The combination of mupirocin and Kayvirus broadens the decolonization effect against Staphylococcus aureus

Staphylococcus aureus strains cause a wide range of infections in humans, often with the potential for complications such as surgical site infections. The production of Panton-Valentin leukocidin (PVL) by certain strains of S. aureus is clinically associated with chronic or recurrent infections, which typically require decolonization, most often with mupirocin. As increased mupirocin use promotes the emergence of resistance, this study investigated the coadministration of mupirocin and therapeutic Kayvirus bacteriophage as a potential strategy to enhance treatment efficacy and prevent the development of new resistance. We collected and evaluated 37 PVL-encoding S. aureus strains from wound samples. Among these, 22% were methicillin-resistant, and 11% were resistant to the tested phage, but all were susceptible to mupirocin. To assess interactions between mupirocin and the phage in PVL-positive strains with varying levels of mupirocin resistance, we used lysogenization by PVL-encoding phage and adaptive laboratory evolution of clinical strains. In mupirocin-susceptible strains, lytic phage efficacy decreased due to altered protein synthesis caused by the interaction of mupirocin with isoleucyl-tRNA synthetase, whereas mupirocin efficacy was unaffected. In contrast, the advantage of combined administration was observed in mupirocin-resistant strains susceptible to phages, as their altered or alternative synthetase allowed protein synthesis to continue, enabling phage proliferation and bacterial lysis, even in the presence of mupirocin. This in vitro study demonstrates that mupirocin in combination with Kayvirus broadens the spectrum of strains susceptible to treatment and that the phage used prevents the development of mupirocin resistance. KEY POINTS: • Mupirocin-phage combination broadens the anti-staphylococcal effect in vitro. • Combination treatment reduces the emergence of mupirocin resistance. • Mupirocin action is not inhibited by phage therapy.