Abstract
Background: Ceftaroline represents a novel fifth-generation cephalosporin to treat infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Methods: Ceftaroline susceptibility of 239 MRSA isolates was assessed by disk diffusion and a MIC test strip following both EUCAST and CLSI guidelines. Non-susceptible isolates were epidemiologically characterized by pulsed-field gel electrophoresis, spa typing, and multilocus sequence typing, and further investigated by PCR and whole genome sequencing to detect penicillin-binding protein (PBP) mutations as well as antibiotic resistance and virulence genes. Results: Fourteen isolates out of two hundred and thirty-nine (5.8%) were non-susceptible to ceftaroline (MIC > 1 mg/L), with differences between the EUCAST and CLSI interpretations. The characterized isolates belonged to seven different pulsotypes and three different clones (ST228/CC5-t041-SCCmecI, ST22/CC22-t18014-SCCmecIV, and ST22/CC22-t022-SCCmecIV), confirming a clonal diffusion of ceftaroline non-susceptible strains. Mutations in PBPs involved PBP2a for ST228-t041-SCCmecI strains and all the other PBPs for ST22-t18014-SCCmecIV and ST22-t022-SCCmecIV clones. All isolates harbored antibiotic resistance and virulence genes with a clonal distribution. Conclusion: Our study demonstrated that ceftaroline non-susceptibile isolates belonged not only to ST228 strains (the most widespread clone in Italy) but also to ST22, confirming the increasing role of these clones in hospital infections.
Highlights
Staphylococcus aureus is a common human commensal, and one of the leading causes of human infections such as endocarditis, bacteremia, osteomyelitis, and skin as well as soft tissue infections [1]
While EUCAST identified seven strains as resistant (MIC > 2 mg/L) and seven strains as susceptible, increased exposure (MIC > 1 mg/L), CLSI interpretation classified all strains as susceptible-dose dependent
The ST22 isolates constituted a different branch of the phylogenetic tree and demonstrated a higher diversity compared to the ST228-t041-SCCmecI isolates (SNPs 1192, Figure 1B), as confirmed by the different spa type
Summary
Staphylococcus aureus is a common human commensal, and one of the leading causes of human infections such as endocarditis, bacteremia, osteomyelitis, and skin as well as soft tissue infections [1]. Ceftaroline demonstrates a broad spectrum against both Gram-positive and Gram-negative bacteria [10] This antibiotic is administered as a prodrug, ceftaroline fosamil, that is rapidly converted into its active form in the plasma [10]. Surveillance studies confirmed the efficacy of ceftaroline against MRSA and other Gram positives, but at the same time identified some non-susceptible and resistant strains [11,12,13]. To gain more information about ceftaroline resistance in Italy, we performed surveillance on the activity of this antibiotic against clinical MRSA strains collected from two hospitals Isolates that were determined to be non-susceptible to ceftaroline (MIC > 1 mg/L) were further investigated to disclose clonal relationships, identify mutations involved in ceftaroline resistance, and characterize antibiotic resistance and virulence traits
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