scholarly journals Subinhibitory Dalbavancin Attenuates Exotoxin Production from Methicillin-Sensitive and Methicillin-Resistant Staphylococcus aureusIn Vitro

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Sarah E. Hobdey ◽  
Eva J. Katahira ◽  
Pamela Dockstader ◽  
Stephen M. Davidson ◽  
Laura Bond ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Toxin Production ◽  
Glycopeptide Antibiotics ◽  
Glycopeptide Antibiotic ◽  
Beta Lactam ◽  
Methicillin Resistant ◽  
Content Type ◽  
Recent Success ◽  
Subinhibitory Concentrations

ABSTRACT This study investigated the effects of subinhibitory doses of the lipoglycopeptide antibiotic dalbavancin on Staphylococcus aureus toxin production in vitro. S. aureus toxin production levels were compared to those seen with the natural glycopeptide antibiotic vancomycin and with representative beta-lactam and oxazolidinone antibiotics. While neither dalbavancin nor vancomycin adversely affected toxin production, of these glycopeptide antibiotics, only dalbavancin significantly attenuated toxin production at subinhibitory concentrations. These findings support the recent success of dalbavancin for treatment of staphylococcal infections.

scholarly journals Exposure of Staphylococcus aureus to Subinhibitory Concentrations of β-Lactam Antibiotics Induces Heterogeneous Vancomycin-Intermediate Staphylococcus aureus

2014 ◽  
Vol 58 (9) ◽  
pp. 5306-5314 ◽  
Author(s):  
Mélanie Roch ◽  
Perrine Clair ◽  
Adriana Renzoni ◽  
Marie-Elisabeth Reverdy ◽  
Olivier Dauwalder ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Prolonged Exposure ◽  
Brain Heart Infusion ◽  
Vancomycin Resistance ◽  
Beta Lactam ◽  
Glycopeptide Resistance ◽  
Content Type ◽  
Beta Lactam Antibiotics ◽  
Subinhibitory Concentrations

ABSTRACTGlycopeptides are known to select for heterogeneous vancomycin-intermediateStaphylococcus aureus(h-VISA) from susceptible strains. In certain clinical situations, h-VISA strains have been isolated from patients without previous exposure to glycopeptides, such as cystic fibrosis patients, who frequently receive repeated treatments with beta-lactam antibiotics. Our objective was to determine whether prolonged exposure to beta-lactam antibiotics can induce h-VISA. We exposed 3 clinical vancomycin-susceptible methicillin-resistantStaphylococcus aureus(MRSA) strains to ceftazidime, ceftriaxone, imipenem, and vancomycin (as a control) at subinhibitory concentrations for 18 daysin vitro. Population analyses showed progressive increases in vancomycin resistance; seven of the 12 derived strains obtained after induction were classified as h-VISA according to the following criteria: area under the curve (AUC) on day 18/AUC of Mu3 of ≥90% and/or growth on brain heart infusion (BHI) agar with 4 mg/liter vancomycin. The derived isolates had thickened cell walls proportional to the level of glycopeptide resistance. Genes known to be associated with glycopeptide resistance (vraSR,yvqF, SA1703,graRS,walKR, andrpoB) were PCR sequenced; node novomutations were observed upon beta-lactam exposure. To determine whethertrfA, a gene encoding a glycopeptide resistance factor, was essential in the selection of h-VISA upon beta-lactam pressure, atrfA-knockout strain was generated by allelic replacement. Indeed, beta-lactam exposure of this mutated strain showed no capacity to induce vancomycin resistance. In conclusion, these results showed that beta-lactam antibiotics at subinhibitory concentrations can induce intermediate vancomycin resistancein vitro. This induction required an intacttrfAlocus. Our results suggest that prior use of beta-lactam antibiotics can compromise vancomycin efficacy in the treatment of MRSA infections.

scholarly journals In VitroActivities of Daptomycin-, Vancomycin-, and Teicoplanin-Loaded Polymethylmethacrylate against Methicillin-Susceptible, Methicillin-Resistant, and Vancomycin-Intermediate Strains of Staphylococcus aureus

2011 ◽  
Vol 55 (12) ◽  
pp. 5480-5484 ◽  
Author(s):  
Yuhan Chang ◽  
Wen-Chien Chen ◽  
Pang-Hsin Hsieh ◽  
Dave W. Chen ◽  
Mel S. Lee ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
High Performance ◽  
Low Dose ◽  
Antibacterial Activities ◽  
High Dose ◽  
Bone Cements ◽  
Antibacterial Effects ◽  
Methicillin Resistant ◽  
Content Type

