Safety of Tedizolid as Suppressive Antimicrobial Therapy for Patients With Complex Implant-Associated Bone and Joint Infection due to Multidrug-Resistant Gram-Positive Pathogens: Results From the TediSAT Cohort Study.
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SUBMITTER: Ferry T
PROVIDER: S-EPMC8320277 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Antimicrobial resistance (AMR) poses a significant worldwide public health crisis that continues to threaten our ability to successfully treat bacterial infections. With the decline in effectiveness of conventional antimicrobial therapies and the lack of new antibiotic pipelines, there is a renewed interest in exploring the potential of metal-based antimicrobial compounds. Antimony-based compounds with a long history of use in medicine have re-emerged as potential antimicrobial agents. We previously synthesized a series of novel organoantimony(V) compounds complexed with cyanoximates with a strong potential of antimicrobial activity against several AMR bacterial and fungal pathogens. Here, five selected compounds were studied for their antibacterial efficacy against three important bacterial pathogens: Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus. Among five tested compounds, SbPh4ACO showed antimicrobial activity against all three bacterial strains with the MIC of 50-100 µg/mL. The minimum bactericidal concentration/MIC values were less than or equal to 4 indicating that the effects of SbPh4ACO are bactericidal. Moreover, ultra-thin electron microscopy revealed that SbPh4ACO treatment caused membrane disruption in all three strains, which was further validated by increased membrane permeability. We also showed that SbPh4ACO acted synergistically with the antibiotics, polymyxin B and cefoxitin used to treat AMR strains of P. aeruginosa and S. aureus, respectively, and that at synergistic MIC concentration 12.5 µg/mL, its cytotoxicity against the cell lines, Hela, McCoy, and A549 dropped below the threshold. Overall, the results highlight the antimicrobial potential of novel antimony-based compound, SbPh4ACO, and its use as a potentiator of other antibiotics against both Gram-positive and Gram-negative bacterial pathogens.ImportanceAntibiotic resistance presents a critical global public health crisis that threatens our ability to combat bacterial infections. In light of the declining efficacy of traditional antibiotics, the use of alternative solutions, such as metal-based antimicrobial compounds, has gained renewed interest. Based on the previously synthesized innovative organoantimony(V) compounds, we selected and further characterized the antibacterial efficacy of five of them against three important Gram-positive and Gram-negative bacterial pathogens. Among these compounds, SbPh4ACO showed broad-spectrum bactericidal activity, with membrane-disrupting effects against all three pathogens. Furthermore, we revealed the synergistic potential of SbPh4ACO when combined with antibiotics, such as cefoxitin, at concentrations that exert no cytotoxic effects tested on three mammalian cell lines. This study offers the first report on the mechanisms of action of novel antimony-based antimicrobial and presents the therapeutic potential of SbPh4ACO in combating both Gram-positive and Gram-negative bacterial pathogens while enhancing the efficacy of existing antibiotics.
| S-EPMC11237720 | biostudies-literature
Project description:BACKGROUND:Telavancin is a lipoglycopeptide bactericidal against gram-positive pathogens. METHODS:Two methodologically identical, double-blind studies (0015 and 0019) were conducted involving patients with hospital-acquired pneumonia (HAP) due to gram-positive pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA). Patients were randomized 1:1 to telavancin (10 mg/kg every 24 h) or vancomycin (1 g every 12 h) for 7-21 days. The primary end point was clinical response at follow-up/test-of-cure visit. RESULTS:A total of 1503 patients were randomized and received study medication (the all-treated population). In the pooled all-treated population, cure rates with telavancin versus vancomycin were 58.9% versus 59.5% (95% confidence interval [CI] for the difference, -5.6% to 4.3%). In the pooled clinically evaluable population (n = 654), cure rates were 82.4% with telavancin and 80.7% with vancomycin (95% CI for the difference, -4.3% to 7.7%). Treatment with telavancin achieved higher cure rates in patients with monomicrobial S. aureus infection and comparable cure rates in patients with MRSA infection; in patients with mixed gram-positive/gram-negative infections, cure rates were higher in the vancomycin group. Incidence and types of adverse events were comparable between the treatment groups. Mortality rates for telavancin-treated versus vancomycin-treated patients were 21.5% versus 16.6% (95% CI for the difference, -0.7% to 10.6%) for study 0015 and 18.5% versus 20.6% (95% CI for the difference, -7.8% to 3.5%) for study 0019. Increases in serum creatinine level were more common in the telavancin group (16% vs 10%). CONCLUSIONS:The primary end point of the studies was met, indicating that telavancin is noninferior to vancomycin on the basis of clinical response in the treatment of HAP due to gram-positive pathogens.
