UC San Diego

Introduction

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 day 1) will lower the inoculum to the level that can be cleared by dalbavancin.

Methods

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 10⁹ CFU/mL as well as low initial inoculum of 10⁷ CFU/mL over 168 h to assess the activity of DAL and DAP monotherapy and in combination.

Results

Single therapies were not bactericidal when evaluated in the 168 h 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 (2 log₁₀ CFU/ml) at a lower inoculum but did not show enhancement (< 2 log₁₀ CFU/ml) at higher initial inoculums (P < 0.01) for all three strains. Similarly, DAP caused initial bacterial reduction up to 4 log₁₀ CFU/ml with regrowth at about 32 h of exposure, which stayed at initial inoculum levels for the duration of the model for all three strains.

Conclusions

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.