Emergence and within-host genetic evolution of methicillin-resistant Staphylococcus aureus resistant to linezolid in a cystic fibrosis patient [Mechanisms of Resistance]

Methicillin resistant Staphylococcus aureus (MRSA) infection has increased in recent years among cystic fibrosis (CF) patients. Linezolid (LZD) is one of the anti staphylococci antibiotic widely used in this context. Although LZD resistance is rare, it has been described as often associated with long term treatments. Thirteen MRSA strains isolated over 5 years from one CF patient were studied for LZD resistance emergence and underwent whole genome sequencing (WGS). Resistance emerged after three 15 day LZD therapeutic regimens over 4 months. It was associated with the G2576T mutation in all the 5 rrl copies along with a very high MIC (>256mg/L) and a strong increase of the generation time. Resistant strains isolated during the ensuing LZD therapeutic regimens and until 13 months after LZD stopped, harbored only 3 or 4 rrl mutated copies, associated with lower MICs (8 to 32mg/L) and low to moderate generation time increase. Despite these differences, whole genome sequencing allowed us to determine that all isolates, including the susceptible one isolated before LZD treatment, belonged to the same lineage. In conclusion, LZD resistance can emerge rapidly in CF patients and persist without linezolid selective pressure in MRSA colonizing strains belonging to the same lineage.

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