Ceftaroline Increases Membrane Binding and Enhances the Activity of Daptomycin against Daptomycin-Nonsusceptible Vancomycin-Intermediate Staphylococcus aureus in a Pharmacokinetic/Pharmacodynamic Model

Abstract

h. Therapeutic enhancement of combinations was defined as >2 log 10 CFU/ml reduction over the most active single agent. The effect of ceftaroline on the membrane charge, cell wall thickness, susceptibility to killing by the human cathelicidin LL37, and daptomycin binding were evaluated. Therapeutic enhancement was observed with daptomycin plus ceftaroline in both strains and vancomycin plus ceftaroline against D592. Ceftaroline exposure enhanced daptomycin-induced depolarization (81.7% versus 72.3%; P ‫؍‬ 0.03) and killing by cathelicidin LL37 (P < 0.01) and reduced cell wall thickness (P < 0.001). Fluorescence-labeled daptomycin was bound over 7-fold more in ceftaroline-exposed cells. Whole-genome sequencing and mutation analysis of these strains indicated that change in daptomycin susceptibility is related to an fmtC (mprF) mutation. The combination of daptomycin plus ceftaroline appears to be potent, with rapid and sustained bactericidal activity against both daptomycinsusceptible and -nonsusceptible strains of MRSA.

Penicillin Binding Protein 1 Is Important in the Compensatory Response of Staphylococcus aureus to Daptomycin-Induced Membrane Damage and Is a Potential Target for β-Lactam–Daptomycin Synergy

“…The mechanisms for this are not fully understood, but some ␤-lactams have been observed to increase binding of DAP to bacterial cell membranes (3,4) or to target binding to membrane regions where DAP is most effective (5). This is consistent with reports of a DAP-␤-lactam "seesaw effect," whereby S. aureus frequently gains susceptibility to ␤-lactams upon acquisition of the DAP-nonsusceptible (DNS) phenotype (6).…”

Deciphering the tRNA-dependent lipid aminoacylation systems in bacteria: Novel components and structural advances

“…With the rise of bacteria that are increasingly resistant to current drugs, new antimicrobials and/or drug combinations must be identified to find effective treatments of managing infections. 108,109 In the last decade, many antibiotics that target bacterial systems that enhance antimicrobial resistance have been developed to potentiate the effect of existing antibiotics (e.g., [110,111]). For instance, multidrug efflux pumps, which have been shown to increase antibiotic resistance, have become a popular target.…”

Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an In Vitro Pharmacokinetic-Pharmacodynamic Model

“…Daptomycin binding was assessed by fluorescence microscopy in the presence and absence of fosfomycin and G-6-P as previously described (24). Briefly, cells were grown to an optical density at 600 nm (OD 600 ) of 0.6, grown for an additional 1 h with or without G-6-P (25 mg/liter) and G-6-P plus FOF (260 mg/liter), and then incubated with 16 mg/liter daptomycin-boron-dipyrromethene (bodipy) for 10 min.…”

“…Samples from each model were collected at 0, 4,8,24,32,48,56, and 72 h and diluted in 0.9% saline. Colony counts were determined by spiral plating appropriate dilutions using an automatic spiral plater (WASP; DW Scientific, West Yorkshire, England) to enumerate CFU/ml and avoid antibiotic carryover.…”

“…Synergy between daptomycin and beta-lactams is believed to be mediated through beta-lactam-induced alterations in surface charge that facilitate an increase in daptomycin binding, leading to enhanced membrane depolarization (23)(24)(25)(26)(27)(28). Since fosfomycin also disrupts cell wall synthesis, it could be theorized that there is a similar mechanism that drives the synergy that has been observed with daptomycin and fosfomycin.…”