ABSTRACTThe objective of this study was to evaluate the antibacterial effects of polymethylmethacrylate (PMMA) bone cements loaded with daptomycin, vancomycin, and teicoplanin against methicillin-susceptibleStaphylococcus aureus(MSSA), methicillin-resistantStaphylococcus aureus(MRSA), and vancomycin-intermediateStaphylococcus aureus(VISA) strains. Standardized cement specimens made from 40 g PMMA loaded with 1 g (low-dose), 4 g (middle-dose) or 8 g (high-dose) antibiotics were tested for elution characteristics and antibacterial activities. The patterns of release of antibiotics from the cement specimens were evaluated usingin vitrobroth elution assay with high-performance liquid chromatography. The activities of broth elution fluid against differentStaphylococcus aureusstrains (MSSA, MRSA, and VISA) were then determined. The antibacterial activities of all the tested antibiotics were maintained after being mixed with PMMA. The cements loaded with higher dosages of antibiotics showed longer elution periods. Regardless of the antibiotic loading dose, the teicoplanin-loaded cements showed better elution efficacy and provided longer inhibitory periods against MSSA, MRSA, and VISA than cements loaded with the same dose of vancomycin or daptomycin. Regarding the choice of antibiotics for cement loading in the treatment ofStaphylococcus aureusinfection, teicoplanin was superior in terms of antibacterial effects.

scholarly journals Comparison of Borate Bioactive Glass and Calcium Sulfate as Implants for the Local Delivery of Teicoplanin in the Treatment of Methicillin-Resistant Staphylococcus aureus-Induced Osteomyelitis in a Rabbit Model

2015 ◽  
Vol 59 (12) ◽  
pp. 7571-7580 ◽  
Author(s):  
Wei-Tao Jia ◽  
Qiang Fu ◽  
Wen-Hai Huang ◽  
Chang-Qing Zhang ◽  
Mohamed N. Rahaman
Keyword(s):  
Staphylococcus Aureus ◽  
Bioactive Glass ◽  
Calcium Sulfate ◽  
Rabbit Model ◽  
Local Delivery ◽  
Methicillin Resistant ◽  
Content Type ◽  
Borate Bioactive Glass ◽  
Phosphate Buffered Saline

ABSTRACTThere is growing interest in biomaterials that can cure bone infection and also regenerate bone. In this study, two groups of implants composed of 10% (wt/wt) teicoplanin (TEC)-loaded borate bioactive glass (designated TBG) or calcium sulfate (TCS) were created and evaluated for their ability to release TECin vitroand to cure methicillin-resistantStaphylococcus aureus(MRSA)-induced osteomyelitis in a rabbit model. When immersed in phosphate-buffered saline (PBS), both groups of implants provided a sustained release of TEC at a therapeutic level for up to 3 to 4 weeks while they were gradually degraded and converted to hydroxyapatite. The TBG implants showed a longer duration of TEC release and better retention of strength as a function of immersion time in PBS. Infected rabbit tibiae were treated by debridement, followed by implantation of TBG or TCS pellets or intravenous injection with TEC, or were left untreated. Evaluation at 6 weeks postimplantation showed that the animals implanted with TBG or TCS pellets had significantly lower radiological and histological scores, lower rates of MRSA-positive cultures, and lower bacterial loads than those preoperatively and those of animals treated intravenously. The level of bone regeneration was also higher in the defects treated with the TBG pellets. The results showed that local TEC delivery was more effective than intravenous administration for the treatment of MRSA-induced osteomyelitis. Borate glass has the advantages of better mechanical strength, more desirable kinetics of release of TEC, and a higher osteogenic capacity and thus could be an effective alternative to calcium sulfate for local delivery of TEC.

scholarly journals Evaluation of Ceftaroline Alone and in Combination against Biofilm-Producing Methicillin-Resistant Staphylococcus aureus with Reduced Susceptibility to Daptomycin and Vancomycin in anIn VitroPharmacokinetic/Pharmacodynamic Model

2015 ◽  
Vol 59 (8) ◽  
pp. 4497-4503 ◽  
Author(s):  
Katie E. Barber ◽  
Jordan R. Smith ◽  
Cortney E. Ireland ◽  
Blaise R. Boles ◽  
Warren E. Rose ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Medical Device ◽  
Bloodstream Infections ◽  
Methicillin Resistant ◽  
Content Type ◽  
Elimination Half ◽  
Antimicrobial Protection ◽  
Mrsa Strains ◽  
Post Hoc

