Characterization of high-level daptomycin resistance in Viridans group Streptococci developed upon in vitro exposure to daptomycin.

Viridans group streptococci (VGS) are part of the normal flora that may cause bacteremia, often leading to endocarditis. We evaluated daptomycin against four clinical strains of VGS (MICs = 1 or 2 µg/ml) using an in vitro-simulated endocardial vegetation model, a simulated bacteremia model, and kill curves. Daptomycin exposure was simulated at 6 mg/kg of body weight and 8 mg/kg every 24 h for endocardial and bacteremia models. Total drug concentrations were used for analyses containing protein (albumin and pooled human serum), and free (unbound) drug concentrations (93% protein bound) were used for analyses not containing protein. Daptomycin MICs in the presence of protein were significantly higher than those in the absence of protein. Despite MICs below or at the susceptible breakpoint, all daptomycin regimens demonstrated limited kill in both pharmacodynamic models. A reduction of approximately 1 to 2 log10 CFU was seen for all isolates and dosages except daptomycin at 6 mg/kg, which achieved a reduction of 2.7 log10 CFU/g against one strain (Streptococcus gordonii 1649) in the endocardial model. Activity was similar in both pharmacodynamic models in the presence or absence of protein. Similar activity was noted in the kill curves over all multiples of the MIC. Regrowth by 24 h was seen even at 8× MIC. Postexposure daptomycin MICs for both pharmacodynamic models increased to >256 µg/ml for all isolates by 24 and 72 h. Despite susceptibility to daptomycin by standard MIC methods, these VGS developed high-level daptomycin resistance (HLDR) after a short duration following drug exposure not attributed to modification or inactivation of daptomycin. Further evaluation is warranted to determine the mechanism of resistance and clinical implications.

Inhibitory and bactericidal activities of daptomycin, vancomycin, and teicoplanin against methicillin-resistant Staphylococcus aureus isolates collected from 1985 to 2007.

The inhibitory and bactericidal activities of daptomycin, vancomycin, and teicoplanin against a collection of 479 methicillin-resistant Staphylococcus aureus isolates were assessed. The isolates were collected from U.S. and European hospitals from 1985 to 2007 and were primarily from blood and abscess cultures. The MICs and minimum bactericidal concentrations (MBCs) of the three agents were determined, and the MBC/MIC ratios were calculated to determine the presence or absence of tolerance. Tolerance was defined as an MBC/MIC ratio of > or = 32 or an MBC/MIC ratio of > or = 16 when the MBC was greater than or equal to the breakpoint for resistance. Tolerance to vancomycin and teicoplanin was observed in 6.1% and 18.8% of the strains, respectively. Tolerance to daptomycin was not observed.

Detection of daptomycin-nonsusceptible strains using the Neo-Sensitab prediffusion method.

Two prediffusion methods with daptomycin (DAP) Neo-Sensitabs were evaluated against a challenge set of 30 Staphylococcus aureus isolates and 30 enterococci. DAP Neo-Sensitabs were prediffused for either 8 or 20 h on Mueller-Hinton agar. Inhibition zones were plotted versus Etest MIC values determined on the same prediffused agar. A generalization to the genus level of the manufacturer's suggested Neo-Sensitabs breakpoints for staphylococci and enterococci was used to interpret the results. DAP-susceptible and DAP-nonsusceptible enterococci, Enterococcus faecium in particular, were not reliably discriminated using a 20-h prediffusion method and the manufacturer's suggested breakpoints. Further development of this testing methodology, such as changing the format to a susceptibility screen followed by a confirmatory MIC, is needed to accurately categorize the DAP susceptibility of enterococcal isolates. Prediffusion for either 8 or 20 h with DAP Neo-Sensitabs discriminated between susceptible and nonsusceptible S. aureus with minimal errors. Both prediffusion methods also detected changes in MIC values between isogenic pairs of susceptible and nonsusceptible S. aureus. These results suggest that a multisite evaluation of either prediffusion method with DAP Neo-Sensitabs against a larger collection of S. aureus is warranted.

In vitro activity of daptomycin against multidrug-resistant Staphylococcus aureus and S. aureus with known virulence factors, including community-acquired methicillin-resistant isolates.

The in vitro activity of daptomycin was evaluated against 360 multidrug-resistant Staphylococcus aureus isolates (including hospital-acquired isolates) and multidrug-susceptible community-acquired methicillin-resistant S. aureus with known virulence genes. All isolates were inhibited at