Ceftaroline Activity against mecC-Containing Staphylococcus aureus.
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ABSTRACT:
SUBMITTER: Lahiri SD
PROVIDER: S-EPMC4540908 | biostudies-literature | 2015 Sep
REPOSITORIES: biostudies-literature
Publications
Ceftaroline Activity against mecC-Containing Staphylococcus aureus.
Lahiri Sushmita D SD Alm Richard A RA
Journal of clinical microbiology 20150701 9
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Project description:The report of methicillin-resistant Staphylococcus aureus (MRSA) encoding a divergent mecA gene in 2011 was highly significant. This homologue, designated mecC, poses diagnostic problems with the potential to be misdiagnosed as methicillin-sensitive S. aureus, with important potential consequences for individual patients and for the surveillance of MRSA. mecC MRSA have now been reported from 13 European countries and have been isolated from 14 different host species, with evidence of a recent increase in Denmark. The emergence of mecC MRSA is a topic of interest to human and veterinary microbiology, and we consider it timely to review here its discovery and subsequent investigation.
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Project description:Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a clinical outcome worse than that in non-CF patients with an increased rate of declined lung function. Telavancin, an approved lipoglycopeptide used to treat infections due to S. aureus, has a dual mode of action causing inhibition of peptidoglycan synthesis and membrane depolarization. MRSA infections in CF patients remain an important problem with no foreseeable decline in prevalence rates. Although telavancin is currently in clinical use for the treatment of complicated skin infections and hospital-acquired pneumonia, the activity against S. aureus infections in CF patients has not been investigated. In this work, we studied the activity of telavancin against CF patient-derived S. aureus strains collected from geographically diverse CF centers in the United States. We found that the telavancin MIC90 was 0.06 μg/ml, 8-fold lower than the ceftaroline or daptomycin MIC90 and 25-fold lower than the linezolid and vancomycin MIC90 We demonstrate that telavancin at serum free concentrations has rapid bactericidal activity, with a decrease of more than 3 log10 CFU/ml being achieved during the first 4 to 6 h of treatment, performing better in this assay than vancomycin and ceftaroline, including against S. aureus strains resistant to ceftaroline. Telavancin resistance was infrequent (0.3%), although we found that it can occur in vitro in both CF- and non-CF patient-derived S. aureus strains by progressive passages with subinhibitory concentrations. Genetic analysis of telavancin-resistant in vitro mutants showed gene polymorphisms in cell wall and virulence genes and increased survival in a Galleria mellonella infection model. Thus, we conclude that telavancin represents a promising therapeutic option for infections in CF patients with potent in vitro activity and a low resistance development potential.
| S-EPMC6125506 | biostudies-literature
Project description:In staphylococci, methicillin resistance is mediated by mecA-encoded penicillin-binding protein 2a (PBP2a), which has a low affinity for beta-lactams. Recently, a novel PBP2a homolog was described as being encoded by mecC, which shares only 70% similarity to mecA. To prove that mecC is the genetic determinant that confers methicillin resistance in Staphylococcus aureus, a mecC knockout strain was generated. The S. aureus ΔmecC strain showed considerably reduced oxacillin and cefoxitin MICs (0.25 and 4 μg/ml, respectively) compared to those of the corresponding wild-type methicillin-resistant S. aureus (MRSA) strain (8 and 16 μg/ml, respectively). Complementing the mutant in trans with wild-type mecC restored the resistance to oxacillin and cefoxitin. By expressing mecC and mecA in different S. aureus clonal lineages, we found that mecC mediates resistance irrespective of the genetic strain background, yielding oxacillin and cefoxitin MIC values comparable to those with mecA. In addition, we showed that mecC expression is inducible by oxacillin, which supports the assumption that a functional beta-lactam-dependent regulatory system is active in MRSA strains possessing staphylococcal cassette chromosome mec (SCCmec) type XI. In summary, we showed that mecC is inducible by oxacillin and mediates beta-lactam resistance in SCCmec type XI-carrying strains as well as in different S. aureus genetic backgrounds. Furthermore, our results could explain the comparatively low MICs for clinical mecC-harboring S. aureus isolates.
