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Les entérocoques, sont des bactéries commensales du tube digestif de l’homme et des animaux, mais certaines espèces, comme Enterococcus faecium, sont aussi des pathogènes opportunistes majeurs souvent multi-résistants aux antibiotiques. Nous avons étudié l’impact de molécules non antibiotiques utilisées dans les unités de soins intensifs, sur la virulence et la résistance d’une souche clinique de E. faecium par une approche microscopique, une analyse du peptidoglycane et une analyse trancriptomique. Ce travail nous a permis de décrire l’effet antibactérien de la caspofungine, molécule antifongique. Nous avons également étudié deux nouveaux mécanismes de résistance chez E. faecium i) la résistance aux lincosamides, streptogramines A et pleuromutilines (phénotype LSAP) par la mutation ponctuelle d’un gène codant pour une protéine ABC de type II. ii) la diminution de sensibilité à la tigécycline due à l’apparition de mutations au sein du gène rpsJ codant pour la protéine ribosomale S10 jouant un rôle dans la formation de la sous-unité 30S du ribosome. Enfin, nous avons participé à une étude sur Enterococcus hirae, espèce qui induirait la production de sous-populations de lymphocytes T permettant d’augmenter l’efficacité in vivo du cyclophosphamide (CTX) dans le traitement de tumeurs chez la souris. Une caractérisation des facteurs de virulence, de la résistance aux antibiotiques et du pouvoir de colonisation d’une collection de souches d’E. hirae a été menée, de même qu’une étude transcriptomique en présence de CTX et une étude de génomique comparative, afin de caractériser cette espèce dans l’optique de son utilisation comme oncobiotique. / Enterococci are commensal bacteria of the human and animal gastrointestinal tract, but some species as Enterococcus faecium, are also major opportunistic pathogens often multiply resistant to antibiotics. We studied the impact of non-antibiotic molecules widely used in intensive care units on fitness, virulence and resistance of a clinical isolate of E. faecium belonging to CC17 by a microscopic approach, a peptidoglycan analysis and a trancriptomic analysis. This work allowed us to demonstratethe antimicrobial effect of caspofungin, molecule known for its antifungal activity. We also characterized two novel resistance mechanisms found in E. faecium: i) resistance to lincosamides, streptogramines A and pleuromutilins (LSAP phenotype) linked to a point mutation in a gene encoding for a type-II ABC protein. ii) decreased susceptibility to tigecycline due to the occurrence of mutations within the rpsJ gene encoding the S10 ribosomal protein that plays a role in 30S ribosomal subunit formation. Finally, we participated to a study concerning Enterococcus hirae, species that induces the production of sub-populations of T lymphocytes that increase the in vivo efficacy of cyclophosphamide (CTX) in the treatment of murine tumors. A characterization of the virulence factors, antibiotic resistance profiles and colonization capacities of a collection of E. hirae isolates was carried out. A transcriptomic study in the presence of CTX and a comparative genomic study were also done, in order to characterize this species in view of its use as an oncobiotic.

Mycobacterium tuberculosis (Mtb) remains a global challenge that has been worsened by the emergence of drug resistant strains of Mtb. We used publicly available Next Generation Sequencing (NGS) and drug susceptibility (DST) data to develop “Resistance sniffer”, an online software program for the rapid prediction of lineage and Mtb drug resistance. Based on the distribution of polymorphisms in the genomes of Mtb, we calculated the power of association between the polymorphisms in different clades of Mtb and resistance to 13 anti-TB drugs. Our data suggests that the development of drug resistance in Mtb is a stepwise process that involves the accumulation of polymorphisms in the Mtb genome. We carefully curated the polymorphisms based on their association powers to create a diagnostic key that captures patterns of these polymorphisms that can be used to predict lineage and drug resistance in Mtb. This diagnosis key was incorporated into the Resistance Sniffer tool, an online software program that we developed for the rapid diagnosis of drug resistance in Mtb. The tool was tested using sequence data from the South Africa Medical Research Council (SA-MRC). Our data suggests that the majority of the strains in SA may have been brought by the arrival of European settlers while the more resistant strains may have been introduced in the region by Asian travellers later on. We next sought to determine non-random associations between polymorphic sites in genomes of Mtb. Using the attributable risk (Ra) statistical methods, we distinguished between functional associations and associations that may have been due to genetic drift events for different Mtb clades. We then integrated the (Ra) data with drug susceptibility and annotation data to generate networks in Cytoscape 3.71. These networks were then used to infer evolutionary trajectories that drive the emergence and fixation of the drug resistant phenotype in different clades of Mtb. We demonstrate that strains from the Lineage 1.2 are associated with less complex functional associations compared to the strains from other clades such as the Asian and Euro-American clades. Our data also shows that the predisposition of strains from the Asian clades to develop multi-drug resistance may be attributed to a complex network of functional interactions of mutations in genes that are involved in several aspects of Mtb physiology such as cell wall modelling, lipid metabolism, stress response and DNA repair. / Dissertation (MSc)--University of Pretoria, 2019. / Biochemistry / MSc / Unrestricted

