Support, Speaker's Bureau)Pfizer (Consultant, Grant/Research Support, Speaker's Bureau)PSI (Consultant, Grant/Research Support, Speaker's Bureau)Roche Diagnostics (Consultant)Scynexis (Consultant, Grant/Research Support, Speaker's Bureau)Shionogi (Consultant) Céline Féger, PhD, Da Volterra (Consultant) Aaron Dane, MSc, Da Volterra (Consultant)Spero theraputics (Consultant) Aaron Dane, MSc, Spero theraputics (Consultant) Marina Varastet, PhD, Da Volterra (Employee) Jean de Gunzburg, PhD, Da Volterra (Board Member, Consultant, Shareholder) Antoine Andremont, PhD, Bioaster (Consultant)Da Volterra (Board Member, Consultant, Shareholder) France Mentré, MD, Da Volterra (Consultant)

The aim of our study was to determine the frequency of extended-spectrum beta-lactamase (ESBL) phenotypes among the enterobacteria present in blood cultures of patients at admission to two university hospitals of Bamako (Mali). During a period of three months, we isolated enterobacteria from blood cultures from patients upon admission to the Point G and Gabriel Toure University Hospitals. The ESBL-positive enterobacteria were initially identified by API 20E strips and VITEK®2 and then confirmed in France by MALDI-TOF mass spectrometry at the Bichat Hospital bacteriology laboratory. Antibiotic susceptibility was determined by the diffusion method as recommended by EUCAST. The species isolated were K. pneumoniae (14/40, 35.0 %), E. coli (11/40, 27.5 %), and E. cloacae (9/40, 22.5 %); 21/34 (61.8 %) had an ESBL phenotype, including 10/14 (71.4 %) K. pneumoniae, 8/11 (72.7 %) E. coli, and 3/9 (33 3 %), E. cloacae. The ESBL strains of K. pneumoniae, E. coli, and E. cloacae were associated, respectively, with resistance to the following antibiotics: gentamicin (10/10, 100 %; 6/8, 75%; 2/3, 67%), amikacin (2/10, 20 %; 0/8, 0%; 0/3, 0%), ofloxacin (8/10, 80. %; 7/8, 87%; 3/3, 100%), cotrimoxazole (10/10, 100 %; 6/8, 75%; 3/3, 100%). Almost two thirds (61.8%) of the enterobacteria isolated from blood cultures produced extended-spectrum beta-lactamases. They retained regular sensitivity only to carbapenems and amikacin.

Background: Antibiotic resistance is a rapidly increasing global emergency that calls for action from all of society. Intestinal multidrugresistant (MDR) bacteria have spread worldwide with extended-spectrum beta-lactamase (ESBL) -producing Enterobacteriaceae (ESBL-PE) as the most prevalent type. The millions of travelers annually visiting regions with poor hygiene contribute substantially to this spread. Our review explores the underlying data and discusses the consequences of the colonization. Methods: PubMed was searched for relevant literature between January 2010 and August 2016. We focused on articles reporting (1) the rate of ESBL-PE acquisition in a group of travelers recruited before/after international travel, (2) fecal carriage of ESBL-PE as explored by culture and, for part of the studies, (3) analysis of factors predisposing to colonization. Results: We reviewed a total of 16 studies focusing on travel-acquired ESBL-PE. The acquisition rates reveal that 2070% of visitors to (sub)tropical regions get colonized by ESBL-PE. The main risk factors predisposing to colonization during travel are destination, travelers diarrhea, and antibiotic use. Conclusions: While most of those colonized remain asymptomatic, acquisition of ESBL-PE may have consequences both at individual and community level. We discuss current efforts to restrict the spread.

