Acquisition of Enterobacterales carrying the colistin resistance gene mcr following travel to the tropics.

BACKGROUND: 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. METHODS: A total of 574 frozen stool samples of travellers returning from tropical regions were 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. RESULTS: 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%). Escherichia 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 genes. CONCLUSIONS: 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.

Unraveling the Diversity of Co-Colonization by CPE.

Antibiotic-resistant bacteria, and more specifically, carbapenem-producing Enterobacterales (CPE) strains, are increasing worldwide. Despite their growing prevalence, in most high-income countries, the detection of CPE is still considered a low-frequency event. Sporadically, patients co-colonized with distinct CPE strains and/or different carbapenemase enzymes are detected. In this paper, we present three cases that illustrate the underlying mechanisms of co-colonization, focusing on horizontal gene transfer (HGT) and patient-to-patient transmission. We also demonstrate the diversity of CPE species and discuss the potential consequences of co-colonization.

An open randomized multicentre Phase 2 trial to assess the safety of DAV132 and its efficacy to protect gut microbiota diversity in hospitalized patients treated with fluoroquinolones.

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.

A nationwide population-based study of Escherichia coli bloodstream infections: incidence, antimicrobial resistance and mortality.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. DISCUSSION: E. coli BSI carries a high burden, with a large proportion of MDR isolates, which are associated with increased incidence and CFR.

Dynamics of extended-spectrum beta-lactamase-producing Enterobacterales colonization in long-term carriers following travel abroad.

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.

AMR in low-resource settings: Médecins Sans Frontières bridges surveillance gaps by developing a turnkey solution, the Mini-Lab.

BACKGROUND: In low- and middle-income countries (LMICs), data related to antimicrobial resistance (AMR) are often inconsistently collected. Humanitarian, private and non-governmental medical organizations (NGOs), working with or in parallel to public medical systems, are sometimes present in these contexts. Yet, what is the role of NGOs in the fight against AMR, and how can they contribute to AMR data collection in contexts where reporting is scarce? How can context-adapted, high-quality clinical bacteriology be implemented in remote, challenging and underserved areas of the world? OBJECTIVES: The aim was to provide an overview of AMR data collection challenges in LMICs and describe one initiative, the Mini-Lab project developed by Médecins Sans Frontières (MSF), that attempts to partially address them. SOURCES: We conducted a literature review using PubMed and Google scholar databases to identify peer-reviewed research and grey literature from publicly available reports and websites. CONTENT: We address the necessity of and difficulties related to obtaining AMR data in LMICs, as well as the role that actors outside of public medical systems can play in the collection of this information. We then describe how the Mini-Lab can provide simplified bacteriological diagnosis and AMR surveillance in challenging settings. IMPLICATIONS: NGOs are responsible for a large amount of healthcare provision in some very low-resourced contexts. As a result, they also have a role in AMR control, including bacteriological diagnosis and the collection of AMR-related data. Actors outside the public medical system can actively contribute to implementing and adapting clinical bacteriology in LMICs and can help improve AMR surveillance and data collection.

Spare and repair the gut microbiota from antibiotic-induced dysbiosis: state-of-the-art.

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.

Prevalence, Risk Factors, and Genetic Characterization of Extended-Spectrum Beta-Lactamase Escherichia coli Isolated From Healthy Pregnant Women in Madagascar.

Antimicrobial resistance is a major public health concern worldwide affecting humans, animals and the environment. However, data is lacking especially in developing countries. Thus, the World Health Organization developed a One-Health surveillance project called Tricycle focusing on the prevalence of ESBL-producing Escherichia coli in humans, animals, and the environment. Here we present the first results of the human community component of Tricycle in Madagascar. From July 2018 to April 2019, rectal swabs from 492 pregnant women from Antananarivo, Mahajanga, Ambatondrazaka, and Toamasina were tested for ESBL-E. coli carriage. Demographic, sociological and environmental risk factors were investigated, and E. coli isolates were characterized (antibiotic susceptibility, resistance and virulence genes, plasmids, and genomic diversity). ESBL-E. coli prevalence carriage in pregnant women was 34% varying from 12% (Toamasina) to 65% (Ambatondrazaka). The main risk factor associated with ESBL-E. coli carriage was the rainy season (OR = 2.9, 95% CI 1.3-5.6, p = 0.009). Whole genome sequencing was performed on 168 isolates from 144 participants. bla CTX-M-15 was the most frequent ESBL gene (86%). One isolate was resistant to carbapenems and carried the bla NDM-5 gene. Most isolates belonged to commensalism associated phylogenetic groups A, B1, and C (90%) and marginally to extra-intestinal virulence associated phylogenetic groups B2, D and F (10%). Multi locus sequence typing showed 67 different sequence types gathered in 17 clonal complexes (STc), the most frequent being STc10/phylogroup A (35%), followed distantly by the emerging STc155/phylogroup B1 (7%), STc38/phylogroup D (4%) and STc131/phylogroup B2 (3%). While a wide diversity of clones has been observed, SNP analysis revealed several genetically close isolates (n = 34/168) which suggests human-to-human transmissions. IncY plasmids were found with an unusual prevalence (23%), all carrying a bla CTX-M-15. Most of them (85%) showed substantial homology (≥85%) suggesting a dissemination of IncY ESBL plasmids in Madagascar. This large-scale study reveals a high prevalence of ESBL-E. coli among pregnant women in four cities in Madagascar associated with warmth and rainfall. It shows the great diversity of E. coli disseminating throughout the country but also transmission of specific clones and spread of plasmids. This highlights the urgent need of public-health interventions to control antibiotic resistance in the country.

