Chlorhexidine induces VanA-type vancomycin resistance genes in enterococci

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Abstract:

Chlorhexidine is a bisbiguanide antiseptic used for infection control. Vancomycin-resistant E. faecium (VREfm) is among the leading causes of hospital-acquired infections. VREfm may be exposed to chlorhexidine at supra- and sub-inhibitory concentrations as a result of chlorhexidine bathing and chlorhexidine-impregnated central venous catheter use.

We used RNA sequencing to investigate how VREfm responds to chlorhexidine gluconate exposure. Among the 35 genes up-regulated ≥10-fold after 15 minutes exposure to the MIC of chlorhexidine gluconate were those encoding VanA-type vancomycin resistance (vanHAX) and those associated with reduced daptomycin susceptibility (liaXYZ). We confirmed that vanA up-regulation was not strain- or species-specific by querying other VanA-type VRE. VanB-type genes were not induced. The vanH promoter was found to be responsive to sub-inhibitory chlorhexidine gluconate in VREfm, as was production of the VanX protein. Using vanH reporter experiments in Bacillus subtilis and deletion analysis in VREfm, we found that this phenomenon is VanR-dependent. Deletion of vanR did not result in increased chlorhexidine susceptibility, demonstrating that vanHAX induction is not protective against chlorhexidine. As expected, VanA-type VRE are more sensitive to ceftriaxone in the presence of sub-MIC chlorhexidine. Unexpectedly, VREfm is more susceptible to vancomycin in the presence of sub-inhibitory chlorhexidine, suggesting that chlorhexidine-induced gene expression changes lead to additional alterations in cell wall synthesis. We conclude that chlorhexidine induces expression of VanA-type vancomycin resistance genes and genes associated with daptomycin non-susceptibility. Overall our results indicate that the impacts of sub-inhibitory chlorhexidine exposure on hospital-associated pathogens should be further investigated in laboratory studies.

Reference:

Bhardwaj, P., Ziegler, E., Adams, H. and Palmer, K.L. (2016) Chlorhexidine induces VanA-type vancomycin resistance genes in enterococci. Antimicrobial Agents and Chemotherapy. January 25th. [Epub ahead of print].

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