Phenotypic Expression of Oxacillin Resistance in Staphylococcus epidermidis : Roles of mecA Transcriptional Regulation and Resistant-Subpopulation Selection

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Abstract
The MICs for many oxacillin-resistant (OR) Staphylococcus epidermidis (ORSE) strains are below the Staphylococcus aureus methicillin or oxacillin resistance breakpoint. The difficulty detecting the OR phenotype in S. epidermidis may be due to extreme heterotypy in resistance expression and/or transcriptional repression of mecA , the OR gene, by MecI. To determine the role of these factors in the phenotypic expression of ORSE, 17 geographically diverse mecI + ORSE isolates representing 14 distinct pulsed-field gel electrophoresis pulse types (>3 band differences) were investigated. Thirteen of the 14 types contained mecI and mecA promoter-operator sequences known to be associated with maximal mecA repression, and in all isolates, mecA transcription was repressed. All 17 were heterotypic in their resistance expression. Oxacillin MICs ranged from 1 to 128 μg/ml and increased for 16 of 17 isolates after β-lactam induction. Allelic replacement inactivation of mecI in three isolates similarly resulted in a four- to sevenfold increase in MIC. In the two of these three isolates producing β-lactamase, mecA transcription was regulated by both mecI and β-lactamase regulatory sequences. Heterotypic expression of resistance in these three isolates was unaffected by either β-lactam induction or mecI inactivation. However, prolonged incubation in concentrations of oxacillin just sufficient to produce a lag in growth (0.5 to 1.0 μg/ml) converted the population resistance expression from heterotypic to homotypic. Homotypic conversion could also be demonstrated in microtiter wells during MIC determinations in one isolate for which the MIC was high. We conclude that the phenotypic expression of S. epidermidis OR in broth can be affected both by mecA transcriptional regulation and by subpopulation resistance expression.