AUTHOR=Kussmann Manuel , Obermueller Markus , Karer Matthias , Kriz Richard , Chen Rui-Yang , Hohl Lena , Schneider Lisa , Burgmann Heinz , Traby Ludwig , Vossen Matthias G. 

TITLE=Synergistic Effect of Cefazolin Plus Fosfomycin Against Staphylococcus aureus in vitro and in vivo in an Experimental Galleria mellonella Model

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.685807

DOI=10.3389/fphar.2021.685807

ISSN=1663-9812

ABSTRACT=<p><bold>Objectives:</bold> This study investigated the synergistic <italic>in vitro</italic> and <italic>in vivo</italic> activity of cefazolin plus fosfomycin against methicillin-susceptible and methicillin-resistant <italic>S. aureus</italic> (MSSA and MRSA) to provide the basis for a potential treatment alternative.</p><p><bold>Methods:</bold> Antimicrobial susceptibility and <italic>in vitro</italic> synergy tests were performed with five MSSA and five MRSA isolates using the broth microdilution and chequerboard assays, respectively. The <italic>in vivo</italic> efficacy of cefazolin plus fosfomycin for the treatment of MRSA infections was assessed using the <italic>Galleria mellonella</italic> survival assay.</p><p><bold>Results:</bold> Using fractional inhibitory concentration index (FICI), the evaluated combination of cefazolin plus fosfomycin showed synergistic <italic>in vitro</italic> activity against all MSSA and MRSA isolates tested. In addition, cefazolin susceptibility was recovered in all MRSA isolates except one fosfomycin-resistant strain when combined with fosfomycin at readily achievable concentrations. The <italic>G. mellonella</italic> survival assay demonstrated highly synergistic <italic>in vivo</italic> activity of cefazolin plus fosfomycin, resulting in a 44–52% reduction in mortality when compared to cefazolin-alone and fosfomycin-alone, respectively.</p><p><bold>Conclusion:</bold> If susceptibility to fosfomycin is either confirmed or can be assumed based on local resistance patterns, combination therapy with cefazolin plus fosfomycin could be a valuable treatment option for empirical as well as targeted therapy of <italic>S. aureus</italic> and MRSA infections. Future studies proving the clinical significance of this combination therapy are therefore warranted.</p>