In vitro and in vivo susceptibility to cefalexin and amoxicillin/clavulanate in canine low-level methicillin-resistant Staphylococcus pseudintermedius

Background Methicillin-resistant Staphylococcus pseudintermedius (MRSP) lineages harbouring staphylococcal cassette chromosome (SCC) mec types IV, V and psi SCCmec57395 usually display low oxacillin MICs (0.5-2 mg/L). Objectives To evaluate how oxacillin MICs correlate with PBP mutations and susceptibility to beta-lactams approved for veterinary use. Methods Associations between MICs and PBP mutations were investigated by broth microdilution, time-kill and genome sequence analyses in 117 canine MRSP strains harbouring these SCCmec types. Clinical outcome was retrospectively evaluated in 11 MRSP-infected dogs treated with beta-lactams. Results Low-level MRSP was defined by an oxacillin MIC <4 mg/L. Regardless of strain genotype, all low-level MRSP isolates (n = 89) were cefalexin susceptible, whereas no strains were amoxicillin/clavulanate susceptible according to clinical breakpoints. Exposure to 2x MIC of cefalexin resulted in complete killing within 8 h. High (>= 4 mg/L) oxacillin MICs were associated with substitutions in native PBP2, PBP3, PBP4 and acquired PBP2a, one of which (V390M in PBP3) was statistically significant by multivariable modelling. Eight of 11 dogs responded to systemic therapy with first-generation cephalosporins (n = 4) or amoxicillin/clavulanate (n = 4) alone or with concurrent topical treatment, including 6 of 7 dogs infected with low-level MRSP. Conclusions Oxacillin MIC variability in MRSP is influenced by mutations in multiple PBPs and correlates with cefalexin susceptibility. The expert rule recommending that strains with oxacillin MIC >= 0.5 mg/L are reported as resistant to all beta-lactams should be reassessed based on these results, which are highly clinically relevant in light of the shortage of effective antimicrobials for systemic treatment of MRSP infections in veterinary medicine.

Automated summary

The study found a correlation between oxacillin MICs and PBP mutations in MRSP strains, as well as their susceptibility to beta-lactams approved for veterinary use. Strains with low-level MRSP had an oxacillin MIC < 4 mg/L and were susceptible to cefalexin, while being less susceptible to amoxicillin/clavulanate. High oxacillin MICs were associated with mutations in multiple PBPs.