| S-EPMC3060890 | biostudies-literature
Project description:Microbes evolve rapidly by modifying their genomes through mutations or through the horizontal acquisition of mobile genetic elements (MGEs) linked with fitness traits such as antimicrobial resistance (AMR), virulence, and metabolic functions. We conducted a multicentric study in India and collected different clinical samples for decoding the genome sequences of bacterial pathogens associated with sepsis, urinary tract infections, and respiratory infections to understand the functional potency associated with AMR and its dynamics. Genomic analysis identified several acquired AMR genes (ARGs) that have a pathogen-specific signature. We observed that blaCTX-M-15, blaCMY-42, blaNDM-5, and aadA(2) were prevalent in Escherichia coli, and blaTEM-1B, blaOXA-232, blaNDM-1, rmtB, and rmtC were dominant in Klebsiella pneumoniae. In contrast, Pseudomonas aeruginosa and Acinetobacter baumannii harbored blaVEB, blaVIM-2, aph(3'), strA/B, blaOXA-23, aph(3') variants, and amrA, respectively. Regardless of the type of ARG, the MGEs linked with ARGs were also pathogen-specific. The sequence type of these pathogens was identified as high-risk international clones, with only a few lineages being predominant and region-specific. Whole-cell proteome analysis of extensively drug-resistant K. pneumoniae, A. baumannii, E. coli, and P. aeruginosa strains revealed differential abundances of resistance-associated proteins in the presence and absence of different classes of antibiotics. The pathogen-specific resistance signatures and differential abundance of AMR-associated proteins identified in this study should add value to AMR diagnostics and the choice of appropriate drug combinations for successful antimicrobial therapy.
| S-EPMC10434301 | biostudies-literature
Project description:Multidrug-resistant pathogens pose a serious threat to human health. For decades, the antibiotic vancomycin has been a potent option when treating Gram-positive multidrug-resistant infections. Nonetheless, in recent decades, we have begun to see an increase in vancomycin-resistant bacteria. Here, we show that the nuclear factor-kappa B (NF-κB) inhibitor N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (IMD0354) was identified as a positive hit through a Caenorhabditis elegans-methicillin-resistant Staphylococcus aureus (MRSA) infection screen. IMD0354 was a potent bacteriostatic drug capable of working at a minimal inhibitory concentration (MIC) as low as 0.06 µg/mL against various vancomycin-resistant strains. Interestingly, IMD0354 showed no hemolytic activity at concentrations as high as 16 µg/mL and is minimally toxic to C. elegans in vivo with 90% survival up to 64 µg/mL. In addition, we demonstrated that IMD0354's mechanism of action at high concentrations is membrane permeabilization. Lastly, we found that IMD0354 is able to inhibit vancomycin-resistant Staphylococcus aureus (VRSA) initial cell attachment and biofilm formation at sub-MIC levels and above. Our work highlights that the NF-κB inhibitor IMD0354 has promising potential as a lead compound and an antimicrobial therapeutic candidate capable of combating multidrug-resistant bacteria.
| S-EPMC7601562 | biostudies-literature
Project description:BackgroundTedizolid is a novel oxazolidinone antibacterial with potent activity against a wide range of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Although tedizolid is approved by the US Food and Drug Administration (FDA) for treatment of patients with acute bacterial skin and skin structure infection, commercial susceptibility testing products for tedizolid are not currently available. This study evaluated the usefulness of applying linezolid susceptibility test results as a surrogate for predicting susceptibility to tedizolid in clinically significant Gram-positive pathogens.MethodsGram-positive isolates (N = 10,702) were obtained from annual surveillance programs conducted between 2009 and 2012, from 3 tedizolid clinical trials, and from a preclinical study of the antibacterial activity of tedizolid. Susceptibility testing of linezolid and tedizolid was performed using the reference broth microdilution method in accordance with Clinical and Laboratory Standards Institute methods.ResultsThe minimum inhibitory concentration (MIC) distribution for tedizolid and linezolid against this set of isolates was consistent with that of previous reports. Scatter plot analysis of relevant subsets of organisms was performed and showed high categorical agreement between linezolid and tedizolid MIC results (>99% for staphylococci and streptococci; >98% for enterococci). Very major error rates (ie, tedizolid false-susceptible errors) were very low and within acceptable limits for a surrogate agent: S. aureus and other staphylococcal species, 0%; Enterococcus spp, 0.2%; and Streptococcus spp, 0%.ConclusionsHigh categorical agreement between MIC values for tedizolid and linezolid and low very major error rates were shown for all organism groups tested, supporting the use of linezolid as a reliable surrogate for tedizolid susceptibility testing.