Modeling the Effect of DAV132, a Novel Colon-Targeted Adsorbent, on Fecal Concentrations of Moxifloxacin and Gut Microbiota Diversity in Healthy Volunteers.

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.

Optimization of an Assay To Determine Colonization Resistance to Clostridioides difficile in Fecal Samples from Healthy Subjects and Those Treated with Antibiotics.

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.

Evaluation of inpatients Clostridium difficile prevalence and risk factors in Cameroon.

BACKGROUND: Clostridium difficile, rarely found in hospitals, is a bacterium responsible for post-antibiotic diarrhea and Pseudomembranous Colitis (CPM). C. difficile selective pressure represents potential public health problem due to the production of toxins A and B serious pathologies effects/consequences. A transversal and analytic study was to assess the risk factors of C. difficile infection and to determine the prevalence of C. difficile in patients received in randomly selected five hospitals in Yaoundé, Cameroon. METHODS: A total of 300 stool samples were collected from consented patients using a transversal and analytic study conducted from 10th July to 10th November 2018 in five hospitals in Cameroon. The detection or diagnostic kit was CerTest C. difficile Glutamate Dehydrogenase + Toxin A + Toxin B based on immuno-chromatographic assay. A univariate and multivariate analysis allowed us to highlight the associated factors. RESULTS: The results showed a prevalence of C. difficile of 27.33% (82/300 stool patients'samples taken). Of these 27.33%, the production of Toxin A and Toxin B were 37.80 and 7.31% respectively. In univariate analysis, hospitalization was a significant (P = 0.01) risk factor favoring C. difficile infection. In multivariate analysis, corticosteroids and quinolones use/administration were significantly (adjusted Odd Ratio, aOR = 14.09, 95% CI: 1.62-122.54, P = 0.02 and aOR = 3.39, 95% CI: 1.00-11.34, P = 0.05 respectively) risk factor for this infection. CONCLUSION: The prevalence of C. difficile infections (CDI) remain high in these settings and may be related not only to permanent steroids and antibiotics. Promoting education to both medical staff and patients on the prevalence and public health impact of C. difficile can be core inimproving rationale prescription of steroids and antibiotics to patients and promote human health and exponential growth in Cameroon.

NSCLC Immunotherapy Efficacy and Antibiotic Use: A Systematic Review and Meta-Analysis.

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.

Antibiotic resistance: Tools for effective translational research.

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.

Increased risk of acquisition and transmission of ESBL-producing Enterobacteriaceae in malnourished children exposed to amoxicillin.

OBJECTIVES: Routine 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. METHODS: We 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. RESULTS: Carriage 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]. CONCLUSIONS: Among 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.

DAV131A Protects Hamsters from Lethal Clostridioides difficile Infection Induced by Fluoroquinolones.

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.

Prevalence of Beta-Lactam and Quinolone/Fluoroquinolone Resistance in Enterobacteriaceae From Dogs in France and Spain-Characterization of ESBL/pAmpC Isolates, Genes, and Conjugative Plasmids.

Quantitative data on fecal shedding of antimicrobial-resistant bacteria are crucial to assess the risk of transmission 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. coli, 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.

Impact of Antibiotic Gut Exposure on the Temporal Changes in Microbiome Diversity.

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.

Ceftriaxone and Cefotaxime Have Similar Effects on the Intestinal Microbiota in Human Volunteers Treated by Standard-Dose Regimens.

Ceftriaxone has a higher biliary elimination than cefotaxime (40% versus 10%), which may result in a more pronounced impact on the intestinal microbiota. We performed a monocenter, randomized open-label clinical trial in 22 healthy volunteers treated by intravenous ceftriaxone (1 g/24 h) or cefotaxime (1 g/8 h) for 3 days. We collected fecal samples for phenotypic analyses, 16S rRNA gene profiling, and measurement of the antibiotic concentration and compared the groups for the evolution of microbial counts and indices of bacterial diversity over time. Plasma samples were drawn at day 3 for pharmacokinetic analysis. The emergence of 3rd-generation-cephalosporin-resistant Gram-negative enteric bacilli (Enterobacterales), Enterococcus spp., or noncommensal microorganisms was not significantly different between the groups. Both antibiotics reduced the counts of total Gram-negative enteric bacilli and decreased the bacterial diversity, but the differences between the groups were not significant. All but one volunteer from each group exhibited undetectable levels of antibiotic in feces. Plasma pharmacokinetic endpoints were not correlated to alteration of the bacterial diversity of the gut. Both antibiotics markedly impacted the intestinal microbiota, but no significant differences were detected when standard clinical doses were administered for 3 days. This might be related to the similar daily amounts of antibiotics excreted through the bile using a clinical regimen. (This study has been registered at ClinicalTrials.gov under identifier NCT02659033.).