Reduced Vancomycin Susceptibility in an<i>In Vitro</i>Catheter-Related Biofilm Model Correlates with Poor Therapeutic Outcomes in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

Abdelhady, Wessam; Bayer, Arnold S.; Seidl, Kati; Nast, Cynthia C.; Kiedrowski, Megan R.; Horswill, Alexander R.; Yeaman, Michael R.; Xiong, Yan Q.

doi:10.1128/aac.02073-12

Cited by 60 publications

(64 citation statements)

References 48 publications

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“…D-Cycloserine and fosfomycin inhibit different steps in the intracellular pathway leading to the biosynthesis of lipid II, the bacterial cell wall precursor (53). In addition, sublethal doses of the glycopeptide antibiotic vancomycin have previously been shown to induce eDNA-dependent biofilm in several vancomycin-susceptible and vancomycin-resistant MRSA strains (44,(54)(55)(56). Vancomycin binds to the terminal D-Ala-D-Ala residues of NAG/NAM peptides, thereby blocking proper cell wall assembly (54).…”

Section: Discussionmentioning

confidence: 99%

Effects of Low-Dose Amoxicillin on Staphylococcus aureus USA300 Biofilms

Mlynek

Callahan

Shimkevitch

et al. 2016

Antimicrob Agents Chemother

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cPrevious studies showed that sub-MIC levels of ␤-lactam antibiotics stimulate biofilm formation in most methicillin-resistant Staphylococcus aureus (MRSA) strains. Here, we investigated this process by measuring the effects of sub-MIC amoxicillin on biofilm formation by the epidemic community-associated MRSA strain USA300. We found that sub-MIC amoxicillin increased the ability of USA300 cells to attach to surfaces and form biofilms under both static and flow conditions. We also found that USA300 biofilms cultured in sub-MIC amoxicillin were thicker, contained more pillar and channel structures, and were less porous than biofilms cultured without antibiotic. Biofilm formation in sub-MIC amoxicillin correlated with the production of extracellular DNA (eDNA). However, eDNA released by amoxicillin-induced cell lysis alone was evidently not sufficient to stimulate biofilm. Sub-MIC levels of two other cell wall-active agents with different mechanisms of action-D-cycloserine and fosfomycin-also stimulated eDNA-dependent biofilm, suggesting that biofilm formation may be a mechanistic adaptation to cell wall stress. Screening a USA300 mariner transposon library for mutants deficient in biofilm formation in sub-MIC amoxicillin identified numerous known mediators of S. aureus ␤-lactam resistance and biofilm formation, as well as novel genes not previously associated with these phenotypes. Our results link cell wall stress and biofilm formation in MRSA and suggest that eDNA-dependent biofilm formation by strain USA300 in low-dose amoxicillin is an inducible phenotype that can be used to identify novel genes impacting MRSA ␤-lactam resistance and biofilm formation.

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Section: Discussionmentioning

confidence: 99%

Effects of Low-Dose Amoxicillin on Staphylococcus aureus USA300 Biofilms

Mlynek

Callahan

Shimkevitch

et al. 2016

Antimicrob Agents Chemother

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“…Vancomycin-intermediate S. aureus (VISA) (4-8 mg l À1 ) and heteroresistant [(h)VISA] isolates have also been associated with endocarditis [1][2][3]7]. VISA and hVISA isolates have multiple phenotypic and metabolic differences compared with susceptible isolates, such as reduced autolysis and gradual thickening of the cell wall, changes in global gene regulators including down-regulation of agr, increased expression of surface adhesins that bind fibrinogen and fibronectin, and attenuated virulence [3,[8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Identification of a distinctive phenotype for endocarditis-associated clonal complex 22 MRSA isolates with reduced vancomycin susceptibility

Marbach

Boakes

Lynham

et al. 2017

Journal of Medical Microbiology

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Purpose. We previously identified an association between CC22 meticillin-resistant Staphylococcus aureus (MRSA) bloodstream infection isolates with an elevated vancomycin MIC (V-MIC) in the susceptible range (1.5-2 mg l À1 ) and endocarditis. This study explores whether these isolates have a specific phenotype consistent with the clinical findings.Methodology. CC22 and CC30 MRSA isolates with high (1.5-2 mg l À1 ) and low ( 0.5 mg l À1 ) V-MICs were tested for fibrinogen and fibronectin binding, virulence in a Galleria mellonella caterpillar model, phenol soluble modulin production and accessory gene regulator (agr) expression.Results. CC22 high V-MIC, but not CC30 high V-MIC isolates, showed sustained fibrinogen binding through a stationary growth phase and increased PSM production, specifically PSMa1, compared with respective low V-MIC isolates. Expression was lower in both CC22 and CC30 high V-MIC isolates compared with respective low V-MIC isolates, although there was no associated reduction in virulence in the caterpillar model. Conclusions.The identification of a distinct phenotype for CC22 high V-MIC isolates supports the hypothesis that bacterial factors contribute to the mechanism underlying their association with endocarditis. Further study of these isolates could shed light on the molecular mechanism of endocarditis in humans.

