Abstract
Objectives: This study investigated the synergistic in vitro and in vivo activity of cefazolin plus fosfomycin against methicillin-susceptible and methicillin-resistant S. aureus (MSSA and MRSA) to provide the basis for a potential treatment alternative. Methods: Antimicrobial susceptibility and in vitro synergy tests were performed with five MSSA and five MRSA isolates using the broth microdilution and chequerboard assays, respectively. The in vivo efficacy of cefazolin plus fosfomycin for the treatment of MRSA infections was assessed using the Galleria mellonella survival assay. Results: Using fractional inhibitory concentration index (FICI), the evaluated combination of cefazolin plus fosfomycin showed synergistic in vitro 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 G. mellonella survival assay demonstrated highly synergistic in vivo activity of cefazolin plus fosfomycin, resulting in a 44–52% reduction in mortality when compared to cefazolin-alone and fosfomycin-alone, respectively. Conclusion: 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 S. aureus and MRSA infections. Future studies proving the clinical significance of this combination therapy are therefore warranted.
Highlights
Over recent years, fosfomycin has raised considerable interest due to its potent activity against a wide spectrum of problematic pathogens including Staphylococcus aureus, the leading cause of bacteremia and infective endocarditis (IE)
According to current guidelines vancomycin or daptomycin are recommended for treatment of bacteremia and IE caused by methicillin-resistant Staphylococcus
A multicenter clinical trial investigating the efficacy and safety of fosfomycin plus imipenem as rescue therapy for complicated methicillin-resistant StaphylococcusCefazolin Plus Fosfomycin Against S.aureus aureus (MRSA) bacteremia and IE showed that this combination therapy is a safe and effective alternative and should be further investigated
Summary
Fosfomycin has raised considerable interest due to its potent activity against a wide spectrum of problematic pathogens including Staphylococcus aureus, the leading cause of bacteremia and infective endocarditis (IE). Daptomycin shows rapid bactericidal activity and is a reliable alternative for severe MRSA infections (Richter et al, 2003; Habib et al, 2015) It possesses some shortcomings, including a strong inoculum effect and notable rates of emergent resistance in patients with leftsided IE, highlighting the need for alternative regimens and rescue therapies (Fowler et al, 2006; Moise et al, 2009; Morrisette et al, 2020). Due to its broad antimicrobial activity against Gram-positive and Gram-negative organisms, fosfomycin has been studied in combination with various beta-lactam antibiotics because of their wide therapeutic range and strong clinical efficacy These combinations have shown highly synergistic activity against MRSA, especially when fosfomycin was studied together with imipenem (Grif et al, 2001; del Río et al, 2016). We selected the narrow-spectrum beta-lactam cefazolin for combination with fosfomycin, which has shown good clinical efficacy and tolerability in the treatment of MSSA infections (Loubet et al, 2018)
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