Evaluation of dalbavancin alone and in combination with β-lactam antibiotics against resistant phenotypes of Staphylococcus aureus

Xhemali, Xhilda; Smith, Jordan R.; Kebriaei, Razieh; Rice, Seth; Stamper, Kyle; Compton, Matthew; Singh, Nivedita B.; Jahanbakhsh, Seyedehameneh; Rybak, Michael J.

doi:10.1093/jac/dky376

Cited by 18 publications

(23 citation statements)

References 16 publications

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“…Consequently, significant controversy exists regarding the current and future roles of vancomycin and teicoplanin in the treatment of serious hVISA-MRSA infections. Our data corroborate with what has been recently reported by other authors, reinforcing the hypothesis that dalbavancin may be a valuable agent against problematic pathogens [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. The interpretation of the slightly higher rate of dalbavancin non-susceptibility among RIF-R/hVISA isolates needs further investigations, although it is possible to assume that the presence of rpoB mutations in these strains [8], already associated with the emergence of vancomycin-intermediate resistance, may affect the antimicrobial activity.…”

Section: Discussionsupporting

confidence: 93%

“…Dalbavancin, a new second-generation semisynthetic lipoglycopeptide, active against Gram-positive pathogens, including MRSA, has recently been approved for the treatment of severe skin infections [4]. The analysis of the bactericidal activity by time-kill curve assays has shown that dalbavancin performs 4-8 times higher activity than vancomycin versus MRSA, and its activity, alone and in association, has also been tested against MRSA, VISA, hVISA and DNS isolates [5,6].…”

Section: Introductionmentioning

confidence: 99%

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In Vitro Activity of Dalbavancin against Refractory Multidrug-Resistant (MDR) Staphylococcus aureus Isolates

et al. 2020

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The high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infections, always treated with vancomycin and daptomycin, has led to the emergence of vancomycin-intermediate (VISA), heteroresistant vancomycin-intermediate (hVISA) and daptomycin non-susceptible (DNS) S. aureus. Even if glycopeptides and daptomycin remain the keystone for treatment of resistant S. aureus, the need for alternative therapies that target MRSA has now become imperative. The in vitro antibacterial and bactericidal activity of dalbavancin was evaluated against clinically relevant S. aureus showing raised antibiotic resistance levels, from methicillin-susceptible to Multidrug-Resistant (MDR) MRSA, including hVISA, DNS and rifampicin-resistant (RIF-R) strains. A total of 124 S. aureus strains were tested for dalbavancin susceptibility, by the broth microdilution method. Two VISA and 2 hVISA reference strains, as well as a vancomycin-resistant (VRSA) reference strain and a methicillin-susceptible Staphylococcus aureus (MSSA) reference strain, were included as controls. Time–kill curves were assayed to assess bactericidal activity. Dalbavancin demonstrated excellent in vitro antibacterial and bactericidal activity against all S. aureus resistance classes, including hVISA and DNS isolates. The RIF-R strains showed the highest percentage of isolates with non-susceptibility, reflecting the correlation between rpoB mutations and VISA/hVISA emergence. Our observations suggest that dalbavancin can be considered as an effective alternative for the management of severe MRSA infections also sustained by refractory phenotypes.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

In Vitro Activity of Dalbavancin against Refractory Multidrug-Resistant (MDR) Staphylococcus aureus Isolates

et al. 2020

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“…All 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 ). 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 ).…”

Section: Introductionmentioning

confidence: 99%

Synergy Between Beta-Lactams and Lipo-, Glyco-, and Lipoglycopeptides, Is Independent of the Seesaw Effect in Methicillin-Resistant Staphylococcus aureus

Zhang

Beltran

Ashford

et al. 2021

Front. Mol. Biosci.

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Methicillin-resistant S. aureus (MRSA) are resistant to beta-lactams, but synergistic activity between beta-lactams and glycopeptides/lipopeptides is common. Many have attributed this synergy to the beta-lactam-glycopeptide seesaw effect; however, this association has not been rigorously tested. 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. We selected for three isogenic strains with reduced susceptibility to vancomycin, daptomycin, and dalbavancin by serial passaging the MRSA strain N315. 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 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. Synergy was more commonly observed with vancomycin and daptomycin based combinations than dalbavancin in time-kills. 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 common among the resistant mutants than the parent strain. Interestingly N315-D1 and N315-DAL0.5 both had mutations in vraTSR and walKR despite their differences in the seesaw effect. 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. In conclusion, the beta-lactam-glycopeptide seesaw effect and beta-lactam-glycopeptide synergy are distinct phenomena. This suggests that the emergence of the seesaw effect may not have clinical importance in terms of predicting synergy. 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.

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“…In CF patients, Staphylococcus aureus (and particularly MRSA) infection is the main challenge of antibiotic therapy, since the persistent infection caused by this bacterium is strongly associated with increased rates of decline in respiratory function and high mortality (Dolce et al, 2019). Thus, new approaches to fight this kind of bacterium are mandatory and should be based on new antimicrobials, most probably combined with conventional ones (Lo et al, 2018;Xhemali et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

Multicomponent Reactions Upon the Known Drug Trimethoprim as a Source of Novel Antimicrobial Agents

et al. 2019

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Novel antibiotic compounds have been prepared through a selective multicomponent reaction upon the known drug Trimethoprim. The Groebke-Blackburn-Bienaymé reaction involving this α-aminoazine, with a range of aldehydes and isocyanides afforded the desired adducts in one-step. The analogs display meaningful structural features of the initial drug together with relevant modifications at several points, keeping antibiotic potency and showing satisfactory antimicrobial profile (good activity levels and reduced growth rates), especially against methicillin-resistant Staphylococcus aureus . The new products may open new possibilities to fight bacterial infections.

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Evaluation of dalbavancin alone and in combination with β-lactam antibiotics against resistant phenotypes of Staphylococcus aureus

Cited by 18 publications

References 16 publications

In Vitro Activity of Dalbavancin against Refractory Multidrug-Resistant (MDR) Staphylococcus aureus Isolates

In Vitro Activity of Dalbavancin against Refractory Multidrug-Resistant (MDR) Staphylococcus aureus Isolates

Synergy Between Beta-Lactams and Lipo-, Glyco-, and Lipoglycopeptides, Is Independent of the Seesaw Effect in Methicillin-Resistant Staphylococcus aureus

Multicomponent Reactions Upon the Known Drug Trimethoprim as a Source of Novel Antimicrobial Agents

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