ABSTRACTAnnually, medical device infections are associated with >250,000 catheter-associated bloodstream infections (CLABSI), with up to 25% mortality.Staphylococcus aureus, a primary pathogen in these infections, is capable of biofilm production, allowing organism persistence in harsh environments, offering antimicrobial protection. With increases inS. aureusisolates with reduced susceptibility to current agents, ceftaroline (CPT) offers a therapeutic alternative. Therefore, we evaluated whether CPT would have a role against biofilm-producing methicillin-resistantS. aureus(MRSA), including those with decreased susceptibilities to alternative agents. In this study, we investigated CPT activity alone or combined with daptomycin (DAP) or rifampin (RIF) against 3 clinical biofilm-producing MRSA strains in anin vitrobiofilm pharmacokinetic/pharmacodynamic (PK/PD) model. Simulated antimicrobial regimens were as follows: 600 mg of CPT every 8 h (q8h) (free maximum concentration of drug [fCmax], 17.04 mg/liter; elimination half-life [t1/2], 2.66 h), 12 mg/kg of body weight/day of DAP (fCmax, 14.7 mg/liter;t1/2, 8 h), and 450 mg of RIF q12h (fCmax, 3.5 mg/liter;t1/2, 3.4 h), CPT plus DAP, and CPT plus RIF. Samples were obtained and plated to determine colony counts. Differences in log10CFU/cm2were evaluated by analysis of variance with Tukey'spost hoctest. The strains were CPT and vancomycin susceptible and DAP nonsusceptible (DNS). CPT displayed activity throughout the experiment. DAP demonstrated initial activity with regrowth at 24 h in all strains. RIF was comparable to the drug-free control, and little benefit was observed when combined with CPT. CPT plus DAP displayed potent activity, with an average log10CFU/cm2reduction of 3.33 ± 1.01 from baseline. CPT demonstrated activity against biofilm-producing DNS MRSA. CPT plus DAP displayed therapeutic enhancement over monotherapy, providing a potential option for difficult-to-treat medical device infections.

scholarly journals In VitroEfficacies and Resistance Profiles of Rifampin-Based Combination Regimens for Biofilm-Embedded Methicillin-Resistant Staphylococcus aureus

2013 ◽  
Vol 57 (11) ◽  
pp. 5717-5720 ◽  
Author(s):  
Hung-Jen Tang ◽  
Chi-Chung Chen ◽  
Kuo-Chen Cheng ◽  
Kuan-Ying Wu ◽  
Yi-Chung Lin ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Fusidic Acid ◽  
Antibacterial Activities ◽  
Methicillin Resistant ◽  
Content Type ◽  
Biofilm Model ◽  
Rifampin Resistance ◽  
Combination Regimens ◽  
Resistant Mutation

ABSTRACTTo compare thein vitroantibacterial efficacies and resistance profiles of rifampin-based combinations against methicillin-resistantStaphylococcus aureus(MRSA) in a biofilm model, the antibacterial activities of vancomycin, teicoplanin, daptomycin, minocycline, linezolid, fusidic acid, fosfomycin, and tigecycline alone or in combination with rifampin against biofilm-embedded MRSA were measured. The rifampin-resistant mutation frequencies were evaluated. Of the rifampin-based combinations, rifampin enhances the antibacterial activities of and even synergizes with fusidic acid, tigecycline, and, to a lesser extent, linezolid, fosfomycin, and minocycline against biofilm-embedded MRSA. Such combinations with weaker rifampin resistance induction activities may provide a therapeutic advantage in MRSA biofilm-related infections.

scholarly journals Novel Combinations of Vancomycin plus Ceftaroline or Oxacillin against Methicillin-Resistant Vancomycin-Intermediate Staphylococcus aureus (VISA) and Heterogeneous VISA

2013 ◽  
Vol 57 (5) ◽  
pp. 2376-2379 ◽  
Author(s):  
B. J. Werth ◽  
C. Vidaillac ◽  
K. P. Murray ◽  
K. L. Newton ◽  
G. Sakoulas ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Inverse Correlation ◽  
Fluorescent Dye ◽  
Beta Lactam ◽  
Significant Inverse Correlation ◽  
Methicillin Resistant ◽  
Content Type ◽  
Time Kill ◽  
Wall Interactions

