Factorial design and post-antibiotic sub-MIC effects of linezolid combined with fosfomycin against vancomycin-resistant enterococci

Yan, Yisong; Guang, Yang; Li, Yaowen; Mao, Jun; Wang, Shuaishuai; Zhang, Na; Liu, Huiping; Huang, Xiaohui

doi:10.21037/atm-21-4595

Cited by 7 publications

(9 citation statements)

References 36 publications

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“…A combination of antibiotics can effectively reduce the dose of the two antibiotics, which in turn can achieve the purpose of bacteriostasis at a lower concentration ( Algharib et al., 2020b ; Hussein et al., 2022 ; Yan et al., 2022 ). Our study successfully achieved the goal of improving antibiotic susceptibility by inhibiting biofilm formation.…”

Section: Discussionmentioning

confidence: 99%

“…Broth Micro-Checkerboard was used for isookanin and five β-lactam antibiotics combination as previously reported with slight modifications ( Rogers et al., 2010 ; Yan et al., 2022 ). Briefly, 50 μL of ploidy dilution antibiotics working solution add it to columns 2-12 of the 96-well plate, and 50 μL of ploidy dilution isookanin solution added it to row A-G of the plate.…”

Section: Methodsmentioning

confidence: 99%

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Down-regulation of β-lactam antibiotics resistance and biofilm formation by Staphylococcus epidermidis is associated with isookanin

Ren

Luo

Chi

et al. 2023

Front. Cell. Infect. Microbiol.

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IntroductionBiofilm formation is the major pathogenicity of Staphylococcus epidermidis (S. epidermidis), which enhances bacterial resistance to antibiotics. Isookanin has potential inhibitory activity on biofilm.MethodThe inhibiting mechanisms of isookanin against biofilm formation through surface hydrophobicity assay, exopolysaccharides, eDNA, gene expression analysis, microscopic visualization, and molecular docking were explored. Additionally, the combination of isookanin and β-lactam antibiotics were evaluated by the broth micro-checkerboard assay.ResultsThe results showed that isookanin could decrease the biofilm formation of S. epidermidis by ≥85% at 250 μg/mL. The exopolysaccharides, eDNA and surface hydrophobicity were reduced after treatment with isookanin. Microscopic visualization analysis showed that there were fewer bacteria on the surface of the microscopic coverslip and the bacterial cell membrane was damaged after treatment with isookanin. The down-regulation of icaB and up-regulation of icaR were observed after treatment with isookanin. Additionally, the RNAIII gene was significantly up-regulated (p < 0.0001) at the mRNA level. Molecular docking showed that isookanin could bind to biofilm-related proteins. This indicated that isookanin can affect biofilm formation at the initial attachment phase and the aggregation phase. The FICI index showed that the combination of isookanin and β-lactam antibiotics were synergistic and could reduce doses of antibiotics by inhibiting biofilm formation.DiscussionThis study improved the antibiotic susceptibility of S. epidermidis through inhibition of the biofilm formation, and provided a guidance for the treatment of antibiotic resistance caused by biofilm

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Down-regulation of β-lactam antibiotics resistance and biofilm formation by Staphylococcus epidermidis is associated with isookanin

Ren

Luo

Chi

et al. 2023

Front. Cell. Infect. Microbiol.

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“…First, in vitro assay data showed that linezolid combined with fosfomycin had a highly synergistic effect, of which the linezolid group showed similar bacteriostatic effects, causing a ~1 log 10 decrease in the three clinical strains after 24 h compared to the initial concentration at 0 h. However, Yan et al showed a trend of gradual drug resistance when a sub-inhibitory concentration of 1 mg/L linezolid was used in the treatment of VRE. 11 According to a survey of 1442 clinically collected Enterococcus isolates in the Czech Republic from 2009 to 2019, linezolid-resistant Enterococcus faecalis (LREF) increased from 0 in 2009 to 36 in 2019. 33 Subsequently, a global statistical analysis showed that of 69,291 Enterococcus isolates, 1646 were LREF isolates, indicating a prevalence rate of 2.2%.…”

Section: Discussionmentioning

confidence: 99%

“…Surprisingly, linezolid combined with fosfomycin exhibited a good synergistic effect and exerted a sustained bactericidal effect. Yan et al further suggested that linezolid combined with fosfomycin could prolong the post-antibiotic effect, 11 which was beneficial for prolonging the treatment time. Jiang et al speculated that the combination of drugs might be a beneficial result of the synergistic closure of their respective mutation selection windows (MSW).…”

