Activity of telavancin against heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) in vitro and in an in vivo mouse model of bacteraemia

Abstract

Objectives: Infections caused by heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) are associated with high rates of vancomycin treatment failure. Telavancin is a bactericidal lipoglycopeptide active in vitro against Gram-positive pathogens including hVISA and vancomycin-intermediate S. aureus (VISA). This study characterizes the microbiological activity of telavancin against vancomycin-susceptible S. aureus (VSSA), hVISA and VISA strains.

Methods: Reference strains of VSSA, hVISA and VISA were assessed for potential telavancin heteroresistance by population analysis. In addition, the efficacies of telavancin (40 mg/kg subcutaneously every 12 h for 4 days) and vancomycin (110 mg/kg subcutaneously every 12 h for 8 days) were compared in a neutropenic murine model (immunocompromised female non-Swiss albino mice) of bacteraemia caused by hVISA strain Mu3. Blood and spleen bacterial titres were quantified from cohorts of mice euthanized pre-treatment and at 24 h intervals post-treatment for 8 days.

Results: Telavancin was active against all strains of S. aureus tested, with MIC values < or =0.5 mg/L. Population analyses revealed no evidence of subpopulations with reduced susceptibility to telavancin. In the murine bacteraemia model of hVISA infection, all animals were bacteraemic pre-treatment and mortality was 100% within 16-24 h post-infection in untreated animals. Treatment with telavancin was associated with lower spleen bacterial titres, lower rates of bacteraemia and lower overall mortality than treatment with vancomycin.

Conclusions: These in vitro and pre-clinical in vivo studies demonstrate that telavancin has the potential to be efficacious in infections caused by hVISA.