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Project description:Staphylococcus aureus, including methicillin-susceptible (MSSA) and -resistant (MRSA) strains, is an important pathogen of bacterial pneumonia. As antibiotic concentrations at the site of infection are responsible for killing, we investigated the activity of human-simulated epithelial lining fluid (ELF) exposures of three antibiotics (ceftaroline, ceftriaxone, and vancomycin) commonly used for treatment of S. aureus pneumonia. An in vitro pharmacodynamic model was used to simulate ELF exposures of vancomycin (1 g every 12 h [q12h]), ceftaroline (600 mg q12h and q8h), and ceftriaxone (2 g q24h and q12h). Four S. aureus isolates (2 MSSA and 2 MRSA) were evaluated over 72 h with a starting inoculum of ? 10(6) CFU/ml. Time-kill curves were constructed, and microbiological response (change in log10 CFU/ml from 0 h and the area under the bacterial killing and regrowth curve [AUBC]) was assessed in duplicate. The change in 72-h log10 CFU/ml was largest for ceftaroline q8h (reductions of >3 log10 CFU/ml against all strains). This regimen also achieved the lowest AUBC against all organisms (P < 0.05). Vancomycin produced reliable bacterial reductions of 0.9 to 3.3 log10 CFU/ml, while the activity of ceftaroline q12h was more variable (reductions of 0.2 to 2.3 log10 CFU/ml against 3 of 4 strains). Both regimens of ceftriaxone were poorly active against MSSA tested (0.1 reduction to a 1.8-log10 CFU/ml increase). Against these S. aureus isolates, ELF exposures of ceftaroline 600 mg q8h exhibited improved antibacterial activity compared with ceftaroline 600 mg q12h and vancomycin, and therefore, this q8h regimen deserves further evaluation for the treatment of bacterial pneumonia. These data also suggest that ceftriaxone should be avoided for S. aureus pneumonia.
| S-EPMC4249498 | biostudies-other
Project description:Implant infections due to bacterial biofilms constitute a major healthcare challenge today. One way to address this clinical need is to modify the implant surface with an antimicrobial nanomaterial. Among such nanomaterials, nanosilver is arguably the most powerful one, due to its strong and broad antimicrobial activity. However, there is still a lack of understanding on how physicochemical characteristics of nanosilver coatings affect their antibiofilm activity. More specifically, the contributions of silver (Ag)+ ion-mediated vs. contact-based mechanisms to the observed antimicrobial activity are yet to be elucidated. To address this knowledge gap, we produce here nanosilver coatings on substrates by flame aerosol direct deposition that allows for facile control of the coating composition and Ag particle size. We systematically study the effect of (i) nanosilver content in composite Ag silica (SiO2) coatings from 0 (pure SiO2) up to 50 wt%, (ii) the Ag particle size and (iii) the coating thickness on the antibiofilm activity against Staphylococcus aureus (S. aureus), a clinically-relevant pathogen often present on the surface of surgically-installed implants. We show that the Ag+ ion concentration in solution largely drives the observed antibiofilm effect independently of Ag size and coating thickness. Furthermore, co-incubation of both pure SiO2 and nanosilver coatings in the same well also reveals that the antibiofilm effect stems predominantly from the released Ag+ ions, which is especially pronounced for coatings featuring the smallest Ag particle sizes, rather than direct bacterial contact inhibition. We also examine the biocompatibility of the developed nanosilver coatings in terms of pre-osteoblastic cell viability and proliferation, comparing it to that of pure SiO2. This study lays the foundation for the rational design of nanosilver-based antibiofilm implant coatings.
