The effectiveness of a multifocal training to improve the treatment of community-acquired MRSA skin and soft tissue infections

Practitioners and researchers have documented an increase in community-acquired methicillin resistant staphylococcus aureus (CA-MRSA) skin and soft tissue infections (SSTIs). This increase is causing stress and concern for the individuals infected and the families of those infected. The impact of a practitioner based multifocal training has not been clearly established. The purpose of this capstone project was to determine the effect of a multifocal training on CA-MRSA SSTIs that educated primary care practitioners about treatment guidelines, Marion County, WV susceptibility data, I&D technique, and a patient education tool versus common treatment practices to increase practitioner\u27s knowledge and utilization of evidence based guidelines in the treatment of CA-MRSA SSTIs. Multifocal trainings educated practitioners concerning CA -MRSA SSTIs in Marion County, West Virginia

Investigating the effectiveness of innovative antimicrobial molecules against bacterial species of clinical interest

L’aumento dell’antibiotico resistenza nei batteri e il conseguente impatto sul trattamento delle infezioni umane rappresentano uno dei principali problemi in tutto il mondo. Lo sviluppo di nuovi e più potenti farmaci è ormai urgente e i Nuovi Inibitori delle Topoisomerasi Batteriche (NBTIs) potrebbero rappresentare una classe di antibiotici importanti poichè in grado di agire contemporaneamente su due target microbici, la DNA girasi e la topoisomerasi IV. In questo studio una serie di NBTIs sintetizzata dai laboratori Angelini, è stata analizzata per la loro attività antimicrobica nei confronti di ceppi di collezione Gram- positivi e -negativi e di ceppi clinici multi-resistenti. Tutte le molecole dimostravano una maggiore capacità di inibire la crescita di Staphylococcus aureus. Tuttavia, l'attività battericida era più evidente nei confronti di Escherichia coli. Negli studi di time-kill, le molecole 73013 e 73015 possedevano un'attività battericida paragonabile ed erano i composti più efficaci. Esse inoltre dimostravano una buona attività antibatterica in vitro contro ceppi clinici multiresistenti di MRSA e di Acinetobacter baumannii. La soppressione della crescita batterica da parte di 73015 e 73016 si osservava dopo 1h di esposizione con tutti i ceppi testati e l'effetto post antibiotico era paragonabile a quello ottenuto con la ciprofloxacina. Le due molecole, rispetto alla ciprofloxacina, usate anche nella selezione di mutanti resistenti di S. aureus inducevano in primis mutazioni puntiformi, nei geni gyrA e gyrB. In conclusione i nuovi composti, possiedono un meccanismo di azione, diverso da quello dei fluorochinoloni, con una buona attività antibatterica in vitro nei confronti di ceppi multi-resistenti e fluorochinoloni resistenti. Questi risultati preliminari, ma molto promettenti, aprono la strada ad ulteriori studi per chiarire le potenzialità di questi NBTI nello sviluppo di nuovi antibiotici ad ampio spettro, contro una vasta gamma di batteri patogeni.The increasing rate of bacterial resistance to clinical antimicrobial agents and its impact on treatment of infectious diseases have begun a unique problem worldwide. The development of newer antimicrobials or with improved activity, is urgently needed, and the Novel Bacterial Topoisomerase Inhibitors (NBTIs) could represent a new class of relevant antibiotics targeting both bacterial DNA gyrase and topoisomerase IV. This work focused on the study of the effectiveness of a series of NBTIs synthesized by Angelini laboratories. Activity of the NBTIs against reference Gram-positive and -negative strains and multi-resistant clinical isolates has been investigated. All NBTIs showed greater activity in growth inhibition against Staphylococcus aureus. However, the bactericidal activity of different molecules was more evident against Escherichia coli. In time-kill studies, two molecules, 73013 and 73015, revealed as the most effective compounds. They also showed good in vitro antibacterial activity against clinical quinolone-resistant MRSA and multi-resistant Acinetobacter baumannii strains. Persistent suppression of bacterial growth after intermittent antimicrobial exposure was observed with each tested drug against all organisms. All strains exhibited a lag in the resumption of normal growth after 1h-exposure to 73015 and 73016 and this effect was comparable to that obtained with ciprofloxacin. The occurrence of resistance to 73015 and 73016 was also investigated in S. aureus. Sequencing analyses of DNA gyrase and topoisomerase IV encoding genes of mutants disclosed that the new molecules induced, by single-step mutations, modification in gyrA and gyrB genes. These findings confirmed the novel mechanism of action of the new compounds, compared to that of fluoroquinolones. These preliminary but promising results designate these molecules as potential candidates to develop a new broad-spectrum antimicrobial agent to be used against a wide range of bacterial pathogens

