Safety and Tolerability of Bacteriophage Therapy in Severe Staphylococcus aureus Infection, bioRxiv, 2019-04-27

AbstractImportanceThe effect of IV administration of a bacteriophage cocktail produced under GMP conditions on patients with severe S. aureus infection, including complicated bacteraemia, endocarditis and septic shock, is unknown.ObjectiveTo assess safety and tolerability of adjunctive bacteriophage therapy in patients with severe S. aureus infections.Design, Setting, ParticipantsObservational, open-label clinical trial of thirteen critically-ill patients admitted to a tertiary-referral hospital with S. aureus bacteraemia (including infective endocarditis, n=6) were assessed by the treating clinician and two consulting infectious diseases physicians to independently verify that routine medical and surgical therapy was optimal and that a poor outcome remained likely. Compassionate access to therapy was approved by both US and Australian regulators and by the Westmead Hospital Human Research Ethics Committee.InterventionA GMP-quality preparation of three combined Myoviridae bacteriophages with specific activity against S. aureus (AB-SA01), was administered intravenously in conjunction with optimal antibiotic therapy.Main Outcome and MeasurementsPhysiological, haematological and biochemical markers of infection, bacterial and bacteriophage kinetics in blood, development of resistance to bacteriophages, and mortality at 28 (D28) and 90 (D90) days were measured. Main outcomes were safety and tolerability.ResultsBacteriophage therapy was initiated 4-10 days after antibiotic commencement, at 109 plaque-forming units (PFU) twice daily. Infecting staphylococci were typical of common local subtypes. Initial input ratio of phages to bacteria in the bloodstream (MOIinput) was &gt;100. Five of the thirteen patients died by D28 and a sixth patient suffered sudden cardiac death on D90. Bacteriophage therapy coincided with a marked reduction in staphylococcal bacterial DNA in the blood and in sepsis-associated inflammatory responses in almost all cases. No bacteriophage-attributable adverse events were identified. Development of bacteriophage resistance was not observed. Population analysis revealed no significant effect of bacteriophage therapy on the gut microflora.Conclusions and RelevanceAdjunctive bacteriophage therapy appears to be safe and well-tolerated in critically ill patients with severe S. aureus infection. Two weeks of twice daily intravenous administration may be a suitable protocol. Controlled trials are needed.Trial RegistrationWestmead Hospital Human Research Ethics Committee approval July 11, 2017; ClinicalTrials.gov Identifier <jatsext-link xmlnsxlink=httpwww.w3.org1999xlink ext-link-type=clintrialgov xlinkhref=NCT03395769>NCT03395769<jatsext-link>, AB-SA01-EAP01 (January 10, 2018); Clinical Trials Notification (Australian Therapeutic Goods Association) CT-2018-CTN-02372-1 (July 23, 2018).Key PointsQuestionIs intravenous (IV) administration of investigational bacteriophage (phage) therapy safe and well-tolerated in patients with severe Staphylococcus aureus infection?FindingsThirteen patients with severe S. aureus infections received AB-SA01, a bacteriophage product prepared according to Good Manufacturing Practices (GMP), as adjunctive therapy to antibiotics. AB-SA01 was well-tolerated with no adverse events identified. Bacterial burden and inflammatory responses were reduced and no phage-resistant staphylococci were isolated during or after therapy.MeaningOur results will inform future randomised controlled trials assessing the antibacterial and anti-inflammatory potential of bacteriophages in the treatment of severe S. aureus infection.

biorxiv clinical-trials 0-100-users 2019

Gephebase, a Database of Genotype-Phenotype Relationships for natural and domesticated variation in Eukaryotes, bioRxiv, 2019-04-25

AbstractGephebase is a manually-curated database compiling our accumulated knowledge of the genes and mutations that underlie natural, domesticated and experimental phenotypic variation in all Eukaryotes — mostly animals, plants and yeasts. Gephebase aims to compile studies where the genotype-phenotype association (based on linkage mapping, association mapping or a candidate gene approach) is relatively well supported or understood. Human disease and aberrant mutant phenotypes in laboratory model organisms are not included in Gephebase and can be found in other databases (eg. OMIM, OMIA, Monarch Initiative). Gephebase contains more than 1700 entries. Each entry corresponds to an allelic difference at a given gene and its associated phenotypic change(s) between two species or between two individuals of the same species, and is enriched with molecular details, taxonomic information, and bibliographic information. Users can easily browse entries for their topic of interest and perform searches at various levels, whether phenotypic, genetic, taxonomic or bibliographic (eg. transposable elements, cis-regulatory mutations, snakes, carotenoid content, an author name). Data can be searched using keywords and boolean operators and is exportable in spreadsheet format. This database allows to perform meta-analysis to extract general information and global trends about evolution, genetics, and the field of evolutionary genetics itself. Gephebase should also help breeders, conservationists and others to identify the most promising target genes for traits of interest, with potential applications such as crop improvement, parasite and pest control, bioconservation, and genetic diagnostic. It is freely available at <jatsext-link xmlnsxlink=httpwww.w3.org1999xlink ext-link-type=uri xlinkhref=httpwww.gephebase.org>www.gephebase.org<jatsext-link>.

biorxiv bioinformatics 0-100-users 2019

 

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