Utveckling av aktiva läkemedelskombinationer av antibiotika och icke-antibiotika

Tidsperiod: 2015-12-01 till 2018-11-30

Projektledare: Lena Friberg

Finansiär: Vetenskapsrådet

Bidragstyp: Projektbidrag

Budget: 3 986 471 SEK

The CO-ACTION project aims to develop and provide a framework for evaluating and validating the effectiveness of antibiotic (AB)- and non-antibiotic (NA) combinations (COMs) in the preclinical setting based on pharmacokinetic/pharmacodynamic (PKPD) principles both for human and veterinary medicine. To fulfill this ambitious goal, 6 work-packages with 6 interacting partners were built involving several steps: screening for CO-ACTION between (ND-)AB and NA, selecting potential synergistic COMs, subsequent validation using PKPD experiments and modelling and finally testing COMs in animal models. Finding optimal COMs is ensured by a continuous feedback between experimental results, PKPD modelling and statistical evaluation. The interaction between existing ND-AB from at least 6 different classes, will be determined using checkerboard experiments and/or specific techniques for NA for well characterized Gram-negative multidrug resistant strains and analysed by interaction modelling. In parallel, an automated system (the oCelloscope) will be applied to allow efficient screening for large numbers of COMs. The CO-ACTION of clearly synergistic COMs will be further quantified using time-kill curves (TKC), both in medium as well as intracellulary, and apply mechanistic PKPD modelling to predict effective dosing regimens in vivo. Mechanisms of interaction and potential emergence of resistance (ER) will be explored. Effectiveness and effect on gut flora of the most promising 3-6 COMs wil