Widespread antibiotic use in clinical medicine and the livestock industry has contributed to the global spread of multidrug-resistant (MDR) bacterial pathogens, including Acinetobacter baumannii We report on a method used to produce a personalized bacteriophage-based therapeutic treatment for a 68-year-old diabetic patient with necrotizing pancreatitis complicated by an MDR A. baumannii infection. Despite multiple antibiotic courses and efforts at percutaneous drainage of a pancreatic pseudocyst, the patient deteriorated over a 4-month period. In the absence of effective antibiotics, two laboratories identified nine different bacteriophages with lytic activity for an A. baumannii isolate from the patient. Administration of these bacteriophages intravenously and percutaneously into the abscess cavities was associated with reversal of the patient's downward clinical trajectory, clearance of the A. baumannii infection, and a return to health. The outcome of this case suggests that the methods described here for the production of bacteriophage therapeutics could be applied to similar cases and that more concerted efforts to investigate the use of therapeutic bacteriophages for MDR bacterial infections are warranted.

Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection

Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria.

The practice of phage therapy, which uses bacterial viruses (phages) to treat bacterial infections, has been around for almost a century. The universal decline in the effectiveness of antibiotics has generated renewed interest in revisiting this practice. Conventionally, phage therapy relies on the use of naturally-occurring phages to infect and lyse bacteria at the site of infection. Biotechnological advances have further expanded the repertoire of potential phage therapeutics to include novel strategies using bioengineered phages and purified phage lytic proteins. Current research on the use of phages and their lytic proteins, specifically against multidrug-resistant bacterial infections, suggests phage therapy has the potential to be used as either an alternative or a supplement to antibiotic treatments. Antibacterial therapies, whether phage- or antibiotic-based, each have relative advantages and disadvantages; accordingly, many considerations must be taken into account when designing novel therapeutic approaches for preventing and treating bacterial infections. Although much is still unknown about the interactions between phage, bacteria, and human host, the time to take phage therapy seriously seems to be rapidly approaching.

Phage therapy: An alternative to antibiotics in the age of multi-drug resistance.

Antimicrobial resistance represents an enormous global health crisis and one of the most serious threats humans face today. Some bacterial strains have acquired resistance to nearly all antibiotics. Therefore, new antibacterial agents are crucially needed to overcome resistant bacteria. In 2017, the World Health Organization (WHO) has published a list of antibiotic-resistant priority pathogens, pathogens which present a great threat to humans and to which new antibiotics are urgently needed the list is categorized according to the urgency of need for new antibiotics as critical, high, and medium priority, in order to guide and promote research and development of new antibiotics. The majority of the WHO list is Gram-negative bacterial pathogens. Due to their distinctive structure, Gram-negative bacteria are more resistant than Gram-positive bacteria, and cause significant morbidity and mortality worldwide. Several strategies have been reported to fight and control resistant Gram-negative bacteria, like the development of antimicrobial auxiliary agents, structural modification of existing antibiotics, and research into and the study of chemical structures with new mechanisms of action and novel targets that resistant bacteria are sensitive to. Research efforts have been made to meet the urgent need for new treatments; some have succeeded to yield activity against resistant Gram-negative bacteria by deactivating the mechanism of resistance, like the action of the β-lactamase Inhibitor antibiotic adjuvants. Another promising trend was by referring to nature to develop naturally derived agents with antibacterial activity on novel targets, agents such as bacteriophages, DCAP(2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2(hydroxymethyl)propane1,3-diol, Odilorhabdins (ODLs), peptidic benzimidazoles, quorum sensing (QS) inhibitors, and metal-based antibacterial agents.

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Resistance of Gram-Negative Bacteria to Current Antibacterial Agents and Approaches to Resolve It

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality1–3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin—a two-subunit exotoxin that is secreted by Enterococcus faecalis5,6—as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis. In patients with alcoholic hepatitis, cytolysin-positive Enterococcus faecalis strains are correlated with liver disease severity and increased mortality, and in mouse models these strains can be specifically targeted by bacteriophages.