Resume A partir de la naissance, chaque etre humain etablit une symbiose avec son microbiote qui joue un role clef dans le maintien de sa sante et de son bien-etre. Cette co-existence symbiotique individuelle est le resultat d’une succession d’enrichissements de la diversite des microorganismes commensaux par des apports exterieurs. Cette diversite se trouve neanmoins menacee depuis peu par des changements drastiques dans nos habitudes de vie comme la prise en charge des naissances, l’environnement exterieur, l’alimentation et les pratiques medicales. Les deux dernieres generations ont ete le cadre de modifications importantes des modes de vies et d’alimentation, avec une augmentation de la sedentarite, une suralimentation et une exposition importante aux medicaments et aux polluants. Nous sommes maintenant en mesure d’evaluer l’impact de ces changements sur la diversite du microbiote intestinal. Parallelement a ces modifications du mode de vie, on a pu observer une explosion de l’incidence de maladies liees a un dysfonctionnement du systeme immunitaire comme les maladies metaboliques, les allergies et les maladies inflammatoires et plus etonnamment des maladies neurodegeneratives et des desordres psychiatriques. Le microbiote est devenu un sujet d’actualite dans la communaute scientifique ainsi que dans les medias grand public. Le nombre de publications scientifiques a augmente d’un facteur trois sur les cinq dernieres annees, les domaines des maladies gastro-intestinales et liees aux dysfonctionnements metaboliques etant les plus etudies. D’un point de vue de la propriete intellectuelle, les familles de brevets traitant du microbiote ont plus que double sur la meme periode. En parallele, les financements provenant soit des organisations etatiques (par exemple du National Institute of Health [NIH] qui finance les recherches essentiellement dans le domaine des allergies, des anti-infectieux, du cancer et des maladies cardio-vasculaires, ou de la Maison Blanche qui a lance l’initiative nationale sur le microbiome) soit des entreprises pharmaceutiques ont suivi la meme tendance et refletent une poussee des investissements et un soutien important de ce domaine de la recherche sur le microbiote. Tous les acteurs majeurs de la sante investissent actuellement dans la recherche sur le microbiome ce qui se traduit par le grand nombre de contrats et de financements signes en 2015. La table ronde des Ateliers de Giens s’est interessee a envisager comment la medecine de demain, en considerant l’homme comme un supra-organisme symbiotique homme–microbes, pourra beneficier du savoir acquis sur les fonctions du microbiote et sur le microbiome en tant qu’outil therapeutique. La reflexion de notre groupe de travail a ete structuree autour de quatre domaines d’innovation qui pourraient beneficier des efforts realises actuellement afin de dechiffrer les interactions entre cellules humaines et le microbiome intestinal, en tant qu’element central de la sante humaine, c’est-a-dire : 1) le developpement d’outils de stratification et de monitorage ; 2) l’identification de cibles originales et de nouvelles drogues a partir du microbiome en tant que partie de notre supra-genome ; 3) l’exploitation du microbiote en tant que cible therapeutique qui peut etre modulable ; et enfin, 4) comme source de biotherapeutiques vivants ou d’adjuvants. Ces quatre chapitres vont permettre de montrer comment le microbiote a modifie notre facon de considerer un grand nombre de maladies chroniques et incurables comme les consequences d’une dysbiose etablie et durable. L’analyse en profondeur du microbiote est le point de depart d’un des plus vastes chantiers de recherches qui permettra l’amelioration de la sante humaine et animale et qui deviendra la source d’innovations medicales pour couvrir les gaps therapeutiques d’aujourd’hui. Nous proposons donc une serie de recommandations que nous adressons aux chercheurs academiques, aux cliniciens ainsi qu’aux autorites de sante, afin que les analyses du microbiote gagnent en fiabilite et solidite. Ceci permettra d’accelerer le processus de decouvertes et ainsi que leurs applications afin que tous puissent en beneficier.

Background Clostridioides difficile infection (CDI) remains a high burden worldwide. DAV131A, a novel adsorbent, reduces residual gut antimicrobial levels, reducing CDI risk in animal models. Objectives We used a validated human gut model to investigate the efficacy of DAV131A in preventing moxifloxacin-induced CDI. Methods C. difficile (CD) spores were inoculated into two models populated with pooled human faeces. Moxifloxacin was instilled (43 mg/L, once daily, 7 days) alongside DAV131A (5 g in 18 mL PBS, three times daily, 14 days, Model A), or PBS (18 mL, three times daily, 14 days, Model B). Selected gut microbiota populations, CD total counts, spore counts, cytotoxin titre and antimicrobial concentrations (HPLC) were monitored daily. We monitored for reduced susceptibility of CD to moxifloxacin. Growth of CD in faecal filtrate and medium in the presence/absence of DAV131A, or in medium pre-treated with DAV131A, was also investigated. Results DAV131A instillation reduced active moxifloxacin levels to below the limit of detection (50 ng/mL), and prevented microbiota disruption, excepting Bacteroides fragilis group populations, which declined by ∼3 log10 cfu/mL. DAV131A delayed onset of simulated CDI by ∼2 weeks, but did not prevent CD germination and toxin production. DAV131A prevented emergence of reduced susceptibility of CD to moxifloxacin. In batch culture, DAV131A had minor effects on CD vegetative growth, but significantly reduced toxin/spores (P Conclusions DAV131A reduced moxifloxacin-induced microbiota disruption and emergence of antibiotic-resistant CD. Delayed onset of CD germination and toxin production indicates further investigations are warranted to understand the clinical benefits of DAV131A in CDI prevention.