| S-EPMC4291835 | biostudies-literature
Project description:The growing antimicrobial resistance to last-line antimicrobials among Gram-positive pathogens remains a major healthcare emergency worldwide. Therefore, the search for new small molecules targeting multidrug-resistant pathogens remains of great importance. In this paper, we report the synthesis and in vitro antimicrobial activity characterisation of novel thiazole derivatives using representative Gram-negative and Gram-positive strains, including tedizolid/linezolid-resistant S. aureus, as well as emerging fungal pathogens. The 4-substituted thiazoles 3h, and 3j with naphthoquinone-fused thiazole derivative 7 with excellent activity against methicillin and tedizolid/linezolid-resistant S. aureus. Moreover, compounds 3h, 3j and 7 showed favourable activity against vancomycin-resistant E. faecium. Compounds 9f and 14f showed broad-spectrum antifungal activity against drug-resistant Candida strains, while ester 8f showed good activity against Candida auris which was greater than fluconazole. Collectively, these data demonstrate that N-2,5-dimethylphenylthioureido acid derivatives could be further explored as novel scaffolds for the development of antimicrobial candidates targeting Gram-positive bacteria and drug-resistant pathogenic fungi.
| S-EPMC9952208 | biostudies-literature
Project description:To survive during colonization or infection of the human body, microorganisms must defeat antimicrobial peptides, which represent a key component of innate host defense in phagocytes and on epithelia. However, is not known how the clinically important group of Gram-positive bacteria sense antimicrobial peptides to coordinate a directed defensive response. By determining the genome-wide gene regulatory response to human beta defensin 3 in the nosocomial pathogen Staphylococcus epidermidis, we discovered an antimicrobial peptide sensor system that controls major specific resistance mechanisms to antimicrobial peptides and is unrelated to the Gram-negative PhoP/PhoQ system. Wild type untreated in triplicate is compared to wild type treated in triplicate along with three mutants in triplicate with and without treatment of human beta defensin 3, totalling 30 samples
2010-05-26 | E-GEOD-7163 | biostudies-arrayexpress
Project description:To survive during colonization or infection of the human body, microorganisms must defeat antimicrobial peptides, which represent a key component of innate host defense in phagocytes and on epithelia. However, is not known how the clinically important group of Gram-positive bacteria sense antimicrobial peptides to coordinate a directed defensive response. By determining the genome-wide gene regulatory response to human beta defensin 3 in the nosocomial pathogen Staphylococcus epidermidis, we discovered an antimicrobial peptide sensor system that controls major specific resistance mechanisms to antimicrobial peptides and is unrelated to the Gram-negative PhoP/PhoQ system. Keywords: Wild type control vs treated vs mutant
2008-02-26 | GSE7163 | GEO
Project description:Gram-negative bacterial resistance to antimicrobials has had an exponential increase at a global level during the last decades and represent an everyday challenge, especially for the hospital practice of our era. Concerted efforts from the researchers and the industry have recently provided several novel promising antimicrobials, resilient to various bacterial resistance mechanisms. There are new antimicrobials that became commercially available during the last five years, namely, cefiderocol, imipenem-cilastatin-relebactam, eravacycline, omadacycline, and plazomicin. Furthermore, other agents are in advanced development, having reached phase 3 clinical trials, namely, aztreonam-avibactam, cefepime-enmetazobactam, cefepime-taniborbactam, cefepime-zidebactam, sulopenem, tebipenem, and benapenem. In this present review, we critically discuss the characteristics of the above-mentioned antimicrobials, their pharmacokinetic/pharmacodynamic properties and the current clinical data.
| S-EPMC10135111 | biostudies-literature
Project description:Due to the rapidly increasing prevalence of multidrug-resistant bacterial strains, the need for new antimicrobial drugs to treat infections has become urgent. Bacteriocins, which are antimicrobial peptides of bacterial origin, are considered potential alternatives to conventional antibiotics and have attracted widespread attention in recent years. Among these bacteriocins, lantibiotics, especially two-component lantibiotics, exhibit potent antimicrobial activity against some clinically relevant Gram-positive pathogens and have potential applications in the pharmaceutical industry. In this study, we characterized a novel two-component lantibiotic termed thusin that consists of Thsα, Thsβ, and Thsβ' (mutation of Thsβ, A14G) and that was isolated from a B. thuringiensis strain BGSC 4BT1. Thsα and Thsβ (or Thsβ') exhibit optimal antimicrobial activity at a 1:1 ratio and act sequentially to affect target cells, and they are all highly thermostable (100°C for 30 min) and pH tolerant (pH 2.0 to 9.0). Thusin shows remarkable efficacy against all tested Gram-positive bacteria and greater activities than two known lantibiotics thuricin 4A-4 and ticin A4, and one antibiotic vancomycin against various bacterial pathogens (Bacillus cereus, Listeria monocytogenes, Staphylococcus aureus (MRSA), Staphylococcus sciuri, Enterococcus faecalis, and Streptococcus pneumoniae). Moreover, thusin is also able to inhibit the outgrowth of B. cereus spores. The potent antimicrobial activity of thusin against some Gram-positive pathogens indicates that it has potential for the development of new drugs.
| S-EPMC4949975 | biostudies-literature