Abstract
The genomic evolution in vivo in persistent infection was critical information for understanding how methicillin-resistant Staphylococcus aureus (MRSA) was adapted to host environments with high antibiotic selective pressure. Thirty-two successive MRSA blood isolates with incremental non-susceptibility to vancomycin (VISA), daptomycin (DRSA), and/or linezolid (LRSA) were isolated from a patient failing multiple courses of antimicrobial therapy during 1,356 days of bacteremia. Whole genome sequencing (WGS) for all consecutive isolates were conducted to characterize the evolutionary pathways, resistance-associated mutations and their temporal relationship with antimicrobial treatment. The WGS-based phylogeny categorized the isogenic strains into three major clades, I (22 isolates), II (7 isolates), and III (3 isolates), respectively, harboring a median (range) of 7 (1–30), 62 (53–65), and 118 (100–130) non-synonymous mutations when compared to the very first isolate. Clade I strains were further grouped into early and late subclades, which, respectively, shared the most recent common ancestor with Clade III strains at day 393.7 and Clade II strain at day 662.5. Clade I and Clade III strains were characterized, respectively, with high rates of VISA (9/22, 40.9%) and VISA-and-DRSA phenotype (2/3, 66.7%). Linezolid-resistance including VISA-DRSA-and-LRSA phenotype was exclusively identified in Clade II strains after eight courses of linezolid treatment. The LRSA displayed a small colony variant phenotype and were associated with G2576T mutations in domain V region of 23S rRNA. Substantial loss of mobile elements or alleles mediating resistance or virulence were identified during the evolution of multi-resistance. However, the gene loss might not be correlated to the development of VISA, DRSA, or LRSA phenotype. In conclusion, MRSA in persistent bacteremia was adapted to harsh host environment through multiple pathways involving both resistance-associated mutations and extensive gene loss.
Highlights
Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a devastating disease associated with high rates of complications and mortality especially in those with underlying conditions (Charles et al, 2004; Tong et al, 2020)
4http://github.com/samtools/bcftools 5http://omgenomics.com/circa 6http://www.mgc.ac.cn/VFs successive strains raised the first question whether all of the successive methicillin-resistant Staphylococcus aureus (MRSA) strains were derived from the same ancestor or the persistent bacteremia was resulted from repeated infections by new strains
Our study demonstrated that to adapt to the host environment with high antibiotic selective pressure, the MRSA ST5 isolates underwent rapid genetic evolution through three major pathways from strains of Clade Ia, respectively, to Clade Ib, Clade II, and Clade III
Summary
Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a devastating disease associated with high rates of complications and mortality especially in those with underlying conditions (Charles et al, 2004; Tong et al, 2020). Treatment failures including persistent bacteremia were frequently identified in patients with medical implant or prothesis, with greater number of comorbidities and greater disease severity or infections with non-susceptible strains (Charles et al, 2004; Murray et al, 2013; Moise et al, 2016; Yang et al, 2018; Tong et al, 2020). Glycopeptide remains the drug of choice for treatment of MRSA bacteremia though accumulating evidence suggested daptomycin treatment may be associated with improved outcome, especially in patients whose diseases were caused by MRSA strains with reduced susceptibility to vancomycin (Murray et al, 2013; Claeys et al, 2016; Yang et al, 2018). An understanding of the in vivo evolution of MRSA strains during the development of incremental resistance to the commonly used anti-MRSA agents including vancomycin, daptomycin, and linezolid may help deploy effective therapeutic strategy against the devastating infectious disease
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