Although the global deleterious impact of antibiotics on the intestinal microbiota is well known, temporal changes in microbial diversity during and after an antibiotic treatment are still poorly characterized. We used plasma and fecal samples collected frequently during treatment and up to one month after from 22 healthy volunteers assigned to a 5-day treatment by moxifloxacin (n = 14) or no intervention (n = 8). Moxifloxacin concentrations were measured in both plasma and feces, and bacterial diversity was determined in feces by 16S rRNA gene profiling and quantified using the Shannon index and number of operational taxonomic units (OTUs). Nonlinear mixed effect models were used to relate drug pharmacokinetics and bacterial diversity over time. Moxifloxacin reduced bacterial diversity in a concentration-dependent manner, with a median maximal loss of 27.5% of the Shannon index (minimum [min], 17.5; maximum [max], 27.7) and 47.4% of the number of OTUs (min, 30.4; max, 48.3). As a consequence of both the long fecal half-life of moxifloxacin and the susceptibility of the gut microbiota to moxifloxacin, bacterial diversity indices did not return to their pretreatment levels until days 16 and 21, respectively. Finally, the model characterized the effect of moxifloxacin on bacterial diversity biomarkers and provides a novel framework for analyzing antibiotic effects on the intestinal microbiome.

International audience; Quantitative data on fecal shedding of antimicrobial-resistant bacteria are crucial to assess the risk of ansmission from dogs to humans. Our first objective was to investigate the prevalence of quinolone/fluoroquinolone-resistant and beta-lactam-resistant Enterobacteriaceae in dogs in France and Spain. Due to the particular concern about possible transmission of extended-spectrum cephalosporin (ESC)-resistant isolates from dogs to their owners, we characterized the ESBL/pAmpC producers collected from dogs. Rectal swabs from 188 dogs, without signs of diarrhea and that had not received antimicrobials for 4 weeks before the study, were quantified for total and resistant Enterobacteriaceae on selective media alone or containing relevant antibiotic concentrations. Information that might explain antibiotic resistance was collected for each dog. Extended-spectrum cephalosporin-resistant isolates were subjected to bacterial species identification (API20E), genetic lineage characterization (MLST), ESBL/pAmpC genes identification (sequencing), and plasmid characterization (pMLST). Regarding beta-lactam resistance, amoxicillin- (AMX) and cefotaxime- (CTX) resistant Enterobacteriaceae were detected in 70 and 18% of the dogs, respectively, whereas for quinolone/fluoroquinolone-resistance, Nalidixic acid- (NAL) and ciprofloxacin- (CIP) resistant Enterobacteriaceae were detected in 36 and 18% of the dogs, respectively. Medical rather than preventive consultation was a risk marker for the presence of NAL and CIP resistance. CTX resistance was mainly due to a combination of specific ESBL/pAmpC genes and particular conjugative plasmids already identified in human patients: bla(CTX-M-1)/IncI1/ST3 (n = 4), bla(CMY-2)/IncI1/ST12 (n = 2), and bla(CTX-M-15)/IncI1/ST31 (n = 1). bla(SHV-12) ( n = 3) was detected in various plasmid lineages (InI1/ST3, IncI1/ST26, and IncFII). ESBL/pAmpC plasmids were located in different genetic lineages of E coil, with the exception of two strains in France (ST6998) and two in Spain (ST602). Our study highlights dogs as a potential source of Q/FQ-resistant and ESBL/pAmpC-producing bacteria that might further disseminate to humans, and notably a serious risk of future acquisition of CTX-M-1 and CMY-2 plasmids by the owners of dogs.

The emergence of antimicrobial resistant infections from food is well documented in the scientific literature but, in this kind of matter, the public opinion is an important policy driver and is vastly forged by traditional media. Here, we propose a text mining study through about 500 articles from two reference daily U.S. newspapers to assess the media coverage of this issue. Our results indicate that, since the middle of the 80s, the two journals considered here adopted a very different narrative around the issue, echoing civil society concerns in one case and the official discourse in the other.