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Title: Development and stability of non-susceptibility to vancomycin in methicillin-resistant staphylococcus aureus
Authors: Doddangoudar, V
Boost, M
O'Donoghue, M 
Appelbaum, P
Issue Date: 2010
Source: 20th European Congress of Clinical Microbiology & Infectious Diseases, Vienna, Austria, 10-13 April, 2010 How to cite?
Abstract: Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) with non-susceptibility to vancomycin (VISA) was first documented in 1997, but the underlying mechanisms remain unclear. Reduced susceptibility is typically reported in isolates from patients who have received vancomycin therapy, usually lasting several weeks. We induced and tracked hVISA/VISA development in MRSA clinical isolates by exposure to sub-inhibitory levels of vancomycin and determined the stability of these non-susceptible phenotypes.
Method: 30 clinical isolates of MRSA were subjected to increasing concentrations of vancomycin based on their initial and subsequent MIC to vancomycin for 60 days. Strains were incubated with vancomycin at 50% MIC for 48h at 370C. The MICs were then determined by standard agar dilution and spiral gradient endpoint (SGE) methods and strains passaged to fresh media. After 60 days, stability of non-susceptibility was determined by transferring the strains to fresh drug-free broth every 48h and determining MIC weekly for a further 60 days. Development and loss of resistance patterns were plotted.
Results: All isolates developed non-susceptibility, with final MICs by 60 days ranging from 6-20µg/ml (mean 10µg/ml, MIC90 20µg/ml). Time required for the VISA development varied from 24-54 days and several distinct patterns of MIC increase were observed. Removal of drug pressure led to loss of non-susceptibility (mean MIC of 2.1µg/ml (range 0.5–5)) in all but one strain (20µg/ml) after 4 weeks.
Conclusion: It is important to recognize the strong potential for MRSA strains to become vancomycin non-susceptible, as currently there is general belief that hVISA/VISA development are rare events. All isolates became vancomycin non-susceptible by 60 days. Of 6 strains reaching an MIC 20µg/ml, equivalent to CLSI resistance definition, one converted to a stable phenotype. Current terminology may need to be re-addressed, as hVISA/VISA can reach 20µg/ml though not having vanA. Whilst non-susceptibility is clearly linked to selective pressure, the rapid development within the period of regular therapy demonstrates that treatment failure could easily occur. Use of SGE provided exact MICs rather than the large stepwise increments of doubling dilutions, allowing patterns of non-susceptibility development to be determined. Further work on non-susceptibility development is continuing, examining the mutations in regulator genes during development and loss of non-susceptibility.
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