Prevalence of Slow-growth Vancomycin Non-susceptibility In Methicillin-resistant Staphylococcus aureus [PublishAheadOfPrint]

We have previsously reported a novel phenotype of vancomycin-intermediate Staphylococcus aureus (VISA) strains, "slow-VISA," in which colonies appear only after 72 h of incubation. Slow-VISA strains can be difficult to detect because prolonged incubation is required and the phenotype is unstable. To develop a method for detection of slow-VISA isolates, we studied 23 slow-VISA isolates derived from heteroVISA clinical strain Mu3. We identified single nucleotide polymorphisms (SNP) in genes involved in various pathways such as purine/pyrimidine synthesis, cell metabolism, and cell-wall peptidoglycan synthesis, which have been implicated in the stringent response. We found that mupirocin, which also induces a stringent response, caused stable expression of vancomycin resistance. On the basis of these results, we developed a method for detection of slow-VISA using mupirocin 0.032 μg/ml (Patent Application No. PCT/JP2017/008975filed on March 7, 2017). Using this method, we detected 53 (15.6%) slow-VISA isolates among clinical methicillin-resistant S.aureus (MRSA) isolates. In contrast, the VISA phenotype was detected in fewer than 1% of isolates. Deep-sequencing analysis showed that slow-VISA clones are present in small numbers among hVISA isolates, and proliferate in the presence of vancomycin. This slow-VISA subpopulation could account in part for the recurrence and persistence of MRSA infection.

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