ABSTRACTWe demonstrated a significant inverse correlation between vancomycin and beta-lactam susceptibilities in vancomycin-intermediateStaphylococcus aureus(VISA) and heterogeneous VISA (hVISA) isolates. Using time-kill assays, vancomycin plus oxacillin or ceftaroline was synergistic against 3 of 5 VISA and 1 of 5 hVISA isolates or 5 of 5 VISA and 4 of 5 hVISA isolates, respectively. Beta-lactam exposure reduced overall vancomycin-Bodipy (dipyrrometheneboron difluoride [4,4-difluoro-4-bora-3a,4a-diaza-s-indacene] fluorescent dye) binding but may have improved vancomycin-cell wall interactions to improve vancomycin activity. Further research is warranted to elucidate the mechanism behind vancomycin and beta-lactam synergy.

scholarly journals In VitroPharmacodynamics of Human Simulated Exposures of Ceftaroline and Daptomycin against MRSA, hVISA, and VISA with and without Prior Vancomycin Exposure

2013 ◽  
Vol 58 (2) ◽  
pp. 672-677 ◽  
Author(s):  
Amira A. Bhalodi ◽  
Mao Hagihara ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Staphylococcus Aureus ◽  
Body Weight ◽  
Sequential Therapy ◽  
Free Drug ◽  
Pharmacodynamic Model ◽  
Prior Exposure ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Infection

ABSTRACTThe effects of prior vancomycin exposure on ceftaroline and daptomycin therapy against methicillin-resistantStaphylococcus aureus(MRSA) have not been widely studied. Humanized free-drug exposures of vancomycin at 1 g every 12 h (q12h), ceftaroline at 600 mg q12h, and daptomycin at 10 mg/kg of body weight q24h were simulated in a 96-hin vitropharmacodynamic model against three MRSA isolates, including one heteroresistant vancomycin-intermediateS. aureus(hVISA) isolate and one VISA isolate. A total of five regimens were tested: vancomycin, ceftaroline, and daptomycin alone for the entire 96 h, and then sequential therapy with vancomycin for 48 h followed by ceftaroline or daptomycin for 48 h. Microbiological responses were measured by the changes in log10CFU during 96 h from baseline. Control isolates grew to 9.16 ± 0.32, 9.13 ± 0.14, and 8.69 ± 0.28 log10CFU for MRSA, hVISA, and VISA, respectively. Vancomycin initially achieved ≥3 log10CFU reductions against the MRSA and hVISA isolates, followed by regrowth beginning at 48 h; minimal activity was observed against VISA. The change in 96-h log10CFU was largest for sequential therapy with vancomycin followed by ceftaroline (−5.22 ± 1.2,P= 0.010 versus ceftaroline) and for sequential therapy with vancomycin followed by ceftaroline (−3.60 ± 0.6,P= 0.037 versus daptomycin), compared with daptomycin (−2.24 ± 1.0), vancomycin (−1.40 ± 1.8), and sequential therapy with vancomycin followed by daptomycin (−1.32 ± 1.0,P> 0.5 for the last three regimens). Prior exposure of vancomycin at 1 g q12h reduced the initial microbiological response of daptomycin, particularly for hVISA and VISA isolates, but did not affect the response of ceftaroline. In the scenario of poor vancomycin response for high-inoculum MRSA infection, a ceftaroline-containing regimen may be preferred.

scholarly journals Susceptibility of Methicillin-Resistant Staphylococcus aureus to Five Quinazolinone Antibacterials

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Sara Ceballos ◽  
Choon Kim ◽  
Yuanyuan Qian ◽  
Shahriar Mobashery ◽  
Mayland Chang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Amino Acid ◽  
Binding Proteins ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Methicillin Resistant ◽  
Content Type ◽  
Penicillin Binding Proteins

ABSTRACT The in vitro activities of five quinazolinone antibacterials, compounds Q1 to Q5, were tested against 210 strains of methicillin-resistant Staphylococcus aureus (MRSA). The MIC50/MIC90 values (in μg/ml) were as follows: Q1, 0.5/2; Q2, 1/4; Q3, 2/4; Q4, 0.06/0.25; and Q5, 0.125/0.5. Several strains with high MIC values (from 8 to >32 μg/ml) for some of these compounds exhibited amino acid changes in the penicillin-binding proteins, which are targeted by these antibacterials.

scholarly journals Updating Molecular Diagnostics for Detecting Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus Isolates in Blood Culture Bottles

2019 ◽  
Vol 57 (11) ◽  
Author(s):  
Fred C. Tenover ◽  
Isabella A. Tickler ◽  
Victoria M. Le ◽  
Scott Dewell ◽  
Rodrigo E. Mendes ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Blood Culture ◽  
False Negative ◽  
The United States ◽  
Molecular Diagnostic ◽  
Methicillin Resistant ◽  
Content Type ◽  
Target Nucleic Acid ◽  
Antimicrobial Resistance Genes

