• Munita, Jose M.
• Panesso, Diana
• Diaz, Lorena
• Reyes, Jinnethe
• Arias, Cesar A.
• Wanger, Audrey
• Murray, Barbara E.
• Tran, Truc T.

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Mutations in<jats:italic>liaFSR</jats:italic>, a three-component regulatory system controlling cell-envelope stress response, were recently linked with the emergence of daptomycin (DAP) resistance in enterococci. Our previous work showed that a<jats:italic>liaF</jats:italic>mutation increased the DAP MIC of a vancomycin-resistant<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Enterococcus faecalis</jats:named-content>strain from 1 to 3 μg/ml (the DAP breakpoint is 4 μg/ml), suggesting that mutations in the<jats:italic>liaFSR</jats:italic>system could be a pivotal initial event in the development of DAP resistance. With the hypothesis that clinical enterococcal isolates with DAP MICs between 3 and 4 μg/ml might harbor mutations in<jats:italic>liaFSR</jats:italic>, we studied 38<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Enterococcus faecium</jats:named-content>bloodstream isolates, of which 8 had DAP MICs between 3 and 4 μg/ml by Etest in Mueller-Hinton agar. Interestingly, 6 of these 8 isolates had predicted amino acid changes in the LiaFSR system. Moreover, we previously showed that among 6 DAP-resistant<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">E. faecium</jats:named-content>isolates (MICs of &gt;4 μg/ml), 5 had mutations in<jats:italic>liaFSR</jats:italic>. In contrast, none of 16<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">E. faecium</jats:named-content>isolates with a DAP MIC of ≤2 μg/ml harbored mutations in this system (<jats:italic>P</jats:italic>&lt; 0.0001). All but one isolate with<jats:italic>liaFSR</jats:italic>changes exhibited DAP MICs of ≥16 μg/ml by Etest using brain heart infusion agar (BHIA), a medium that better supports enterococcal growth. Our findings provide a strong association between DAP MICs within the upper susceptibility range and mutations in the<jats:italic>liaFSR</jats:italic>system. Concomitant susceptibility testing on BHIA may be useful for identifying these<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">E. faecium</jats:named-content>first-step mutants. Our results also suggest that the current DAP breakpoint for<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">E. faecium</jats:named-content>may need to be reevaluated.</jats:p>

Topics

• impedance spectroscopy
• susceptibility