Investigating the effectiveness of innovative antimicrobial molecules against bacterial species of clinical interest

openL’aumento dell’antibiotico resistenza nei batteri e il conseguente impatto sul trattamento delle infezioni umane rappresentano uno dei principali problemi in tutto il mondo. Lo sviluppo di nuovi e più potenti farmaci è ormai urgente e i Nuovi Inibitori delle Topoisomerasi Batteriche (NBTIs) potrebbero rappresentare una classe di antibiotici importanti poichè in grado di agire contemporaneamente su due target microbici, la DNA girasi e la topoisomerasi IV. In questo studio una serie di NBTIs sintetizzata dai laboratori Angelini, è stata analizzata per la loro attività antimicrobica nei confronti di ceppi di collezione Gram- positivi e -negativi e di ceppi clinici multi-resistenti. Tutte le molecole dimostravano una maggiore capacità di inibire la crescita di Staphylococcus aureus. Tuttavia, l'attività battericida era più evidente nei confronti di Escherichia coli. Negli studi di time-kill, le molecole 73013 e 73015 possedevano un'attività battericida paragonabile ed erano i composti più efficaci. Esse inoltre dimostravano una buona attività antibatterica in vitro contro ceppi clinici multiresistenti di MRSA e di Acinetobacter baumannii. La soppressione della crescita batterica da parte di 73015 e 73016 si osservava dopo 1h di esposizione con tutti i ceppi testati e l'effetto post antibiotico era paragonabile a quello ottenuto con la ciprofloxacina. Le due molecole, rispetto alla ciprofloxacina, usate anche nella selezione di mutanti resistenti di S. aureus inducevano in primis mutazioni puntiformi, nei geni gyrA e gyrB. In conclusione i nuovi composti, possiedono un meccanismo di azione, diverso da quello dei fluorochinoloni, con una buona attività antibatterica in vitro nei confronti di ceppi multi-resistenti e fluorochinoloni resistenti. Questi risultati preliminari, ma molto promettenti, aprono la strada ad ulteriori studi per chiarire le potenzialità di questi NBTI nello sviluppo di nuovi antibiotici ad ampio spettro, contro una vasta gamma di batteri patogeni.The increasing rate of bacterial resistance to clinical antimicrobial agents and its impact on treatment of infectious diseases have begun a unique problem worldwide. The development of newer antimicrobials or with improved activity, is urgently needed, and the Novel Bacterial Topoisomerase Inhibitors (NBTIs) could represent a new class of relevant antibiotics targeting both bacterial DNA gyrase and topoisomerase IV. This work focused on the study of the effectiveness of a series of NBTIs synthesized by Angelini laboratories. Activity of the NBTIs against reference Gram-positive and -negative strains and multi-resistant clinical isolates has been investigated. All NBTIs showed greater activity in growth inhibition against Staphylococcus aureus. However, the bactericidal activity of different molecules was more evident against Escherichia coli. In time-kill studies, two molecules, 73013 and 73015, revealed as the most effective compounds. They also showed good in vitro antibacterial activity against clinical quinolone-resistant MRSA and multi-resistant Acinetobacter baumannii strains. Persistent suppression of bacterial growth after intermittent antimicrobial exposure was observed with each tested drug against all organisms. All strains exhibited a lag in the resumption of normal growth after 1h-exposure to 73015 and 73016 and this effect was comparable to that obtained with ciprofloxacin. The occurrence of resistance to 73015 and 73016 was also investigated in S. aureus. Sequencing analyses of DNA gyrase and topoisomerase IV encoding genes of mutants disclosed that the new molecules induced, by single-step mutations, modification in gyrA and gyrB genes. These findings confirmed the novel mechanism of action of the new compounds, compared to that of fluoroquinolones. These preliminary but promising results designate these molecules as potential candidates to develop a new broad-spectrum antimicrobial agent to be used against a wide range of bacterial pathogens.SCIENZE DELLA VITA E DELL'AMBIENTEembargoed_20181001DI SANTE, LauraDI SANTE, Laur

