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Title: Development of antimicrobial resistance in Acinetobacter spp and methicillin-resistant Staphylococcus aureus
Author: Davies, Sarah Elisabeth
ISNI:       0000 0004 2730 4207
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2009
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Background: Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA) represent the most worrying Gram-negative and Gram-positive nosocomial pathogens of the present age. They are of increasing concern in the clinical environment due to their multi-drug resistance and the dwindling therapeutic options available. A. baumannii is the most frequently isolated clinical species of the genus, and is able to rapidly acquire resistance. Hypermutators, most frequently deficient in mismatch repair (MMR) via defects in the mutS gene, have been associated with antimicrobial resistance in several bacterial populations. To date, however, the potential role of MMR-deficient mutators in the development of resistance in clinical Acinetobacter spp. has not been investigated. Biocides, most notably chlorhexidine (CHX), are increasingly used in the hospital environment to prevent bacterial spread. This has led to concerns about the development of reduced biocide susceptibility and associated antibiotic resistance in hospital bacterial populations, where there is frequent exposure to both of these factors. The effect of CHX upon defined clinical MRSA isolates is examined here. Methods: The mutS gene of clinical Acinetobacter spp. isolates with varying sensitivities was sequenced and compared to establish whether any variations were present. Mutation studies were performed on isolates by challenging them with ciprofloxacin to determine whether different mutS types correlated with any variation in their ability to develop significant fluoroquinolone resistance. The response of clinical MRSA isolates to a range of CHX concentrations was examined with susceptibility testing methods, and effects were compared with standard strains. Determination of post-exposure minimum inhibitory concentrations (MICs) of a range of antibiotics enabled evaluation of whether exposure to CHX had an effect on susceptibility to antibiotics. Results: Variation was observed in the mutS gene of clinical Acinetobacter spp. isolates, with greater homology observed as resistance increased. A highly conserved and previously unreported amino acid sequence was discovered in resistant isolates. Nonresistant isolates with this ‘R-type’ mutS sequence appeared to have a greater ability to develop significant ciprofloxacin resistance. Clinical MRSA isolates had varying susceptibility to CHX, and there were differences in the susceptibility of standard strains compared to clinical isolates. CHX residues exerted a prolonged minimal inhibitory effect, and several increases in antibiotic MICs following CHX exposure were observed. Conclusions: The correlation of the mutS sequence with mutation ability suggests that defects in the mutS gene may have a role to play in the ability of certain Acinetobacter spp. to rapidly acquire resistance. This could have implications for the treatment of Acinetobacter spp. infections, and may enable quick determination of which clinical isolates have the potential to develop clinically significant resistance. Incomplete eradication due to the prolonged minimal effect of CHX residues may act as a selective pressure in the hospital environment, allowing survival of reduced susceptibility MRSA isolates. Increases in antibiotic MICs following CHX exposure is of grave concern for the future of biocide usage.
Supervisor: Amyes, Sebastian G. B. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: acinetobacter ; methicillin-resistant Staphylococcus aureus ; MRSA ; antimicrobial resistance ; MutS bacterial protein ; chlorhexidine