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“…The other half of the survivors were left untreated for an additional 3 days for assessment of relapse. At sacrifice, catheters were quantitatively cultured by using standard assays of CFU counts per catheter (25). In addition, animals were serially imaged daily after infected-catheter implantation for bioluminescent signals (BLS) with the IVIS (Caliper Life Sciences).…”

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confidence: 99%

Comparative Efficacies of Tedizolid Phosphate, Linezolid, and Vancomycin in a Murine Model of Subcutaneous Catheter-Related Biofilm Infection Due to Methicillin-Susceptible and -Resistant Staphylococcus aureus

Bayer

Abdelhady

et al. 2016

Antimicrob Agents Chemother

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bTedizolid, a novel oxazolidinone, exhibits bacteriostatic activity through inhibition of protein synthesis. The efficacies of tedizolid, linezolid, and vancomycin were compared in a murine catheter-related biofilm infection caused by methicillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) strains engineered for bioluminescence. We observed significantly improved efficacy in terms of decreased S. aureus densities and bioluminescent signals in the tedizolid-treated group versus the linezolid-and vancomycin-treated groups in the model of infection caused by the MSSA and MRSA strains. Staphylococcus aureus is a leading cause of skin and skin structure infections and is particularly associated with intravenous (i.v.) catheters (1-4). Despite the current use of newer antibiotics, infections due to S. aureus remain a significant problem. The emergence of methicillin-resistant S. aureus (MRSA) and high rates of vancomycin clinical failures emphasize this public health threat (5, 6). Therefore, potential alternative strategies for the treatment of such infections are urgently needed.Tedizolid is a novel oxazolidinone derivative that has potent activity against staphylococci and enterococci (7, 8). It exerts bacteriostatic microbial activity through inhibition of protein synthesis by binding to the 50S ribosomal subunit of the bacteria. It has been reported that tedizolid is more active against staphylococci and enterococci than linezolid is in vitro (9, 10).In this investigation, we evaluated (i) the MICs (11) and in vitro killing activities (12, 13) of tedizolid, linezolid, and vancomycin against lux mutant methicillin-susceptible S. aureus (MSSA) (Xen29) and MRSA (Xen30) strains (4, 14, 15), (ii) the influence of these antibiotics on biofilm formation (16,17), and (iii) the real-time in vivo efficacy of tedizolid versus that of linezolid and vancomycin in a well-characterized model of murine subcutaneous catheter-related infection (18) caused by the MSSA or MRSA strain by using a novel bioluminescence in vivo imaging system (IVIS).The IVIS was developed to provide a sensitive and noninvasive technique for rapid and real-time monitoring of therapeutic efficacy (4,14,(19)(20)(21). In the murine subcutaneous catheter-related infection model, BALB/c mice (female, 18 to 22 g; Jackson Laboratory) were infected by implanting a precolonized Teflon catheter segment (1 cm) inoculated with the bioluminescent strains at 1 ϫ 10 6 CFU/catheter. At 3 days after catheter implantation, animals were randomized to receive (i) control treatment with the vehicle, (ii) tedizolid phosphate at 10 mg/kg i.v. twice a day (bid), (iii) linezolid at 80 mg/kg i.v. bid, or (iv) vancomycin at 110 mg/kg subcutaneously (s.c.) bid. These antibiotic doses were chosen to simulate pharmacokinetic values similar to those achieved by the recommended dosing of humans, i.e., 200 mg of tedizolid i.v. once daily (22), 600 mg of linezolid i.v. bid (23), and 1 g of vancomycin i.v. bid (24). Treatments lasted 3 and 6 days for MSS...

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Reduced Vancomycin Susceptibility in anIn VitroCatheter-Related Biofilm Model Correlates with Poor Therapeutic Outcomes in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

Cited by 60 publications

References 48 publications

Effects of Low-Dose Amoxicillin on Staphylococcus aureus USA300 Biofilms

Effects of Low-Dose Amoxicillin on Staphylococcus aureus USA300 Biofilms

Identification of a distinctive phenotype for endocarditis-associated clonal complex 22 MRSA isolates with reduced vancomycin susceptibility

Comparative Efficacies of Tedizolid Phosphate, Linezolid, and Vancomycin in a Murine Model of Subcutaneous Catheter-Related Biofilm Infection Due to Methicillin-Susceptible and -Resistant Staphylococcus aureus

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