Rational Design of a Potent Two-Phage Cocktail Against a Contemporary Acinetobacter baumannii Strain Recovered from a Burned Patient at the Lausanne University Hospital

<i>Acinetobacter baumannii</i> is a critical public health threat, particularly with the rise in multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains that limit treatment options. Phage therapy, which uses bacteriophages to target bacteria, offers a promising alternative. We isolated an XDR strain (Ab125) from a burn wound infection and screened 34 phages, identifying vB_AbaM_3098 as the only effective candidate. However, resistance rapidly emerged, producing a derivative strain (Ab139). Interestingly, Ab139, though resistant to vB_AbaM_3098, became susceptible to six previously inactive phages. While various potential determinants were identified through comparative genomics and proteomics, the mechanism causing phage resistance to vB_AbaM_3098 and simultaneous susceptibility to other phages remains to be elucidated. Among the six new candidates, vB_AbaM_3014 was the most promising. While each phage alone allowed bacterial regrowth, combining vB_AbaM_3098 and vB_AbaM_3014 completely suppressed Ab125 growth. In a <i>Galleria mellonella</i> infection model, this cocktail achieved 90% survival after five days compared to 0% in untreated controls. Notably, the cocktail combined one phage with modest activity and another inactive phage against the parental strain; together, they produced strong bactericidal effects. These findings highlight both the complexity of phage cocktail design and their promise as adjunct therapies against drug-resistant <i>A. baumannii</i>.