Best Practices: Antibiotic Stewardship and the Implementation of Evidence-Based Guidelines During Upper Respiratory Infections Among Rural, Primary Care Patients Sandra Kay Johnson, Doctor of Nursing Practice Candidate East Tennessee State University College of Nursing Abstract Antimicrobial resistance is a challenging clinical issue seen in the treatment of upper respiratory infections (URIs). Purpose/Aims: The purpose of this project is to implement an antibiotic stewardship (AS) program using antibiotic prescribing guidelines for URIs and clinic-wide patient education. The aim was to reduce antibiotic overuse. Processes: This quality improvement (QI) project was conducted at a rural clinic. Participants included the nurse practitioners and office staff. The target population included adult patients, ages 18 and up, who presented with upper respiratory symptoms. URI prescribing guidelines were used to compare antibiotic prescribing practices pre- and post-intervention. The initiative includes a provider education session and educational videos, posters, and scientific literature, which is available to those assessing the clinic. Educational materials were from the Centers for Disease Control and Prevention, the United States Department of Health and Human Services, and the National Center for Emerging Zoonotic Infectious Diseases. The Knowledge-to-Action framework was used to translate research into practice and data was collected through the administration of questionnaires and the review of EMRs. Results: Preliminary results suggest patient preferences, outside of guidelines, may influence prescribing behaviors. Limitations: The sample of providers was small and may not be characteristic of a larger group. Conclusions: This QI initiative was driven by the need to improve practice and educate patients regarding AS during upper respiratory-related illnesses. Preliminary evidence shows interventions such as patient education, implementation of guidelines, and identification of barriers and facilitators are all vital components of AS.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / We analyzed the association between antibiotic resistance and recurrent urinary tract infection (rUTI) by Escherichia coli. Susceptibility levels to 14 antimicrobial agents and the presence of extended-spectrum β-lactamases (ESBL) were established using MicroScan. Incidences of multidrug resistant (MDR), extensively drug resistant (XDR), and ESBL-producer isolates as well as rUTIs were estimated. The time to recurrence was established adjusted for number of antibiotic-resistant families and MDR as predictors of interest, respectively. Overall, 8,553 urinary tract infection (UTI) cases related to E. coli, including 963 rITU, were analyzed with levels of resistance >30% in all cases, except for amikacin, nitrofurantoin, and carbapenems. The incidence of rUTI was of 11.3%, being 46.5%, 24.3%, and 42.5% for MDR, XDR, and ESBLs, respectively. Bivariate analysis showed that rUTI was associated with age, gender, resistance to specific antimicrobials, MDR, and XDR. The number of antibiotic families tested as resistant, MDR, XDR, gender, and age were associated with time to recurrence when adjusted for number of antibiotic families, and MDR, gender, and age were related when adjusted for MDR. High rates of antibiotic resistance to the usual antibiotics was observed in E. coli causing UTI, with female sex, age, and antibiotic resistance being risk factors for the development of rUTI. / Fondo Nacional de Desarrollo Científico, Tecnológico y de Innovación Tecnológica / Revisión por pares

Due to the increasing prevalence of multi-drug resistant (MDR) bacteria, it is now important to begin the search for novel means of defending against such resistant infections. Enterobacteriaceae is a clinically relevant family of bacteria that has shown extensive resistance to many antibiotics, especially after biofilm formation. Inhibitory poly-microbial interactions within this family have been observed. It is known that Citrobacter freundii (CF) growth is significantly inhibited by Klebsiella pneumoniae (KP) through a secreted protein. In this study, the potential KP bacteriocin was screened for its inhibitory effects on CF at various phases of biofilm development. The suspected KP bacteriocin was also tested for its ability to decrease the dosage of antibiotics necessary to inhibit CF growth. Using spectrophotometric analysis, it was shown that the combined treatment of streptomycin and the KP protein allowed a decrease in the minimum inhibitory concentration of streptomycin needed from 50 μM to 32 μM. The combined treatment also yielded increased inhibition at the initial attachment phase of CF infection, as well as after biofilm development. The study uses the secreted KP protein to show the use of poly-microbial interactions within clinical applications. Future projects concerning this KP molecule can pursue the use of a C. elegans model to determine its efficacy in vitro.

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