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

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.

In Vitro and In Vivo Synergism of Fosfomycin in Combination with Meropenem or Polymyxin B against KPC-2-Producing Klebsiella pneumoniae Clinical Isolates

“…Synergism with fosfomycin in the G. mellonella model was previously reported, but to the best of our knowledge, there is no report in the literature testing fosfomycin alone and in combination to treat larvae infected with KPC-KPN. Kussmann and collaborators also reported high synergistic in vivo activity of fosfomycin combined with cefazolin resulting in a 44-54% reduction of larvae mortality infected with Staphylococcus aureus, which agreed with their in vitro data [31]. Thus, the concordance between the in vitro and in vivo (G. mellonella) results supports the use of this model to select the most appropriate therapeutic regimens [32][33][34].…”

Galleria Mellonella Larvae as an In vitro Model for Testing Microbial Pathogenicity

“…For example, the synergistic effects of the antibiotics cefazolin and fosfomycin against S. aureus were investigated in the G. mellonella model. The addition of as little as 0.8 mg/kg fosfomycin to cefazolin restored cefazolin sensitivity of MRSA strains (Kussmann et al 2021).…”

The Synergistic Antimicrobial Effect and Mechanism of Nisin and Oxacillin against Methicillin-Resistant Staphylococcus aureus

“…Based on the MICs, 50 µL of different concentration of OX, NIS and OX + NIS with 2, 1, 1/2, 1/4, 1/8, 1/16 and 1/32MIC, separately, was added into the well with 150µL MRSA strain suspension (OD 600 = 0.1) in a 96-well microplate; BC well contains 200 µL sterilized TSB medium; PC well contains 150 µL cell suspension (OD 600 = 0.1) and 50 µL TSB medium. After incubating at 37 °C for 16–18 h, the FICI was calculated as follows [ 25 ]: FICI = (MIC of Nisin in OX + NIS/MIC of Nisin) + (MIC Oxacillin in OX + NIS/MIC of Oxacillin). …”