Activity of telavancin against heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) in vitro and in an in vivo mouse model of bacteraemia.
OBJECTIVE
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.
Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA 94080, USA. shegde@theravance.com
Sharath S
SS
Hegde
Robert
R
Skinner
Stacey R
SR
Lewis
Kevin M
KM
Krause
Johanne
J
Blais
Bret M
BM
Benton
D000617:Aminoglycosides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D016470:Bacteremia / Q000188:drug therapy; D001769:Blood / Q000382:microbiology; D004195:Disease Models, Animal; D005260:Female; D000077427:Lipoglycopeptides; D051379:Mice; D008826:Microbial Sensitivity Tests; D013154:Spleen / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects*; D016896:Treatment Outcome; D020713:Vancomycin Resistance
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000077427:Lipoglycopeptides; C487637:telavancin