|Author:||Doddangoudar, Vijaya Chandranna|
|Title:||Vancomycin intermediate-resistant Staphylococcus aureus : characterization of resistance development, detection and treatment strategies|
Hong Kong Polytechnic University -- Dissertations
|Pages:||xxxii, 376 leaves : ill. ; 30 cm.|
|Abstract:||Since the emergence of vancomycin non-susceptible Staphylococcus aureus (hVISA/VISA) efforts have been made to develop a reliable detection method, understand the mechanism of non-susceptibility development and loss, and improve the treatment of VISA infection. While several methods have been introduced for detection of hVISA/VISA, rapid and correct detection remains difficult due to their various limitations. These limitations could delay appropriate therapy. Therefore, a rapid and reliable resistance detection method is required. The genetic changes associated with development and loss of hVISA/VISA has been tracked in few strains and remains unclear. More work is required to identify important determinants associated with non-susceptibility. Identification of such changes could support development of a molecular detection method. Vancomycin remains the drug of choice for methicillin-resistant S. aureus (MRSA) treatment and with the high prevalence of MRSA in Hong Kong, it is not surprising that hVISA/VISA has been reported. VISA has been reported worldwide and determination of the level of hVISA/VISA in Hong Kong is important for formulating infection control guidelines. Additionally, resistance acquisition by MRSA against currently available antibiotics is of concern. Efforts have been made towards the development of new molecules and several new agents are in the pipeline, but such agents are expensive, have possible unknown side effects and may not be available for some time. In response to these problems, this work aimed to evaluate the spiral gradient endpoint (SGE) as a non-susceptibility detection method, further the understanding of non-susceptibility development and loss by examining genotypic and phenotypic changes, estimate hVISA/VISA prevalence in Hong Kong, and to study the effects of Traditional Chinese Medicine (TCM) herbal extracts alone and in combination with vancomycin against VISA.|
SGE was found to have good reproducibility, there being excellent correlation between MICs generated by SGE and agar dilution (r² = 0.950). Tracking genotypic and phenotypic changes in both clinical and laboratory-induced VISA strains indicated the importance of mutations in vraS and graR during development and loss of non-susceptibility, in the development of stable phenotypes, and ability to reach an elevated MIC (20 mg/L) in the absence of vanA. This study has also demonstrated the role of stop codons in delaying non-susceptibility development and formation of stable phenotypes. The prevalence rate of hVISA/VISA in Hong Kong hospital was found to be 14.53% (48/330 isolates). Additionally, it was found that strains showing non-susceptible subpopulations rapidly progressed to non-susceptibility in the presence of 2 mg/L vancomycin and that SGE was effective in detecting such strains. Of the three TCM herbs investigated for antimicrobial activity, Radix scutellariae was found to be effective against VISA both alone and in combination with vancomycin at 2 g/L and 0.25 g/L respectively. In summary, SGE offers a reliable alternative for the detection of hVISA/VISA. Mutations in vraS and graR appear to be important for development of non-susceptibility. In particular the presence of stop codons in two component-regulatory systems appears to be important in non-susceptibility development and loss. The prevalence rate of vancomycin non-susceptibility in local isolates were relatively high and testing revealed additional strains with, resistant sub-populations which could rapidly progress to VISA. Antimicrobial-activity of RS indicated that this herb may have the potential to be used in treatment of MRSA and VISA infections, alone and in combination with vancomycin.
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