Section: Discussionmentioning

confidence: 99%

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Assessing the Emergence of Resistance in vitro and Invivo: Linezolid Combined with Fosfomycin Against Fosfomycin-Sensitive and Resistant Enterococcus

Li¹,

Peng²,

Zhang³

et al. 2022

IDR

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Purpose We aimed to evaluate the synergistic effect of linezolid and fosfomycin on fosfomycin-sensitive and -resistant Enterococcus clinical isolates in vitro and in vivo and whether the emergence of fosfomycin resistance in Enterococcus is associated with changes in strain virulence, from the perspective of fitness cost. Methods The synergistic effect of linezolid and fosfomycin was studied via in vitro checkerboard and static time-kill assays, as well as based on the in vivo survival rate and hemolymph load of a Galleria mellonella infection model. Fosfomycin resistance was induced via a stepwise increase in concentration. Changes in the virulence of the strains after drug resistance were investigated using the G. mellonella infection model and reverse transcription quantitative polymerase chain reaction (RT-qPCR). In vitro and in vivo growth curves and competitive experiments were used to study the fitness cost of the strain. Finally, a static time-kill assay was performed to explore the effect of the combined medication. Results In vitro and in vivo data showed that linezolid combined with fosfomycin had a good synergistic effect on Enterococcus treatment. The G. mellonella infection model and RT-qPCR data showed that the virulence of the resistant strains was weakened to varying degrees. A survival curve and competition experimental data showed that this was related to the fitness cost of strains while acquiring resistance and negatively impacted linezolid treatment; however, the combination still showed a good synergistic effect in drug-resistant strains. Conclusion Linezolid combined with fosfomycin had a synergistic effect on both fosfomycin-sensitive and -resistant Enterococcus strains. Strains incur fitness costs as they develop drug resistance, which leads to a decrease in virulence. There is an interaction between fitness cost, virulence, and drug resistance, which indirectly affects drug treatment.

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Clinical drug interactions between linezolid and other antibiotics: For adverse drug event monitoring

Shu,

Huo,

Yin

et al. 2024

Pharmacology Res & Perspec

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Detailed data on safety associated with drug–drug interactions (DDIs) between Linezolid (LZD) and other antibiotics are limited. The aim of this study was to investigate the safety signals related to these DDIs and to provide a reference for clinically related adverse drug event monitoring. Adverse event (AE) information from 1 January 2004 to 16 June 2022 of the target antibiotics including LZD using alone or in combination with LZD was extracted from the OpenVigil FDA data platform for safety signal analysis. The combined risk ratio model, reporting ratio method, Ω shrinkage measure model, and chi‐square statistics model were used to analyze the safety signals related to DDIs. Meanwhile, we evaluated the correlation and the influence of sex and age between the drug(s) and the target AE detected. There were 18991 AEs related to LZD. There were 2293, 1726, 4449, 821, 2431, 1053, and 463 AE reports when LZD was combined with amikacin, voriconazole, meropenem, clarithromycin, levofloxacin, piperacillin‐tazobactam, and azithromycin, respectively. Except for azithromycin, there were positive safety signals related to DDIs between LZD and these antibiotics. These DDIs might influence the incidence of 13, 16, 7, 7, 6, and 15 types of AEs, respectively, and is associated with higher reporting rates of AEs compared with use alone. Moreover, sex and age might influence the occurrence of AEs. We found that the combinations of LZD and other antibiotics are related to multiple AEs, such as hepatotoxicity, drug resistance and electrocardiogram QT prolonged, but further research is still required to investigate their underlying mechanisms. This study can provide a new reference for the safety monitoring of LZD combined with other antibiotics in clinical practice.

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Factorial design and post-antibiotic sub-MIC effects of linezolid combined with fosfomycin against vancomycin-resistant enterococci

Cited by 7 publications

References 36 publications

Down-regulation of β-lactam antibiotics resistance and biofilm formation by Staphylococcus epidermidis is associated with isookanin

Down-regulation of β-lactam antibiotics resistance and biofilm formation by Staphylococcus epidermidis is associated with isookanin

Assessing the Emergence of Resistance in vitro and Invivo: Linezolid Combined with Fosfomycin Against Fosfomycin-Sensitive and Resistant Enterococcus

Clinical drug interactions between linezolid and other antibiotics: For adverse drug event monitoring

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