Abstract
Daptomycin remains as one of the main treatment options for Methicillin-Resistant Staphylococcus aureus (MRSA). Sporadic resistance cases reported in patients treated with either daptomycin or glycopeptides are a growing concern. In a previous study, we described a clinical case of a patient with a community-acquired MRSA infection resistant to daptomycin and with intermediate resistance to vancomycin who developed a recurrent infection with a susceptible isogenic strain. In the present work, we further investigated the sequential events to determine whether the switch from a daptomycin resistance to a susceptible phenotype was due to a phenomenon of resistance reversion or recurrent infection with a susceptible strain. Pairwise competition experiments showed that the susceptible clinical recurrent SA6850 strain had increased fitness when compared to the resistant counterpart SA6820 strain. In fact, although we have demonstrated that reversion of daptomycin resistance to daptomycin susceptible can occur in vitro after serial passages in drug-free media, phylogenetic analysis suggested that the in vivo process was the result of a recurrent infection with a previous susceptible isolate carried by the patient rather than a resistance reversion of the strain. Whole genome sequence of evolved strains showed that daptomycin resistance in MRSA is associated with a high fitness cost mediated by mutations in mprF gene, revealed as a key element of the biological cost. Moreover, we determined that daptomycin resistance-associated fitness cost was independent of vancomycin intermediate resistance phenotype, as demonstrated in additional clinical MRSA vancomycin susceptible strains. This study highlights important observations as, despite daptomycin offers a useful treatment option for the patients with persistent infections, it has to be carefully monitored. The high fitness cost associated to daptomycin resistance may explain the reduced dissemination of daptomycin resistance and the absence of daptomycin reported outbreaks.
Highlights
Staphylococcus aureus is one of the most common human pathogens isolated from both community-acquired (CA) and hospital-acquired (HA) infections
By using competition and phylogenetic analyses of the successive isolates originated from the same patient, we show that DAP resistance in Methicillin-Resistant Staphylococcus aureus (MRSA) is associated with a high fitness cost mediated by mutations in mprF gene, and that in vivo conversion of DAP resistance to a susceptible phenotype was a recurrent infection rather than reversion
The three isolates were shown to be classified as the same clone by PFGE and MLST (Errecalde et al, 2013) corresponding to ST5SCCmec type IV-PVL+, one of the main community-acquired clones circulating in Argentina; the high homology between these strains was confirmed by the phylogenetic tree based on rpoC (Supplementary Figure S1). These results were consistent with two hypotheses: (i) the susceptible SA6850 strain could be an in vivo revertant of the resistant SA6820 or (ii) it could be a recurrence of a previous version of the strain that the patient carried before acquisition of the DAP resistance
Summary
Staphylococcus aureus is one of the most common human pathogens isolated from both community-acquired (CA) and hospital-acquired (HA) infections. Antibiotic management of those infections has become complex over the last decades due to large spreads of multiresistant strains, notably methicillin resistant S. aureus (MRSA) and vancomycin intermediate S. aureus (VISA) (Stryjewski and Corey, 2014). Daptomycin (DAP), a calcium-dependent lipopeptide antibiotic with potent bactericidal activity (Kanafani and Corey, 2007), is the main alternative for the treatment of MRSA infections in cases of vancomycin-reduced susceptibility or vancomycin treatment failure (Liu et al, 2011). S. aureus strains with minimal inhibitory concentration (MIC) ≤ 1 mg/L are classified as DAP susceptible (DAP-S) according to Clinical and Standard Laboratory Institute (CLSI, 2015). The term resistant (DAP-R) will be used in the present study to simplify the understanding
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