<i>Staphylococcus aureus</i> virulence gene studies : a comparative microarray based approach

The development and application of a partial composite S. aureus virulence-associated gene micro array is described. Epidemic, pandemic and sporadic lineages of healthcare associated(HA-) and community-associated (CA-) S. aureus were compared. The clonal population structure was supported but further evidence for large-scale recombination events was obtained. Phage structural genes linked with the CA phenotype were identified and in silico analysis revealed these to be correlated with phage serogroup. CA strains generally carried a PVL-associated phage either of the A or Fb serogroup, whilst the HA strains predominantly carried sero group B phage. It is proposed that carriage of PVL associated phage rather than the specific pvl genes is correlated with the CA phenotype.These findings further support the role of the accessory genome in shaping the epidemiology of S. aureus.The microarray was used to study gene expression in isogenic strains differing by a deletion in the agr locus. Microarray analysis revealed significant differences between the levels of expression of several genes of the normal and mutant strains. However, RNAIII levels in the non-mutant strain were found to be cell density independent, indicating that the expected quorum sensing mechanism was not functional.Expression profiles of cells grown under biofilm simulating conditions were compared to their planktonic counterparts. Biofilm cells displayed a typical expression profile that was different from both the actively growing planktonic exponential cells and the planktonic stationary cells. The strongest feature of the biofilm state was high level expression of the haemolysin genes. This model therefore is amenable to exploitation in studies designed to improve our understanding of the mechanisms underlining biofilm survival and regulation after long periods of growth

Efficient surveillance for healthcare-associated infections spreading between hospitals

Early detection of new or novel variants of nosocomial pathogens is a public health priority. We show that, for healthcare-associated infections that spread between hospitals as a result of patient movements, it is possible to design an effective surveillance system based on a relatively small number of sentinel hospitals. We apply recently developed mathematical models to patient admission data from the national healthcare systems of England and The Netherlands. Relatively short detection times are achieved once 10-20% hospitals are recruited as sentinels and only modest reductions are seen as more hospitals are recruited thereafter. Using a heuristic optimization approach to sentinel selection, the same expected time to detection can be achieved by recruiting approximately half as many hospitals. Our study provides a robust evidence base to underpin the design of an efficient sentinel hospital surveillance system for novel nosocomial pathogens, delivering early detection times for reduced expenditure and effort

ANTIMICROBIAL CHARACTERIZATION AND THERAPEUTIC APPLICATIONS OF NOVEL SYNTHETIC THIAZOLE COMPOUNDS AGAINST MULTIDRUG-RESISTANT STAPHYLOCOCCI AND ENTEROCOCCI

