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Antistaphylococcal activity of DX-619 alone and in combination with vancomycin, teicoplanin, and linezolid assessed by time-kill synergy testing.

ABSTRACT: Time-kill synergy studies testing in vitro activity of DX-619 alone and with added vancomycin, teicoplanin, or linezolid against 101 Staphylococcus aureus strains showed synergy between DX-619 and teicoplanin at 12 to 24 h in 72 strains and between DX-619 and vancomycin in 28 strains. No synergy was found with linezolid, and no antagonism was observed with any combination.

SUBMITTER: Credito K

PROVIDER: S-EPMC1855475 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Antistaphylococcal activity of DX-619 alone and in combination with vancomycin, teicoplanin, and linezolid assessed by time-kill synergy testing.

Credito Kim K Lin Genrong G Appelbaum Peter C PC

Antimicrobial agents and chemotherapy 20070129 4

Time-kill synergy studies testing in vitro activity of DX-619 alone and with added vancomycin, teicoplanin, or linezolid against 101 Staphylococcus aureus strains showed synergy between DX-619 and teicoplanin at 12 to 24 h in 72 strains and between DX-619 and vancomycin in 28 strains. No synergy was found with linezolid, and no antagonism was observed with any combination. ...[more]

PMID: 17261625

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Project description:Vancomycin and teicoplanin are the glycopeptides currently in use for the treatment of infections caused by invasive beta-lactam-resistant gram-positive organisms. We conducted a systematic review and meta-analysis of randomized controlled trials that have compared vancomycin and teicoplanin administered systemically for the treatment of suspected or proven infections. A comprehensive search of trials without year, language, or publication status restrictions was performed. The primary outcome was all-cause mortality. Two reviewers independently extracted the data. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled by using the fixed-effect model (RRs of >1 favor vancomycin). Twenty-four trials were included. All-cause mortality was similar overall (RR, 0.95; 95% CI, 0.74 to 1.21), and there was no significant heterogeneity. In trials that used adequate allocation concealment, the results favored teicoplanin (RR, 0.82; 95% CI, 0.63 to 1.06), while in trials with unknown methods or inadequate concealment, the results favored vancomycin (RR, 3.61; 95% CI, 1.27 to 10.30). The latter trials might have recruited more severely ill patients. No other variable affected the RRs for mortality, including the assessment of glycopeptides administered empirically or for proven infections, neutropenia, the participant's age, and drug dosing. There were no significant differences between teicoplanin and vancomycin with regard to clinical failure (RR, 0.92; 95% CI, 0.81 to 1.05), microbiological failure (RR, 1.24; 95% CI, 0.93 to 1.65), and other efficacy outcomes. Lower RRs (in favor of teicoplanin) for clinical failure were observed with a lower risk of bias and when treatment was initiated for infections caused by gram-positive organisms rather than empirically. Total adverse events (RR, 0.61; 95% CI, 0.50 to 0.74), nephrotoxicity (RR, 0.44; 95% CI, 0.32 to 0.61), and red man syndrome were significantly less frequent with teicoplanin. Teicoplanin is not inferior to vancomycin with regard to efficacy and is associated with a lower adverse event rate than vancomycin.

Project description:The precise mechanism and effects of antibiotics in host gene expression and immunomodulation in MRSA infection is unknown. Using a well characterized Methicillin Resistant Staphylococcus aureus (MRSA) isolate USA300 in a murine model of infection, we determined that linezolid and vancomycin induced differential production of bacterial toxins and host cytokines, differences in host gene expression, and differences in immunomodulators during MRSA bloodstream infection. A total of 35 A/J mice, categorized into seven groups (no infection; no infection with linezolid; no infection with vancomycin; 2 hour post-infection (hpi) S. aureus; 24 hpi S. aureus; 24 hpi S. aureus with linezolid; and 24 hpi S. aureus with vancomycin), were used in this study. Mice were injected with USA300 (6 x 106 CFU/g via i.p. route), then intravenously treated with linezolid (25 mg/kg) or vancomycin (25 mg/kg) at 2 hpi. Control and S. aureus infected mice were euthanized at each time point (2 h or 24h) following injection. Whole blood RNA was used for microarray; three cytokines and two S. aureus toxins [PantonValentine Leukocidin (PVL) and alpha hemolysin] were quantified in mouse serum by ELISA. S. aureus CFUs were significantly reduced in blood and kidney after linezolid or vancomycin treatment in S. aureus-infected mice. In vivo IL-1β in mouse serum was significantly reduced in both linezolid (p=0.001) and vancomycin (p=0.006) treated mice compared to untreated ones. IL-6 was significantly reduced only in linezolid treated (p<0.001) but not in vancomycin treated mice. However, another proinflammatory cytokine, TNF-α, did not exhibit altered levels in either linezolid or vancomycin treated mice (p=0.3 and p=0.51 respectively). In vivo level of bacterial toxin, Panton-Valentine leukocidin, in mouse serum was significantly reduced only in linezolid treated mice (p=0.02) but not in vancomycin treated mice. There was no significant effect of either treatment in in vivo level of alpha hemolysin production. Unsupervised hierarchical clustering using the gene expression data from 35 microarrays revealed distinct clustering based on infection status and treatment group. Study of the antibiotic-specific difference in gene expression identified the number of genes uniquely expressed in response to S. aureus infection, infection with linezolid treatment, and infection with vancomycin treatment. Pathway associations study for the differentially expressed genes in each comparison group (Control vs. 24 h S. aureus infection, 24 h S. aureus infection vs. 24 h S. aureus linezolid, and 24 h S. aureus infection vs. 24 h S. aureus vancomycin) in mice using Kyoto Encyclopedia of Genes and Genomes (KEGG) identified toll-like receptor signaling pathway to be common to every comparison groups studied. Glycerolipid metabolism pathway was uniquely associated only with linezolid treatment comparison group. The findings of this study provide the evidence that protein synthesis inhibitor like linezolid does a better job in treating MRSA sepsis compared to cell wall acting antibiotics like vancomycin.

Dataset Information

Antistaphylococcal activity of DX-619 alone and in combination with vancomycin, teicoplanin, and linezolid assessed by time-kill synergy testing.

Publications

Antistaphylococcal activity of DX-619 alone and in combination with vancomycin, teicoplanin, and linezolid assessed by time-kill synergy testing.

Similar Datasets

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