Targeting Dalbavancin Inoculum Effect: Adjunctive Single Dose of Daptomycin.

Abstract

Daptomycin (DAP) has proven to be a viable alternative amid vancomycin resistance; however, the use of DAP post vancomycin treatment has led to the development of DAP non-susceptible (DNS) strains. Dalbavancin (DAL), a novel single-dosed lipoglycopeptide, has shown enhanced activity against highly resistant Staphylococcus aureus strains. However, on the basis of previous reports and our observations, DAL does not demonstrate similar activity at high versus low inoculum levels. Therefore, we hypothesized that addition of DAP even at minimal concentrations (single dose on day1) will lower the inoculum to the level that can be cleared by dalbavancin. Isolates from methicillin-resistant S.aureus (MRSA)-infected patients with varying susceptibility profiles were evaluated using broth microdilution methods. Two DNS-VISA strains (vancomycin intermediate resistant S.aureus) and one MRSA strain were further evaluated in a one-compartment PK/PD model using a high starting initial inoculum of 109CFU/mL as well as low initial inoculum of 107CFU/mL over 168h to assess the activity of DAL and DAP monotherapy and in combination. Single therapies were not bactericidal when evaluated in the 168h in vitro one-compartment model with an initial inoculum of 109; however, the combination of DAL plus single dose of DAP resulted in enhanced killing at the end of the 168-h exposure. DAL single therapy caused reduction in colony counts down to detection limit (2log10 CFU/ml) at a lower inoculum but did not show enhancement (< 2log10 CFU/ml) at higher initial inoculums (P < 0.01) for all three strains. Similarly, DAP caused initial bacterial reduction up to 4log10 CFU/ml with regrowth at about 32h of exposure, which stayed at initial inoculum levels for the duration of the model for all three strains. Dalbavancin inoculum effect is a major issue in bacterial infections with high bacterial loads and the combination of DAL plus single dose of DAP showed promise in eradicating resistant S.aureus strains at high inoculums.