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Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease

Oral Phage Therapy of Acute Bacterial Diarrhea With Two Coliphage Preparations: A Randomized Trial in Children From Bangladesh

Panel performance for Temporal Dominance of Sensations

The invention concerns Lactobacillus reuteri for use in the prevention or treatment of microbiota dysbiosis, in particular, decreased levels of Actinobacteria and increased levels of Proteobacteria, in young mammals and in the prevention or treatment of disorders associated therewith. The microbiota dysbiosis may have been cause by numerous factors including being born by caesarean section, exposure to antibiotics in utero or after birth, or, parenteral feeding, hospitalizing, psychological stress or by gastrointestinal dysfunctions. The disorders that may be treated or prevented by preventing or treating microbiota dysbiosis include propensity to infection, allergy, type I diabetes mellitus, insulin resistance, type 2 diabetes, celiac disease, peripheral and central adiposity, obesity, necrotizing enterocolitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, and functional gastrointestinal disorders such as IBS, functional diarrhea, functional constipation, recurrent abdominal pain, and dyspepsia.

Use of l. reuteri for recovery of microbiota dysbiosis in early life

FIELD: medicine; pharmaceuticals.SUBSTANCE: invention refers to preventing or treating microbiota dysbiosis in a child. Disclosed is the use of Lactobacillus reuteri for the prevention or treatment of microbiota dysbiosis in a child aged to about three years, who is at risk or suffers dysbiosis of microbiota, where introduction of L. reuteri increases concentration of actinobacteria or maintains levels of actinobacteria and/or reduces levels of proteobacteria or maintains levels of proteobacteria, so that the levels of actinobacteria and/or proteobacteria are not significantly different from those observed in children not dysbiosis microbiota, where the child is born or will be born by Cesarean section, exposed or exposed to antibiotics during intrauterine development or after birth or received or receives parenteral nutrition, where Lactobacillus reuteri is Lactobacillus reuteri DSM 17938 and where Lactobacillus reuteri is administered to an infant or infant beginning to walk in a daily dose of 1 x 10to 1 x 10or a pregnant or nursing mother or infant in form of composition containing 1 x 10to 1 x 10 CFU/g of a dry composition.EFFECT: invention provides complete microbiota recovery specific for an infant.11 cl, 3 dwg, 2 tbl, 2 ex

Using lactobacillus reuteri for recovering microbiota after dysbiosis at early stages of development

L'invention concerne Lactobacillus reuteri pour une utilisation dans la prevention ou le traitement de dysbioses microbiote, en particulier, des niveaux reduits de Actinobacteria et des niveaux accrus de Proteobacteries, chez de jeunes mammiferes et dans la prevention ou le traitement de troubles associes a celui-ci. La dysbiose du microbiote peut avoir ete causee par de nombreux facteurs comprenant un accouchement par cesarienne, une exposition a des antibiotiques in utero ou apres la naissance ou, une alimentation parenterale, une hospitalisation, un stress psychologique ou par des dysfonctionnements gastro-intestinaux. Les troubles qui peuvent etre traites ou prevenus par la prevention ou le traitement de dysbiose du microbiote comprennent la propension a une infection, une allergie, le diabete sucre de type I, d'insulinoresistance, le diabete de type 2, une maladie cœliaque, l'adiposite peripherique et central, l'obesite, l'enterocolite necrosante neonatale, une maladie inflammatoire intestinale, telle que la maladie de Crohn et la colite ulcereuse, et des troubles gastro-intestinaux fonctionnels tels que le Syndrome du colon Irritable, la constipation fonctionnelle, la diarrhee fonctionnelle, une douleur abdominale recurrente et la dyspepsie.

Tara Neville

Papers

Oral Phage Therapy of Acute Bacterial Diarrhea With Two Coliphage Preparations: A Randomized Trial in Children From Bangladesh

Panel performance for Temporal Dominance of Sensations

Use of l. reuteri for recovery of microbiota dysbiosis in early life

Using lactobacillus reuteri for recovering microbiota after dysbiosis at early stages of development

Utilisation de l. reuteri pour la récupération d'une dysbiose du microbiote dans la phase précoce