12/8/2023 0 Comments Synergy gas vermont![]() ![]() aureus VISA) or daptomycin exhibit the seesaw effect, and for most such clinical isolates, the emergence of the seesaw effect cannot be assessed due to absence of the parent strain. Not all MRSA with reduced susceptibility to vancomycin ( i.e., vancomycin intermediate S. There are a few well-characterized examples of such clinical strain pairs, but this is not something that can be easily determined through routine monitoring by clinical laboratories ( Vignaroli et al., 2011 Werth et al., 2013a). While the seesaw effect is assumed to be a common feature of strains with reduced susceptibility to vancomycin or daptomycin, to measure it requires the comparison between a parent strain that is initially susceptible to vancomycin or daptomycin and isogenic strains that develop reduced susceptibility. ![]() While it is intuitive that the seesaw effect between beta-lactams and glyco-, lipo-, and lipoglycopeptides could be related to synergy between these agents, this association has not been rigorously tested. Some investigators have attributed this synergy to the “seesaw effect” ( Renzoni et al., 2017 Molina et al., 2020), a phenomenon where the susceptibility to beta-lactams increases with declining vancomycin or daptomycin susceptibility ( Sieradzki and Tomasz, 1997 Ortwine et al., 2013). Further work is warranted to characterize strains that don’t exhibit beta-lactam synergy to identify which strains should be targeted with combination therapy and which ones cannot and to further investigate the potential role of CLs in mediating synergy.Īll MRSA are resistant to traditional beta-lactams, but when combined with glycopeptides, lipopeptides, or lipoglycopeptides, synergistic antimicrobial activity is commonly observed, especially among strains with reduced susceptibility to the latter antimicrobial classes ( Mehta et al., 2012 Werth et al., 2013b Xhemali et al., 2018). This suggests that the emergence of the seesaw effect may not have clinical importance in terms of predicting synergy. In conclusion, the beta-lactam-glycopeptide seesaw effect and beta-lactam-glycopeptide synergy are distinct phenomena. Lipidomic analysis of all strains exposed to individual beta-lactams at subinhibitory concentrations suggested that in general, the abundance of cardiolipins (CLs) and most free fatty acids (FFAs) positively correlated with the presence of synergistic effects while abundance of phosphatidylglycerols (PGs) and lysylPGs mostly negatively correlated with synergistic effects. Interestingly N315-D1 and N315-DAL0.5 both had mutations in vraTSR and walKR despite their differences in the seesaw effect. Synergy was more common among the resistant mutants than the parent strain. Among the beta-lactams, cefoxitin and nafcillin were the most likely to exhibit synergy using the concentrations tested, while cephalexin was the least likely to exhibit synergy. Synergy was more commonly observed with vancomycin and daptomycin based combinations than dalbavancin in time-kills. We observed that the seesaw effect with each beta-lactam was variable and the emergence of the seesaw effect for a particular beta-lactam was not necessary for synergy between that beta-lactam and vancomycin, daptomycin, or dalbavancin. We used whole genome sequencing to identify genetic variants that emerged and tested for synergy between vancomycin, daptomycin, or dalbavancin in combination with 6 beta-lactams with variable affinity for staphylococcal penicillin binding proteins (PBPs), including nafcillin, meropenem, ceftriaxone, ceftaroline, cephalexin, and cefoxitin, using time-kills. We selected for three isogenic strains with reduced susceptibility to vancomycin, daptomycin, and dalbavancin by serial passaging the MRSA strain N315. The objective of this study was to determine whether the seesaw effect is necessary for synergy and to measure the impact of beta-lactam exposure on lipid metabolism. Many have attributed this synergy to the beta-lactam-glycopeptide seesaw effect however, this association has not been rigorously tested. aureus (MRSA) are resistant to beta-lactams, but synergistic activity between beta-lactams and glycopeptides/lipopeptides is common. 3Department of Laboratory Medicine and Pathology, School of Medicine, University of Washington, Seattle, WA, United States.2Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, United States.1Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, United States.Ashford 2 Kelsi Penewit 3 Adam Waalkes 3 Elizabeth A. ![]()
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