| S-EPMC7613819 | biostudies-literature
Project description:There are limited data available on the epidemiology and prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in the human population that encode the recently described mecA homologue, mecC. To address this knowledge gap we undertook a prospective prevalence study in England to determine the prevalence of mecC among MRSA isolates.Three hundred and thirty-five sequential MRSA isolates from individual patients were collected from each of six clinical microbiology laboratories in England during 2011-12. These were tested by PCR or genome sequencing to differentiate those encoding mecA and mecC. mecC-positive isolates were further characterized by multilocus sequence typing, spa typing, antimicrobial susceptibility profile and detection of PBP2a using commercially available kits.Nine out of the 2010 MRSA isolates tested were mecC positive, indicating a prevalence among MRSA in England of 0.45% (95% CI 0.24%-0.85%). The remainder were mecA positive. Eight out of these nine mecC MRSA isolates belonged to clonal complex 130, the other being sequence type 425. Resistance to non-?-lactam antibiotics was rare among these mecC MRSA isolates and all were phenotypically identified as MRSA using oxacillin and cefoxitin according to BSAC disc diffusion methodology. However, all nine mecC isolates gave a negative result using three different commercial PBP2a detection assays.mecC MRSA are currently rare among MRSA isolated from humans in England and this study provides an important baseline prevalence rate to monitor future changes, which may be important given the increasing prevalence of mecC MRSA reported in Denmark.
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Project description:Reports of methicillin-resistant Staphylococcus aureus (MRSA) harboring the mecC gene have increased in the UK since first being described. To our diagnostic S. aureus multiplex PCR, a mecC primer set was designed and implemented, and then the prevalence in our patient population was investigated. Fewer than 1% of the clinical isolates possessed the mecC gene, confirming that mecA remains the dominant genetic determinant of MRSA in East London.
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Project description:IntroductionThere have been limited advances in the treatment of bone and joint infections, which currently involves a combination of surgery and antibiotic administration. There is a timely need in orthopedics to develop more effective and less invasive forms of antimicrobial prophylaxis and treatment. The antibacterial effect of adult tissue-derived mesenchymal stem cells (MSCs) has recently been investigated against Escherichia coli and Staphylococcus aureus. The main mechanism of action is postulated to be via MSC production of the cationic antimicrobial peptide, LL-37.MethodsThis study examines the antimicrobial activity of adipose-derived human MSCs (ASCs) on S. aureus, specifically examining the role of LL-37 and regulation of its expression. Bacteria colony-forming unit (CFU) assay was used to assess antimicrobial activity.ResultsOur results showed that the ASC-conditioned medium significantly inhibited the growth of S. aureus under standard culture conditions with or without the continued presence of ASCs. Also, the treatment of ASCs with 1,25-dihydroxy vitamin D3 elevated LL-37 expression and enhanced their antimicrobial activity. In support, treatment with the vitamin D receptor inhibitor, GW0742, blocked the antimicrobial activity of ASCs.ConclusionOur findings clearly demonstrate the antimicrobial activity of adult ASCs against S. aureus and implicate a key regulatory role for vitamin D. Further testing in in vivo models is being pursued to assess the potential application of ASCs as a biocompatible, adjunct treatment for musculoskeletal infections.
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Project description:Daptomycin is recommended for the treatment of Staphylococcus aureus infections due to its bactericidal activity. However, its mechanism of action is poorly understood. The involvement of reactive oxygen species (ROS) in the bactericidal activity of daptomycin has been proved against planktonic S. aureus, but not against the biofilm of S. aureus. Therefore, we evaluated if ROS contributes to the effect of daptomycin against biofilm of S. aureus. Biofilms of wild type, catalase deficient and daptomycin-resistant S. aureus strains were grown in microtiter-plates. After three days, the biofilms were exposed to daptomycin with or without thiourea in the presence of a ROS indicator. After overnight incubation, the amount of ROS and the percentage of surviving bacteria were determined. The bacterial survival was higher and the amount of ROS was lower in the wild type than in the catalase deficient biofilm, demonstrating a protective effect of catalase against daptomycin. The induction of cytotoxic ROS formation by daptomycin was verified by the addition of thiourea, which reduced the amount of ROS and protected the wild type biofilm against high concentrations of daptomycin. Accordingly, only the highest concentration of daptomycin reduced the bacterial survival and increased the ROS formation in the resistant biofilm. In conclusion, daptomycin induced the production of cytotoxic levels of endogenous ROS in S. aureus biofilm and the presence of catalase protected the biofilm against the lethality of the induced ROS.
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