Preprint Article Version 1 This version is not peer-reviewed

Combined Use of the Ab105-2фΔCI Lytic Mutant Phage and Different Antibiotics in Clinical Isolates of Multiresistant Acinetobacter Baumannii

Version 1 : Received: 30 September 2019 / Approved: 2 October 2019 / Online: 2 October 2019 (08:42:31 CEST)

A peer-reviewed article of this Preprint also exists.

Blasco, L.; Ambroa, A.; Lopez, M.; Fernandez-Garcia, L.; Bleriot, I.; Trastoy, R.; Ramos-Vivas, J.; Coenye, T.; Fernandez-Cuenca, F.; Vila, J.; Martinez-Martinez, L.; Rodriguez-Baño, J.; Pascual, A.; Cisneros, J.M.; Pachon, J.; Bou, G.; Tomas, M. Combined Use of the Ab105-2φΔCI Lytic Mutant Phage and Different Antibiotics in Clinical Isolates of Multi-Resistant Acinetobacter baumannii. Microorganisms 2019, 7, 556. Blasco, L.; Ambroa, A.; Lopez, M.; Fernandez-Garcia, L.; Bleriot, I.; Trastoy, R.; Ramos-Vivas, J.; Coenye, T.; Fernandez-Cuenca, F.; Vila, J.; Martinez-Martinez, L.; Rodriguez-Baño, J.; Pascual, A.; Cisneros, J.M.; Pachon, J.; Bou, G.; Tomas, M. Combined Use of the Ab105-2φΔCI Lytic Mutant Phage and Different Antibiotics in Clinical Isolates of Multi-Resistant Acinetobacter baumannii. Microorganisms 2019, 7, 556.

Journal reference: Microorganisms 2019, 7, 556
DOI: 10.3390/microorganisms7110556

Abstract

The global health emergency caused by multi-drug resistant bacteria has led to the search for and development of new antimicrobial agents. Phage therapy is an abandoned antimicrobial therapy that has been resumed in recent years. In this study, we mutated a lysogenic phage from Acinetobacter baumannii into a lytic phage (Ab105-2phiΔCI) showing antimicrobial activity against A.baumannii clinical strains (such as Ab177_GEIH-2000 which showed MICs to meropenem and imipenem of 32 µg/ml and 16 µg/ml, respectively as well as belonging to GEIH-REIPI Spanish Multicenter A. baumannii Study II 2000/2010, Umbrella Genbank Bioproject PRJNA422585). We then enhanced the time kill curves (in vitro) and in Galleria mellonella survival assays (in vivo) antimicrobial activity of the new lytic phage by combining it with carbapenem antibiotics (meropenem and imipenem). We observed in vitro, an antimicrobial synergistic effect (from 4 log to 7 log CFU/ml) with meropenem plus lytic phage in all combinations analysed (0.1, 1 and 10 MOI of Ab105-2phiΔCI mutant as well as 1/4 and 1/8 MIC of meropenem). Moreover, we had a decrease in bacterial growth of 8 log CFU/ml for the combination of imipenem at 1/4 MIC plus lytic phage (Ab105-2phiΔCI mutant) and of 4 log CFU/ml for the combination of imipenem at 1/8 MIC plus lytic phage (Ab105-2phiΔCI mutant) in both MOI 1 and 10. These results were confirmed in in vivo (G. mellonella) obtaining a higher effectiveness in the combination of imipenem and Ab105-2phiΔCI mutant (P<0.05 by Log Rank-Matel Cox test). This approach could help to reduce the emergence of phage resistant bacteria and restore sensitivity to the antibiotics when used to combat multiresistant strains of Acinetobacter baumannii.

Subject Areas

Acinetobacter baumannii; multiresistant; mutant lytic phage; phage therapy; antibiotic-phage synergy.

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