ABSTRACT Molecular diagnostic tests can be used to provide rapid identification of staphylococcal species in blood culture bottles to help improve antimicrobial stewardship. However, alterations in the target nucleic acid sequences of the microorganisms or their antimicrobial resistance genes can lead to false-negative results. We determined the whole-genome sequences of 4 blood culture isolates of Staphylococcus aureus and 2 control organisms to understand the genetic basis of genotype-phenotype discrepancies when using the Xpert MRSA/SA BC test (in vitro diagnostic medical device [IVD]). Three methicillin-resistant S. aureus (MRSA) isolates each had a different insertion of a genetic element in the staphylococcal cassette chromosome (SCCmec)-orfX junction region that led to a misclassification as methicillin-susceptible S. aureus (MSSA). One strain contained a deletion in spa, which produced a false S. aureus-negative result. A control strain of S. aureus that harbored an SCCmec element but no mecA (an empty cassette) was correctly called MSSA by the Xpert test. The second control contained an SCCM1 insertion. The updated Xpert MRSA/SA BC test successfully detected both spa and SCCmec variants of MRSA and correctly identified empty-cassette strains of S. aureus as MSSA. Among a sample of 252 MSSA isolates from the United States and Europe, 3.9% contained empty SCCmec cassettes, 1.6% carried SCCM1, <1% had spa deletions, and <1% contained SCCmec variants other than those with SCCM1. These data suggest that genetic variations that may interfere with Xpert MRSA/SA BC test results remain rare. Results for all the isolates were correct when tested with the updated assay.

scholarly journals Candida albicans Impacts Staphylococcus aureus Alpha-Toxin Production via Extracellular Alkalinization

mSphere ◽  
2019 ◽  
Vol 4 (6) ◽  
Author(s):  
Olivia A. Todd ◽  
Mairi C. Noverr ◽  
Brian M. Peters
Keyword(s):  
Staphylococcus Aureus ◽  
Candida Albicans ◽  
Quorum Sensing ◽  
Bacterial Pathogen ◽  
Toxin Production ◽  
Extracellular Ph ◽  
Morbidity And Mortality ◽  
Alpha Toxin ◽  
Content Type

ABSTRACT Candida albicans and Staphylococcus aureus are common causes of nosocomial infections with severe morbidity and mortality. Murine polymicrobial intra-abdominal infection (IAI) with C. albicans and S. aureus results in acute mortality dependent on the secreted cytolytic effector alpha-toxin. Here, we confirmed that alpha-toxin is elevated during polymicrobial growth compared to monomicrobial growth in vitro. Therefore, this study sought to unravel the mechanism by which C. albicans drives enhanced staphylococcal alpha-toxin production. Using a combination of functional and genetic approaches, we determined that an intact agr quorum sensing regulon is necessary for enhanced alpha-toxin production during coculture and that a secreted candidal factor likely is not implicated in elevating agr activation. As the agr system is pH sensitive, we observed that C. albicans raises the pH during polymicrobial growth and that this correlates with increased agr activity and alpha-toxin production. Modulation of the pH could predictably attenuate or activate agr activity during coculture. By using a C. albicans mutant deficient in alkalinization (stp2Δ/Δ), we confirmed that modulation of the extracellular pH by C. albicans can drive agr expression and toxin production. Additionally, the use of various Candida species (C. glabrata, C. dubliniensis, C. tropicalis, C. parapsilosis, and C. krusei) demonstrated that those capable of raising the extracellular pH correlated with elevated agr activity and alpha-toxin production during coculture. Overall, we demonstrate that alkalinization of the extracellular pH by the Candida species leads to sustained activation of the staphylococcal agr system. IMPORTANCE Candida albicans and Staphylococcus aureus are commonly coisolated from central venous catheters and deep-seated infections, including intra-abdominal sepsis. Thus, they represent a significant cause of nosocomial morbidity and mortality. Yet how these organisms behave in the context of polymicrobial growth remains poorly understood. In this work, we set out to determine the mechanism by which activation of the staphylococcal agr quorum sensing system and production of its major virulence effector alpha-toxin is enhanced during coculture with C. albicans. Surprisingly, we likely ruled out that a secreted candidal factor drives this process. Instead, we demonstrated that alkalinization of the extracellular milieu by C. albicans and other Candida species correlated with elevated agr activity. Thus, we propose a mechanism where modulation of the extracellular pH by fungal opportunists can indirectly alter virulence of a bacterial pathogen. Uncovering molecular events that drive interkingdom pathogenicity mechanisms may enhance surveillance and treatment for devastating polymicrobial infections.

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