Emergence of Daptomycin-Nonsusceptible Methicillin-ResistantStaphylococcus aureusClinical Isolates Among Daptomycin-Naive Patients in Korea

Abstract

This study was conducted to assess emergence of daptomycin-nonsusceptible (DAP-NS) phenotype in DAP-naive patients with invasive Staphylococcus aureus (ISA) infections in Korea. A total of 208 S. aureus clinical isolates were selected from a previous prospective study on ISA infections and evaluated for DAP-NS. Although DAP has never been introduced in Korea, five DAP-NS S. aureus strains (2.4%) were identified among 208 S. aureus strains collected from ISA infections. The DAP-NS phenotype was observed only in methicillin-resistant S. aureus (MRSA) strains, but not in methicillin-susceptible S. aureus strains. One DAP-NS MRSA strain belonged to sequence type 72 (ST72) and four were ST5 MRSA strains, three of which were heteroresistant vancomycin (VAN)-intermediate S. aureus. All these five DAP-NS MRSA strains were from healthcare-associated infections without prior exposure to VAN within 30 days. While the ST72 MRSA strain exhibited DAP-NS phenotype via charge repulsion mechanism, four ST5 DAP-NS S. aureus strains had charge-independent DAP-NS mechanism. None of the five DAP-NS strains displayed significant increase in cell wall thickness, indicating that altered cell wall thickness was not associated with the observed DAP-NS phenotype.

Genetic Factors Associated with Increased Host Defense Antimicrobial Peptide Resistance in Sequence Type 5 Healthcare-Associated MRSA Clinical Isolates

“…Previous studies have demonstrated that SNPs within specific domains of MprF are often associated with increased synthesis or translocation of positively charged L-PG, and thus contributes to HD-CAP resistance via charge repulsion mechanisms [ 32 , 34 , 35 , 38 ]. The two mprF SNPs (I375M and I461T) identified in the ST72 CA-/LA-MRSA strains in this study were reported in a previous publication in a daptomycin-nonsusceptible (DAP-NS) ST72 MRSA strain that displayed an enhanced surface positive charge versus DAP-susceptible MRSA strains [ 39 ]. However, in a recent publication [ 10 ], the 18 ST72 MRSA-IV strains with the I375M and I461T mutations were shown to have reduced levels of surface positive charge compared to those of the ST5 HA-MRSA strains.…”

“…Therefore, to determine whether the I375M and I461T mutations in the mprF ORF are directly linked to the enhanced surface positive charge, and thus the HD-CAP resistance phenotype of ST5 HA-MRSA strains, the Newman ∆ mprF strains expressing the mprF genes from ST72 MRSA ( mprF I375M+I461T) or ST5 MRSA ( mprF ) strains were subjected to cytochrome c binding assays. As presented in Figure 1 , complementation of the Newman ∆ mprF strain with mprF I375M+I461T did not result in an enhanced surface positive charge versus the Newman ∆ mprF strain expressing a nonmutated form of mprF , suggesting that the two SNPs (I375M and I461T) are likely not involved in the previously observed increase in the surface positive charge of the ST5 HA-MRSA II strains [ 10 , 39 ]. Bayer et al also reported frequent SNPs within mprF ORFs among clinical DAP-NS MRSA strains, but only a limited number of SNPs within the hot spot loci of mprF were shown to be linked to the gain-of-function phenotype that resulted in enhanced surface positive charge [ 40 ].…”

Effect of genetic background on the evolution of Vancomycin-Intermediate Staphylococcus aureus (VISA)

“…Mutated genes and/or mutated gene patterns associated with isolates with the highest level of vancomycin resistance were not appreciably different than those found in isolates with a lower resistance, likely indicating that individual mutations played a large role in the resistance achieved versus genes overall. The cross-resistance of vancomycin and daptomycin in VISA strains has been well-studied (Cui et al, 2006;Nam et al, 2018). NRS70 and NRS384 endpoint strains were thus tested for development of daptomycin resistance by Etest.…”

Multilocus sequence type-dependent activity of human and animal cathelicidins against community-, hospital-, and livestock-associated methicillin-resistant Staphylococcus aureus isolates

“…A total of 45 MRSA isolates derived from humans (n = 19), pigs (n = 14), and chickens (n = 12) were used in this study ( Table 1 ). All human and pig isolates were selected from previous studies [ 11 , 22 , 23 ]: eight isolates of ST5 HA-MRSA-II, eleven isolates of ST72 CA-MRSA-IV, eight isolates of ST398 LA-MRSA-V, and six isolates of ST541 LA-MRSA-V. As shown in Table 1 , MLST analyses revealed that 12 chicken-associated MRSA isolates were ST692 LA-MRSA-V and six ST188 LA-MRSA-IV. Except for eight ST5 HA-MRSA-II isolates, which belonged to agr type II, all other 37 MRSA isolates were agr type I.…”

“…A total of 45 MRSA isolates of human and animal origin were used in this investigation ( Table 1 ). All human isolates were selected from two previous studies from our laboratory: eight ST5 HA-MRSA and eleven ST72 CA-MRSA isolates [ 22 , 23 ]. Nine ST398 LA-MRSA and six ST541 LA-MRSA isolates were selected from a previous investigation of LA-MRSA in healthy pigs [ 11 ].…”