For more than a century, antibiotics have been valuable allies in combating an array of bacterial infections. However, each year nearly 23,000 people in the United States of America and 25,000 people in Europe die due to infections that are recalcitrant to currently available antimicrobials. The emergence of drug-resistant bacterial species, namely methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), has limited the efficacy of several classes of antibiotics. Compounding this problem further is that many large pharmaceutical companies have left the field of antibacterial drug discovery given the high cost of innovation and low return on investment. Collectively, this highlights an urgent, unmet need to identify and develop new antibacterial agents that attack unique molecular targets in bacterial pathogens. Here, we investigate the antibacterial activity of a new series of phenylthiazole antibiotics against a panel of clinically-relevant ‘ESKAPE’ pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). The lead compound 1 was identified through whole-cell screening of libraries of substituted thiazoles and thiadiazoles. Subsequent derivatives were constructed in an attempt to enhance potency, decrease toxicity to host tissues, and improve the lead compound’s drug-like properties. Broth microdilution assay results show that the lead 1 and two derivatives (2 and 3) possess potent activity against Gram-positive bacterial pathogens including MRSA, methicillin-resistant Staphylococcus pseudintermedius (an emerging pathogen of importance in veterinary medicine) and VRE, inhibiting the growth of clinical isolates at concentrations as low as 0.5 µg/mL. The presence of the outer membrane and efflux pumps appears to impede the antibacterial activity of the phenylthiazoles against Gram-negative bacteria. MRSA and VRE mutants resistant to the phenylthiazoles could not be isolated, both via single-step and multi-step resistance selection analysis. The compounds exerted a rapid bactericidal effect, targeting cell wall synthesis as deduced from Bacterial Cytological Profiling. Transposon mutagenesis suggested three possible targets: YubA, YubB and YubD. YubB is undecaprenyl diphosphate phosphatase (UPPP) and UPPP as well as undecaprenyl diphosphate synthase (UPPS) were inhibited by 1, as confirmed by traditional enzyme inhibition assays. YubA and YubD are annotated as transporters and may also be targets since 1 collapsed the proton motive force in membrane vesicles. This indicates the phenylthiazole antibacterial agents have a unique mechanism of action that involves inhibition of key enzymes involved in peptidoglycan biosynthesis and potential transporters. This may contribute to the inability to generate bacterial mutants exhibiting resistance to the phenylthiazoles. The compounds were not toxic up to 20-40 µg/mL against different human cell lines including keratinocytes (HaCaT), kidney cells (HEK293), and colorectal cells (HRT-18). Additionally, the compounds were found to be non-toxic (at 20 µg/mL) in a Caenorhabditis elegans animal model. Closer inspection of the physicochemical profile and in silico pharmacokinetic profile of the lead 1 and more metabolically-stable analogue 3 revealed potential application for use topically (for localized skin infections), intravenously (for systemic infections), and as decolonizing agents. Utilizing a murine skin infection model, 1 and 3 were found to significantly reduce the burden of MRSA in infected lesions by more than 96%. Furthermore, both compounds (at 20 µg/mL) were potent in vivo, reducing the burden of VRE in infected C. elegans. Taken altogether, the results indicate that phenylthiazoles 1 and 3 are promising novel topical antibacterial agents and decolonizing agents for use in the treatment of drug-resistant staphylococcal and enterococcal infections

Microbicidal Effects of α- and θ-Defensins Against Antibiotic-Resistant \u3cem\u3eStaphylococcus aureus\u3c/em\u3e and \u3cem\u3ePseudomonas aeruginosa\u3c/em\u3e

Antibiotic-resistant bacterial pathogens threaten public health. Because many antibiotics target specific bacterial enzymes or reactions, corresponding genes may mutate under selection and lead to antibiotic resistance. Accordingly, antimicrobials that selectively target overall microbial cell integrity may offer alternative approaches to therapeutic design. Naturally occurring mammalian α- and θ-defensins are potent, non-toxic microbicides that may be useful for treating infections by antibiotic-resistant pathogens because certain defensin peptides disrupt bacterial, but not mammalian, cell membranes. To test this concept, clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), including vancomycin heteroresistant strains, and ciprofloxacin-resistant Pseudomonas aeruginosa (CipR-PA) were tested for sensitivity to α-defensins Crp-4, RMAD-4 and HNPs 1-3, and to RTD-1, macaque θ-defensin-1. In vitro, 3 μM Crp-4, RMAD-4 and RTD-1 reduced MRSA cell survival by 99%, regardless of vancomycin susceptibility. For PA clinical isolates that differ in fluoroquinolone resistance and virulence phenotype, peptide efficacy was independent of strain ciprofloxacin resistance, site of isolation or virulence factor expression. Thus, Crp-4, RMAD-4 and RTD-1 are effective in vitro antimicrobials against clinical isolates of MRSA and CipR-PA, perhaps providing templates for development of α- and θ-defensin-based microbicides against antibiotic resistant or virulent infectious agents

ACYLATED NANOFIBROUS CHITOSAN BIOMATERIALS FOR PROLONGED BIOFILM INHIBITION AND PAIN MITIGATION

ACYLATED NANOFIBROUS CHITOSAN BIOMATERIALS FOR PROLONGED BIOFILM INHIBITION AND PAIN MITIGATIO

Communicable and Environmental Diseases and Emergency Preparedness 2010-2012 Annual Report

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